Treatment of female sexual dysfunction using phosphodiesterase inhibitors

• US 6,469,016 B1
• Filed: 02/08/2000
• Issued: 10/22/2002
• Est. Priority Date: 10/28/1997
• Status: Expired due to Term

• Current Assignee: Vivus Incorporated
• Original Assignee: Vivus Incorporated
• Inventors: Wilson, Leland F., Place, Virgil A., Gesundheit, Neil, Doherty, Paul C. Jr., Spivack, Alfred P., Bennett, Sean R., Hanamoto, Mark S.
• Primary Examiner(s): Criares, Theodore J.
• Application Number:
  US09/499,959
• Time in Patent Office: 987 Days
• Field of Search: 514/341, 514/261, 514/262
• US Class Current: 514/234.5
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/15 Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
• CPC Class Codes: A61K 31/21 Esters, e.g. nitroglycerine, selenocyanates
• CPC Class Codes: A61K 31/295 Iron group metal compounds
• CPC Class Codes: A61K 31/48 Ergoline derivatives, e.g. lysergic acid, ergotamine
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/557 Eicosanoids, e.g. leukotrienes or prostaglandins
• CPC Class Codes: A61K 31/5575 having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
• CPC Class Codes: A61K 31/5585 having five-membered rings containing oxygen as the only ring hetero atom, e.g. prostacyclin
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0034 Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
• CPC Class Codes: A61K 9/02 Suppositories; Bougies; Bases therefor; Ovulesapparatus for making A61J3/08; devices for introducing into the body A61M31/00
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/02 for disorders of the vagina
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: B82Y 5/00 : Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Abstract

Methods and formulations for treating female sexual dysfunction are provided. A pharmaceutical composition formulated so as to contain a selected vasoactive agent is administered to the vagina, vulvar area or urethra of the individual undergoing treatment. Suitable vasoactive agents are vasodilators, including naturally occurring prostaglandins, synthetic prostaglandin derivatives, endothelial-derived relaxation factors, vasoactive intestinal polypeptide agonists, smooth muscle relaxants, leukotriene inhibitors, and others. The formulations are also useful for preventing the occurrence of yeast infections, improving vaginal muscle tone and tissue health, enhancing vaginal lubrication, and minimizing excess collagen deposition. A clitoral drug delivery device is also provided.

Claims

1. A method for treating sexual dysfunction in a female individual, comprising administering to the vagina and/or vulvar area of the individual a pharmaceutical formulation that comprises an effective amount of a vasoactive agent selected from the group consisting of a Type V phosphodiesterase inhibitor, pharmaceutically acceptable salts, esters, analogs, derivatives, prodrugs and inclusion complexes thereof, and combinations of any of the foregoing.

2. The method of claim 1, wherein the pharmaceutical formulation further includes a pharmaceutically acceptable carrier suited to vaginal and/or vulvar drug administration.

3. The method of claim 1, wherein the pharmaceutical formulation is contained within a delivery system that provides a predetermined agent release profile.

4. The method of claim 3, wherein the agent release profile is pulsatile.

5. The method of claim 3, wherein the agent release profile is continuous.

6. The method of claim 3, wherein the agent release profile is cyclical.

7. The method of claim 3, wherein the agent release profile is diurnal.

8. The method of claim 1, wherein the pharmaceutical formulation is administered vaginally.

9. The method of claim 8, wherein the pharmaceutical formulation is in the form of an ointment, cream, gel, solid, solution, suspension, foam or liposomal composition.

10. The method of claim 8, wherein the pharmaceutical formulation is contained within a vaginal ring, tampon, suppository, sponge, pillow, puff, or osmotic pump system.

11. The method of claim 1, wherein the pharmaceutical formulation is administered to the vulvar area of the individual.

12. The method of claim 8, wherein the method further comprises co-administering an androgenic agent to the vulvar area of the individual in combination with vaginal administration of the vasoactive agent.

13. The method of claim 12, wherein the androgenic agent is testosterone or a testosterone ester.

14. The method of claim 1, wherein the sexual dysfunction is an excitement stage dysfunction.

15. The method of claim 14, wherein the sexual dysfunction involves touch sensation impairment, loss of clitoral sensation, dyspareunia, or a combination thereof.

16. The method of claim 1, wherein the sexual dysfunction involves dyspareunia.

17. The method of claim 1, wherein the vasoactive agent is selected from the group consisting of a Type V phosphodiesterase inhibitor and pharmaceutically acceptable salts thereof.

18. The method of claim 17, wherein the Type V phosphodiesterase inhibitor is selected from the group consisting of zaprinast, N-(3-chlorophenyl)-4-phenyl-1-phthalazinamine (MY5445), dipyridamole, pyrazolopyrimidinones, griseolic acid derivatives, 2-phenlypurinones, phenylpyridone derivatives, pyrimidines, pyrimidopyrimidines, purines, quinazolines, quinazolinones, quinoxalines, benzimidazoles, cycloheptimidazoles, phenylpyrimidinones, imidazoquinazolines, and imidazoquinoxalinones or aza analogues thereof.

19. The method of claim 18, wherein the Type V phosphodiesterase inhibitor is zaprinast.

20. The method of claim 18, wherein the Type V phosphodiesterase inhibitor is a pyrazolopyrimidinione.

21. The method of claim 20, wherein the pyrazolopyrimidinone has the structural formula

wherein:

R¹ is H, C₁-C₃ alkyl, C₁-C₃ perfluoroalkyl, or C₃-C₅ cycloalkyl;

R² is H;

C₁-C₆ alkyl optionally substituted with C₃-C₆ cycloalkyl;

C₁-C₃ perfluoroalkyl;

or C₃-C₆ cycloalkyl;

R³ is C₁-C₆ alkyl optionally substituted with C₃-C₆ cycloalkyl;

C₁-C₆ perfluoroalkyl;

C₃-C₅ cycloalkyl;

C₃-C₆ alkenyl;

or C₃-C₆ alkynyl;

R⁴ is C₁-C₄ alkyl optionally substituted with OH, NR⁵R⁶, CN, CONR⁵R⁶ or CO₂R⁷;

C₂-C₄ alkenyl optionally substituted with CN, CONR⁵R⁶ or CO₂R⁷;

C₂-C₄ alkanoyl optionally substituted with NR⁵R⁶;

(hydroxy)C₂-C₄ alkyl optionally substituted with NR⁵R⁶;

(C₂-C₃ alkoxy)C₁-C₂ alkyl optionally substituted with OH or NR⁵R⁶;

CONR⁵R⁶;

CO₂R⁷;

halo;

NR⁵R⁶;

NHSO₂NR⁵R⁶;

NHSO₂R⁸;

SO₂NR⁹R¹⁰;

or phenyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, thiazolyl, thienyl or triazolyl any of which is optionally substituted with methyl;

R⁵ and R⁶ are each independently H or C₁-C₄ alkyl, or together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidino, morpholino, 4-N(R¹¹)-piperazinyl or imidazolyl group wherein said group is optionally substituted with methyl or OH;

R⁷ is H or C₁-C₄ alkyl;

R⁸ is C₁-C₃ alkyl optionally substituted with NR⁵R⁶;

R⁹ and R¹⁰ together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidino, morpholino or 4-N(R¹²)-piperazinyl group wherein said group is optionally substituted with C₁-C₄ alkyl, C₁-C₃ alkoxy, NR¹³R¹⁴ or CONR¹³R¹⁴;

R¹¹ is H;

C₁-C₃ alkyl optionally substituted with phenyl;

(hydroxy)C₂-C₃ alkyl;

or C₁-C₄ alkanoyl;

R¹² is H;

C₁-C₂ alkyl;

(C₁-C₃ alkoxy)C₂-C₆ alkyl;

(hydroxy)C₂-C₆ alkyl;

(R¹³R¹⁴N)C₂-C₆ alkyl;

(R¹³R¹⁴NOC)C₁-C₆ alkyl;

CONR¹³R¹⁴;

CSNR¹³R¹⁴;

or C(NH)NR¹³R¹⁴;

R¹³ and R¹⁴ are each independently H;

C₁-C₄ alkyl;

(C₁-C₃ alkoxy)C₂-C₄ alkyl;

or (hydroxy)C₂-C₄ alkyl.

22. The method of claim 21, wherein the pyrazolopyrimidinone is selected from the group consisting of 5-(2-ethoxy-5-morpholinoacetylphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-(5-morpholino-acetyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-allyloxy-5-(4-methyl-1-piperazinylsulfonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-[4-(2-propyl)-1-piperazinylsulfonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-[4-(2-hydroxyethyl)-1-piperazinylsulfonylphenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[5-[4-(2-hydroxyethyl)-1-piperazinylsulfonyl]-2-n-propoxyphenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-(4-methyl-1-piperazinylcarbonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, and 5-[2-ethoxy-5-(1-methyl-2-imidazolyl)phenyl]-1-methyl-3n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.

23. The method of claim 22, wherein the pyrazolopyrimidinone is 5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.

24. The method of claim 18, wherein the Type V phosphodiesterase inhibitor is selected from the group consisting of 1,3-dimethyl-5-benzylpyrazolo[4,3-d]pyrimidine-7-one, 2-(2-propoxyphenyl)-6-purinone, 6-(2-propoxyphenyl)-1,2-dihydro-2-oxypyridine-3-carboxamide, 2-(2-propoxyphenyl)-pyrido[2,3-d]pyrimid-4(3H)-one, 7-methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydro-pyrimido[4,5-d]pyrimidine, 6-hydroxy-2-(2-propoxyphenyl)-pyrimidine-4-carboxamide, 1-ethyl-3-methylimidazo[1,5a]quinoxalin-4(5H)-one, 4-phenyl-methylamino-6-chloro-2-(1-imidazoloyl)quinazoline, 5-ethyl-8-[3-(N-cyclohexyl-N-methyl-carbamoyl)-propyloxy]-4,5-dihydro-4-oxo-pyrido[3,2-e]-pyrrolo[1,2-a]pyrazine, 5′

-methyl-3′

-(phenylmethyl)-spiro[cyclopentane-1,7′

(8′

H)-(3′

H)-imidazo[2,1-b]purin]4′

(5′

H)-one, 1-[6-chloro-4-(3,4methylenedioxybenzyl)-aminoquinazolin-2-yl)piperidine-4-carboxylic acid, (6R, 9S)-2-(4-trifluoromethyl-phenyl)methyl-5-methyl-3,4,5,6a,7,8,9,9a-octahydrocyclopent[4,5]-imidazo[2,1-b]-purin-4-one, 1-t-butyl-3-phenylmethyl-6-(4-pyridyl)pyrazolo[3,4-d]-pyrimid-4-one, 1-cyclopentyl-3-methyl-6-(4-pyridyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimid-4-one, 2-butyl-1-(2-chlorobenzyl)6-ethoxy-carbonylbenzimidaole, and 2-(4-caraboxypiperidino)-4-(3,4-methylene-dioxybenzyl)amino-6-nitroquinazoline, and 2-phenyl-8-ethoxycycloheptimidazole.

25. The method of claim 18, wherein the Type V phosphodiesterase inhibitor is tadalafil.

26. The method of claim 1, wherein the pharmaceutical formulation further includes a steroid.

27. The method of claim 26, wherein the steroid is selected from the group consisting of progestins, estrogens and mixtures thereof.

28. The method of claim 1, wherein the pharmaceutical formulation further includes a compound selected from the group consisting of steroid agonists, partial agonists and antagonists.

29. The method of claim 28, wherein the compound is selected from the group consisting of steroid agonists and partial agonists.

30. The method of claim 28, wherein the compound is selected from the group consisting of tamoxifen, cenchroman, cloriphene, droloxifene, raloxifene and pharmaceutically acceptable salts thereof.

31. The method of claim 2, wherein the pharmaceutical formulation additionally includes a detergent in an amount effective to increase the solubility of the vasoactive agent in the carrier and the bioavailability of the agent following administration.

32. A method for improving vaginal muscle tone and tissue health in a female individual, comprising vaginally administering to such individual a pharmaceutical formulation that comprises a vasoactive agent selected from the group consisting of a Type V phosphodiesterase inhibitor, pharmaceutically acceptable salts, esters, analogs, derivatives, prodrugs and inclusion complexes thereof, and combinations of any of the foregoing, in combination with a pharmaceutically acceptable carrier.

33. The method of claim 32, wherein the vasoactive agent is selected from the group consisting of a Type V phosphodiesterase inhibitor and pharmaceutically acceptable salts thereof.

34. A method for enhancing vaginal lubrication in a female individual, comprising vaginally administering to such individual a pharmaceutical formulation that comprises a vasoactive agent selected from the group consisting of a Type V phosphodiesterase inhibitor, pharmaceutically acceptable salts, esters, analogs, derivatives, prodrugs and inclusion complexes thereof, and combinations of any of the foregoing, in combination with a pharmaceutically acceptable carrier.

35. The method of claim 34, wherein the vasoactive agent is selected from the group consisting of a Type V phosphodiesterase inhibitor and pharmaceutically acceptable salts thereof.

36. A method for treating sexual dysfunction in a female individual, comprising administering to the vagina and/or vulvar area of the individual (a) a therapeutically effective amount of a Type V phosphodiesterase inhibitor or a pharmaceutically acceptable salt or ester thereof, and (b) a therapeutically effective amount of an additional active agent selected from the group consisting of additional vasodilators, androgenic agents, and combinations thereof.

37. The method of claim 36, wherein the additional active agent is an additional vasodilator.

38. The method of claim 37, wherein the additional vasodilator is selected from the group consisting of prostaglandins, endothelial-derived relaxation factors, vasoactive intestinal polypeptide agonists, smooth muscle relaxants, leukotriene inhibitors, and combinations thereof.

39. The method of claim 38, wherein the additional vasodilator is a prostaglanidin.

40. The method of claim 39, wherein the prostaglandin is PGE₀, PGE₁, PGE₂, or a combination thereof.

41. The method of claim 40, wherein the prostaglandin is PGE₁.

42. The method of claim 37, wherein the additional vasodilator is a nitrovasodilater.

43. The method of claim 36, wherein the additional active agent is an androgenic agent.

44. The method of claim 43, wherein the androgenic agent is selected from the group consisting of androsterone, androsterone acetate, androsterone, androstenediol, androstenedione, ethylestrenol, oxandrolone, nandrolone, stanozolol, dromostanolone, testosterone, dehydroepiandrosterone, 5α

-dihydrotestosterone, methyl testosterone, testolactone, oxymetholone, fluoxymesterone, and pharmaceutically acceptable esters thereof.

45. The method of claim 37, wherein the androgenic agent is selected from the group consisting of testosterone, 5α

-dihydrotestosterone, and pharmaceutically acceptable esters thereof.

46. The method of claim 45, wherein the androgenic agent is testosterone.

47. The method of claim 45, wherein the androgenic agent is 5α

-dihydrotestosterone.

48. The method of claim 45, wherein the androgenic agent is a testosterone ester.

49. The method of claim 48, wherein the testosterone ester is selected from the group consisting of testosterone enanthate, testosterone propionate, testosterone cypionate, testosterone phenylacetate, testosterone acetate, testosterone isobutyrate, testosterone buciclate, testosterone heptanoate, testosterone decanoate, testosterone undecanoate, testosterone caprate and testosterone isocaprate.

50. The method of claim 49, wherein the testosterone ester is testosterone propionate.

51. The method of claim 45, wherein the androgenic agent is a 5α

-dihydrotestoserone ester.

52. The method of claim 51, wherein the 5α

-dihydrotestosterone ester is selected from the group consisting of the 5α

-dihydrotestosterone enanthate, 5α

-dihydrotestosterone propionate, 5α

-dihydrotestosterone cypionate, 5α

-dihydrotestosterone phenylacetate, 5α

-dihydrotestosterone acetate, 5α

-dihydrotestosterone isobutyrate, 5α

-dihydrotestosterone buciclate, 5α

-dihydrotestosterone heptanoate, 5α

-dihydrotestosterone decanoate, 5α

-dihydrotestosterone undecanoate, 5α

-dihydrotestosterone caprate and 5α

-dihydrotestosterone isocaprate.

53. The method of claim 36, wherein the sexual dysfunction is an excitement stage dysfunction.

54. The method of claim 53, wherein the sexual dysfunction involves touch sensation impairment, loss of clitoral sensation, dyspareunia, or a combination thereof.

55. The method of claim 36, wherein the sexual dysfunction involves dyspareunia.

56. The method of claim 36, wherein the Type V phosphodiesterase inhibitor is selected from the group consisting of zaprinast, N-(3-chlorophenyl)-4-phenyl-1-phthalazinamine (MY5445), dipyridamole, pyrazolopyrimidinones, griseolic acid derivatives, 2-phenylpurinones, phenylpyridone derivatives, pyrimidines, pyrimidopyrimidines, purines, quinazolines, quinazolinones, quinoxalines, benzimidazoles, cycloheptimidazoles, phenylpyrimidinones, imidazoquinazolines, and imidazoquinoxalinones or aza analogues thereof.

57. The method of claim 36, wherein the vasoactive agent is selected from the group consisting of a Type V phosphodiesterase inhibitor and pharmaceutically acceptable salts thereof.

58. The method of claim 57, wherein the Type V phosphodiesterase inhibitor is zaprinast.

59. The method of claim 57, wherein the Type V phosphodiesterase inhibitor is a pyrazolopyrimidinone.

60. The method of claim 59, wherein the pyrazolopyrimidinone has the structural formula having the structural formula

wherein:

R¹ is H, C₁-C₃ alkyl, C₁-C₃ perfluoroalkyl, or C₃-C₅ cycloalkyl;

R² is H;

C₁-C₆ alkyl optionally substituted with C₃-C₆ cycloalkyl;

C₁-₃ perfluoroalkyl;

or C₃-C₆ cycloalkyl;

R³ is C₁-C₆ alkyl optionally substituted with C₃-C₆ cycloalkyl;

C₁-C₆ perfluoroalkyl;

C₃-C₅ cycloalkyl;

C₃-C₆ alkenyl;

or C₃-C₆ alkynyl;

R⁴ is C₁-C₄ alkyl optionally substituted with OH, NR⁵R⁶, CN, CONR⁵R⁶ or CO₂R⁷;

C₂-C₄ alkenyl optionally substituted with CN, CONR⁵R⁶ or CO₂R⁷;

C₂-C₄ alkanoyl optionally substituted with NR⁵R⁶;

(hydroxy)C₂-C₄ alkyl optionally substituted with NR⁵R⁶;

(C₂-C³ alkoxy)C₁-C₂ alkyl optionally substituted with OH or NR⁵R⁶;

CONR⁵R⁶;

CO₂R⁷;

halo;

NR⁵R⁶;

NHSO₂NR⁵R⁶;

NHSO₂R⁸;

SO₂NR⁹R¹⁰;

or phenyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, thiazolyl, thienyl or triazolyl any of which is optionally substituted with methyl;

R⁵ and R⁶ are each independently H or C₁-C₄ alkyl, or together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidino, morpholino, 4-N(R¹¹)-piperazinyl or imidazolyl group wherein said group is optionally substituted with methyl or OH;

R⁷ is H or C₁-C₄ alkyl;

R⁸ is C₁-C₃ alkyl optionally substituted with NR⁵R⁶;

R⁹ and R¹⁰ together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidino, morpholino or 4-N(R¹²)-piperazinyl group wherein said group is optionally substituted with C₁-C₄ alkyl, C₁-C₃ alkoxy, NR¹³R¹⁴ or CONR¹³R¹⁴;

R¹¹ is H;

C₁-₃ alkyl optionally substituted with phenyl;

(hydroxy)C₂-C₃ alkyl;

or C₁-C₄ alkanoyl;

R¹² is H;

C₁-C₂ alkyl;

(C₁-C₃ alkoxy)C₂-C₆ alkyl;

(hydroxy)C₂-C₆ alkyl;

(R¹³R¹⁴N)C₂-C₆ alkyl;

(R¹³R¹⁴NOC)C₁-C₆ alkyl;

CONR¹³R¹⁴;

CSNR¹³R¹⁴;

or C(NH)NR¹³R¹⁴;

R¹³ and R¹⁴ are each independently H;

C₁-C₄ alkyl;

(C₁-C₃ alkoxy)C₂-C₄ alkyl;

or (hydroxy)C₂-C₄ alkyl.

61. The method of claim 60, wherein the pyrazolopyrimidinone is selected from the group consisting of 5-(2-ethoxy-5-morpholinoacetylphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-(5-morpholino-acetyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1.6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-allyloxy-5-(4-methyl-1-piperazinylsulfonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-[4-(2-propyl)-1-piperazinylsulfonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-[4-(2-hydroxyethyl)-1-piperazinylsulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[5-[4-(2-hydroxyethyl)-1-piperazinylsulfonyl]-2-n-propoxyphenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-(4-methyl-1-piperazinylcarbonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, and 5-[2-ethoxy-5-(1-methyl-2imidazolyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7one.

62. The method of claim 61, wherein the pyrazolopyrimidinone is 5-(4-methyl-1-piperazinylsulfonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7one.

63. The method of claim 57, wherein the Type V phosphodiesterase inhibitor is selected from the group consisting of 1,3-dimethyl-5-benzylpyrazolo[4,3-d]pyrimidine-7-one, 2-(2-propoxyphenyl)-6-purinone, 6-(2-propoxyphenyl)-1,2-dihydro-2-oxypyridine-3-carboxamide, 2-2-propoxyphenyl)-pyrido[2,3-d]pyrimid-4(3H)-one, 7-methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydro-pyrimido[4,5-d]pyrimidine, 6-hydroxy-2-(2-propoxyphenyl)-pyrimidine-4-carboxamide, 1-ethyl-3-methyl-imidazo[1,5a]quinoxalin-4(5H)-one, 4-phenyl-methylamino-6-chloro-2-(1-imidazoyloyl)quinazoline, 5-ethyl-8-[3-(N-cyclohexyl-N-methyl-carbamoyl)-propyloxy]-4,5-dihydro-4-oxo-pyrido-3,2-c]-pyrrolo[1,2-a]pyrazine, 5′

-methyl-3′

-(phenylmethyl)-spiro[cyclopentane-1,7′

(8′

H)-(3′

H)-imidazo[2,1-b]purin]4′

(5′

H)-one, 1-[6-chloro-4-(3,4-methylenedioxybenzyl)-aminoquinazolin-2-yl)piperidine-4-carboxylic acid, (6R,9S)-2-(4-trifluoromethyl-phenyl)methyl-5-methyl-3,4,5,6a,7,8,9,9a,-octahydrocyclopent[4,5]-imidazo[2,1-b]-purin-4-one, 1-t-butyl-3-phenylmethyl-6-(4-pyridyl)pyrazolo[3,4-d]-pyrimid-4one, 1-cyclopentyl-3-methyl-6-(4-pyridyl)-4,5-dihydro-1H-pyrazolo[3,4d]pyrimid-4-one, 2-butyl-1-(2-chlorobenzyl)6-ethoxy-carbonylbenzimidaole, and 2-(4-carboxypiperidino)-4-(3,4-methylene-dioxybenzyl)amino-6-nitroquinazoline, and 2-phenyl-8-ethoxycycloheptimidazole.

64. The method of claim 57, wherein the Type V phosphodiesterase inhibitor is tadalafil.