US20030195165A1 - Method for obtaining and using a combination of a purine and a nitrogen monoxide donor for preventing or treating sexual dysfunction - Google Patents
Method for obtaining and using a combination of a purine and a nitrogen monoxide donor for preventing or treating sexual dysfunction Download PDFInfo
- Publication number
- US20030195165A1 US20030195165A1 US10/248,060 US24806002A US2003195165A1 US 20030195165 A1 US20030195165 A1 US 20030195165A1 US 24806002 A US24806002 A US 24806002A US 2003195165 A1 US2003195165 A1 US 2003195165A1
- Authority
- US
- United States
- Prior art keywords
- purine
- nitric oxide
- oxide donor
- donor agent
- arginine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 title claims abstract description 96
- 238000000034 method Methods 0.000 title claims abstract description 51
- 201000001880 Sexual dysfunction Diseases 0.000 title claims description 8
- 231100000872 sexual dysfunction Toxicity 0.000 title claims description 8
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 title description 26
- 239000002840 nitric oxide donor Substances 0.000 claims abstract description 41
- 230000001568 sexual effect Effects 0.000 claims abstract description 28
- 241000282414 Homo sapiens Species 0.000 claims abstract description 15
- 230000000638 stimulation Effects 0.000 claims abstract description 11
- 230000004044 response Effects 0.000 claims abstract description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 38
- 239000004475 Arginine Substances 0.000 claims description 23
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 23
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 claims description 22
- 230000000694 effects Effects 0.000 claims description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- 239000002126 C01EB10 - Adenosine Substances 0.000 claims description 11
- 229960005305 adenosine Drugs 0.000 claims description 11
- UDMBCSSLTHHNCD-KQYNXXCUSA-N adenosine 5'-monophosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O UDMBCSSLTHHNCD-KQYNXXCUSA-N 0.000 claims description 11
- 229960002006 linsidomine Drugs 0.000 claims description 9
- FKDHHVKWGRFRTG-UHFFFAOYSA-N linsidomine Chemical compound [N-]1OC(=N)C=[N+]1N1CCOCC1 FKDHHVKWGRFRTG-UHFFFAOYSA-N 0.000 claims description 9
- 239000000243 solution Substances 0.000 claims description 9
- 239000000843 powder Substances 0.000 claims description 8
- 230000035946 sexual desire Effects 0.000 claims description 7
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims description 6
- 229930024421 Adenine Natural products 0.000 claims description 6
- 229960000643 adenine Drugs 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 239000002775 capsule Substances 0.000 claims description 5
- 239000012458 free base Substances 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 4
- 239000000499 gel Substances 0.000 claims description 4
- 230000002685 pulmonary effect Effects 0.000 claims description 4
- 239000003826 tablet Substances 0.000 claims description 4
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 claims description 3
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 3
- 239000000839 emulsion Substances 0.000 claims description 3
- 239000008187 granular material Substances 0.000 claims description 3
- 239000007937 lozenge Substances 0.000 claims description 3
- XLFWDASMENKTKL-UHFFFAOYSA-N molsidomine Chemical compound O1C(N=C([O-])OCC)=C[N+](N2CCOCC2)=N1 XLFWDASMENKTKL-UHFFFAOYSA-N 0.000 claims description 3
- 229960004027 molsidomine Drugs 0.000 claims description 3
- 150000002826 nitrites Chemical class 0.000 claims description 3
- 239000002674 ointment Substances 0.000 claims description 3
- 229940082615 organic nitrates used in cardiac disease Drugs 0.000 claims description 3
- 239000000829 suppository Substances 0.000 claims description 3
- BQMKAHQKDSZAIQ-UHFFFAOYSA-N tetrasodium;iron(3+);nitroxyl anion;pentacyanide Chemical compound [Na+].[Na+].[Na+].[Na+].[Fe+3].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].O=[N-] BQMKAHQKDSZAIQ-UHFFFAOYSA-N 0.000 claims description 3
- 239000006216 vaginal suppository Substances 0.000 claims description 3
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 claims 8
- 239000000203 mixture Substances 0.000 claims 5
- ZKHQWZAMYRWXGA-KQYNXXCUSA-N Adenosine triphosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-N 0.000 claims 2
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- -1 transdermal device Substances 0.000 claims 2
- 229940120293 vaginal suppository Drugs 0.000 claims 2
- 229940079593 drug Drugs 0.000 abstract description 16
- 239000003814 drug Substances 0.000 abstract description 16
- 239000004480 active ingredient Substances 0.000 abstract description 9
- 238000002360 preparation method Methods 0.000 abstract description 2
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- UDMBCSSLTHHNCD-UHFFFAOYSA-N Coenzym Q(11) Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(O)=O)C(O)C1O UDMBCSSLTHHNCD-UHFFFAOYSA-N 0.000 description 8
- LNQVTSROQXJCDD-UHFFFAOYSA-N adenosine monophosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(CO)C(OP(O)(O)=O)C1O LNQVTSROQXJCDD-UHFFFAOYSA-N 0.000 description 8
- 210000005226 corpus cavernosum Anatomy 0.000 description 8
- 239000000126 substance Substances 0.000 description 7
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 6
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 6
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- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 4
- 229930064664 L-arginine Natural products 0.000 description 4
- 235000014852 L-arginine Nutrition 0.000 description 4
- 230000001800 adrenalinergic effect Effects 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- 230000010339 dilation Effects 0.000 description 3
- 230000001856 erectile effect Effects 0.000 description 3
- 230000002349 favourable effect Effects 0.000 description 3
- 210000003899 penis Anatomy 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 150000003212 purines Chemical class 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 229940124549 vasodilator Drugs 0.000 description 3
- 239000003071 vasodilator agent Substances 0.000 description 3
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 2
- RVEWUBJVAHOGKA-WOYAITHZSA-N Arginine glutamate Chemical compound OC(=O)[C@@H](N)CCC(O)=O.OC(=O)[C@@H](N)CCCNC(N)=N RVEWUBJVAHOGKA-WOYAITHZSA-N 0.000 description 2
- 206010057671 Female sexual dysfunction Diseases 0.000 description 2
- 108010003205 Vasoactive Intestinal Peptide Proteins 0.000 description 2
- 102400000015 Vasoactive intestinal peptide Human genes 0.000 description 2
- 206010047791 Vulvovaginal dryness Diseases 0.000 description 2
- UCTWMZQNUQWSLP-UHFFFAOYSA-N adrenaline Chemical compound CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 description 2
- 229960004246 arginine glutamate Drugs 0.000 description 2
- 108010013835 arginine glutamate Proteins 0.000 description 2
- 230000037007 arousal Effects 0.000 description 2
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- 230000007423 decrease Effects 0.000 description 2
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- 239000007926 intracavernous injection Substances 0.000 description 2
- VBUWHHLIZKOSMS-RIWXPGAOSA-N invicorp Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)C(C)C)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 VBUWHHLIZKOSMS-RIWXPGAOSA-N 0.000 description 2
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- YFJCRJZTDYDCRZ-MCDZGGTQSA-N (2r,3r,4s,5r)-2-(6-aminopurin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol;hydrochloride Chemical class Cl.C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YFJCRJZTDYDCRZ-MCDZGGTQSA-N 0.000 description 1
- HYHSBSXUHZOYLX-UHFFFAOYSA-N 2-amino-5-[[1-(carboxymethylamino)-3-nitrososulfanyl-1-oxopropan-2-yl]amino]-5-oxopentanoic acid Chemical compound OC(=O)C(N)CCC(=O)NC(CSN=O)C(=O)NCC(O)=O HYHSBSXUHZOYLX-UHFFFAOYSA-N 0.000 description 1
- QGXLVXZRPRRCRP-IDIVVRGQSA-L Adenosine 5'-phosphate disodium Chemical class [Na+].[Na+].C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])([O-])=O)[C@@H](O)[C@H]1O QGXLVXZRPRRCRP-IDIVVRGQSA-L 0.000 description 1
- XTWYTFMLZFPYCI-UHFFFAOYSA-N Adenosine diphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O XTWYTFMLZFPYCI-UHFFFAOYSA-N 0.000 description 1
- 102400000967 Bradykinin Human genes 0.000 description 1
- 101800004538 Bradykinin Proteins 0.000 description 1
- JQJPBYFTQAANLE-UHFFFAOYSA-N Butyl nitrite Chemical class CCCCON=O JQJPBYFTQAANLE-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
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- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 1
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- YWXYYJSYQOXTPL-SLPGGIOYSA-N isosorbide mononitrate Chemical compound [O-][N+](=O)O[C@@H]1CO[C@@H]2[C@@H](O)CO[C@@H]21 YWXYYJSYQOXTPL-SLPGGIOYSA-N 0.000 description 1
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- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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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
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
-
- 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
-
- 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
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- 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
Definitions
- the invention relates to obtaining a drug intended to prevent or treat sexual dysfunction in men or women.
- the invention relates in particular to obtaining a drug able to combat disorders of physiological and/or anatomical response to sexual stimulation in human beings.
- a drug contains a purine and a nitric oxide donor in combination.
- the erectile tissue of the penis is a spongy tissue able to fill with blood.
- the arteries of the penis are controlled by the adrenergic tonus that keeps them in spasm so that no appreciable blood flow fills the corpus cavernosum.
- the nervi erigentes inhibit the adrenergic tonus and release certain mediators favoring dilation of the arteries of the penis, causing blood to accumulate in the corpus cavernosum. The latter enlarges, while the increase in its internal pressure causes it to harden.
- vasodilation results in particular in vasodilation of the blood vessels irrigating the genital organs. This vasodilation brings about in particular swelling and erectile response of the clitoris, and congestion of the vaginal wall vessels with exudation of vaginal fluids.
- vasodilators Of the known vasodilators, a distinction is made between those with antagonist effects on a-adrenergic receptors (phentolamine for example) which inhibit adrenergic tonus thus favoring dilation of the arteries, and those that play the role of nitric oxide (NO) donors, either directly or during their metabolism. It is known that the endothelial cells that coat the interior of blood vessels are able to secrete a substance that dilates the arteries, this substance being nitric oxide. It has been established that nitric oxide stimulates synthesis of cyclic guanosine monophosphate (or cGMP) which brings about relaxation of the muscles of the arteries.
- cGMP cyclic guanosine monophosphate
- nitric oxide is the main physiological neurotransmitter brought into play by the nonadrenergic and noncholinergic peripheral neurons innervating the corpus cavernosum and its arteries, and that its release at the effector synapse is an important factor in inducing erection; see in particular Burnett et al., Science 257:401-403 (1992) and Fajfer et al., New Eng. J. Med. 326:90-94 (1992).
- International application WO 92/21346 recommends administration of a nitric oxide donor, linsidomine, for treating erectile dysfunction.
- Substances acting on dilation of the arteries by producing nitric oxide that may be cited as examples are arginine, sodium nitroprussiate, organic nitrates (glycerol trinitrate, isosorbide mononitrate or dinitrate), organic nitrites (amyl or butyl nitrites), thionitrites as described in document WO 96/16645 (e.g. S-nitrosocysteine, S-nitrosoglutathion), molsidomine, and, where applicable, pharmaceutically acceptable salts of these compounds.
- nitric oxide donor is understood to be any agent able to produce in vivo, directly or indirectly, nitric oxide (NO) or any metabolic precursor of such an agent, as well as any agent able to favor production of endogenous nitric oxide, for example phosphodiesterase inhibitors that have the indirect effect of increasing the level of nitric oxide.
- Nitric oxide donors are in particular the substances referred to hereinabove. Nitric oxide donor activity is obtained by the presence of such an agent.
- purine is understood to be purine bases, particularly adenine, purine-based nucleosides, particularly adenosine, as well as the corresponding phosphates, particularly AMP, ADP, and ATP, as well as their pharmaceutically acceptable salts (for example adenine or adenosine hydrochloride, or adenosine-phosphate sodium salts). More generally, “purine” is understood to be any substance able to act on the purine receptors. Such substances are known or can be detected by known methods. Purine activity is activity obtained by the presence of a purine as defined above.
- a compound has both purine activity and nitric oxide donor activity, it can be used as a single active ingredient in the drug obtained according to the invention.
- the drug obtained according to the invention is used so that effective doses, that can be determined by simple routine experiments, for example the tests just referred to, are administered to the treated individual. It should be noted that several active purines and many nitric oxide donors are known, as are their active doses. It is also easy to determine the effective doses with the aid of such tests. When the effects of the combination are compared with the effects of each of its active ingredients, it is found that in general the combination enables the doses of at least one of the active ingredients to be reduced. Combinations with a synergistic effect can thus be selected.
- the object of the invention is to use a combination of a purine and a nitric oxide donor agent, with the exception of the use, in combination, of adenosine and linsidomine, as active ingredients in the preparation of a drug intended to prevent or treat disorders of physiological and/or anatomical response to sexual stimulation, and in particular to prevent or treat nonorganic erectile dysfunction.
- This drug is administered to subjects who need it, i.e. persons who have experienced such disorders or fear that they will occur.
- the active ingredients of a drug obtained according to the invention can be supplied separately, each in an appropriate pharmaceutical form, and provided in one package.
- the drug in a single pharmaceutical form containing the two active ingredients, or the single active ingredient in the case where the latter has both types of activity (purine activity and nitric oxide donor activity), possibly with the addition of an appropriate pharmaceutical excipient.
- the drug obtained according to the invention can be administered by the oral, sublingual, nasal, pulmonary, vaginal, rectal, or transdermal route, or by intracavernous injection.
- oral administration in particular in the form of gel capsules, drinkable solutions or emulsions, powders, gels, granulates, lozenges, or tablets
- nasally for example solutions administered in the form of drops or sprays
- pulmonary route solutions in pressurized aerosol dispensers
- rectally suppositories
- cutaneously for example ointments or transdermal devices also known as patches
- transmucosally for example sublingually (solutions in pressurized dispensers, or tablets that crumble in the mouth) or vaginally (particularly vaginal creams or suppositories), or by the intracavernous route (injectable suspensions or solutions).
- the drugs obtained according to the invention are in particular those containing no adenosine, and those containing no linsidomine.
- adenosine monophosphate AMP
- adenosine triphosphate ATP
- L-arginine is a precursor of endogenous nitric oxide, and its administration relaxes the muscles of the arteries and corpus cavernosum, this relaxation being necessary for an erection to be achieved.
- Administration of 2800 mg L-arginine per day is reported to have a favorable effect on erectile dysfunction in approximately 40% of cases; see A. W. Zorgniotti and E. F. Lizza, Int. J. Impotence Res ., 6, 33-36 (1994).
- Arginine can be used in the non-salt or salt form (particularly as the hydrochloride, glutamate, aspartate, or citrate).
- the drug according to the invention gives favorable results in men suffering from temporary erectile dysfunction, and also in subjects with chronic erectile dysfunction.
- improvements are found in particular with at least one of the following disorders: loss or decline of sexual desire, absence of orgasm or difficulty in achieving orgasm, vaginal dryness, reduction in intensity of sexual pleasure, etc.
- the drug obtained according to the invention can be used either over long periods in the case of chronic erectile dysfunction (for example treatments lasting several weeks, several times a year) or in episodic treatments for temporary and/or recent erectile dysfunction, or as a one-time treatment.
- Such a drug can for example be prepared in a pharmaceutical form allowing administration of 30 to 150 mg of AMP in one or two doses, and also allowing administration of a sufficient dose of arginine, for example one dose of 1 to 8 g per day, usually 1.5 to 3 g, in one or two doses, said dose being calculated by weight of arginine in the freebase form.
- a dose of 50 to 100 mg of AMP and 1 to 2 g per day of L-arginine may be administered to adults for a course of treatment lasting 2 to 4 weeks.
- 60 to 120 mg AMP and 1.5 to 4 g L-arginine in the oral or sublingual form for example can be administered in a single dose approximately 30 minutes to 2 hours before the planned sexual encounter.
- AMP can be replaced in particular by equivalent quantities of ATP.
- the invention also relates to a method of preventing or treating male or female sexual dysfunction in which a drug as defined above is administered.
- Tests have been performed on female volunteers aged 30 to 55, suffering from at least one of the following disorders: loss of sexual desire, inability to achieve orgasm, decreased intensity of sexual pleasure, or vaginal dryness.
- Packets containing 3 g arginine glutamate and 60 mg AMP in the powder form for suspension in water were given to the test subjects, with the request that they take one packet of powder once a day for two weeks.
- test subjects noted the effects observed by self-evaluating sexual desire, achievement of orgasm, intensity of sexual pleasure, and vaginal lubrication. The majority of test subjects found improvements in at least two of the criteria used for this study.
- the invention also relates to a non-therapeutic method for increasing sexual desire and/or sexual capacity and/or favoring sexual activity and/or improving the intensity of sexual pleasure and/or favoring accomplishment of satisfactory sexual encounters, in individuals who wish the above even though they do not suffer from the sexual dysfunctions defined above.
- This method includes the fact of administering to such individuals a purine and a nitric acid donor, for example between two hours and half an hour before a planned sexual activity.
- the doses administered can be chosen from the dose ranges indicated hereinabove.
- the AMP can be replaced by an equivalent quantity of ATP.
Abstract
A method for using, in combination, a purine and a nitric oxide donor as active ingredients in the preparation of a drug for preventing or treating disorders of physiological and/or anatomical response to sexual stimulation in human beings.
Description
- The invention relates to obtaining a drug intended to prevent or treat sexual dysfunction in men or women. The invention relates in particular to obtaining a drug able to combat disorders of physiological and/or anatomical response to sexual stimulation in human beings. Such a drug contains a purine and a nitric oxide donor in combination.
- It is known that, in men, the erection process is as described schematically below. The erectile tissue of the penis, called corpus cavernosum, is a spongy tissue able to fill with blood. In the resting state, the arteries of the penis are controlled by the adrenergic tonus that keeps them in spasm so that no appreciable blood flow fills the corpus cavernosum. Upon an appropriate stimulation, the nervi erigentes inhibit the adrenergic tonus and release certain mediators favoring dilation of the arteries of the penis, causing blood to accumulate in the corpus cavernosum. The latter enlarges, while the increase in its internal pressure causes it to harden. As it enlarges, it crushes the cavernous veins against the envelope of the erectile body, preventing evacuation of the blood it contains, which maintains the rigidity. After ejaculation, adrenaline is once again released locally, the flow of blood into the arteries also decreases, the pressure in the corpus cavernosum drops, and the blood accumulated in the corpus cavernosum can be evacuated by the veins that are no longer compressed, causing loss of rigidity and return to the resting state.
- In women, sexual arousal results in particular in vasodilation of the blood vessels irrigating the genital organs. This vasodilation brings about in particular swelling and erectile response of the clitoris, and congestion of the vaginal wall vessels with exudation of vaginal fluids.
- It is known that a fairly high proportion of men (between 10 and 50% depending on the population studied and the age group) suffers from permanent or temporary erectile dysfunction. These difficulties may be organic, in which case they require specific treatments adapted to each cause. However, the majority of erectile dysfunctions are not organic, and are often of psychological origin.
- In women as well, the physiological response to sexual arousal and its anatomical manifestations may be temporarily altered, sometimes permanently, even with no detectable organic cause. The difficulties most frequently observed include the absence of sexual desire even after stimulation, difficulty in achieving orgasm, low intensity of sexual pleasure, and decreased or even absent natural vaginal lubrication. They often lead to a lack of interest in sexual activity. These disorders of physiological and/or anatomical response to sexual stimulation are termed "female sexual dysfunction" in the present patent application. According to some estimates, the frequency of temporary or chronic sexual dysfunction in women is equivalent to that of erectile dysfunction in men.
- Hence it is desirable to have treatments enabling the severity and/or duration of these disorders to be reduced, or prevent their appearance, and to restore the ability to achieve satisfactory sexual intercourse in subjects, men or women, who have such disorders or fear that they will occur.
- For cases of male impotence, various treatments have been proposed. In severe forms, intracavernous injection of vasoactive substances may give good results. In the case of moderate or incipient erectile dysfunction, oral treatments are more appropriate and are generally better accepted. A number of products, often of plant origin, have been proposed for this purpose. The use of an oral vasodilator (WO 96/33705; WO 96/16644) and a transdermal, transmucosal, intranasal, or rectal vasodilator (WO 95/05172) has also been proposed.
- Of the known vasodilators, a distinction is made between those with antagonist effects on a-adrenergic receptors (phentolamine for example) which inhibit adrenergic tonus thus favoring dilation of the arteries, and those that play the role of nitric oxide (NO) donors, either directly or during their metabolism. It is known that the endothelial cells that coat the interior of blood vessels are able to secrete a substance that dilates the arteries, this substance being nitric oxide. It has been established that nitric oxide stimulates synthesis of cyclic guanosine monophosphate (or cGMP) which brings about relaxation of the muscles of the arteries. It is also known that nitric oxide is the main physiological neurotransmitter brought into play by the nonadrenergic and noncholinergic peripheral neurons innervating the corpus cavernosum and its arteries, and that its release at the effector synapse is an important factor in inducing erection; see in particular Burnett et al.,Science 257:401-403 (1992) and Fajfer et al., New Eng. J. Med. 326:90-94 (1992). International application WO 92/21346 recommends administration of a nitric oxide donor, linsidomine, for treating erectile dysfunction.
- Substances acting on dilation of the arteries by producing nitric oxide that may be cited as examples are arginine, sodium nitroprussiate, organic nitrates (glycerol trinitrate, isosorbide mononitrate or dinitrate), organic nitrites (amyl or butyl nitrites), thionitrites as described in document WO 96/16645 (e.g. S-nitrosocysteine, S-nitrosoglutathion), molsidomine, and, where applicable, pharmaceutically acceptable salts of these compounds.
- It is known that other agents are involved in the physiological phenomenon of turgidity of erectile bodies. Examples of these agents are prostaglandins, vasoactive peptides such as bradykinin, the neuropeptide known as vasoactive intestinal peptide (or VIP), neuropeptide Y, etc. Also, rabbit studies have shown that purines are able to induce relaxation of the corpus cavernosum; see Wu H-Y et al.,Int. J. Impotence Res. 5, 161-167 (1993). It has also been shown that intravenous injection of adenosine triphosphate induces erection in dogs; see Takahashi Y. et al., Int. J. Impotence Res. 4, 27-34 (1992). Purines are reported to act as nonadrenergic noncholinergic neurotransmitters.
- It has now been discovered that the combination of purine activity and nitric oxide donor activity gives favorable results in prevention and treatment of disorders of physiological and anatomical response to sexual stimulation in humans (men or women) allowing said disorders to be combatted by a synergistic effect.
- In the present application, "nitric oxide donor" is understood to be any agent able to produce in vivo, directly or indirectly, nitric oxide (NO) or any metabolic precursor of such an agent, as well as any agent able to favor production of endogenous nitric oxide, for example phosphodiesterase inhibitors that have the indirect effect of increasing the level of nitric oxide. Nitric oxide donors are in particular the substances referred to hereinabove. Nitric oxide donor activity is obtained by the presence of such an agent.
- In the present application, "purine" is understood to be purine bases, particularly adenine, purine-based nucleosides, particularly adenosine, as well as the corresponding phosphates, particularly AMP, ADP, and ATP, as well as their pharmaceutically acceptable salts (for example adenine or adenosine hydrochloride, or adenosine-phosphate sodium salts). More generally, "purine" is understood to be any substance able to act on the purine receptors. Such substances are known or can be detected by known methods. Purine activity is activity obtained by the presence of a purine as defined above.
- If a compound has both purine activity and nitric oxide donor activity, it can be used as a single active ingredient in the drug obtained according to the invention.
- To study the effects of agents intended to treat disorders of physiological and anatomical response to sexual stimulation in men and women, known methods such as the tests described by Boolell M. et al,Int. J. of Impotence Res., 8, 47-52 (1996) and PCT WO 95/05172, or the tests described hereinbelow, may be used.
- The drug obtained according to the invention is used so that effective doses, that can be determined by simple routine experiments, for example the tests just referred to, are administered to the treated individual. It should be noted that several active purines and many nitric oxide donors are known, as are their active doses. It is also easy to determine the effective doses with the aid of such tests. When the effects of the combination are compared with the effects of each of its active ingredients, it is found that in general the combination enables the doses of at least one of the active ingredients to be reduced. Combinations with a synergistic effect can thus be selected.
- Hence, the object of the invention is to use a combination of a purine and a nitric oxide donor agent, with the exception of the use, in combination, of adenosine and linsidomine, as active ingredients in the preparation of a drug intended to prevent or treat disorders of physiological and/or anatomical response to sexual stimulation, and in particular to prevent or treat nonorganic erectile dysfunction. This drug is administered to subjects who need it, i.e. persons who have experienced such disorders or fear that they will occur.
- The active ingredients of a drug obtained according to the invention can be supplied separately, each in an appropriate pharmaceutical form, and provided in one package.
- However, to facilitate simultaneous administration of the active ingredients, it is generally preferable to prepare the drug in a single pharmaceutical form containing the two active ingredients, or the single active ingredient in the case where the latter has both types of activity (purine activity and nitric oxide donor activity), possibly with the addition of an appropriate pharmaceutical excipient.
- The drug obtained according to the invention can be administered by the oral, sublingual, nasal, pulmonary, vaginal, rectal, or transdermal route, or by intracavernous injection.
- For this purpose, it may be provided in any form enabling oral administration (in particular in the form of gel capsules, drinkable solutions or emulsions, powders, gels, granulates, lozenges, or tablets), nasally (for example solutions administered in the form of drops or sprays), by the pulmonary route (solutions in pressurized aerosol dispensers), rectally (suppositories), cutaneously (for example ointments or transdermal devices also known as patches), or transmucosally, for example sublingually (solutions in pressurized dispensers, or tablets that crumble in the mouth) or vaginally (particularly vaginal creams or suppositories), or by the intracavernous route (injectable suspensions or solutions).
- These pharmaceutical forms are prepared in the usual manner and can contain appropriate classical excipients and vehicles.
- The drugs obtained according to the invention are in particular those containing no adenosine, and those containing no linsidomine.
- The following may be cited of the combinations used according to the invention: adenosine monophosphate (AMP), or adenosine triphosphate (ATP), with arginine.
- L-arginine is a precursor of endogenous nitric oxide, and its administration relaxes the muscles of the arteries and corpus cavernosum, this relaxation being necessary for an erection to be achieved. Administration of 2800 mg L-arginine per day is reported to have a favorable effect on erectile dysfunction in approximately 40% of cases; see A. W. Zorgniotti and E. F. Lizza,Int. J. Impotence Res., 6, 33-36 (1994).
- Arginine can be used in the non-salt or salt form (particularly as the hydrochloride, glutamate, aspartate, or citrate).
- The drug according to the invention gives favorable results in men suffering from temporary erectile dysfunction, and also in subjects with chronic erectile dysfunction. In women, improvements are found in particular with at least one of the following disorders: loss or decline of sexual desire, absence of orgasm or difficulty in achieving orgasm, vaginal dryness, reduction in intensity of sexual pleasure, etc.
- The drug obtained according to the invention can be used either over long periods in the case of chronic erectile dysfunction (for example treatments lasting several weeks, several times a year) or in episodic treatments for temporary and/or recent erectile dysfunction, or as a one-time treatment.
- Such a drug can for example be prepared in a pharmaceutical form allowing administration of 30 to 150 mg of AMP in one or two doses, and also allowing administration of a sufficient dose of arginine, for example one dose of 1 to 8 g per day, usually 1.5 to 3 g, in one or two doses, said dose being calculated by weight of arginine in the freebase form.
- For example, a dose of 50 to 100 mg of AMP and 1 to 2 g per day of L-arginine may be administered to adults for a course of treatment lasting 2 to 4 weeks. As a one-time treatment, 60 to 120 mg AMP and 1.5 to 4 g L-arginine in the oral or sublingual form for example can be administered in a single dose approximately 30 minutes to 2 hours before the planned sexual encounter.
- AMP can be replaced in particular by equivalent quantities of ATP.
- The invention also relates to a method of preventing or treating male or female sexual dysfunction in which a drug as defined above is administered.
- Tests have been performed on female volunteers aged 30 to 55, suffering from at least one of the following disorders: loss of sexual desire, inability to achieve orgasm, decreased intensity of sexual pleasure, or vaginal dryness. Packets containing 3 g arginine glutamate and 60 mg AMP in the powder form for suspension in water were given to the test subjects, with the request that they take one packet of powder once a day for two weeks.
- The test subjects noted the effects observed by self-evaluating sexual desire, achievement of orgasm, intensity of sexual pleasure, and vaginal lubrication. The majority of test subjects found improvements in at least two of the criteria used for this study.
- Similar tests were performed on men aged 38 to 70 suffering from incipient sexual dysfunction. They were asked to take the contents of one packet of powder per day for 10 days and also to ingest the contents of an additional package 30 minutes to two hours before planned sexual activity. Approximately 60% of the individuals tested found that the quality or frequency of erection improved.
- The invention also relates to a non-therapeutic method for increasing sexual desire and/or sexual capacity and/or favoring sexual activity and/or improving the intensity of sexual pleasure and/or favoring accomplishment of satisfactory sexual encounters, in individuals who wish the above even though they do not suffer from the sexual dysfunctions defined above. This method includes the fact of administering to such individuals a purine and a nitric acid donor, for example between two hours and half an hour before a planned sexual activity. The doses administered can be chosen from the dose ranges indicated hereinabove.
- The following example illustrates the invention.
EXAMPLE Powder packets for drinkable suspensions Powder packets with the following contents are prepared: AMP: 60 mg Arginine glutamate: 3 g Aroma excipient: 0.5 g - The AMP can be replaced by an equivalent quantity of ATP.
- It is advisable to ingest the contents of one packet every day after suspending it in water. The contents of an additional packet can also be ingested 30 minutes to 2 hours before planned sexual activity.
Claims (44)
1. A method of treating a human being having or suspected of having a sexual dysfunction or a disorder of physiological and/or anatomical response to sexual stimulation, comprising:
administering to a human being having or suspected of having a sexual dysfunction or a disorder of physiological and/or anatomical response to sexual stimulation a purine and a nitric oxide donor agent, wherein said human being is not administered adenosine and linsidomine in combination.
2. The method of claim 1 , wherein said nitric oxide donor agent contains no linsidomine.
3. The method of claim 1 , wherein said purine contains no adenosine.
4. The method of claim 1 , wherein said purine is at least one member selected from the group consisting of adenine, adenosine, AMP, ADP and ATP.
5. The method of claim 4 , wherein said purine is adenosine and said nitric oxide donor agent contains no linsidomine.
6. The method of claim 1 , wherein said purine is at least one member selected from the group consisting of adenine, AMP, ADP and ATP.
7. The method of claim 1 , wherein said nitric oxide donor agent is at least one member selected from the group consisting of arginine, sodium nitroprussiate, organic nitrates, organic nitrites, thionitrites, molsidomine and pharmaceutically acceptable salts thereof.
8. The method of claim 1 , wherein said nitric oxide donor agent is arginine.
9. The method of claim 1 , wherein said purine and said nitric oxide donor agent are administered in the form of a capsule, gel capsule, drinkable solution or emulsion, granule, gel, cream, powder, lozenge, tablet, ointment, transdermal device, vaginal suppository, suppository, or solution.
10. The method of claim 9 , wherein said purine and said nitric oxide donor agent are administered by injection, by intranasal administration or by pulmonary administration.
11. The method of claim 1 , wherein said purine and said nitric oxide donor agent are administered in a single pharmaceutical form containing said purine and said nitric oxide donor agent.
12. The method of claim 1 , wherein said purine and said nitric oxide donor agent are administered in separate pharmaceutical forms, each pharmaceutical form containing one of said purine and said nitric oxide donor agent.
13. The method of claim 1 , wherein said purine is present in an amount of 30 to 150 mg per one or two doses.
14. The method of claim 1 , wherein said nitric oxide donor agent is arginine and said arginine is present in an amount of 1 to 8 g per one or two doses, calculated as the weight of arginine in free base form.
15. The method of claim 1 , wherein said nitric oxide donor agent is arginine and said arginine is present in an amount of 1.5 to 3 g per one or two doses, calculated as the weight of arginine in free base form.
16. The method of claim 1 , wherein said purine is AMP and said AMP is present in an amount of 30 to 150 mg per one or two doses.
17. The method of claim 1 , wherein said purine is AMP and said AMP is present in an amount of 50 to 100 mg per one or two doses.
18. The method of claim 1 , wherein said purine is AMP or ATP.
19. The method of claim 1 , wherein said purine is AMP or ATP and said nitric oxide donor agent is arginine.
20. The method of claim 1 , wherein said purine and said nitric oxide donor agent are a single compound having both purine and nitric oxide donor agent activities.
21. The method of claim 1 , wherein said human being is a man.
22. The method of claim 1 , wherein said human being is a woman.
23. A method of at least one of enhancing sexual desire, enhancing sexual pleasure, increasing sexual capacity and increasing sexual stimulation in human beings, comprising:
administering to a human being not suffering from a sexual dysfunction a purine and a nitric oxide donor agent, wherein said human being desires to enhance his or her sexual desire and/or sexual pleasure by administration of said purine and said nitric oxide donor agent, and wherein said human being is not administered adenosine and linsidomine in combination.
24. The method of claim 23 , wherein said nitric oxide donor agent contains no linsidomine.
25. The method of claim 23 , wherein said purine contains no adenosine.
26. The method of claim 23 , wherein said purine is at least one member selected from the group consisting of adenine, adenosine, AMP, ADP and ATP.
27. The method of claim 26 , wherein said purine is adenosine and said nitric oxide donor agent contains no linsidomine.
28. The method of claim 23 , wherein said purine is at least one member selected from the group consisting of adenine, AMP, ADP and ATP.
29. The method of claim 23 , wherein said nitric oxide donor agent is at least one member selected from the group consisting of arginine, sodium nitroprussiate, organic nitrates, organice nitrites, thionitrites, molsidomine and pharmaceutically acceptable salts thereof.
30. The method of claim 23 , wherein said nitric oxide donor agent is arginine.
31. The method of claim 23 , wherein said composition is in the form of a capsule, gel capsule, drinkable solution or emulsion, granule, gel, cream, powder, lozenge, tablet, ointment, transdermal device, vaginal suppository, suppository, or solution.
32. The method of claim 31 , wherein said composition is administered by injection, by intranasal administration or by pulmonary administration.
33. The method of claim 23 , wherein said purine and said nitric oxide donor agent are administered in a single composition.
34. The method of claim 23 , wherein said purine and said nitric oxide donor agent are administered in separate compositions, each composition containing one of said purine and said nitric oxide donor agent.
35. The method of claim 23 , wherein said purine is present in an amount of 30 to 150 mg per one or two doses.
36. The method of claim 23 , wherein said nitric oxide donor agent is arginine and said arginine is present in an amount of 1 to 8 g per one or two doses, calculated as the weight of arginine in free base form.
37. The method of claim 23 , wherein said nitric oxide donor agent is arginine and said arginine is present in an amount of 1.5 to 3 g per one or two doses, calculated as the weight of arginine in free base form.
38. The method of claim 23 , wherein said purine is AMP and said AMP is present in an amount of 30 to 150 mg per one or two doses.
39. The method of claim 23 , wherein said purine is AMP and said AMP is present in an amount of 50 to 100 mg per one or two doses.
40. The method of claim 23 , wherein said purine is AMP or ATP.
41. The method of claim 23 , wherein said purine is AMP or ATP and said nitric oxide donor agent is arginine.
42. The method of claim 23 , wherein said purine and said nitric oxide donor agent are a single compound having both purine and nitric oxide donor agent activities.
43. The method of claim 23 , wherein said human being is a man.
44. The method of claim 23 , wherein said human being is a woman.
Applications Claiming Priority (4)
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FR9815237A FR2786699B1 (en) | 1998-12-02 | 1998-12-02 | MEDICINE, IN PARTICULAR FOR PREVENTING OR TREATING SEXUAL DYSFUNCTIONS |
PCT/FR1999/002993 WO2000032202A1 (en) | 1998-12-02 | 1999-12-02 | Method for obtaining and using a combination of a purine and a nitrogen monoxide donor for preventing or treating sexual dysfunction |
US09/614,694 US6506736B1 (en) | 1998-12-02 | 2000-07-12 | Method for obtaining and using a combination of a purine nucleotide and nitrogen monoxide donor for treating sexual dysfunction |
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US10/248,060 Abandoned US20030195165A1 (en) | 1998-12-02 | 2002-12-13 | 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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US09/614,694 Expired - Lifetime US6506736B1 (en) | 1998-12-02 | 2000-07-12 | Method for obtaining and using a combination of a purine nucleotide and nitrogen monoxide donor for treating sexual dysfunction |
Country Status (12)
Country | Link |
---|---|
US (2) | US6506736B1 (en) |
EP (1) | EP1137420B1 (en) |
JP (1) | JP2002531408A (en) |
AT (1) | ATE358490T1 (en) |
AU (1) | AU1564500A (en) |
CY (1) | CY1106702T1 (en) |
DE (1) | DE69935733T2 (en) |
DK (1) | DK1137420T3 (en) |
ES (1) | ES2285865T3 (en) |
FR (1) | FR2786699B1 (en) |
PT (1) | PT1137420E (en) |
WO (1) | WO2000032202A1 (en) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2786699B1 (en) * | 1998-12-02 | 2002-10-04 | Philippe Gorny | MEDICINE, IN PARTICULAR FOR PREVENTING OR TREATING SEXUAL DYSFUNCTIONS |
WO2007075151A1 (en) * | 2005-12-29 | 2007-07-05 | Victor Pavlovich Kutnyak | Composite vasodilator based on a no-group donator and a promoter |
FR3005262A1 (en) | 2013-05-02 | 2014-11-07 | Philippe Gorny | NOVEL PHARMACEUTICAL OR DIETETIC COMPOSITIONS FOR TOTALLY MASKING AMERTUME OF HIGH-DOSE ARGININE SALTS, IN LIQUID OR SEMI-LIQUID FORM. |
FR3012039A1 (en) * | 2013-10-22 | 2015-04-24 | Philippe Olivier Gorny | MEDICINE OR DIETETIC PRODUCT AND USE THEREOF FOR PREVENTING OR TREATING SEXUAL DYSFUNCTIONS IN MAN AND WOMEN |
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US5422343A (en) * | 1992-12-21 | 1995-06-06 | Otsuka Pharmaceutical Factory, Inc. | Prophylactic and therapeutic composition for MRSA infection |
US5492911A (en) * | 1991-05-27 | 1996-02-20 | Christian Stief | Linsidomine for the treatment for erectile dysfunctions |
US5594032A (en) * | 1994-11-10 | 1997-01-14 | Gonzalez-Cadavid; Nestor F. | Amelioration of human erectile dysfunction by treatment with iNOS, inducers of iNOS or iNOS cDNA |
US5612060A (en) * | 1995-05-25 | 1997-03-18 | Alexander; J. Wesley | Enhancement of transplant graft survival through nutritional immunomodulation and immunosuppressive therapy |
US5824669A (en) * | 1996-03-22 | 1998-10-20 | Nitromed, Inc. | Nitrosated and nitrosylated compounds and compositions and their use for treating respiratory disorders |
US5877216A (en) * | 1997-10-28 | 1999-03-02 | Vivus, Incorporated | Treatment of female sexual dysfunction |
US5910316A (en) * | 1992-08-24 | 1999-06-08 | The United States Of America, As Represented By The Department Of Health And Human Services | Use of nitric oxide-releasing agents to treat impotency |
US6007824A (en) * | 1998-07-09 | 1999-12-28 | Duckett; Melvin J. | Natural composition and method for the treatment of sexual dysfunction |
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US6506736B1 (en) * | 1998-12-02 | 2003-01-14 | Philippe Gorny | Method for obtaining and using a combination of a purine nucleotide and nitrogen monoxide donor for treating sexual dysfunction |
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JPS63179827A (en) * | 1987-01-20 | 1988-07-23 | Fuso Yakuhin Kogyo Kk | Stable drug containing adenosine triphosphate and magnesium ion |
RU2064792C1 (en) * | 1992-03-02 | 1996-08-10 | Свистов Александр Сергеевич | Antianginal liquid agent for transdermal use |
GB2268871A (en) * | 1992-07-04 | 1994-01-26 | Bio Nutritional Health Service | Composition for use as a food or food supplement |
DK100392D0 (en) * | 1992-08-10 | 1992-08-10 | Gea Farmaceutisk Fabrik As | 3- AND 5-SUBSTITUTED 1,2,3,4-OXATRIAZOL-5 IMIN COMPOUNDS AND PROCEDURES FOR THE PRODUCTION THEREOF, PHARMACEUTICAL PREPARATION CONTAINING THESE COMPOUNDS AND THE USE OF THE COMPOUNDS FOR PREPARATION |
BR9203277A (en) * | 1992-08-21 | 1994-03-01 | Cesar Roberto Dias Nahoum | USE OF ERETOGENIC DRUGS AND THEIR APPLICATION METHODOLOGIES |
JP4526047B2 (en) * | 1995-11-08 | 2010-08-18 | 雪印乳業株式会社 | Strength enhancer |
GB9608408D0 (en) * | 1996-04-23 | 1996-06-26 | Adams Michael A | Treatment of erectile dysfunction |
US6124461A (en) * | 1998-05-26 | 2000-09-26 | Saint Louis University, Health Services Center, Research Administration | Compounds, compositions, and methods for treating erectile dysfunction |
WO2000000212A1 (en) * | 1998-06-26 | 2000-01-06 | Nutracorp Scientific, Inc. | Promoting nitric oxide and cyclic gmp activity |
-
1998
- 1998-12-02 FR FR9815237A patent/FR2786699B1/en not_active Expired - Fee Related
-
1999
- 1999-12-02 EP EP99958233A patent/EP1137420B1/en not_active Expired - Lifetime
- 1999-12-02 ES ES99958233T patent/ES2285865T3/en not_active Expired - Lifetime
- 1999-12-02 DK DK99958233T patent/DK1137420T3/en active
- 1999-12-02 PT PT99958233T patent/PT1137420E/en unknown
- 1999-12-02 WO PCT/FR1999/002993 patent/WO2000032202A1/en active IP Right Grant
- 1999-12-02 JP JP2000584897A patent/JP2002531408A/en active Pending
- 1999-12-02 AU AU15645/00A patent/AU1564500A/en not_active Abandoned
- 1999-12-02 DE DE69935733T patent/DE69935733T2/en not_active Expired - Lifetime
- 1999-12-02 AT AT99958233T patent/ATE358490T1/en active
-
2000
- 2000-07-12 US US09/614,694 patent/US6506736B1/en not_active Expired - Lifetime
-
2002
- 2002-12-13 US US10/248,060 patent/US20030195165A1/en not_active Abandoned
-
2007
- 2007-07-04 CY CY20071100889T patent/CY1106702T1/en unknown
Patent Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
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US5492911A (en) * | 1991-05-27 | 1996-02-20 | Christian Stief | Linsidomine for the treatment for erectile dysfunctions |
US5910316A (en) * | 1992-08-24 | 1999-06-08 | The United States Of America, As Represented By The Department Of Health And Human Services | Use of nitric oxide-releasing agents to treat impotency |
US5422343A (en) * | 1992-12-21 | 1995-06-06 | Otsuka Pharmaceutical Factory, Inc. | Prophylactic and therapeutic composition for MRSA infection |
US5594032A (en) * | 1994-11-10 | 1997-01-14 | Gonzalez-Cadavid; Nestor F. | Amelioration of human erectile dysfunction by treatment with iNOS, inducers of iNOS or iNOS cDNA |
US5612060A (en) * | 1995-05-25 | 1997-03-18 | Alexander; J. Wesley | Enhancement of transplant graft survival through nutritional immunomodulation and immunosuppressive therapy |
US5824669A (en) * | 1996-03-22 | 1998-10-20 | Nitromed, Inc. | Nitrosated and nitrosylated compounds and compositions and their use for treating respiratory disorders |
US5877216A (en) * | 1997-10-28 | 1999-03-02 | Vivus, Incorporated | Treatment of female sexual dysfunction |
US6127363A (en) * | 1997-10-28 | 2000-10-03 | Vivus, Inc. | Local administration of Type IV phosphodiesterase inhibitors for the treatment of erectile dysfunction |
US6007824A (en) * | 1998-07-09 | 1999-12-28 | Duckett; Melvin J. | Natural composition and method for the treatment of sexual dysfunction |
US6506736B1 (en) * | 1998-12-02 | 2003-01-14 | Philippe Gorny | Method for obtaining and using a combination of a purine nucleotide and nitrogen monoxide donor for treating sexual dysfunction |
Also Published As
Publication number | Publication date |
---|---|
PT1137420E (en) | 2007-07-04 |
DE69935733T2 (en) | 2007-12-27 |
ES2285865T3 (en) | 2007-11-16 |
AU1564500A (en) | 2000-06-19 |
US6506736B1 (en) | 2003-01-14 |
WO2000032202A1 (en) | 2000-06-08 |
FR2786699A1 (en) | 2000-06-09 |
JP2002531408A (en) | 2002-09-24 |
DE69935733D1 (en) | 2007-05-16 |
ATE358490T1 (en) | 2007-04-15 |
CY1106702T1 (en) | 2012-05-23 |
FR2786699B1 (en) | 2002-10-04 |
EP1137420A1 (en) | 2001-10-04 |
EP1137420B1 (en) | 2007-04-04 |
DK1137420T3 (en) | 2007-08-06 |
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Legal Events
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AS | Assignment |
Owner name: ADENOMED B.V., NETHERLANDS Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:GORNY, PHILIPPE;REEL/FRAME:013678/0727 Effective date: 20030115 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |