WO2009071094A2 - Combination treatment of ischemic effects - Google Patents

Combination treatment of ischemic effects Download PDF

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Publication number
WO2009071094A2
WO2009071094A2 PCT/DK2008/050292 DK2008050292W WO2009071094A2 WO 2009071094 A2 WO2009071094 A2 WO 2009071094A2 DK 2008050292 W DK2008050292 W DK 2008050292W WO 2009071094 A2 WO2009071094 A2 WO 2009071094A2
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alkyl
compounds
receptor agonist
substituted
medicament
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PCT/DK2008/050292
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French (fr)
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WO2009071094A3 (en
Inventor
Jacob Gotfredsen
Uno Jakob Weber
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Neurokey A/S
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to the use of a combination of compounds for the induction of hypothermia for the prophylaxis and treatment of ischemia.
  • Ischemia is the lack of oxygenated blood flow to various body parts and may result from apoplexia, cardiac arrest and asphyxia.
  • Cerebral ischemia is an ischemic condition where the brain or parts of the brain do not receive enough blood flow to maintain normal neurological function. Cerebral ischemia can be the result of various serious diseases such as stroke and cardiac arrest, or the result of arterial obstruction such as strangulation. Severe or prolonged cerebral ischemia will result in unconsciousness, brain damage or death.
  • hypothermia counteracts ischemic brain damage by several mechanisms:
  • Ischemia induces opening of the blood-brain barrier, a process that seems to be very sensitive to brain temperature [15]. This is evident from studies of tracers and their migration across the blood-brain barrier, in which hypothermia attenuates extravasation several hours after ischemia [16] and prevents vasogenic oedema [17]. 2. Reperfusion after brain ischemia results in the production of free radicals, which causes peroxidation and destruction of membrane lipids [18]. Hypothermia prevents the production of free radicals such as hydroxyl and nitric oxide during reperfusion after brain ischemia [19;20;24].
  • Amino acids such as glutamate, aspartate, and glycine, act as excitotoxic neurotransmitters by over stimulation of neurons in the vicinity of ischemic damage, which causes further injury. Hypothermia lowers the release and may even cause a more rapid reuptake of these transmitters [21 -23]. Release of excitotoxic neurotransmitters might also cause progressive neuronal death in the penumbra in stroke patients [22], and hypothermia after cerebral ischemia could attenuate this process.
  • hypothermia By lowering of neutrophil and microglial activation after ischemia, hypothermia also has an anti-inflammatory effect [30;31].
  • Apoptosis and DNA changes are crucial stages in delayed neuronal death after transient cerebral ischemia [32].
  • Hypothermia directly inhibits apoptosis [33] and may also increase endogenous production of the anti-apoptotic protein Bcl-2 [34].
  • Hypothermia may even have effects at the DNA level: A slight lowering of brain temperature results in less DNA fragmentation [35] and less apoptosis [36].
  • hypothermia Induction of hypothermia by lowering of the core temperature of the body has been attempted by mechanical cooling devices such as surface cooling and cooling using catheters placed in a large vessel.
  • mechanical cooling devices such as surface cooling and cooling using catheters placed in a large vessel.
  • these mechanical inducers of hypothermia have been shown to have considerable unwanted side effects. These side effects include shivering, serious infections and lung puncture. Shivering causes an increased exertion of the heart of the patient, and this will in some cases result in ischemia of the heart and thereby increased morbidity and mortality.
  • a pharmaceutical composition comprising a combination of compounds capable of inducing hypothermia would not only solve the problem of reducing or preventing the effects of ischemia, such as tissue damaging effects, but also be relevant as a safer and less expensive alternative to the currently employed mechanical methods.
  • the present invention relates to the induction of hypothermia in humans in a predictable and dose responsive fashion by use of a pharmaceutical composition comprising at least one compound and/or a combination of compounds capable of inducing hypothermia, thereby benefiting patients suffering from illnesses characterized by tissue anoxia.
  • a pharmaceutical composition comprising at least one compound and/or a combination of compounds capable of inducing hypothermia, thereby benefiting patients suffering from illnesses characterized by tissue anoxia.
  • the inventors have found that such hypothermic effects can be obtained in humans as a result of several classes of compounds: • Vanilloid receptor agonists, capsaicinoids or capsaicinoid-like agonists reaching and binding to vanilloid receptors.
  • Adenosine receptor agonists adenosine analogs or adenosine uptake inhibitors and agonist compounds reaching and binding to adenosine receptors.
  • Neurotensin receptor agonists neurotensin analogs and compounds reaching and binding neurotensin receptors.
  • Thyroxine derivatives thyroid hormone receptor agonists and trace amine- associated receptor agonists.
  • the present invention discloses the use of a combination of compounds, wherein at least two or more compounds are selected among vanilloid receptor agonists, and cannabinoids and cannabimimetic compounds, and adenosine or adenosine analogs, and neurotensin or neurotensin analogs or a compound having at least 50% sequence identity to human neurotensin, and thyroxine derivatives, and cytochrome c oxidase inhibitors, and oxygen tension reducers, for the induction of hypothermia for the preparation of a medicament for the treatment of ischemia in an individual in need thereof.
  • cytochrome c oxidase inhibitor for the induction of hypothermia for the preparation of a medicament for the treatment of ischemia in an individual in need thereof is disclosed.
  • an oxygen tension reducer for the induction of hypothermia for the preparation of a medicament for the treatment of ischemia in an individual in need thereof is disclosed.
  • a kit of parts comprising the medicament as herein disclosed is yet an aspect of the present invention.
  • the present invention relates to a combination comprising two or more compounds selected from the group consisting of a vanilloid receptor agonist, a cannabinoid or a cannabimimetic compound, an adenosine, or an adenosine analog, or an adenosine receptor agonist, or an adenosine uptake inhibitor, a neurotensin, or a neurotensin analog, or a neurotensin receptor agonist, or a neurotensin mimetic compound, a thyroxine derivative, a cytochrome c oxidase inhibitor, or an oxygen tension reducer, for use in the treatment of ischemia in an individual in need thereof by induction of hypothermia in said individual, with the proviso that if one compound is a) then the second compound is not b).
  • Adenosine is a nucleoside composed of adenine attached to a ribose (ribofuranose) moiety via a ⁇ -N9-glycosidic bond as described by the formula below.
  • Adenosine analog is any compound with a structure based on an adenosine and thus includes but is not limited to 5'-AMP, ADP, ATP and the like.
  • a vanilloid receptor agonist is a vanilloid compound.
  • a cannabinoid receptor agonist is a cannabinoid or a cannabimimetic compound.
  • An adenosine receptor agonist is an adenosine, adenosine analog or adenosine-like compound.
  • a neurotensin receptor agonist is a neurotensin or a neurotensin analog or a synthetic neurotensin or an artificial neurotensin or a neurotensin mimetic compound.
  • a thyroxine receptor agonist is a thyroxine derivative or a thyronine.
  • an agonist is a compound capable of inducing hypothermia by binding to a receptor.
  • a vanilloid receptor antagonist is a substance capable of inhibiting the effect of a vanilloid receptor agonist.
  • a cannabinoid receptor antagonist is a substance capable of inhibiting the effect of a cannabinoid receptor agonist.
  • An adenosine receptor antagonist is a substance capable of inhibiting the effect of an adenosine receptor agonist.
  • a neurotensin receptor antagonist is a substance capable of inhibiting the effect of a neurotensin receptor agonist.
  • a thyroxine receptor antagonist is substance capable of inhibiting the effect of a thyroxine receptor agonist.
  • Alcohol A class of organic compounds containing one or more hydroxyl groups (OH). In this context a saturated or unsaturated, branched or unbranched hydrocarbon group sitting as a substituent on a larger molecule.
  • Alicvclic group means a cyclic hydrocarbon group having properties resembling those of aliphatic groups.
  • Aliphatic group in the context of the present invention, the term "aliphatic group” means a saturated or unsaturated linear or branched hydrocarbon group. This term is used to encompass alkyl, alkenyl, and alkynyl groups, for example.
  • Alkoxyl group covers an alkyl linked to a larger moiety by oxygen.
  • Alkyl group means a saturated linear or branched hydrocarbon group including, for example, methyl, ethyl, isopropyl, t-butyl, heptyl, dodecyl, octadecyl, amyl, 2- ethylhexyl, and the like.
  • Alkenyl group means an unsaturated, linear or branched hydrocarbon group with one or more carbon-carbon double bonds, such as a vinyl group.
  • Alkynyl group means an unsaturated, linear or branched hydrocarbon group with one or more carbon-carbon triple bonds.
  • Amphiphil substance containing both polar, water-soluble and nonpolar, water- insoluble groups.
  • Aromatic group the term "aromatic group” or "aryl group” means a mono- or polycyclic aromatic hydrocarbon group.
  • Apoptosis is a process of suicide by a cell in a multi-cellular organism. It is one of the main types of programmed cell death (PCD), and involves an orchestrated series of biochemical events leading to a characteristic cell morphology and death. Asystole: Cessation of electrical activity in the ventricles of the heart. Without electrical activity the heart ceases to contract and the result is cardiac arrest.
  • PCD programmed cell death
  • Cerebral ischemia Global cerebral ischemia is an ischemic condition where the brain does not receive enough blood flow to maintain normal neurological function. Cerebral ischemia can be the result of various diseases/conditions such as cardiac arrest, or the result of arterial obstruction such as strangulation.
  • Coma A prolonged period of unconsciousness following brain injury or metabolic disorders.
  • the person in coma may have a simple reflex in response to touch or pain, but essentially there is no meaningful response to external stimuli.
  • Cannabinoid Compound capable of binding to a cannabinoid receptor and isolated from or identical to a compound isolated from an organism such a plant or animal. In the present context any compound capable of binding a cannabinoid receptor. Also, the term cannabinoid is used as a general term covering both cannabinoid and cannabimimetic compounds.
  • Cannabimimetic Compound capable of binding to a cannabinoid receptor and produced or synthesized chemically by standard techniques known in the art. In the present context any compound capable of binding a cannabinoid receptor.
  • Capsaicinoid Compound capable of binding to a capsaicinoid receptor / vanilloid receptor and isolated from or identical to a compound isolated from an organism such as a plant or animal. In the present context any compound capable of binding a capsaicinoid receptor / vanilloid receptor.
  • a capsaicinoid may also be referred to as a vanilloid receptor agonist.
  • Capsaicinoid-like Compound capable of binding to a capsaicinoid receptor / vanilloid receptor and produced or synthesized chemically by standard techniques known in the art. In the present context any compound capable of binding a capsaicinoid receptor / vanilloid receptor.
  • a capsaicinoid-like compound may also be referred to as a vanilloid receptor agonist.
  • Combination of compounds generally covers a combination of at least two compounds selected from the group consisting of vanilloid receptor agonist, capsaicinoid, capsaicinoid-like, cannabinoid and cannabimimetic compound, adenosine, adenosine analogs and derivatives, neurotensin, neurotensin analogs, thyroxine derivatives, thyronamine, cytochrome c oxidase inhibitors and oxygen tension reducers.
  • the term may also include combinations of other compounds or drugs or the like.
  • Compound A chemical substance formed from two or more elements, held together by chemical bonds, with a fixed ratio determining the composition. The elements lose their individual chemical properties and the compound has new properties.
  • vanilloid receptor agonist vanilloid receptor agonist
  • capsaicinoid capsaicinoid-like, cannabinoid and cannabimimetic compound
  • adenosine adenosine analogs and derivatives
  • neurotensin neurotensin analogs and peptides having at least 50% sequence identity to human neurotensin (NT or NT1 -13) of SEQ
  • ID NO. 1 thyroxine derivative, thyronamine, cytochrome c oxidase inhibitor and oxygen tension reducers.
  • Cyclic group means a closed ring hydrocarbon group that is classified as an alicyclic group, aromatic group, or heterocyclic group.
  • Cvcloalkenyl means a monovalent unsaturated carbocyclic radical consisting of one, two or three rings, of three to eight carbons per ring, which can optionally be substituted with one or two substituents selected from the group consisting of hydroxy, cyano, lower alkenyl, lower alkoxy, lower haloalkoxy, alkenylthio, halo, haloalkenyl, hydroxyalkenyl, nitro, alkoxycarbonenyl, amino, alkenylamino, alkenylsulfonyl, arylsulfonyl, alkenylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkenylaminocarbonyl, arylaminocarbonyl, alkenylcarbonylamino and arylcarbonylamino.
  • Cvcloalkyl means a monovalent saturated carbocyclic radical consisting of one, two or three rings, of three to eight carbons per ring, which can optionally be substituted with one or two substituents selected from the group consisting of hydroxy, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylamino- sulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino and arylcarbonylamino.
  • Cationic group A chemical group capable of functioning as a proton donor when a compound comprising the chemical group is dissolved in a solvent, preferably when dissolved in water.
  • Cytochrome c oxidase inhibitor means a compound that binds to and interferes with the function of cytochrome c oxidase; a mitochondrial transmembrane complex involved in metabolism. These include but are not limited to H 2 S (hydrogen sulfide); cyanide (CN) or its derivates such as hydrogen cyanide (HCN) or sodium nitroprusside (Na 2 [Fe(CN) 5 NO] ⁇ H 2 O); Azide and its derivates; Carbon monoxide (CO); and/or Sodium sulfide (Na 2 S).
  • H 2 S hydrogen sulfide
  • CN cyanide
  • HN hydrogen cyanide
  • Azide and its derivates such as hydrogen cyanide (HCN) or sodium nitroprusside (Na 2 [Fe(CN) 5 NO] ⁇ H 2 O)
  • Azide and its derivates Carbon monoxide (CO); and/
  • Form a ring means that the atoms mentioned are connected through a bond when the ring structure is formed.
  • Global ischemia Anoxia resultant from ceased blood supply to the entire body resulting in tissue damage through a variety of mechanisms including apoptosis.
  • Global cerebral ischemia Anoxia resultant from ceased blood supply to the entire brain resulting in tissue damage through a variety of mechanisms including apoptosis.
  • Group (Moiety / substitution) as is well understood in this technical area, a large degree of substitution is not only tolerated, but is often advisable. Substitution is anticipated on the materials of the present invention.
  • group and “moiety” are used to differentiate between chemical species that allow for substitution or that may be substituted and those that do not allow or may not be so substituted.
  • group when the term "group” is used to describe a chemical substituent, the described chemical material includes the unsubstituted group and that group with O, N, or S atoms, for example, in the chain as well as carbonyl groups or other conventional substitution.
  • alkyl group is intended to include not only pure open chain saturated hydrocarbon alkyl substituents, such as methyl, ethyl, propyl, t-butyl, and the like, but also alkyl substituents bearing further substituents known in the art, such as hydroxy, alkoxy, alkylsulfonyl, halogen atoms, cyano, nitro, amino, carboxyl, etc.
  • alkyl group includes ether groups, haloalkyls, nitroalkyls, carboxyalkyls, hydroxyalkyls, sulfoalkyls, etc.
  • alkyl moiety is limited to the inclusion of only pure open chain saturated hydrocarbon alkyl substituents, such as methyl, ethyl, propyl, t-butyl, and the like.
  • alkenyl group and “alkenyl moiety”; to "alkynyl group” and “alkynyl moiety”; to "cyclic group” and “cyclic moiety; to "alicyclic group” and “alicyclic moiety”; to "aromatic group” or “aryl group” and to “aromatic moiety” or “aryl moiety”; as well as to "heterocyclic group” and “heterocyclic moiety”.
  • Heterocyclic group means a closed ring hydrocarbon in which one or more of the atoms in the ring is an element other than carbon (e.g., nitrogen, oxygen, sulphur, etc.).
  • Heterocvclyl means a monovalent saturated cyclic radical, consisting of one to two rings, of three to eight atoms per ring, incorporating one or two ring heteroatoms (chosen from N, O or S(O) 0 - 2 , and which can optionally be substituted with one or two substituents selected from the group consisting of hydroxyl, oxo, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminofarbonyl, aryl- aminocarbonyl, alkylcarbonylamin
  • Heteroaryl means a monovalent aromatic cyclic radical having one to three rings, of four to eight atoms per ring, incorporating one or two heteroatoms (chosen from nitrogen, oxygen, or sulphur) within the ring which can optionally be substituted with one or two substituents selected from the group consisting of hydroxy, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, aryl- aminocarbonyl, alkylcarbonlamino and arylcarbonylamino. Hypothermia: Lowering
  • Ischemia Restriction in blood supply with resultant dysfunction or damage of tissue. Ischemia includes ischaemia and ischaemia.
  • Ischemic tissue damage Tissue damage due to ischemia.
  • Lactic acidosis is a condition caused by the buildup of lactic acid in the body. An important cause of lactic acidosis is inadequate oxygen supply to tissues. Lactic acidosis leads to acidification of the blood (acidosis), and is considered a distinct form of metabolic acidosis.
  • Moieties of a particular compound cover group(s) or part(s) of said particular compound.
  • Neurotensin is the 13 amino acid peptide of SEQ ID NO. 1.
  • Neurotensin analog is any sequence having at least 50% sequence identity to mature neurotensin of SEQ ID NO. 1 .
  • Neurotensin receptors are transmembrane receptors which bind neurotensin. Two of the receptors encoded by the NTSR1 and NTSR2 genes contain 7 transmembrane helices and are G protein-coupled. The third receptor has a single transmembrane domain and is encoded by the SORT1 gene.
  • Neurotensin receptor agonist is a compound capable of imposing an agonizing effect of a neurotensin receptor and include but is not limited to neurotensin, neuromedin, NT64D, NT64L, NT65L, NT66D, NT66L, NT67L, NT69L, NT71 , NT72, NT73, NT74, NT75, NT76, NT77, Trp1 1 NT, Contakin-G, EISAI-1 , EISAI-2, JMV2004, JMV2012, JMV431 , JMV449, JMV457, JMV458, large neuromedin, large neurotensin, [ 125 l]neurotensin, Thr10contulakin-G, D-Trp1 1 -neurotensin, levocabastine, SR48692, xenin, PD-149163 and CGX-1 160.
  • Oxygen tension reducers reduces the concentration of oxygen around or within
  • composition refers to any chemical or biological material, compound, composition or combinations of any of these especially combinations of compounds, capable of inducing a desired therapeutic effect when properly administered to a patient.
  • Some drugs are sold in an inactive form that is converted in vivo into a metabolite with pharmaceutical activity.
  • pharmaceutical composition and “medicament” encompass both the inactive drug and the active metabolite.
  • Pulseless electrical activity The electrical activity of the heart continues in a normal or abnormal pattern, but one that is consistent with contractions of the heart. But either due to damage to the heart muscle, blockage of the main arteries leading from the heart or lack of blood flowing to the heart there is no effective blood flow. The result is cardiac arrest.
  • Substituted lower alkyl means a lower alkyl having one to three substituents selected from the group consisting of hydroxyl, alkoxy, amino, amido, carboxyl, acyl, halogen, cyano, nitro and thiol.
  • Thyroxine derivatives the term as used herein is meant to cover all forms and processed derivatives of the thyroid hormones, including thyroxine (T 4 ), triiodothyronine (T 3 ), thyronamine, 3-lodothyronamine, 3,5-Diiodothyronamine, and 3,5,3'-triiodothyronamine.
  • T 4 thyroxine
  • T 3 triiodothyronine
  • thyronamine 3-lodothyronamine
  • 3,5-Diiodothyronamine 3,5,3'-triiodothyronamine
  • the term is also used to encompass thyroid hormone receptor agonists and trace amine-associated receptor agonists, and these terms may be used interchangably herein.
  • Vanilloid receptor agonist A capsaicinoid or capsaicinoid-like compound capable of binding a vanilloid receptor / capsaicinoid receptor.
  • Ventricular fibrillation Very fast irregular electrical activity in the ventricles of the heart. Individual beats cannot be distinguished and the heart is in stand-still or vibrating slightly. The result is cardiac arrest.
  • Ventricular tachycardia Very fast electrical activity in the ventricles of the heart. The electrical activity maintains a pattern where individual contractions can be distinguished. Ventricular tachycardia may be associated with normal cardiac function, reduced cardiac function or functional cardiac arrest. This depends on the rate of the tachycardia and the state of the heart muscle.
  • the principle of the present invention is the use of a combination of vanilloid receptor agonists and/or cannabinoids and/or cannabimimetic compounds and/or adenosine and/or adenosine analogs and/or neurotensin and/or neurotensin analogs and/or thyroxine derivatives and/or cytochrome c oxidase inhibitors and/or oxygen tension reducers with the proviso that if the combination comprises two compounds, said two compounds are not vanilloid receptor agonists and cannabinoids or vanilloid receptor agonists and cannabimimetic compounds, for induction of hypothermia, such as for alleviating the effects of ischemia, such as but not limited to tissue damaging effects of ischemia.
  • Ischemia is the reduction or abolition of blood supply to a tissue.
  • the associated deficiency of oxygen and nutrients may lead to cell death (necrosis) in areas of the affected tissue.
  • the damage induced by the lack of oxygenated blood in the brain occurs in two stages. First cellular metabolism is arrested due to lack of oxygen and some cells and tissue will die within minutes as a consequence hereof. Secondly a cascade of processes such as apoptosis is initiated and continues up to 12 hours after the event that initially induced the ischemic state has been abolished.
  • the tissue damaged by the second cascade can be crucial and cause greater harm to the individual than the primary damage happening within the first minutes of ischemia.
  • the current invention is aimed at correcting ischemia of the brain thereby minimizing the damage to the central nervous system.
  • the invention does so by administering a drug to induce hypothermia in patients.
  • the hypothermic effect is presumed to counteract ischemic damage by several mechanisms in the brain: Prevention of the blood-brain-barrier disruption that happens soon after ischemic onset that allows oedema formation from extravasation; Diminishing of the oxygen-based free-radical production; Reduction of the excitotoxic-neurotransmitter release that overstimulates neighboring neurons; Lowering of the metabolic rate and subsequent energy depletion; and anti-inflammatory action.
  • Induction of hypothermia has a neuroprotective effect.
  • Ischemia may occur under various circumstances; of special relevance to the present invention are the circumstances relating to cardiovascular diseases, asphyxia and traumatic brain injuries.
  • compounds of the present invention are administered to prevent or treat or treat and prevent tissue damaging effects subsequent to or in conjunction with ischemia.
  • Cardiovascular diseases Cardiovascular disease is the most common cause of death and of physical as well as mental impairment in the developed world. A similar development is seen in the rest of the world as it emulates the lifestyle of the Western hemisphere with its fatty diets, lack of exercise and increasing average lifespan.
  • cardiovascular diseases myocardial infarction, acute coronary syndrome, cardiac arrest and stroke, but many less common cardiovascular diseases may be equally detrimental to the individual affected. These less common diseases include among others arterial aneurism, subarachnoid haemorrhage, arteriosclerosis (or atherosclerosis), angina pectoris, hypertension, hypercholesterolemia, cardiac arrhythmia, cardiomegaly, cardiomyopathy, heart valve regurgitation and heart valve stenosis.
  • Myocardial infarction (heart attack) is a result of an atherosclerotic plaque slowly building up in the inner lining of a coronary artery which then suddenly ruptures, partially or totally occluding the artery and preventing blood flow.
  • Cardiac arrest is the abrupt cessation of normal circulation of the blood due to failure of the heart to contract effectively. Brain damage is likely to occur after 3-4 minutes without medical intervention, except in cases of hypothermia.
  • Stroke is an acute neurological injury, lasting more than 24 hours, in which the blood supply to a part of the brain is interrupted, either by a clot in the artery or if the artery bursts.
  • Arterial aneurism is a localized ballooning of an artery by more than 50% of the diameter of the vessel. Aneurysms most commonly occur in the arteries at the base of the brain and in the aorta. This bulge in an artery carries the risk of bursting and leading to internal hemorrhage. The larger an aneurysm becomes, the more likely it is to burst.
  • Subarachnoid haemorrhage is bleeding into the subarachnoid space surrounding the brain, i.e., the area between the arachnoid and the pia mater. It may arise due to trauma or spontaneously, and is a medical emergency, which can lead to death or severe disability even if recognized and treated in an early stage.
  • Arteriosclerosis is a disease in which arterial walls harden over years or decades as a result of the formation of collagen and calcium deposits.
  • Atherosclerosis is the most common subgroup of arterioscleosis, and is characterised by a chronic inflammatory response in the walls of arteries, in large part due to the accumulation of macrophage white blood cells ('foam cells') and promoted by low density lipoproteins (LDL; plasma proteins that carry cholesterol and triglycerides) without adequate removal of fats and cholesterol from the macrophages by functional high density lipoproteins (HDL).
  • Hypertension or high blood pressure is a medical condition wherein the blood pressure is chronically elevated.
  • Hypercholesterolemia is the presence of high levels of cholesterol in the blood. It is a derangement that can contribute to many forms of disease, most notably cardiovascular disease.
  • Arrhythmia is a group of conditions in which the muscle contraction of the heart is irregular or is faster or slower than normal. Some arrhythmias are life threatening medical emergencies that can cause cardiac arrest and sudden death. Cardiomegaly is a medical condition wherein the heart is enlarged. It can often be associated with other serious medical conditions. Cardiomyopathy is the deterioration of the function of the myocardium (i.e., the actual heart muscle). People with cardiomyopathy are at risk of arrhythmia and/or sudden cardiac death.
  • Heart valve regurgitation also known as heart valve insufficiency, is the abnormal leaking of blood through heart valves.
  • Heart valve stenosis is a heart condition caused by the incomplete opening of a heart valve, typically the aortic valve or the mitral valve, impairing blood flow through the heart.
  • Each of the cardiovascular diseases mentioned, as well as others not mentioned, may cause ischemia of organs. This ischemia, whether of the brain, heart or other organs, may lead to death or impairment if not treated rapidly.
  • cardiovascular diseases such as, but not limited to: myocardial infarction, acute coronary syndrome, cardiac arrest, stroke, arterial aneurism, subarachnoid haemorrhage, arteriosclerosis, angina pectoris, hypertension, hypercholesterolemia, cardiac arrhythmia, cardiomegaly, cardiomyopathy, heart valve regurgitation and heart valve stenosis.
  • the medicament is for the treatment or prophylaxis of ischemia due to cardiac arrest, myocardial infarction, acute coronary syndrome, stroke, arterial aneurisms, sub-arachnoid haemorrhage or angina pectoris.
  • Sudden cardiac arrest victims may be subjected to early CPR, early defibrillation and early advanced care. Further tests and treatments may include cardiac catheterization, electrophysiologic tests, coronary artery bypass surgery, balloon angioplasty or PTCA, antiarrhythmic medicine, implantable cardioverter / defibrillator, implantable pacemaker and heart transplant.
  • acute treatment may include clot-busters (e.g. tPA) or surgical intervention (e.g. aneurysm clipping, and endovascular procedures such as insertion of "coils").
  • Preventive treatment includes the administration of anticoagulants/anti-platelet. It may furthermore include carotid endarterectomy and angioplasty and/or stents.
  • Patients suffering a heart attack may have one or several treatments and procedures done to survive and diagnose the condition: These include resuscitation (early CPR, early defibrillation, early advanced care), thrombolysis, coronary angioplasty (also known as Percutaneous Transluminal
  • Coronary Angioplasty [PTCA], Percutaneous Coronary Interventions [PCI], Balloon Angioplasty and Coronary Artery Balloon Dilation), and coronary artery bypass graft surgery (CABG).
  • PCI Percutaneous Coronary Interventions
  • CABG coronary artery bypass graft surgery
  • Asphyxia is a common cause of death and of physical as well as mental impairment in perinatals, neonatals or newborns, children and adults of all ages.
  • WHO World Health Organization
  • the perinatal period commences at 22 completed weeks (154 days) of gestation (the time when birth weight is normally 500 g), and ends seven completed days after birth or delivery.
  • the neonatal period is most often and herein defined as four weeks after birth; regardless of whether or not birth occurs prematurely.
  • a premature infant is born after a gestation period of less than the normal time (about 266 days in the human).
  • Asphyxia can be divided into perinatal asphyxia and non-perinatal asphyxia.
  • Perinatal asphyxia is the medical condition resulting from deprivation of oxygen to an infant long enough to cause apparent harm; the infant may at the time of oxygen deprivation still reside in the mothers uterus and/or birth canal, it may occur during the process of delivery or may occur immediately after delivery. It results most commonly from a drop in maternal blood pressure or interference during delivery with blood flow to the infant's brain, but may also stem from umbilical cord entaglement. This can occur due to inadequate circulation or perfusion, impaired respiratory effort, or inadequate ventilation. Extreme degrees of asphyxia can cause cardiac arrest and death. Hypoxic damage can occur to most of the infant's organs, but brain damage is of most concern and perhaps the least likely to quickly and completely heal.
  • At least one compound hereof is administered to the infant while it resides within the uterus and/or birthcanal, i.e. as soon as asphyxia is determined.
  • Asphyxia may be determined for example by measuring the pH of the blood of the infant.
  • Non-perinatal asphyxia is a condition of severely deficient supply of oxygen to the body that arises from being unable to breathe normally. Common causes hereof include drowning, strangulation and exposure to toxic gasses. Asphyxia causes generalized hypoxia, which primarily affects the tissues and organs most sensitive to hypoxia first, such as the brain, hence resulting in cerebral hypoxia. The absence of effective remedial action will very rapidly lead to unconsciousness, brain damage and death.
  • Treatment by administration of the medicament defined in this patent may be carried out in conjunction with test and treatments of diseases and accidents including asphyxia (perinatal asphyxia, and non-perinatal asphyxia including, but not limited to, drowning, strangulation and exposure to toxic gasses).
  • diseases and injuries may require early CPR, early defibrillation and both early and continued advanced care as well as other tests and treatments not specified.
  • Traumatic brain injury is a common cause of death and of physical as well as mental impairment throughout the world. TBI may result from accidents, be due to violence or be self-inflicted.
  • Traumatic brain injury also called intracranial injury, or simply head injury, occurs when a sudden trauma causes brain damage.
  • TBI can result from a closed head injury or a penetrating head injury.
  • Parts of the brain that can be damaged include the cerebral hemispheres, cerebellum, and brain stem.
  • Symptoms of a TBI can be mild, moderate, or severe, depending on the extent of the damage to the brain.
  • Outcome can be anything from complete recovery to permanent disability or death. Ischemia is a significant factor contributing to the neurological damage frequently seen in patients suffering from TBI.
  • Treatment by administration of the medicament defined in this patent may also be carried out in conjunction with test and treatments in relation to traumatic head injury (closed head injury or penetrating head injury). Such injuries may require early CPR, early defibrillation and both early and continued advanced care as well as other tests and treatments not specified.
  • Elevated body temperature Individuals suffering from elevated body temperatures due to an infection, ischemic damage, heat- or sunstroke or the like will also benefit from the administration of the compounds of the present invention.
  • Fever also known as pyrexia, or a febrile response
  • Fever is a frequent medical symptom that describes an increase in especially internal body temperature to levels above normal. Fever is most accurately characterized as a temporary elevation in the body's thermoregulatory set-point, meaning that the temperature is raised by the body in a controlled manner. Fever is a symptom of many different diseases such as infectious diseases, immunological diseases, cancers metabolic disorders and more.
  • Hyperpyrexia is an extreme degree of fever, where the set body temperature is elevated greater than or equal to 41 degree Celsius. Such a high temperature is considered a medical emergency and requires immediate medical attention. Fever and hyperpyrexia differ from hyperthermia.
  • Hyperthermia is an increase in body temperature over the body's thermoregulatory set-point, due to excessive heat production or insufficient thermoregulation, or both. Hyperthermia may be caused by heat- or sunstroke, exposure, dehydration and more.
  • a special variant of hyperthermia is malignant hyperthermia which may arise due to administration of general anesthesia.
  • hypothermia in individuals in whom the initial temperature prior to treatment is above the normal temperature for said individual.
  • individuals may be individuals suffering from fever, hyperthermia, malign hyperthermia, hyperpyrexia or other. It is common that individuals suffering from a heart attack or stroke e.g. suffering from ischemia develop a fever and it is an object of the present invention to reduce the fever and induce hypothermia in such individuals.
  • Individuals otherwise suffering from fever, hyperthermia, malign hyperthermia, hyperpyrexia or other may benefit by administration of the compound of the present invention to reduce the elevated temperature to normal that is to within 35 to 39 degree Celsius, such as to within 35.5 to 38.5 degree Celsius, such as to within 36 to 38 degree Celsius, such as to within 37 degree Celsius +/- 0.6 degree Celsius, or to reduce their body temperature further to hypothermic levels as described above.
  • the individuals with elevated body temperatures may have any temperature considered to be above normal, which is any temperature above 36 degree Celsius.
  • the temperature of the individual in need of treatment according to the present invention may thus be a temperature of above 36 degree Celsius, such as above
  • 36.5 degree Celsius such as above 37 degree Celsius, such as above 37.5 degree Celsius, such as above 38 degree Celsius, such as above 38.5 degree Celsius, such as above 39 degree Celsius, such as above 39.5 degree Celsius, such as above 40 degree Celsius, such as above 40.5 degree Celsius, such as above 41 degree Celsius such as above 41 .5 degree Celsius such as above 42 degree Celsius, such as above 42.5 degree Celsius, such as above 43 degree Celsius, such as above 43.5 degree Celsius and higher.
  • Pre-operative administration The outcome of several types of surgery is improved if the individual undergoing the surgery is placed under hyperthermia prior to or during the surgery. Examples of such operations are neurosurgeries, thorax surgeries and especially cardiac surgeries. The lowering of the body temperature slows down the metabolic rate and thus reduces the need for e.g. oxygen during the surgery giving more time to the surgeon to perform complicated procedures.
  • the compounds of the present invention are preferably administered pre-operatively. It is also an aspect of the invention to provide a combination of compounds for the induction of hypothermia in an individual in need of surgery prior to and/or during transportation of said individual.
  • a specific procedure in which it is of interest to lower the body temperature is in the case of organ transplants, where it is beneficial that the organs to be transplanted are cooled prior to removal and especially prior to and during transport before transplantation into the recipient. It is furthermore of interest for the preservation of organs, tissues, and cells that hypothermia may be induced in these by induction of hypothermia in the individual from which these are taken. Either prior to or after removal, stasis (very low or no detectable metabolic rate) may be induced by further administration of the compounds of the present invention.
  • hypothermia is the lowering of the core temperature of the body below normal level. Normal body temperature in an adult human measured rectally over 24 hours is 37 degree Celsius +/- 0.6 degree Celsius and is thus variable between individuals, and over time within the individual. Hypothermia as a medical condition is usually defined as the effects seen on the body once the core temperature drops below 35 degree Celsius. It may become critical, if the body temperature falls below 32 °C. In the present application hypothermia is defined as the lowering of the core body temperature below normal levels. This implies that any temperature below the normal core body temperature of the specific individual with its natural variations at the given point in time of the day, or period, herein is defined as being hypothermic. In particular, hypothermia is a temperature below 35.5 °C, such as below 35 °C, such as below 34.5 °C, such as below 34.0 °C.
  • Body temperature may be measured by a variety of means by mercury, electronic or plastic strip thermometers on different areas of the body such as the forehead, mouth, armpit, ear or rectum. It is presently understood, that the temperature referred to in the present application is the core body temperature, and that some of the above methods of measurement will indicate a different temperature than the core temperature.
  • hypothermia induction of hypothermia in an individual can follow a predictable course and be responsive to the dose in which the combination of compounds capable of inducing hypothermia is administered.
  • the induction of the hypothermic condition may be rapid or slow depending on the situation of the individual in need of treatment. Also depending on the severity of the ischemic condition, it is of interest to provide a medicament for retaining the individual in the hypothermic state for variable durations of time.
  • a combination of compounds comprising two or more of the group consisting of vanilloid receptor agonists and/or cannabinoids or cannabimimetic compounds and/or adenosine receptor agonists and/or neurotensin receptor agonists and/or thyroxine derivatives, and/or cytoshrome c oxidase inhibitors and/or oxygen tension reducers, with the proviso that if the combination of compounds comprise two compounds said two compounds are not one cannabinoid or cannabimimetic compound and one vanilloid receptor agonist, may be used depending on dosage within a range of temperatures or for the induction of hypothermia to a specific temperature.
  • a combination of compounds comprising two or more of the group consisting of vanilloid receptor agonists and/or cannabinoids or cannabimimetic compounds and/or adenosine receptor agonists and/or neurotensin receptor agonists and/or thyroxine derivatives, and/or cytoshrome c oxidase inhibitors and/or oxygen tension reducers, with the proviso that if the combination of compounds comprise two compounds said two compounds are not one cannabinoid or cannabimimetic compound and one vanilloid receptor agonist, may furthermore be used for an initial rapid decrease in core body temperature, and the subsequent maintenance of the reached temperature over a prolonged period. It is furthermore beneficial if the hypothermic state can be reversed in a rapid and controlled fashion either slowly or rapidly depending on the status of the individual.
  • the combination of compounds is capable of inducing hypothermia to any range of temperatures between 37 and 31 degree Celsius, such as between 36.5 and 31.5 degree Celsius, such as between 36 and 32 degree Celsius, such as between 35.5 and 32.5 degree Celsius, such as between 35 and 33 degree Celsius, such as between 34.5 and 33.5 degree Celsius.
  • the ranges may furthermore be between 37 and 34 degree Celsius, such as between 36.5 and 34.5 degrees, such as 36 and 35 degrees, alternatively between 34 and 31 degree, such as between 33.5 and 31.5 degree, such as 33 and 32 degree Celsius, alternatively between 36 and 33 degree or 35 and 32 degree Celsius.
  • the combination of compounds of the present invention is capable of inducing hypothermia in the range of between 36 to 32 degree Celsius, more preferably between 35 and 33 degree Celsius.
  • the temperature range or specific temperature a given combination of compounds is capable of inducing is herein also referred to as the target temperature of the combination of compounds and/or the medicament comprising the combination of compounds.
  • the person in need of the hypothermic treatment e.g. the administration of a combination of compounds of the present invention suffers from ischemia, or is in need of surgery such as neurosurgery or cardiac surgery, e.g. the compound is administered pre-operatively.
  • An aspect of the present invention regards the treatment of an individual in need thereof by the use of a combination of compounds of the present invention for the induction of hypothermia.
  • the individuals in need of the treatment are individuals suffering from conditions that are benefitted by the induction of hypothermia and/or reduction in body and/or brain temperature.
  • Such individuals include but are not limited to: individuals suffering from or at risk of suffering from ischemia, elevated body termperatures due to fever, hyperthermia, hyperpyrexia, malign hyperpyrexia or are in need of treatment, such as but not limited to surgery, wherein the outcome of the procedure or the procedure itself is benefitted by a reduction in temperature of the individual undergoing the treatment and/or surgery.
  • vanilloid receptors or cannabinoid receptors or adenosine receptor or neurotensin receptors or thyroxine derivative receptors or cytochrome c oxidase as well as several co-receptors as described in the above and in a few cases may bind both vanilloid and cannabinoid receptors; a combination of compounds according to the present invention has a positive synergistic effect.
  • the positive synergistic effect putatively occurs by inducing several responses that converge, cross, or supplement each other.
  • hypothermia depends on the characteristics of the individual compounds of the combinations and these characteristics may be to reach different target temperatures or different ranges of target temperatures, reaching the target temperatures at various speeds (varying peak effect times), the duration of the induced hypothermia, the lifetime of the active compounds, a minimizing of side effects and so on.
  • It is therefore an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
  • a combination of 6 compounds It is therefore an object of the present invention to provide a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
  • a combination of 5 compounds it is therefore an object of the present invention to provide a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor.
  • a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one neurotensin receptor agonist and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one thyroxine derivative and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
  • It is therefore an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one thyroxine derivative.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one cytochrome c oxidase inhibitor.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one adenosine receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
  • D A combination of 4 compounds
  • It is therefore an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one neurotensin receptor agonist.
  • a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one thyroxine derivative.
  • a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one cytochrome c oxidase inhibitor.
  • a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one thyroxine derivative.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one cytochrome c oxidase inhibitor.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one neurotensin receptor agonist and at least one thyroxine derivative.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one neurotensin receptor agonist and at least one cytochrome c oxidase inhibitor.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one neurotensin receptor agonist and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one thyroxine derivative.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one cytochrome c oxidase inhibitor.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor.
  • a medicament or composition comprising at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor.
  • a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one neurotensin receptor agonist and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one neurotensin receptor agonist and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one adenosine receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one adenosine receptor agonist and at least one thyroxine derivative and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one vanilloid receptor agonist a and at least one adenosine receptor agonist and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one thyroxine derivative and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one adenosine receptor agonist at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
  • E A combination of 3 compounds
  • It is therefore an object of the present invention to provide a medicament or composition comprising at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one thyroxine derivative.
  • a medicament or composition comprising at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one cytochrome c oxidase inhibitor.
  • a medicament or composition comprising at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one neurotensin receptor agonist and at least one thyroxine derivative.
  • a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one neurotensin receptor agonist and at least one cytochrome c oxidase inhibitor.
  • a medicament or composition comprising at least one cannabinoid or cannabimimetic compound a and at least one neurotensin receptor agonist and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one cannabinoid or cannabimimetic compound at least one neurotensin receptor agonist and at least one thyroxine derivative.
  • a medicament or composition comprising at least one cannabinoid or cannabimimetic compound at least one neurotensin receptor agonist and at least one cytochrome c oxidase inhibitor.
  • a medicament or composition comprising at least one cannabinoid or cannabimimetic compound at least one neurotensin receptor agonist and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one neurotensin receptor agonist and at least one thyroxine derivative.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one neurotensin receptor agonist and at least one cytochrome c oxidase inhibitor.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one neurotensin receptor agonist and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one adenosine receptor agonist and at least one thyroxine derivative.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one adenosine receptor agonist and at least one cytochrome c oxidase inhibitor.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one adenosine receptor agonist and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one thyroxine derivative.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one cytochrome c oxidase inhibitor.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor.
  • a medicament or composition comprising at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one neurotensin receptor agonist and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one adenosine receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor.
  • a medicament or composition comprising at least one adenosine receptor agonist and at least one thyroxine derivative and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one adenosine receptor agonist and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor.
  • a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one thyroxine derivative and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one thyroxine derivative and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one neurotensin receptor agonist.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one adenosine receptor agonist and at least one neurotensin receptor agonist.
  • a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one neurotensin receptor agonist.
  • a medicament or composition comprising at least one neurotensin receptor agonist and at least one cytochrome c oxidase inhibitor.
  • a medicament or composition comprising at least one neurotensin receptor agonist and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one adenosine receptor agonist and at least one thyroxine derivative.
  • a medicament or composition comprising t least one adenosine receptor agonist and at least one cytochrome c oxidase inhibitor.
  • a medicament or composition comprising at least one adenosine receptor agonist and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one cannabinoid or cannabimimetic compound nd at least one thyroxine derivative.
  • a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one cytochrome c oxidase inhibitor.
  • a medicament or composition comprising at least one cannabinoid or cannabimimetic compound agonist and at least one oxygen tension reducer.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one thyroxine derivative.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one cytochrome c oxidase inhibitor.
  • a medicament or composition comprising at least one vanilloid receptor agonist and at least one neurotensin receptor agonist.
  • a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist.
  • a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one neurotensin receptor agonist.
  • a medicament or composition comprising at least one adenosine receptor agonist and at least one neurotensin receptor agonist.
  • the medicament may thus comprise compounds of the present invention wherein at least one compound induces hypothermia rapidly, or alternatively wherein at least one compound induces hypothermia slowly.
  • the medicament may furthermore comprise at least one compound that induces hypothermia over an extended time period, alternatively wherein at least one compound induces hypothermia for a short time period.
  • Cannabinoids and cannabimimetic compounds are a group of chemicals which activate the body's cannabinoid receptors, CB1 and CB2. Before other types were discovered, the term referred to a unique group of secondary metabolites found in the cannabis plant, which are responsible for the plant's peculiar pharmacological effects. Cannabinoids are generally grouped into five classes based mainly on chemical composition and in part on origin: • The eicosanoids, also referred to as endocannabinoids are produced in the bodies of humans and other animals
  • Cannabinoids act as a bioregulatory mechanism for most life processes, which reveals why medical cannabis has been cited as treatments for many diseases and ailments in anecdotal reports and scientific literature. Some of these ailments include: pain, arthritic conditions, migraine headaches, anxiety, epileptic seizures, insomnia, loss of appetite, GERD (chronic heartburn), nausea, glaucoma, AIDS wasting syndrome, depression, bipolar disorder (particularly depression-manic-normal), multiple sclerosis, menstrual cramps, Parkinson's, trigeminal neuralgia (tic douloureux), high blood pressure, irritable bowel syndrome, and bladder incontinence. Cannabinoids and cannabimimetic compounds (CB1/CB2 agonists) have furthermore received interest as putatively neuroprotective substances.
  • CB1/CB2 agonists cannabimimetic compounds
  • Cannabinoids are generally termed such due to their ability to bind one or more of the cannabinoid receptors CB1 and CB2. Receptors
  • CB1 and CB2 cannabinoid receptors
  • CB1 receptors are found primarily in the brain, specifically in the basal ganglia and in the limbic system, including the hippocampus. They are also found in the cerebellum and in both male and female reproductive systems. CB1 receptors are essentially absent in the medulla oblongata, the part of the brain that is responsible for respiratory and cardiovascular functions. Thus, there is not a risk of respiratory or cardiovascular failure as there is with many other drugs. CB1 receptors appear to be responsible for the euphoric and anticonvulsive effects of cannabis.
  • CB2 receptors are almost exclusively found in the immune system, with the greatest density in the spleen. CB2 receptors appear to be responsible for the antiinflammatory and possible other therapeutic effects of cannabis.
  • hypothermia the behavioural effects, including hypothermia, seen when introducing animals to cannabinoids seems to be due to other factors besides CB1 receptor stimulation [46;49]. Inducing hypothermia by cannabinoids is therefore not solely equivalent to stimulating the CB1 receptor. Furthermore, there is evidence in the literature for other receptors than CB1 and CB2 as recipients of the cannabinoid ligands.
  • the receptors to which the cannabinoids and cannabimimetic compounds of the present invention may bind includes, apart from CB1 and CB2: a third CB receptor, herein termed CB3, GABA (gamma-aminobutyric acid) receptors, the NMDA (N- methyl-D-aspartate) receptor, the 5-HT(1 A) receptor, also known as the serotonin receptor, the Delta opioid receptor (DOR) and TRPV1 (transient receptor potential vanilloid 1 ). It is furthermore within the scope of the invention that at least one compound of the combination of compounds of the invention may bind CB1 , CB2 or CB3 co-receptors. Compounds capable of binding any of the above-mentioned receptors thus fall within the scope of the present invention. Structure
  • the cannabinoids of this application are, based on their structure, categorized as follows: classic cannabinoids, non-classic cannabinoids, aminoalkylindoles, eicosanoids (endogenous cannabinoids) and other compounds that fall out of the classification. Compounds belonging to any of these categories fall within the scope of the present invention.
  • combinations of compounds of the invention are capable of inducing hypothermia in an individual.
  • At least one compound of the combination of compounds of the invention are capable of binding a cannabinoid receptor.
  • the present invention concerns the use of a combination of compounds wherein at least one compound comprises a structure of one of the general formulas illustrated in the below for cannabinoid and cannabimimetic compounds.
  • R is a chemical bond or a chemical moiety as defined in the above.
  • R may be any moiety substituted any amount of times according to the following non-limiting list, whereby R is: C, H, S, N, O, optionally substituted one or more times with C, H, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, diphenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(d- 4 )-alkyl, heteroaryl-(d- 4 )-alkyl, heterocyclyl-(Ci- 4 )-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl or phosphate, optionally further substituted one or more times with C, S, N, O, P, OH, H, phenyl, amine (NH), halogen, substituted lower alkyl or alkyl such as (CrC
  • R may furthermore be a chemical bond, or a pharmaceutically acceptable addition salt or hydrate thereof.
  • Phosphate residues have been implicated in the reduction of toxicity of certain cannabinoids without altering their hypothermic effect. It is therefore an object of the present invention that any of the cannabinoid and/or cannabimimetic compounds of the invention may carry one or more phosphate groups bound as phosphate esters.
  • the present invention concerns the use of a combination of compounds wherein at least one compound is a cannabinoid or cannabimimetic compound such as a classic or non-classic cannabinoid comprising the general formula (I):
  • R1 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(d- 4 )-alkyl, heteroaryl-(Ci- 4 )-alkyl, heterocyclyl-(d- 4 )-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl or phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(d- 4 )-alkyl, heteroaryl-(Ci- 4 )-
  • R3 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C 1 .
  • R4 is selected from the group of: C, H, S, N, O, optionally substituted with C, H, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, diphenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl- (Ci- 4 )-alkyl, heteroaryl-(Ci. 4 )-alkyl, heterocyclyl-(Ci.).
  • the present invention concerns the use of a combination of compounds wherein at least one compound is a cannabinoid or cannabimimetic compound such as a compound comprising the general formula (I) wherein R1 is C, O, N optionally substituted with O, OH, alkyl, alkenyl, alkynyl, or phosphate, optionally further substituted with methyl, alkyl or phosphate, when R2 is C substituted with C, O, P, H, OH, 0S02, phosphate, alkyl, alkenyl, alkynyl such as (C1 -CX), phenyl any of which may be substituted with methyl, dimethyl, sulfonyl, heterocycloalkyl, fluoride, phenyl or phosphate, when R3 is C, O, N, S, optionally substituted with O, OH, alkyl, alkenyl, alkynyl, or phosphate, optionally further substituted one or
  • the present invention concerns the use of a combination of compounds wherein at least one compound is a cannabinoid or cannabimimetic compound such as a compound comprising the general formula (I) wherein R1 is C, optionally substituted with H, OH, OCH 3 or phosphate, when R2 is C substituted with C, O, OSO 2 , alkyl such as (C 3 -Cn) any of which may be further substituted with methyl, dimethyl, alkyl such as (CrC x ), phenyl, phosphate or further substituted by fluoride, phosphate, methyl, dimethyl when R3 is C which may be substituted with C, O, N, OH, phosphate, any of which may be substituted with C, ethyl, phosphate, alkyl such as (CrC 2 ) wherein C 2 binds to R4 when R4 is C, optionally further substituted by methyl, dimethyl or phosphate when R4 as defined in claim 8
  • the present invention also concerns the use of a combination of compounds wherein at least one compound is a cannabinoid or cannabimimetic compound such as a classic or non-classic cannabinoid comprising the general formula (II):
  • R1 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(Ci_ 4 )-alkyl, heteroaryl-(Ci- 4 )-alkyl, heterocyclyl-(Ci_ 4 )-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally bonding with the C in the ring next to R5, optionally further substituted one or more times with C, S, N, O, OH, phenyl, phosphate, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl
  • R2 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, any of which may or may not be branched or comprise substituents such as phosphate, heterocycloalkyl, cycloalkyl, cycloalkenyl, methyl, dimethyl, or may be further substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, sulfonyl, any of which may or may not be branched or comprise substituents such as hydrogen, alkyl, alkenyl, alkynyl, fluoride, phosphate, heterocycloalkyl, cycloalkyl, cycloalkenyl, dimethyl, phenyl and preferably is C substituted with C, O, P, H, OH, OSO 2 , phosphate, alkyl,
  • R3 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(d- 4 )-alkyl, heteroaryl-(Ci- 4 )-alkyl, heterocyclyl-(d- 4 )-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(d- 4 )-alkyl, heteroaryl-(Ci- 4 )-
  • R4 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C 1 _ 4 )-alkyl, heteroaryl-(Ci- 4 )-alkyl, heterocyclyl-(Ci- 4 )-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(d- 4 )-alkyl, heteroary
  • R5 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C 1 _ 4 )-alkyl, heteroaryl-(Ci_ 4 )-alkyl, heterocyclyl-(Ci_ 4 )-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally bonding with R1 , optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci-
  • the present invention concerns the use of a cannabinoid or cannabimimetic compound such as a compound comprising the general formula (II) wherein R1 is C, O, N optionally substituted with O, OH, alkyl, alkenyl, alkynyl, or phosphate, optionally further substituted with alkyl or phosphate, when R2 is C substituted with C, O, P, H, OH, 0S02, phosphate, alkyl, alkenyl, alkynyl such as (C1 -CX), phenyl any of which may be substituted with methyl, dimethyl, sulfonyl, heterocycloalkyl, fluoride, phenyl or phosphate, when R3 is C, O, N, OH, phosphate optionally substituted one or more times with alkyl, OH, phosphate any of which may connect with R4 thus forming a ring, when R4 is C, N, O, P,
  • the present invention concerns the use of a cannabinoid or cannabimimetic compound such as a compound comprising the general formula (II) wherein R1 is C, optionally substituted with H, OH, OCH 3 or phosphate when R2 is C substituted with C, O, OSO 2 , alkyl such as (C 3 -C 8 ) any of which may be further substituted with methyl, dimethyl, alkyl such as (CrC x ), phenyl, phosphate or further substituted by fluoride, phosphate, methyl, dimethyl when R3 is O, OH, NH, optionally connecting with R4, when R4 is C, optionally connecting with R3 and optionally substituted with methyl, dimethyl or methyn, when R5 is C, CO, optionally substituted with C, methyl, methyn (CH2), optionally substituted with CH20H and wherein x is an integer of from 1 to 15.
  • R1 is C, optionally substituted with H,
  • R2 An additional element of importance for especially CB1 receptor recognition is the side chain of R2. It is preferably a lipophilic carbon chain comprising from 1 to 15 carbon atoms, preferably from 3 to 1 1 carbon atoms. It may have any number and type of substituents, especially methyl and/or dimethyl groups. The methyl groups are preferably close to the phenol group, as this appears to induce the greatest effect of the drug. Interestingly, it appears that shorter side chains increase the intensity and decrease the duration of the activity of these compounds.
  • the present invention concerns the use of a combination of compounds, wherein at least one compound is a cannabinoid or cannabimimetic compound such as an eicosanoids or other cannabinoid compound comprising the general formula (III):
  • R1 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(d- 4 )-alkyl, heteroaryl-(Ci- 4 )-alkyl, heterocyclyl-(d- 4 )-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(d- 4 )-alkyl, heteroaryl-(Ci- 4 )-
  • R2 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C 1 _ 4 )-alkyl, heteroaryl-(Ci_ 4 )-alkyl, heterocyclyl-(Ci_ 4 )-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, 0CH3, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(d- 4 )-alky
  • the present invention concerns the use of a cannabinoid or cannabimimetic compound such as a compound comprising the general formula (III) wherein R1 is (CI -C x ) saturated or unsaturated, and optionally is substituted one or more times with lower alkyl, alkenyl, alkynyl, O, OH, N, when R2 is C, N, O, NH2 optionally substituted one ore more times with lower alkyl, alkenyl, alkynyl, phenyl, OH, NH2 cycloalkane, methyl or 0CH3 and wherein x is an integer of from 1 to 30.
  • R1 is (CI -C x ) saturated or unsaturated, and optionally is substituted one or more times with lower alkyl, alkenyl, alkynyl, O, OH, N, when R2 is C, N, O, NH2 optionally substituted one ore more times with lower alkyl, alkenyl,
  • the present invention concerns the use of a cannabinoid or cannabimimetic compound such as a compound comprising the general formula wherein R1 is (CrC x ), is saturated or unsaturated and optionally substituted with methyl, dimethyl, O, or N when R2 is N, O, NH2 optionally substituted with C, CH2OH, CH(CH2)2 (cyclopropane), optionally further substituted one or more times with CH2OH, CH2CI and wherein x is an integer of from 1 to 21.
  • the present invention concerns the use of a combination of compounds wherein at least one compound is a cannabinoid or cannabimimetic compound such as an aminoalkylindole or other cannabinoid compound comprising the general formula (IV):
  • R1 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(d- 4 )-alkyl, heteroaryl-(Ci- 4 )-alkyl, heterocyclyl-(Ci_ 4 )-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci_ 4 )-alkyl, heteroaryl-(Ci_ 4
  • R2 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(Ci- 4 )-alkyl, heteroaryl-(Ci- 4 )-alkyl, heterocyclyl-(Ci- 4 )-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(d- 4 )-alkyl, heteroaryl-(d-(d-
  • R3 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(Ci_ 4 )-alkyl, heteroaryl-(Ci- 4 )-alkyl, heterocyclyl-(Ci_ 4 )-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci_ 4 )-alkyl, heteroaryl-(Ci_ 4
  • R4 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C 1 _ 4 )-alkyl, heteroaryl-(Ci_ 4 )-alkyl, heterocyclyl-(Ci_ 4 )-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(C 1 _ 4 )-alkyl,
  • the present invention concerns the use of a cannabinoid or cannabimimetic compound such as a compound comprising the general formula (IV) wherein R1 is C, O , N optionally substituted with O, phosphate, N, C, lower alkyl, OH, optionally further substituted with lower alkyl, OH or phosphate, when R2 is C, N, O, optionally substituted with C, O, N, phosphate, lower alkyl optionally further substituted with lower alkyl, OH, phosphate, any of which may bond with R3, when R3 is C, N, O, alkyl, alkenyl, alkynyl, optionally substituted with C, N, O, OH, phosphate, halogen any of which may bond R2, when R4 is C, N, O optionally substituted with C, N, O, OH, lower alkyl, alkenyl, alkynyl, phosphate, optionally further substituted one or more times with O,
  • the present invention concerns the use of a cannabinoid or cannabimimetic compound such as a compound comprising the general formula (IV) wherein, wherein R1 is C, substituted with O, further substituted with methyl when R2 is C, substituted with O, further substituted with C optionally bond forming with R3 when R3 is (CI -Cx) and wherein x is an integer of from 1 to 3, optionally substituted one or more times with O, dichloro-phenyl or morpholine when R4 is C, optionally substituted with C, O and/or diphenyl, optionally further substituted with morpholine.
  • a cannabinoid or cannabimimetic compound such as a compound comprising the general formula (IV) wherein, wherein R1 is C, substituted with O, further substituted with methyl when R2 is C, substituted with O, further substituted with C optionally bond forming with R3 when R3 is (CI -Cx) and wherein x is an integer
  • cannabinoid or cannabimimetic compounds specially relevant for the present invention include, but are not limited to classic cannabinoids such as (names in parenthesis are alternative names): delta-9-THC (Tetrahydrocanna-binol), delta-8-THC, delta-8-THC phosphate, Cannabinol (CBN), Cannabidiol (CBD), Cannabidiol-type CBD, Cannabidivarin (CBDV), Cannabichromene-type CBG,
  • classic cannabinoids such as (names in parenthesis are alternative names): delta-9-THC (Tetrahydrocanna-binol), delta-8-THC, delta-8-THC phosphate, Cannabinol (CBN), Cannabidiol (CBD), Cannabidiol-type CBD, Cannabidivarin (CBDV), Cannabichromene-type CBG,
  • Cannabigerol-type CBG Tetrahydrocanna-bivarin (THCV, THV), Tetrahydrocanna- binol- and cannabinol-type THC or CBN
  • Iso-Tetrahydro-cannabinol-type iso-THC Cannabielsion-type CBE, Cannabicyclo l-type CBL, Cannabicitran-type CBT, HU- 308, JWH-133, JWH-139, JWH-051 , L-759633, L-759656, HU-210 ((-)-1 1 -OH-delta- 8-tetrahydrocannabinol-dimethylheptyl), HU-21 1 (Dexanabinol, 7-hydroxy-D6- tetrahydrocannabinol 1 ,1 -dimethylheptyl), Desacetyl-L-nandrolol, Nabilone and Levonantradol, non
  • Palmitoylethanol-amine Virodhamine (O-arachidonoyl-ethanolamine), Palmitoyl ethanolamide, Oleamide, other cannabinoid compounds such as: Arvanil, Metanandamide, ACEA, ACPA, BAY 38-7271 (also known as KN38-7271 ) and O- 1812. Phosphate derivatives of these compounds are especially relevant for the present invention.
  • cannabinoid or cannabimimetic compounds examples include anandamide, delta-9-THC, delta-8-THC, cannabidiol, HU-210, BAY 38-7271 , WIN 55,212 and CP55940 and the phosphate derivatives of these.
  • the compounds of the present invention may apart from inducing hypothermia, induce secondary effects or have other characteristics. These may be related to the cannabinoid nature of the compounds and may thus be more or less desirable. It is preferable that the compounds of the invention do not induce any adverse psychotropic effects.
  • the compound may furthermore have analgesic, anticonvulsive, anti-inflammatory, anti-anxiety, anti-nausea, pulse-lowering and blood- pressure modifying effects. Of these, it is preferable that the compound has analgesic effects.
  • a compound of the present invention may be hydrophilic or hydrophobic. To facilitate the administration of a compound according to the present invention it is preferable for a compound to be hydrophilic. A preferred compound is moreover metabolically stable.
  • a preferred cannabinoid or cannabimimetic compound of the present invention is a compound capable of binding a cannabinoid receptor, such as CB1 , thereby inducing hypothermia in an individual to a temperature in the range of 36 to 32 degree Celsius, and where said compound is hydrophilic.
  • Antagonists to cannabinoid and cannabimimetic compound function It is an object of the present invention to provide compounds that are capable of obviating the effect of the compounds that induce hypothermia. These compounds are herein termed antagonists and exert their antagonistic effect by blocking the ability of any of the cannabinoids or cannabimimetic compounds herein described in binding to their receptors. The purpose of such an antagonist is to provide an additional safety mechanism whereby it is possible to stop the decline in core body temperature, stabilize the core body temperature and/or raise the core body temperature of an individual.
  • An embodiment of the present invention thus comprises the use of a compound according to any of the above for the preparation of a medicament for antagonizing the induction of hypothermia in an individual.
  • antagonists include but are not limited to: Rimonabant (SR141716), Acomplia, SR147778, SR141716A, SR144528, CP-272,871 , NIDA-41020, LY320135, AM251 , AM281 , AM630, WIN56098 and WIN54461.
  • Cannabinoids and cannabimimetic compounds have been used for a variety of purposes over time. It is an object of the present invention to provide a novel use of these compounds for the induction of hypothermia, especially for the preparation of a medicament comprising two or more compounds of the group consisting of vanilloid receptor agonists and/or cannabinoids or cannabimimetic compounds and/or adenosine receptor agonists and/or neurotensin receptor agonists and/or thyroxine derivatives and/or cytochrome c oxidase inhibitors and/or oxygen tension reducers, with the proviso that if the combination of compounds comprises two compounds said two compounds are not one cannabinoid or cannabimimetic compound and one vanilloid receptor agonist for the induction of hypothermia in an individual.
  • Vanilloid receptor agonists Vanilloid receptor agonists
  • Vanilloid receptor agonists are a group of chemicals which are capable of binding the Vanilloid Receptor 1 (VR1 ), also known as the Transient Receptor Potential Cation Channel, Subfamily V (TRPV1 ).
  • the term vanilloid receptor agonist covers several groups of compounds including capsaicinoids and capsaicinoid-like compounds such as resiniferanoids and unsaturated dealdehydes.
  • capsaicinoid referred to a group of secondary metabolites produced by plants belonging to the genus Capsicum, such as chili peppers. These compounds are the active components of chili peppers that produce the sensation of burning in the mouth, when ingested.
  • Vanilloid receptor agonists may be divided into two classes based on origin and chemical composition:
  • Non-classical vanilloid receptor agonists a group wherein the members generally do not comprise a vanillamide moiety.
  • Vanilloid receptor agonists are irritants for mammals, but have no effect on birds, indicating that the compounds may have evolved as a deterrent for herbivores.
  • the various vanilloid receptor agonists have different pungencies as measured on the Scoville scale, with capsaicin and dihydrocapsaicin being the most potent of the classical vanilloid receptor agonists.
  • capsaicin as a medicament is known both anecdotally and scientifically and is today widely used as a medicine to treat or relieve various ailments.
  • the main clinical use of capsaicin is in the form of a topical ointment to successfully treat the pain of neuralgia such as caused by an infection with herpes zoster (shingles), diabetic neuropathy, rheumatism, fibromyalgia, various types of arthritis such as osteoarthritis or rheumatoid arthritis, and other forms of chronic pain.
  • Capsaicin desensitizes nerves from pain by eliminating unneeded nerve cells through necrotic death and helps arthritis sufferers by lowering the levels of Decapeptide Substance P (DSP) in the synovial fluid of joints. Capsaicin breaks down DSP, which can destroy cartilage and also magnify the sensing of pain. Recently studies demonstrate that capsaicin is a potent anticancer agent. Capsaicin induces apoptosis in pancreatic and prostate cancer cells with no significant damage to the surrounding healthy cells. Capsaicin is known to affect NF-kB, and it is believed that it is through this protein, that capsaicin activates apoptotic proteins, leading to cell death.
  • DSP Decapeptide Substance P
  • capsaicin-containing candy provides significant pain relief of ulcers in the mouth which often develop in chemotherapy patients.
  • Capsaicin pastes and balms are used to treat muscle and joint pains and medications containing vanilloid receptor agonists are used as an anti-inflammatory agent as the chemicals causes blood vessels to dilate.
  • Capsaicin has furthermore been mentioned as a remedy to reduce serum cholesterol levels, relieve psoriasis and treat headaches, migraines and chronic sinus infections.
  • Vanilloid receptor agonists have furthermore received interest as putatively neuroprotective substances. The neuroprotective effect is at least in part mediated by induction of hypothermia, as described in the below.
  • vanilloid receptor agonist any compound which can be defined as a vanilloid receptor agonist, capsaicinoid or capsaicinoid-like compound these being classical or non-classical vanilloid receptor agonist or compounds that otherwise bind vanilloid receptors falls within the scope of the present invention.
  • vanilloid receptor agonist capsaicinoid or capsaicinoid-like are used interchangeably herein.
  • the sensation of burning pain elicited by vanilloid receptor agonists occurs by the selective activation of sensory neurons that convey information about noxious stimuli to the central nervous system.
  • the selectivity is based primarily on the presence of the VR1 / TRPV1 receptor, a nonselective cation channel to which the vanilloid receptor agonists, capsaicinoids and capsaicinoid-like compounds bind as agonists.
  • TRPV1 is also activated by extracellular protons, and temperatures in the noxious range, suggesting that it functions as a transducer of painful thermal stimuli in vivo.
  • the vanilloid receptor agonists By binding to the TRPV1 receptor, the vanilloid receptor agonists produce the same effect that excessive heat or abrasive damage would cause, explaining why the spiciness of capsaicin, without causing an actual chemical burn, is described as eliciting a burning sensation.
  • vanilloid receptor agonists A number of different mechanisms have been proposed to account for the various effects of vanilloid receptor agonists.
  • the vanilloid receptors that are likely to be multimeric, non-selective cation channels composed of 6 transmembrane domains, will upon activation induce Ca 2+ entry and subsequent release of sensory neuropeptides like calcitonin gene-related peptide (CGRP) and tachykinins (e.g. substance P) in addition to somatostatin.
  • CGRP calcitonin gene-related peptide
  • tachykinins e.g. substance P
  • the TRPV1 receptor was originally named the Vanilloid Receptor 1 (VR1 ), as a vanilloid moiety constitutes an essential component of classical vanilloid receptor agonists, but has since changed name to TRPV1 due to the receptors extended homology with other TRP family members.
  • TRPV1 is a member of the subfamily of TRPV receptors, which includes TRPV1 -6. Several of these receptors render the cells expressing them sensitive to heat at different intervals, mechanic pressure and various compounds such as vanilloid receptor agonists, camphor and others. Combinations of the subtypes and various oligomers of the vanilloid receptors may account for the variations in physiological outcome observed following activation of receptors by different vanilloid receptor agonists.
  • the oligomeric structure of the receptors increase the likelihood of discovering active substances with specificity for certain of the many organs that harbors vanilloid receptor agonists, thereby activating only parts of the vanilloid receptor system.
  • Vanilloid receptors are abundant in many organs of the body including neuronal tissues of the preoptic area, locus ceruleus, medial hypothalamus, reticular formation, and ventral thalamus. Vanilloid receptors have furthermore been found in non-neuronal "port of entry" tissues (e.g., skin, gut, airways, conjunctiva), the various cell types lining such tissues (i.e., keratin ocytes, epithelia, endothelia, etc.), and also in various peripheral non-neuronal tissues of rodents and humans (e.g., kidney, lung, testis, pancreas, spleen, liver, stomach, skin, vascular smooth muscle, placenta, cornea, uterus, and bladder).
  • the hypothalamus, with its abundance of vanilloid receptors, is of particular interest to this invention: It is a likely component in vanilloid receptor mediated hypothermia as it contains the temperature regulating centres of the CNS.
  • Receptors other than TRPV1 have been implicated in causing hypothermia upon binding of agonists hereto. Although some data suggests that capsaicin causes hypothermia by a cannabinoid receptor (CB1 and CB2) independent mechanism, there are hypothermia inducing vanilloid receptor agonists that are capable of interacting both with TRPV1 and especially CB2. Apart from TRPV3 mentioned above as a modulator of TRPV1 activity, the prokineticin receptors 1 and 2 (PKR1 and PKR2) have been shown to interact with TRPV1 and modulate its activity.
  • CB1 and CB2 cannabinoid receptor
  • Receptors to which the vanilloid receptor agonists, capsaicinoids and capsaicinoid- like compounds of the present invention may bind includes, apart from TRPV1 and the other TRPV subfamily members, TRPV2, -3, -4, -5 and -6, CB1 , CB2 and a third CB receptor, herein termed CB3, PKR1 and PKR2, GABA (gamma-aminobutyric acid) receptors, the NMDA (N-methyl-D-aspartate) receptor, the 5-HT(1A) receptor, also known as the serotonin receptor, the Delta opioid receptor (DOR).
  • TRPV1 and the other TRPV subfamily members TRPV2, -3, -4, -5 and -6
  • CB1 , CB2 and a third CB receptor herein termed CB3, PKR1 and PKR2
  • GABA gamma-aminobutyric acid
  • NMDA N-methyl-D
  • At least one of compound of the combination of compounds of the invention may bind TRPV1 co-receptors.
  • Compounds capable of binding any of the above-mentioned receptors thus fall within the scope of the present invention.
  • At least one compound of the combination of compounds of the present invention binds TRPV1 and/or a TRPV1 associated receptor.
  • TRPV1 receptor for the induction of hypothermia in mammals is the dramatic hypothermic response that is elicited by systemic administration of capsaicin, a response which is absent in mice lacking the TRPV1 gene.
  • vanilloid receptor agonists of this application are, largely based on their structure, categorized as follows: classic vanilloid receptor agonists and non-classic vanilloid receptor agonists. Compounds belonging to any of these categories fall within the scope of the present invention.
  • combinations of compounds of the invention are capable of inducing hypothermia in an individual.
  • At least one compound of the combination of compounds of the invention is capable of binding the TRPV1 receptor and/or a receptor associated herewith. Accordingly, in the broadest aspect the present invention concerns the use of a combination of compounds, wherein at least one compound is a vanilloid receptor agonist comprising a structure of one of the general formulas of vanilloid receptor agonists illustrated in the below. In these illustrations R is a chemical bond or a chemical moiety as defined in the above.
  • R may be any moiety substituted any amount of times according to the following non-limiting list, whereby R is: C, H, S, N, O, optionally substituted one or more times with C, H, S, N, O, B, P, OH, CHO, hydrogen, alkoxy, alkyl, alkenyl, alkynyl, phenyl, diphenyl, benzyl, amine (NH), halogen, substituted lower alkyl, alkenyl, aryl, heterocyclic group, heterocycloalkyl, heteroaryl, aryl-(Ci_ 4 )-alkyl, heteroaryl-(Ci_ 4 )-alkyl, heterocyclyl-(Ci_ 4 )-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkyl, cycloalkenyl or phosphate, optionally further substituted one or more times with C, S, N, O, P, OH, H, phen
  • the present invention concerns the use of a combination of compounds wherein at least one compound is a vanilloid receptor agonist such as a classic or non-classic vanilloid receptor agonist comprising the general formula (I):
  • R1 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, any of which may or may not be branched or comprise substituents such as phosphate, cycloalkyl, heterocycloalkyl, cycloalkenyl, methyl, ethyl, dimethyl, or may be further substituted one or more times with C, S, N, O, P, OH, methoxy, ethoxy, acetyl, alkoxy, alkyl, alkenyl, alkynyl, sulfonyl or phenyl any of which may or may not be branched or comprise substituents such as hydrogen, methyl, ethyl, alkyl, alkenyl, alkynyl, alkoxy, phosphate, cycloalkyl, heterocycloalkyl, cycloalkenyl
  • R2 is selected from the group of: C, S, N, O, optionally substituted one or more times with C, S, N, O, P, OH, hydrogen, alkoxy, alkyl, alkenyl, alkynyl, phenyl, diphenyl, benzyl, amine (NH), halogen, substituted lower alkyl, alkenyl, aryl, heterocycloalkyl, heteroaryl, aryl-(d- 4 )-alkyl, heteroaryl-(d- 4 )-alkyl, heterocyclyl-(Ci- 4 )-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl or phosphate, optionally further substituted one or more times with C, S, N, O, P, OH, H, COOH, phenyl, amine (NH), halogen, alkoxy, substituted lower alkyl, alkyl or alkenyl such as (
  • the present invention concerns the use of a combination of compounds wherein at least one compound is a vanilloid receptor agonist comprising the general formula (I) wherein R1 is C substituted with C, O, P, H, OH, phosphate, alkyl, alkenyl, alkynyl any of which may be (CrC v ), or phenyl, any of which may be further substituted one or more times with O, OH, methyl, dimethyl, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, acetyl, phenyl, methoxy, ethoxy, alkoxy or phosphate, any of which may be further substituted with methyl, ethyl or phenyl and R2 is C, substituted one or more times with C, N, O, P, OH, hydrogen, alkoxy, alkyl, alkenyl, amine (NH), halogen, substituted lower alkyl
  • the present invention concerns the use of a combination of compounds wherein at least one compound is a vanilloid receptor agonist comprising the general formula (I) wherein R1 is C substituted with alkyl, alkenyl, any of which may be (C 4 -C w ) any of which may be further substituted one or more times with O, OH, acetyl, methoxy, ethoxy or methyl any of which may be further substituted one or more times with methyl, ethyl, cycloalkenyl or phenyl and w is an integer of from 5 to 18, and R2 is C substituted with either: cycloalkenyl further substituted at least twice with any of OH or methoxy, or: lower alkyl such as (CrC 2 ) at least once and further substituted one or more times with OH, COOH, Chloride, methyl or cycloalkenyl, optionally further substituted one or more times with OH or methoxy.
  • R1 is C substituted
  • the present invention furthermore concerns the use of a combination of compounds wherein at least one compound is a vanilloid receptor agonist such as a non-classic vanilloid receptor agonist comprising the general formula (II):
  • R1 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, B, P, OH, hydrogen, alkyl, alkenyl, alkynyl, any of which may or may not be branched or comprise substituents such as phosphate, cycloalkyl, heterocyclyl, heterocyclic group, cycloalkenyl, methyl, ethyl, dimethyl, or may be further substituted one or more times with C, S, N, O, P, OH, methoxy, ethoxy, acetyl, alkoxy, alkyl, alkenyl, alkynyl, sulfonyl or phenyl cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclic group any of which may or may not be branched or comprise substituents such as C, O, H, OH, methyl, ethyl, alkyl, alkenyl
  • R2 is selected from the group of C, S, N, O, optionally substituted at least once with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, any of which may or may not be branched or comprise substituents such as phosphate, cycloalkyl, heterocycloalkyl, cycloalkenyl, methyl, ethyl, dimethyl, or may be further substituted one or more times with C, N, O, P, OH, methoxy, ethoxy, acetyl, alkoxy, alkyl, alkenyl, alkynyl, or phenyl any of which may or may not be branched or comprise substituents such as hydrogen, methyl, ethyl, alkyl, alkenyl, alkynyl, alkoxy, phosphate, cycloalkyl, heterocycloalkyl, cycloalkenyl, dimethyl or pheny
  • R3 is selected from the group of C, S, N, O, optionally substituted with C, S, N, O, B, P, OH, hydrogen, methoxy, ethoxy, acetyl, alkoxy, alkyl, alkenyl, alkynyl, any of which may or may not be branched or comprise substituents such as phosphate, cycloalkyl, heterocycloalkyl, cycloalkenyl, methyl, ethyl, dimethyl, or may be further substituted one or more times with C, S, N, O, P, OH, methoxy, ethoxy, acetyl, alkoxy, alkyl, alkenyl, alkynyl, or phenyl any of which may or may not be branched or comprise substituents such as hydrogen, methyl, ethyl, alkyl, alkenyl, alkynyl, alkoxy, phosphate, cycloalkyl, hetero
  • R4 is selected from the group of C, S, N, O, optionally substituted with C, S, N, O, B, P, OH, hydrogen, methoxy, ethoxy, acetyl, alkoxy, alkyl, alkenyl, alkynyl, any of which may or may not be branched or comprise substituents such as phosphate, cycloalkyl, heterocycloalkyl, cycloalkenyl, methyl, ethyl, dimethyl, or may be further substituted one or more times with C, S, N, O, P, OH, methoxy, ethoxy, acetyl, alkoxy, alkyl, alkenyl, alkynyl, or phenyl any of which may or may not be branched or comprise substituents such as hydrogen, methyl, ethyl, alkyl, alkenyl, alkynyl, alkoxy, phosphate, cycloalkyl, hetero
  • R5 is selected from the group of C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, any of which may or may not be branched or comprise substituents such as phosphate, cycloalkyl, heterocycloalkyl, cycloalkenyl, methyl, ethyl, dimethyl, or may be further substituted one or more times with C, S, N, O, P, OH, CHO, hydrogen, methoxy, ethoxy, acetyl, alkoxy, alkyl, alkenyl, alkynyl, sulfonyl or phenyl any of which may or may not be branched or comprise substituents such as hydrogen, methyl, ethyl, alkyl, alkenyl, alkynyl, alkoxy, phosphate, cycloalkyl, heterocycloalkyl, cyclo
  • R6 is selected from the group of C, S, N, O, optionally substituted with C, S, N, O, B, P, OH, CHO, hydrogen, alkyl, alkenyl, alkynyl, any of which may or may not be branched or comprise substituents such as phosphate, cycloalkyl, heterocycloalkyl, cycloalkenyl, methyl, ethyl, dimethyl, or may be further substituted one or more times with C, N, O, P, OH, methoxy, ethoxy, acetyl, alkoxy, alkyl, alkenyl, alkynyl, or phenyl any of which may or may not be branched or comprise substituents such as hydrogen, methyl, ethyl, alkyl, alkenyl, alkynyl, alkoxy, phosphate, dimethyl or phenyl and preferably is C substituted with C, O, P, H, OH,
  • the present invention concerns the use of a combination of compounds wherein at least one compound is a vanilloid receptor agonist comprising the general formula (I) wherein R1 is C substituted with C, N, O, B, P, OH, hydrogen, alkyl, alkenyl, alkynyl, any of which may or may not be branched or comprise substituents such as phosphate, cycloalkyl, heterocyclyl, heterocyclic group, cycloalkenyl, methyl, ethyl, dimethyl, or may be further substituted one or more times with C, N, O, P, OH, methoxy, ethoxy, acetyl, alkoxy, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclic group any of which may or may not be branched or comprise substituents such as C, O, H, OH, methyl, ethyl, alkyl, alkenyl
  • the present invention concerns the use of a combination of compounds wherein at least one compound is a vanilloid receptor agonist comprising the general formula (I) wherein R1 is C substituted with alkyl or alkenyl which may be (C4-C z ), Boron, or heterocyclic group forming a ring with R6 thus comprising a pyrrolidine further substituted one or more times with O, methyl, alicyclic groups attached to one another, these being saturated or unsaturated or a heterocyclic group comprising said Boron, N and O, and being further substituted at least once with O, methyl or C further substituted at least once with cycloalkenyl, cycloalkyl, heterocyclyl further substituted at least once with O, OH, methyl, alkenyl, further substituted with lower alkyl and cycloalkenyl; R2 is C substituted with OH or hydrogen; R3 is C substituted with OH, methoxy, lower alkyl (C1 - C
  • the classical vanilloid receptor agonist compounds are preferable especially regarding the classical vanilloid receptor agonist compounds, as they seem to ensure a more favorable degree of vanilloid receptor activation.
  • These modifications include an unbranched alkyl side chain of a certain minimum length, as shorter chain analogues decrease in potency and thus are not capable of inducing hypothermia to a satisfactory degree.
  • the compounds of the present invention have relatively long alkyl or alkenyl chains (counted from R1 in the above formula) such as chains longer than 6 carbon atoms.
  • the length of the alkyl / alkenyl chain is between 6 and 25 carbon atoms, most preferably between 7 and 18 carbon atoms, even more preferably between 8 and 9 carbon atoms.
  • vanilloid receptor agonists examples include, but are not limited to classic vanilloid receptor agonists such as (names in parenthesis are alternative names): Capsaicin (C; 8-methyl-N-vallilyl-6- nonenamide), Dihydrocapsaicin (DHC), Nordihydro-capsaicin (NDHC), Homodihydro-capsaicin (HDHC), Homocapsaicin (HC), Olvanil (N-9-Z- octadecenoyl-vanillamide), Rinvanil (vanillamide of ricinoleic acid), Arvanil (N- vanillylarachidonamide), PhAR (phenylacetylrinvanil), Nuvanil, Farvanil (vanillamide of farnesic acid), Ac-Rinvanil, Retvanil (vanillamide of retinoic acid), Nonivamide, and Ervanil (vanillamide of eruci)
  • non-classical vanilloid receptor agonist compounds specially relevant for the present invention include, but are not limited to compounds such as (names in parenthesis are alternative names): Resiniferatoxin (RTX), Anandamide (arachidonyl ethanolamine), N-arachidonoyldopamine (NADA), N-arachidonoyl-L- serine (ARA-S), Arachidonyl-2-chloroethylamide, 2-aminoethoxydiphenyl borate (2- APB), Evodiamine, Propofol, Isovelleral, Scutigeral, 12-hydroperoxyeicosatetraenoic acid, Alpha-sanshool, Beta-sanshool, Gamma-sanshool, Delta-sanshool, Alpha- hydroxy-sanshool, Beta-hydroxy-sanshool, Piperine, Zingerone, and Bv8.
  • RTX Resiniferatoxin
  • Anandamide arachi
  • vanilloid receptor agonist compounds may apart from inducing hypothermia induce secondary effects or have other characteristics. These may be related to the capsaicinoid nature of the compounds and may thus be more or less desirable. It is preferable that the compounds of the invention do not induce any blood-pressure modifying effects or induce hyperalgesic, nocifensive, plasma extravasation, peripheral vasodilatation, bronchoconstriction, bradycardia, or apnea effects among others. A potential analgetic effect may not be considered an adverse effect and may even, depending on the application of this invention, be desirable.
  • a compound of the present invention may be hydrophilic or hydrophobic. To facilitate the administration of a compound according to the present invention it is preferable for a compound to be hydrophilic. A preferred compound is moreover metabolically stable.
  • a preferred vanilloid receptor agonist of the present invention is a compound capable of binding the TRPV1 receptor, thereby inducing hypothermia in an individual to a temperature in the range of 36 to 32 degree Celsius, and where said compound is hydrophilic.
  • Examples of preferred or especially relevant vanilloid receptor agonists include: Capsaicin and compounds closely related to capsaicin such as: Dihydrocapsaicin (DHC), Nordihydro-capsaicin (NDHC), Homodihydro-capsaicin (HDHC), and
  • Homocapsaicin other especially relevant compounds include resiniferatoxin and compounds closely related hereto.
  • Antagonists of vanilloid receptor agonist function It is an object of the present invention to provide compounds that are capable of obviating the effect of the vanilloid receptor agonists that induce hypothermia. These compounds are herein termed antagonists and exert their antagonistic effect by blocking the ability of any of the vanilloid receptor agonists, capsaicinoids or capsaicinoid-like compounds herein described in binding to their receptors.
  • the purpose of such an antagonist is to provide an additional safety mechanism whereby it is possible to stop the decline in core body temperature, stabilize the core body temperature and/or raise the core body temperature of an individual.
  • An embodiment of the present invention thus comprises the use of a compound according to any of the above for the preparation of a medicament for antagonizing the induction of hypothermia in an individual.
  • antagonists include but are not limited to: 5-iodoresiniferatoxin, Aminoquinazoline (Aminoquinazoline 70), 6-iodo-nordihydrocapsaicin, IBTU (N-(4- cholorobenzyl)-N'-(4-hydroxy-3-iodo-5-methoxybenzyl)thiourea), KJM429 and JYL1421 , A-425619, AMG9810, SB 366791 , Adenosine and Capsazepine.
  • Vanilloid receptor agonists Vanilloid receptor agonists, capsaicinoids and capsaicinoid-like compounds have been used for a variety of purposes over time. It is an object of the present invention to provide a novel use of these compounds for the induction of hypothermia, especially for the preparation of a medicament comprising two or more compounds of the group consisting of vanilloid receptor agonists and/or cannabinoids or cannabimimetic compounds and/or adenosine receptor agonists and/or neurotensin receptor agonists and/or thyroxine derivatives and/or cytochrome c oxidase inhibitors and/or oxygen tension reducers, with the proviso that if the combination of compounds comprises two compounds said two compounds are not one cannabinoid or cannabimimetic compound and one vanilloid receptor agonist for the induction of hypothermia in an individual.
  • Adenosine is present in all body fluids and acts on four well-defined G protein- coupled receptors.
  • adenosine receptors are denoted adenosine receptors, but may also be called P1 receptors to distinguish them from the receptors for nucleotides, which belong either to the family of transmitter-gated ion channels (P2X receptors) or the family of G protein-coupled receptors (P2Y receptors).
  • the adenosine receptors are a class of G-protein coupled receptors with adenosine as endogenous ligand. In humans, there are four adenosine receptors (A1 , A2A, A2B, A3), each encoded by a separate gene (ADORA1 , ADORA2A, ADORA2B, and ADORA3).
  • the adenosine A1 receptor has been found to be ubiquitous throughout the entire body. This receptor has an inhibitory function on most of the tissues in which it rests. In the brain, it slows metabolic activity by a combination of actions. Presynaptically, it reduces vesicle release while postsynaptically it has been found to stabilize the magnesium on the NMDA receptor.
  • the A1 and A2A receptors of endogenous adenosine are both believed to play a role in regulating myocardial oxygen consumption and coronary blood flow. Stimulation of the A1 receptor has a myocardial depressant effect by decreasing the conduction of electrical impulses and suppressing pacemaker cell function, resulting in a decrease in heart rate.
  • the A2A receptor is responsible for regulating myocardial blood flow by vasodilating the coronary arteries, which increases blood flow to the myocardium, but may lead to hypotension. In normal physiological states, both of these receptors serve as protective mechanisms. However, in altered cardiac function, such as hypoperfusion caused by hypotension, heart attack or cardiac arrest caused by nonperfusing bradycardias, adenosine has a negative effect on physiological functioning by preventing necessary compensatory increases in heart rate and blood pressure that attempt to maintain cerebral perfusion.
  • Specific antagonists include KW6002 and SCH-58261 , while specific agonists include CGS21680 and ATL-146e.
  • the integral A2B receptor membrane protein stimulates adenylate cyclase activity in the presence of adenosine. This protein also interacts with netrin-1 , which is involved in axon elongation.
  • the A3 adenosine receptor has been shown to inhibit some specific signal pathways of adenosine. It inhibits growth in human melanoma cells.
  • Specific antagonists include MRS1 191 , MRS1523 and MRE3008F20, while specific agonists include Cl- IB-MECA and MRS3558. Examples of adenosine receptor agonists
  • further compounds to be included in the combination of compounds according to the present invention are selected from adenosine or adenosine analogs, adenosine receptor agonists or an adenosine uptake inhibitors, ie. in one embodiment, the invention relates to administration of at least one compound capable of increasing the amount of adenosine in the individual being treated.
  • Adenosine analogs include 5'-AMP, ATP, ADP, adenine nucleotides, as well as other substituted adenosine compounds, insofar the substituted adenosine compounds are capable of being an adenosine receptor agonist.
  • An adenosine receptor agonist is any compound capable of having an agonizing effect on the adenosine receptor.
  • An adenosine receptor agonist is 5'-(N-ethyl-carboxamido)-adenosine (NECA).
  • compounds of the present invention include but is not limited to one or more of the following compounds :5'-AMP, (R)-PIA, (S)-PIA, AB-NECA, CCPA, CGS 21680, CGS 21680, CGS 24012, 2-chloroadenosine, 2-hexynyl-NECA, IB-MECA, N(6)-cyclopentyladenosine, (R,S)-PHPNECA, IAB-MECA, IB-MECA, Cl- IB-MECA, cyclopentyladenosine, I-ABA, IAB-MECA, MCP-NECA, MPC-MECA, PENECA, AB-MECA, APNEA, CV-1674, CV-1808, cyclopentyladenosine, 2- hexynyl-NECA, metrifudil, N(6)-cyclohexyladenosine, LUF5831 and Tecadenoson (CV-510).
  • the adenosine receptor agonist is selected from the group consisting of NECA, (R)-PIA, (S)-PIA, AB-NECA, CCPA, CGS 21680, CGS 21680, CGS 24012, 2-chloroadenosine, 2-hexynyl-NECA, IB- MECA, N(6)-cyclopentyladenosine, (R,S)-PHPNECA, IAB-MECA, IB-MECA, CI-IB- MECA, cyclopentyladenosine, I-ABA, IAB-MECA, MCP-NECA, MPC-MECA, PENECA, AB-MECA, APNEA, CV-1674, CV-1808, cyclopentyladenosine, 2- hexynyl-NECA, metrifudil, N(6)-cyclohexyladenosine, LUF5831 and Tecadenoson (CV-510).
  • NECA NECA
  • the combination of compounds of the present invention comprises the adenosine uptake inhibitor dipyridamole or theofyllin.
  • Adenosine receptor agonists such as adenosine analogs 5'-AMP, ATP, ADP, adenine nucleotides, as well as other substituted adenosine compounds, have been used for a variety of purposes over time.
  • NTS1 , NTS2 and NTS3 The tridecapeptide neurotensin (NT) mediates its central and peripheral effects through interaction with three identified receptor subtypes, referred to as NTS1 , NTS2 and NTS3 (Sortilin 1 ).
  • NTS1 and NTS2 belong to the 7 transmembrane domain/GPCR family, whereas Sortilin 1 is a single transmembrane domain receptor.
  • the present invention relates to the effect of the NT ligand and analogues thereof through the two GPCRs NTS1 and NTS2.
  • Neurotensin first isolated from bovine hypothalami by Carraway and Leeman in 1973, was also found in the intestine.
  • NT was synthesised from a precursor that contains another peptide, Neuromedin N, closely related to NT in terms of sequence and activity. Cerebral administration of isolated NT modulates dopaminergic transmission and leads to hypothermic (WO 04/049901 ) and naloxone-independent analgesic responses. In the periphery, NT induces hypotension, decreases gastric acid secretion, and activates lipid digestion.
  • administration of the combination of compounds of the present invention, including NT leads to a surprisingly improved effect of neuroprotection in connection with ischemia.
  • NTS1 receptor a high affinity NT binding site later cloned as the NTS1 receptor, and a lower affinity NT binding site (sensitive to the H1 anti-histamine levocabastine); the NTS2 receptor.
  • NTS1 Activation of NTS1 is probably responsible for the observed effects of NT on cancer cell proliferation and food intake. However, the most convincing implication of NTS1 is related to the NT-dopamine interactions in the brain. Indeed, NT modulates dopamine transmisssion in the nigro-striatal and mesocorticolimbic pathways through NTS1.
  • NTS2 has been described to be responsible for the analgesic response of centrally administered NT. This observation is enhanced by the cerebral localisation of both its messenger RNA and its protein in structures implicated in the descending control of nociceptive imputs, especially in the periaqueductal gray and dorsal raphe. However, the expression of NTS2 immunoreactivity in areas devoid of neurotensinergic inputs indicates that NT might not be the exclusive endogenous ligand for NTS2.
  • Neurotensin receptor agonists and analogues of neurotensin have been used for a variety of purposes over time. It is an object of the present invention to provide a novel use of these compounds for the preparation of a medicament comprising neurotensin or neurotensin analogs in combination with vanilloid receptor agonists and/or cannabinoids or cannabimimetic compounds and/or adenosine receptor agonists and/or thyroxine derivatives and/or cytochrome c oxidase inhibitors and/or oxygen tension reducers for the induction of hypothermia, especially for the preparation of a medicament comprising two or more compounds of the group consisting of vanilloid receptor agonists and/or cannabinoids or cannabimimetic compounds and/or adenosine receptor agonists and/or neurotensin receptor agonists and/or thyroxine derivatives and/or cytochrome c oxidase inhibitors and/or oxygen tension reducers, with the
  • one of the two or more compounds according to the present invention are selected from the group consisting of NT64D, NT64L, NT65L, NT66D, NT66L, NT67L, NT69L, NT71 , NT72, NT73, NT74, NT75, NT76, NT77, Trp1 1 NT, Contakin-G, EISAI- 1 , EISAI-2, JMV2004, JMV2012, JMV431 , JMV449, JMV457, JMV458, large neuromedin, large neurotensin, neuromedin, neurotensin, [ 125 l]neurotensin, Thr10contulakin-G, D-Trp1 1 -neurotensin, levocabastine, SR48692, xenin, PD-149163 and CGX-1 160.
  • NT64D L-Arg L-Arg L-Pro D-neo-Trp L-IIe L- Leu
  • NT64L L-Arg L-Arg L-Pro L-neo-Trp L-IIe L-Leu
  • NT65L L-Arg L-Arg L-Pro L- neo-Trp tert-Leu L-Leu
  • NT66D D-Lys L-Arg L-Pro D-neo-Trp ert-Leu L-Leu
  • NT66L D-Lys L-Arg L-Pro L-neo-Trp tert-Leu L-Leu
  • NT67L D-Lys L-Arg L-Pro L- neo-Trp L-IIe L-Leu
  • NT69L N-methyl- L-Lys L-Pro L-neo-Trp tert-Leu L-Le
  • the thyroid hormones thyroxine (T 4 ) and triiodothyronine (T 3 ), are tyrosine-based hormones produced by the thyroid gland.
  • the major form of thyroid hormone in the blood is thyroxine (T 4 ).
  • Thyroxine is converted to the active T 3 (three to four times more potent than T 4 ) within cells by deiodinases (5'-iodinase). These are further processed by decarboxylation and deiodination to produce the thyronamines.
  • TSG thyroxine-binding globulin
  • TTR transthyretin
  • TBPA thyroxine-binding prealbumin
  • the thyroid hormones and their derivatives are involved in the regulation of several metabolic processes within the body.
  • the thyroxine derivatives increase the basal metabolic rate, affect protein synthesis and increase the body's sensitivity to catecholamines (such as adrenaline). These hormones also regulate protein, fat, and carbohydrate metabolism, affecting how human cells use energetic compounds.
  • Thyroid hormone leads to heat generation in human.
  • the thyronamines function via an unknown mechanism to inhibit neuronal activity; this plays an important role in the hibernation cycles of mammals, and one effect of administering the thyronamines is a severe drop in body temperature.
  • Thyronamine refers both to a molecule, and to derivatives of that molecule: a family of decarboxylated and deiodinated metabolites of the thyroid hormones thyroxine (T4) and 3,5,3'-triiodothyronine (T3).
  • the group includes apart from the above: Thyronamine (TOAM); 3-lodothyronamine (T1 AM), 3,5-Diiodothyronamine (T2AM); 3,5,3'-Triiodothyronamine (T3AM).
  • thyroxine derivatives includes both the thyroid hormones and their derivates; thyronamines and compounds that in structure resemble either the thyroid hormones, their derivatives or the thyronamines.
  • at least one of the two or more compounds of the present invention are selected from the group consisting of, but not limited to: thyroxine, 3,5,3'-triiodothyronine, thyronamine; 3-lodothyronamine; 3,5-diiodothyronamine; and 3,5,3'-triiodothyronamine.
  • T 3 and T 4 cross the cell membrane, probably via amino acid importins, and function via a well-studied set of nuclear receptors in the nucleus of the cell, the thyroid hormone receptors.
  • T ⁇ and T o a are positively charged and do not cross the membrane; they are believed to function via the trace amine-associated receptor TAAR1 (TAR1 , TA1 ), a G-protein-coupled receptor located in the cell membrane.
  • TR The thyroid hormone receptor
  • the thyroid hormone receptor is a type of nuclear receptor that is activated by binding thyroid hormone.
  • the term 'thyroxine derivative receptor' may refer to any receptor capable of binding of the thyroid hormones or their derivates such as thyronamines.
  • Thyroxine derivatives have been used for a variety of purposes over time. It is an object of the present invention to provide a novel use of these compounds for the induction of hypothermia, especially for the preparation of a medicament comprising two or more compounds of the group consisting of vanilloid receptor agonists and/or cannabinoids or cannabimimetic compounds and/or adenosine receptor agonists and/or neurotensin receptor agonists and/or thyroxine derivatives and/or cytochrome c oxidase inhibitors and/or oxygen tension reducers, with the proviso that if the combination of compounds comprises two compounds said two compounds are not one cannabinoid or cannabimimetic compound and one vanilloid receptor agonist for the induction of hypothermia in an individual.
  • cytochrome c oxidase or Complex IV is a large transmembrane protein complex found in bacteria and the mitochondrion. It is the last enzyme in the respiratory electron transport chain of mitochondria (or bacteria) located in the mitochondrial (or bacterial) membrane. It receives an electron from each of four cytochrome c molecules, and transfers them to one oxygen molecule, thereby converting molecular oxygen to two molecules of water. In the process, it binds four protons from the inner aqueous phase to make water, and in addition translocates four protons across the membrane, helping to establish a transmembrane difference of proton electrochemical potential that the ATP synthase then uses to synthesize ATP.
  • cytochrome c oxidase Several compounds have been found to bind to cytochrome c oxidase, which is very important for metabolism. By interfering with the function of cytochrome c oxidase the cellular and ultimately bodily metabolic rate is slowed causing among other things a reduction of body temperature / induction of hypothermia.
  • H 2 S hydrogen sulfide
  • CN cyanide
  • HN hydrogen cyanide
  • Na 2 [Fe(CN) 5 NO] ⁇ H 2 O sodium nitroprusside
  • CO Carbon monoxide
  • Na 2 S Sodium sulfide
  • Cytochrome c oxidase inhibitors have been used for a variety of purposes over time. It is an object of the present invention to provide a novel use of these compounds for the induction of hypothermia, especially for the preparation of a medicament comprising a cytochrome c oxidase inhibitor compound for the induction of hypothermia.
  • Hemoglobin an intracellular protein of erythrocytes, is the primary vehicle for transporting oxygen in the blood.
  • Hb Hemoglobin
  • Each Hb molecule has a limited capacity for holding oxygen molecules; how much of that capacity is filled by oxygen is called the oxygen saturation (SO 2 ).
  • the amount of oxygen bound to the hemoglobin at any time is related, in large part, to the partial pressure of oxygen to which the Hb is exposed (PO 2 ).
  • the partial pressure of oxygen In the lungs, at the alveolar-capillary interface, the partial pressure of oxygen is typically high, and therefore the oxygen binds readily to Hb.
  • the Hb releases the oxygen into the tissue.
  • hemoglobin-oxygen binding can be affected by several factors; an increase in the affinity of Hb for oxygen (easier to bind but harder to release oxygen) is caused by decreased temperature, 2,3-DGP or PCO2 or an increase in pH.
  • Oxygen saturation may be measured directly via a blood sample (ex vivo) or via a non-invasive pulse oximeter, which is a medical device that indirectly measures the oxygen saturation of a patient's blood.
  • a blood-oxygen monitor displays the percentage of arterial hemoglobin in the oxyhemoglobin configuration. Acceptable normal ranges are from 95 to 10O percent, although values down to 90% are common.
  • Oxygen tension reducers have been used for a variety of purposes over time. It is an object of the present invention to provide a novel use of these compounds for the induction of hypothermia, especially for the preparation of a medicament comprising an oxygen tension reducer compound for the induction of hypothermia.
  • the induction of hypothermia by any combination of the herein described compounds is performed by preparing, producing and thus providing a medicament or pharmaceutical composition comprising a combination of two or more compounds of the group consisting of vanilloid receptor agonists and/or cannabinoids or cannabimimetic compounds and/or adenosine receptor agonists and/or neurotensin receptor agonists and/or thyroxine derivatives and/or cytochrome c oxidase inhibitors and/or oxygen tension reducers.
  • the medicament of the present invention thus comprises a combination of compounds for the induction of hypothermia in an individual in need thereof for the treatment and/or prophylaxis of ischemia in said individual.
  • the present invention provides a medicament comprising a combination of compounds wherein at least one compound induces hypothermia slowly.
  • the present invention provides a medicament comprising a combination of compounds and a further active ingredient selected from the group of: analgesics, opioids, GABAs and adrenergic antagonists.
  • the present invention further provides a pharmaceutical formulation, for medicinal application, which comprises a combination of compounds of the present invention or pharmaceutically acceptable salts thereof, as herein defined, and a pharmaceutically acceptable carrier therefor.
  • the combinations of compounds of the present invention may be formulated in a wide variety of oral administration dosage forms.
  • the pharmaceutical compositions and dosage forms may comprise the combinations of compounds of the invention or their pharmaceutically acceptable salts or a crystal forms thereof as the active components.
  • the pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, wetting agents, tablet disintegrating agents, or an encapsulating material.
  • the combinations of compounds of the present invention may be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol.
  • oily or non-aqueous carriers, diluents, solvents or vehicles examples include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.
  • Oils useful in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils useful in such formulations include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.
  • Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts
  • suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides; (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulphates, and sulfosuccinates, (c) non-ionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylenepolypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl-. beta.-aminopropionates, and 2-alkyl- imidazoline quaternary ammonium salts, and (e) mixtures thereof.
  • the parenteral formulations typically will contain from about 0.5 to about 25% by weight of the active ingredient in solution. Preservatives and buffers may be used. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more non-ionic surfactants having a hydrophile - lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations will typically range from about 5to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • HLB hydrophile - lipophile balance
  • parenteral formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use.
  • sterile liquid excipient for example, water
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
  • the medicament of the present invention comprises a pharmaceutically acceptable carrier.
  • salts of the instant compounds where they can be prepared, are also intended to be covered by this invention. These salts will be ones which are acceptable in their application to a pharmaceutical use. By that it is meant that the salt will retain the biological activity of the parent compound and the salt will not have untoward or deleterious effects in its application and use in treating diseases.
  • compositions are prepared in a standard manner. If the parent compound is a base it is treated with an excess of an organic or inorganic acid in a suitable solvent. If the parent compound is an acid, it is treated with an inorganic or organic base in a suitable solvent.
  • the combination of compounds of the invention may be administered in the form of an alkali metal or earth alkali metal salt thereof, concurrently, simultaneously, or together with a pharmaceutically acceptable carrier or diluent, especially and preferably in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parenteral (including subcutaneous) route, in an effective amount.
  • a pharmaceutically acceptable salt means any salt of the compounds mentioned.
  • it means a pharmaceutically acceptable acid addition salt.
  • Pharmaceutically acceptable acid addition salts of the compounds include salts derived from non-toxic inorganic acids such as hydrochloric, nitric, phosphoric, sulphuric, hydrobromic, hydriodic, hydrofluoric, phosphorous and the like, as well as the salts derived from non-toxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
  • Such salts thus include sulphate, pyrosulphate, bisulphate, sulphite, bisulphite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like.
  • An aspect of the present invention regards the pH of the medicament.
  • the pH of the medicament depends on the administration form, as the pH of the medicament preferably is suitable for the route of administration chosen.
  • An embodiment of the present invention comprises a medicament wherein the pH of the composition is between pH 5 and pH 9, such as between pH 5.5 and 8.5 such as between pH 6 and 8, such as between pH 6.5 and 7.5. Most preferably the pH of the medicament is in accordance with the route of administration and the tissue to which the medicament is administered.
  • the present invention provides a composition comprising a combination of compounds, wherein the pH of the composition is between pH 5 and pH 9.
  • the invention provides a combination of compounds for the production of a medicament for the treatment of ischemia in an individual. Ischemia may arise due to various circumstances and thus it is an object of the present invention to treat ischemia arising from a plurality of medical indications.
  • cardiovascular diseases such as myocardial infarction, cardiac arrest, stroke, arterial aneurism, subarachnoid haemorrhage, arteriosclerosis, angina pectoris, hypertension, hypercholesterolemia, cardiac arrhythmia, cardiomegaly, cardiomyopathy, heart valve regurgitation and heart valve stenosis, perinatal asphyxia and non-perinatal asphyxia as well as traumatic brain injury.
  • Individuals at risk of suffering from ischemia are often individuals who have previously suffered from an event that was capable of or did induce ischemia such as a heart attack, stroke or other. These individuals may benefit from having rapid access to pills, capsules, ampoules, pre-loaded syringes, suppositories or other administration forms of the medicaments of the present invention for self- administration. It is envisioned that these individuals at the onslaught of a new ischemic attack self-administer a dose of the compounds of the present invention prior to receiving medical aid by medical professionals. This is of relevance, as the faster the temperature drops, the better the chances of reducing the detrimental effects of the ischemic attack.
  • compounds of the present invention are used alone or in combination to treat adverse effects of ischemia in the kidney.
  • the present invention provides a combination of compounds for treating effects of ischemia, wherein the ischemia is due to cardiovascular diseases such as myocardial infarction, cardiac arrest, stroke, arterial aneurism, subarachnoid haemorrhage, arteriosclerosis, angina pectoris, hypertension, hypercholesterolemia, cardiac arrhythmia, cardiomegaly, cardiomyopathy, heart valve regurgitation and heart valve stenosis.
  • cardiovascular diseases such as myocardial infarction, cardiac arrest, stroke, arterial aneurism, subarachnoid haemorrhage, arteriosclerosis, angina pectoris, hypertension, hypercholesterolemia, cardiac arrhythmia, cardiomegaly, cardiomyopathy, heart valve regurgitation and heart valve stenosis.
  • Another group of indications are the situations where an individual has an increased body temperature such as fever, hyperpyrexia, hyperthermia or other. It is an aspect of the present invention to provide a combination of compounds / and or medicaments for the purpose
  • an aspect of the present invention to provide means for selectively inducing hypothermia in either the brain or the body or both simultaneously. This is of relevance, as a severe stroke is known to cause an increase in brain temperature, often subsequently followed by an increase in body temperature.
  • hypothermia in the brain
  • it is an aspect of the present invention to induce hypothermia in the brain just as it is an aspect of the present invention to induce hypothermia in the body without, as far as it is physically possible, inducing hypothermia in the brain.
  • an aspect of the present invention to induce hypothermia and/or lower the body temperature of an individual in need thereof.
  • the present invention provides a combination of compounds for treating effects of ischemia, wherein the ischemia is due to asphyxia such as: perinatal asphyxia and/or non-perinatal asphyxia.
  • the target temperature of the medicament is the core body temperature that can be reached upon administering the medicament according to the present invention as prescribed according to potency, dosage and so on.
  • Various ranges and specific hypothermic / reduced core body temperatures that fall within the scope of the present invention are equal to the temperatures that the combinations of compounds themselves may induce as listed in the section on hypothermia.
  • An embodiment of the present invention is thus a medicament capable of inducing hypothermia below 36 °C, such as below 35.5 °C, such as below 35 °C, such as below 34.5 °C, such as below 34.0 °C, such as in the range of between 36 to 32 degree Celsius, and more preferably between 35 and 33 degree Celsius.
  • the combinations of compounds of this invention will often show a peak in hypothermia inducing effect 30 minutes to 120 minutes after administration, but may potentially peak sooner or later than described by this interval.
  • the hypothermia inducing effect will frequently last from 1 hour to 12 hours, but may potentially last shorter or longer than described by this interval.
  • the compounds / medicaments / treatments herein may be given while the individual receiving the treatment is surrounded by any given temperature.
  • the temperature of the surroundings, especially the room in which the individual resides, is not of relevance to the treatment.
  • the treatment will reduce the temperature of the individual and/or induce hypothermia whether the room temperature is ambient, high or low such as at any temperature between 5 and 45 degree Celsius.
  • the main routes of drug delivery, in the treatment method are intravenous, oral, and topical, as will be described below.
  • Other drug-administration methods such as subcutaneous injection or via inhalation, which are effective to deliver the drug to a target site or to introduce the drug into the bloodstream, are also contemplated.
  • the mucosal membrane to which the pharmaceutical preparation of the invention is administered may be any mucosal membrane of the individual to which the biologically active substance is to be given, e.g. in the nose, vagina, eye, mouth, genital tract, lungs, gastrointestinal tract, or rectum, preferably the mucosa of the nose, mouth or rectum.
  • Combinations of compounds of the invention may be administered parenterally, that is by intravenous, intramuscular, intraspinal, subcutaneous, intraarterial, intracardiac, intraosseous, intradermal, intrathecal, transdermal, transmucosal, inhalational, epidural, sublingual, intravitreal, intranasal, intrarectal, intravaginal or intraperitoneal administration.
  • Appropriate dosage forms for such administration may be prepared by conventional techniques.
  • the combination of compounds may also be administered by inhalation, that is by intranasal and oral inhalation administration.
  • Appropriate dosage forms for such administration such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques.
  • the combinations of compounds according to the invention may be administered with at least one other compound.
  • the compounds may be administered simultaneously, either as separate formulations or combined in a unit dosage form, or administered sequentially.
  • a preferred embodiment of the present invention is a medicament for administration by injection, suppository, oral administration, sublingual tablet or spray, cutaneous administration, or inhalation. More preferably the administration form is by injection, wherein the injection is intravenous, intramuscular, intraspinal, intraperitoneal, subcutaneous, a bolus or a continuous administration.
  • Intravenous injection is also the preferred mode of administration of medicaments comprising vanilloid receptor agonists, as these may act as irritants under certain circumstances. Therefore, the combinations of compounds of the present invention, depending on the specific active substances, may preferably be administered as capsules rather than tablets or suppositories, and preferably as intravenous injections rather than subcutaneous or intramuscular injections.
  • the combination of compounds of the present invention is administered by injection, suppository, oral administration, sublingual tablet or spray, cutaneous administration, or inhalation.
  • the combination of compounds of the present invention is administered by injection, wherein the injection is intravenous, intramuscular, intraspinal, intraperitoneal, subcutaneous, a bolus or a continuous administration.
  • the combination of compounds of the present invention is administered at intervals of 30 minutes to 48 hours.
  • the combination of compounds of the present invention is administered at intervals of 1 to 6 hours.
  • the individual that may benefit from the administration of a medicament as described herein may be an individual suffering from ischemia or at risk of suffering from ischemia. If the individual is at risk of suffering from ischemia the preferred administration form of the medicament may be suppository, oral administration or inhalation. Preferably, the individual is an individual suffering from ischemia. Also, the individual may have an elevated body temperature and may be in need of a reduction hereof; alternatively the medicaments of the present invention may be given pre-operatively to lower the body temperature of the individual prior to and/or during surgery
  • the preferred administration form for an individual suffering from ischemia is an injection, such as an intravenous, intramuscular, intraspinal, intraperitoneal or subcutaneous injection. Being in need of treatment thus indicates that the health of the individual is benefitted by the administration of the at least one compound of the present invention.
  • the individual may be any human being, male or female, at any age.
  • the ischemic condition and/or elevated temperature to be treated or prevented in the individual may relate to the age of the individual, the general health of the individual and whether or not the individual has a prior history of suffering from diseases or disorders that may have or have induced ischemic conditions and/or elevated temperatures in the individual.
  • the dosage of the combinations of compounds according to the invention depends on the combination in question; however, the amount of the combination is also closely related to the pharmaceutical composition of the medicament, any third or more compound of the medicament or any further active ingredient of the medicament.
  • the optimal quantity and spacing of individual dosages of a compound or a pharmaceutically acceptable salt thereof will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of a compound or a pharmaceutically acceptable salt thereof given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
  • the daily oral dosage regimen will preferably be from about 0.01 to about 80 mg/kg of total body weight.
  • the daily parenteral dosage regimen will be from about 0.001 to about 80 mg/kg of total body weight.
  • the daily oral dosage regimen will preferably be from about 0.01 to about 80 mg/kg of total body weight.
  • the daily parenteral dosage regimen will be from about 0.01 to about 2,400 mg/kg of total body weight, preferably, the dosage of the medicament according to the present invention is between 10 ⁇ g to 10 mg pr kg total body weight, such as between 100 ⁇ g to 1 mg pr kg total body weight, depending on the compound of choice.
  • cannabinoids, vanilloids, adenosins, neurotensins, thyroxine derivatives, cytochrome c oxidase inhibitors and oxygen tension reducers vary with respect to potency and affinity for the receptor as well as with respect to molecular weight.
  • the dosage of the medicament according to the present invention is between 1 ⁇ g to 100 mg pr kg total body weight, such as between 10 ⁇ g to 50 mg pr kg total body weight, for example between 20 ⁇ g to 20 mg pr kg total body weight, such as 100 ⁇ g to 10 mg, for example 500 ⁇ g to 1 mg depending on the compound of choice.
  • the preferred dosage may be between 1 ⁇ g and 1 mg pr kg total body weight, such as between 10 ⁇ g and 100 ⁇ g pr kg total body weight, such as or about 10 ⁇ g, 20 ⁇ g, 30 ⁇ g, 40 ⁇ g, 50 ⁇ g, 60 ⁇ g, 70 ⁇ g, 80 ⁇ g, 90 ⁇ g, 100 ⁇ g, 200 ⁇ g, 300 ⁇ g, 400 ⁇ g, 500 ⁇ g, 600 ⁇ g, 700 ⁇ g, 800 ⁇ g, 900 ⁇ g, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg or 100 mg pr kg total body weight, again depending on the compound chosen.
  • 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg or 100 mg pr kg total body weight again depending on the compound chosen.
  • the preferred dosage range may be between 100 ⁇ g and 100 mg pr kg total body weight, such as between 200 ⁇ g and 90 mg, between 300 ⁇ g and 80 mg, such as between 400 ⁇ g and 70 mg, such as between 500 ⁇ g and 60 mg, such as between 600 ⁇ g and 50 mg, such as between 700 ⁇ g and 40 mg, such as between 800 ⁇ g and 30 mg, such as between 900 ⁇ g and 20 mg, such as between 1 mg and 10 mg pr kg total body weight.
  • the dosage may be found in the range of from 100 ⁇ g to 2000 ⁇ g, such as 200 ⁇ g to 1800 ⁇ g, or 300 ⁇ g to 1600 ⁇ g, 400 ⁇ g to 1400 ⁇ g, 500 ⁇ g to 1200 ⁇ g, 600 ⁇ g to 1000 ⁇ g or 500 ⁇ g to 2000 ⁇ g.
  • the exact dosage may be calculated based on the calf study model described in Example 15.
  • the preferred dosages of a cannabinoid compound such as, but not limited to HU-210 and KN38-7271 (BAY38-7271 ), is between 1 ⁇ g and 1 mg pr kg total body weight, such as between 10 ⁇ g and 100 ⁇ g pr kg total body weight, such as or about 10 ⁇ g, 20 ⁇ g, 30 ⁇ g, 40 ⁇ g, 50 ⁇ g, 60 ⁇ g, 70 ⁇ g, 80 ⁇ g, 90 ⁇ g or 100 ⁇ g pr kg total body weight.
  • the dosage may depend on the administration form. For example, it is preferable to administer HU-210 in the range of from 10 ⁇ g and 100 ⁇ g pr kg total body weight intravenously.
  • the dosage regime will be between 2 and 1000 microgram/kg of total body weight, such as between 4 and 900 microgram/kg of total body weight, such as between 6 and 800 microgram/kg of total body weight, such as between 8 and 700 microgram/kg of total body weight, such as between 10 and 600 microgram/kg of total body weight.
  • the dosage regime will be between 15 and 500 microgram/kg of total body weight, more preferably between 20 and 400 microgram/kg of total body weight.
  • At least 40 microgram/kg of total body weight such as at least 50 microgram/kg of total body weight, such as at least 60 microgram/kg of total body weight, such as at least 70 microgram/kg of total body weight, such as at least 80 microgram/kg of total body weight, such as at least 100 microgram/kg of total body weight.
  • the dosages mentioned are the dosages for inducing hypothermia as defined herein.
  • the dosage may be administered as one single bolus or divided into two or more dosages given over a period of time; alternatively it may be administered by continuous IV.
  • hypothermic effect may be maintained by administering one or more dosages some hours after the first dosage, such as at least 6 hours later, or such as at least 12 hours later. Such additional dosages may be of the same amount as the first dosage or an amount being at the most one-half or one-quarter of the first dosage.
  • the dosage regime will be between 0.25 and 600 mg/kg of total body weight, such as between 0.5 and 500 mg/kg of total body weight, 1 and 400 mg/kg of total body weight, 2 and 300 mg/kg of total body weight, 3 and 200 mg/kg of total body weight.
  • the dosage regime will be between 4 and 150 mg/kg of total body weight, more preferably between 5 and 100 mg/kg of total body weight.
  • At least 10 mg/kg of total body weight such as at least 20 mg/kg of total body weight, such as at least 30 mg/kg of total body weight, such as at least 40 mg/kg of total body weight, such as at least 50 mg/kg of total body weight, such as at least 60 mg/kg of total body weight, such as at least 100 mg/kg of total body weight.
  • the dosages mentioned are the dosages for inducing hypothermia as defined herein.
  • the dosage may be administered as one single bolus or divided into two or more dosages given over a period of time; alternatively it may be administered by continuous IV. Additionally the hypothermic effect may be maintained by administering one or more dosages some hours after the first dosage, such as at least 6 hours later, or such as at least 12 hours later.
  • Such additional dosages may be of the same amount as the first dosage or an amount being at the most one-half or one-quarter of the first dosage.
  • the preferred dosages of a vanilloid compound such as, but not limited to dihydrocapsaicin, is between 10 ⁇ g and 2000 ⁇ g pr kg total body weight, such as between 100 ⁇ g and 1000 ⁇ g such as or about 10 ⁇ g, 20 ⁇ g, 30 ⁇ g, 40 ⁇ g, 50 ⁇ g, 60 ⁇ g, 70 ⁇ g, 80 ⁇ g, 90 ⁇ g or 100 ⁇ g pr kg total body weight, or 150 ⁇ g, 200 ⁇ g, 250 ⁇ g, 300 ⁇ g, 350 ⁇ g, 400 ⁇ g, 450 ⁇ g, 500 ⁇ g, 600 ⁇ g, 700 ⁇ g, 800 ⁇ g, 900 ⁇ g, 1000, 1500 ⁇ g or 2000 ⁇ g pr kg total body weight when injected in the individual intravenously.
  • a vanilloid compound such as, but not limited to dihydrocapsaicin
  • dihydrocapsaicin and other vanilloids may be injected intramuscularly at dosages between 100 ⁇ g and 100 mg pr kg total body weight, such as between 200 ⁇ g and 90 mg, between 300 ⁇ g and 80 mg, such as between 400 ⁇ g and 70 mg, such as between 500 ⁇ g and 60 mg, such as between 600 ⁇ g and 50 mg, such as between 700 ⁇ g and 40 mg, such as between 800 ⁇ g and 30 mg, such as between 900 ⁇ g and 20 mg, such as between 1 mg and 10 mg pr kg total body weight.
  • the dosage may be found in the range of from 100 ⁇ g to 2000 ⁇ g, such as 200 ⁇ g to 1800 ⁇ g, or 300 ⁇ g to 1600 ⁇ g, 400 ⁇ g to 1400 ⁇ g, 500 ⁇ g to 1200 ⁇ g, 600 ⁇ g to 1000 ⁇ g, or 500 ⁇ g to 2000 ⁇ g pr kg total body weight.
  • the optimal dosage of a drug in combination with at least one other drug according to the present invention thus varies for a given class of drugs. It follows from the administration of at least two drugs, such as two or more drugs, that the simultaneous administration of at least two drugs may result in an advantageous reduction in the dosage required for each drug to be effective. A reduction in dosage for each of the at least two drugs when given simultaneously may occur without a reduction in the desired effect of the drug. A reduction in dosage for each of the at least two drugs may thus provide an effective means of reducing unwanted side- effects resulting from the administration of otherwise optimal dosages of each of the at east two drugs.
  • a reduction in dosage for each of the at least two drugs when given simultaneously may be in the order of 5 to 75% of the otherwise optimal dosages of each of the at least two drugs, for example 5 to 10%, such as 10 to 15%, for example 15 to 20%, such as 20 to 25%, for example 25 to 30%, such as 30 to 35%, for example 35 to 40%, such as 40 to 45%, for example 45 to 50%, such as 50 to 55%, for example 55 to 60%, such as 60 to 65%, for example 65 to 70%, such as 70 to 75% of the otherwise optimal dosages of each of the at least two drugs.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human and animal individuals, each unit containing a predetermined quantity of a combination of compounds, alone or in together with other agents, calculated in an amount sufficient to produce the desired effect in association with a pharmaceutically acceptable diluent, carrier, or vehicle.
  • the specifications for the unit dosage forms of the present invention depend on the particular combination employed and the effect to be achieved, as well as the pharmaco-dynamics associated with each of the compounds of the combination in the host.
  • the dose administered should be an "effective amount” or an amount necessary to achieve an "effective level" in the individual patient.
  • the effective level is used as the preferred endpoint for dosing, the actual dose and schedule can vary, depending on inter-individual differences in pharmacokinetics, drug distribution, and metabolism.
  • the "effective level” can be defined, for example, as the blood or tissue level desired in the individual that corresponds to a concentration of one or more combinations according to the invention.
  • the effective level can also be defined as the amount needed pr kg body weight, in other words the concentration, required to reach the peak effect for a specific combination of compounds.
  • the effective level depends on the severity of the ischemic condition, such as total amount of tissue experiencing hyp- or anoxia, the duration of the ischemic condition, whether it is the first or a subsequent ischemic attack of the individual and so forth.
  • the dosage of the medicament according to the present invention is between 10 ⁇ g to 80 mg pr kg total body weight, such as between 100 ⁇ g to 1 mg pr kg total body weight.
  • the medicament may be administered in any suitable dosage regime, suitable as to the potency of the combination of compounds / the drug, the target temperature to be reached, the speed of action of the combination, the metabolic stability of the combination, the duration of the treatment and how often the medicament optimally is to be administered.
  • a medicament to be administered at intervals of 30 minutes to 48 hours such as intervals of 1 to 47 hours, 2 to 45 hours, 3 to 43 hours, 4 to 41 hours, 5 to 39 hours, 6 to 37 hours, 7 to 35 hours, 8 to 3 hours, 9 to 31 hours, 10 to 29 hours, 1 1 to 27 hours, 12 to 25 hours, 13 to 23 hours, 14 to 21 hours, 15 to 19 hours 16 to 18 hours.
  • a medicament to be administered at intervals of 30 minutes to 24 hours such as 1 to 23 hours, 2 to 22 hours, 3 to 20 hours, 4 to 18 hours, 5 to 16 hours, 6 to 14 hours, 7 to 12 hours or 8 to 10 hours.
  • the administration occurs at intervals of 1 to 6 hours, such as 2 to 5 hours, 3 to 4 hours.
  • the optimal administration interval depends on the duration of the hypothermic treatment.
  • the duration of the treatment depends among other things on the severity of the ischemic condition. It is within the scope of the present invention to provide medicaments for the induction of hypothermia wherein the duration of the treatment is from 6 to 72 hours, such as from 7 to 69 hours, such as from 8 to 66 hours, 9 to 63 hours, 10 to 60 hours, 1 1 to 57 hours, 12 to 54 hours, 13 to 51 hours, 14 to 48 hours, 15 to 45 hours, 16 to 42 hours, 17 to 39 hours, 18 to 36 hours, 1 to 35 hours, 20 to 32 hours, 21 to 29 hours, 22 to 26 hours 23 to 25 hours.
  • the duration of the treatment is between 6 and 48 hours, more preferably between 6 and 24 hours.
  • the compounds of medicament of the present invention are administered at a dosage of between 10 ⁇ g to 80 mg pr kg body mass either sequentially or consecutively.
  • the medicament may thus comprise compounds of the present invention wherein at least one compound induces hypothermia rapidly, or alternatively wherein at least one compound induces hypothermia slowly.
  • rapidly means within a few hours, such as within 2 hours, for example within 1 hour, such as within 30 minutes, for example within 15 minutes;
  • slowly means after several hours, such as after 3 hours, for example 4 hours, such as after 5 hours, for example 6 hours, such as after 7 hours, for example 8 hours, such as after 9 hours, for example 10 hours, such as after 1 1 hours, for example 12 hours, such as after 13 hours, for example 14 hours, such as after 15 hours, for example 16 hours, such as after 17 hours, for example 18 hours, such as after 19 hours, for example 20 hours.
  • a rapidly acting compound or combination of compounds may be administered prior to admission to the hospital such as at the scene of the complication or en route in an ambulance by medically trained personnel.
  • the individual suffering from the ischemic insult will thus already be experiencing a reduction in core body temperature upon arrival at a place of proper facilities enhancing the treatment and reducing the extent of the ischemic insult.
  • the duration of the treatment with compounds of the present invention is from 6 to 72 hours.
  • An embodiment of the present invention is a pharmaceutical composition comprising a combination of compounds as herein described and furthermore comprising a further active ingredient.
  • the further active ingredient may increase the hypothermic effect of the combination of compounds of the invention, or may have an alternative medical effect such as inducing pain relief or vasodilation.
  • the further active ingredient may thus be selected from the non-limiting group of: analgesics, opioids, GABAs and adrenergic antagonists.
  • the further active ingredient may thus be an antipyretic.
  • Antipyretics are drugs that reduce body temperature in situations such as fever; however, they will not affect the normal body temperature if one does not have fever. Antipyretics cause the hypothalamus to override an interleukin-induced increase in temperature. The body will then work to lower the temperature and the result is a reduction in fever. It is an object of the present invention to induce hypothermia in an individual. To prevent a possible overshoot in the body's attempt to regain its normal temperature at the completion of the hypothermia-inducing treatment, an antipyretic may be provided in combination with the compounds of the present invention.
  • NSAIDs Nonsteroidal anti-inflammatory drugs
  • It is an aspect of the present invention to provide a medicament comprising a combination consisting of: vanilloid receptor agonists and/or cannabinoids and/or cannabimimetic compounds and/or adenosine and/or adenosine analogs and/or neurotensin and/or neurotensin analogs and/or thyroxine derivatives and/or cytochrome c oxidase inhibitors and/or oxygen tension reducers which may be formulated and /or administered together with an antipyretic drug simultaneously or sequentially.
  • the further active ingredient may also be an analgesic (or painkiller).
  • Analgesics are a diverse group of drugs that relieve pain.
  • Analgesic drugs act in various ways on the peripheral and central nervous systems and include paracetamol (acetaminophen); the non-steroidal anti- inflammatory drugs (NSAIDs) such as the salicylates - aspirin, ibuprofen, naproxen; opioids such as morphine, codeine, oxycodone, hydrocodone, diamorphine, pethidine; synthetic drugs with opioid properties such as tramadol and buprenorphine; and various others.
  • paracetamol acetaminophen
  • NSAIDs non-steroidal anti- inflammatory drugs
  • opioids such as morphine, codeine, oxycodone, hydrocodone, diamorphine, pethidine
  • synthetic drugs with opioid properties such as tramadol and buprenorphine; and various others.
  • Demerol and desflurane both of which are analgesics may also be administered especially for the purpose of reducing shivering as the individual to whom the compounds of the present invention are administered is brought down in temperature. It is especially relevant to use analgesics when inducing actual hypothermia e.g. temperatures below normal.
  • kits may be specifically targeted to persons at risk of suffering from ischemic attacks, such that the kit, apart from instructions, comprises pharmaceutical forms of the medicaments that allow self administration of the medicaments and devices with which to administer the medicaments.
  • An alternative embodiment is an ambulance kit that facilitates the administration of the medicaments of the present invention in a manner most efficient for the rescue personnel.
  • a 57-year-old woman is taken care of by the ambulance staff that finds her in ventricular fibrillation approximately 5 minutes after having collapsed without warning.
  • the patient is immediately defibrillated and spontaneous circulation and ventilations occurred.
  • On arrival to the hospital 21 minutes after having collapsed, the patient has a palpable pulse.
  • Staff at the emergency room has been alerted in advance.
  • the patient is evaluated and the physician in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain.
  • hypothermia therapy is initiated as described in this invention. Two or more of the compounds described in the following are administered simultaneously or consecutively:
  • Cannabinoid receptor agonists Including, but not limited to HU-210
  • Vanilloid receptor agonists Including, but not limited to dihydrocapsaicin
  • Adenosine receptor agonists including, but not limited to 5'-AMP
  • Thyroxine derivatives thyroid hormone receptor agonists and trace amine- associated receptor agonists
  • hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1 -8 bolus injections of any or all of the compounds may be required.
  • concurrent treatments and examinations are not influenced by the administration of the hypothermia-inducing drug. Such other treatments and examinations proceed uninterrupted.
  • Hypothermia therapy is initiated as described in this invention.
  • Two compounds are administered: 1 .
  • hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1 -8 additional bolus injections may be required.
  • a 66-year-old man is undergoing elective heart surgery. He suffers from irregular cardiac rhythm during the procedure and goes into cardiac arrest with much impaired circulation for 6 minutes after which the surgical team manages to restore circulation. Subsequent to restoration of circulation, the surgeon in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain.
  • hypothermia therapy is initiated as described in this invention. Two compounds are administered:
  • HU-210 e.g. 100 microgram/kg body weight
  • delta-8-THC phosphate e.g. 40 mg/kg body weight
  • a third cannabinoid agonist e.g. a third cannabinoid agonist
  • the dose will likely be in the interval 0.01 mg/kg to 80 mg/kg.
  • hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1 -8 additional bolus injections may be required.
  • hypothermia therapy is initiated as described in this invention. Two compounds are administered:
  • An intravenous bolus injection of HU-210 e.g. 100 microgram/kg body weight
  • delta-8-THC phosphate e.g. 40 mg/kg body weight
  • a third cannabinoid agonist e.g. 40 mg/kg body weight
  • hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1 -8 additional bolus injections may be required.
  • Example 5 Perinatal asphyxia A newborn baby suffers cerebral ischemia during delivery as the umbilical cord gets wrapped around his neck. The APGAR score 10 minutes after delivery is 6. The patient is evaluated and the physician in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain.
  • hypothermia therapy is initiated as described in this invention. Two compounds are administered:
  • HU-210 e.g. 100 microgram/kg body weight
  • delta-8-THC phosphate e.g. 40 mg/kg body weight
  • a third cannabinoid agonist e.g. a third cannabinoid agonist
  • the dose will likely be in the interval 0.01 mg/kg to 80 mg/kg.
  • hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1 -8 additional bolus injections may be required.
  • concurrent treatments and examinations are not influenced by the administration of the hypothermia-inducing drug. Such other treatments and examinations proceed uninterrupted.
  • a 9-year-old boy is in a coma when he is rescued out of a burning house. CRP is commenced on the spot but he is not awake when the ambulance arrives at hospital after a 15 minutes drive. The patient is evaluated and the physician in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain and other tissues.
  • hypothermia therapy is initiated as described in this invention. Two compounds are administered:
  • HU-210 e.g. 100 microgram/kg body weight
  • delta-8-THC phosphate e.g. 40 mg/kg body weight
  • a third cannabinoid agonist e.g. a third cannabinoid agonist
  • the dose will likely be in the interval 0.01 mg/kg to 80 mg/kg.
  • hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1 -8 additional bolus injections may be required.
  • hypothermia therapy is initiated as described in this invention. Two compounds are administered:
  • HU-210 e.g. 100 microgram/kg body weight
  • delta-8-THC phosphate e.g. 40 mg/kg body weight
  • a third cannabinoid agonist e.g. a third cannabinoid agonist
  • the dose will likely be in the interval 0.01 mg/kg to 80 mg/kg.
  • hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1 -8 additional bolus injections may be required.
  • a 29-year-old man suffers continuous pains in the back of his head for two weeks after which he suddenly collapses and slips into a coma.
  • the patient is diagnosed with a stroke.
  • the patient is evaluated and the physician in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain.
  • hypothermia therapy is initiated as described in this invention. Two compounds are administered:
  • HU-210 e.g. 100 microgram/kg body weight
  • delta-8-THC phosphate e.g. 40 mg/kg body weight
  • a third cannabinoid agonist e.g. a third cannabinoid agonist
  • the dose will likely be in the interval 0.01 mg/kg to 80 mg/kg.
  • the purpose of hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1 -8 additional bolus injections may be required.
  • a 55-year-old man is admitted to hospital 18 minutes after experiencing nausea, shortness of breath, and severe chest pains.
  • the patient who is suffering myocardial infarction is evaluated by the physician in charge who decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the heart and other tissues.
  • hypothermia therapy is initiated as described in this invention. Two compounds are administered:
  • HU-210 e.g. 100 microgram/kg body weight
  • delta-8-THC phosphate e.g. 40 mg/kg body weight
  • a third cannabinoid agonist e.g. a third cannabinoid agonist
  • the dose will likely be in the interval 0.01 mg/kg to 80 mg/kg.
  • hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1 -8 additional bolus injections may be required.
  • a 41 -year-old man receives a severe blow to the head from a falling brick on a construction site.
  • the patient is still unconscious when he 24 minutes after the trauma is brought to the Emergency Room.
  • the patient is evaluated and the physician in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain.
  • Hypothermia therapy is initiated as described in this invention.
  • Two compounds are administered: 1 .
  • hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1 -8 additional bolus injections may be required.
  • a 60-year-old woman is feeling rather well two days after major surgery when she suddenly slips into a coma. Following acute surgery, brought on by a pulmonary embolism, she is stabilized. The patient is evaluated and the physician in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain and other tissues.
  • hypothermia therapy is initiated as described in this invention.
  • Two compounds are administered: 1.
  • the dose will likely be in the interval 0.01 mg/kg to 80 mg/kg.
  • hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1 -8 additional bolus injections may be required.
  • Relative humidity 55% (+/- 5%)
  • Type of temperature probe PC Based pyrogen testing system, Ellab APT 91
  • Modulation of CB and TRPV1 activities will be assessed in vitro by measuring cannabinoid and/or cannabimimetic compound and vanilloid receptor agonist induced Ca2+ flux, respectively. This will be done using FLIPR and HEK293 cells stably expressing recombinant human (h) and rat (r) TRPV1 (hTRPV1 -HEK293 and rTRPV1 -HEK293, respectively) and recombinant human (h) and rat (r) CB receptors (hCB1 -HEK293, hCB2-H293, rCB1 -HEK293 and rCB2-H293) and especially in cells co-expressing human or rat TRPVI and CB receptors (hTRPV1 -hCB1 -HEK293 and hTRPV1 -hCB2-HEK293).
  • Intracellular Ca2+ levels will be measured in CB, TRPV1 and coCB/TRPVI -expressing cells during exposure to compounds and combinations of compounds. A concentration dependent increase in Ca2+ influx will be observed.
  • the efficacy of vanilloid agonists will be estimated by comparing these to the maximum response induced by capsaicin, likewise the efficacy of cannabinoids will be estimated by comparing these to the maximum response induced by cannabidiol.
  • a combination of capsaicin and cannabidiol will be used as reference for measuring combinations of drugs.
  • the compound may be tested in the porcine study model.
  • the porcine model is used because the body weight of the pigs is comparable to the body weight of humans.
  • the efficacy of a compound tested in the porcine model may be correlated with the efficacy of the cannabinoid or vanilloid compound tested in the same porcine study model.
  • the evaluation is carried out on "dansk landrace" pigs with a body weight of 70-90 kilo.
  • the pigs will not be sedated; they will be fed twice a day; and they will be subjected to a day cycle consisting of 12 hours of light followed by 12 hours of dark.
  • Drug administration is carried out on "dansk landrace" pigs with a body weight of 70-90 kilo.
  • the pigs will not be sedated; they will be fed twice a day; and they will be subjected to a day cycle consisting of 12 hours of light followed by 12 hours of dark.
  • the compound investigated are administered i.v. as bolus injections and may consist of 1 solitary injection, alternatively 2-4 repeated injections within a timeframe of 24 hours from the initial injection. Generally 4 different doses plus vehicle are tested producing varying degrees of hypothermic responses.
  • Temperature is measured using a temperature probe that is surgically positioned in a femoral artery two weeks prior to commencement of the study.
  • the probe is connected to telemetry equipment (e.g. implanted telemetry from Data Sciences International) ensuring the required readouts.
  • Temperature is measured every 15 minutes from 1 hour prior to drug administration to 12 hours after drug administration, and every 30 minutes subsequently until 24 hours after drug administration. Temperature measurement will be conducted via a permanent femoral artery temperature probe (telemetry).
  • the minimum temperature as well as a graph of the temperature at each point of measurement is recorded for each dose of compound or compound mixture.
  • Blood pressure, heart rate and ECG will be registered every 15 minutes from 1 hour prior to drug administration to 12 hours after drug administration, and every 30 minutes subsequently until 24 hours after drug administration.
  • the combination treatment may be tested in the calf study model.
  • the calf model is used because the body weight of the calves is comparable to the body weight of humans. Study subjects
  • the evaluation is carried out on male "sortbroget malkeko/Holstein" calves with a body weight of 75-85 kilo or 70-90 kilo.
  • the calves are positioned in individual booths; they are not sedated; are fed twice a day (milk at 8:00 A.M. and hay/food pills at an unspecified hour, depending on the effects of the compounds examined); and are subjected to a day cycle consisting of 16 hours of light followed by 8 hours of dark.
  • the ambient temperature is 20°C+/-2°C.
  • Drug administration/device-based therapy The compounds investigated (vanilloid receptor agonists and/or cannabinoids and/or cannabimimetic compounds and/or adenosine and/or adenosine analogs and/or neurotensin and/or neurotensin) are administered i.v. (in the jugular vein) and/or i.p. and/or s.c. as bolus injections and may consist of 1 solitary injection, alternatively 2-
  • the drugs administered are combined with physical hypothermia therapy, either surface hypothermia therapy or invasive hypothermia therapy, as defined:
  • Invasive hypothermia therapy such as: • Intravenous administration of cold fluids ( ⁇ 37°C), e.g. saline
  • Temperature is measured using a temperature probe (ADInstruments) that is surgically positioned in vena cava cranialis one week prior to commencement of the study.
  • the probe is connected to a Powerlab ensuring the required read-outs.
  • Temperature is measured 100 times/second and compounded every 15 minutes from 1 hour prior to drug administration to 24 hours subsequent to administration.
  • Blood pressure and heart rate is measured 100 times/second and compounded every 15 minutes from 1 hour prior to drug administration to 24 hours subsequent to administration. Data is collected using a Powerlab.
  • Zhang Y, Wong KC, Zhang Z The effect of intraischemic mild hypothermia on focal cerebral ischemia/reperfusion injury. Acta Anaesthesiol Sin 2001 ; 39(2):65-69.
  • Yamashita K, Eguchi Y, Kajiwara K, lto H Mild hypothermia ameliorates ubiquitin synthesis and prevents delayed neuronal death in the gerbil hippocampus. Stroke 1991 ; 22(12):1574-1581.
  • KiI HY Zhang J, Piantadosi CA: Brain temperature alters hydroxyl radical production during cerebral ischemia/reperfusion in rats. J Cereb Blood Flow Metab 1996; 16(1 ):100-106.
  • Kawase T, ladecola C Effects of moderate hypothermia on leukocyte- endothelium interaction in the rat pial microvasculature after transient middle cerebral artery occlusion. Stroke 1999; 30(8):1679-1686. (31 ) lnamasu J, Suga S, Sato S, Horiguchi T, Akaji K, Mayanagi K, Kawase T: Post- ischemic hypothermia delayed neutrophil accumulation and microglial activation following transient focal ischemia in rats. J Neuroimmunol 2000; 109(2):66-74.

Abstract

The present invention relates to the induction of hypothermia in humans, male and female, at any age, in a predictable and dose responsive fashion by use of a pharmaceutical composition comprising a combination of two or more compounds selected among (1) vanilloid receptor agonists, capsaicinoids or capsaicinoid-like agonists reaching and binding to vanilloid receptors, and (2) cannabinoids or cannabimimetic agonists reaching and binding to cannabinoid receptors, and (3) adenosine receptor agonists, and (4) neurotensin receptor agonists, and (5) thyroxine derivatives, and (6) cytochrome c inhibitors, and (7) oxygen tension reducers, with the proviso that if the first compound is (1) then the second is not (2), thereby inducing hypothermia, thus benefiting patients suffering from illnesses characterized by tissue anoxia.

Description

Combination treatment of ischemic effects
Field of invention
The present invention relates to the use of a combination of compounds for the induction of hypothermia for the prophylaxis and treatment of ischemia. Ischemia is the lack of oxygenated blood flow to various body parts and may result from apoplexia, cardiac arrest and asphyxia.
Background of invention
Ischemia is the lack of oxygenated blood flow to various body parts and organs. Cerebral ischemia is an ischemic condition where the brain or parts of the brain do not receive enough blood flow to maintain normal neurological function. Cerebral ischemia can be the result of various serious diseases such as stroke and cardiac arrest, or the result of arterial obstruction such as strangulation. Severe or prolonged cerebral ischemia will result in unconsciousness, brain damage or death.
The neuroprotective efficacy of induced hypothermia following or during ischemia of the brain is evident in experimental animal models of stroke [1 -1 1]. In humans, two trials conducted in cardiac arrest patients have shown improved neurological outcome of inducing hypothermia [12;13]. The therapeutic hypothermia did not increase the complication rate in these two trials and the use of induced hypothermia in comatose survivors of cardiac arrest is now recommended internationally [14].
Hypothermia counteracts ischemic brain damage by several mechanisms:
1. Ischemia induces opening of the blood-brain barrier, a process that seems to be very sensitive to brain temperature [15]. This is evident from studies of tracers and their migration across the blood-brain barrier, in which hypothermia attenuates extravasation several hours after ischemia [16] and prevents vasogenic oedema [17]. 2. Reperfusion after brain ischemia results in the production of free radicals, which causes peroxidation and destruction of membrane lipids [18]. Hypothermia prevents the production of free radicals such as hydroxyl and nitric oxide during reperfusion after brain ischemia [19;20;24].
3. Amino acids, such as glutamate, aspartate, and glycine, act as excitotoxic neurotransmitters by over stimulation of neurons in the vicinity of ischemic damage, which causes further injury. Hypothermia lowers the release and may even cause a more rapid reuptake of these transmitters [21 -23]. Release of excitotoxic neurotransmitters might also cause progressive neuronal death in the penumbra in stroke patients [22], and hypothermia after cerebral ischemia could attenuate this process.
4. During ischemia, cellular metabolism in the penumbra undergoes significant changes. As the neurons continue to fire, potassium ions flood into the extracellular space, calcium ions flow into the neurons leading to cytoskeletal degradation, and ATP concentrations fall as energy depletion continues [25]. Hypothermia reduces calcium influx and the subsequent breakdown of intracellular structures [26], improves potassium ion homoeostasis [27], and helps metabolic functions such as calcium or calmodulin-dependent protein kinase activity to recover [28;29].
5. By lowering of neutrophil and microglial activation after ischemia, hypothermia also has an anti-inflammatory effect [30;31].
6. Apoptosis and DNA changes are crucial stages in delayed neuronal death after transient cerebral ischemia [32]. Hypothermia directly inhibits apoptosis [33] and may also increase endogenous production of the anti-apoptotic protein Bcl-2 [34]. Hypothermia may even have effects at the DNA level: A slight lowering of brain temperature results in less DNA fragmentation [35] and less apoptosis [36].
Induction of hypothermia by lowering of the core temperature of the body has been attempted by mechanical cooling devices such as surface cooling and cooling using catheters placed in a large vessel. However, these mechanical inducers of hypothermia have been shown to have considerable unwanted side effects. These side effects include shivering, serious infections and lung puncture. Shivering causes an increased exertion of the heart of the patient, and this will in some cases result in ischemia of the heart and thereby increased morbidity and mortality.
The regulation of the core temperature of the body by a pharmaceutical composition comprising a combination of compounds capable of inducing hypothermia would not only solve the problem of reducing or preventing the effects of ischemia, such as tissue damaging effects, but also be relevant as a safer and less expensive alternative to the currently employed mechanical methods.
Summary of invention
The present invention relates to the induction of hypothermia in humans in a predictable and dose responsive fashion by use of a pharmaceutical composition comprising at least one compound and/or a combination of compounds capable of inducing hypothermia, thereby benefiting patients suffering from illnesses characterized by tissue anoxia. The inventors have found that such hypothermic effects can be obtained in humans as a result of several classes of compounds: • Vanilloid receptor agonists, capsaicinoids or capsaicinoid-like agonists reaching and binding to vanilloid receptors.
• Cannabinoids or cannabimimetic agonists reaching and binding to cannabinoid receptors.
• Adenosine receptor agonists, adenosine analogs or adenosine uptake inhibitors and agonist compounds reaching and binding to adenosine receptors.
• Neurotensin receptor agonists, neurotensin analogs and compounds reaching and binding neurotensin receptors.
• Thyroxine derivatives, thyroid hormone receptor agonists and trace amine- associated receptor agonists.
• Cytochrome c oxidase inhibitors.
• Oxygen tension reducers.
Thus the present invention discloses the use of a combination of compounds, wherein at least two or more compounds are selected among vanilloid receptor agonists, and cannabinoids and cannabimimetic compounds, and adenosine or adenosine analogs, and neurotensin or neurotensin analogs or a compound having at least 50% sequence identity to human neurotensin, and thyroxine derivatives, and cytochrome c oxidase inhibitors, and oxygen tension reducers, for the induction of hypothermia for the preparation of a medicament for the treatment of ischemia in an individual in need thereof.
In one embodiment of the present invention, the use of a cytochrome c oxidase inhibitor for the induction of hypothermia for the preparation of a medicament for the treatment of ischemia in an individual in need thereof is disclosed.
In another embodiment of the present invention, the use of an oxygen tension reducer for the induction of hypothermia for the preparation of a medicament for the treatment of ischemia in an individual in need thereof is disclosed.
It is also an aspect of the present invention to provide a medicament comprising a combination of compounds capable of inducing hypothermia in an individual.
A kit of parts comprising the medicament as herein disclosed is yet an aspect of the present invention.
Furthermore, the use of a combination of compounds according to the present invention for the preparation of a medicament for obviating the induction of hypothermia in an individual in need thereof is an aspect of the present invention.
Detailed description of the invention
In a main aspect, the present invention relates to a combination comprising two or more compounds selected from the group consisting of a vanilloid receptor agonist, a cannabinoid or a cannabimimetic compound, an adenosine, or an adenosine analog, or an adenosine receptor agonist, or an adenosine uptake inhibitor, a neurotensin, or a neurotensin analog, or a neurotensin receptor agonist, or a neurotensin mimetic compound, a thyroxine derivative, a cytochrome c oxidase inhibitor, or an oxygen tension reducer, for use in the treatment of ischemia in an individual in need thereof by induction of hypothermia in said individual, with the proviso that if one compound is a) then the second compound is not b).
Definitions Adenosine: Adenosine is a nucleoside composed of adenine attached to a ribose (ribofuranose) moiety via a β-N9-glycosidic bond as described by the formula below.
Figure imgf000006_0001
Adenosine analog: An adenosine analog is any compound with a structure based on an adenosine and thus includes but is not limited to 5'-AMP, ADP, ATP and the like.
Agonist: A vanilloid receptor agonist is a vanilloid compound. A cannabinoid receptor agonist is a cannabinoid or a cannabimimetic compound. An adenosine receptor agonist is an adenosine, adenosine analog or adenosine-like compound. A neurotensin receptor agonist is a neurotensin or a neurotensin analog or a synthetic neurotensin or an artificial neurotensin or a neurotensin mimetic compound. A thyroxine receptor agonist is a thyroxine derivative or a thyronine. In the context of the present invention, an agonist is a compound capable of inducing hypothermia by binding to a receptor.
Antagonist: A vanilloid receptor antagonist is a substance capable of inhibiting the effect of a vanilloid receptor agonist. A cannabinoid receptor antagonist is a substance capable of inhibiting the effect of a cannabinoid receptor agonist. An adenosine receptor antagonist is a substance capable of inhibiting the effect of an adenosine receptor agonist. A neurotensin receptor antagonist is a substance capable of inhibiting the effect of a neurotensin receptor agonist. A thyroxine receptor antagonist is substance capable of inhibiting the effect of a thyroxine receptor agonist. Alcohol: A class of organic compounds containing one or more hydroxyl groups (OH). In this context a saturated or unsaturated, branched or unbranched hydrocarbon group sitting as a substituent on a larger molecule.
Alicvclic group: means a cyclic hydrocarbon group having properties resembling those of aliphatic groups.
Aliphatic group: in the context of the present invention, the term "aliphatic group" means a saturated or unsaturated linear or branched hydrocarbon group. This term is used to encompass alkyl, alkenyl, and alkynyl groups, for example.
Alkoxyl group: the term "alkoxyl group" or "alkoxy" covers an alkyl linked to a larger moiety by oxygen.
Alkyl group: means a saturated linear or branched hydrocarbon group including, for example, methyl, ethyl, isopropyl, t-butyl, heptyl, dodecyl, octadecyl, amyl, 2- ethylhexyl, and the like.
Alkenyl group: means an unsaturated, linear or branched hydrocarbon group with one or more carbon-carbon double bonds, such as a vinyl group.
Alkynyl group: means an unsaturated, linear or branched hydrocarbon group with one or more carbon-carbon triple bonds.
Amphiphil: substance containing both polar, water-soluble and nonpolar, water- insoluble groups.
Aromatic group: the term "aromatic group" or "aryl group" means a mono- or polycyclic aromatic hydrocarbon group.
Apoptosis: Apoptosis is a process of suicide by a cell in a multi-cellular organism. It is one of the main types of programmed cell death (PCD), and involves an orchestrated series of biochemical events leading to a characteristic cell morphology and death. Asystole: Cessation of electrical activity in the ventricles of the heart. Without electrical activity the heart ceases to contract and the result is cardiac arrest.
Cerebral ischemia: Global cerebral ischemia is an ischemic condition where the brain does not receive enough blood flow to maintain normal neurological function. Cerebral ischemia can be the result of various diseases/conditions such as cardiac arrest, or the result of arterial obstruction such as strangulation.
Coma: A prolonged period of unconsciousness following brain injury or metabolic disorders. The person in coma may have a simple reflex in response to touch or pain, but essentially there is no meaningful response to external stimuli.
Cannabinoid: Compound capable of binding to a cannabinoid receptor and isolated from or identical to a compound isolated from an organism such a plant or animal. In the present context any compound capable of binding a cannabinoid receptor. Also, the term cannabinoid is used as a general term covering both cannabinoid and cannabimimetic compounds.
Cannabimimetic: Compound capable of binding to a cannabinoid receptor and produced or synthesized chemically by standard techniques known in the art. In the present context any compound capable of binding a cannabinoid receptor.
Capsaicinoid: Compound capable of binding to a capsaicinoid receptor / vanilloid receptor and isolated from or identical to a compound isolated from an organism such as a plant or animal. In the present context any compound capable of binding a capsaicinoid receptor / vanilloid receptor. A capsaicinoid may also be referred to as a vanilloid receptor agonist.
Capsaicinoid-like: Compound capable of binding to a capsaicinoid receptor / vanilloid receptor and produced or synthesized chemically by standard techniques known in the art. In the present context any compound capable of binding a capsaicinoid receptor / vanilloid receptor. A capsaicinoid-like compound may also be referred to as a vanilloid receptor agonist. Combination of compounds: Herein the term generally covers a combination of at least two compounds selected from the group consisting of vanilloid receptor agonist, capsaicinoid, capsaicinoid-like, cannabinoid and cannabimimetic compound, adenosine, adenosine analogs and derivatives, neurotensin, neurotensin analogs, thyroxine derivatives, thyronamine, cytochrome c oxidase inhibitors and oxygen tension reducers. The term may also include combinations of other compounds or drugs or the like.
Compound: A chemical substance formed from two or more elements, held together by chemical bonds, with a fixed ratio determining the composition. The elements lose their individual chemical properties and the compound has new properties.
Herein a term covering all of the following: vanilloid receptor agonist, capsaicinoid, capsaicinoid-like, cannabinoid and cannabimimetic compound, adenosine, adenosine analogs and derivatives, neurotensin, neurotensin analogs and peptides having at least 50% sequence identity to human neurotensin (NT or NT1 -13) of SEQ
ID NO. 1 , thyroxine derivative, thyronamine, cytochrome c oxidase inhibitor and oxygen tension reducers.
Cyclic group: means a closed ring hydrocarbon group that is classified as an alicyclic group, aromatic group, or heterocyclic group.
Cvcloalkenyl: means a monovalent unsaturated carbocyclic radical consisting of one, two or three rings, of three to eight carbons per ring, which can optionally be substituted with one or two substituents selected from the group consisting of hydroxy, cyano, lower alkenyl, lower alkoxy, lower haloalkoxy, alkenylthio, halo, haloalkenyl, hydroxyalkenyl, nitro, alkoxycarbonenyl, amino, alkenylamino, alkenylsulfonyl, arylsulfonyl, alkenylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkenylaminocarbonyl, arylaminocarbonyl, alkenylcarbonylamino and arylcarbonylamino.
Cvcloalkyl: means a monovalent saturated carbocyclic radical consisting of one, two or three rings, of three to eight carbons per ring, which can optionally be substituted with one or two substituents selected from the group consisting of hydroxy, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylamino- sulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino and arylcarbonylamino.
Cationic group: A chemical group capable of functioning as a proton donor when a compound comprising the chemical group is dissolved in a solvent, preferably when dissolved in water.
Cytochrome c oxidase inhibitor: means a compound that binds to and interferes with the function of cytochrome c oxidase; a mitochondrial transmembrane complex involved in metabolism. These include but are not limited to H2S (hydrogen sulfide); cyanide (CN) or its derivates such as hydrogen cyanide (HCN) or sodium nitroprusside (Na2[Fe(CN)5NO]^H2O); Azide and its derivates; Carbon monoxide (CO); and/or Sodium sulfide (Na2S).
Form a ring: means that the atoms mentioned are connected through a bond when the ring structure is formed.
Global ischemia: Anoxia resultant from ceased blood supply to the entire body resulting in tissue damage through a variety of mechanisms including apoptosis.
Global cerebral ischemia: Anoxia resultant from ceased blood supply to the entire brain resulting in tissue damage through a variety of mechanisms including apoptosis.
Group: (Moiety / substitution) as is well understood in this technical area, a large degree of substitution is not only tolerated, but is often advisable. Substitution is anticipated on the materials of the present invention. As a means of simplifying the discussion and recitation of certain terminology used throughout this application, the terms "group" and "moiety" are used to differentiate between chemical species that allow for substitution or that may be substituted and those that do not allow or may not be so substituted. Thus, when the term "group" is used to describe a chemical substituent, the described chemical material includes the unsubstituted group and that group with O, N, or S atoms, for example, in the chain as well as carbonyl groups or other conventional substitution. Where the term "moiety" is used to describe a chemical compound or substituent, only an unsubstituted chemical material is intended to be included. For example, the phrase "alkyl group" is intended to include not only pure open chain saturated hydrocarbon alkyl substituents, such as methyl, ethyl, propyl, t-butyl, and the like, but also alkyl substituents bearing further substituents known in the art, such as hydroxy, alkoxy, alkylsulfonyl, halogen atoms, cyano, nitro, amino, carboxyl, etc. Thus, "alkyl group" includes ether groups, haloalkyls, nitroalkyls, carboxyalkyls, hydroxyalkyls, sulfoalkyls, etc. On the other hand, the phrase "alkyl moiety" is limited to the inclusion of only pure open chain saturated hydrocarbon alkyl substituents, such as methyl, ethyl, propyl, t-butyl, and the like. The same definitions apply to "alkenyl group" and "alkenyl moiety"; to "alkynyl group" and "alkynyl moiety"; to "cyclic group" and "cyclic moiety; to "alicyclic group" and "alicyclic moiety"; to "aromatic group" or "aryl group" and to "aromatic moiety" or "aryl moiety"; as well as to "heterocyclic group" and "heterocyclic moiety".
Heterocyclic group: the term "heterocyclic group" means a closed ring hydrocarbon in which one or more of the atoms in the ring is an element other than carbon (e.g., nitrogen, oxygen, sulphur, etc.).
Heterocvclyl means a monovalent saturated cyclic radical, consisting of one to two rings, of three to eight atoms per ring, incorporating one or two ring heteroatoms (chosen from N, O or S(O)0-2, and which can optionally be substituted with one or two substituents selected from the group consisting of hydroxyl, oxo, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminofarbonyl, aryl- aminocarbonyl, alkylcarbonylamino, or arylcarbonylamino.
Heteroaryl means a monovalent aromatic cyclic radical having one to three rings, of four to eight atoms per ring, incorporating one or two heteroatoms (chosen from nitrogen, oxygen, or sulphur) within the ring which can optionally be substituted with one or two substituents selected from the group consisting of hydroxy, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, aryl- aminocarbonyl, alkylcarbonlamino and arylcarbonylamino. Hypothermia: Lowering of the body temperature below normal level.
Ischemia: Restriction in blood supply with resultant dysfunction or damage of tissue. Ischemia includes ischaemia and ischaemia.
Ischemic tissue damage: Tissue damage due to ischemia.
Lactic acidosis: Lactic acidosis is a condition caused by the buildup of lactic acid in the body. An important cause of lactic acidosis is inadequate oxygen supply to tissues. Lactic acidosis leads to acidification of the blood (acidosis), and is considered a distinct form of metabolic acidosis.
Moieties of a particular compound cover group(s) or part(s) of said particular compound.
Neurotensin: Neurotensin is the 13 amino acid peptide of SEQ ID NO. 1.
Neurotensin analog: A neurotensin analog is any sequence having at least 50% sequence identity to mature neurotensin of SEQ ID NO. 1 .
Neurotensin receptor: The neurotensin receptors are transmembrane receptors which bind neurotensin. Two of the receptors encoded by the NTSR1 and NTSR2 genes contain 7 transmembrane helices and are G protein-coupled. The third receptor has a single transmembrane domain and is encoded by the SORT1 gene.
Neurotensin receptor agonist: is a compound capable of imposing an agonizing effect of a neurotensin receptor and include but is not limited to neurotensin, neuromedin, NT64D, NT64L, NT65L, NT66D, NT66L, NT67L, NT69L, NT71 , NT72, NT73, NT74, NT75, NT76, NT77, Trp1 1 NT, contulakin-G, EISAI-1 , EISAI-2, JMV2004, JMV2012, JMV431 , JMV449, JMV457, JMV458, large neuromedin, large neurotensin, [125l]neurotensin, Thr10contulakin-G, D-Trp1 1 -neurotensin, levocabastine, SR48692, xenin, PD-149163 and CGX-1 160. Oxygen tension reducers: reduces the concentration of oxygen around or within the body. These include but are not limited to: Carbon monoxide (CO), Sodium sulfide (Na2S) and hydrogen sulfide (H2S).
Pharmaceutical composition: or drug, medicament or agent refers to any chemical or biological material, compound, composition or combinations of any of these especially combinations of compounds, capable of inducing a desired therapeutic effect when properly administered to a patient. Some drugs are sold in an inactive form that is converted in vivo into a metabolite with pharmaceutical activity. For purposes of the present invention, the terms "pharmaceutical composition" and "medicament" encompass both the inactive drug and the active metabolite.
Pulseless electrical activity: The electrical activity of the heart continues in a normal or abnormal pattern, but one that is consistent with contractions of the heart. But either due to damage to the heart muscle, blockage of the main arteries leading from the heart or lack of blood flowing to the heart there is no effective blood flow. The result is cardiac arrest.
Substituted lower alkyl means a lower alkyl having one to three substituents selected from the group consisting of hydroxyl, alkoxy, amino, amido, carboxyl, acyl, halogen, cyano, nitro and thiol.
Thyroxine derivatives: the term as used herein is meant to cover all forms and processed derivatives of the thyroid hormones, including thyroxine (T4), triiodothyronine (T3), thyronamine, 3-lodothyronamine, 3,5-Diiodothyronamine, and 3,5,3'-triiodothyronamine. The term is also used to encompass thyroid hormone receptor agonists and trace amine-associated receptor agonists, and these terms may be used interchangably herein.
Vanilloid receptor agonist: A capsaicinoid or capsaicinoid-like compound capable of binding a vanilloid receptor / capsaicinoid receptor.
Ventricular fibrillation: Very fast irregular electrical activity in the ventricles of the heart. Individual beats cannot be distinguished and the heart is in stand-still or vibrating slightly. The result is cardiac arrest. Ventricular tachycardia: Very fast electrical activity in the ventricles of the heart. The electrical activity maintains a pattern where individual contractions can be distinguished. Ventricular tachycardia may be associated with normal cardiac function, reduced cardiac function or functional cardiac arrest. This depends on the rate of the tachycardia and the state of the heart muscle.
The principle of the present invention is the use of a combination of vanilloid receptor agonists and/or cannabinoids and/or cannabimimetic compounds and/or adenosine and/or adenosine analogs and/or neurotensin and/or neurotensin analogs and/or thyroxine derivatives and/or cytochrome c oxidase inhibitors and/or oxygen tension reducers with the proviso that if the combination comprises two compounds, said two compounds are not vanilloid receptor agonists and cannabinoids or vanilloid receptor agonists and cannabimimetic compounds, for induction of hypothermia, such as for alleviating the effects of ischemia, such as but not limited to tissue damaging effects of ischemia.
Ischemia
Ischemia is the reduction or abolition of blood supply to a tissue. The associated deficiency of oxygen and nutrients may lead to cell death (necrosis) in areas of the affected tissue. The damage induced by the lack of oxygenated blood in the brain occurs in two stages. First cellular metabolism is arrested due to lack of oxygen and some cells and tissue will die within minutes as a consequence hereof. Secondly a cascade of processes such as apoptosis is initiated and continues up to 12 hours after the event that initially induced the ischemic state has been abolished. The tissue damaged by the second cascade can be crucial and cause greater harm to the individual than the primary damage happening within the first minutes of ischemia.
In one embodiment, the current invention is aimed at correcting ischemia of the brain thereby minimizing the damage to the central nervous system. The invention does so by administering a drug to induce hypothermia in patients. The hypothermic effect is presumed to counteract ischemic damage by several mechanisms in the brain: Prevention of the blood-brain-barrier disruption that happens soon after ischemic onset that allows oedema formation from extravasation; Diminishing of the oxygen-based free-radical production; Reduction of the excitotoxic-neurotransmitter release that overstimulates neighboring neurons; Lowering of the metabolic rate and subsequent energy depletion; and anti-inflammatory action. Induction of hypothermia has a neuroprotective effect.
It is an object of the present invention to provide a combination of compounds capable of inducing hypothermia in an individual and further to provide the use of said combination of compounds for the production of a medicament for the treatment of ischemia in an individual.
Ischemia may occur under various circumstances; of special relevance to the present invention are the circumstances relating to cardiovascular diseases, asphyxia and traumatic brain injuries.
It is thus within the scope of the present invention to provide means for reducing the risk of ischemia as well as treating ischemia in an individual, under circumstances where ischemia is brought about by for example: cardiovascular diseases, asphyxia and traumatic brain injuries.
In a highly preferred embodiment, compounds of the present invention are administered to prevent or treat or treat and prevent tissue damaging effects subsequent to or in conjunction with ischemia.
Cardiovascular diseases Cardiovascular disease is the most common cause of death and of physical as well as mental impairment in the developed world. A similar development is seen in the rest of the world as it emulates the lifestyle of the Western hemisphere with its fatty diets, lack of exercise and increasing average lifespan.
The main causes of death and disability among cardiovascular diseases are myocardial infarction, acute coronary syndrome, cardiac arrest and stroke, but many less common cardiovascular diseases may be equally detrimental to the individual affected. These less common diseases include among others arterial aneurism, subarachnoid haemorrhage, arteriosclerosis (or atherosclerosis), angina pectoris, hypertension, hypercholesterolemia, cardiac arrhythmia, cardiomegaly, cardiomyopathy, heart valve regurgitation and heart valve stenosis.
Each of the abovementioned diseases follow a course of events leading to ischemia, and are thus all of interest in relation to the present invention. Myocardial infarction (heart attack) is a result of an atherosclerotic plaque slowly building up in the inner lining of a coronary artery which then suddenly ruptures, partially or totally occluding the artery and preventing blood flow. Cardiac arrest is the abrupt cessation of normal circulation of the blood due to failure of the heart to contract effectively. Brain damage is likely to occur after 3-4 minutes without medical intervention, except in cases of hypothermia. Stroke is an acute neurological injury, lasting more than 24 hours, in which the blood supply to a part of the brain is interrupted, either by a clot in the artery or if the artery bursts. Arterial aneurism is a localized ballooning of an artery by more than 50% of the diameter of the vessel. Aneurysms most commonly occur in the arteries at the base of the brain and in the aorta. This bulge in an artery carries the risk of bursting and leading to internal hemorrhage. The larger an aneurysm becomes, the more likely it is to burst. Subarachnoid haemorrhage (SAH) is bleeding into the subarachnoid space surrounding the brain, i.e., the area between the arachnoid and the pia mater. It may arise due to trauma or spontaneously, and is a medical emergency, which can lead to death or severe disability even if recognized and treated in an early stage. Arteriosclerosis is a disease in which arterial walls harden over years or decades as a result of the formation of collagen and calcium deposits. Atherosclerosis is the most common subgroup of arterioscleosis, and is characterised by a chronic inflammatory response in the walls of arteries, in large part due to the accumulation of macrophage white blood cells ('foam cells') and promoted by low density lipoproteins (LDL; plasma proteins that carry cholesterol and triglycerides) without adequate removal of fats and cholesterol from the macrophages by functional high density lipoproteins (HDL). Hypertension or high blood pressure is a medical condition wherein the blood pressure is chronically elevated. Hypercholesterolemia is the presence of high levels of cholesterol in the blood. It is a derangement that can contribute to many forms of disease, most notably cardiovascular disease. Arrhythmia is a group of conditions in which the muscle contraction of the heart is irregular or is faster or slower than normal. Some arrhythmias are life threatening medical emergencies that can cause cardiac arrest and sudden death. Cardiomegaly is a medical condition wherein the heart is enlarged. It can often be associated with other serious medical conditions. Cardiomyopathy is the deterioration of the function of the myocardium (i.e., the actual heart muscle). People with cardiomyopathy are at risk of arrhythmia and/or sudden cardiac death. Heart valve regurgitation, also known as heart valve insufficiency, is the abnormal leaking of blood through heart valves. Heart valve stenosis is a heart condition caused by the incomplete opening of a heart valve, typically the aortic valve or the mitral valve, impairing blood flow through the heart.
Each of the cardiovascular diseases mentioned, as well as others not mentioned, may cause ischemia of organs. This ischemia, whether of the brain, heart or other organs, may lead to death or impairment if not treated rapidly.
It is an object of the present invention to provide a combination of compounds for the production of a medicament for the treatment or prophylaxis of an individual suffering from or at risk of suffering from of ischemia due cardiovascular diseases such as, but not limited to: myocardial infarction, acute coronary syndrome, cardiac arrest, stroke, arterial aneurism, subarachnoid haemorrhage, arteriosclerosis, angina pectoris, hypertension, hypercholesterolemia, cardiac arrhythmia, cardiomegaly, cardiomyopathy, heart valve regurgitation and heart valve stenosis.
Preferably, the medicament is for the treatment or prophylaxis of ischemia due to cardiac arrest, myocardial infarction, acute coronary syndrome, stroke, arterial aneurisms, sub-arachnoid haemorrhage or angina pectoris.
All of the above-mentioned cardiovascular diseases require specific diagnostic tests and treatments. These tests and treatments, as specified for sudden cardiac arrest, stroke and heart attack in the below, may be carried out in conjunction with the administration of medicaments defined in this patent.
Sudden cardiac arrest victims may be subjected to early CPR, early defibrillation and early advanced care. Further tests and treatments may include cardiac catheterization, electrophysiologic tests, coronary artery bypass surgery, balloon angioplasty or PTCA, antiarrhythmic medicine, implantable cardioverter / defibrillator, implantable pacemaker and heart transplant. Depending on whether patients suffer an ischemic or hemorrhagic stroke, acute treatment may include clot-busters (e.g. tPA) or surgical intervention (e.g. aneurysm clipping, and endovascular procedures such as insertion of "coils"). Preventive treatment includes the administration of anticoagulants/anti-platelet. It may furthermore include carotid endarterectomy and angioplasty and/or stents.
Patients suffering a heart attack (myocardial infarction) may have one or several treatments and procedures done to survive and diagnose the condition: These include resuscitation (early CPR, early defibrillation, early advanced care), thrombolysis, coronary angioplasty (also known as Percutaneous Transluminal
Coronary Angioplasty [PTCA], Percutaneous Coronary Interventions [PCI], Balloon Angioplasty and Coronary Artery Balloon Dilation), and coronary artery bypass graft surgery (CABG).
Asphyxia
Asphyxia (suffocation) is a common cause of death and of physical as well as mental impairment in perinatals, neonatals or newborns, children and adults of all ages. According to WHO (World Health Organization), the perinatal period commences at 22 completed weeks (154 days) of gestation (the time when birth weight is normally 500 g), and ends seven completed days after birth or delivery. The neonatal period is most often and herein defined as four weeks after birth; regardless of whether or not birth occurs prematurely. A premature infant is born after a gestation period of less than the normal time (about 266 days in the human).
Asphyxia can be divided into perinatal asphyxia and non-perinatal asphyxia.
Perinatal asphyxia is the medical condition resulting from deprivation of oxygen to an infant long enough to cause apparent harm; the infant may at the time of oxygen deprivation still reside in the mothers uterus and/or birth canal, it may occur during the process of delivery or may occur immediately after delivery. It results most commonly from a drop in maternal blood pressure or interference during delivery with blood flow to the infant's brain, but may also stem from umbilical cord entaglement. This can occur due to inadequate circulation or perfusion, impaired respiratory effort, or inadequate ventilation. Extreme degrees of asphyxia can cause cardiac arrest and death. Hypoxic damage can occur to most of the infant's organs, but brain damage is of most concern and perhaps the least likely to quickly and completely heal. In severe cases, an infant may survive, but with damage to the brain manifested as developmental delay and spasticity. In one embodiment of the present invention at least one compound hereof is administered to the infant while it resides within the uterus and/or birthcanal, i.e. as soon as asphyxia is determined. Asphyxia may be determined for example by measuring the pH of the blood of the infant.
Non-perinatal asphyxia is a condition of severely deficient supply of oxygen to the body that arises from being unable to breathe normally. Common causes hereof include drowning, strangulation and exposure to toxic gasses. Asphyxia causes generalized hypoxia, which primarily affects the tissues and organs most sensitive to hypoxia first, such as the brain, hence resulting in cerebral hypoxia. The absence of effective remedial action will very rapidly lead to unconsciousness, brain damage and death.
Each kind of asphyxia mentioned, as well as others not mentioned, may cause ischemia of organs and is thus an object of the present invention.
It is an aspect of the present invention to provide a combination of compounds for the treatment of an individual suffering from ischemia due to asphyxia such as: perinatal asphyxia and/or non-perinatal asphyxia.
Treatment by administration of the medicament defined in this patent may be carried out in conjunction with test and treatments of diseases and accidents including asphyxia (perinatal asphyxia, and non-perinatal asphyxia including, but not limited to, drowning, strangulation and exposure to toxic gasses). Such diseases and injuries may require early CPR, early defibrillation and both early and continued advanced care as well as other tests and treatments not specified.
Traumatic brain injury
Traumatic brain injury (TBI) is a common cause of death and of physical as well as mental impairment throughout the world. TBI may result from accidents, be due to violence or be self-inflicted.
Traumatic brain injury, also called intracranial injury, or simply head injury, occurs when a sudden trauma causes brain damage. TBI can result from a closed head injury or a penetrating head injury. Parts of the brain that can be damaged include the cerebral hemispheres, cerebellum, and brain stem. Symptoms of a TBI can be mild, moderate, or severe, depending on the extent of the damage to the brain. Outcome can be anything from complete recovery to permanent disability or death. Ischemia is a significant factor contributing to the neurological damage frequently seen in patients suffering from TBI.
It is an aspect of the present invention to provide a combination of compounds for the treatment of an individual suffering from ischemia due to traumatic brain injury.
Treatment by administration of the medicament defined in this patent may also be carried out in conjunction with test and treatments in relation to traumatic head injury (closed head injury or penetrating head injury). Such injuries may require early CPR, early defibrillation and both early and continued advanced care as well as other tests and treatments not specified.
Other indications
Elevated body temperature Individuals suffering from elevated body temperatures due to an infection, ischemic damage, heat- or sunstroke or the like will also benefit from the administration of the compounds of the present invention.
Fever (also known as pyrexia, or a febrile response) is a frequent medical symptom that describes an increase in especially internal body temperature to levels above normal. Fever is most accurately characterized as a temporary elevation in the body's thermoregulatory set-point, meaning that the temperature is raised by the body in a controlled manner. Fever is a symptom of many different diseases such as infectious diseases, immunological diseases, cancers metabolic disorders and more.
Hyperpyrexia is an extreme degree of fever, where the set body temperature is elevated greater than or equal to 41 degree Celsius. Such a high temperature is considered a medical emergency and requires immediate medical attention. Fever and hyperpyrexia differ from hyperthermia. Hyperthermia is an increase in body temperature over the body's thermoregulatory set-point, due to excessive heat production or insufficient thermoregulation, or both. Hyperthermia may be caused by heat- or sunstroke, exposure, dehydration and more. A special variant of hyperthermia is malignant hyperthermia which may arise due to administration of general anesthesia.
It is an object of the present invention to provide a combination of compounds for the induction of hypothermia and/or lowering of body temperature in an individual with an elevated body temperature, such as an individual suffering from fever, hyperpyrexia and/or hyperthermia.
Furthermore it is an object of the present invention to induce hypothermia in individuals in whom the initial temperature prior to treatment is above the normal temperature for said individual. These individuals may be individuals suffering from fever, hyperthermia, malign hyperthermia, hyperpyrexia or other. It is common that individuals suffering from a heart attack or stroke e.g. suffering from ischemia develop a fever and it is an object of the present invention to reduce the fever and induce hypothermia in such individuals. Individuals otherwise suffering from fever, hyperthermia, malign hyperthermia, hyperpyrexia or other may benefit by administration of the compound of the present invention to reduce the elevated temperature to normal that is to within 35 to 39 degree Celsius, such as to within 35.5 to 38.5 degree Celsius, such as to within 36 to 38 degree Celsius, such as to within 37 degree Celsius +/- 0.6 degree Celsius, or to reduce their body temperature further to hypothermic levels as described above.
The individuals with elevated body temperatures may have any temperature considered to be above normal, which is any temperature above 36 degree Celsius. The temperature of the individual in need of treatment according to the present invention may thus be a temperature of above 36 degree Celsius, such as above
36.5 degree Celsius, such as above 37 degree Celsius, such as above 37.5 degree Celsius, such as above 38 degree Celsius, such as above 38.5 degree Celsius, such as above 39 degree Celsius, such as above 39.5 degree Celsius, such as above 40 degree Celsius, such as above 40.5 degree Celsius, such as above 41 degree Celsius such as above 41 .5 degree Celsius such as above 42 degree Celsius, such as above 42.5 degree Celsius, such as above 43 degree Celsius, such as above 43.5 degree Celsius and higher.
Pre-operative administration The outcome of several types of surgery is improved if the individual undergoing the surgery is placed under hyperthermia prior to or during the surgery. Examples of such operations are neurosurgeries, thorax surgeries and especially cardiac surgeries. The lowering of the body temperature slows down the metabolic rate and thus reduces the need for e.g. oxygen during the surgery giving more time to the surgeon to perform complicated procedures.
It is an object of the present invention to provide a combination of compounds for the induction of hypothermia in an individual prior to surgery. The compounds of the present invention are preferably administered pre-operatively. It is also an aspect of the invention to provide a combination of compounds for the induction of hypothermia in an individual in need of surgery prior to and/or during transportation of said individual.
A specific procedure in which it is of interest to lower the body temperature is in the case of organ transplants, where it is beneficial that the organs to be transplanted are cooled prior to removal and especially prior to and during transport before transplantation into the recipient. It is furthermore of interest for the preservation of organs, tissues, and cells that hypothermia may be induced in these by induction of hypothermia in the individual from which these are taken. Either prior to or after removal, stasis (very low or no detectable metabolic rate) may be induced by further administration of the compounds of the present invention. Therefore it is an object of the present invention to administer a combination of compounds herein disclosed for the induction of hypothermia in an individual and in the organs, tissues and cells of said individual, prior to the excision of the organs, tissues and cells for the purpose of transplantation, implantation, cryopreservation or other.
Hypothermia
Hypothermia is the lowering of the core temperature of the body below normal level. Normal body temperature in an adult human measured rectally over 24 hours is 37 degree Celsius +/- 0.6 degree Celsius and is thus variable between individuals, and over time within the individual. Hypothermia as a medical condition is usually defined as the effects seen on the body once the core temperature drops below 35 degree Celsius. It may become critical, if the body temperature falls below 32 °C. In the present application hypothermia is defined as the lowering of the core body temperature below normal levels. This implies that any temperature below the normal core body temperature of the specific individual with its natural variations at the given point in time of the day, or period, herein is defined as being hypothermic. In particular, hypothermia is a temperature below 35.5 °C, such as below 35 °C, such as below 34.5 °C, such as below 34.0 °C.
Body temperature may be measured by a variety of means by mercury, electronic or plastic strip thermometers on different areas of the body such as the forehead, mouth, armpit, ear or rectum. It is presently understood, that the temperature referred to in the present application is the core body temperature, and that some of the above methods of measurement will indicate a different temperature than the core temperature.
It is of importance, that induction of hypothermia in an individual can follow a predictable course and be responsive to the dose in which the combination of compounds capable of inducing hypothermia is administered. The induction of the hypothermic condition may be rapid or slow depending on the situation of the individual in need of treatment. Also depending on the severity of the ischemic condition, it is of interest to provide a medicament for retaining the individual in the hypothermic state for variable durations of time. A combination of compounds comprising two or more of the group consisting of vanilloid receptor agonists and/or cannabinoids or cannabimimetic compounds and/or adenosine receptor agonists and/or neurotensin receptor agonists and/or thyroxine derivatives, and/or cytoshrome c oxidase inhibitors and/or oxygen tension reducers, with the proviso that if the combination of compounds comprise two compounds said two compounds are not one cannabinoid or cannabimimetic compound and one vanilloid receptor agonist, may be used depending on dosage within a range of temperatures or for the induction of hypothermia to a specific temperature. A combination of compounds, comprising two or more of the group consisting of vanilloid receptor agonists and/or cannabinoids or cannabimimetic compounds and/or adenosine receptor agonists and/or neurotensin receptor agonists and/or thyroxine derivatives, and/or cytoshrome c oxidase inhibitors and/or oxygen tension reducers, with the proviso that if the combination of compounds comprise two compounds said two compounds are not one cannabinoid or cannabimimetic compound and one vanilloid receptor agonist, may furthermore be used for an initial rapid decrease in core body temperature, and the subsequent maintenance of the reached temperature over a prolonged period. It is furthermore beneficial if the hypothermic state can be reversed in a rapid and controlled fashion either slowly or rapidly depending on the status of the individual.
It is thus an object of the present invention to provide a combination of compounds for the production of a medicament for the induction of hypothermia in an individual suffering from ischemia, wherein the combination of compounds is capable of inducing hypothermia to any range of temperatures between 37 and 31 degree Celsius, such as between 36.5 and 31.5 degree Celsius, such as between 36 and 32 degree Celsius, such as between 35.5 and 32.5 degree Celsius, such as between 35 and 33 degree Celsius, such as between 34.5 and 33.5 degree Celsius. The ranges may furthermore be between 37 and 34 degree Celsius, such as between 36.5 and 34.5 degrees, such as 36 and 35 degrees, alternatively between 34 and 31 degree, such as between 33.5 and 31.5 degree, such as 33 and 32 degree Celsius, alternatively between 36 and 33 degree or 35 and 32 degree Celsius. Preferably, the combination of compounds of the present invention is capable of inducing hypothermia in the range of between 36 to 32 degree Celsius, more preferably between 35 and 33 degree Celsius.
It is also an object of the present invention to provide a combination of compounds capable of inducing hypothermia to a specific temperature such as 37 degree Celsius, 36.5 degree Celsius, 36 degree Celsius, 35.5 degree Celsius, 35 degree Celsius, 34.5 degree Celsius, 34 degree Celsius, 33.5 degree Celsius, 33 degree Celsius, 32.5 degree Celsius, 32 degree Celsius, 31.5 degree Celsius or 31 degree Celsius or most preferably, the combination of compounds of the present invention is capable of inducing hypothermia to any of the above specific temperatures within a range of +/- 0.5 degree Celsius, such as the range being between +/- 0.4 degree Celsius, such as between +/-0.3 degree Celsius, such as between +/- 0.2 degree Celsius, or such as between +/- 0.1 degree Celsius. The temperature range or specific temperature a given combination of compounds is capable of inducing is herein also referred to as the target temperature of the combination of compounds and/or the medicament comprising the combination of compounds.
Preferably, the person in need of the hypothermic treatment e.g. the administration of a combination of compounds of the present invention suffers from ischemia, or is in need of surgery such as neurosurgery or cardiac surgery, e.g. the compound is administered pre-operatively.
It is also an object of the present invention to provide a combination of compounds capable of inducing hypothermia / reducing body temperature to a specific temperature such as 39 degree Celsius, 38.5 degree Celsius, 38 degree Celsius, 37.5 degree Celsius, 37 degree Celsius, 36.5 degree Celsius, 36 degree Celsius, 35.5 degree Celsius, 35 degree Celsius, or most preferably, the combination of compounds of the present invention is capable of inducing hypothermia to any of the above specific temperatures within a range of +/- 0.5 degree Celsius, the range thus being between +/- 0.4 degree Celsius, such as between +/-0.3 degree Celsius, such as between +/- 0.2 degree Celsius, or such as between +/- 0.1 degree Celsius.
An aspect of the present invention regards the treatment of an individual in need thereof by the use of a combination of compounds of the present invention for the induction of hypothermia. The individuals in need of the treatment are individuals suffering from conditions that are benefitted by the induction of hypothermia and/or reduction in body and/or brain temperature. Such individuals include but are not limited to: individuals suffering from or at risk of suffering from ischemia, elevated body termperatures due to fever, hyperthermia, hyperpyrexia, malign hyperpyrexia or are in need of treatment, such as but not limited to surgery, wherein the outcome of the procedure or the procedure itself is benefitted by a reduction in temperature of the individual undergoing the treatment and/or surgery.
Combination of compounds
A treatment consisting of a combination of compounds comprising two or more of the group consisting of vanilloid receptor agonists and/or cannabinoids or cannabimimetic compounds and/or adenosine receptor agonists and/or neurotensin receptor agonists and/or thyroxine derivatives and/or cytochrome c oxidase inhibitors and/or oxygen tension reducers, with the proviso that if the combination of compounds comprise two compounds said two compounds are not one cannabinoid or cannabimimetic compound and one vanilloid receptor agonist, either as an integrated drug, administered simultaneously, or administered consecutively, is superior to any treatment based on the solitary use of any single cannabinoid receptor agonist or vanilloid receptor agonist or adenosine receptor agonist or neurotensin receptor agonist or thyroxine derivative or cytochrome c oxidase inhibitor or oxygen tension reducer.
As six of the seven classes of compounds bind either vanilloid receptors or cannabinoid receptors or adenosine receptor or neurotensin receptors or thyroxine derivative receptors or cytochrome c oxidase as well as several co-receptors as described in the above and in a few cases may bind both vanilloid and cannabinoid receptors; a combination of compounds according to the present invention has a positive synergistic effect. The positive synergistic effect putatively occurs by inducing several responses that converge, cross, or supplement each other. These responses may include a cross binding of the receptors, the activation of a larger number of receptors than possible with a single compound, activation of scores of co-receptors to either of the main receptors of the two classes of drugs and so on. It is surprising, that the combination of compounds comprising two or more of the group consisting of vanilloid receptor agonists and/or cannabinoids or cannabimimetic compounds and/or adenosine receptor agonists and/or neurotensin receptor agonists and/or thyroxine derivatives and/or cytochrome c oxidase inhibitors and/or oxygen tension reducers, with the proviso that if the combination of compounds comprise two compounds said two compounds are not one cannabinoid or cannabimimetic compound and one vanilloid receptor agonist, has an effect superior to either of the seven classes of compounds on their own.
The induction of hypothermia depends on the characteristics of the individual compounds of the combinations and these characteristics may be to reach different target temperatures or different ranges of target temperatures, reaching the target temperatures at various speeds (varying peak effect times), the duration of the induced hypothermia, the lifetime of the active compounds, a minimizing of side effects and so on. A: All seven compounds
It is therefore an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
B: A combination of 6 compounds It is therefore an object of the present invention to provide a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
C: A combination of 5 compounds it is therefore an object of the present invention to provide a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer. For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one neurotensin receptor agonist and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer. For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one thyroxine derivative and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
It is therefore an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one thyroxine derivative.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one cytochrome c oxidase inhibitor.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one oxygen tension reducer. For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one adenosine receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer. D: A combination of 4 compounds
It is therefore an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one neurotensin receptor agonist.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one thyroxine derivative.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one cytochrome c oxidase inhibitor.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one thyroxine derivative.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one cytochrome c oxidase inhibitor.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one oxygen tension reducer. For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one neurotensin receptor agonist and at least one thyroxine derivative.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one neurotensin receptor agonist and at least one cytochrome c oxidase inhibitor.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one neurotensin receptor agonist and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one thyroxine derivative.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one cytochrome c oxidase inhibitor.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor. For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one neurotensin receptor agonist and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one thyroxine derivative and at least one oxygen tension reducer. For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one neurotensin receptor agonist and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one adenosine receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one adenosine receptor agonist and at least one thyroxine derivative and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist a and at least one adenosine receptor agonist and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer. For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one thyroxine derivative and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one adenosine receptor agonist at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer. E: A combination of 3 compounds
It is therefore an object of the present invention to provide a medicament or composition comprising at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one thyroxine derivative.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one cytochrome c oxidase inhibitor.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one adenosine receptor agonist and at least one neurotensin receptor agonist and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one neurotensin receptor agonist and at least one thyroxine derivative.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one neurotensin receptor agonist and at least one cytochrome c oxidase inhibitor.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one cannabinoid or cannabimimetic compound a and at least one neurotensin receptor agonist and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one cannabinoid or cannabimimetic compound at least one neurotensin receptor agonist and at least one thyroxine derivative. For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one cannabinoid or cannabimimetic compound at least one neurotensin receptor agonist and at least one cytochrome c oxidase inhibitor.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one cannabinoid or cannabimimetic compound at least one neurotensin receptor agonist and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one neurotensin receptor agonist and at least one thyroxine derivative.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one neurotensin receptor agonist and at least one cytochrome c oxidase inhibitor.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one neurotensin receptor agonist and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one adenosine receptor agonist and at least one thyroxine derivative.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one adenosine receptor agonist and at least one cytochrome c oxidase inhibitor.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one adenosine receptor agonist and at least one oxygen tension reducer. For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one thyroxine derivative.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one cytochrome c oxidase inhibitor.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one neurotensin receptor agonist and at least one thyroxine derivative and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one neurotensin receptor agonist and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one adenosine receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor. For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one adenosine receptor agonist and at least one thyroxine derivative and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one adenosine receptor agonist and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one thyroxine derivative and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one thyroxine derivative and at least one cytochrome c oxidase inhibitor.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one thyroxine derivative and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one cytochrome c oxidase inhibitor and at least one oxygen tension reducer. For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one cannabinoid or cannabimimetic compound and at least one neurotensin receptor agonist.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one adenosine receptor agonist and at least one neurotensin receptor agonist.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist and at least one neurotensin receptor agonist.
E: A combination of 2 compounds
It is thereforean object of the present invention to provide a medicament or composition comprising at least one neurotensin receptor agonist and at least one thyroxine derivative.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one neurotensin receptor agonist and at least one cytochrome c oxidase inhibitor.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one neurotensin receptor agonist and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one adenosine receptor agonist and at least one thyroxine derivative. For the same reason, it is an object of the present invention to provide a medicament or composition comprising t least one adenosine receptor agonist and at least one cytochrome c oxidase inhibitor.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one adenosine receptor agonist and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one cannabinoid or cannabimimetic compound nd at least one thyroxine derivative.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one cytochrome c oxidase inhibitor.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one cannabinoid or cannabimimetic compound agonist and at least one oxygen tension reducer.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one thyroxine derivative.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one cytochrome c oxidase inhibitor.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one oxygen tension reducer. For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one adenosine receptor agonist.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one vanilloid receptor agonist and at least one neurotensin receptor agonist.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one adenosine receptor agonist.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one cannabinoid or cannabimimetic compound and at least one neurotensin receptor agonist.
For the same reason, it is an object of the present invention to provide a medicament or composition comprising at least one adenosine receptor agonist and at least one neurotensin receptor agonist.
The medicament may thus comprise compounds of the present invention wherein at least one compound induces hypothermia rapidly, or alternatively wherein at least one compound induces hypothermia slowly. The medicament may furthermore comprise at least one compound that induces hypothermia over an extended time period, alternatively wherein at least one compound induces hypothermia for a short time period.
Cannabinoids
Cannabinoids and cannabimimetic compounds are a group of chemicals which activate the body's cannabinoid receptors, CB1 and CB2. Before other types were discovered, the term referred to a unique group of secondary metabolites found in the cannabis plant, which are responsible for the plant's peculiar pharmacological effects. Cannabinoids are generally grouped into five classes based mainly on chemical composition and in part on origin: • The eicosanoids, also referred to as endocannabinoids are produced in the bodies of humans and other animals
• Classical cannabinoids, a group which includes natural cannabinoids found in larger or smaller amounts in the hemp plant Cannabis sativa. • Non-classical cannabinoids
• Aminoalkylindoles
• Other compounds that are capable of binding cannabinoid receptors, but fall out of the four previous categories.
The current understanding recognizes the role that endocannabinoids play in almost every major life function in the human body. Cannabinoids act as a bioregulatory mechanism for most life processes, which reveals why medical cannabis has been cited as treatments for many diseases and ailments in anecdotal reports and scientific literature. Some of these ailments include: pain, arthritic conditions, migraine headaches, anxiety, epileptic seizures, insomnia, loss of appetite, GERD (chronic heartburn), nausea, glaucoma, AIDS wasting syndrome, depression, bipolar disorder (particularly depression-manic-normal), multiple sclerosis, menstrual cramps, Parkinson's, trigeminal neuralgia (tic douloureux), high blood pressure, irritable bowel syndrome, and bladder incontinence. Cannabinoids and cannabimimetic compounds (CB1/CB2 agonists) have furthermore received interest as putatively neuroprotective substances.
Several mechanisms have been proposed to account for the neuroprotective effects of various cannabinoids and cannabimimetic substances such as prevention of excitotoxicity by cannabinoid CB1 -mediated inhibition of glutamatergic transmission, reduction of calcium influx, anti-oxidant activity, activation of the phosphatidylinositol 3-kinase/protein kinase B pathway, induction of phosphorylation of extracellular regulated kinases and the expression of transcription factors and neutrophins, lowering of the cerebrovasoconstriction and induction of hypothermia.
Any compound which can be defined as a cannabinoid or cannabimimetic compound falls within the scope of the present invention. The two terms cannabinoids and cannabimimetic are used interchangeably herein. Cannabinoids are generally termed such due to their ability to bind one or more of the cannabinoid receptors CB1 and CB2. Receptors
There are currently two known types of cannabinoid receptors, CB1 and CB2, which are common in animals, and have been found in mammals, birds, fish, and reptiles.
CB1 receptors are found primarily in the brain, specifically in the basal ganglia and in the limbic system, including the hippocampus. They are also found in the cerebellum and in both male and female reproductive systems. CB1 receptors are essentially absent in the medulla oblongata, the part of the brain that is responsible for respiratory and cardiovascular functions. Thus, there is not a risk of respiratory or cardiovascular failure as there is with many other drugs. CB1 receptors appear to be responsible for the euphoric and anticonvulsive effects of cannabis.
CB2 receptors are almost exclusively found in the immune system, with the greatest density in the spleen. CB2 receptors appear to be responsible for the antiinflammatory and possible other therapeutic effects of cannabis.
Researchers have noted that the behavioural effects, including hypothermia, seen when introducing animals to cannabinoids seems to be due to other factors besides CB1 receptor stimulation [46;49]. Inducing hypothermia by cannabinoids is therefore not solely equivalent to stimulating the CB1 receptor. Furthermore, there is evidence in the literature for other receptors than CB1 and CB2 as recipients of the cannabinoid ligands.
The receptors to which the cannabinoids and cannabimimetic compounds of the present invention may bind includes, apart from CB1 and CB2: a third CB receptor, herein termed CB3, GABA (gamma-aminobutyric acid) receptors, the NMDA (N- methyl-D-aspartate) receptor, the 5-HT(1 A) receptor, also known as the serotonin receptor, the Delta opioid receptor (DOR) and TRPV1 (transient receptor potential vanilloid 1 ). It is furthermore within the scope of the invention that at least one compound of the combination of compounds of the invention may bind CB1 , CB2 or CB3 co-receptors. Compounds capable of binding any of the above-mentioned receptors thus fall within the scope of the present invention. Structure
The cannabinoids of this application are, based on their structure, categorized as follows: classic cannabinoids, non-classic cannabinoids, aminoalkylindoles, eicosanoids (endogenous cannabinoids) and other compounds that fall out of the classification. Compounds belonging to any of these categories fall within the scope of the present invention.
It is within the scope of the invention that the combinations of compounds of the invention are capable of inducing hypothermia in an individual.
It is furthermore within the scope of the invention that at least one compound of the combination of compounds of the invention are capable of binding a cannabinoid receptor.
Accordingly, in the broadest aspect the present invention concerns the use of a combination of compounds wherein at least one compound comprises a structure of one of the general formulas illustrated in the below for cannabinoid and cannabimimetic compounds. In these illustrations R is a chemical bond or a chemical moiety as defined in the above. R may be any moiety substituted any amount of times according to the following non-limiting list, whereby R is: C, H, S, N, O, optionally substituted one or more times with C, H, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, diphenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(d-4)-alkyl, heteroaryl-(d-4)-alkyl, heterocyclyl-(Ci-4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl or phosphate, optionally further substituted one or more times with C, S, N, O, P, OH, H, phenyl, amine (NH), halogen, substituted lower alkyl or alkyl such as (CrCx) any of which may be further substituted one or more times with methyl, dimethyl, alkyl such as (CrCx), phenyl, sulphate, phosphate, halogen or further substituted by fluoride, sulphate, phosphate, methyl, dimethyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci_4)-alkyl, heteroaryl-(Ci-4)-alkyl, heterocyclyl-(Ci_4)-alkyl, cycloalkylalkyl, dicycloalkyl, tricycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, nitro, halogen or alcohol, and wherein x is an integer of from 1 to 30, and of which any of the mentioned substituents capable thereof may form a ring with another R. R may furthermore be a chemical bond, or a pharmaceutically acceptable addition salt or hydrate thereof. Phosphate residues have been implicated in the reduction of toxicity of certain cannabinoids without altering their hypothermic effect. It is therefore an object of the present invention that any of the cannabinoid and/or cannabimimetic compounds of the invention may carry one or more phosphate groups bound as phosphate esters.
For each general formula, a more specific choice of substituent for a given R is listed along with along with a preferred and a more preferred list of substituent groups.
The present invention concerns the use of a combination of compounds wherein at least one compound is a cannabinoid or cannabimimetic compound such as a classic or non-classic cannabinoid comprising the general formula (I):
Figure imgf000047_0001
- wherein R1 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(d-4)-alkyl, heteroaryl-(Ci-4)-alkyl, heterocyclyl-(d-4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl or phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(d-4)-alkyl, heteroaryl-(Ci-4)-alkyl, heterocyclyl-(Ci-4)- alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, or nitro, and preferably is C, O, N optionally substituted with O, OH, alkyl, alkenyl, alkynyl, or phosphate, optionally further substituted with methyl, alkyl or phosphate and more preferably is C, optionally substituted with H, OH, OCH3 or phosphate and - wherein R2 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, any of which may or may not be branched or comprise substituents such as phosphate, cycloalkyl, heterocycloalkyl, cycloalkenyl, methyl, dimethyl, or may be further substituted one or more times with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, sulfonyl, any of which may or may not be branched or comprise substituents such as hydrogen, alkyl, alkenyl, alkynyl, fluoride, phosphate, cycloalkyl, heterocycloalkyl, cycloalkenyl, dimethyl, phenyl and preferably is C substituted with C, O, P, H, OH, OSO2, phosphate, alkyl, alkenyl, alkynyl such as (CrCx), phenyl any of which may be substituted with methyl, dimethyl, sulfonyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, fluoride, phenyl, phosphate, and more preferably is C substituted with C, O, OSO2, alkyl such as (C3- C11) any of which may be further substituted with methyl, dimethyl, alkyl such as (C1- Cx), phenyl, phosphate or further substituted by fluoride, phosphate, methyl, dimethyl and wherein x is an integer of from 1 to 20 and
- wherein R3 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C1.4)-alkyl, heteroaryl-(C1-4)-alkyl, heterocyclyl-(C1-4)-alkyl, cycloalkylalkyl, cycloalkenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, methyl, phenyl, diheterocycle, amine (NH), halogen, substituted lower alkyl, aryl, lower alcohol, heterocyclyl, heteroaryl, aryl-(C1.4)-alkyl, heteroaryl-(C1.4)-alkyl, heterocyclyl-(C1-4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, or nitro, preferably is C, O, N, S, optionally substituted with O, OH, alkyl, alkenyl, alkynyl, or phosphate, optionally further substituted one or more times with methyl, diheterocycle, lower alcohol, alkyl or phosphate more preferably is C which may be substituted with C, O, N, OH, phosphate, any of which may be substituted one or more times with C, ethyl, methyl, phosphate, diheterocycle, lower alcohol, alkyl such as (C1-C2) wherein C2 binds to R4 when R4 is C, optionally further substituted by methyl, dimethyl or phosphate and
- wherein R4 is selected from the group of: C, H, S, N, O, optionally substituted with C, H, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, diphenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl- (Ci-4)-alkyl, heteroaryl-(Ci.4)-alkyl, heterocyclyl-(Ci.4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, substituted lower alkyl, alkyl such as (CrCx) any of which may be further substituted with methyl, dimethyl, alkyl such as (CrCx), phenyl, phosphate or further substituted by fluoride, phosphate, methyl, dimethyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci-4)-alkyl, heteroaryl-(Ci-4)-alkyl, heterocyclyl-(Ci-4)-alkyl, cycloalkylalkyl, dicycloalkyl, tricycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, or nitro, (alcohol) and preferably is C, H, N, O optionally substituted with alkyl, alkenyl, alkynyl, alcohol, phenyl, diphenyl, dicycloalkyl, tricycloalkyl, cycloalkenyl any of which may bond with R1 or R3 forming a ring, optionally further substituted with one or more alkyl, alkenyl, alkynyl, OH, and more preferably is C, H, (C1 -Cy), dicycloalkyl, or tricycloalkyl, cycloalkenyl any C of which may bond with R1 or R3 forming a ring, and optionally is substituted with methyl, dimethyl, phenyl, diphenyl, optionally further substituted with alkyl and/or OH and wherein x is an integer of from 1 to 15 and y is an integer of from 1 to 8.
Preferably, the present invention concerns the use of a combination of compounds wherein at least one compound is a cannabinoid or cannabimimetic compound such as a compound comprising the general formula (I) wherein R1 is C, O, N optionally substituted with O, OH, alkyl, alkenyl, alkynyl, or phosphate, optionally further substituted with methyl, alkyl or phosphate, when R2 is C substituted with C, O, P, H, OH, 0S02, phosphate, alkyl, alkenyl, alkynyl such as (C1 -CX), phenyl any of which may be substituted with methyl, dimethyl, sulfonyl, heterocycloalkyl, fluoride, phenyl or phosphate, when R3 is C, O, N, S, optionally substituted with O, OH, alkyl, alkenyl, alkynyl, or phosphate, optionally further substituted one or more times with methyl, diheterocycle, lower alcohol, alkyl or phosphate, when R4 is C, H, N, O optionally substituted with alkyl, alkenyl, alkynyl, alcohol, phenyl, diphenyl, dicycloalkyl, tricycloalkyl, cycloalkenyl any of which may bond with R1 or R3 forming a ring, optionally further substituted with one or more alkyl, alkenyl, alkynyl or OH.
Most preferably, the present invention concerns the use of a combination of compounds wherein at least one compound is a cannabinoid or cannabimimetic compound such as a compound comprising the general formula (I) wherein R1 is C, optionally substituted with H, OH, OCH3 or phosphate, when R2 is C substituted with C, O, OSO2, alkyl such as (C3-Cn) any of which may be further substituted with methyl, dimethyl, alkyl such as (CrCx), phenyl, phosphate or further substituted by fluoride, phosphate, methyl, dimethyl when R3 is C which may be substituted with C, O, N, OH, phosphate, any of which may be substituted with C, ethyl, phosphate, alkyl such as (CrC2) wherein C2 binds to R4 when R4 is C, optionally further substituted by methyl, dimethyl or phosphate when R4 as defined in claim 8 is C, (C1 -C8) any C of which may bond with R3 and optionally is substituted with methyl, dimethyl, phenyl, diphenyl optionally further substituted with an alcohol and wherein x is an integer of from 1 to 15.
The present invention also concerns the use of a combination of compounds wherein at least one compound is a cannabinoid or cannabimimetic compound such as a classic or non-classic cannabinoid comprising the general formula (II):
Figure imgf000050_0001
- wherein R1 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(Ci_4)-alkyl, heteroaryl-(Ci-4)-alkyl, heterocyclyl-(Ci_4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally bonding with the C in the ring next to R5, optionally further substituted one or more times with C, S, N, O, OH, phenyl, phosphate, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(C1_4)-alkyl, heteroaryl-(Ci_4)-alkyl, heterocyclyl-(Ci_4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, or nitro, and preferably is C, O, N optionally substituted with O, OH, alkyl, alkenyl, alkynyl, or phosphate, optionally further substituted with alkyl or phosphate and more preferably is C, optionally substituted one or more times with H, O, OH, OCH3 or phosphate and
- wherein R2 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, any of which may or may not be branched or comprise substituents such as phosphate, heterocycloalkyl, cycloalkyl, cycloalkenyl, methyl, dimethyl, or may be further substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, sulfonyl, any of which may or may not be branched or comprise substituents such as hydrogen, alkyl, alkenyl, alkynyl, fluoride, phosphate, heterocycloalkyl, cycloalkyl, cycloalkenyl, dimethyl, phenyl and preferably is C substituted with C, O, P, H, OH, OSO2, phosphate, alkyl, alkenyl, alkynyl such as (CrCx), phenyl any of which may be substituted with methyl, dimethyl, sulfonyl, heterocycloalkyl, fluoride, phenyl, phosphate, and more preferably is C substituted with C, O, OSO2, alkyl such as (C3-Cn) any of which may be further substituted with methyl, dimethyl, alkyl such as (CrCx), phenyl, phosphate or further substituted by fluoride, phosphate, methyl, dimethyl and wherein x is an integer of from 1 to 15, and
- wherein R3 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(d-4)-alkyl, heteroaryl-(Ci-4)-alkyl, heterocyclyl-(d-4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(d-4)-alkyl, heteroaryl-(Ci-4)-alkyl, heterocyclyl-(Ci-4)- alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, or nitro, any of which may connect with R4 and preferably is C, O, N, OH, phosphate optionally substituted one or more times with alkyl, OH, phosphate any of which may connect with R4 and more preferably is O, OH, NH, optionally connecting with R4 thus forming a ring and
- wherein R4 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C1_4)-alkyl, heteroaryl-(Ci-4)-alkyl, heterocyclyl-(Ci-4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(d-4)-alkyl, heteroaryl-(d-4)-alkyl, heterocyclyl-(d-4)- alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, or nitro, any of which may connect with R3 and preferably is C, N, O, P, OH, lower substituted alkyl, alkenyl, alkynyl, phenyl, optionally substituted with OH, methyl, dimethyl any of which may connect with R3 and more preferably is C, optionally connecting with R3 and optionally substituted with methyl, dimethyl or methyn and
- wherein R5 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C1_4)-alkyl, heteroaryl-(Ci_4)-alkyl, heterocyclyl-(Ci_4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally bonding with R1 , optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci-4)-alkyl, heteroaryl-(Ci- 4)-alkyl, heterocyclyl-(Ci-4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, phosphate or nitro, and preferably is C, N, O, optionally substituted with C, O, CH20H, methyl, dimethyl, alkyl, alkenyl, alkynyl, phenyl, phosphate and more preferably is C, CO, optionally substituted with C, methyl, methyn (CH2), optionally substituted with CH20H.
Preferably, the present invention concerns the use of a cannabinoid or cannabimimetic compound such as a compound comprising the general formula (II) wherein R1 is C, O, N optionally substituted with O, OH, alkyl, alkenyl, alkynyl, or phosphate, optionally further substituted with alkyl or phosphate, when R2 is C substituted with C, O, P, H, OH, 0S02, phosphate, alkyl, alkenyl, alkynyl such as (C1 -CX), phenyl any of which may be substituted with methyl, dimethyl, sulfonyl, heterocycloalkyl, fluoride, phenyl or phosphate, when R3 is C, O, N, OH, phosphate optionally substituted one or more times with alkyl, OH, phosphate any of which may connect with R4 thus forming a ring, when R4 is C, N, O, P, OH, lower substituted alkyl, alkenyl, alkynyl, phenyl, optionally substituted one or more times with OH, methyl and/or dimethyl any of which may connect with R3, when R5 is C, N, O, optionally substituted with C, O, CH2OH, methyl, dimethyl, alkyl, alkenyl, alkynyl, phenyl or phosphate.
Most preferably, the present invention concerns the use of a cannabinoid or cannabimimetic compound such as a compound comprising the general formula (II) wherein R1 is C, optionally substituted with H, OH, OCH3 or phosphate when R2 is C substituted with C, O, OSO2, alkyl such as (C3-C8) any of which may be further substituted with methyl, dimethyl, alkyl such as (CrCx), phenyl, phosphate or further substituted by fluoride, phosphate, methyl, dimethyl when R3 is O, OH, NH, optionally connecting with R4, when R4 is C, optionally connecting with R3 and optionally substituted with methyl, dimethyl or methyn, when R5 is C, CO, optionally substituted with C, methyl, methyn (CH2), optionally substituted with CH20H and wherein x is an integer of from 1 to 15.
In relation to the classic and non-classic cannabinoids and cannabimimetic compounds illustrated here by the general formulas (I) and (II), the presence of a phenolic hydroxyl group seems to play an essential role for ensuring high affinity binding of the compounds to the cannabinoid receptors.
An additional element of importance for especially CB1 receptor recognition is the side chain of R2. It is preferably a lipophilic carbon chain comprising from 1 to 15 carbon atoms, preferably from 3 to 1 1 carbon atoms. It may have any number and type of substituents, especially methyl and/or dimethyl groups. The methyl groups are preferably close to the phenol group, as this appears to induce the greatest effect of the drug. Interestingly, it appears that shorter side chains increase the intensity and decrease the duration of the activity of these compounds.
The present invention concerns the use of a combination of compounds, wherein at least one compound is a cannabinoid or cannabimimetic compound such as an eicosanoids or other cannabinoid compound comprising the general formula (III):
R1 R2
- wherein R1 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(d-4)-alkyl, heteroaryl-(Ci-4)-alkyl, heterocyclyl-(d-4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(d-4)-alkyl, heteroaryl-(Ci-4)-alkyl, heterocyclyl-(Ci-4)- alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, or nitro, and preferably is (CI -Cx) is saturated or unsaturated and optionally is substituted one or more times with lower alkyl, alkenyl, alkynyl, O, OH, N and wherein x is an integer of from 1 to 30, more preferably is (C1 -CY), is saturated or unsaturated and optionally substituted with methyl, dimethyl, O, or N and wherein Y is an integer of from 15 to 21 and
- wherein R2 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C1_4)-alkyl, heteroaryl-(Ci_4)-alkyl, heterocyclyl-(Ci_4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, 0CH3, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(d-4)-alkyl, heteroaryl-(Ci-4)-alkyl, heterocyclyl-(Ci-4)- alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, or nitro, and preferably is C, N, O, NH2 optionally substituted one ore more times with lower alkyl, alkenyl, alkynyl, phenyl, OH, NH2 cycloalkane, methyl, 0CH3, and more preferably is N, O, NH2 optionally substituted with C, CH20H, CH(CH2)2, C2H4, C3H6, optionally further substituted one or more times with NH2, OH, CH20H, CH2CI, phenyl, CH3 and/or 0CH3.
Preferably, the present invention concerns the use of a cannabinoid or cannabimimetic compound such as a compound comprising the general formula (III) wherein R1 is (CI -Cx) saturated or unsaturated, and optionally is substituted one or more times with lower alkyl, alkenyl, alkynyl, O, OH, N, when R2 is C, N, O, NH2 optionally substituted one ore more times with lower alkyl, alkenyl, alkynyl, phenyl, OH, NH2 cycloalkane, methyl or 0CH3 and wherein x is an integer of from 1 to 30.
Most preferably, the present invention concerns the use of a cannabinoid or cannabimimetic compound such as a compound comprising the general formula wherein R1 is (CrCx), is saturated or unsaturated and optionally substituted with methyl, dimethyl, O, or N when R2 is N, O, NH2 optionally substituted with C, CH2OH, CH(CH2)2 (cyclopropane), optionally further substituted one or more times with CH2OH, CH2CI and wherein x is an integer of from 1 to 21.
The present invention concerns the use of a combination of compounds wherein at least one compound is a cannabinoid or cannabimimetic compound such as an aminoalkylindole or other cannabinoid compound comprising the general formula (IV):
Figure imgf000055_0001
- wherein R1 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(d-4)-alkyl, heteroaryl-(Ci-4)-alkyl, heterocyclyl-(Ci_4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci_4)-alkyl, heteroaryl-(Ci_4)-alkyl, heterocyclyl-(Ci_4)- alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, or nitro, and preferably is C, O , N optionally substituted with O, phosphate, N, C, lower alkyl, OH, optionally further substituted with lower alkyl, OH, phosphate and more preferably is C, substituted with O, further substituted with methyl and
- wherein R2 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(Ci-4)-alkyl, heteroaryl-(Ci-4)-alkyl, heterocyclyl-(Ci-4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(d-4)-alkyl, heteroaryl-(d-4)-alkyl, heterocyclyl-(d-4)- alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, or nitro, any of which may bond with R3, and preferably is C, N, O, optionally substituted with C, O, N, phosphate, lower alkyl optionally further substituted with lower alkyl, OH, phosphate, any of which may bond with R3 and more preferably is C, substituted with O, further substituted with C optionally bond forming with R3 and
- wherein R3 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(Ci_4)-alkyl, heteroaryl-(Ci-4)-alkyl, heterocyclyl-(Ci_4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci_4)-alkyl, heteroaryl-(Ci_4)-alkyl, heterocyclyl-(Ci_4)- alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, or nitro, any of which may bond R2 and preferably is C, N, O, alkyl, alkenyl, alkynyl, optionally substituted with C, N, O, OH, phosphate, halogen any of which may bond R2 and more preferably is (C1 -Cx) and wherein x is an integer of from 1 to 3, optionally substituted one or more times with O, dichloro- phenyl or morpholine and any of which may bond R2 and
- wherein R4 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C1_4)-alkyl, heteroaryl-(Ci_4)-alkyl, heterocyclyl-(Ci_4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(C1_4)-alkyl, heteroaryl-(Ci_4)-alkyl, heterocyclyl-(Ci_4)- alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, or nitro, and preferably is C, N, O optionally substituted with C, N, O, OH, lower alkyl, alkenyl, alkynyl, phosphate, optionally further substituted one or more times with O, OH, phenyl, diphenyl, morpholino, and halogen, and more preferably is C, optionally substituted with C, O and/or diphenyl, optionally further substituted with morpholine.
Preferably, the present invention concerns the use of a cannabinoid or cannabimimetic compound such as a compound comprising the general formula (IV) wherein R1 is C, O , N optionally substituted with O, phosphate, N, C, lower alkyl, OH, optionally further substituted with lower alkyl, OH or phosphate, when R2 is C, N, O, optionally substituted with C, O, N, phosphate, lower alkyl optionally further substituted with lower alkyl, OH, phosphate, any of which may bond with R3, when R3 is C, N, O, alkyl, alkenyl, alkynyl, optionally substituted with C, N, O, OH, phosphate, halogen any of which may bond R2, when R4 is C, N, O optionally substituted with C, N, O, OH, lower alkyl, alkenyl, alkynyl, phosphate, optionally further substituted one or more times with O, OH, phenyl, diphenyl, morpholino, and/or halogen.
Most preferably, the present invention concerns the use of a cannabinoid or cannabimimetic compound such as a compound comprising the general formula (IV) wherein, wherein R1 is C, substituted with O, further substituted with methyl when R2 is C, substituted with O, further substituted with C optionally bond forming with R3 when R3 is (CI -Cx) and wherein x is an integer of from 1 to 3, optionally substituted one or more times with O, dichloro-phenyl or morpholine when R4 is C, optionally substituted with C, O and/or diphenyl, optionally further substituted with morpholine.
Examples of cannabinoid or cannabimimetic compounds
Examples of cannabinoid or cannabimimetic compounds specially relevant for the present invention include, but are not limited to classic cannabinoids such as (names in parenthesis are alternative names): delta-9-THC (Tetrahydrocanna-binol), delta-8-THC, delta-8-THC phosphate, Cannabinol (CBN), Cannabidiol (CBD), Cannabidiol-type CBD, Cannabidivarin (CBDV), Cannabichromene-type CBG,
Cannabigerol-type CBG, Tetrahydrocanna-bivarin (THCV, THV), Tetrahydrocanna- binol- and cannabinol-type THC or CBN, Iso-Tetrahydro-cannabinol-type iso-THC, Cannabielsion-type CBE, Cannabicyclo l-type CBL, Cannabicitran-type CBT, HU- 308, JWH-133, JWH-139, JWH-051 , L-759633, L-759656, HU-210 ((-)-1 1 -OH-delta- 8-tetrahydrocannabinol-dimethylheptyl), HU-21 1 (Dexanabinol, 7-hydroxy-D6- tetrahydrocannabinol 1 ,1 -dimethylheptyl), Desacetyl-L-nandrolol, Nabilone and Levonantradol, non-classic cannabinoids such as: CP-55940, CP55244 and CP47497, aminoalkylindoles such as: R(+)WIN55212, S(-)WIN-55213, JWH-015 and L-768242, eicosanoids / endogenous cannabinoids such as: Anandamide (arachidonyl ethanolamine), 2-Arachidonyl-glycerol (2-AG, Noladin ether),
Palmitoylethanol-amine, Virodhamine (O-arachidonoyl-ethanolamine), Palmitoyl ethanolamide, Oleamide, other cannabinoid compounds such as: Arvanil, Metanandamide, ACEA, ACPA, BAY 38-7271 (also known as KN38-7271 ) and O- 1812. Phosphate derivatives of these compounds are especially relevant for the present invention.
Examples of especially relevant cannabinoid or cannabimimetic compounds are anandamide, delta-9-THC, delta-8-THC, cannabidiol, HU-210, BAY 38-7271 , WIN 55,212 and CP55940 and the phosphate derivatives of these.
Preferred cannabinoid and/or cannabimimetic compounds The compounds of the present invention may apart from inducing hypothermia, induce secondary effects or have other characteristics. These may be related to the cannabinoid nature of the compounds and may thus be more or less desirable. It is preferable that the compounds of the invention do not induce any adverse psychotropic effects. The compound may furthermore have analgesic, anticonvulsive, anti-inflammatory, anti-anxiety, anti-nausea, pulse-lowering and blood- pressure modifying effects. Of these, it is preferable that the compound has analgesic effects. Furthermore, a compound of the present invention may be hydrophilic or hydrophobic. To facilitate the administration of a compound according to the present invention it is preferable for a compound to be hydrophilic. A preferred compound is moreover metabolically stable.
A preferred cannabinoid or cannabimimetic compound of the present invention is a compound capable of binding a cannabinoid receptor, such as CB1 , thereby inducing hypothermia in an individual to a temperature in the range of 36 to 32 degree Celsius, and where said compound is hydrophilic. Antagonists to cannabinoid and cannabimimetic compound function It is an object of the present invention to provide compounds that are capable of obviating the effect of the compounds that induce hypothermia. These compounds are herein termed antagonists and exert their antagonistic effect by blocking the ability of any of the cannabinoids or cannabimimetic compounds herein described in binding to their receptors. The purpose of such an antagonist is to provide an additional safety mechanism whereby it is possible to stop the decline in core body temperature, stabilize the core body temperature and/or raise the core body temperature of an individual.
An embodiment of the present invention thus comprises the use of a compound according to any of the above for the preparation of a medicament for antagonizing the induction of hypothermia in an individual.
Examples of antagonists include but are not limited to: Rimonabant (SR141716), Acomplia, SR147778, SR141716A, SR144528, CP-272,871 , NIDA-41020, LY320135, AM251 , AM281 , AM630, WIN56098 and WIN54461.
Novel use of cannabinoids and cannabimimetic compounds Cannabinoids and cannabimimetic compounds have been used for a variety of purposes over time. It is an object of the present invention to provide a novel use of these compounds for the induction of hypothermia, especially for the preparation of a medicament comprising two or more compounds of the group consisting of vanilloid receptor agonists and/or cannabinoids or cannabimimetic compounds and/or adenosine receptor agonists and/or neurotensin receptor agonists and/or thyroxine derivatives and/or cytochrome c oxidase inhibitors and/or oxygen tension reducers, with the proviso that if the combination of compounds comprises two compounds said two compounds are not one cannabinoid or cannabimimetic compound and one vanilloid receptor agonist for the induction of hypothermia in an individual.
Vanilloid receptor agonists
Vanilloid receptor agonists are a group of chemicals which are capable of binding the Vanilloid Receptor 1 (VR1 ), also known as the Transient Receptor Potential Cation Channel, Subfamily V (TRPV1 ). The term vanilloid receptor agonist covers several groups of compounds including capsaicinoids and capsaicinoid-like compounds such as resiniferanoids and unsaturated dealdehydes. Before other types were discovered or synthesized, the term capsaicinoid referred to a group of secondary metabolites produced by plants belonging to the genus Capsicum, such as chili peppers. These compounds are the active components of chili peppers that produce the sensation of burning in the mouth, when ingested. Vanilloid receptor agonists may be divided into two classes based on origin and chemical composition:
• Classical vanilloid receptor agonists, a group which includes naturally occurring compounds of chili peppers and other vanillamide derivatives.
• Non-classical vanilloid receptor agonists, a group wherein the members generally do not comprise a vanillamide moiety.
Vanilloid receptor agonists are irritants for mammals, but have no effect on birds, indicating that the compounds may have evolved as a deterrent for herbivores. The various vanilloid receptor agonists have different pungencies as measured on the Scoville scale, with capsaicin and dihydrocapsaicin being the most potent of the classical vanilloid receptor agonists.
The use of capsaicin as a medicament is known both anecdotally and scientifically and is today widely used as a medicine to treat or relieve various ailments. The main clinical use of capsaicin is in the form of a topical ointment to successfully treat the pain of neuralgia such as caused by an infection with herpes zoster (shingles), diabetic neuropathy, rheumatism, fibromyalgia, various types of arthritis such as osteoarthritis or rheumatoid arthritis, and other forms of chronic pain. Capsaicin desensitizes nerves from pain by eliminating unneeded nerve cells through necrotic death and helps arthritis sufferers by lowering the levels of Decapeptide Substance P (DSP) in the synovial fluid of joints. Capsaicin breaks down DSP, which can destroy cartilage and also magnify the sensing of pain. Recently studies demonstrate that capsaicin is a potent anticancer agent. Capsaicin induces apoptosis in pancreatic and prostate cancer cells with no significant damage to the surrounding healthy cells. Capsaicin is known to affect NF-kB, and it is believed that it is through this protein, that capsaicin activates apoptotic proteins, leading to cell death. In another cancer-related application, capsaicin-containing candy provides significant pain relief of ulcers in the mouth which often develop in chemotherapy patients. Capsaicin pastes and balms are used to treat muscle and joint pains and medications containing vanilloid receptor agonists are used as an anti-inflammatory agent as the chemicals causes blood vessels to dilate. Capsaicin has furthermore been mentioned as a remedy to reduce serum cholesterol levels, relieve psoriasis and treat headaches, migraines and chronic sinus infections. Vanilloid receptor agonists have furthermore received interest as putatively neuroprotective substances. The neuroprotective effect is at least in part mediated by induction of hypothermia, as described in the below.
Any compound which can be defined as a vanilloid receptor agonist, capsaicinoid or capsaicinoid-like compound these being classical or non-classical vanilloid receptor agonist or compounds that otherwise bind vanilloid receptors falls within the scope of the present invention. The terms vanilloid receptor agonist, capsaicinoid or capsaicinoid-like are used interchangeably herein.
Receptors
The sensation of burning pain elicited by vanilloid receptor agonists occurs by the selective activation of sensory neurons that convey information about noxious stimuli to the central nervous system. The selectivity is based primarily on the presence of the VR1 / TRPV1 receptor, a nonselective cation channel to which the vanilloid receptor agonists, capsaicinoids and capsaicinoid-like compounds bind as agonists. TRPV1 is also activated by extracellular protons, and temperatures in the noxious range, suggesting that it functions as a transducer of painful thermal stimuli in vivo. By binding to the TRPV1 receptor, the vanilloid receptor agonists produce the same effect that excessive heat or abrasive damage would cause, explaining why the spiciness of capsaicin, without causing an actual chemical burn, is described as eliciting a burning sensation.
A number of different mechanisms have been proposed to account for the various effects of vanilloid receptor agonists. The vanilloid receptors, that are likely to be multimeric, non-selective cation channels composed of 6 transmembrane domains, will upon activation induce Ca2+ entry and subsequent release of sensory neuropeptides like calcitonin gene-related peptide (CGRP) and tachykinins (e.g. substance P) in addition to somatostatin. This in turn induces a range of actions that may vary depending on tissue types, and include vasodilatation, plasma protein extravasation and immune cell accumulation in the innervated area as well as systemic anti-inflammatory and analgesic actions. To date it is not known exactly which mechanisms are responsible for the hypothermic effect of vanilloid receptor agonists, but it is speculated that the abovementioned reactions may play a part in it.
The TRPV1 receptor was originally named the Vanilloid Receptor 1 (VR1 ), as a vanilloid moiety constitutes an essential component of classical vanilloid receptor agonists, but has since changed name to TRPV1 due to the receptors extended homology with other TRP family members. TRPV1 is a member of the subfamily of TRPV receptors, which includes TRPV1 -6. Several of these receptors render the cells expressing them sensitive to heat at different intervals, mechanic pressure and various compounds such as vanilloid receptor agonists, camphor and others. Combinations of the subtypes and various oligomers of the vanilloid receptors may account for the variations in physiological outcome observed following activation of receptors by different vanilloid receptor agonists. The oligomeric structure of the receptors increase the likelihood of discovering active substances with specificity for certain of the many organs that harbors vanilloid receptor agonists, thereby activating only parts of the vanilloid receptor system.
Vanilloid receptors are abundant in many organs of the body including neuronal tissues of the preoptic area, locus ceruleus, medial hypothalamus, reticular formation, and ventral thalamus. Vanilloid receptors have furthermore been found in non-neuronal "port of entry" tissues (e.g., skin, gut, airways, conjunctiva), the various cell types lining such tissues (i.e., keratin ocytes, epithelia, endothelia, etc.), and also in various peripheral non-neuronal tissues of rodents and humans (e.g., kidney, lung, testis, pancreas, spleen, liver, stomach, skin, vascular smooth muscle, placenta, cornea, uterus, and bladder). The hypothalamus, with its abundance of vanilloid receptors, is of particular interest to this invention: It is a likely component in vanilloid receptor mediated hypothermia as it contains the temperature regulating centres of the CNS.
Receptors other than TRPV1 have been implicated in causing hypothermia upon binding of agonists hereto. Although some data suggests that capsaicin causes hypothermia by a cannabinoid receptor (CB1 and CB2) independent mechanism, there are hypothermia inducing vanilloid receptor agonists that are capable of interacting both with TRPV1 and especially CB2. Apart from TRPV3 mentioned above as a modulator of TRPV1 activity, the prokineticin receptors 1 and 2 (PKR1 and PKR2) have been shown to interact with TRPV1 and modulate its activity. Receptors to which the vanilloid receptor agonists, capsaicinoids and capsaicinoid- like compounds of the present invention may bind, includes, apart from TRPV1 and the other TRPV subfamily members, TRPV2, -3, -4, -5 and -6, CB1 , CB2 and a third CB receptor, herein termed CB3, PKR1 and PKR2, GABA (gamma-aminobutyric acid) receptors, the NMDA (N-methyl-D-aspartate) receptor, the 5-HT(1A) receptor, also known as the serotonin receptor, the Delta opioid receptor (DOR). It is furthermore within the scope of the invention that at least one of compound of the combination of compounds of the invention may bind TRPV1 co-receptors. Compounds capable of binding any of the above-mentioned receptors thus fall within the scope of the present invention.
Preferably, at least one compound of the combination of compounds of the present invention binds TRPV1 and/or a TRPV1 associated receptor. The importance of the TRPV1 receptor for the induction of hypothermia in mammals is the dramatic hypothermic response that is elicited by systemic administration of capsaicin, a response which is absent in mice lacking the TRPV1 gene.
Structure
The vanilloid receptor agonists of this application are, largely based on their structure, categorized as follows: classic vanilloid receptor agonists and non-classic vanilloid receptor agonists. Compounds belonging to any of these categories fall within the scope of the present invention.
It is within the scope of the invention that the combinations of compounds of the invention are capable of inducing hypothermia in an individual.
It is furthermore within the scope of the invention that at least one compound of the combination of compounds of the invention is capable of binding the TRPV1 receptor and/or a receptor associated herewith. Accordingly, in the broadest aspect the present invention concerns the use of a combination of compounds, wherein at least one compound is a vanilloid receptor agonist comprising a structure of one of the general formulas of vanilloid receptor agonists illustrated in the below. In these illustrations R is a chemical bond or a chemical moiety as defined in the above. R may be any moiety substituted any amount of times according to the following non-limiting list, whereby R is: C, H, S, N, O, optionally substituted one or more times with C, H, S, N, O, B, P, OH, CHO, hydrogen, alkoxy, alkyl, alkenyl, alkynyl, phenyl, diphenyl, benzyl, amine (NH), halogen, substituted lower alkyl, alkenyl, aryl, heterocyclic group, heterocycloalkyl, heteroaryl, aryl-(Ci_4)-alkyl, heteroaryl-(Ci_4)-alkyl, heterocyclyl-(Ci_4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl or phosphate, optionally further substituted one or more times with C, S, N, O, P, OH, H, phenyl, amine (NH), halogen, alkoxy, substituted lower alkyl or alkyl, alkenyl or alkynyl such as (CrCv), acetyl, sulfonyl, phenyl, cycloalkyl, cycloalkenyl, heterocyclyl or heterocyclic group any of which may or may not be branched or be further substituted one or more times with C, O, P, methyl, dimethyl, alkyl or alkenyl such as (CrCv), alkoxy, phenyl, sulphate, phosphate, halogen or further substituted by fluoride, sulphate, phosphate, methyl, dimethyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci_4)-alkyl, heteroaryl-(Ci-4)-alkyl, heterocyclyl-(Ci-4)-alkyl, cycloalkylalkyl, dicycloalkyl, tricycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, nitro, halogen or alcohol, and further substituted at least once with O, OH, methyl, alkenyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, dimethyl or phenyl further substituted with alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl and wherein v is an integer of from 1 to 30, and of which any of the mentioned substituents capable thereof may form a ring with another R. R may furthermore be a chemical bond, or a pharmaceutically acceptable addition salt or hydrate of any of the above.
For each general formula, a more specific choice of substituent for a given R is listed along with along with a preferred and a more preferred list of substituent groups.
The present invention concerns the use of a combination of compounds wherein at least one compound is a vanilloid receptor agonist such as a classic or non-classic vanilloid receptor agonist comprising the general formula (I):
H
Figure imgf000064_0001
- wherein R1 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, any of which may or may not be branched or comprise substituents such as phosphate, cycloalkyl, heterocycloalkyl, cycloalkenyl, methyl, ethyl, dimethyl, or may be further substituted one or more times with C, S, N, O, P, OH, methoxy, ethoxy, acetyl, alkoxy, alkyl, alkenyl, alkynyl, sulfonyl or phenyl any of which may or may not be branched or comprise substituents such as hydrogen, methyl, ethyl, alkyl, alkenyl, alkynyl, alkoxy, phosphate, cycloalkyl, heterocycloalkyl, cycloalkenyl, dimethyl or phenyl and preferably is C substituted with C, O, P, H, OH, phosphate, alkyl, alkenyl, alkynyl any of which may be (CrCv), or phenyl, any of which may be substituted with O, OH, methyl, dimethyl, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, phenyl, methoxy, ethoxy, alkoxy or phosphate, any of which may be further substituted with methyl, ethyl or phenyl and more preferably is C substituted with alkyl, alkenyl, any of which may be (C4-Cw) any of which may be further substituted with O, OH, methoxy, ethoxy or methyl any of which may be further substituted with methyl, ethyl, or phenyl, wherein v is an integer of from 1 to 30 and w is an integer of from 5 to 18, and;
- wherein R2 is selected from the group of: C, S, N, O, optionally substituted one or more times with C, S, N, O, P, OH, hydrogen, alkoxy, alkyl, alkenyl, alkynyl, phenyl, diphenyl, benzyl, amine (NH), halogen, substituted lower alkyl, alkenyl, aryl, heterocycloalkyl, heteroaryl, aryl-(d-4)-alkyl, heteroaryl-(d-4)-alkyl, heterocyclyl-(Ci- 4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl or phosphate, optionally further substituted one or more times with C, S, N, O, P, OH, H, COOH, phenyl, amine (NH), halogen, alkoxy, substituted lower alkyl, alkyl or alkenyl such as (CrCv), cycloalkenyl, sulphate, phosphate, aryl, heterocyclyl, heteroaryl, aryl-(C1_4)-alkyl, heteroaryl-(Ci-4)-alkyl, heterocyclyl-(Ci_4)-alkyl, cycloalkylalkyl, dicycloalkyl, tricycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, cyano, amino, nitro, or alcohol, any of which may be further substituted one or more times with OH, methyl, dimethyl, alkyl or alkenyl such as (CrCv), alkoxy, phenyl, sulphate, phosphate, aryl, heteroaryl, carboxy, amino, nitro, alcohol or halogen and preferably is C, substituted one or more times with C, N, O, P, OH, hydrogen, alkoxy, alkyl, alkenyl, amine (NH), halogen, substituted lower alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl or phosphate, optionally further substituted one or more times with C, N, O, OH, COOH, hydrogen, amine (NH), halogen, alkoxy, substituted lower alkyl or alkenyl such as (CrCx), phosphate, cycloalkenyl, alkoxy, carboxy or halogen, any of which may be further substituted one or more times with OH, methyl, dimethyl, alkyl or alkenyl such as (CrCx), alkoxy, phenyl, sulphate, phosphate, carboxy or halogen and more preferably is C substituted with either: cycloalkenyl further substituted at least twice with any of OH or methoxy, or: lower alkyl such as (CrC2) at least once and further substituted one or more times with OH, COOH, Chloride, methyl or cycloalkenyl, optionally further substituted one or more times with OH or methoxy and wherein v is an integer of from 1 to 30 and x is an integer of from 1 to 5.
Preferably, the present invention concerns the use of a combination of compounds wherein at least one compound is a vanilloid receptor agonist comprising the general formula (I) wherein R1 is C substituted with C, O, P, H, OH, phosphate, alkyl, alkenyl, alkynyl any of which may be (CrCv), or phenyl, any of which may be further substituted one or more times with O, OH, methyl, dimethyl, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, acetyl, phenyl, methoxy, ethoxy, alkoxy or phosphate, any of which may be further substituted with methyl, ethyl or phenyl and R2 is C, substituted one or more times with C, N, O, P, OH, hydrogen, alkoxy, alkyl, alkenyl, amine (NH), halogen, substituted lower alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl or phosphate, optionally further substituted one or more times with C, N, O, OH, COOH, hydrogen, amine (NH), halogen, alkoxy, substituted lower alkyl or alkenyl such as (CrCx), phosphate, cycloalkenyl, alkoxy, carboxy or halogen, any of which may be further substituted one or more times with OH, methyl, dimethyl, alkyl or alkenyl such as (CrCx), alkoxy, phenyl, sulphate, phosphate, carboxy or halogen and wherein v is an integer of from 1 to 30 wherein x is an integer of from 1 to 5.
Most preferably, the present invention concerns the use of a combination of compounds wherein at least one compound is a vanilloid receptor agonist comprising the general formula (I) wherein R1 is C substituted with alkyl, alkenyl, any of which may be (C4-Cw) any of which may be further substituted one or more times with O, OH, acetyl, methoxy, ethoxy or methyl any of which may be further substituted one or more times with methyl, ethyl, cycloalkenyl or phenyl and w is an integer of from 5 to 18, and R2 is C substituted with either: cycloalkenyl further substituted at least twice with any of OH or methoxy, or: lower alkyl such as (CrC2) at least once and further substituted one or more times with OH, COOH, Chloride, methyl or cycloalkenyl, optionally further substituted one or more times with OH or methoxy.
The present invention furthermore concerns the use of a combination of compounds wherein at least one compound is a vanilloid receptor agonist such as a non-classic vanilloid receptor agonist comprising the general formula (II):
R4 R6
R3 R1
^ R2 ^
- wherein R1 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, B, P, OH, hydrogen, alkyl, alkenyl, alkynyl, any of which may or may not be branched or comprise substituents such as phosphate, cycloalkyl, heterocyclyl, heterocyclic group, cycloalkenyl, methyl, ethyl, dimethyl, or may be further substituted one or more times with C, S, N, O, P, OH, methoxy, ethoxy, acetyl, alkoxy, alkyl, alkenyl, alkynyl, sulfonyl or phenyl cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclic group any of which may or may not be branched or comprise substituents such as C, O, H, OH, methyl, ethyl, alkyl, alkenyl, alkynyl, alkoxy, phosphate, further substituted at least once with O, OH, methyl, alkenyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, dimethyl or phenyl further substituted with alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl and preferably is C substituted with C, N, O, B, P, OH, hydrogen, alkyl, alkenyl, alkynyl, any of which may or may not be branched or comprise substituents such as phosphate, cycloalkyl, heterocyclyl, heterocyclic group, cycloalkenyl, methyl, ethyl, dimethyl, or may be further substituted one or more times with C, N, O, P, OH, methoxy, ethoxy, acetyl, alkoxy, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclic group any of which may or may not be branched or comprise substituents such as C, O, H, OH, methyl, ethyl, alkyl, alkenyl, alkoxy, phosphate, further substituted at least once with O, OH, methyl, alkenyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, further substituted with alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl and more preferably is C substituted with alkyl or alkenyl which may be (C4-Cw), B, or heterocyclyl forming a ring with R6 thus comprising a pyrrolidine further substituted one or more times with O, methyl, alicyclic groups attached to one another, these being saturated or unsaturated or a heterocyclic group comprising said B, N and O, and being further substituted at least once with O, methyl or C further substituted at least once with cycloalkenyl, cycloalkyl, heterocyclyl further substituted at least once with O, OH, methyl, alkenyl, further substituted with lower alkyl and cycloalkenyl; wherein any of the above may form at least one bond with any of R2, R3, R4, R5 and/or R6, and w is an integer of from 5 to 18, and;
- wherein R2 is selected from the group of C, S, N, O, optionally substituted at least once with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, any of which may or may not be branched or comprise substituents such as phosphate, cycloalkyl, heterocycloalkyl, cycloalkenyl, methyl, ethyl, dimethyl, or may be further substituted one or more times with C, N, O, P, OH, methoxy, ethoxy, acetyl, alkoxy, alkyl, alkenyl, alkynyl, or phenyl any of which may or may not be branched or comprise substituents such as hydrogen, methyl, ethyl, alkyl, alkenyl, alkynyl, alkoxy, phosphate, cycloalkyl, heterocycloalkyl, cycloalkenyl, dimethyl or phenyl and preferably is C substituted with C, O, P, H, OH, phosphate, alkyl, alkenyl, alkynyl any of which may be (CrCv), or phenyl, any of which may be substituted with O, OH, methyl, dimethyl, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, phenyl, methoxy, ethoxy, alkoxy or phosphate, and more preferably is C substituted at least once with OH or hydrogen, and wherein any of the above may form at least one bond with any of R1 , and/or R3, and wherein v is an integer of from 1 to 30; and
- wherein R3 is selected from the group of C, S, N, O, optionally substituted with C, S, N, O, B, P, OH, hydrogen, methoxy, ethoxy, acetyl, alkoxy, alkyl, alkenyl, alkynyl, any of which may or may not be branched or comprise substituents such as phosphate, cycloalkyl, heterocycloalkyl, cycloalkenyl, methyl, ethyl, dimethyl, or may be further substituted one or more times with C, S, N, O, P, OH, methoxy, ethoxy, acetyl, alkoxy, alkyl, alkenyl, alkynyl, or phenyl any of which may or may not be branched or comprise substituents such as hydrogen, methyl, ethyl, alkyl, alkenyl, alkynyl, alkoxy, phosphate, cycloalkyl, heterocycloalkyl, cycloalkenyl, dimethyl or phenyl and preferably is C substituted with C, O, P, H, OH, phosphate, acetyl, alkoxy, alkyl, alkenyl, any of which may be (CrCv), or phenyl, optionally substituted with O, OH, methyl, dimethyl, alkyl, alkenyl, phenyl, methoxy, ethoxy, alkoxy or phosphate, and more preferably is C substituted with OH, methoxy, lower alkyl (C1 - CY) and may at any point form a ring with R4, and wherein any of the above may form at least one bond with any of R2, and/or R4, and wherein v is an integer of from 1 to 30, and γ is an integer of 2 or 3; and
- wherein R4 is selected from the group of C, S, N, O, optionally substituted with C, S, N, O, B, P, OH, hydrogen, methoxy, ethoxy, acetyl, alkoxy, alkyl, alkenyl, alkynyl, any of which may or may not be branched or comprise substituents such as phosphate, cycloalkyl, heterocycloalkyl, cycloalkenyl, methyl, ethyl, dimethyl, or may be further substituted one or more times with C, S, N, O, P, OH, methoxy, ethoxy, acetyl, alkoxy, alkyl, alkenyl, alkynyl, or phenyl any of which may or may not be branched or comprise substituents such as hydrogen, methyl, ethyl, alkyl, alkenyl, alkynyl, alkoxy, phosphate, cycloalkyl, heterocycloalkyl, cycloalkenyl, dimethyl or phenyl and preferably is C substituted with C, O, P, H, OH, phosphate, acetyl, alkoxy, alkyl, alkenyl, any of which may be (CrCv), or phenyl, optionally substituted with O, OH, methyl, dimethyl, alkyl, alkenyl, phenyl, methoxy, ethoxy, alkoxy or phosphate, and more preferably is C substituted with OH, methoxy, lower alkyl (C1 - CY) and may at any point form a ring with R4, and wherein any of the above may form at least one bond with any of R2, and/or R4, and wherein x is an integer of from 1 to 30; and γ is an integer of 2 or 3; and
- wherein R5 is selected from the group of C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, any of which may or may not be branched or comprise substituents such as phosphate, cycloalkyl, heterocycloalkyl, cycloalkenyl, methyl, ethyl, dimethyl, or may be further substituted one or more times with C, S, N, O, P, OH, CHO, hydrogen, methoxy, ethoxy, acetyl, alkoxy, alkyl, alkenyl, alkynyl, sulfonyl or phenyl any of which may or may not be branched or comprise substituents such as hydrogen, methyl, ethyl, alkyl, alkenyl, alkynyl, alkoxy, phosphate, cycloalkyl, heterocycloalkyl, cycloalkenyl, dimethyl or phenyl and preferably is C substituted at least once with C, O, P, H, OH, CHO, phosphate, alkyl, alkenyl, any of which may be (CrCv), or phenyl, any of which may be substituted with O, OH, methyl, dimethyl, alkyl, alkenyl, methoxy, ethoxy, alkoxy or phosphate, and more preferably is C substituted one or more times with hydrogen, OH, CHO or methyl which may form a ring with R6 wherein v is an integer of from 1 to 30, and;
- wherein R6 is selected from the group of C, S, N, O, optionally substituted with C, S, N, O, B, P, OH, CHO, hydrogen, alkyl, alkenyl, alkynyl, any of which may or may not be branched or comprise substituents such as phosphate, cycloalkyl, heterocycloalkyl, cycloalkenyl, methyl, ethyl, dimethyl, or may be further substituted one or more times with C, N, O, P, OH, methoxy, ethoxy, acetyl, alkoxy, alkyl, alkenyl, alkynyl, or phenyl any of which may or may not be branched or comprise substituents such as hydrogen, methyl, ethyl, alkyl, alkenyl, alkynyl, alkoxy, phosphate, dimethyl or phenyl and preferably is C substituted with C, O, P, H, OH, CHO, phosphate, alkyl, alkenyl, any of which may be (d-Cv), or phenyl, any of which may be substituted with O, OH, methyl, dimethyl, alkyl, alkenyl, methoxy, ethoxy, alkoxy or phosphate, and more preferably is C substituted one or more times with hydrogen, CHO, lower alkyl (C1 -Cγ) or methyl, which may form at least one bond with R5, or be at least one bond forming a ring with R1 , wherein the at least one bond between any of R1 , R2, R3, R4 and/or R5 may be single or double bonds and wherein v is an integer of from 1 to 30; and γ is an integer of 2 or 3.
Preferably, the present invention concerns the use of a combination of compounds wherein at least one compound is a vanilloid receptor agonist comprising the general formula (I) wherein R1 is C substituted with C, N, O, B, P, OH, hydrogen, alkyl, alkenyl, alkynyl, any of which may or may not be branched or comprise substituents such as phosphate, cycloalkyl, heterocyclyl, heterocyclic group, cycloalkenyl, methyl, ethyl, dimethyl, or may be further substituted one or more times with C, N, O, P, OH, methoxy, ethoxy, acetyl, alkoxy, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclic group any of which may or may not be branched or comprise substituents such as C, O, H, OH, methyl, ethyl, alkyl, alkenyl, alkoxy, phosphate, further substituted at least once with O, OH, methyl, alkenyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, further substituted with alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl any of the above of which may form bonds with R2, and/or R6, and R2 preferably is C substituted with C, O, P, H, OH, phosphate, alkyl, alkenyl, alkynyl any of which may be (CrCv), or phenyl, any of which may be substituted with O, OH, methyl, dimethyl, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, phenyl, methoxy, ethoxy, alkoxy or phosphate, and R3 preferably is C substituted with C, O, P, H, OH, phosphate, acetyl, alkoxy, alkyl, alkenyl, any of which may be (CrCv), or phenyl, any of which may be substituted with O, OH, methyl, dimethyl, alkyl, alkenyl, phenyl, methoxy, ethoxy, alkoxy or phosphate, and R4 preferably is C substituted with C, O, P, H, OH, phosphate, acetyl, alkoxy, alkyl, alkenyl, any of which may be (d-Cv), or phenyl, optionally substituted with O, OH, methyl, dimethyl, alkyl, alkenyl, phenyl, methoxy, ethoxy, alkoxy or phosphate, and R5 preferably is C substituted at least once with C, O, P, H, OH, CHO, phosphate, alkyl, alkenyl, any of which may be (d-Cv), or phenyl, any of which may be substituted with O, OH, methyl, dimethyl, alkyl, alkenyl, methoxy, ethoxy, alkoxy or phosphate, and R6 preferably is C substituted with C, O, P, H, OH, CHO, phosphate, alkyl, alkenyl, any of which may be (CrCv), or phenyl, any of which may be substituted with O, OH, methyl, dimethyl, alkyl, alkenyl, methoxy, ethoxy, alkoxy or phosphate, and wherein v is an integer of from 1 to 30.
Most preferably, the present invention concerns the use of a combination of compounds wherein at least one compound is a vanilloid receptor agonist comprising the general formula (I) wherein R1 is C substituted with alkyl or alkenyl which may be (C4-Cz), Boron, or heterocyclic group forming a ring with R6 thus comprising a pyrrolidine further substituted one or more times with O, methyl, alicyclic groups attached to one another, these being saturated or unsaturated or a heterocyclic group comprising said Boron, N and O, and being further substituted at least once with O, methyl or C further substituted at least once with cycloalkenyl, cycloalkyl, heterocyclyl further substituted at least once with O, OH, methyl, alkenyl, further substituted with lower alkyl and cycloalkenyl; R2 is C substituted with OH or hydrogen; R3 is C substituted with OH, methoxy, lower alkyl (C1 - Cz) and may at any point form a ring with R4; R4 is C substituted with OH, methoxy, lower alkyl (C1 - Cz) and may at any point form a ring with R3; R5 is C substituted one or more times with hydrogen, OH, CHO or methyl which may form a ring with R6; and R6 is C substituted one or more times with hydrogen, CHO, lower alkyl (C1 -Cz) or methyl, which may form at least one bond with R5, or be forming a ring with R1 , wherein the at least one bond between any of R1 , R2, R3, R4, R5 and/or R6 may be single or double bonds and γ is an integer of either 2 or 3, and z is an integer of either 5 or 12.
Certain molecular modifications are preferable especially regarding the classical vanilloid receptor agonist compounds, as they seem to ensure a more favorable degree of vanilloid receptor activation. These modifications include an unbranched alkyl side chain of a certain minimum length, as shorter chain analogues decrease in potency and thus are not capable of inducing hypothermia to a satisfactory degree. It is therefore preferable that the compounds of the present invention have relatively long alkyl or alkenyl chains (counted from R1 in the above formula) such as chains longer than 6 carbon atoms. Preferably the length of the alkyl / alkenyl chain is between 6 and 25 carbon atoms, most preferably between 7 and 18 carbon atoms, even more preferably between 8 and 9 carbon atoms.
In contrast hereto, substitution in the aromatic ring seems to abolish activity altogether and modification of many of the TRPV1 capsaicinoid and capsaicinoid- like agonists by halogenation of the aromatic ring tends to yield potent antagonists.
Examples of vanilloid receptor agonists Examples of vanilloid receptor agonists specially relevant for the present invention include, but are not limited to classic vanilloid receptor agonists such as (names in parenthesis are alternative names): Capsaicin (C; 8-methyl-N-vallilyl-6- nonenamide), Dihydrocapsaicin (DHC), Nordihydro-capsaicin (NDHC), Homodihydro-capsaicin (HDHC), Homocapsaicin (HC), Olvanil (N-9-Z- octadecenoyl-vanillamide), Rinvanil (vanillamide of ricinoleic acid), Arvanil (N- vanillylarachidonamide), PhAR (phenylacetylrinvanil), Nuvanil, Farvanil (vanillamide of farnesic acid), Ac-Rinvanil, Retvanil (vanillamide of retinoic acid), Nonivamide, and Ervanil (vanillamide of erucic acid).
Examples of non-classical vanilloid receptor agonist compounds specially relevant for the present invention include, but are not limited to compounds such as (names in parenthesis are alternative names): Resiniferatoxin (RTX), Anandamide (arachidonyl ethanolamine), N-arachidonoyldopamine (NADA), N-arachidonoyl-L- serine (ARA-S), Arachidonyl-2-chloroethylamide, 2-aminoethoxydiphenyl borate (2- APB), Evodiamine, Propofol, Isovelleral, Scutigeral, 12-hydroperoxyeicosatetraenoic acid, Alpha-sanshool, Beta-sanshool, Gamma-sanshool, Delta-sanshool, Alpha- hydroxy-sanshool, Beta-hydroxy-sanshool, Piperine, Zingerone, and Bv8.
Preferred vanilloid receptor agonist compounds The vanilloid receptor agonists of the present invention may apart from inducing hypothermia induce secondary effects or have other characteristics. These may be related to the capsaicinoid nature of the compounds and may thus be more or less desirable. It is preferable that the compounds of the invention do not induce any blood-pressure modifying effects or induce hyperalgesic, nocifensive, plasma extravasation, peripheral vasodilatation, bronchoconstriction, bradycardia, or apnea effects among others. A potential analgetic effect may not be considered an adverse effect and may even, depending on the application of this invention, be desirable. Furthermore, a compound of the present invention may be hydrophilic or hydrophobic. To facilitate the administration of a compound according to the present invention it is preferable for a compound to be hydrophilic. A preferred compound is moreover metabolically stable.
A preferred vanilloid receptor agonist of the present invention is a compound capable of binding the TRPV1 receptor, thereby inducing hypothermia in an individual to a temperature in the range of 36 to 32 degree Celsius, and where said compound is hydrophilic.
Examples of preferred or especially relevant vanilloid receptor agonists include: Capsaicin and compounds closely related to capsaicin such as: Dihydrocapsaicin (DHC), Nordihydro-capsaicin (NDHC), Homodihydro-capsaicin (HDHC), and
Homocapsaicin; other especially relevant compounds include resiniferatoxin and compounds closely related hereto.
Antagonists of vanilloid receptor agonist function It is an object of the present invention to provide compounds that are capable of obviating the effect of the vanilloid receptor agonists that induce hypothermia. These compounds are herein termed antagonists and exert their antagonistic effect by blocking the ability of any of the vanilloid receptor agonists, capsaicinoids or capsaicinoid-like compounds herein described in binding to their receptors. The purpose of such an antagonist is to provide an additional safety mechanism whereby it is possible to stop the decline in core body temperature, stabilize the core body temperature and/or raise the core body temperature of an individual.
An embodiment of the present invention thus comprises the use of a compound according to any of the above for the preparation of a medicament for antagonizing the induction of hypothermia in an individual.
Examples of antagonists include but are not limited to: 5-iodoresiniferatoxin, Aminoquinazoline (Aminoquinazoline 70), 6-iodo-nordihydrocapsaicin, IBTU (N-(4- cholorobenzyl)-N'-(4-hydroxy-3-iodo-5-methoxybenzyl)thiourea), KJM429 and JYL1421 , A-425619, AMG9810, SB 366791 , Adenosine and Capsazepine.
Novel use of compounds Vanilloid receptor agonists, capsaicinoids and capsaicinoid-like compounds have been used for a variety of purposes over time. It is an object of the present invention to provide a novel use of these compounds for the induction of hypothermia, especially for the preparation of a medicament comprising two or more compounds of the group consisting of vanilloid receptor agonists and/or cannabinoids or cannabimimetic compounds and/or adenosine receptor agonists and/or neurotensin receptor agonists and/or thyroxine derivatives and/or cytochrome c oxidase inhibitors and/or oxygen tension reducers, with the proviso that if the combination of compounds comprises two compounds said two compounds are not one cannabinoid or cannabimimetic compound and one vanilloid receptor agonist for the induction of hypothermia in an individual.
Adenosine
Adenosine is present in all body fluids and acts on four well-defined G protein- coupled receptors.
Adenosine receptors
These receptors are denoted adenosine receptors, but may also be called P1 receptors to distinguish them from the receptors for nucleotides, which belong either to the family of transmitter-gated ion channels (P2X receptors) or the family of G protein-coupled receptors (P2Y receptors). The adenosine receptors are a class of G-protein coupled receptors with adenosine as endogenous ligand. In humans, there are four adenosine receptors (A1 , A2A, A2B, A3), each encoded by a separate gene (ADORA1 , ADORA2A, ADORA2B, and ADORA3).
The adenosine A1 receptor has been found to be ubiquitous throughout the entire body. This receptor has an inhibitory function on most of the tissues in which it rests. In the brain, it slows metabolic activity by a combination of actions. Presynaptically, it reduces vesicle release while postsynaptically it has been found to stabilize the magnesium on the NMDA receptor. The A1 and A2A receptors of endogenous adenosine are both believed to play a role in regulating myocardial oxygen consumption and coronary blood flow. Stimulation of the A1 receptor has a myocardial depressant effect by decreasing the conduction of electrical impulses and suppressing pacemaker cell function, resulting in a decrease in heart rate. This makes adenosine a useful medication for treating and diagnosing tachyarrhythmias, or excessively fast heart rates. This effect on the A1 receptor also explains why there is a brief moment of cardiac standstill when adenosine is administered as a rapid IV push during cardiac resuscitation. The rapid infusion causes a momentary myocardial stunning effect.
In comparison, the A2A receptor is responsible for regulating myocardial blood flow by vasodilating the coronary arteries, which increases blood flow to the myocardium, but may lead to hypotension. In normal physiological states, both of these receptors serve as protective mechanisms. However, in altered cardiac function, such as hypoperfusion caused by hypotension, heart attack or cardiac arrest caused by nonperfusing bradycardias, adenosine has a negative effect on physiological functioning by preventing necessary compensatory increases in heart rate and blood pressure that attempt to maintain cerebral perfusion.
Recent research on adenosine receptor function and adenosine receptor antagonists such as theophylline has led to several randomized controlled trials using these receptor antagonists to treat bradyasystolic arrest.
Specific antagonists include KW6002 and SCH-58261 , while specific agonists include CGS21680 and ATL-146e.
The integral A2B receptor membrane protein stimulates adenylate cyclase activity in the presence of adenosine. This protein also interacts with netrin-1 , which is involved in axon elongation.
The A3 adenosine receptor has been shown to inhibit some specific signal pathways of adenosine. It inhibits growth in human melanoma cells. Specific antagonists include MRS1 191 , MRS1523 and MRE3008F20, while specific agonists include Cl- IB-MECA and MRS3558. Examples of adenosine receptor agonists
In addition to the vanilloid and cannabinoid compounds mentioned above, further compounds to be included in the combination of compounds according to the present invention are selected from adenosine or adenosine analogs, adenosine receptor agonists or an adenosine uptake inhibitors, ie. in one embodiment, the invention relates to administration of at least one compound capable of increasing the amount of adenosine in the individual being treated.
Adenosine analogs include 5'-AMP, ATP, ADP, adenine nucleotides, as well as other substituted adenosine compounds, insofar the substituted adenosine compounds are capable of being an adenosine receptor agonist.
An adenosine receptor agonist is any compound capable of having an agonizing effect on the adenosine receptor. One example of an adenosine receptor agonist is 5'-(N-ethyl-carboxamido)-adenosine (NECA).
Further combination of compounds of the present invention include but is not limited to one or more of the following compounds :5'-AMP, (R)-PIA, (S)-PIA, AB-NECA, CCPA, CGS 21680, CGS 21680, CGS 24012, 2-chloroadenosine, 2-hexynyl-NECA, IB-MECA, N(6)-cyclopentyladenosine, (R,S)-PHPNECA, IAB-MECA, IB-MECA, Cl- IB-MECA, cyclopentyladenosine, I-ABA, IAB-MECA, MCP-NECA, MPC-MECA, PENECA, AB-MECA, APNEA, CV-1674, CV-1808, cyclopentyladenosine, 2- hexynyl-NECA, metrifudil, N(6)-cyclohexyladenosine, LUF5831 and Tecadenoson (CV-510).
Thus, it is an embodiment of the present invention to administer 5'-AMP in combination with other compounds of the present invention.
In another embodiment of the present invention the adenosine receptor agonist is selected from the group consisting of NECA, (R)-PIA, (S)-PIA, AB-NECA, CCPA, CGS 21680, CGS 21680, CGS 24012, 2-chloroadenosine, 2-hexynyl-NECA, IB- MECA, N(6)-cyclopentyladenosine, (R,S)-PHPNECA, IAB-MECA, IB-MECA, CI-IB- MECA, cyclopentyladenosine, I-ABA, IAB-MECA, MCP-NECA, MPC-MECA, PENECA, AB-MECA, APNEA, CV-1674, CV-1808, cyclopentyladenosine, 2- hexynyl-NECA, metrifudil, N(6)-cyclohexyladenosine, LUF5831 and Tecadenoson (CV-510).
In one embodiment the combination of compounds of the present invention comprises the adenosine uptake inhibitor dipyridamole or theofyllin.
Novel use of compounds
Adenosine receptor agonists such as adenosine analogs 5'-AMP, ATP, ADP, adenine nucleotides, as well as other substituted adenosine compounds, have been used for a variety of purposes over time. It is an object of the present invention to provide a novel use of these compounds for the induction of hypothermia, especially for the preparation of a medicament comprising two or more compounds of the group consisting of vanilloid receptor agonists and/or cannabinoids or cannabimimetic compounds and/or adenosine receptor agonists and/or neurotensin receptor agonists and/or thyroxine derivatives and/or cytochrome c oxidase inhibitors and/or oxygen tension reducers, with the proviso that if the combination of compounds comprises two compounds said two compounds are not one cannabinoid or cannabimimetic compound and one vanilloid receptor agonist for the induction of hypothermia in an individual.
Neurotensin
The tridecapeptide neurotensin (NT) mediates its central and peripheral effects through interaction with three identified receptor subtypes, referred to as NTS1 , NTS2 and NTS3 (Sortilin 1 ). NTS1 and NTS2 belong to the 7 transmembrane domain/GPCR family, whereas Sortilin 1 is a single transmembrane domain receptor. The present invention relates to the effect of the NT ligand and analogues thereof through the two GPCRs NTS1 and NTS2.
Neurotensin, first isolated from bovine hypothalami by Carraway and Leeman in 1973, was also found in the intestine. Classically, NT was synthesised from a precursor that contains another peptide, Neuromedin N, closely related to NT in terms of sequence and activity. Cerebral administration of isolated NT modulates dopaminergic transmission and leads to hypothermic (WO 04/049901 ) and naloxone-independent analgesic responses. In the periphery, NT induces hypotension, decreases gastric acid secretion, and activates lipid digestion. However, administration of the combination of compounds of the present invention, including NT, leads to a surprisingly improved effect of neuroprotection in connection with ischemia.
Neurotensin receptors
The existence of two distinct receptor sites for NT has been evidenced by ligand binding studies on rat brain synaptic membranes: a high affinity NT binding site later cloned as the NTS1 receptor, and a lower affinity NT binding site (sensitive to the H1 anti-histamine levocabastine); the NTS2 receptor.
Activation of NTS1 is probably responsible for the observed effects of NT on cancer cell proliferation and food intake. However, the most convincing implication of NTS1 is related to the NT-dopamine interactions in the brain. Indeed, NT modulates dopamine transmisssion in the nigro-striatal and mesocorticolimbic pathways through NTS1.
NTS2 has been described to be responsible for the analgesic response of centrally administered NT. This observation is enhanced by the cerebral localisation of both its messenger RNA and its protein in structures implicated in the descending control of nociceptive imputs, especially in the periaqueductal gray and dorsal raphe. However, the expression of NTS2 immunoreactivity in areas devoid of neurotensinergic inputs indicates that NT might not be the exclusive endogenous ligand for NTS2.
Novel use of compounds
Neurotensin receptor agonists and analogues of neurotensin have been used for a variety of purposes over time. It is an object of the present invention to provide a novel use of these compounds for the preparation of a medicament comprising neurotensin or neurotensin analogs in combination with vanilloid receptor agonists and/or cannabinoids or cannabimimetic compounds and/or adenosine receptor agonists and/or thyroxine derivatives and/or cytochrome c oxidase inhibitors and/or oxygen tension reducers for the induction of hypothermia, especially for the preparation of a medicament comprising two or more compounds of the group consisting of vanilloid receptor agonists and/or cannabinoids or cannabimimetic compounds and/or adenosine receptor agonists and/or neurotensin receptor agonists and/or thyroxine derivatives and/or cytochrome c oxidase inhibitors and/or oxygen tension reducers, with the proviso that if the combination of compounds comprises two compounds said two compounds are not one cannabinoid or cannabimimetic compound and one vanilloid receptor agonist for the induction of hypothermia in an individual.
Thus, in an aspect one of the two or more compounds according to the present invention are selected from the group consisting of NT64D, NT64L, NT65L, NT66D, NT66L, NT67L, NT69L, NT71 , NT72, NT73, NT74, NT75, NT76, NT77, Trp1 1 NT, contulakin-G, EISAI- 1 , EISAI-2, JMV2004, JMV2012, JMV431 , JMV449, JMV457, JMV458, large neuromedin, large neurotensin, neuromedin, neurotensin, [125l]neurotensin, Thr10contulakin-G, D-Trp1 1 -neurotensin, levocabastine, SR48692, xenin, PD-149163 and CGX-1 160.
Some abbereviations are listed herein: NT64D (L-Arg L-Arg L-Pro D-neo-Trp L-IIe L- Leu), NT64L (L-Arg L-Arg L-Pro L-neo-Trp L-IIe L-Leu), NT65L (L-Arg L-Arg L-Pro L- neo-Trp tert-Leu L-Leu), NT66D (D-Lys L-Arg L-Pro D-neo-Trp ert-Leu L-Leu), NT66L (D-Lys L-Arg L-Pro L-neo-Trp tert-Leu L-Leu), NT67L (D-Lys L-Arg L-Pro L- neo-Trp L-IIe L-Leu), NT69L (N-methyl- L-Lys L-Pro L-neo-Trp tert-Leu L-Leu), NT71 (N-methyl- DAB.sup.$ L-Pro L-neo-Trp tert-Leu L-Leu), NT72 (D-Lys L-Pro L- neo-Trp tert-Leu L-Leu), NT73 (D-Lys L-Pro L-neo-Trp L-IIe L-Leu), NT74 (DAB L- Pro L-neo-Trp tert-Leu L-Leu), NT75 (DAB L-Pro L-neo-Trp L-IIe L-Leu), NT76 (L- Arg D-Orn L-Pro L-neo-Trp L-IIe L-Leu), NT77 (L-Arg D-Orn L-Pro L-neo-Trp tert- Leu L-Leu), Trp1 1 NT, EISAI-1 , EISAI-2, JMV2004, JMV2012, JMV431 , JMV449 (H- Lys-psi(CH2NH)Lys-Pro-Tyr-lle-Leu-OH), JMV457, JMV458, SR48692, PD-149163, CGX-1 160, KK13, KK14, PD-149163, CGX-1 160).
Thyroxine derivatives
The thyroid hormones, thyroxine (T4) and triiodothyronine (T3), are tyrosine-based hormones produced by the thyroid gland. The major form of thyroid hormone in the blood is thyroxine (T4). Thyroxine is converted to the active T3 (three to four times more potent than T4) within cells by deiodinases (5'-iodinase). These are further processed by decarboxylation and deiodination to produce the thyronamines. Most of the thyroid hormone circulating in the blood is bound to transport proteins, such as thyroxine-binding globulin (TBG), transthyretin or "thyroxine-binding prealbumin" (TTR or TBPA), or albumin.
The thyroid hormones and their derivatives are involved in the regulation of several metabolic processes within the body. The thyroxine derivatives increase the basal metabolic rate, affect protein synthesis and increase the body's sensitivity to catecholamines (such as adrenaline). These hormones also regulate protein, fat, and carbohydrate metabolism, affecting how human cells use energetic compounds. Thyroid hormone leads to heat generation in human. For example, the thyronamines function via an unknown mechanism to inhibit neuronal activity; this plays an important role in the hibernation cycles of mammals, and one effect of administering the thyronamines is a severe drop in body temperature.
Thyronamine refers both to a molecule, and to derivatives of that molecule: a family of decarboxylated and deiodinated metabolites of the thyroid hormones thyroxine (T4) and 3,5,3'-triiodothyronine (T3). The group includes apart from the above: Thyronamine (TOAM); 3-lodothyronamine (T1 AM), 3,5-Diiodothyronamine (T2AM); 3,5,3'-Triiodothyronamine (T3AM). Herein the term thyroxine derivatives includes both the thyroid hormones and their derivates; thyronamines and compounds that in structure resemble either the thyroid hormones, their derivatives or the thyronamines. Thus in an aspect of the present invention at least one of the two or more compounds of the present invention are selected from the group consisting of, but not limited to: thyroxine, 3,5,3'-triiodothyronine, thyronamine; 3-lodothyronamine; 3,5-diiodothyronamine; and 3,5,3'-triiodothyronamine.
Thyroxine derivative receptors
T3 and T4 cross the cell membrane, probably via amino acid importins, and function via a well-studied set of nuclear receptors in the nucleus of the cell, the thyroid hormone receptors. T^ and Toa are positively charged and do not cross the membrane; they are believed to function via the trace amine-associated receptor TAAR1 (TAR1 , TA1 ), a G-protein-coupled receptor located in the cell membrane.
The thyroid hormone receptor (TR) is a type of nuclear receptor that is activated by binding thyroid hormone. There are three forms of the thyroid hormone receptor designated alpha-1 , beta-1 and beta-2 that are able to bind thyroid hormone. There are two TR-alpha receptor splice variants encoded by the THRA gene and two TR- beta isoform splice variants encoded by the THRB gene: TR-α1 (widely expressed and especially high expression in cardiac and skeletal muscles); TR-α2 (homologous with viral oncogen c-erb-A, also widely expressed but unable to bind hormone); TR-β1 (predominately expressed in brain, liver and kidney); TR-β2 (expression primarily limited to the hypothalamus and pituitary).
According to the present invention, the term 'thyroxine derivative receptor' may refer to any receptor capable of binding of the thyroid hormones or their derivates such as thyronamines.
Novel use of compounds
Thyroxine derivatives have been used for a variety of purposes over time. It is an object of the present invention to provide a novel use of these compounds for the induction of hypothermia, especially for the preparation of a medicament comprising two or more compounds of the group consisting of vanilloid receptor agonists and/or cannabinoids or cannabimimetic compounds and/or adenosine receptor agonists and/or neurotensin receptor agonists and/or thyroxine derivatives and/or cytochrome c oxidase inhibitors and/or oxygen tension reducers, with the proviso that if the combination of compounds comprises two compounds said two compounds are not one cannabinoid or cannabimimetic compound and one vanilloid receptor agonist for the induction of hypothermia in an individual.
Cytochrome c oxidase inhibitors
The enzyme cytochrome c oxidase or Complex IV is a large transmembrane protein complex found in bacteria and the mitochondrion. It is the last enzyme in the respiratory electron transport chain of mitochondria (or bacteria) located in the mitochondrial (or bacterial) membrane. It receives an electron from each of four cytochrome c molecules, and transfers them to one oxygen molecule, thereby converting molecular oxygen to two molecules of water. In the process, it binds four protons from the inner aqueous phase to make water, and in addition translocates four protons across the membrane, helping to establish a transmembrane difference of proton electrochemical potential that the ATP synthase then uses to synthesize ATP. Several compounds have been found to bind to cytochrome c oxidase, which is very important for metabolism. By interfering with the function of cytochrome c oxidase the cellular and ultimately bodily metabolic rate is slowed causing among other things a reduction of body temperature / induction of hypothermia.
Compounds that fall into this category are objects of the present invention and include, but are not limited to: H2S (hydrogen sulfide); cyanide (CN) or its derivates such as hydrogen cyanide (HCN) or sodium nitroprusside (Na2[Fe(CN)5NO]^H2O); Azide and its derivates; Carbon monoxide (CO); and/or Sodium sulfide (Na2S). Thus these compounds may be used in combination with one or more of any of the other herein mentioned compounds.
Novel use of compounds Cytochrome c oxidase inhibitors have been used for a variety of purposes over time. It is an object of the present invention to provide a novel use of these compounds for the induction of hypothermia, especially for the preparation of a medicament comprising a cytochrome c oxidase inhibitor compound for the induction of hypothermia. It is also an object of the present invention to provide a novel use of these compounds for the induction of hypothermia, especially for the preparation of a medicament comprising two or more compounds of the group consisting of vanilloid receptor agonists and/or cannabinoids or cannabimimetic compounds and/or adenosine receptor agonists and/or neurotensin receptor agonists and/or thyroxine derivatives and/or cytochrome c oxidase inhibitors and/or oxygen tension reducers, with the proviso that if the combination of compounds comprises two compounds said two compounds are not one cannabinoid or cannabimimetic compound and one vanilloid receptor agonist for the induction of hypothermia in an individual.
Oxygen tension reducers
Reducing the concentration of oxygen around or within the body has the effect on several organisms, that it sends them into a state of suspended animation / hibernation with reduced core body temperatures as one consequence hereof. Several compounds are capable of inhibiting the oxygen utilization of the body and thereby mimic lack of oxygen in the environment / body. These compounds are thus able to induce hypothermia and are objects of the present invention. These compounds, some of which also fall into the category of being cytochrome c oxides inhibitors, include, but are not limited to: Carbon monoxide (CO), Sodium sulfide (Na2S) and hydrogen sulfide (H2S). Any oxygen tension reducer may be used in combination with any of the herein mention compounds or in any combination of several of these.
Hemoglobin (Hb), an intracellular protein of erythrocytes, is the primary vehicle for transporting oxygen in the blood. Each Hb molecule has a limited capacity for holding oxygen molecules; how much of that capacity is filled by oxygen is called the oxygen saturation (SO2).
The amount of oxygen bound to the hemoglobin at any time is related, in large part, to the partial pressure of oxygen to which the Hb is exposed (PO2). In the lungs, at the alveolar-capillary interface, the partial pressure of oxygen is typically high, and therefore the oxygen binds readily to Hb. As the blood circulates to other body tissue in which the partial pressure of oxygen is less, the Hb releases the oxygen into the tissue.
The effectiveness of hemoglobin-oxygen binding can be affected by several factors; an increase in the affinity of Hb for oxygen (easier to bind but harder to release oxygen) is caused by decreased temperature, 2,3-DGP or PCO2 or an increase in pH.
Oxygen saturation may be measured directly via a blood sample (ex vivo) or via a non-invasive pulse oximeter, which is a medical device that indirectly measures the oxygen saturation of a patient's blood. A blood-oxygen monitor displays the percentage of arterial hemoglobin in the oxyhemoglobin configuration. Acceptable normal ranges are from 95 to 10O percent, although values down to 90% are common.
Novel use of compounds
Oxygen tension reducers have been used for a variety of purposes over time. It is an object of the present invention to provide a novel use of these compounds for the induction of hypothermia, especially for the preparation of a medicament comprising an oxygen tension reducer compound for the induction of hypothermia. It is also an object of the present invention to provide a novel use of these compounds for the induction of hypothermia, especially for the preparation of a medicament comprising two or more compounds of the group consisting of vanilloid receptor agonists and/or cannabinoids or cannabimimetic compounds and/or adenosine receptor agonists and/or neurotensin receptor agonists and/or thyroxine derivatives and/or cytochrome c oxidase inhibitors and/or oxygen tension reducers, with the proviso that if the combination of compounds comprises two compounds said two compounds are not one cannabinoid or cannabimimetic compound and one vanilloid receptor agonist for the induction of hypothermia in an individual.
Medicament
The induction of hypothermia by any combination of the herein described compounds is performed by preparing, producing and thus providing a medicament or pharmaceutical composition comprising a combination of two or more compounds of the group consisting of vanilloid receptor agonists and/or cannabinoids or cannabimimetic compounds and/or adenosine receptor agonists and/or neurotensin receptor agonists and/or thyroxine derivatives and/or cytochrome c oxidase inhibitors and/or oxygen tension reducers. The medicament of the present invention thus comprises a combination of compounds for the induction of hypothermia in an individual in need thereof for the treatment and/or prophylaxis of ischemia in said individual.
It is an aspect of the present invention to provide a medicament comprising a combination of compounds capable of inducing hypothermia in an individual in need thereof.
It is also an aspect of the present invention to provide a medicament comprising a combination of compounds for prophylactic and/or therapeutic applications.
It is further an aspect of the present invention to provide a medicament comprising a combination of compounds for therapeutic applications.
It is an aspect of the present invention to provide a medicament comprising a combination of compounds capable of inducing hypothermia in an individual in need thereof of between 32 and 36 degree Celsius. It is also an aspect of the present invention to provide a medicament comprising a combination of compounds wherein at least one compound induces hypothermia rapidly.
In another aspect the present invention provides a medicament comprising a combination of compounds wherein at least one compound induces hypothermia slowly.
In a further embodiment the present invention provides a medicament comprising a combination of compounds and a further active ingredient selected from the group of: analgesics, opioids, GABAs and adrenergic antagonists.
Pharmaceutical composition
Whilst it is possible for the compounds or salts of the present invention to be administered as the raw chemical, it is preferred to present them in the form of a pharmaceutical formulation. Accordingly, the present invention further provides a pharmaceutical formulation, for medicinal application, which comprises a combination of compounds of the present invention or pharmaceutically acceptable salts thereof, as herein defined, and a pharmaceutically acceptable carrier therefor.
The combinations of compounds of the present invention may be formulated in a wide variety of oral administration dosage forms. The pharmaceutical compositions and dosage forms may comprise the combinations of compounds of the invention or their pharmaceutically acceptable salts or a crystal forms thereof as the active components. The pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, wetting agents, tablet disintegrating agents, or an encapsulating material.
The combinations of compounds of the present invention may be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Examples of oily or non-aqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.
Oils useful in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils useful in such formulations include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.
Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts, and suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides; (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulphates, and sulfosuccinates, (c) non-ionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylenepolypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl-. beta.-aminopropionates, and 2-alkyl- imidazoline quaternary ammonium salts, and (e) mixtures thereof.
The parenteral formulations typically will contain from about 0.5 to about 25% by weight of the active ingredient in solution. Preservatives and buffers may be used. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more non-ionic surfactants having a hydrophile - lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations will typically range from about 5to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol. The parenteral formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
Thus, in one embodiment the medicament of the present invention comprises a pharmaceutically acceptable carrier.
Pharmaceutically acceptable salts
Pharmaceutically acceptable salts of the instant compounds, where they can be prepared, are also intended to be covered by this invention. These salts will be ones which are acceptable in their application to a pharmaceutical use. By that it is meant that the salt will retain the biological activity of the parent compound and the salt will not have untoward or deleterious effects in its application and use in treating diseases.
Pharmaceutically acceptable salts are prepared in a standard manner. If the parent compound is a base it is treated with an excess of an organic or inorganic acid in a suitable solvent. If the parent compound is an acid, it is treated with an inorganic or organic base in a suitable solvent.
The combination of compounds of the invention may be administered in the form of an alkali metal or earth alkali metal salt thereof, concurrently, simultaneously, or together with a pharmaceutically acceptable carrier or diluent, especially and preferably in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parenteral (including subcutaneous) route, in an effective amount.
A pharmaceutically acceptable salt means any salt of the compounds mentioned. In particular, it means a pharmaceutically acceptable acid addition salt. Pharmaceutically acceptable acid addition salts of the compounds include salts derived from non-toxic inorganic acids such as hydrochloric, nitric, phosphoric, sulphuric, hydrobromic, hydriodic, hydrofluoric, phosphorous and the like, as well as the salts derived from non-toxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulphate, pyrosulphate, bisulphate, sulphite, bisulphite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like.
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An aspect of the present invention regards the pH of the medicament. The pH of the medicament depends on the administration form, as the pH of the medicament preferably is suitable for the route of administration chosen. An embodiment of the present invention comprises a medicament wherein the pH of the composition is between pH 5 and pH 9, such as between pH 5.5 and 8.5 such as between pH 6 and 8, such as between pH 6.5 and 7.5. Most preferably the pH of the medicament is in accordance with the route of administration and the tissue to which the medicament is administered.
Thus, in an embodiment the present invention provides a composition comprising a combination of compounds, wherein the pH of the composition is between pH 5 and pH 9.
Indications
The invention provides a combination of compounds for the production of a medicament for the treatment of ischemia in an individual. Ischemia may arise due to various circumstances and thus it is an object of the present invention to treat ischemia arising from a plurality of medical indications.
These indications include, but are not limited to, cardiovascular diseases such as myocardial infarction, cardiac arrest, stroke, arterial aneurism, subarachnoid haemorrhage, arteriosclerosis, angina pectoris, hypertension, hypercholesterolemia, cardiac arrhythmia, cardiomegaly, cardiomyopathy, heart valve regurgitation and heart valve stenosis, perinatal asphyxia and non-perinatal asphyxia as well as traumatic brain injury.
Thus, it is an aspect of the present invention to provide a combination of compounds for the induction of hypothermia in an individual suffering from or at risk of suffering from ischemia.
Individuals at risk of suffering from ischemia are often individuals who have previously suffered from an event that was capable of or did induce ischemia such as a heart attack, stroke or other. These individuals may benefit from having rapid access to pills, capsules, ampoules, pre-loaded syringes, suppositories or other administration forms of the medicaments of the present invention for self- administration. It is envisioned that these individuals at the onslaught of a new ischemic attack self-administer a dose of the compounds of the present invention prior to receiving medical aid by medical professionals. This is of relevance, as the faster the temperature drops, the better the chances of reducing the detrimental effects of the ischemic attack.
It is also an aspect of the present invention to provide a combination of compounds for the prophylaxis and/or treatment of ischemia in connection with cardiovascular diseases, asphyxia and/or traumatic brain injuries.
In a preferred embodiment compounds of the present invention are used alone or in combination to treat adverse effects of ischemia in the kidney.
It is also an aspect of the present invention to provide prophylaxis and/or treatment of ischemia or tissue damaging effects occurring during or after ischemia in the kidney or nephroischemia.
In one embodiment, the present invention provides a combination of compounds for treating effects of ischemia, wherein the ischemia is due to cardiovascular diseases such as myocardial infarction, cardiac arrest, stroke, arterial aneurism, subarachnoid haemorrhage, arteriosclerosis, angina pectoris, hypertension, hypercholesterolemia, cardiac arrhythmia, cardiomegaly, cardiomyopathy, heart valve regurgitation and heart valve stenosis. Another group of indications are the situations where an individual has an increased body temperature such as fever, hyperpyrexia, hyperthermia or other. It is an aspect of the present invention to provide a combination of compounds / and or medicaments for the purpose of inducing hypothermia and/or lowering the body temperature of these individuals.
It is furthermore an aspect of the present invention to provide means for selectively inducing hypothermia in either the brain or the body or both simultaneously. This is of relevance, as a severe stroke is known to cause an increase in brain temperature, often subsequently followed by an increase in body temperature. Thus it is an aspect of the present invention to induce hypothermia in the brain, just as it is an aspect of the present invention to induce hypothermia in the body without, as far as it is physically possible, inducing hypothermia in the brain. Likewise it is as often stated herein an aspect of the present invention to induce hypothermia and/or lower the body temperature of an individual in need thereof.
In a further embodiment, the present invention provides a combination of compounds for treating effects of ischemia, wherein the ischemia is due to asphyxia such as: perinatal asphyxia and/or non-perinatal asphyxia.
Target temperature and peak effect
The target temperature of the medicament is the core body temperature that can be reached upon administering the medicament according to the present invention as prescribed according to potency, dosage and so on. Various ranges and specific hypothermic / reduced core body temperatures that fall within the scope of the present invention are equal to the temperatures that the combinations of compounds themselves may induce as listed in the section on hypothermia.
An embodiment of the present invention is thus a medicament capable of inducing hypothermia below 36 °C, such as below 35.5 °C, such as below 35 °C, such as below 34.5 °C, such as below 34.0 °C, such as in the range of between 36 to 32 degree Celsius, and more preferably between 35 and 33 degree Celsius. The combinations of compounds of this invention will often show a peak in hypothermia inducing effect 30 minutes to 120 minutes after administration, but may potentially peak sooner or later than described by this interval. The hypothermia inducing effect will frequently last from 1 hour to 12 hours, but may potentially last shorter or longer than described by this interval.
It is an object of the present invention to provide medicaments suitable for a quick induction of hypothermia which may be of long or short duration and medicaments suitable for a slow reduction in core body temperature which may be of long or short duration.
It is an aspect of the present invention that the compounds / medicaments / treatments herein may be given while the individual receiving the treatment is surrounded by any given temperature. In other words, the temperature of the surroundings, especially the room in which the individual resides, is not of relevance to the treatment. The treatment will reduce the temperature of the individual and/or induce hypothermia whether the room temperature is ambient, high or low such as at any temperature between 5 and 45 degree Celsius.
Administration
The main routes of drug delivery, in the treatment method are intravenous, oral, and topical, as will be described below. Other drug-administration methods, such as subcutaneous injection or via inhalation, which are effective to deliver the drug to a target site or to introduce the drug into the bloodstream, are also contemplated.
The mucosal membrane to which the pharmaceutical preparation of the invention is administered may be any mucosal membrane of the individual to which the biologically active substance is to be given, e.g. in the nose, vagina, eye, mouth, genital tract, lungs, gastrointestinal tract, or rectum, preferably the mucosa of the nose, mouth or rectum.
Combinations of compounds of the invention may be administered parenterally, that is by intravenous, intramuscular, intraspinal, subcutaneous, intraarterial, intracardiac, intraosseous, intradermal, intrathecal, transdermal, transmucosal, inhalational, epidural, sublingual, intravitreal, intranasal, intrarectal, intravaginal or intraperitoneal administration. Appropriate dosage forms for such administration may be prepared by conventional techniques. The combination of compounds may also be administered by inhalation, that is by intranasal and oral inhalation administration. Appropriate dosage forms for such administration, such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques.
The combinations of compounds according to the invention may be administered with at least one other compound. The compounds may be administered simultaneously, either as separate formulations or combined in a unit dosage form, or administered sequentially.
A preferred embodiment of the present invention is a medicament for administration by injection, suppository, oral administration, sublingual tablet or spray, cutaneous administration, or inhalation. More preferably the administration form is by injection, wherein the injection is intravenous, intramuscular, intraspinal, intraperitoneal, subcutaneous, a bolus or a continuous administration.
It has previously been demonstrated that administration of cannabinoids by the intravenous route produced a greater hypothermic response than that produced by the intraperitoneal route [50]. Therefore the most preferable mode of administration of a medicament comprising a cannabinoid is by intravenous injection. Intravenous injection is also the preferred mode of administration of medicaments comprising vanilloid receptor agonists, as these may act as irritants under certain circumstances. Therefore, the combinations of compounds of the present invention, depending on the specific active substances, may preferably be administered as capsules rather than tablets or suppositories, and preferably as intravenous injections rather than subcutaneous or intramuscular injections.
In one embodiment, the combination of compounds of the present invention is administered by injection, suppository, oral administration, sublingual tablet or spray, cutaneous administration, or inhalation. In another embodiment, the combination of compounds of the present invention is administered by injection, wherein the injection is intravenous, intramuscular, intraspinal, intraperitoneal, subcutaneous, a bolus or a continuous administration.
In one embodiment, the combination of compounds of the present invention is administered at intervals of 30 minutes to 48 hours.
In one embodiment, the combination of compounds of the present invention is administered at intervals of 1 to 6 hours.
Individual
The individual that may benefit from the administration of a medicament as described herein may be an individual suffering from ischemia or at risk of suffering from ischemia. If the individual is at risk of suffering from ischemia the preferred administration form of the medicament may be suppository, oral administration or inhalation. Preferably, the individual is an individual suffering from ischemia. Also, the individual may have an elevated body temperature and may be in need of a reduction hereof; alternatively the medicaments of the present invention may be given pre-operatively to lower the body temperature of the individual prior to and/or during surgeryThe preferred administration form for an individual suffering from ischemia is an injection, such as an intravenous, intramuscular, intraspinal, intraperitoneal or subcutaneous injection. Being in need of treatment thus indicates that the health of the individual is benefitted by the administration of the at least one compound of the present invention.
The individual may be any human being, male or female, at any age. The ischemic condition and/or elevated temperature to be treated or prevented in the individual may relate to the age of the individual, the general health of the individual and whether or not the individual has a prior history of suffering from diseases or disorders that may have or have induced ischemic conditions and/or elevated temperatures in the individual.
Dosage
The dosage of the combinations of compounds according to the invention depends on the combination in question; however, the amount of the combination is also closely related to the pharmaceutical composition of the medicament, any third or more compound of the medicament or any further active ingredient of the medicament.
It will be recognized by one of skill in the art that the optimal quantity and spacing of individual dosages of a compound or a pharmaceutically acceptable salt thereof will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of a compound or a pharmaceutically acceptable salt thereof given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
For all methods of use disclosed herein for the combinations of compounds, the daily oral dosage regimen will preferably be from about 0.01 to about 80 mg/kg of total body weight. The daily parenteral dosage regimen will be from about 0.001 to about 80 mg/kg of total body weight.
For all methods of use disclosed herein for the compounds, the daily oral dosage regimen will preferably be from about 0.01 to about 80 mg/kg of total body weight. The daily parenteral dosage regimen will be from about 0.01 to about 2,400 mg/kg of total body weight, preferably, the dosage of the medicament according to the present invention is between 10 μg to 10 mg pr kg total body weight, such as between 100 μg to 1 mg pr kg total body weight, depending on the compound of choice. It has been found that cannabinoids, vanilloids, adenosins, neurotensins, thyroxine derivatives, cytochrome c oxidase inhibitors and oxygen tension reducers vary with respect to potency and affinity for the receptor as well as with respect to molecular weight.
Preferably, the dosage of the medicament according to the present invention is between 1 μg to 100 mg pr kg total body weight, such as between 10 μg to 50 mg pr kg total body weight, for example between 20 μg to 20 mg pr kg total body weight, such as 100 μg to 10 mg, for example 500 μg to 1 mg depending on the compound of choice. It follows, that the preferred dosage may be between 1 μg and 1 mg pr kg total body weight, such as between 10 μg and 100 μg pr kg total body weight, such as or about 10 μg, 20 μg, 30 μg, 40 μg, 50 μg, 60 μg, 70 μg, 80 μg, 90 μg, 100 μg, 200 μg, 300 μg, 400 μg, 500 μg, 600 μg, 700 μg, 800 μg, 900 μg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg or 100 mg pr kg total body weight, again depending on the compound chosen.
Also, the preferred dosage range may be between 100 μg and 100 mg pr kg total body weight, such as between 200 μg and 90 mg, between 300 μg and 80 mg, such as between 400 μg and 70 mg, such as between 500 μg and 60 mg, such as between 600 μg and 50 mg, such as between 700 μg and 40 mg, such as between 800 μg and 30 mg, such as between 900 μg and 20 mg, such as between 1 mg and 10 mg pr kg total body weight. Alternatively, the dosage may be found in the range of from 100 μg to 2000 μg, such as 200 μg to 1800 μg, or 300 μg to 1600 μg, 400 μg to 1400 μg, 500 μg to 1200 μg, 600 μg to 1000 μg or 500 μg to 2000 μg.
For any other receptor agonist compound according to the invention the exact dosage may be calculated based on the calf study model described in Example 15.
Based hereon, the preferred dosages of a cannabinoid compound such as, but not limited to HU-210 and KN38-7271 (BAY38-7271 ), is between 1 μg and 1 mg pr kg total body weight, such as between 10 μg and 100 μg pr kg total body weight, such as or about 10 μg, 20 μg, 30 μg, 40 μg, 50 μg, 60 μg, 70 μg, 80 μg, 90 μg or 100 μg pr kg total body weight. The dosage may depend on the administration form. For example, it is preferable to administer HU-210 in the range of from 10 μg and 100 μg pr kg total body weight intravenously.
For one of the compounds in this invention, HU-210, the dosage regime will be between 2 and 1000 microgram/kg of total body weight, such as between 4 and 900 microgram/kg of total body weight, such as between 6 and 800 microgram/kg of total body weight, such as between 8 and 700 microgram/kg of total body weight, such as between 10 and 600 microgram/kg of total body weight. Preferably, the dosage regime will be between 15 and 500 microgram/kg of total body weight, more preferably between 20 and 400 microgram/kg of total body weight. More preferably at least 40 microgram/kg of total body weight, such as at least 50 microgram/kg of total body weight, such as at least 60 microgram/kg of total body weight, such as at least 70 microgram/kg of total body weight, such as at least 80 microgram/kg of total body weight, such as at least 100 microgram/kg of total body weight. The dosages mentioned are the dosages for inducing hypothermia as defined herein. The dosage may be administered as one single bolus or divided into two or more dosages given over a period of time; alternatively it may be administered by continuous IV.
Additionally the hypothermic effect may be maintained by administering one or more dosages some hours after the first dosage, such as at least 6 hours later, or such as at least 12 hours later. Such additional dosages may be of the same amount as the first dosage or an amount being at the most one-half or one-quarter of the first dosage.
For another compound in this invention, delta-8-THC phosphate, the dosage regime will be between 0.25 and 600 mg/kg of total body weight, such as between 0.5 and 500 mg/kg of total body weight, 1 and 400 mg/kg of total body weight, 2 and 300 mg/kg of total body weight, 3 and 200 mg/kg of total body weight. Preferably, the dosage regime will be between 4 and 150 mg/kg of total body weight, more preferably between 5 and 100 mg/kg of total body weight. More preferably at least 10 mg/kg of total body weight, such as at least 20 mg/kg of total body weight, such as at least 30 mg/kg of total body weight, such as at least 40 mg/kg of total body weight, such as at least 50 mg/kg of total body weight, such as at least 60 mg/kg of total body weight, such as at least 100 mg/kg of total body weight. The dosages mentioned are the dosages for inducing hypothermia as defined herein. The dosage may be administered as one single bolus or divided into two or more dosages given over a period of time; alternatively it may be administered by continuous IV. Additionally the hypothermic effect may be maintained by administering one or more dosages some hours after the first dosage, such as at least 6 hours later, or such as at least 12 hours later. Such additional dosages may be of the same amount as the first dosage or an amount being at the most one-half or one-quarter of the first dosage.
Likewise, the preferred dosages of a vanilloid compound such as, but not limited to dihydrocapsaicin, is between 10 μg and 2000 μg pr kg total body weight, such as between 100 μg and 1000 μg such as or about 10 μg, 20 μg, 30 μg, 40 μg, 50 μg, 60 μg, 70 μg, 80 μg, 90 μg or 100 μg pr kg total body weight, or 150 μg, 200 μg, 250 μg, 300 μg, 350 μg, 400 μg, 450 μg, 500 μg, 600 μg, 700 μg, 800 μg, 900 μg, 1000, 1500 μg or 2000 μg pr kg total body weight when injected in the individual intravenously. Alternatively, dihydrocapsaicin and other vanilloids may be injected intramuscularly at dosages between 100 μg and 100 mg pr kg total body weight, such as between 200 μg and 90 mg, between 300 μg and 80 mg, such as between 400 μg and 70 mg, such as between 500 μg and 60 mg, such as between 600 μg and 50 mg, such as between 700 μg and 40 mg, such as between 800 μg and 30 mg, such as between 900 μg and 20 mg, such as between 1 mg and 10 mg pr kg total body weight. Alternatively, the dosage may be found in the range of from 100 μg to 2000 μg, such as 200 μg to 1800 μg, or 300 μg to 1600 μg, 400 μg to 1400 μg, 500 μg to 1200 μg, 600 μg to 1000 μg, or 500 μg to 2000 μg pr kg total body weight.
The optimal dosage of a drug in combination with at least one other drug according to the present invention thus varies for a given class of drugs. It follows from the administration of at least two drugs, such as two or more drugs, that the simultaneous administration of at least two drugs may result in an advantageous reduction in the dosage required for each drug to be effective. A reduction in dosage for each of the at least two drugs when given simultaneously may occur without a reduction in the desired effect of the drug. A reduction in dosage for each of the at least two drugs may thus provide an effective means of reducing unwanted side- effects resulting from the administration of otherwise optimal dosages of each of the at east two drugs.
A reduction in dosage for each of the at least two drugs when given simultaneously may be in the order of 5 to 75% of the otherwise optimal dosages of each of the at least two drugs, for example 5 to 10%, such as 10 to 15%, for example 15 to 20%, such as 20 to 25%, for example 25 to 30%, such as 30 to 35%, for example 35 to 40%, such as 40 to 45%, for example 45 to 50%, such as 50 to 55%, for example 55 to 60%, such as 60 to 65%, for example 65 to 70%, such as 70 to 75% of the otherwise optimal dosages of each of the at least two drugs.
The term "unit dosage form" as used herein refers to physically discrete units suitable as unitary dosages for human and animal individuals, each unit containing a predetermined quantity of a combination of compounds, alone or in together with other agents, calculated in an amount sufficient to produce the desired effect in association with a pharmaceutically acceptable diluent, carrier, or vehicle. The specifications for the unit dosage forms of the present invention depend on the particular combination employed and the effect to be achieved, as well as the pharmaco-dynamics associated with each of the compounds of the combination in the host. The dose administered should be an "effective amount" or an amount necessary to achieve an "effective level" in the individual patient.
Since the "effective level" is used as the preferred endpoint for dosing, the actual dose and schedule can vary, depending on inter-individual differences in pharmacokinetics, drug distribution, and metabolism. The "effective level" can be defined, for example, as the blood or tissue level desired in the individual that corresponds to a concentration of one or more combinations according to the invention. The effective level can also be defined as the amount needed pr kg body weight, in other words the concentration, required to reach the peak effect for a specific combination of compounds. Also, the effective level depends on the severity of the ischemic condition, such as total amount of tissue experiencing hyp- or anoxia, the duration of the ischemic condition, whether it is the first or a subsequent ischemic attack of the individual and so forth.
More preferably, the dosage of the medicament according to the present invention is between 10 μg to 80 mg pr kg total body weight, such as between 100 μg to 1 mg pr kg total body weight.
Dosage regime and Duration of treatment
The medicament may be administered in any suitable dosage regime, suitable as to the potency of the combination of compounds / the drug, the target temperature to be reached, the speed of action of the combination, the metabolic stability of the combination, the duration of the treatment and how often the medicament optimally is to be administered.
It is within the scope of the invention to provide a medicament to be administered at intervals of 30 minutes to 48 hours, such as intervals of 1 to 47 hours, 2 to 45 hours, 3 to 43 hours, 4 to 41 hours, 5 to 39 hours, 6 to 37 hours, 7 to 35 hours, 8 to 3 hours, 9 to 31 hours, 10 to 29 hours, 1 1 to 27 hours, 12 to 25 hours, 13 to 23 hours, 14 to 21 hours, 15 to 19 hours 16 to 18 hours. It is also within the scope of the present invention to provide a medicament to be administered at intervals of 30 minutes to 24 hours, such as 1 to 23 hours, 2 to 22 hours, 3 to 20 hours, 4 to 18 hours, 5 to 16 hours, 6 to 14 hours, 7 to 12 hours or 8 to 10 hours. Preferably, the administration occurs at intervals of 1 to 6 hours, such as 2 to 5 hours, 3 to 4 hours.
The optimal administration interval depends on the duration of the hypothermic treatment. The duration of the treatment depends among other things on the severity of the ischemic condition. It is within the scope of the present invention to provide medicaments for the induction of hypothermia wherein the duration of the treatment is from 6 to 72 hours, such as from 7 to 69 hours, such as from 8 to 66 hours, 9 to 63 hours, 10 to 60 hours, 1 1 to 57 hours, 12 to 54 hours, 13 to 51 hours, 14 to 48 hours, 15 to 45 hours, 16 to 42 hours, 17 to 39 hours, 18 to 36 hours, 1 to 35 hours, 20 to 32 hours, 21 to 29 hours, 22 to 26 hours 23 to 25 hours. Preferably, the duration of the treatment is between 6 and 48 hours, more preferably between 6 and 24 hours.
In one embodiment, the compounds of medicament of the present invention are administered at a dosage of between 10 μg to 80 mg pr kg body mass either sequentially or consecutively.
The medicament may thus comprise compounds of the present invention wherein at least one compound induces hypothermia rapidly, or alternatively wherein at least one compound induces hypothermia slowly. In the present context rapidly means within a few hours, such as within 2 hours, for example within 1 hour, such as within 30 minutes, for example within 15 minutes; whereas slowly means after several hours, such as after 3 hours, for example 4 hours, such as after 5 hours, for example 6 hours, such as after 7 hours, for example 8 hours, such as after 9 hours, for example 10 hours, such as after 1 1 hours, for example 12 hours, such as after 13 hours, for example 14 hours, such as after 15 hours, for example 16 hours, such as after 17 hours, for example 18 hours, such as after 19 hours, for example 20 hours. A rapidly acting compound or combination of compounds may be administered prior to admission to the hospital such as at the scene of the complication or en route in an ambulance by medically trained personnel. The individual suffering from the ischemic insult will thus already be experiencing a reduction in core body temperature upon arrival at a place of proper facilities enhancing the treatment and reducing the extent of the ischemic insult. In one embodiment, the duration of the treatment with compounds of the present invention is from 6 to 72 hours.
Further active ingredient
An embodiment of the present invention is a pharmaceutical composition comprising a combination of compounds as herein described and furthermore comprising a further active ingredient. The further active ingredient may increase the hypothermic effect of the combination of compounds of the invention, or may have an alternative medical effect such as inducing pain relief or vasodilation.
The further active ingredient may thus be selected from the non-limiting group of: analgesics, opioids, GABAs and adrenergic antagonists.
The further active ingredient may thus be an antipyretic. Antipyretics are drugs that reduce body temperature in situations such as fever; however, they will not affect the normal body temperature if one does not have fever. Antipyretics cause the hypothalamus to override an interleukin-induced increase in temperature. The body will then work to lower the temperature and the result is a reduction in fever. It is an object of the present invention to induce hypothermia in an individual. To prevent a possible overshoot in the body's attempt to regain its normal temperature at the completion of the hypothermia-inducing treatment, an antipyretic may be provided in combination with the compounds of the present invention.
There are at least 3 classes of antipyretic medications all of which are of relevance to the present invention, that include, but are not limited to: (1 ) Salicylates - aspirin (acetylsalicylic acid), choline salicylate (Arthropan), magnesium salicylate (Arthriten), and sodium salicylate (Scot-Tussin Original); (2) Acetaminophen / Paracetamol (Panodil / Tylenol); and (3) Nonsteroidal anti-inflammatory drugs (NSAIDs) - ibuprofen (Advil), naproxen (Naprosyn, Aleve), and ketoprofen.
It is an aspect of the present invention to provide a medicament comprising a combination consisting of: vanilloid receptor agonists and/or cannabinoids and/or cannabimimetic compounds and/or adenosine and/or adenosine analogs and/or neurotensin and/or neurotensin analogs and/or thyroxine derivatives and/or cytochrome c oxidase inhibitors and/or oxygen tension reducers which may be formulated and /or administered together with an antipyretic drug simultaneously or sequentially.
The further active ingredient may also be an analgesic (or painkiller). Some drugs that are antipyretics will also have an analgesic effect, and thus there will be an overlap between these two groups. Analgesics are a diverse group of drugs that relieve pain. Analgesic drugs act in various ways on the peripheral and central nervous systems and include paracetamol (acetaminophen); the non-steroidal anti- inflammatory drugs (NSAIDs) such as the salicylates - aspirin, ibuprofen, naproxen; opioids such as morphine, codeine, oxycodone, hydrocodone, diamorphine, pethidine; synthetic drugs with opioid properties such as tramadol and buprenorphine; and various others. Demerol and desflurane both of which are analgesics may also be administered especially for the purpose of reducing shivering as the individual to whom the compounds of the present invention are administered is brought down in temperature. It is especially relevant to use analgesics when inducing actual hypothermia e.g. temperatures below normal.
Kit of parts Another embodiment of the present invention comprises a kit of parts, wherein the kit includes at least one pharmaceutical composition according to any of the above, a means for administering said composition and the instruction(s) on how to do so. It is within the scope of the present invention to include multiple dosages of the same composition or several different compositions. In a preferred embodiment the kit of parts further comprises a further active ingredient.
One kit may be specifically targeted to persons at risk of suffering from ischemic attacks, such that the kit, apart from instructions, comprises pharmaceutical forms of the medicaments that allow self administration of the medicaments and devices with which to administer the medicaments.
An alternative embodiment is an ambulance kit that facilitates the administration of the medicaments of the present invention in a manner most efficient for the rescue personnel. Examples
Example 1 - Cardiac arrest
A 57-year-old woman is taken care of by the ambulance staff that finds her in ventricular fibrillation approximately 5 minutes after having collapsed without warning. The patient is immediately defibrillated and spontaneous circulation and ventilations occurred. On arrival to the hospital, 21 minutes after having collapsed, the patient has a palpable pulse. Staff at the emergency room has been alerted in advance. The patient is evaluated and the physician in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain.
Hypothermia therapy is initiated as described in this invention. Two or more of the compounds described in the following are administered simultaneously or consecutively:
1 . Cannabinoid receptor agonists. Including, but not limited to HU-210
(intravenous bolus injection of e.g. 100 microgram/kg body weight) and/or delta-8-THC phosphate (intravenous bolus injection of e.g. 40 mg/kg body weight) 2. Vanilloid receptor agonists. Including, but not limited to dihydrocapsaicin
(subcutaneous or intravenous bolus injection of 0.01 mg/kg to 80 mg/kg)
3. Adenosine receptor agonists (including, but not limited to 5'-AMP)
4. Neurotensin receptor agonists
5. Thyroxine derivatives, thyroid hormone receptor agonists and trace amine- associated receptor agonists
6. Cytochrome c oxidase inhibitors
7. Oxygen tension reducers
The purpose of hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1 -8 bolus injections of any or all of the compounds may be required. At the hospital, concurrent treatments and examinations are not influenced by the administration of the hypothermia-inducing drug. Such other treatments and examinations proceed uninterrupted.
Example 2 - Cardiac arrest
A 22-year-old male athlete collapses when doing sports. Medical staff finds ventricular fibrillation/ventricular tachycardia approximately 6 minutes after collapse. He is successfully defibrillated and the patient is rushed to the hospital. In the ambulance, the physician present in the ambulance team decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain.
Hypothermia therapy is initiated as described in this invention. Two compounds are administered: 1 . An intravenous bolus injection of HU-210 (e.g. 100 microgram/kg body weight) or delta-8-THC phosphate (e.g. 40 mg/kg body weight) or a third cannabinoid agonist, and 2. A subcutaneous or intravenous bolus injection of a vanilloid agonist as described in this invention. The dose will likely be in the interval 0.01 mg/kg to 80 mg/kg.
The purpose of hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1 -8 additional bolus injections may be required.
At the hospital, concurrent treatments and examinations are not influenced by the administration of the hypothermia-inducing drug. Such other treatments and examinations proceed uninterrupted.
Example 3 - Cardiac arrest
A 66-year-old man is undergoing elective heart surgery. He suffers from irregular cardiac rhythm during the procedure and goes into cardiac arrest with much impaired circulation for 6 minutes after which the surgical team manages to restore circulation. Subsequent to restoration of circulation, the surgeon in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain.
Hypothermia therapy is initiated as described in this invention. Two compounds are administered:
1. An intravenous bolus injection of HU-210 (e.g. 100 microgram/kg body weight) or delta-8-THC phosphate (e.g. 40 mg/kg body weight) or a third cannabinoid agonist, and
2. A subcutaneous or intravenous bolus injection of a vanilloid agonist as described in this invention. The dose will likely be in the interval 0.01 mg/kg to 80 mg/kg.
The purpose of hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1 -8 additional bolus injections may be required.
At the hospital, concurrent treatments and examinations are not influenced by the administration of the hypothermia-inducing drug. Such other treatments and examinations proceed uninterrupted.
Example 4 - Cardiac arrest
An electrician accidentally receives a high-voltage jolt and immediately slips into a coma. The company physician manages to resuscitate the cardiac arrest patient after just 7 minutes. The patient is rushed to hospital where the physician in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain.
Hypothermia therapy is initiated as described in this invention. Two compounds are administered:
1 . An intravenous bolus injection of HU-210 (e.g. 100 microgram/kg body weight) or delta-8-THC phosphate (e.g. 40 mg/kg body weight) or a third cannabinoid agonist, and 2. A subcutaneous or intravenous bolus injection of a vanilloid agonist as described in this invention. The dose will likely be in the interval 0.01 mg/kg to 80 mg/kg.
The purpose of hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1 -8 additional bolus injections may be required.
At the hospital, concurrent treatments and examinations are not influenced by the administration of the hypothermia-inducing drug. Such other treatments and examinations proceed uninterrupted.
Example 5 - Perinatal asphyxia A newborn baby suffers cerebral ischemia during delivery as the umbilical cord gets wrapped around his neck. The APGAR score 10 minutes after delivery is 6. The patient is evaluated and the physician in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain.
Hypothermia therapy is initiated as described in this invention. Two compounds are administered:
1 . An intravenous bolus injection of HU-210 (e.g. 100 microgram/kg body weight) or delta-8-THC phosphate (e.g. 40 mg/kg body weight) or a third cannabinoid agonist, and
2. A subcutaneous or intravenous bolus injection of a vanilloid agonist as described in this invention. The dose will likely be in the interval 0.01 mg/kg to 80 mg/kg.
The purpose of hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1 -8 additional bolus injections may be required. At the hospital, concurrent treatments and examinations are not influenced by the administration of the hypothermia-inducing drug. Such other treatments and examinations proceed uninterrupted.
Example 6 - Asphyxia
A 9-year-old boy is in a coma when he is rescued out of a burning house. CRP is commenced on the spot but he is not awake when the ambulance arrives at hospital after a 15 minutes drive. The patient is evaluated and the physician in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain and other tissues.
Hypothermia therapy is initiated as described in this invention. Two compounds are administered:
1. An intravenous bolus injection of HU-210 (e.g. 100 microgram/kg body weight) or delta-8-THC phosphate (e.g. 40 mg/kg body weight) or a third cannabinoid agonist, and
2. A subcutaneous or intravenous bolus injection of a vanilloid agonist as described in this invention. The dose will likely be in the interval 0.01 mg/kg to 80 mg/kg.
The purpose of hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1 -8 additional bolus injections may be required.
At the hospital, concurrent treatments and examinations are not influenced by the administration of the hypothermia-inducing drug. Such other treatments and examinations proceed uninterrupted.
Example 7 - Stroke
A 78-year-old woman is admitted to hospital 50 minutes after experiencing sudden onset lack of mobility of the left arm and leg and as well and difficulties speaking. The patient is diagnosed with a stroke. The patient is evaluated and the physician in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain. Hypothermia therapy is initiated as described in this invention. Two compounds are administered:
1. An intravenous bolus injection of HU-210 (e.g. 100 microgram/kg body weight) or delta-8-THC phosphate (e.g. 40 mg/kg body weight) or a third cannabinoid agonist, and
2. A subcutaneous or intravenous bolus injection of a vanilloid agonist as described in this invention. The dose will likely be in the interval 0.01 mg/kg to 80 mg/kg.
The purpose of hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1 -8 additional bolus injections may be required.
At the hospital, concurrent treatments and examinations are not influenced by the administration of the hypothermia-inducing drug. Such other treatments and examinations proceed uninterrupted.
Example 8 - Stroke
A 29-year-old man suffers continuous pains in the back of his head for two weeks after which he suddenly collapses and slips into a coma. The patient is diagnosed with a stroke. The patient is evaluated and the physician in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain.
Hypothermia therapy is initiated as described in this invention. Two compounds are administered:
1 . An intravenous bolus injection of HU-210 (e.g. 100 microgram/kg body weight) or delta-8-THC phosphate (e.g. 40 mg/kg body weight) or a third cannabinoid agonist, and
2. A subcutaneous or intravenous bolus injection of a vanilloid agonist as described in this invention. The dose will likely be in the interval 0.01 mg/kg to 80 mg/kg. The purpose of hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1 -8 additional bolus injections may be required.
At the hospital, concurrent treatments and examinations are not influenced by the administration of the hypothermia-inducing drug. Such other treatments and examinations proceed uninterrupted.
Example 9 - Myocardial infarction
A 55-year-old man is admitted to hospital 18 minutes after experiencing nausea, shortness of breath, and severe chest pains. The patient who is suffering myocardial infarction is evaluated by the physician in charge who decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the heart and other tissues.
Hypothermia therapy is initiated as described in this invention. Two compounds are administered:
1. An intravenous bolus injection of HU-210 (e.g. 100 microgram/kg body weight) or delta-8-THC phosphate (e.g. 40 mg/kg body weight) or a third cannabinoid agonist, and
2. A subcutaneous or intravenous bolus injection of a vanilloid agonist as described in this invention. The dose will likely be in the interval 0.01 mg/kg to 80 mg/kg.
The purpose of hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1 -8 additional bolus injections may be required.
At the hospital, concurrent treatments and examinations are not influenced by the administration of the hypothermia-inducing drug. Such other treatments and examinations proceed uninterrupted. Example 10 - Traumatic brain injury
A 41 -year-old man receives a severe blow to the head from a falling brick on a construction site. The patient is still unconscious when he 24 minutes after the trauma is brought to the Emergency Room. The patient is evaluated and the physician in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain.
Hypothermia therapy is initiated as described in this invention. Two compounds are administered: 1 . An intravenous bolus injection of HU-210 (e.g. 100 microgram/kg body weight) or delta-8-THC phosphate (e.g. 40 mg/kg body weight) or a third cannabinoid agonist, and 2. A subcutaneous or intravenous bolus injection of a vanilloid agonist as described in this invention. The dose will likely be in the interval 0.01 mg/kg to 80 mg/kg.
The purpose of hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1 -8 additional bolus injections may be required.
At the hospital, concurrent treatments and examinations are not influenced by the administration of the hypothermia-inducing drug. Such other treatments and examinations proceed uninterrupted.
Example 11 - Pulmonary embolism
A 60-year-old woman is feeling rather well two days after major surgery when she suddenly slips into a coma. Following acute surgery, brought on by a pulmonary embolism, she is stabilized. The patient is evaluated and the physician in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain and other tissues.
Hypothermia therapy is initiated as described in this invention. Two compounds are administered: 1. An intravenous bolus injection of HU-210 (e.g. 100 microgram/kg body weight) or delta-8-THC phosphate (e.g. 40 mg/kg body weight) or a third cannabinoid agonist, and
2. A subcutaneous or intravenous bolus injection of a vanilloid agonist as described in this invention. The dose will likely be in the interval 0.01 mg/kg to 80 mg/kg.
The purpose of hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication 1 -8 additional bolus injections may be required.
At the hospital, concurrent treatments and examinations are not influenced by the administration of the hypothermia-inducing drug. Such other treatments and examinations proceed uninterrupted.
Example 12 - Modified pyrogenicity test on rabbits
Each combination of compounds in a low, medium and high dose will be screened initially on 3 rabbits. Temperature, blood pressure, pulse will be measured for 72 hours following administration of active substances. These parameters will be recorded as follows:
Continuous recording (time=0-3h), every 30 minutes (time=3-6h), every 1 hour (time=6-12h), every 2 hours (time=12-24h), every 6 hours (time=24-48h), every 12 hours (time=48-72h)
These are the specifics of the initial screening: Type of rabbits: New Zealand White, Charles River
Weight: >1.5 kg
Gender: Female
Room temperature: 210C (+/- 10C)
Relative humidity: 55% (+/- 5%) Type of temperature probe: PC Based pyrogen testing system, Ellab APT 91
Cage type: Pro Plast Noryl, 2475 cm2 Number of rabbits in a cage: 1
Water and food access: Ad lib in cage.
12-hour light period: Yes
Example 13 - Receptor studies
Modulation of CB and TRPV1 activities will be assessed in vitro by measuring cannabinoid and/or cannabimimetic compound and vanilloid receptor agonist induced Ca2+ flux, respectively. This will be done using FLIPR and HEK293 cells stably expressing recombinant human (h) and rat (r) TRPV1 (hTRPV1 -HEK293 and rTRPV1 -HEK293, respectively) and recombinant human (h) and rat (r) CB receptors (hCB1 -HEK293, hCB2-H293, rCB1 -HEK293 and rCB2-H293) and especially in cells co-expressing human or rat TRPVI and CB receptors (hTRPV1 -hCB1 -HEK293 and hTRPV1 -hCB2-HEK293). Intracellular Ca2+ levels will be measured in CB, TRPV1 and coCB/TRPVI -expressing cells during exposure to compounds and combinations of compounds. A concentration dependent increase in Ca2+ influx will be observed. The efficacy of vanilloid agonists will be estimated by comparing these to the maximum response induced by capsaicin, likewise the efficacy of cannabinoids will be estimated by comparing these to the maximum response induced by cannabidiol. A combination of capsaicin and cannabidiol will be used as reference for measuring combinations of drugs.
Example 14 - Porcine study model
In order to evaluate an effective hypothermic dose of a receptor agonist compound according to the invention, the compound may be tested in the porcine study model. The porcine model is used because the body weight of the pigs is comparable to the body weight of humans. The efficacy of a compound tested in the porcine model may be correlated with the efficacy of the cannabinoid or vanilloid compound tested in the same porcine study model.
Study subjects
The evaluation is carried out on "dansk landrace" pigs with a body weight of 70-90 kilo. The pigs will not be sedated; they will be fed twice a day; and they will be subjected to a day cycle consisting of 12 hours of light followed by 12 hours of dark. Drug administration
The compound investigated are administered i.v. as bolus injections and may consist of 1 solitary injection, alternatively 2-4 repeated injections within a timeframe of 24 hours from the initial injection. Generally 4 different doses plus vehicle are tested producing varying degrees of hypothermic responses.
Hypothermic effect
The primary effect evaluated is hypothermia. Temperature is measured using a temperature probe that is surgically positioned in a femoral artery two weeks prior to commencement of the study. The probe is connected to telemetry equipment (e.g. implanted telemetry from Data Sciences International) ensuring the required readouts.
Temperature is measured every 15 minutes from 1 hour prior to drug administration to 12 hours after drug administration, and every 30 minutes subsequently until 24 hours after drug administration. Temperature measurement will be conducted via a permanent femoral artery temperature probe (telemetry).
The minimum temperature as well as a graph of the temperature at each point of measurement is recorded for each dose of compound or compound mixture.
Other effects
Blood pressure, heart rate and ECG will be registered every 15 minutes from 1 hour prior to drug administration to 12 hours after drug administration, and every 30 minutes subsequently until 24 hours after drug administration.
Example 15 - Calf study model
In order to evaluate a sought after hypothermic effect of a combination treatment, according to the invention, the combination treatment may be tested in the calf study model. The calf model is used because the body weight of the calves is comparable to the body weight of humans. Study subjects
The evaluation is carried out on male "sortbroget malkeko/Holstein" calves with a body weight of 75-85 kilo or 70-90 kilo. The calves are positioned in individual booths; they are not sedated; are fed twice a day (milk at 8:00 A.M. and hay/food pills at an unspecified hour, depending on the effects of the compounds examined); and are subjected to a day cycle consisting of 16 hours of light followed by 8 hours of dark. The ambient temperature is 20°C+/-2°C.
Drug administration/device-based therapy The compounds investigated (vanilloid receptor agonists and/or cannabinoids and/or cannabimimetic compounds and/or adenosine and/or adenosine analogs and/or neurotensin and/or neurotensin) are administered i.v. (in the jugular vein) and/or i.p. and/or s.c. as bolus injections and may consist of 1 solitary injection, alternatively 2-
8 repeated injections within a timeframe of 12-24 hours from the initial injection.
Generally 4 different doses plus vehicle are tested producing varying degrees of hypothermic responses.
The drugs administered are combined with physical hypothermia therapy, either surface hypothermia therapy or invasive hypothermia therapy, as defined:
Surface hypothermia therapy, such as:
• Applying ice, cold water, or other liquid or firm elements to the skin, mucous membranes, or in proximity hereof • Dressing patients in thermo-vests, thermo-hats, or other garments capable of inducing hypothermia
• Using mist-, flow-, or other tents in order to induce hypothermia
Invasive hypothermia therapy, such as: • Intravenous administration of cold fluids (<37°C), e.g. saline
• Insertion of cooling agents such as metallic coils, tubes, or other foreign bodies in blood vessels, body cavities or in other bodily locations Hypothermic effect
The primary effect evaluated is hypothermia. Temperature is measured using a temperature probe (ADInstruments) that is surgically positioned in vena cava cranialis one week prior to commencement of the study. The probe is connected to a Powerlab ensuring the required read-outs.
Temperature is measured 100 times/second and compounded every 15 minutes from 1 hour prior to drug administration to 24 hours subsequent to administration.
Other effects
Blood pressure and heart rate is measured 100 times/second and compounded every 15 minutes from 1 hour prior to drug administration to 24 hours subsequent to administration. Data is collected using a Powerlab.
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(50) Hosko MJ, Schmeling WT, Hardman HF: Evidence for a Caudal Brainstem Site of Action for Cannabinoid Induced Hypothermia. Brain Research Bulletin. 1981 , Vol. 6, p. 253.
Sequence listing
SEQ ID NO 1 : Neurotensin NT(M 3) QLYENKPRRP YIL
SEQ ID NO. 2: NT64D
L-Arg L-Arg L-Pro D-neo-Trp L-IIe L-Leu
SEQ ID NO. 3: NT64L L-Arg L-Arg L-Pro L-neo-Trp L-IIe L-Leu
SEQ ID NO. 4:NT65L
L-Arg L-Arg L-Pro L-neo-Trp tert-Leu L-Leu SEQ ID NO. 5: NT66D
D-Lys LArg L-Pro D-neo-Trp tert-Leu L-Leu
SEQ ID NO. 6: NT66L D-Lys L-Arg L-Pro L-neo-Trp tert-Leu L-Leu
SEQ ID NO. 7: NT67L
D-Lys L-Arg L-Pro L-neo-Trp L-IIe L-Leu
SEQ ID NO. 8: NT69L N-methyl-Arg L-Lys L-Pro L-neo-Trp tert-Leu L-Leu SEQ ID NO.9:NT69U
N-methyl-Arg L-Arg L-Pro L-neo-Trp tert-Leu L-Leu SEQ ID NO.10: NT71
N-methyl-ARG Diaminobutyric acid L-Pro L-neo-Trp tert-Leu L-Leu
SEQ ID NO.11: NT72 D-Lys L-Pro L-neo-Trp tert-Leu L-Leu
SEQ ID NO.12: NT73
D-Lys L-Pro L-neo-Trp L-IIe L-Leu
SEQ ID NO.13:NT74 Diaminobutyric acid L-Pro L-neo-Trp tert-Leu L-Leu
SEQ ID NO.14:NT75
Diaminobutyric acid L-Pro L-neo-Trp L-IIe L-Leu SEQ ID NO.15: NT76
L-Arg D-ornithine L-Pro L-neo-Trp L-IIe L-Leu
SEQ ID NO.16: NT77
L-Arg D-ornithine L-Pro L-neo-Trp tert-Leu L-Leu
SEQ ID NO 17: Neuromedin IPYIL
SEQ ID NO 18:JMV-449 H-Lys-psi-(CH2NH)-Lys-Pro-Tyr-lle-Leu-OH
SEQ ID NO 19:CGX-1160
MQTAYWVMVMMMVWIAAPLSEGGKLNDVIRGLVPDDITPQLILGSLISRRQSEEGGSNATK
KPYILRASDQVASGP

Claims

Claims
1. A combination comprising two or more compounds selected from the group consisting of a. a vanilloid receptor agonist, b. a cannabinoid or a cannabimimetic compound, c. an adenosine, or an adenosine analog, or an adenosine receptor agonist, or an adenosine uptake inhibitor d. a neurotensin, or a neurotensin analog, or a neurotensin receptor agonist, or a neurotensin mimetic compound e. a thyroxine derivative f. a cytochrome c oxidase inhibitor g. an oxygen tension reducer for use for induction of hypothermia in an individual, with the proviso that if one compound is a) then the second compound is not b).
2. The use of a compound according to claim 1 , wherein the two or more compounds are capable of binding a vanilloid receptor and/or a cannabinoid receptor and/or an adenosine receptor and/or a neurotensin receptor and/or a thyroxine derivative receptor and/or cytochrome c oxidase and/or capable of reducing oxygen tension.
3. The use of a compound according to any of claims 1 and 2, wherein the vanilloid receptor agonist is selected from the group of classical vanilloid receptor agonists, non-classical vanilloid receptor agonists and other vanilloid receptor binding compounds; and the cannabinoid is selected from the group of classical cannabinoids, non-classical cannabinoids, eicosanoids, aminoalkylindoles and other cannabinoid receptor binding compounds; and the adenosine receptor agonist is selected from the group of adenine nucleotides; and the neurotensin receptor agonist is selected from the group of natural and artificial neurotensins; and the thyroxine derivative is selected from the group of natural and artificial thyroid hormones and its thyronamine derivates; and the cytochrome c inhibitor is selected from the group of natural and artificial cytochrome c inhibitors; and the oxygen tension reducer is selected from the group of natural and artificial oxygen tension reducers.
4. The use of a combination of compounds according to any of claims 1 to 3, comprising a classic or non-classic vanilloid receptor agonist of the general formula (I):
H
Figure imgf000123_0001
wherein R1 and R2 are chemical moieties or chemical bonds.
5. The use of a vanilloid receptor agonist as defined in claim 4, wherein R1 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, any of which may or may not be branched or comprise substituents such as phosphate, cycloalkyl, heterocycloalkyl, cycloalkenyl, methyl, ethyl, dimethyl, or may be further substituted one or more times with C, S, N, O, P, OH, methoxy, ethoxy, acetyl, alkoxy, alkyl, alkenyl, alkynyl, sulfonyl or phenyl any of which may or may not be branched or comprise substituents such as hydrogen, methyl, ethyl, alkyl, alkenyl, alkynyl, alkoxy, phosphate, cycloalkyl, heterocycloalkyl, cycloalkenyl, dimethyl or phenyl and preferably is C substituted with C, O, P, H, OH, phosphate, alkyl, alkenyl, alkynyl any of which may be (d-Cv), or phenyl, any of which may be substituted with O, OH, methyl, dimethyl, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, phenyl, methoxy, ethoxy, alkoxy or phosphate, any of which may be further substituted with methyl, ethyl or phenyl and more preferably is C substituted with alkyl, alkenyl, any of which may be (C4-Cw) any of which may be further substituted with O, OH, methoxy, ethoxy or methyl any of which may be further substituted with methyl, ethyl, or phenyl, wherein v is an integer of from 1 to 30 and w is an integer of from 5 to 18.
6. The use of a combination of compounds according to any of claims 1 to 3, comprising a classic or non-classic cannabinoid of the general formula:
Figure imgf000124_0001
wherein R1 , R2, R3 and R4 individually is a chemical moiety or a chemical bond.
7. The use of a cannabinoid as defined in claim 6, wherein R1 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(d-4)-alkyl, heteroaryl-(d-4)-alkyl, heterocyclyl-(Ci-4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl or phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(C1_4)-alkyl, heteroaryl-(Ci_4)-alkyl, heterocyclyl-(Ci_4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, or nitro, and preferably is C, O, N optionally substituted with O, OH, alkyl, alkenyl, alkynyl, or phosphate, optionally further substituted with methyl, alkyl or phosphate and more preferably is C, optionally substituted with H, OH, OCH3 or phosphate.
8. The use of a combination of compounds according to any of claims 1 to 3, wherein the two or more compounds comprise at least one cannabinoid which is a classical cannabinoid of the general formula:
Figure imgf000124_0002
wherein R1 , R2, R3, R4 and R5 individually is a chemical moiety or a chemical bond.
9. The use of a cannabinoid as defined in claim 8, wherein R1 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(Ci_4)-alkyl, heteroaryl-(Ci_4)-alkyl, heterocyclyl-(Ci_4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally bonding with the C in the ring next to R5, optionally further substituted one or more times with C, S, N, O, OH, phenyl, phosphate, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci-4)- alkyl, heteroaryl-(Ci_4)-alkyl, heterocyclyl-(Ci_4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, or nitro, and preferably is C, O, N optionally substituted with O, OH, alkyl, alkenyl, alkynyl, or phosphate, optionally further substituted with alkyl or phosphate and more preferably is C, optionally substituted one or more times with H, O, OH, OCH3 or phosphate.
10. The use of a combination of compounds according to any of claims 1 to 3, wherein the cannabinoid or cannabimimetic compound is an eicosanoid or other of the general formula:
R1 R2
wherein R1 and R2 individually is a chemical moiety or a chemical bond.
1 1 . The use of a cannabinoid or cannabimimetic compound of claim 10, wherein R1 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(Ci_4)-alkyl, heteroaryl-(Ci-4)-alkyl, heterocyclyl-(Ci-4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(d-4)-alkyl, heteroaryl-(Ci-4)-alkyl, heterocyclyl-(Ci- 4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, or nitro, and preferably is (CI -Cx) is saturated or unsaturated and optionally is substituted one or more times with lower alkyl, alkenyl, alkynyl, O, OH, N and wherein x is an integer of from 1 to 30, more preferably is (C1 -CY), is saturated or unsaturated and optionally substituted with methyl, dimethyl, O, or N and wherein Y is an integer of from 15 to 21.
12. The use of a combination of compounds according to any of claims 1 to 3, wherein the at least one cannabinoid is an aminoalkylindole of the general formula:
Figure imgf000126_0001
wherein R1 , R2, R3 and R4 individually is a chemical moiety or a chemical bond.
13. The use of a cannabinoid as defined in claim 12, wherein R1 is selected from the group of: C, S, N, O, optionally substituted with C, S, N, O, P, OH, hydrogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, amine (NH), halogen, substituted lower alkyl, aryl, heterocycloalkyl, heteroaryl, aryl-(C1_4)-alkyl, heteroaryl-(d-4)-alkyl, heterocyclyl-(Ci-4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, phosphate, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, methyl, substituted lower alkyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci-4)-alkyl, heteroaryl-(Ci-4)-alkyl, heterocyclyl-(Ci-4)-alkyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, alkoxy, carboxy, halogen, trifluoromethyl, cyano, amino, or nitro, and preferably is C, O , N optionally substituted with O, phosphate, N, C, lower alkyl, OH, optionally further substituted with lower alkyl, OH, phosphate and more preferably is C, substituted with O, further substituted with methyl.
14. The combination treatment according to claim 1 , wherein the adenosine analog is 5'-AMP.
15. The combination treatment according to claim 1 , wherein the adenosine receptor agonist is selected from the group consisting of NECA, (R)-PIA, (S)-PIA, AB- NECA, CCPA, CGS 21680, CGS 21680, CGS 24012, 2-chloroadenosine, 2-hexynyl-NECA, IB-MECA, N(6)-cyclopentyladenosine, (R,S)-PHPNECA, IAB-MECA, IB-MECA, CI-IB-MECA, cyclopentyladenosine, I-ABA, IAB-MECA, MCP-NECA, MPC-MECA, PENECA, AB-MECA, APNEA, CV- 1674, CV-1808, cyclopentyladenosine, 2-hexynyl-NECA, metrifudil, N(6)-cyclohexyladenosine, LUF5831 and Tecadenoson (CV-510).
16. The combination treatment according to claim 1 , wherein the adenosine uptake inhibitor is dipyridamole or theofyllin.
17. The combination treatment according to claim 1 , wherein the neurotensin analog is selected from the group consisting of NT64D, NT64L, NT65L, NT66D, NT66L, NT67L, NT69L, NT71 , NT72, NT73, NT74, NT75, NT76, NT77, Trp1 1 NT, contulakin-G, EISAI- 1 , EISAI-2, JMV2004, JMV2012, JMV431 , JMV449,
JMV457, JMV458, large neuromedin, large neurotensin, neuromedin, neurotensin, [125l]neurotensin, Thr10contulakin-G, D-Trp1 1 -neurotensin, levocabastine, SR48692, xenin, PD-149163 and CGX-1 160.
18. The combination treatment according to claim 1 , wherein the thyroxine derivative is selected from the group consisting of Thyroxine (T4), 3,5,3'-triiodothyronine (T3), Thyronamine (TOAM); 3-lodothyronamine (T1AM), 3,5-Diiodothyronamine (T2AM) and 3,5,3'-Triiodothyronamine (T3AM).
19. The combination treatment according to claim 1 , wherein the cytochrome c oxidase inhibitor is selected from the group consisting of hydrogen sulfide (H2S), cyanide (CN) or its derivates such as hydrogen cyanide (HCN) or sodium nitroprusside (Na2[Fe(CN)5NO]^H2O), Azide and its derivates, Carbon monoxide (CO) and Sodium sulfide (Na2S).
20. The combination treatment according to claim 1 , wherein the oxygen tension reducer is selected from the group consisting of Carbon monoxide (CO), Sodium sulfide (Na2S) and hydrogen sulfide (H2S).
21 . The use according to claim 1 , wherein the two or more compounds are selected among the vanilloid receptor agonist of any of claims 4 to 5 and the cannabinoid or cannabimimetic compound of any of claims 6 to 13 and the adenosine compound of any of claims 14 to 16 and the neurotensin or neurotensin analog of claim 17 and the thyroxine derivative of claim 18 and the cytochrome c oxidase inhibitor of claim 19 and the oxygen tension reducer of claim 20.
22. The use according to claim 1 , wherein the at least one vanilloid receptor agonist is the vanilloid receptor agonist of any of claims 4 to 5 and the cannabinoid or cannabimimetic compound is the cannabinoid of any of claims 6 to 13 and the adenosine or adenosine analog or adenosine receptor agonist or adenosine uptake inhibitor of any of claims 14 to 16 and the neurotensin or neurotensin analog or neurotensin receptor agonist of claim 17 and the thyroxine derivative of claim 18 and the cytochrome c oxidase inhibitor of claim 19 and the oxygen tension reducer of claim 20.
23. The use according to any of claims 1 to 3 for the manufacture of a medicament according to claims 4 to 22 for the induction of hypothermia in an individual suffering from or at risk of suffering from ischemia.
24. The use according to any of claims 1 to 3 for the manufacture of a medicament according to any of claims 4 to 23 for prophylaxis and/or treatment of ischemia in connection with cardiovascular diseases, asphyxia and/or traumatic brain injuries.
25. The use according to any of claims 1 to 3 and/or 23, wherein the ischemia is due to cardiovascular diseases such as: myocardial infarction, cardiac arrest, stroke, arterial aneurism, subarachnoid haemorrhage, arteriosclerosis, angina pectoris, hypertension, hypercholesterolemia, cardiac arrhythmia, cardiomegaly, cardiomyopathy, heart valve regurgitation and heart valve stenosis.
26. The use according to any of claims 1 to 3 and/or 23, wherein the ischemia is due to asphyxia such as: perinatal asphyxia and/or non-perinatal asphyxia.
27. A medicament comprising a combination of compounds according to any of claims 4 to 20 capable of inducing hypothermia in an individual as defined in any of claims 1 to 3 and 21 to 26.
28. The medicament according to claim 27, for prophylactic and/or therapeutic applications.
29. The medicament according to any of claims 27 or 28, for therapeutic applications.
30. The medicament according to any of claims 27 to 29, wherein the medicament induces hypothermia of between 32 and 36 degree Celsius.
31 . The medicament according to any of claims 27 to 30, comprising at least two compounds selected from the vanilloid receptor agonist of any of claims 4 to 5 and the cannabinoid or cannabimimetic compound of any of claims 6 to 13 and the adenosine compound of any of claims 14 to 16 and the neurotensin or neurotensin analog of claim 17 and the thyroxine derivative of claim 18 and the cytochrome c oxidase inhibitor of claim 19 and the oxygen tension reducer of claim 20.
32. The medicament according to claim 31 , wherein at least one compound induces hypothermia rapidly.
33. The medicament according to any of claims 31 and 32, wherein at least one compound induces hypothermia slowly.
34. The medicament according to any of claims 27 to 33, comprising a further active ingredient.
35. The medicament according to claim 34, wherein the further active ingredient is selected from the group of: neurotensins, analgesics, opioids, GABAs and adrenergic antagonists.
36. The medicament according to any of claims 27 to 35, comprising a pharmaceutically acceptable carrier.
37. The medicament according to any of claims 27 to 36, wherein the pH of the composition is between pH 5 and pH 9.
38. The medicament according to any of claims 27 to 37, for administration by injection, suppository, oral administration, sublingual tablet or spray, cutaneous administration, or inhalation.
39. The medicament according to claim 38, wherein the injection is intravenous, intramuscular, intraspinal, intraperitoneal, subcutaneous, a bolus or a continuous administration.
40. The medicament according to any of claims 27 to 39, wherein administration occurs at intervals of 30 minutes to 48 hours.
41 . The medicament according to any of claims 27 to 40, wherein administration occurs at intervals of 1 to 6 hours.
42. The medicament according to any of claims 27 to 41 , wherein the duration of the treatment is from 6 to 72 hours.
43. The medicament according to any of claims 27 to 42, wherein the dosage of the medicament is between 10 μg to 80 mg pr kg body mass.
44. A kit of parts comprising the medicament as defined in any of claims 27 to 43.
45. Use of a combination of compounds according to any of claims 4 to 20 for the preparation of a medicament for obviating the use according to claim 1.
46. A method for inducing hypothermia in an individual comprising administering to said individual an effective amount of a combination of compounds as defined in any of claims 1 to 20.
47. Combination of compounds for use in induction of hypothermia in a human being for treatment of ischemic damages, wherein the compound is as defined in any of claims 1 to 20.
48. Combination of compounds for use in induction of hypothermia in a human being suffering from or at risk of suffering from ischemia, wherein the compound is as defined in any of claims 1 to 20.
49. The combination of compounds according to claim 47 or 48, for prophylaxis and/or treatment of ischemic damages in connection with cardiovascular diseases, asphyxia, traumatic brain injuries and/or organ transplantation.
50. The combination of compounds according to claim 49, wherein the ischemia is due to cardiovascular diseases such as: myocardial infarction, acute coronary syndrome, cardiac arrest, stroke, arterial aneurism, subarachnoid haemorrhage, arteriosclerosis, angina pectoris, hypertension, hypercholesterolemia, cardiac arrhythmia, cardiomegaly, cardiomyopathy, cardiac surgery, heart valve regurgitation and heart valve stenosis.
51. The combination of compounds according to claim 49, wherein the ischemia is due to asphyxia such as: perinatal asphyxia and/or non-perinatal asphyxia.
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