WO1994004120A2 - Methods of treating sexual dysfunction in animals with and h agonist - Google Patents
Methods of treating sexual dysfunction in animals with and h agonist Download PDFInfo
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- WO1994004120A2 WO1994004120A2 PCT/BR1993/000027 BR9300027W WO9404120A2 WO 1994004120 A2 WO1994004120 A2 WO 1994004120A2 BR 9300027 W BR9300027 W BR 9300027W WO 9404120 A2 WO9404120 A2 WO 9404120A2
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- agonist
- histamine
- agent
- phentolamine
- antagonist
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- XLSZMDLNRCVEIJ-UHFFFAOYSA-N Cc1c[nH]cn1 Chemical compound Cc1c[nH]cn1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- Virag in 1982, was the first to demonstrate the erectogenic effect of a vasoactive drug injected directly into the patient's epigastric artery.
- the type of therapy in which the patients conduct their own treatment via intracavemous administration of drugs is called self-injection therapy.
- the present invention provides for the use of a histamine H 2 receptor agonist and/or a histamine H 3 receptor agonist, or pharmaceutically acceptable salts thereof, alone or in combination with other agents, for the treatment of erectile dysfunction's in animals, and human beings.
- Adaikan et al. showed that corpus cavern ⁇ sum muscle of the human penis contains both H 1 and H 2 histamine receptors.
- histamine can cause three types of effects on such muscle: a contraction in 62.5% of the cases; relaxation in 28.3% and a biphasic response of contraction followed by relaxation, in 9.4% of them.
- the contractile response of histamine is antagonized by mepyramine, an H 1 receptor antagonist, but not by prostaglandin antagonists, nor by phentolamine, an ⁇ -adrenoreceptor blocker.
- the relaxant effect of histamine was selectively blocked by bu ⁇ mamide, a selective H 2 -receptor antagonist, but not by propanolol, a ⁇ -adrenoreceptor blocker, Adaikan et al, Euro. J. of Pharm., 45, pp 261-265 (1977).
- sulpiride a dopaminergic D 2 -rece ⁇ tor antagonist possessing tranquilizing actions.
- sulpiride also produces penile tumescence and even erection, supporting the hypothesis of the presence of D 2 -receptors in human cavernous smooth muscle fibers and/or their adrenergic nerve terminals.
- the combination of histamine and sulpiride enhanced the degree and duration of penile rigidity .
- histamine may be a physiological, non-adrenergic, non-cholinergic transmitter of human penile erection.
- Adaikan, P. G. in World Book of Impotence, Ed. by Tom F. Lue, Smith-Gordon and Nishimura Co., 52 - 54, (1992).
- histamine itself is not ideal, although it is surprisingly free of undesirable collateral effects at either the local or systemic level, following intracavemous injection of doses of histamine capable of inducing erection, Nahoum et al. Int. J. Impotence Res., 2, Suppl. 2, 321 - 322 (1990). Histamine releases adrenaline from suprarrenal glands by an H 1 - receptor-mediated mechanism. Staskewska-Barczak, J. el al., Br. J. Pharmacol., 25 (30): 728-742 (1965); West, G.B. Prog. Drup Res., 28:9-52 (1984).
- histamine injection may be dangerous in hypertensive individuals, especially when afflicted by pheochromocytoma.
- histamine may cause bronchospasm in asthmatic patients, Laitienen et al, Am. Rev. respirat. Diseases, 1 14, 291 - 295 (1976), Brown et al, J. Appl. Physiol, 42, 221 - 227 (1977).
- H 1 receptors in human skin, limits the concentration of histamine which may be used in a topical preparation.
- the dose of histamine which must be used to cause expressive erection will also cause the organ to show signs of local irritation.
- topical preparations of histamine in combination with another agent which could reduce the amount of histamine needed would be of interest and is further described herein.
- H 2 receptor agonists demonstrates the same erectogenic actions of histamine due to its H 2 receptor activation without the negative side effects of histamine and H 1 receptor activity.
- a preferred pharmaceutical composition for use herein comprises the H 2 agonist, N-[2-(5-Methyl-4-imidazoIyl)methyl-thio)ethyl]- N'-[3-(4-imidazolyl) ⁇ ropyl ]-guanidine) and p h a r m a c e u t i c a l l y a c c e p t a b l e s a l t s thereof (herein referred to as Impromidine).
- Preferred salt forms for use in the composition are the trihydrochloride, dihydrochloride and dioxalate salts.
- a further aspect of this invention is the use of H 2 receptor agonists in combination with at least one other therapeutically active agent.
- agents include other known facilitating, potentiating agents and/or erectogenic agents, such as but not limited to those described below.
- a preferred H 2 agonist for combination use herein is Impromidine and pharmaceutically acceptable salts thereof .
- a preferred combination comprises and H 2 agonist, such as Impromidine and at least one therapeutic agent selected from sulpiride, papaverine, phentolamine, PGEl, histamine, phenoxybenzamine, an H 3 agonist or an H 1 antagonist.
- Penile erection comprises three basic physiological mechanisms:
- Het is a 4-imiazolyl, 5-methyl-4-imidazolyl, 5-ethyl-4-imidazolyl, 5-halogeno-4-imidazolyl, 2-thiazolyl, 3-isothiazolyl, 4-halogeno-3-isothiazolyl, 2-pyridyl, 3-methyl-2-pyridyl, 3- ethyl-2-pyridyl, 3-halogeno-2-pyridyl, 3-hydroxy-2-pyridyl, 3-methoxy-2-pyridyl or 3- ethoxy-2-pyridyl ring; Het' is a 4-imidazole ring;
- halogeno is bromo or chloro; or a hydrate or pharmaceutically acceptable salt or hydrated salt thereof.
- Het is a thiazolyl or 5-methyl-4-imidazolyl. More preferably Het is 5-methyl-4-imidazolyl.
- the acid addition salts include those with hydrochloric, hydrobromic, hydriodic, sulphuric, maleic and oxalate. Preferred salts are the hydrochloric and oxalate.
- a preferred compound is N-[3-(4-Imidazolyl)propyl]-N'-[2-(4-methyl-5-imidazolylmethyl-thio)ethyl]guanidine and salts thereof, preferably the di-and tri- hydrochloride salts or the dioxalate salt, most preferably the tri-hydrochloride salt.
- Exemplified compounds of Formula (II) are:
- WO 91/17146 discloses compounds wherein the amine function of the compounds of Formula (III) is blocked to allow a bond which hydrolyzes slowly.
- Compounds of WO 91/17147 correspond to the formula:
- R 5 is a cyclic aryl or heteroaryl group, optionally bonded to R 6 and is optionally mono- or poly- substituted with R 7 ;
- R 6 is H, OH, CH 3 , O-alkyl, COOH or CO 2 alkyl, halogen, CF 3 , alkyl, or an aliphatic or cyclic chain, aromatic or not; optionally R 6 may be equal to R 5 and R 7 ;
- R 4 is H, OH, CH 3 , OR 6 , COOR 6 , halogen, CF 3 , or optionally substituted alkyl; or pharmaceutically acceptable salts thereof.
- R 7 is OH, methoxy, methyl, dimethylamino, halogen or COOCH 3 and R 6 is phenyl, hydrogen or methyl.
- R 7 is OH, methyl, dimethylamino, or halogen, and R 6 is hydrogen or methyl.
- Pharmaceutically acceptable acid addition salts for use herein include hydrochloric, hydrobromic, sulphuric, phosphoric, acetic, citric, maleic, lactic, ascorbic, fumaric, oxalic, methansulphonic and ethanesulphonic acids.
- X is O or CH 2 , and the respective N-methyl derivatives thereof as well as N-methylated S-[2-(4(5)-imidazolyl)-ethyl]isothiourea and its N-methylated version and hydrates or pharmaceutically acceptable salts thereof.
- medicaments used to treat impotency or sexual dysfunction which may be used in combination with the H 2 or H 3 agonists include those well known to those skilled in thee art as well as those found in US Patent No.'s 5,190,967; 5,177,070; 4,663,318; 5,147,855; 4,663,318; 5,145,852; 5,104,655; 4,931,445; 4,521,421; and WO 92/21346 whose disclosures are incorporated by reference herein in their entirety.
- R is hydrogen, or C 1-6 alkyl, C 3-7 cycloalkyl C 1-6 alkyl, C 3-6 alkenyl, C 3-6 alkynyl, C 3-7 cycloalkyl, arylC 1 -5 alkyl, CHO;
- R 1 and R 2 may be the same or different and represent hydrogen, halogen, C 1 -4 alkyl, C 1 -4 alkoxy, hydroxyl, cyano, nitro and NR 3 R 4 ;
- Vasoactive intestinal peptide and active fragments coupled to hydrophobic moieties thereof is disclosed in US Patent No. 5,147,855.
- Various long aliphatic carboxylic acid chains are attached to the N-terminus of the 28 amino acid peptide (VIP), such as CH 3 (CH 2 ) 16 CO- , in particular steryl-NEP is preferred.
- US Patent No. 5,145,852 discloses a composition of papaverine, an ⁇ -blocker, a phoshopdiesterase inhibitor (PDE) and optionally PGEl, a dopaminergic agent, and an atropinic agent (an anticholinergic agent).
- PDE phoshopdiesterase inhibitor
- PGEl phoshopdiesterase inhibitor
- a dopaminergic agent a dopaminergic agent
- an atropinic agent an anticholinergic agent.
- Suggested PDE agents are dipyridamol type inhibitors, and the suggested dopaminergic agent is piribedil, the ⁇ 1 -blocker ifenprodil tartrate, yohimbine as an ⁇ 2 blocker, and for the prostaglandin, alpostil is suggested.
- 104, 655 discloses polyunsaturated fatty acids in the form of mono-, di- and tri-glycerides or in complexes with natural or synthetic phospholipids.
- ximenic or ximeninic acid alone, as a mono-, di- and tri-glyceride or phospholipid complex is preferred.
- US Patent No. 4,931,445 discloses the use of etoperidone and pharmaceutically acceptable salts thereof, specifically the hydrochloride salt for use in treatment of male sexual impotence.
- US Patent 4,521,421 teaches the use of sulpiride to prevent sexual stimulate responses to erectogenic agents contrary the its use herein as an adjunct with histamine and the H 2 and H 3 agonists.
- Linsidomin 3-morphonino-sydnoimine
- a nitric oxide donor for the treatment of erectile dysfunction in both animals and humans.
- Linsidomin is an active metabolite of molsidomine, used in coronary heart disease and also a nitric oxide donor.
- Endothelium derived relaxing factor believed to be a closely related substance to nitric oxide, have been recognized as important factors in the modulation of corporeal smooth muscle tone. Ignarro, L.J. et al. Biochem. Bophys. Res. Comm., 170: 843-850 (1990); Holmquist F., et al.. Acta Phvsiol. Scand., 141:441-442 (1991).
- Another aspect of the present invention for treatment of male and female sexual dysfunction in a animal, including human beings is the use in such treatment of an H 3 agonist, or a pharmaceutical composition comprising an H 3 agonist in a pharmaceutically acceptable carrier or diluent.
- the H 3 agonist used herein may also be administered in combination with a known, second therapeutically active compound.
- another aspect of the present invention is a pharmaceutical composition comprising an H 3 agonist and at least one additional therapeutically active agent in a pharmaceutically acceptable carrier or diluent for treatment of sexual dysfunctions in an animal.
- Such agents include, but are not limited to sulpiride, papaverine, phentolamine, PGE 1 , histamine, phenoxybenzamine , an H 2 agonist, or an H 1 antagonist.
- Preferred H 2 agonists for use as a co-administered agent is Impromidine or Dimaprit, more preferably Impromidine.
- brompheneramine promethiazine, and pyrilamine.
- dopamine agonists such as apomorphine and bromocriptine and opioid agonists such as naltrexone.
- Fabbri et al. Psychoneuro-endocrinology, 14, (1/ 2), 103-111 (1989).
- erectile dysfunction or “male sexual dysfuntion” refers to certain disorders of the cavemous tissue of the penis and possibly the associated fascia which produce impotence, the inability to attain a sexually functional erection.
- sexual dysfunction refers to both male and female sexual dysfunctions, and includes for women orgasmic dysfunctions related to clitoridal
- mammals includes mammals, preferably human beings, but also includes the areas of animal husbandry for which such treatment may be necessary, such as but not limited to poultry farming.
- Creams, ointments or pastes are semi-solid formulations of the active ingredient for external application to the skin or for intra-urethral use. They may be made by mixing the active ingredient(s) in finely-divided or powdered form, alone or in solution, or suspension in an aqueous or non-aqueous fluid, and optionally utilize a greasy or non-greasy base.
- a sterile, single use application is especially preferred for ease of application, which, in addition to optionally containing sterile, disinfected swabs and enclosed usage
- single use injections also offer application ease and contains per dose, an effective amount of an erection producing substance of an H 2 or H 3 agonist, preferably of
- the prepared injections may be kept in light impermeable containers, if necessary.
- the compounds of Formula (I) are light sensitive and should be kept such containers. They may also be developed in such a way so that the active ingredient and any second non-physically compatible second therapeutic agent can be mixed directly before the injection. This can take place, for example, in two containers, ampoules, or needles.
- photoprotective agents it is also possible to add photoprotective agents to the (parenteral) preparations if neccesary.
- photostabilizers are disodium edetate (EDTA), sodium
- metabisulphite sodium thiosulphate, di-methionine, sodium benzoate, glycerin, methyl paraben, glutathione, urocanic acid, thiourea, and sodium urate.
- the preferred solvent or carrier is water, or saline or a combination solvent with is admixable with water.
- solvents include but are not limited to various alcohols, i.e. ethanol, or isopropyl alcohol, benzyl alcohol; 2-octyl dodecane, polyethylene glycol, glycerin, propylene glycol and derivatives thereof, dioxane (diethylene dioxide), dimethyl sulfoxide, dimethyl formamide, methylcellulsolve, cellusolve, and cyclohexanone, etc., are suitable if not deleterious to the mammal.
- phosphate magnesium stearate
- animal and vegetable fats solid, high molecular polymers (such as polyethylene glycol).
- oils of varying viscosity such as the silicon oils, or fatty alcohols, such as isotridexyl alcohol, 2-octyldodecane, cetylstearyl alcohol or oleyl alcohol, fatty acids such as oleic acids.
- oils such as natural or hydrogenated vegetable oils, almond oil, cottonseed oil, peanut- oil, or soybean oil, ethylene glycol, or fish oils containing primarily long-chain triglycerides; for example polyoxyethylene glycolated natural or hydrogenated vegetable oils, such as olive oil, sesame oil, peanut oil; hydrogenated castor oils; safflower or sunflower oils, or soybean oil may be used.
- the aforementioned materials have the characteristic of being spreadable, i.e. they are easily distributed on the skin.
- anti-microbials or preservatives such as p-hyroxybenzoic acid ester, or benzoic acid (sodium salt), methylparaben or propylparaben;
- the absorption or penetration enhancers most preferably used in the compositions according to the present invention are the aliphatic sulfoxides of the formula RSOR', wherein R is an alkyl, substituted alkyl, alkenyl, or hetero group containing up to 12 carbon atoms, and R' is a low molecular weight alkyl or hydroxy-substituted alkyl group. The most commonly used of these, is dimethylsulfoxide.
- a group of penetration enhancers which can also be used are the 1 -substituted azacyclopenten-2-ones, described in more detail in U.S. Pat. No. 4,444,762 to Jajadhyaksha, which patent is hereby incorporated by reference. These compounds have the structural formula:
- the amount of active drug containing compositions to be retained in the urethra is preferred to be about or below 100 ⁇ l and more preferably about 50 ⁇ l.
- WO 91/16021 provides for devices to insert a suppository as well as coating the exterior of the urethral suppositor, also disclosed are devices for delivery of ointments, pastes, etc into the urethra. Such devices and coatings would also be applicable to the instant invention herein.
- the present invention may also be applied topically via a transdermal delivery system.
- a transdermal delivery system is disclosed in US Patent No. 5,152,997 whose disclosure is incorporated by reference herein in its entirety.
- Topical and intraurethral administration of active agents typically require higher doses and as above for the prostaglandins, such as PGE 1 , papaverine, and the ⁇ -adrenergic agents, phentolamine, and phenoxybenzamine are well known to those skilled in the art.
- the unit dosage application for PGEl is in the range of from about 50 to 500 ⁇ g, preferably from about 25 to 250 ⁇ g.
- the range of from about 1,000 to 25,000 mcg, for phentolamine, prazosin, and doxazosin range from about 200 to 1000 ⁇ g per dose with from about 50 to 2,000 ⁇ g being preferred.
- a third agent such as phentolamine, papaverine, PGEl or sulpiride
- the reduction in doses of the H 2 / H 3 and histamine agents is ultimately at the discretion of the physician.
- the use of multiple intraurethral suppositories would allow for improved incremental dosing of both the H 2 or H 3 agonist with histamine and optionally a third agent such as sulpiride, papaverine, phentolamine, prazosin, or PGE 1 .
- Impromidine trihydrochloride Solutions of 50 mcg/ml of Impromidine trihydrochloride is dissolved in an isotonic solution and buffered to physiologic pH of 5.5 to 6 with sodium hydroxide. The solution is packaged in 0.5 ml or 1ml ampoules or any suitable size ampoules as may be necessary, including multiple dose vials. Similar solutions may be made using saline and/or sterile water optionally buffered with different agents. Altematively the amount of Impromidine trihydrochloride may be varied to further concentrate or dilute the volume. In a similar manner to these examples a different salt form, for instance the di-hydrochloride or di-oxalate salts may be utilized.
- a solution for topical application is prepared having 200 mcg Impromidine dihydrochloride, 2 ml isopropyl myristate and 10 ml ethanol and packaged in 2 ml dosages.
- Impromidine tri-hydrochloride may be utilized in a similar manner to these examples.
- a different salt form for instance the di-hydrochloride or di-oxalate salts may be utilized.
- a different H 2 agonist such as Dimaprit may be utilized, or alteratively a second therapeutic agent may be included.
- Such agents include histamine , R- ⁇ -methyl histamine or an H 1 antagonist.
- Impromidine hydrochloride 9 g of a mixture of mono and diglycerides of palmitinate and stearic acid, 3 g cetylstearyl alcohol with approx. 12 mol ethylene oxide, 10 g 2-octyldodecane, 5 g thick paraffin, 1 - 2 % benzyl alcohol, 500 mg PHB-ester and demineralized water.
- a mixture of 2.5 g oleic acid decylester, 2.5 g isopropylmyristate, 4 g thin paraffin, 0.9 g polyethylene stearate, 0.6 g sorbitan and glycerin fat acid ester are bonded at 70 degree C for 10 minutes and stirred.
- the melted mixture is put in a 75 degree Co warm solution of 50 g demineralized water, 300mcg Impromidine tri-hydrochloride and 100 mg allantoin and stirred, then cooled to 45 degree C.
- a carbopol film made up of 10 g ethanol, 0.7 g carbopol 934 (weakly bonded polyacrylic acid) and 22.95 g demineralized water develops, which is removed with turrax, swelled to 2 h and neutralized with 0.15 g soda lime. Upon reaching 40 degree C, 1 g collagen is added. Finally, the raw emulsion is homogenized, if necessary, after the addition of 0.6 g of perfume oil, at 20 to 25 degree C in a high pressure homogenizer. As in the above noted examples the amount of Impromidine may be varied from 200 to 10,000 mcg and alternative salt forms may be used as well.
- Impromidine hydrochloride 150 mg gelatin, 4.7 mg phenol are topped off with 1 ml of distilled water, placed in vials and filled to 1 ml.
- Impromidine may be varied from 200 to 10,000 mcg and alternative salt forms may be used as well.
- Impromidine hydrochloride In a mixture of 3.5 ml miglyol 812 and 0.08 g benzyl alcohol, 200 mcg Impromidine hydrochloride is suspended. This suspension is filled into a container with a valve. Then, 5 ml freon 12 is filled into the container via the valve, under pressure. By shaking, the freonchlorinated cfc. is released into the miglyol-benzyl-alcohol mixture. As in the above noted examples the amount of Impromidine may be varied from 200 to 10,000 mcg and alternative salt forms may be used as well.
- a) 250 mcg Impromidine is dissolved in a mixture of cetostearyl alcohol 7.2g, polyethylene glycol 1000 monocetylether 1.8g, white petroleum, 15g., liquid paraffin 6g., purified water to 100g (and any necessary preservatives). Altematively, 250 mcg of Dimaprit may be used.
- 250 mcg Impromidine is dissolved in a mixture of liquid paraffin 10g., cetostearyl alcohol 20gm., polyethylene glycol 1000monocetyl ether 5g, purified water to 100g (and any necessary preservatives). Altematively, 300 mcg of Dimaprit or any of its pharmaceutically acceptable salts may be used instead.
- Impromidine is dissolved in a mixture of cetostearyl alcohol 8. Ig, sodium lauryl sulphate 0.9g, white petroleum 15g., liquid paraffin 6g., sodium phosphate 2.5g, citric acid monohydrate 0.5 g., purified water to 100g (and any necessary preservatives).
- Impromidine may be varied from 200 to 10,000 mcg and alternative salt forms may be used as well.
- Suitable suppository bases for inclusion with the active ingredients include: a) Macrogel 6000 (50gm.), Macrogel 1540 (30gm) water and medicament (20gm);
- Witepsol H Suppository Base Imwitor 742 2-3 gm, or up to 8g. plus medicament;
- Witepsol W Suppository Base Imwitor 742, 2-3gm., or up to 8g plus medicament.
- a second therapeutic agent may be added or altematively the examples could be formulated using an H 3 agonist such as R- ⁇ -methyl histamine.
- the erectogenic activity of histamine alone or in combination with phentolamine was compared to that of papaverine. These effects were studied in four patients having psychogenic and four patients having erectile disfunction of organic origin. The patients were submitted in consecutive fashion to respectively: the vehicle of the preparations (5% mannitol in phosphate buffer); papaverine (60 mg); histamine hydrochloride (30 and 60 ⁇ g); and these same doses of histamine in combination with 5 mg of phentolamine mesylate.
- H 1 antagonists (mepyramine or chlorpheniramine, 20-100 ug) potentiated the erotogenic effect of histamine in a manner similar to that caused by phentolamine. This similarity points towards the usefulness of the substitution of ⁇ -adrenergic antagonists, like phentolamine, by H 1 antagonist, when using histamine or its H 2 or H 3 agonists as primary erectogenic agents.
- Impromidine Three animals were given 3.5 ⁇ g of only Impromidine. Responses were nil, partial or full in each of the animals. Six animals were given 3.5 ⁇ g of Impromidine in combination with 200 ⁇ g of phentolamine. In 3 of such animals the erectile responses varied between 60 to 80% of maximum. The remaining animals presented full erections. In all but one animal responses lasted between 10 and 40 minutes. The last animal remained in full erection for 3 hours.
- Impromidine 200 ⁇ g
- phentolamine dissolved in a mixture of 5% mannitol and 5% DMSO
- 9 individuals 7 normal volunteers and 2 impotent patients.
- 0.7 ml of the drugs' mixture were instilled into the urethra using a 1 ml plastic seringe fitted with a pippete-type tip.
- the fluid outflow was prevented by temporarily sealing of the urinary meatus with dermal adhesive tape which was kept in place until a definite erectile response was observed, or for a maximal period of 90 minutes.
- histamine as well as its H 2 agonists, particularly Impromidine, exhibit erectogenic activity of diagnostic and therapeutic value in the management of erectile dysfunction in mammals; b) such agents activity is potentiated both regarding its intensily and duration, by concurrent or sequential administration of adequate secondary agents; c) these agents, alone or in combination, showed adequate pharmacologic activity by either intracavemous and topical, mostly transurethral or transbalanic application; d) H 3 agonists, alone or in combination with other secondary agents, must be considered as being able to facilitate, potentiate or induce full penile erections in mammals.
- H 3 agonists alone or in combination with other secondary agents, must be considered as being able to facilitate, potentiate or induce full penile erections in mammals.
Abstract
Description
Claims
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE69332713T DE69332713D1 (en) | 1992-08-21 | 1993-08-18 | Use of histamine-2 agonists to treat sexual dysfunction |
CA002142875A CA2142875A1 (en) | 1992-08-21 | 1993-08-18 | The use of h2 and h3 agonists to treat sexual dysfunction |
AT93918819T ATE233091T1 (en) | 1992-08-21 | 1993-08-18 | USE OF HISTAMINE-2 AGONISTS TO TREAT SEXUAL DISORDERS |
KR1019950700672A KR100331754B1 (en) | 1992-08-21 | 1993-08-18 | Pharmaceutical compositions for the treatment of erectile dysfunction or insensitivity in animals |
JP50569694A JP2002510277A (en) | 1992-08-21 | 1993-08-18 | New composition |
EP93918819A EP0655914B1 (en) | 1992-08-21 | 1993-08-18 | Use of Histamine-2 agonists for treatment of sexual dysfunction |
AU49371/93A AU678996C (en) | 1992-08-21 | 1993-08-18 | Method of treating sexual dysfunction in animals with an H agonist |
US08/381,945 US5908853A (en) | 1992-08-21 | 1993-08-18 | Compositions |
NZ255278A NZ255278A (en) | 1992-08-21 | 1995-02-15 | Treatment of sexual dysfunction using an h2 agonist (heterocyclic substituted n-methyl thioethyl guanidine or aminopropylisothiourea derivatives) |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
BR929203277A BR9203277A (en) | 1992-08-21 | 1992-08-21 | USE OF ERETOGENIC DRUGS AND THEIR APPLICATION METHODOLOGIES |
BR920,3277 | 1992-08-21 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO1994004120A2 true WO1994004120A2 (en) | 1994-03-03 |
WO1994004120A3 WO1994004120A3 (en) | 1994-05-26 |
Family
ID=4054796
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/BR1993/000027 WO1994004120A2 (en) | 1992-08-21 | 1993-08-18 | Methods of treating sexual dysfunction in animals with and h agonist |
Country Status (13)
Country | Link |
---|---|
US (1) | US5908853A (en) |
EP (1) | EP0655914B1 (en) |
JP (1) | JP2002510277A (en) |
KR (1) | KR100331754B1 (en) |
AT (1) | ATE233091T1 (en) |
BR (1) | BR9203277A (en) |
CA (1) | CA2142875A1 (en) |
DE (1) | DE69332713D1 (en) |
NZ (1) | NZ255278A (en) |
OA (1) | OA10251A (en) |
TW (1) | TW418090B (en) |
WO (1) | WO1994004120A2 (en) |
ZA (1) | ZA936118B (en) |
Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
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WO1997042946A1 (en) * | 1996-05-15 | 1997-11-20 | Biotec Centre S.A. | ALPHA BLOCKERS (e.g. MOXISYLYTE AND/OR DERIVATIVES THEREOF) FOR TREATING ERECTILE DYSFUNCTION |
DE19728103A1 (en) * | 1997-07-02 | 1999-01-07 | Winfried Dr Med Heinicke | Composition for treatment of erectile dysfunction |
WO1999020265A1 (en) * | 1997-10-21 | 1999-04-29 | Alcon Laboratories, Inc. | Compositions containing histamine h2 agonists and methods of use in treating dry eye |
EP0934744A1 (en) * | 1998-01-30 | 1999-08-11 | Futura Medical Limited | Nitroglycerin preparation for treatment of erectile dysfunction |
FR2774593A1 (en) * | 1998-02-12 | 1999-08-13 | Philippe Gorny | OBTAINING A MEDICINE TO COMBAT FEMALE SEXUAL DYSFUNCTIONS |
WO1999065475A2 (en) * | 1998-06-19 | 1999-12-23 | Schering Corporation | Combination of phentolamine and apomorphine for the treatment of human sexual function and dysfunction |
WO2000032202A1 (en) * | 1998-12-02 | 2000-06-08 | Philippe Gorny | Method for obtaining and using a combination of a purine and a nitrogen monoxide donor for preventing or treating sexual dysfunction |
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US6472425B1 (en) | 1997-10-31 | 2002-10-29 | Nitromed, Inc. | Methods for treating female sexual dysfunctions |
WO2003086372A2 (en) * | 2002-04-10 | 2003-10-23 | University Of Florida | Methods of treating medication-, substance-, disease-, and other medical condition-related sexual dysfunction |
US6747063B2 (en) * | 1996-04-23 | 2004-06-08 | Cellegy Pharmaceuticals, Inc. | Combination therapy for treatment of erectile dysfunction |
US6825234B2 (en) | 1998-12-10 | 2004-11-30 | Nexmed (Holdings) , Inc. | Compositions and methods for amelioration of human female sexual dysfunction |
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US20070191320A1 (en) * | 1998-12-10 | 2007-08-16 | Nexmed Holdings, Inc. | Methods of treatment for female sexual arousal disorder |
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4293562A (en) * | 1979-07-02 | 1981-10-06 | Arnold Ritter | Methods of obtaining anorexic effects using a combination of amphetamines and cimetidine |
US5059603A (en) * | 1989-06-12 | 1991-10-22 | Centuries Laboratories, Inc. | Method and composition for treating impotence |
Family Cites Families (27)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4013659A (en) * | 1973-07-13 | 1977-03-22 | Smith Kline & French Laboratories Limited | Certain n,n'-disubstituted guanidine compounds and their use |
ZA771408B (en) * | 1976-03-29 | 1978-04-26 | Smith Kline French Lab | Pharmaceutical compositions |
JPS52156913A (en) * | 1976-06-21 | 1977-12-27 | Toko Yakuhin Kogyo Kk | Production of injectionable medicine |
US4127118B1 (en) * | 1977-03-16 | 1995-12-19 | Alvaro Latorre | Method of effecting and enhancing an erection |
US4311707A (en) * | 1979-02-12 | 1982-01-19 | American Cyanamid Company | Process for topically producing cutaneous vasodilation for the treatment of vasospastic or ischemic conditions |
US4521421A (en) * | 1983-09-26 | 1985-06-04 | Eli Lilly And Company | Treatment of sexual dysfunction |
DE3413371C1 (en) * | 1984-04-09 | 1986-01-02 | Esselte Pendaflex Corp., Garden City, N.Y. | label |
US4840952A (en) * | 1985-11-01 | 1989-06-20 | Bristol-Myers Company | Method for treatment of male impotence |
US4863911A (en) * | 1986-08-04 | 1989-09-05 | University Of Florida | Method for treating male sexual dysfunction |
EP0266968A3 (en) * | 1986-11-03 | 1988-08-24 | Gérard G. Cohen | Gelled ointment of vasodilating agent |
US4801587A (en) * | 1987-03-02 | 1989-01-31 | Gene Voss | Impotence ointment |
US5256652A (en) * | 1987-11-12 | 1993-10-26 | Pharmedic Co. | Topical compositions and methods for treatment of male impotence |
IT1221826B (en) * | 1988-06-08 | 1990-07-12 | Medico Harvey Srl Centro | PREPARED FOR TOPICAL USE FOR THE THERAPEUTIC TREATMENT OF IMPOTENTIA COEUNDI |
US5242931A (en) * | 1988-06-09 | 1993-09-07 | Kyowa Hakko Kogyo Co., Ltd. | Tricyclic compounds as TXA2 antagonists |
IL87055A (en) * | 1988-07-08 | 1994-06-24 | Illana Gozes | Conjugates of vasoactive intestinal peptide (vip) and of fragments thereof and pharmaceutical compositions comprising them |
SE463851B (en) * | 1988-09-02 | 1991-02-04 | Amsu Ltd | COMPOSITION FOR TREATMENT OF ERECT DYSFUNCTION THROUGH URETRA |
US4931445A (en) * | 1988-10-06 | 1990-06-05 | Irwin Goldstein | Agents for treatment of male impotence |
DE3943519A1 (en) * | 1989-04-27 | 1991-01-17 | Stief Georg | Treatment of erectile dysfunction - with peptide aspartic-acid -leucine -glutamine -alanine |
FR2649613B1 (en) * | 1989-07-11 | 1991-09-27 | Virag Ronald | VASO-ACTIVE MEDICINE |
IT1252603B (en) * | 1990-04-19 | 1995-06-19 | Giorgio Cavallini | 2,4-DIAMINO-6 PIPERIDINO PIRIMIDINA-3 TOPICAL OXIDE ON THE GLAND IN THE TREATMENT OF ERECTILE IMPOTENCES |
US5242391A (en) * | 1990-04-25 | 1993-09-07 | Alza Corporation | Urethral insert for treatment of erectile dysfunction |
IT1247678B (en) * | 1990-05-31 | 1994-12-28 | Alberto Reale | METHOD FOR THE TREATMENT OF MALE ERECTIVE IMPOTENCE |
US5270323A (en) * | 1990-05-31 | 1993-12-14 | Pfizer Inc. | Method of treating impotence |
GB9012469D0 (en) * | 1990-06-05 | 1990-07-25 | Glaxo Group Ltd | Medicaments |
EP0484581B1 (en) * | 1990-11-08 | 1994-06-15 | Roche Diagnostics GmbH | Use of thromboxane A2 receptor antagonists for preventing degenerative processes in penile tissues |
US5177070A (en) * | 1991-11-15 | 1993-01-05 | Ciba-Geigy Corporation | Method of treating physiologic male erectile impotence |
US5773457A (en) * | 1995-02-15 | 1998-06-30 | Cesar Roberto Dias Nahoum | Compositions |
-
1992
- 1992-08-21 BR BR929203277A patent/BR9203277A/en not_active Application Discontinuation
-
1993
- 1993-08-18 KR KR1019950700672A patent/KR100331754B1/en not_active IP Right Cessation
- 1993-08-18 CA CA002142875A patent/CA2142875A1/en not_active Abandoned
- 1993-08-18 US US08/381,945 patent/US5908853A/en not_active Expired - Fee Related
- 1993-08-18 EP EP93918819A patent/EP0655914B1/en not_active Expired - Lifetime
- 1993-08-18 JP JP50569694A patent/JP2002510277A/en not_active Ceased
- 1993-08-18 WO PCT/BR1993/000027 patent/WO1994004120A2/en active IP Right Grant
- 1993-08-18 AT AT93918819T patent/ATE233091T1/en not_active IP Right Cessation
- 1993-08-18 DE DE69332713T patent/DE69332713D1/en not_active Expired - Lifetime
- 1993-08-20 TW TW082106721A patent/TW418090B/en not_active IP Right Cessation
- 1993-08-20 ZA ZA936118A patent/ZA936118B/en unknown
-
1995
- 1995-02-15 NZ NZ255278A patent/NZ255278A/en unknown
- 1995-02-16 OA OA60612A patent/OA10251A/en unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4293562A (en) * | 1979-07-02 | 1981-10-06 | Arnold Ritter | Methods of obtaining anorexic effects using a combination of amphetamines and cimetidine |
US5059603A (en) * | 1989-06-12 | 1991-10-22 | Centuries Laboratories, Inc. | Method and composition for treating impotence |
Non-Patent Citations (7)
Title |
---|
Am. J. Med. Sci., Vol. 286(3), issued Nov/Dec 1983, PIERCE, J.R., "Cimetidine-Associated Depression and Loss of Libido in a Woman", pages 31-34, see entire article. * |
Brit. Med. Jl., issued 10 March 1979, PEDENS, N.R. et al., "Male Sexual Dysfunction During Treatment: Cimetidine", pages 559-560, entire article. * |
Brit. Med. Journal, Vol. 1, issued 12 May 1979, ADAKHAN et al., "Male Sexual Dysfunction During Treatment with Cimetidine", pages 1282-1283, see entire article. * |
CHEM. ABSTRACTS, Vol. 113, No. 7, issued 13 August 1990, DIEL et al., "Sexual Side Effects of Histamini-H Receptor Antagonists. What is Definite?", Abstract 51928+, Med. Khn. (Munich)(1990):85(5):332-339 (German). * |
Science, Vol. 218, issued 29 October 1982, ANANDS et al., "Prenatal and Neonatal Exposure to Cimetidine Results in Gonadal and Sexual Dysfunction in Adult Males", pages 493-494, entire article. * |
See also references of EP0655914A1 * |
The Lancet, issued 29 April 1989, KASSIANOS, "Impotence and Nizatidine", see Abstract page 963. * |
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US6747063B2 (en) * | 1996-04-23 | 2004-06-08 | Cellegy Pharmaceuticals, Inc. | Combination therapy for treatment of erectile dysfunction |
FR2748658A1 (en) * | 1996-05-15 | 1997-11-21 | Biotec Centre Sa | USE OF "ALPHA-BLOCKING" COMPOUNDS, IN PARTICULAR MOXISYLYTE AND / OR DERIVATIVES THEREOF, FOR THE TREATMENT OF ERECTILE DYSFUNCTIONS BY TRANSMUCOSAL BALAN |
WO1997042946A1 (en) * | 1996-05-15 | 1997-11-20 | Biotec Centre S.A. | ALPHA BLOCKERS (e.g. MOXISYLYTE AND/OR DERIVATIVES THEREOF) FOR TREATING ERECTILE DYSFUNCTION |
DE19728103A1 (en) * | 1997-07-02 | 1999-01-07 | Winfried Dr Med Heinicke | Composition for treatment of erectile dysfunction |
EP1028720A1 (en) * | 1997-10-20 | 2000-08-23 | Asivi, LLC | Methods, compositions, and kits for enhancing female sexual desire and responsiveness |
EP1028720A4 (en) * | 1997-10-20 | 2006-02-08 | Vivus Inc | Methods, compositions, and kits for enhancing female sexual desire and responsiveness |
WO1999020265A1 (en) * | 1997-10-21 | 1999-04-29 | Alcon Laboratories, Inc. | Compositions containing histamine h2 agonists and methods of use in treating dry eye |
US6274160B1 (en) | 1997-10-21 | 2001-08-14 | Alcon Laboratories, Inc. | Methods of use of histamine H2 agonists in treating dry eye |
US6472425B1 (en) | 1997-10-31 | 2002-10-29 | Nitromed, Inc. | Methods for treating female sexual dysfunctions |
EP0934744A1 (en) * | 1998-01-30 | 1999-08-11 | Futura Medical Limited | Nitroglycerin preparation for treatment of erectile dysfunction |
WO1999040917A1 (en) * | 1998-02-12 | 1999-08-19 | Medical & Pharma Development And Investment Company Limited | Combination of an alpha-adrenergic antagonist and a nitrogen oxide donor for treating female sexual dysfunction |
FR2774593A1 (en) * | 1998-02-12 | 1999-08-13 | Philippe Gorny | OBTAINING A MEDICINE TO COMBAT FEMALE SEXUAL DYSFUNCTIONS |
WO1999065475A3 (en) * | 1998-06-19 | 2000-04-06 | Schering Corp | Combination of phentolamine and apomorphine for the treatment of human sexual function and dysfunction |
WO1999065475A2 (en) * | 1998-06-19 | 1999-12-23 | Schering Corporation | Combination of phentolamine and apomorphine for the treatment of human sexual function and dysfunction |
WO2000032202A1 (en) * | 1998-12-02 | 2000-06-08 | Philippe Gorny | Method for obtaining and using a combination of a purine and a nitrogen monoxide donor for preventing or treating sexual dysfunction |
FR2786699A1 (en) * | 1998-12-02 | 2000-06-09 | Philippe Gorny | MEDICINE, IN PARTICULAR FOR PREVENTING OR TREATING SEXUAL DYSFUNCTIONS |
WO2000033825A2 (en) * | 1998-12-10 | 2000-06-15 | Nexmed Holdings, Inc. | Compositions and methods for amelioration of human female sexual dysfunction |
US6486207B2 (en) * | 1998-12-10 | 2002-11-26 | Nexmed (Holdings), Inc. | Compositions and methods for amelioration of human female sexual dysfunction |
AU760112B2 (en) * | 1998-12-10 | 2003-05-08 | Ferring International Center S.A. | Compositions and methods for amelioration of human female sexual dysfunction |
WO2000033825A3 (en) * | 1998-12-10 | 2000-11-16 | Nexmed Holdings Inc | Compositions and methods for amelioration of human female sexual dysfunction |
US6825234B2 (en) | 1998-12-10 | 2004-11-30 | Nexmed (Holdings) , Inc. | Compositions and methods for amelioration of human female sexual dysfunction |
WO2003086372A2 (en) * | 2002-04-10 | 2003-10-23 | University Of Florida | Methods of treating medication-, substance-, disease-, and other medical condition-related sexual dysfunction |
WO2003086372A3 (en) * | 2002-04-10 | 2004-03-25 | Univ Florida | Methods of treating medication-, substance-, disease-, and other medical condition-related sexual dysfunction |
EP2027857A3 (en) * | 2007-08-21 | 2009-04-29 | Mcneil-PPC, Inc | Anhydrous compositions useful for attaining enhanced sexual wellness |
Also Published As
Publication number | Publication date |
---|---|
EP0655914A1 (en) | 1995-06-07 |
KR950702823A (en) | 1995-08-23 |
ATE233091T1 (en) | 2003-03-15 |
AU678996B2 (en) | 1997-06-19 |
BR9203277A (en) | 1994-03-01 |
NZ255278A (en) | 1999-05-28 |
EP0655914B1 (en) | 2003-02-26 |
WO1994004120A3 (en) | 1994-05-26 |
DE69332713D1 (en) | 2003-04-03 |
OA10251A (en) | 1997-10-07 |
TW418090B (en) | 2001-01-11 |
US5908853A (en) | 1999-06-01 |
CA2142875A1 (en) | 1994-03-03 |
JP2002510277A (en) | 2002-04-02 |
KR100331754B1 (en) | 2002-10-04 |
AU4937193A (en) | 1994-03-15 |
ZA936118B (en) | 1995-04-20 |
EP0655914A4 (en) | 1998-04-22 |
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