WO2009071097A1 - Use of hypothermia inducing drugs - Google Patents

Use of hypothermia inducing drugs Download PDF

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Publication number
WO2009071097A1
WO2009071097A1 PCT/DK2008/050295 DK2008050295W WO2009071097A1 WO 2009071097 A1 WO2009071097 A1 WO 2009071097A1 DK 2008050295 W DK2008050295 W DK 2008050295W WO 2009071097 A1 WO2009071097 A1 WO 2009071097A1
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body weight
hypothermia
neurotensin
compound
ischemia
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PCT/DK2008/050295
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French (fr)
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Jacob Gotfredsen
Uno Jakob Weber
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Neurokey A/S
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Publication of WO2009071097A1 publication Critical patent/WO2009071097A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids
    • 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 compounds for the induction of hypothermia, such as 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].
  • 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 -24]. Re- lease 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 hypo- thermia 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 compound capable of inducing hypothermia would not only solve the problem of preventing the effects of ischemia, but also be relevant as a safer and less expensive alternative to the currently employed mechanical methods.
  • the present inventors have found that it is possible to medically induce hypothermia in human beings by administration of a neurotensin or a neurotensin analogue.
  • 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 a compound capable of inducing hypothermia, thereby benefiting patients suffering from illnesses characterized by tissue ischemia and anoxia.
  • a pharmaceutical composition comprising a compound capable of inducing hypothermia, thereby benefiting patients suffering from illnesses characterized by tissue ischemia and anoxia.
  • the inventors have found that such hypothermic effects can be obtained in humans as a result of compounds such as neurotensins or neurotensin agonists reaching and binding to neurotensin receptors.
  • the present invention discloses the use of a compound for the induction of hypothermia for the preparation of a medicament for the treatment of ischemia in an individual. It is also an aspect of the present invention to provide a medicament comprising a compound 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.
  • a neurotensin receptor agonist is a neurotensin or a neurotensin mimetic compound.
  • an agonist is a compound capable of inducing hypothermia by binding to a receptor.
  • a neurotensin receptor antagonist is a substance capable of inhibiting the effect of a neurotensin receptor agonist.
  • Alcohol A class of organic compounds containing one or more hydroxyl groups (OH).
  • OH hydroxyl groups
  • 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.
  • 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.
  • 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.
  • Ischemia Restriction in blood supply with resultant dysfunction or damage of tissue.
  • Ischemic tissue damage Tissue damage due to ischemia.
  • a neurotensin mimetic compound is any compound capable of mimicking the natural neurotensin thus inducing a similar physiological response as that caused by natural neurotensin, such as a neurotensin analog.
  • 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 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 also known as Sortilin has a single transmembrane domain and is encoded by the SORTI 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,
  • NT64D 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
  • NT NT64D
  • NT65L is a compound capable of imposing an agonizing
  • composition refers to any chemical or biological material, compound, or composition 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.
  • 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.
  • the principle of the present invention is the use of neurotensins and/or neurotensin mimetic compounds for induction of hypothermia, such as for alleviating the 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 are initiated and continue 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 that results from activation of microglia and other cell types; Reduction of the excitotoxic-neurotransmitter release that over- stimulates neighboring neurons; Lowering of the metabolic rate and subsequent energy depletion; and anti-inflammatory action.
  • 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.
  • 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, su- barachnoid haemorrhage, arteriosclerosis, 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”).
  • clot-busters e.g. tPA
  • 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 An- gioplasty [PTCA], Percutaneous Coronary Interventions [PCI], Balloon Angioplasty and Coronary Artery Balloon Dilation), and coronary artery bypass graft surgery (CABG).
  • resuscitation early CPR, early defibrillation, early advanced care
  • thrombolysis also known as Percutaneous Transluminal Coronary An- gioplasty [PTCA], Percutaneous Coronary Interventions [PCI], Balloon Angioplasty and Coronary Artery Balloon Dilation
  • PTCA Percutaneous Transluminal Coronary An- gioplasty
  • PCI Percutaneous Coronary Interventions
  • Balloon Angioplasty and Coronary Artery Balloon Dilation Balloon Angioplasty and Coronary Art
  • 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.
  • Perina- tal 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.
  • 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
  • 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 compound 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.
  • 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 hyperther- mia 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 compound of the present invention is preferably administered pre-operatively. It is also an aspect of the invention to provide a compound 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 it is an object of the present invention to administer a compound as 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 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.
  • induction of hypothermia in an individual can follow a predictable course and be responsive to the dose in which the compound 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 single compound 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 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.
  • 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 compound for the production of a medicament for the induction of hypothermia in an individual suffering from ischemia, wherein the compound 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, or between 34 and 32 degree, such as 33 and 32 degree Celsius, alternatively between 36 and 33 degree or 35 and 32 degree Celsius.
  • the compound of the present is capable of inducing hypothermia in the range of between 36 to 32 degree Celsius, and more preferably between 35 and 33 degree Celsius.
  • the temperature range or specific temperature a given compound is capable of inducing is herein also referred to as the target temperature of the compound and/or the medicament comprising the compound.
  • An aspect of the present invention regards the treatment of an individual in need thereof by the use of a compound 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 temperatures due to fever, hyperthermia, hyperpyrexia, malign hyperpyrexia or are in need of treatment, such but not limited to surgery, wherein the outcome of the procedure or the procedure itself is benefitted by a reducing in temperature of the individual undergoing the treatment and/or surgery.
  • 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 relate 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 synthesized 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 transmission 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 localization of both its messenger RNA and its protein in structures implicated in the descending control of nociceptive inputs, 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 for the induction of hypothermia in a human being, especially for the preparation of a medicament comprising a compound of the group consisting neurotensin receptor agonists for the induction of hypothermia in an individual.
  • the one or more compounds the present invention are selected from the group consisting of neurotensin, NT64D, NT64L, NT65L, NT66D, NT66L, NT67L, NT69L, NT71 , NT72, NT73, NT74, NT75, NT76, NT77, Trp1 1 NT, contu- lakin-G, EISAI-1 , EISAI-2, JMV2004, JMV2012, JMV431 , JMV449, JMV457, JMV458, large neuromedin, large neurotensin, neuromedin, [ 125 l]neurotensin, Thr1 Ocontulakin-G, D-Trp1 1 -neurotensin, levocabastine, SR48692, xenin, PD- 149163, CGX-1 160 and the neurotensin analogues KK13 and KK14.
  • compounds of the present invention have at least 95% sequence identity to peptide members of the group consisting of NT64D, NT64L, NT65L, NT66D, NT66L, NT67L, NT69L, NT71 , NT72, NT73, NT74, NT75, NT76, NT77, Trp1 1 NT,
  • compounds of the present invention have at least 90% sequence identity to peptide members of the group consisting of NT64D, NT64L, NT65L, NT66D, NT66L, NT67L, NT69L, NT71 , NT72, NT73, NT74, NT75, NT76, NT77, Trp1 1 NT,
  • compounds of the present invention have at least 85% sequence identity to peptide members of the group consisting of NT64D, NT64L, NT65L, NT66D, NT66L, NT67L, NT69L, NT71 , NT72, NT73, NT74, NT75, NT76, NT77, Trp1 1 NT,
  • compounds of the present invention have at least 80% sequence identity to peptide members of 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, Thr1 Ocontulakin-G, D-Trp1 1 -neurotensin, levocabastine, SR48692, xenin, PD-149163 and CGX-1 160.
  • compounds of the present invention have at least 75% sequence identity to peptide members of the group consisting of NT64D, NT64L, NT65L, NT66D, NT66L, NT67L, NT69L, NT71 , NT72, NT73, NT74, NT75, NT76, NT77, Trp1 1 NT,
  • compounds of the present invention have at least 70% sequence identity to peptide members of the group consisting of NT64D, NT64L, NT65L, NT66D, NT66L, NT67L, NT69L, NT71 , NT72, NT73, NT74, NT75, NT76, NT77, Trp1 1 NT,
  • compounds of the present invention have at least 65% sequence identity to peptide members of the group consisting of NT64D, NT64L, NT65L, NT66D, NT66L, NT67L, NT69L, NT71 , NT72, NT73, NT74, NT75, NT76, NT77, Trp1 1 NT,
  • compounds of the present invention have at least 60% sequence identity to peptide members of the group consisting of NT64D, NT64L, NT65L, NT66D, NT66L, NT67L, NT69L, NT71 , NT72, NT73, NT74, NT75, NT76, NT77, Trp1 1 NT,
  • compounds of the present invention have at least 55% sequence identity to peptide members of the group consisting of NT64D, NT64L, NT65L, NT66D, NT66L, NT67L, NT69L, NT71 , NT72, NT73, NT74, NT75, NT76, NT77, Trp1 1 NT,
  • compounds of the present invention have at least 50% sequence identity to peptide members of the group consisting of NT64D, NT64L, NT65L, NT66D, NT66L, NT67L, NT69L, NT71 , NT72, NT73, NT74, NT75, NT76, NT77, Trp1 1 NT,
  • 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
  • the compounds of the present invention may, apart from inducing hypothermia, induce secondary effects or have other characteristics. These may be related to the nature of the compounds and may thus be more or less desirable.
  • a preferred compound of the present invention is a compound capable of binding a neurotensin 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 and metabolically stable.
  • These compounds are herein termed antagonists and exert their antagonistic effect by blocking the ability of any of the neurotensin or neurotensin mimetic 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 includes but is not limited to: SR142948A, SR48692 and SR48527.
  • the induction of hypothermia by any of the herein described compounds is performed by preparing, producing and thus providing a medicament or pharmaceutical composition comprising at least one of said compounds.
  • the medicament of the present invention is thus for the induction of hypothermia in an individual for the treatment and/or prophylaxis of ischemia in said individual.
  • the present invention provides a medicament comprising a compound and a further active ingredient selected from the group of: analgesics, opioids, GABAs and adrenergic antagonists.
  • 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 compound of the present invention or a pharmaceutically acceptable salt thereof, as herein defined, and a pharmaceutically acceptable carrier there for.
  • the 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 compounds of the invention or its pharmaceutically acceptable salt or a crystal form thereof as the active component.
  • 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 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 alkanola- mides, and polyoxyethylenepolypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl-. beta.-aminopropionates, and 2-alkyl-imidazoline quater- nary 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 pre- pared from sterile powders, granules, and tablets of the kind previously described.
  • 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 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, hydro- bromic, 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, monohydro- genphosphate, 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, methanesul- fonate, 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 pref- erably 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 invention provides a compound 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, 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, perinatal asphyxia and non-perinatal asphyxia as well as traumatic brain injury.
  • Individuals at risk of suffering from ischemia are often individuals who have previ- ously 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 compound 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 of inducing hypothermia and/or lowering the body temperature of these individuals.
  • 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 com- pounds 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 present invention are equal to the temperatures that the compound itself 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 in the range of between 36 to 32 degree Celsius, and more preferably between 35 and 33 degree Celsius.
  • Another embodiment is the reduction of body temperature from an elevated 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 compound 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 compound is capable of inducing is herein also referred to as the target temperature of the compound or the combination of compounds and/or the medicament comprising the compound.
  • 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 compound / medicament / treatment 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.
  • 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.
  • the subcutaneous and intramuscular forms of parenteral administration are generally preferred.
  • Appropriate dosage forms for such administration may be prepared by conventional techniques.
  • the 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 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, intracerebral, intraperitoneal, subcutaneous, a bolus or a continuous administration.
  • a highly preferred embodiment of the present invention is a medicament for intraperitoneal administration.
  • the most preferable mode of administration of a medicament comprising a compound according to the present invention for the induction of hypothermia in an individual suffering from ischemia is by intravenous injection.
  • 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, infant or old.
  • 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 compound according to the invention depends on the compound in question; however, the amount of the compound is also closely related to the pharmaceutical composition of the medicament, any second compound of the medicament or any second 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 intravenous dosage regimen will preferably be from about 0.01 to 50 mg/kg of total body weight, such as between 0.01 and 50 mg/kg body weight, for example between 0.02 and 50 mg/kg body weight, such as between 0.03 and 50 mg/kg body weight, for example between 0.04 and 50 mg/kg body weight, such as between 0.05 and 50 mg/kg body weight, for example between 0.06 and 50 mg/kg body weight, such as between 0.07 and 50 mg/kg body weight, for example between 0.08 and 50 mg/kg body weight, such as between 0.09 and 50 mg/kg body weight, for example between 0.1 and 50 mg/kg body weight, such as between 0.2 and 50 mg/kg body weight, for example between 0.3 and 50 mg/kg body weight, such as between 0.4 and 50 mg/kg body weight, for example between 0.5 and 50 mg/kg body weight, such as between 0.6 and 50 mg/kg body weight, for example between 0.7 and 50 mg/kg body weight, such as between 0.8 and 50 mg/kg body
  • mg/kg body weight such as between 50 and 0.1 mg/kg body weight, for example between 50 and 0.09 mg/kg body weight, such as between 50 and 0.08 mg/kg body weight, for example between 50 and 0.07 mg/kg body weight, such as between 50 and 0.06 mg/kg body weight, for example between 50 and 0.05 mg/kg body weight, such as between 50 and 0.04 mg/kg body weight, for example between 50 and 0.03 mg/kg body weight, such as between 50 and 0.02 mg/kg body weight, for example between 50 and 0.01 mg/kg body weight.
  • the intravenous dosage regimen will preferably be from about 0.01 to 50 mg/kg of total body weight, such as 0.01 to 0.02 mg/kg body weight, for example 0.02 to 0.03 mg/kg body weight, such as 0.01 to 0.02 mg/kg body weight, for example 0.02 to 0.03 mg/kg body weight, such as 0.03 to 0.04 mg/kg body weight, for example 0.04 to 0.05 mg/kg body weight, such as 0.05 to 0.06 mg/kg body weight, for example 0.06 to 0.07 mg/kg body weight, such as 0.07 to 0.08 mg/kg body weight, for example 0.08 to 0.09 mg/kg body weight, such as 0.09 to 0.1 mg/kg body weight, for example 0.1 to 0.2 mg/kg body weight, such as 0.2 to 0.3 mg/kg body weight, for example 0.3 to 0.4 mg/kg body weight, such as 0.4 to 0.5 mg/kg body weight, for example 0.5 to 0.6 mg/kg body weight, such as 0.6 to 0.7
  • the intraperitoneal dosage regimen will be from 0.01 to 50 mg/kg of total body weight, such as between 10 ⁇ g to 1 mg pr kg total body weight, depending on the neurotensin of choice. It has been found that neurotensins varies with respect to potency and affinity for the neurotensin receptor as well as with respect to molecular weight.
  • the exact dosage may be calculated based on the calf study model described in Example 15.
  • 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 compound, alone or in combination 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 compound or compounds employed and the effect to be achieved, as well as the pharmacodynamics associated with each compound 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 a compound according to the invention. 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.
  • the medicament may be administered in any suitable dosage regime, suitable as to the potency of the compound / drug, the target temperature to be reached, the speed of action of the compound, the metabolic stability of the compound, 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 24 hours, such as intervals of 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 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
  • a pharmaceutical composition comprising a compound as herein described and furthermore comprising a second (or further) active ingredient.
  • the second active ingredient may increase the hypothermic effect of the compound of the invention, or may have an alternative medical effect such as inducing pain relief or vasodilation.
  • the second active ingredient may thus be selected from the non-limiting group of: analgesics, opiods, 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 hy- pothalamus 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
  • a medicament comprising neurotensin and/or neurotensin analogs 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 buprenor- phine; 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 buprenor- phine; 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 ven- tricular 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.
  • a subcutaneous or intravenous bolus injection of a compound of this invention is administered.
  • the dose is in the interval 0.5 mg/kg to 50 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 subcutaneous or intravenous bolus injection of a compound of this invention is ad- ministered. The dose is in the interval 0.5 mg/kg to 50 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).
  • addi- tional 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 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.
  • a subcutaneous or intravenous bolus injection of a compound of this invention is administered. The dose is in the interval 0.5 mg/kg to 50 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 subcutaneous or intravenous bolus injection of a compound of this invention is administered.
  • the dose is in the interval 0.5 mg/kg to 50 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 rec- ommendation). Depending on the individual's response to the medication 1 -8 additional bolus injections may be required.
  • 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.
  • a subcutaneous or intravenous bolus injection of a compound of this invention is administered.
  • the dose is in the interval 0.5 mg/kg to 50 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 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.
  • a subcutaneous or intravenous bolus injection of a compound of this invention is administered. The dose is in the interval 0.5 mg/kg to 50 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 rec- ommendation). Depending on the individual's response to the medication 1 -8 additional bolus injections may be required.
  • a 78-year-old woman is admitted to hospital 50 minutes after experiencing sudden onset lack of mobility of the left arm and leg as well as 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.
  • a subcutaneous or intravenous bolus injection of a compound of this invention is administered.
  • the dose is in the interval 0.5 mg/kg to 50 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).
  • addi- tional 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.
  • a subcutaneous or intravenous bolus injection of a compound of this invention is administered.
  • the dose is in the interval 0.5 mg/kg to 50 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 rec- ommendation). Depending on the individual's response to the medication 1 -8 additional bolus injections may be required.
  • a 55-year-olm 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.
  • a subcutaneous or intravenous bolus injection of a compound of this invention is administered. The dose is in the interval 0.5 mg/kg to 50 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).
  • addi- tional 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.
  • a subcutaneous or intravenous bolus injection of a compound of this invention is administered.
  • the dose is in the interval 0.5 mg/kg to 50 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 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.
  • a subcutaneous or intravenous bolus injection of a compound of this invention is administered. The dose is in the interval 0.5 mg/kg to 50 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.
  • TRPV1 activity is assessed in vitro by measuring vanilloid receptor agonist induced Ca 2+ flux using FLIPR and HEK293 cells stably expressing recombinant human and rat TRPVI (hTRPV1 -HEK293 and rTRPV1 -HEK293, respec- tively). Intracellular Ca 2+ level is measured in TRPV1 -expressing cells during exposure to compounds. A concentration dependent increase in Ca 2+ influx is observed using both human and rat cell lines. The efficacy of agonists is estimated by comparing it to the maximum response induced by capsaicin.
  • the compound is 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.
  • 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.
  • hypothermia 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.
  • telemetry equipment e.g. implanted telemetry from Data Sciences International
  • 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 is 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 treatment by neurotensin compounds according to the invention, the treatment is 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.
  • 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; they 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 they are subjected to a day cycle consisting of 16 hours of light fol- lowed by 8 hours of dark.
  • the ambient temperature is 20°C+/-2°C.
  • the compounds investigated are administered i.v. (in the jugular vein) and/or i.p. and/or s.c. as bolus injections and consists of 1 solitary injection, alternatively 2-8 repeated injections within a timeframe of 12-24 hours from the initial injection.
  • Temperature is measured using a temperature probe (ADInstruments) that is surgically positioned in vena cava crani- alis 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 of the neurotensin compounds.
  • 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 after the com- pounds have been administered. Data is collected using a Powerlab. References
  • Fujishima M Hypothermia inhibits ischemia-induced efflux of amino acids and neuronal damage in the hippocampus of aged rats. Brain Res 2000; 884(1 -2):23- 30.
  • 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.
  • Pulsinelli W Pathophysiology of acute ischaemic stroke. Lancet 1992; 339(8792):533-536.
  • Eguchi Y, Yamashita K, Iwamoto T, lto H Effects of brain temperature on calmodulin and microtubule-associated protein 2 immunoreactivity in the gerbil hippocampus following transient forebrain ischemia. J Neurotrauma 1997; 14(2):109-1 18.
  • Handler CM Bradley EA, Geller EB, Adler MW: A study of the physiological mechanisms contributing to neurotensin induced hypothermia Life Sci. (1993) 54:95-100
  • SEQ ID NO. 8 NT69L N-methyl-Arg L-Lys L-Pro L-neo-Trp tert-Leu L-Leu

Abstract

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 a neurotensin or a neurotensin analog or a synthetic neurotensin or a neurotensin receptor agonist, thereby inducing hypothermia, thus benefiting patients suffering from illnesses characterized by tissue anoxia.

Description

Use of hypothermia inducing drugs
Field of invention
The present invention relates to the use of compounds for the induction of hypothermia, such as 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 co- matose 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].
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 -24]. Re- lease 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 hypo- thermia 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 compound capable of inducing hypothermia would not only solve the problem of preventing the effects of ischemia, but also be relevant as a safer and less expensive alternative to the currently employed mechanical methods.
Katz et al [37-38], Kokko et al [39] and Handler et al [40] have demonstrated hypothermic effect of neurotensin analogues in rats whereas induction of hypothermia in mice has been demonstrated by Merritt et al [41]. Medical induction of hypothermia in animals having a body weight of 300 g and 30 g for rats and mice respectively differs significantly from induction of hypothermia in humans having an average body weight of 70-75 kg, i.e. a 250- and 2500-fold difference in body weight respectively, and thus volume that has to be reduced in temperature when inducing hypothermia.
Summary of invention
The present inventors have found that it is possible to medically induce hypothermia in human beings by administration of a neurotensin or a neurotensin analogue. Thus, 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 a compound capable of inducing hypothermia, thereby benefiting patients suffering from illnesses characterized by tissue ischemia and anoxia. The inventors have found that such hypothermic effects can be obtained in humans as a result of compounds such as neurotensins or neurotensin agonists reaching and binding to neurotensin receptors.
Thus the present invention discloses the use of a compound for the induction of hypothermia for the preparation of a medicament for the treatment of ischemia in an individual. It is also an aspect of the present invention to provide a medicament comprising a compound 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 compound according for the preparation of a medicament for obviating the induction of hypothermia in an individual, is an aspect of the present invention.
Detailed description of the invention
Definitions
Agonist: A neurotensin receptor agonist is a neurotensin or a neurotensin mimetic compound. In the context of the present invention, an agonist is a compound capable of inducing hypothermia by binding to a receptor.
Antagonist: A neurotensin receptor antagonist is a substance capable of inhibiting the effect of a neurotensin 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: the term "alicyclic 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.
Alkyl group: the term "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: the term "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: the term "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.
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: neurotensin, neurotensin analogs and peptides having at least 50% sequence identity to human neurotensin (NT or NT1 - 13) of SEQ ID NO. 1.
Hypothermia: Lowering of the body temperature below normal level.
Ischemia: Restriction in blood supply with resultant dysfunction or damage of tissue.
Ischemic tissue damage: Tissue damage due to ischemia.
Mimetic: A neurotensin mimetic compound is any compound capable of mimicking the natural neurotensin thus inducing a similar physiological response as that caused by natural neurotensin, such as a neurotensin analog.
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 also known as Sortilin has a single transmembrane domain and is encoded by the SORTI 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, levocabas- tine, SR48692, xenin, PD-149163 and CGX-1 160.
Pharmaceutical composition: or drug, medicament or agent refers to any chemical or biological material, compound, or composition 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.
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.
The principle of the present invention is the use of neurotensins and/or neurotensin mimetic compounds for induction of hypothermia, such as for alleviating the 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 are initiated and continue 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 that results from activation of microglia and other cell types; Reduction of the excitotoxic-neurotransmitter release that over- stimulates neighboring neurons; Lowering of the metabolic rate and subsequent energy depletion; and anti-inflammatory action.
It is an object of the present invention to provide a compound capable of inducing hypothermia in an individual and further to provide the use of said compound 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.
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, su- barachnoid haemorrhage, arteriosclerosis, 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 compound 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 medicament 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 An- gioplasty [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. Perina- tal 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 compound 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 compound 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 compound 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 hyperther- mia is malignant hyperthermia which may arise due to administration of general anesthesia.
It is an object of the present invention to provide a compound 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 compound for the induction of hypothermia in an individual prior to surgery. The compound of the present invention is preferably administered pre-operatively. It is also an aspect of the invention to provide a compound 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 compound as 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 compound 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 single compound 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 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 compound for the production of a medicament for the induction of hypothermia in an individual suffering from ischemia, wherein the compound 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, or between 34 and 32 degree, such as 33 and 32 degree Celsius, alternatively between 36 and 33 degree or 35 and 32 degree Celsius. Preferably, the compound of the present is capable of inducing hypothermia in the range of between 36 to 32 degree Celsius, and more preferably between 35 and 33 degree Celsius.
It is also an object of the present invention to provide a compound 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 compound 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 compound is capable of inducing is herein also referred to as the target temperature of the compound and/or the medicament comprising the compound.
It is also an object of the present invention to provide a compound 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 compound 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 compound 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 temperatures due to fever, hyperthermia, hyperpyrexia, malign hyperpyrexia or are in need of treatment, such but not limited to surgery, wherein the outcome of the procedure or the procedure itself is benefitted by a reducing in temperature of the individual undergoing the treatment and/or surgery.
Neurotensins
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 relate 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 synthesized 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. o
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 transmission 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 localization of both its messenger RNA and its protein in structures implicated in the descending control of nociceptive inputs, 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 for the induction of hypothermia in a human being, especially for the preparation of a medicament comprising a compound of the group consisting neurotensin receptor agonists for the induction of hypothermia in an individual.
Thus, in an aspect the one or more compounds the present invention are selected from the group consisting of neurotensin, NT64D, NT64L, NT65L, NT66D, NT66L, NT67L, NT69L, NT71 , NT72, NT73, NT74, NT75, NT76, NT77, Trp1 1 NT, contu- lakin-G, EISAI-1 , EISAI-2, JMV2004, JMV2012, JMV431 , JMV449, JMV457, JMV458, large neuromedin, large neurotensin, neuromedin, [125l]neurotensin, Thr1 Ocontulakin-G, D-Trp1 1 -neurotensin, levocabastine, SR48692, xenin, PD- 149163, CGX-1 160 and the neurotensin analogues KK13 and KK14.
In another aspect compounds of the present invention have at least 95% sequence identity to peptide members of 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, Thr1 Ocontulakin-G, D-Trp1 1 -neurotensin, levocabastine, SR48692, xenin, PD-149163 and CGX-1 160.
In a further aspect compounds of the present invention have at least 90% sequence identity to peptide members of 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, Thr1 Ocontulakin-G, D-Trp1 1 -neurotensin, levocabastine, SR48692, xenin, PD-149163 and CGX-1 160.
In yet another aspect compounds of the present invention have at least 85% sequence identity to peptide members of 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, Thr1 Ocontulakin-G, D-Trp1 1 -neurotensin, levocabastine, SR48692, xenin, PD-149163 and CGX-1 160.
In a further aspect compounds of the present invention have at least 80% sequence identity to peptide members of 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, Thr1 Ocontulakin-G, D-Trp1 1 -neurotensin, levocabastine, SR48692, xenin, PD-149163 and CGX-1 160. In another aspect compounds of the present invention have at least 75% sequence identity to peptide members of 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.
In yet another aspect compounds of the present invention have at least 70% sequence identity to peptide members of 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.
In yet another aspect compounds of the present invention have at least 65% sequence identity to peptide members of 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.
In yet another aspect compounds of the present invention have at least 60% sequence identity to peptide members of 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.
In yet another aspect compounds of the present invention have at least 55% sequence identity to peptide members of 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.
In yet another aspect compounds of the present invention have at least 50% sequence identity to peptide members of 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 of the compound abbreviations are listed in the following: 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- He 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), JMV449 (H-Lys-psi(CH2NH)Lys-Pro-Tyr-lle-Leu-OH),
Preferred compound
The compounds of the present invention may, apart from inducing hypothermia, induce secondary effects or have other characteristics. These may be related to the nature of the compounds and may thus be more or less desirable.
A preferred compound of the present invention is a compound capable of binding a neurotensin 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 and metabolically stable. Antagonists
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 neurotensin or neurotensin mimetic 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 includes but is not limited to: SR142948A, SR48692 and SR48527.
Medicament
The induction of hypothermia by any of the herein described compounds is performed by preparing, producing and thus providing a medicament or pharmaceutical composition comprising at least one of said compounds. The medicament of the present invention is thus for the induction of hypothermia in an individual 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 compound 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 compound for prophylactic and/or therapeutic applications.
It is further an aspect of the present invention to provide a medicament comprising a compound for therapeutic applications. It is an aspect of the present invention to provide a medicament comprising a compound capable of inducing hypothermia in an individual in need thereof of between 32 and 36 degree Celsius.
In a further embodiment the present invention provides a medicament comprising a compound 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 compound of the present invention or a pharmaceutically acceptable salt thereof, as herein defined, and a pharmaceutically acceptable carrier there for.
The 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 compounds of the invention or its pharmaceutically acceptable salt or a crystal form thereof as the active component. 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 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 alkanola- mides, and polyoxyethylenepolypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl-. beta.-aminopropionates, and 2-alkyl-imidazoline quater- nary 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 pre- pared from sterile powders, granules, and tablets of the kind previously described. 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 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, hydro- bromic, 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, monohydro- genphosphate, 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, methanesul- fonate, 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 pref- erably 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.
Indications
The invention provides a compound 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, 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, perinatal asphyxia and non-perinatal asphyxia as well as traumatic brain injury.
Thus, it is an aspect of the present invention to provide a compound 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 previ- ously 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 compound 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 compound 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 com- pounds for treating effects of ischemia, wherein the ischemia is due to asphyxia such as: perinatal asphyxia and/or non-perinatal asphyxia.
Target temperature
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 present invention are equal to the temperatures that the compound itself 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 in the range of between 36 to 32 degree Celsius, and more preferably between 35 and 33 degree Celsius.
Another embodiment is the reduction of body temperature from an elevated 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 compound 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 compound is capable of inducing is herein also referred to as the target temperature of the compound or the combination of compounds and/or the medicament comprising the compound.
The use of a compound 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 a medicament suitable for a quick induction of hypothermia which may be of long or short duration and a medicament 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 compound / medicament / treatment 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.
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. The subcutaneous and intramuscular forms of parenteral administration are generally preferred. Appropriate dosage forms for such administration may be prepared by conventional techniques. The 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 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, intracerebral, intraperitoneal, subcutaneous, a bolus or a continuous administration.
A highly preferred embodiment of the present invention is a medicament for intraperitoneal administration.
The most preferable mode of administration of a medicament comprising a compound according to the present invention for the induction of hypothermia in an individual suffering from ischemia is by intravenous injection.
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 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, infant or old. 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 compound according to the invention depends on the compound in question; however, the amount of the compound is also closely related to the pharmaceutical composition of the medicament, any second compound of the medicament or any second 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 compounds, the intravenous dosage regimen will preferably be from about 0.01 to 50 mg/kg of total body weight, such as between 0.01 and 50 mg/kg body weight, for example between 0.02 and 50 mg/kg body weight, such as between 0.03 and 50 mg/kg body weight, for example between 0.04 and 50 mg/kg body weight, such as between 0.05 and 50 mg/kg body weight, for example between 0.06 and 50 mg/kg body weight, such as between 0.07 and 50 mg/kg body weight, for example between 0.08 and 50 mg/kg body weight, such as between 0.09 and 50 mg/kg body weight, for example between 0.1 and 50 mg/kg body weight, such as between 0.2 and 50 mg/kg body weight, for example between 0.3 and 50 mg/kg body weight, such as between 0.4 and 50 mg/kg body weight, for example between 0.5 and 50 mg/kg body weight, such as between 0.6 and 50 mg/kg body weight, for example between 0.7 and 50 mg/kg body weight, such as between 0.8 and 50 mg/kg body weight, for example between 0.9 and 50 mg/kg body weight, such as between 1.0 and 50 mg/kg body weight, for example between 1 .1 and 50 mg/kg body weight, such as between 1 .2 and 50 mg/kg body weight, for example between 1.3 and 50 mg/kg body weight, such as between 1 .4 and 50 mg/kg body weight, for example between 1 .5 and 50 mg/kg body weight, such as between 1 .6 and 50 mg/kg body weight, for example between 1 .7 and 50 mg/kg body weight, such as between 1.8 and 50 mg/kg body weight, for example between 1 .9 and 50 mg/kg body weight, such as between 2.0 and 50 mg/kg body weight, for example between 2.1 and 50 mg/kg body weight, such as between 2.2 and 50 mg/kg body weight, for example between 2.3 and 50 mg/kg body weight, such as between 2.4 and 50 mg/kg body weight, for example between 2.5 and 50 mg/kg body weight, such as between 2.6 and 50 mg/kg body weight, for example between 2.7 and 50 mg/kg body weight, such as between 2.8 and 50 mg/kg body weight, for example between 2.9 and 50 mg/kg body weight, such as between 3.0 and 50 mg/kg body weight, for example between 3.1 and 50 mg/kg body weight, such as between 3.2 and 50 mg/kg body weight, for example between 3.3 and 50 mg/kg body weight, such as between 3.4 and 50 mg/kg body weight, for example between 3.5 and 50 mg/kg body weight, such as between 3.6 and 50 mg/kg body weight, for example between 3.7 and 50 mg/kg body weight, such as between 3.8 and 50 mg/kg body weight, for example between 3.9 and 50 mg/kg body weight, such as between 4.0 and 50 mg/kg body weight, for example between 4.1 and 50 mg/kg body weight, such as between 4.2 and 50 mg/kg body weight, for example between 4.3 and 50 mg/kg body weight, such as between 4.4 and 50 mg/kg body weight, for example between 4.5 and 50 mg/kg body weight, such as between 4.6 and 50 mg/kg body weight, for example between 4.7 and 50 mg/kg body weight, such as between 4.8 and 50 mg/kg body weight, for example between 4.9 and 50 mg/kg body weight, such as between 5.0 and 50 mg/kg body weight, for example between 5.1 and 50 mg/kg body weight, such as between 5.2 and 50 mg/kg body weight, for example between 5.3 and 50 mg/kg body weight, such as between 5.4 and 50 mg/kg body weight, for example between 5.5 and 50 mg/kg body weight, such as between 5.6 and 50 mg/kg body weight, for example between 5.7 and 50 mg/kg body weight, such as between 5.8 and 50 mg/kg body weight, for example between 5.9 and 50 mg/kg body weight, such as between 6.0 and 50 mg/kg body weight, for example between 6.1 and 50 mg/kg body weight, such as between 6.2 and 50 mg/kg body weight, for example between 6.3 and 50 mg/kg body weight, such as between 6.4 and 50 mg/kg body weight, for example between 6.5 and 50 mg/kg body weight, such as between 6.6 and 50 mg/kg body weight, for example between 6.5 and 50 mg/kg body weight, such as between 6.6 and 50 mg/kg body weight, for example between 6.7 and 50 mg/kg body weight, such as between 6.8 and 50 mg/kg body weight, for example between 6.9 and 50 mg/kg body weight, such as between 7.0 and 50 mg/kg body weight, for example between 7.1 and 50 mg/kg body weight, such as between 7.2 and 50 mg/kg body weight, for example between 7.3 and 50 mg/kg body weight, such as between 7.4 and 50 mg/kg body weight, for example between 7.5 and 50 mg/kg body weight, such as between 7.6 and 50 mg/kg body weight, for example between 7.7 and 50 mg/kg body weight, such as between 7.8 and 50 mg/kg body weight, for example between 7.9 and 50 mg/kg body weight, such as between 8.0 and 50 mg/kg body weight, for example between 8.1 and 50 mg/kg body weight, such as between 8.2 and 50 mg/kg body weight, for example between 8.3 and 50 mg/kg body weight, such as between 8.4 and 50 mg/kg body weight, for example between 8.5 and 50 mg/kg body weight, such as between 8.6 and 50 mg/kg body weight, for example between 8.7 and 50 mg/kg body weight, such as between 8.8 and 50 mg/kg body weight, for example between 8.9 and 50 mg/kg body weight, such as between 9.0 and 50 mg/kg body weight, for example between 9.1 and 50 mg/kg body weight, such as between 9.2 and 50 mg/kg body weight, for example between 9.3 and 50 mg/kg body weight, , such as between 9.4 and 50 mg/kg body weight, for example between 9.5 and 50 mg/kg body weight, such as between 9.6 and 50 mg/kg body weight, for example between 9.7 and 50 mg/kg body weight, such as between 9.8 and 50 mg/kg body weight, for example between 9.9 and 50 mg/kg body weight, such as between 10 and 50 mg/kg body weight, for example between 1 1 and 50 mg/kg body weight, such as between 12 and 50 mg/kg body weight, for example between 13 and 50 mg/kg body weight, such as between 14 and 50 mg/kg body weight, for example between 15 and 50 mg/kg body weight, such as between 16 and 50 mg/kg body weight, for example between 17 and 50 mg/kg body weight, such as between 18 and 50 mg/kg body weight, for example between 19 and 50 mg/kg body weight, such as between 20 and 50 mg/kg body weight, for example between 21 and 50 mg/kg body weight, such as between 22 and 50 mg/kg body weight, for example between 23 and 50 mg/kg body weight, such as between 24 and 50 mg/kg body weight, for example between 25 and 50 mg/kg body weight, such as between 26 and 50 mg/kg body weight, for example between 27 and 50 mg/kg body weight, such as between 28 and 50 mg/kg body weight, for example between 29 and 50 mg/kg body weight, such as between 30 and 50 mg/kg body weight, for example between 31 and 50 mg/kg body weight, such as between 32 and 50 mg/kg body weight, for example between 33 and 50 mg/kg body weight, such as between 34 and 50 mg/kg body weight, for example between 35 and 50 mg/kg body weight, such as between 36 and 50 mg/kg body weight, for example between 37 and 50 mg/kg body weight, such as between 38 and 50 mg/kg body weight, for example between 39 and 50 mg/kg body weight, such as between 40 and 50 mg/kg body weight, for example between 41 and 50 mg/kg body weight, such as between 42 and 50 mg/kg body weight, for example between 43 and 50 mg/kg body weight, such as between 44 and 50 mg/kg body weight, for example between 45 and 50 mg/kg body weight, such as between 46 and 50 mg/kg body weight, for example between 47 and 50 mg/kg body weight, such as between 48 and 50 mg/kg body weight, for example between 50 and 49 mg/kg body weight, such as between 50 and 48 mg/kg body weight, for example between 50 and 47 mg/kg body weight, such as between 50 and 46 mg/kg body weight, for example between 50 and 45 mg/kg body weight, such as between 50 and 44 mg/kg body weight, for example between 50 and 43 mg/kg body weight, such as between 50 and 42 mg/kg body weight, for example between 50 and 41 mg/kg body weight, such as between 50 and 40 mg/kg body weight, for example between 50 and 39 mg/kg body weight, such as between 50 and 38 mg/kg body weight, for example between 50 and 37 mg/kg body weight, such as between 50 and 36 mg/kg body weight, for example between 50 and 35 mg/kg body weight, such as between 50 and 34 mg/kg body weight, for example between 50 and 33 mg/kg body weight, such as between 50 and 32 mg/kg body weight, for example between 50 and 31 mg/kg body weight, such as between 50 and 30 mg/kg body weight, for example between 50 and 30 mg/kg body weight, such as between 50 and 29 mg/kg body weight, for example between 50 and 28 mg/kg body weight, such as between 50 and 27 mg/kg body weight, for example between 50 and 26 mg/kg body weight, such as between 50 and 25 mg/kg body weight, for example between 50 and 24 mg/kg body weight, such as between 50 and 23 mg/kg body weight, for example between 50 and 23 mg/kg body weight, such as between 50 and 22 mg/kg body weight, for example between 50 and 21 mg/kg body weight, such as between 50 and 20 mg/kg body weight, for example between 50 and 19 mg/kg body weight, such as between 50 and 18 mg/kg body weight, for example between 50 and 17 mg/kg body weight, such as between 50 and 16 mg/kg body weight, for example between 50 and 15 mg/kg body weight, such as between 50 and 14 mg/kg body weight, for example between 50 and 13 mg/kg body weight, such as between 50 and 12 mg/kg body weight, for example between 50 and 1 1 mg/kg body weight, such as between 50 and 10 mg/kg body weight, for example between 50 and 9.9 mg/kg body weight, such as between 50 and 9.8 mg/kg body weight, for example between 50 and 9.7 mg/kg body weight, such as between 50 and 9.6 mg/kg body weight, for example between 50 and 9.5 mg/kg body weight, such as between 50 and 9.4 mg/kg body weight, for example between 50 and 9.3 mg/kg body weight, such as between 50 and 9.2 mg/kg body weight, for example between 50 and 9.1 mg/kg body weight, such as between 50 and 9.0 mg/kg body weight, for example between 50 and 8.9 mg/kg body weight, such as between 50 and 8.8 mg/kg body weight, for example between 50 and 8.7 mg/kg body weight, such as between 50 and 8.6 mg/kg body weight, for example between 50 and 8.5 mg/kg body weight, such as between 50 and 8.4 mg/kg body weight, for example between 50 and 8.3 mg/kg body weight, such as between 50 and 8.2 mg/kg body weight, for example between 50 and 8.1 mg/kg body weight, such as between 50 and 8.0 mg/kg body weight, for example between 50 and 7.9 mg/kg body weight, such as between 50 and 7.8 mg/kg body weight, for example between 50 and 7.7 mg/kg body weight, such as between 50 and 7.6 mg/kg body weight, for example between 50 and 7.5 mg/kg body weight, such as between 50 and 7.4 mg/kg body weight, for example between 50 and 7.3 mg/kg body weight, such as between 50 and 7.2 mg/kg body weight, for example between 50 and 7.1 mg/kg body weight, such as between 50 and 7.0 mg/kg body weight, for example between 50 and 6.9 mg/kg body weight, such as between 50 and 6.8 mg/kg body weight, for example between 50 and 6.7 mg/kg body weight, such as between 50 and 6.6 mg/kg body weight, for example between 50 and 6.5 mg/kg body weight, such as between 50 and 6.4 mg/kg body weight, for example between 50 and 6.3 mg/kg body weight, such as between 50 and 6.2 mg/kg body weight, for example between 50 and 6.1 mg/kg body weight, such as between 50 and 6.0 mg/kg body weight, for example between 50 and 5.9 mg/kg body weight, such as between 50 and 5.8 mg/kg body weight, for example between 50 and 5.7 mg/kg body weight, such as between 50 and 5.6 mg/kg body weight, for example between 50 and 5.5 mg/kg body weight, such as between 50 and 5.4 mg/kg body weight, for example between 50 and 5.3 mg/kg body weight, such as between 50 and 5.2 mg/kg body weight, for example between 50 and 5.1 mg/kg body weight, such as between 50 and 5.0 mg/kg body weight, for example between 50 and 4.9 mg/kg body weight, such as between 50 and 4.8 mg/kg body weight, for example between 50 and 4.7 mg/kg body weight, such as between 50 and 4.6 mg/kg body weight, for example between 50 and 4.5 mg/kg body weight, such as between 50 and 4.4 mg/kg body weight, for example between 50 and 4.3 mg/kg body weight, such as between 50 and 4.2 mg/kg body weight, for example between 50 and 4.1 mg/kg body weight, such as between 50 and 4.0 mg/kg body weight, for example between 50 and 3.9 mg/kg body weight, such as between 50 and 3.8 mg/kg body weight, for example between 50 and 3.7 mg/kg body weight, such as between 50 and 3.6 mg/kg body weight, for example between 50 and 3.5 mg/kg body weight, such as between 50 and 3.4 mg/kg body weight, for example between 50 and 3.3 mg/kg body weight, such as between 50 and 3.2 mg/kg body weight, for example between 50 and 3.1 mg/kg body weight, such as between 50 and 3.0 mg/kg body weight, for example between 50 and 2.9 mg/kg body weight, such as between 50 and 2.8 mg/kg body weight, for example between 50 and 2.7 mg/kg body weight, such as between 50 and 2.6 mg/kg body weight, for example between 50 and 2.5 mg/kg body weight, such as between 50 and 2.4 mg/kg body weight, for example between 50 and 2.3 mg/kg body weight, such as between 50 and 2.2 mg/kg body weight, for example between 50 and 2.1 mg/kg body weight, such as between 50 and 2.0 mg/kg body weight, for example between 50 and 1.9 mg/kg body weight, such as between 50 and 1.8 mg/kg body weight, for example between 50 and 1 .7 mg/kg body weight, such as between 50 and 1.6 mg/kg body weight, for example between 50 and 1.5 mg/kg body weight, such as between 50 and mg/kg body weight, for example between 50 and 1.4 mg/kg body weight, such as between 50 and 1 .3 mg/kg body weight, for example between 50 and 1.2 mg/kg body weight, such as between 50 and 1.1 mg/kg body weight, for example between 50 and 1 .0 mg/kg body weight, such as between 50 and 0.9 mg/kg body weight, for example between 50 and 0.8 mg/kg body weight, such as between 50 and 0.7 mg/kg body weight, for example between 50 and 0.6 mg/kg body weight, such as between 50 and 0.5 mg/kg body weight, for example between 50 and 0.4 mg/kg body weight, such as between 50 and 0.3 mg/kg body weight, for example between 50 and 0.2 O
mg/kg body weight, such as between 50 and 0.1 mg/kg body weight, for example between 50 and 0.09 mg/kg body weight, such as between 50 and 0.08 mg/kg body weight, for example between 50 and 0.07 mg/kg body weight, such as between 50 and 0.06 mg/kg body weight, for example between 50 and 0.05 mg/kg body weight, such as between 50 and 0.04 mg/kg body weight, for example between 50 and 0.03 mg/kg body weight, such as between 50 and 0.02 mg/kg body weight, for example between 50 and 0.01 mg/kg body weight.
In other words, for all methods of use disclosed herein for the compounds, the intravenous dosage regimen will preferably be from about 0.01 to 50 mg/kg of total body weight, such as 0.01 to 0.02 mg/kg body weight, for example 0.02 to 0.03 mg/kg body weight, such as 0.01 to 0.02 mg/kg body weight, for example 0.02 to 0.03 mg/kg body weight, such as 0.03 to 0.04 mg/kg body weight, for example 0.04 to 0.05 mg/kg body weight, such as 0.05 to 0.06 mg/kg body weight, for example 0.06 to 0.07 mg/kg body weight, such as 0.07 to 0.08 mg/kg body weight, for example 0.08 to 0.09 mg/kg body weight, such as 0.09 to 0.1 mg/kg body weight, for example 0.1 to 0.2 mg/kg body weight, such as 0.2 to 0.3 mg/kg body weight, for example 0.3 to 0.4 mg/kg body weight, such as 0.4 to 0.5 mg/kg body weight, for example 0.5 to 0.6 mg/kg body weight, such as 0.6 to 0.7 mg/kg body weight, for example 0.7 to 0.8 mg/kg body weight, such as 0.8 to 0.9 mg/kg body weight, for example 0.9 to 1.0 mg/kg body weight, such as 1.0 to 1.1 mg/kg body weight, for example 1 .1 to 1.2 mg/kg body weight, such as 1.2 to 1.3 mg/kg body weight, for example 1 .3 to 1.4 mg/kg body weight, such as 1 .4 to 1.5 mg/kg body weight, for example 1 .5 to 1.6 mg/kg body weight, such as 1.6 to 1.7 mg/kg body weight, for example 1 .7 to 1.8 mg/kg body weight, such as 1 .8 to 1.9 mg/kg body weight, for example 1.9 to 2.0 mg/kg body weight, such as 2.0 to 2.5 mg/kg body weight, for example 2.5 to 3.0 mg/kg body weight, such as 3.0 to 3.5 mg/kg body weight, for example 3.5 to 4.0 mg/kg body weight, such as 4.0 to 4.5 mg/kg body weight, for example 4.5 to 5.0 mg/kg body weight, such as 5 to 6 mg/kg body weight, for example 6 to 7 mg/kg body weight, such as 7 to 8 mg/kg body weight, for example 8 to 9 mg/kg body weight, such as 9 to 10 mg/kg body weight, for example 10 to 15 mg/kg body weight, such as 15 to 20 mg/kg body weight, for example 20 to 25 mg/kg body weight, such as 25 to 30 mg/kg body weight, for example 30 to 35 mg/kg body weight, such as 35 to 40 mg/kg body weight, for example 40 to 45 mg/kg body weight, such as 45 to 50 mg/kg body weight. o
The intraperitoneal dosage regimen will be from 0.01 to 50 mg/kg of total body weight, such as between 10 μg to 1 mg pr kg total body weight, depending on the neurotensin of choice. It has been found that neurotensins varies with respect to potency and affinity for the neurotensin receptor as well as with respect to molecular weight.
For any other neurotensin receptor agonist compound according to the invention the exact dosage may be calculated based on the calf study model described in Example 15.
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 compound, alone or in combination 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 compound or compounds employed and the effect to be achieved, as well as the pharmacodynamics associated with each compound 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 a compound according to the invention. 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.
Dosage regime and Duration of treatment
The medicament may be administered in any suitable dosage regime, suitable as to the potency of the compound / drug, the target temperature to be reached, the speed of action of the compound, the metabolic stability of the compound, 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 24 hours, such as intervals of 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.
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.
Second active ingredient
An embodiment of the present invention is a pharmaceutical composition comprising a compound as herein described and furthermore comprising a second (or further) active ingredient. The second active ingredient may increase the hypothermic effect of the compound of the invention, or may have an alternative medical effect such as inducing pain relief or vasodilation.
The second active ingredient may thus be selected from the non-limiting group of: analgesics, opiods, 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 hy- pothalamus 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 (Ar- thriten), 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 neurotensin and/or neurotensin analogs 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 buprenor- phine; 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 compound according to any of the above, a means for administering said compound 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 second 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 ven- tricular 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. A subcutaneous or intravenous bolus injection of a compound of this invention is administered. The dose is in the interval 0.5 mg/kg to 50 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 2 - Cardiac arrest
A 22-year-old male athlete collapses when doing sports. Medical staff finds ventricu- lar 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. A subcutaneous or intravenous bolus injection of a compound of this invention is ad- ministered. The dose is in the interval 0.5 mg/kg to 50 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 addi- tional 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. A subcutaneous or intravenous bolus injection of a compound of this invention is administered. The dose is in the interval 0.5 mg/kg to 50 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. A subcutaneous or intravenous bolus injection of a compound of this invention is administered. The dose is in the interval 0.5 mg/kg to 50 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 rec- ommendation). 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. A subcutaneous or intravenous bolus injection of a compound of this invention is administered. The dose is in the interval 0.5 mg/kg to 50 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. A subcutaneous or intravenous bolus injection of a compound of this invention is administered. The dose is in the interval 0.5 mg/kg to 50 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 rec- ommendation). 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 as well as 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. A subcutaneous or intravenous bolus injection of a compound of this invention is administered. The dose is in the interval 0.5 mg/kg to 50 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 addi- tional 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. A subcutaneous or intravenous bolus injection of a compound of this invention is administered. The dose is in the interval 0.5 mg/kg to 50 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 rec- ommendation). 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-olm 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. A subcutaneous or intravenous bolus injection of a compound of this invention is administered. The dose is in the interval 0.5 mg/kg to 50 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 addi- tional 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. A subcutaneous or intravenous bolus injection of a compound of this invention is administered. The dose is in the interval 0.5 mg/kg to 50 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. A subcutaneous or intravenous bolus injection of a compound of this invention is administered. The dose is in the interval 0.5 mg/kg to 50 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 active substance in a low, medium and high dose is screened initially on 3 rabbits. Temperature, blood pressure, pulse will be measured for 72 hours following administration of active substances. These parameters are 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 TRPV1 activity is assessed in vitro by measuring vanilloid receptor agonist induced Ca2+ flux using FLIPR and HEK293 cells stably expressing recombinant human and rat TRPVI (hTRPV1 -HEK293 and rTRPV1 -HEK293, respec- tively). Intracellular Ca2+ level is measured in TRPV1 -expressing cells during exposure to compounds. A concentration dependent increase in Ca2+ influx is observed using both human and rat cell lines. The efficacy of agonists is estimated by comparing it to the maximum response induced by capsaicin.
Example 14 - Porcine study model
In order to evaluate an effective hypothermic dose of a receptor agonist compound according to the invention, the compound is 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 is 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 treatment by neurotensin compounds according to the invention, the treatment is 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; they 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 they are subjected to a day cycle consisting of 16 hours of light fol- lowed 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 consists 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.
Hypothermic effect
The primary effect evaluated is hypothermia. Temperature is measured using a temperature probe (ADInstruments) that is surgically positioned in vena cava crani- alis 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 of the neurotensin compounds.
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 after the com- pounds have been administered. Data is collected using a Powerlab. References
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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 L-Arg 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:NT69L"
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. 1 1 : 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 compound for use in induction of controlled hypothermia in a human being, wherein said compound is a neurotensin receptor agonist.
2. The compound according to claim 1 , wherein said compound is selected from the group consisting of neurotensin, NT64D, NT64L, NT65L, NT66D, NT66L, NT67L, NT69L, NT71 , NT72, NT73, NT74, NT75, NT76, NT77, Trp1 1 NT, contu- lakin-G, EISAI-1 , EISAI-2, JMV2004, JMV2012, JMV431 , JMV449, JMV457, JMV458, large neuromedin, large neurotensin, neuromedin, [125l]neurotensin,
Thr10contulakin-G, D-Trp1 1 -neurotensin, levocabastine, SR48692, xenin, PD- 149163, CGX-1 160, KK13 and KK14.
3. A medicament comprising a compound according to any of claims 1 to 2 capable of inducing hypothermia in an individual.
4. The medicament according to claim 3, for prophylactic and/or therapeutic applications.
5. The medicament according to claim 3, for therapeutic applications.
6. The medicament according to any of claims 1 to 5, wherein the medicament induces hypothermia of between 32 and 36 degree Celsius.
7. The medicament according to any of claims 3 to 6, comprising a second active ingredient.
8. The medicament according to claim 7, wherein the second active ingredient is selected from the group of: analgesics, opiods, GABAs and adrenergic antago- nists.
9. The medicament according to any of claims 3 to 8, comprising a pharmaceutically acceptable carrier.
10. The medicament according to any of claims 3 to 9, wherein the pH of the composition is between pH 5 and pH 9.
1 1. The medicament according to any of claims 3 to 10, for administration by injec- tion, suppository, oral administration, sublingual tablet or spray, cutaneous administration, or inhalation.
12. The medicament according to claim 1 1 , wherein the injection is intravenous, intramuscular, intraspinal, intraperitoneal, subcutaneous, a bolus or a continuous administration.
13. The medicament according to any of claims 5 to 12, wherein administration occurs at intervals of 30 minutes to 48 hours.
14. The medicament according to any of claims 5 to 12, wherein administration occurs at intervals of 1 to 6 hours.
15. The medicament according to any of claims 5 to 14, wherein the duration of the treatment is from 6 to 72 hours.
16. The medicament according to any of claims 5 to 15, wherein the dosage of the medicament is between 0.01 mg to 50 mg per kg body mass.
17. The medicament according to any of claims 5 to 16 for use in induction of hypo- thermia in a human being suffering from or at risk of suffering from ischemia.
18. The medicament according to any of claims 5 to 16 for use in induction of hypothermia in a human being for treatment of ischemic damages.
19. The medicament according to any of claims 5 to 18, for prophylaxis and/or treatment of ischemic damages in connection with cardiovascular diseases, asphyxia, traumatic brain injuries and/or organ transplantation.
20. The medicament according to any of claims 5 to 18, wherein the ischemia is due to cardiovascular diseases such as: myocardial infarction, acute coronary syn- drome, 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.
21 . The medicament according to claim 18, wherein the ischemia is due to asphyxia such as: perinatal asphyxia and/or non-perinatal asphyxia.
22. The medicament according to any of claims 5 to 18, wherein the ischemia is kidney ischemia.
23. A neurotensin receptor antagonist for use in reverting hypothermia in a human being.
24. The neurotensin receptor antagonist according to claim 23, wherein the antagonist is SR142948A, SR48692 and SR48527.
25. A method for treating ischemia in an individual in need thereof comprising administering to said individual an effective amount of a medicament as defined in any of claims 5 to 24.
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US9622670B2 (en) 2010-07-09 2017-04-18 Potrero Medical, Inc. Method and apparatus for pressure measurement
US9931044B2 (en) 2010-07-09 2018-04-03 Potrero Medical, Inc. Method and apparatus for pressure measurement
US10758135B2 (en) 2010-07-09 2020-09-01 Potrero Medical, Inc. Method and apparatus for pressure measurement
EP3328494A4 (en) * 2015-08-01 2019-04-03 Stephen J. Petti Compositions and methods for combination pharmacological treatments to induce a prolonged, mild decrease in core body temperature
US10357466B2 (en) 2015-08-01 2019-07-23 Stephen J. Petti Compositions and methods for combination pharmacological treatments to induce a prolonged, mild decrease in core body temperature
US10772852B2 (en) 2015-08-01 2020-09-15 Stephen J. Petti Compositions and methods for combination pharmacological treatments to induce a prolonged, mild decrease in core body temperature

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