WO1999022731A1 - Method and composition for treatment of sexual dysfunction - Google Patents

Method and composition for treatment of sexual dysfunction Download PDF

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Publication number
WO1999022731A1
WO1999022731A1 PCT/AU1998/000906 AU9800906W WO9922731A1 WO 1999022731 A1 WO1999022731 A1 WO 1999022731A1 AU 9800906 W AU9800906 W AU 9800906W WO 9922731 A1 WO9922731 A1 WO 9922731A1
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Prior art keywords
milrinone
alpha
injection
atropine
erection
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PCT/AU1998/000906
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French (fr)
Inventor
Jakov Vaisman
Original Assignee
Vaysman, Pyotr
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Priority to CA002315221A priority Critical patent/CA2315221A1/en
Priority to EP98952416A priority patent/EP1028726A1/en
Priority to AU10116/99A priority patent/AU1011699A/en
Publication of WO1999022731A1 publication Critical patent/WO1999022731A1/en

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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
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants

Definitions

  • the present invention relates to the treatment of erectogenic dysfunction in males, and to the treatment of anorgasmia in women.
  • Milrinone is a type III PDE inhibitor, which functions as a positive inotrope and vasodilator in its conventional clinical use, but has various adverse reactions. These include ventricular arrhymias, ventricular extopic activity, ventricular tachycardia, and ventricular fibrillation. It is accordingly not desirable administer large doses, particularly when many patients are middle aged and older men who may well be susceptible to cardiovascular or circulatory disorders. Trials by the inventor have indicated that Milrinone is not effective as an erectogenic agent when administered alone at safe doses. Milrinone is a powerful vasoactive substance, and administration of substantial doses by, for example, penile injection carries a risk of deleteriously effecting the circulatory system as a whole. It is one object of the present invention to provide a composition including milrinone which is as or more effective than existing compositions in the treatment of impotence. It is a further object of the present invention to provide an improved method of treatment for impotence.
  • Another object of the present invention is to provide a new composition and method of treatment for female anorgasmia.
  • the present invention provides in one aspect a composition for use in the treatment of sexual dysfunction, comprising an effective amount of milrinone, a pharmaceutically acceptable carrier or diluent, and one or more agents selected from the group comprising an alpha-adrenergic blocker, a phosphodiesterase inhibitor, a PGE prostaglandin type E, an atropinic agent, with the alpha blocker itself being composed of one part alpha 1 and one part alpha 2.
  • the present invention comprises a method of treating sexual dysfunction in a mammal, which comprises administering to said mammal a effective amount of a composition comprising in combination Milrinone, and one or more therapeutically active agents selected from the group comprising an alpha-adrenergic blocker composed of one part alpha 1 and one part alpha 2, a phosphodiesterase inhibitor, a PGE type prostaglandin, and an atropinic agent.
  • a composition comprising in combination Milrinone, and one or more therapeutically active agents selected from the group comprising an alpha-adrenergic blocker composed of one part alpha 1 and one part alpha 2, a phosphodiesterase inhibitor, a PGE type prostaglandin, and an atropinic agent.
  • the composition is administered by intracavemous injection, topical, transdermal, or intraurethrally.
  • the present invention comprises the use of milrinone in the manufacture of a medicament for the treatment of sexual dysfunction, said medicament comprising an effective amount of milrinone and a pharmaceutically acceptable carrier or diluent.
  • the medicament further comprises one or more further therapeutic agents which either facilitate, potentiate or are erectogenic.
  • additional therapeutic agents are selected from the group comprising an alpha-adrenergic blocker composed of one part alpha 1 and one part alpha 2, a phosphodiesterase inhibitor, a PGE prostaglandin type, and an atropinic agent .
  • the present invention will be described and exemplified in relation to several particular compositions and comparative trials as set out below. It is emphasised, however, that the precise dosage and treatment regime will be determined by the attending physician, depending upon the particular circumstances of each patient - for example age, response to particular medications, general health and cardiovascular condition. Hence, the precise dosages and elements of the therapeutic compositions will vary in any true clinical situation.
  • he erectogenic activity of milrinone alone or in combination with papaverine, chlorpromazine, phentolamine, atropine, yohimbine and prostaglandin E1 was compared to that of combinations of papaverine, chlorpromazine, phentolamine, atropine, yohimbine and prostaglandin E1.
  • Phentolamine Atropine versus Phentolamine. Atropine. Milrinone: After the injection of phentolamine 2 mg. and atropine 0.2 mg. into 9 patients, all 9 showed no response (grades 1).
  • the mean latency time between injection and erection was 9 minutes and the mean duration of erection was 78 minutes.
  • Atropine Milrinone: After the injection of papaverine 1 1.25 mg., phentolamine 2 mg. and atropine 0.2 mg. into 14 patients, 8 (57%) achieved erections with rigidity of grades 4 to 5 and the other 6 (43%) had tumescence without rigidity (grade 3).
  • the mean latency time between injection and erection was 8 minutes and the mean duration of erection was 98 minutes.
  • milrinone acts on a post-receptor level via the inhibition of phosphodiesterase (the consequent increase in cyclic adenosine monophosphate attenuates the ⁇ 1 (alpha 1) receptor-mediated contraction of the smooth muscle cell, possibly by interfering with the calcium ion-mobilisation).
  • alpha blocking properties of yohimbine seem to be at least as effective as phentolamine if not more so, whereas prostaglandin E1 acts via a membrane- receptor.
  • Atropine works by potentiating the action of the other active products on pathological erectile tissue by interfering with the mechanisms that trigger the relaxation of smooth muscle, especially the EDRF (Endothelium Releasing Factor).
  • milrinone included at a relatively low dose in a composition for the treatment of impotence enhances the effectiveness of the composition in a way which does not correlate with the activity of Milrinone alone or with the activity of the other components of the composition even when theses other components are used in combination.
  • a further advantage of the present invention is that it allows prostaglandin
  • prostaglandin E1 produces significant side effects (pain at the site of the injection) while other patients have only a weak response to weak response to prostaglandin E1 (due to a low receptor density). It will be understood that analogues to the components described above may exhibit similar clinical activity to those particularly discussed, and that the present invention is not limited to the specific compounds discussed above in combination with Milrinone.

Abstract

Disclosed is a composition and method of treatment for sexual dysfunction, in both male and female mammals. The composition is preferably a combination of a relatively low dose of milrinone, in combination with one or more of an alpha-adrenergic blocker, a phosphodiesterase inhibitor, a PGE prostaglandin type, or an atropinic agent. The composition is preferably administered via intracavernosal injection, or for females via a topical composition.

Description

Method and Composition for Treatment of Sexual Dysfunction Technical Field
The present invention relates to the treatment of erectogenic dysfunction in males, and to the treatment of anorgasmia in women. Background Art
It has been known to treat erectogenic dysfunction in men using so-called self injection therapy, following from the work of Virag - for example, see R Virag et al, Intercavernous Injection of Papave ne as a Diagnostic and Therapeutic Method in Erectile Failure, Angiologyn ,35, pp 79-87 (1984). Various compounds have been used in this treatment technique. For example, in US patent No. 5474535 to Place et al, there is a disclosure of a large group of therapeutic agents suitable for use in the treatment of impotence, with a preferred composition being a combination of alpha blockers and prostaglandin. Various agents and combinations have been described in the literature. However, the improvement of the treatment regimes and the compositions used has been largely a matter of trial and error. Whilst many patients can be helped with existing treatments, there is a minority who do not achieve erection using existing drug therapies. There is still no well understood theoretical regime which can predict the likely effectiveness or otherwise of any particular compound or combination of compounds, and hence it is not possible to predict whether a given combination will be more or less efficacious than the components given alone.
In an abstract by Stief et al, published in International Journal of Impotence Research, Basic and Clinical Studies, Stockton, v. 8 No. 3, September 1996, p. 127, Abstract D20 , trials are disclosed in which Milrinone was tested for its effects on samples of tissue from human and rabbit corpus cavemosum. In vivo trials were also conducted, and erectile response was reported in humans from treatment with Milrinone alone.
In an abstract by Sparwasser et al, also published in International Journal of Impotence Research, Basic and Clinical Studies, Stockton, v. 8 No. 3, September 1996, p. 127, Abstract D22, trials were conducted using cavemosal tissue to determine the efficacy of various PDE inhibitors, including Milrinone. The abstract suggests that on the basis of the tissue trials Milrinone may be an effective treatment for erectogenic dysfunction.
Milrinone is a type III PDE inhibitor, which functions as a positive inotrope and vasodilator in its conventional clinical use, but has various adverse reactions. These include ventricular arrhymias, ventricular extopic activity, ventricular tachycardia, and ventricular fibrillation. It is accordingly not desirable administer large doses, particularly when many patients are middle aged and older men who may well be susceptible to cardiovascular or circulatory disorders. Trials by the inventor have indicated that Milrinone is not effective as an erectogenic agent when administered alone at safe doses. Milrinone is a powerful vasoactive substance, and administration of substantial doses by, for example, penile injection carries a risk of deleteriously effecting the circulatory system as a whole. It is one object of the present invention to provide a composition including milrinone which is as or more effective than existing compositions in the treatment of impotence. It is a further object of the present invention to provide an improved method of treatment for impotence.
It is postulated by the inventor that one cause of female anorgasmia is the inability of some women to achieve rigidity of the clitoris during sexual activity, and that accordingly similar pharmacological agents and compositions, suitably reformulated for topical use, may be effective in the treatment of female anorgasmia. Accordingly, another object of the present invention is to provide a new composition and method of treatment for female anorgasmia. Summary of the Invention
The present invention provides in one aspect a composition for use in the treatment of sexual dysfunction, comprising an effective amount of milrinone, a pharmaceutically acceptable carrier or diluent, and one or more agents selected from the group comprising an alpha-adrenergic blocker, a phosphodiesterase inhibitor, a PGE prostaglandin type E, an atropinic agent, with the alpha blocker itself being composed of one part alpha 1 and one part alpha 2.
According to one other aspect, the present invention comprises a method of treating sexual dysfunction in a mammal, which comprises administering to said mammal a effective amount of a composition comprising in combination Milrinone, and one or more therapeutically active agents selected from the group comprising an alpha-adrenergic blocker composed of one part alpha 1 and one part alpha 2, a phosphodiesterase inhibitor, a PGE type prostaglandin, and an atropinic agent.
Preferably, the composition is administered by intracavemous injection, topical, transdermal, or intraurethrally.
According to another aspect the present invention comprises the use of milrinone in the manufacture of a medicament for the treatment of sexual dysfunction, said medicament comprising an effective amount of milrinone and a pharmaceutically acceptable carrier or diluent.
Preferably, the medicament further comprises one or more further therapeutic agents which either facilitate, potentiate or are erectogenic. Most preferably the additional therapeutic agents are selected from the group comprising an alpha-adrenergic blocker composed of one part alpha 1 and one part alpha 2, a phosphodiesterase inhibitor, a PGE prostaglandin type, and an atropinic agent .
It has been discovered by the inventor that when Milrinone is administered in combination with other erectogenic agents, a strong synergistic effect occurs, to the extent that these combinations are more effective than combinations previously used, and much more effective than the components when given alone. Some patients who did not achieve erection using conventional therapies achieved erection using the inventive therapy. Description
The present invention will be described and exemplified in relation to several particular compositions and comparative trials as set out below. It is emphasised, however, that the precise dosage and treatment regime will be determined by the attending physician, depending upon the particular circumstances of each patient - for example age, response to particular medications, general health and cardiovascular condition. Hence, the precise dosages and elements of the therapeutic compositions will vary in any true clinical situation. In the trial set out below, he erectogenic activity of milrinone alone or in combination with papaverine, chlorpromazine, phentolamine, atropine, yohimbine and prostaglandin E1 was compared to that of combinations of papaverine, chlorpromazine, phentolamine, atropine, yohimbine and prostaglandin E1.
These effects were studied in 176 patients with multiple pathogenic factors. The grade of erection was determined by palpation and inspection of the penis by the same doctor in all patients, according to a scale from one to five (one (1) - no erection, two (2) - slight tumescence, three (3) - full tumescence without rigidity, four (4) - incomplete rigidity and five (5) - full rigidity). The latent period between injection and erection, duration of the erection and side effects were also recorded.
Arterial blood flow was evaluated by Doppler ultrasound and an average flow velocity of 20-25 cm per second was assumed as the lower limit of normal. STUDY RESULTS Milrinone Only;
After the injection of milrinone 1 mg. alone into 12 patients, 5 (41%) showed no response or slight tumescence only (grades 1 to 2), 4 (33%) had tumescence without rigidity (grade 3) and the other 3 (25%) achieved erections with rigidity of grades 4 to 5 and the other. The mean latency time between injection and erection was 12 minutes and the mean duration of erection was 28 minutes. Atropine onlv:
After the injection of atropine 0J2 mg. into 9 patients, all 9 showed no response (grades 1).
Atropine vs Atropine Milrinone:
After the injection of atropine 0J2 mg. into 11 patients, all 11 showed no response (grades 1).
After the injection of milrinone 0.38 mg. and atropine 0.12 mg. into the same 11 patients, 7 (64%) achieved erections with rigidity of grades 4 to 5 and the other 4 (36%) had tumescence without rigidity (grade 3). The mean latency time between injection and erection was 10 minutes and the mean duration of erection was 43 minutes. Chlorpromazine. Atropine versus Chlorpromazine. Atropine. Milrinone:
After the injection of chlorpromazine 3J mg. and atropine 0.12 mg. into 8 patients, all 8 showed no response (grades 1).
After the injection of milrinone 0.38 mg., chlorpromazine 3.1 mg. and atropine 0.12 mg. into the same 8 patients, 5 (62%) achieved erections with rigidity of grades 4 to 5 and the other 3 (38%) had tumescence without rigidity
(grade 3). The mean latency time between injection and erection was 11 minutes and the mean duration of erection was 39 minutes.
Phentolamine. Atropine versus Phentolamine. Atropine. Milrinone: After the injection of phentolamine 2 mg. and atropine 0.2 mg. into 9 patients, all 9 showed no response (grades 1).
After the injection of milrinone 0.38 mg., phentolamine 2 mg. and atropine
0.2 mg. into the same 9 patients, 6 (67%) achieved erections with rigidity of grades 4 to 5 and the other 3 (33%) had tumescence without rigidity (grade 3). The mean latency time between injection and erection was 8 minutes and the mean duration of erection was 58 minutes.
Papaverine. Chlorpromazine. Atropine versus Papaverine. Chlorpromazine.
Atropine. Milrinone:
After the injection of papaverine 11.25 mg., chlorpromazine 3J mg. and atropine 0J2 mg. into 13 patients, 7 (54%) achieved erections with rigidity of grades 4 to 5 and the other 6 (46%) had tumescence without rigidity (grade 3).
The mean latency time between injection and erection was 9 minutes and the mean duration of erection was 78 minutes.
After the injection of milrinone 0.38 mg., papaverine 11.25 mg., chlorpromazine 3.1 mg. and atropine 0J2 mg. into the same 13 patients, 11
(84%) achieved erections with rigidity of grades 4 to 5 and the other 2 (16%) had tumescence without rigidity (grade 3). The mean latency time between injection and erection was 9 minutes and the mean duration of erection was 96 minutes. Papaverine. Phentolamine. Atropine versus Papaverine. Phentolamine.
Atropine. Milrinone: After the injection of papaverine 1 1.25 mg., phentolamine 2 mg. and atropine 0.2 mg. into 14 patients, 8 (57%) achieved erections with rigidity of grades 4 to 5 and the other 6 (43%) had tumescence without rigidity (grade 3).
The mean latency time between injection and erection was 8 minutes and the mean duration of erection was 98 minutes.
After the injection of milrinone 0.38 mg., papaverine 11.25 mg., phentolamine 2 mg. and atropine 0.2 mg. into the same 14 patients, 12 (85%) achieved erections with rigidity of grades 4 to 5 and the other 2 (15%) had tumescence without rigidity (grade 3). The mean latency time between injection and erection was 7 minutes and the mean duration of erection was 126 minutes. Papaverine. Chlorpromazine. Atropine. Yohimbine versus Papaverine. Chlorpromazine. Atropine. Yohimbine. Milrinone:
After the injection of papaverine 15 mg., chlorpromazine 5 mg., atropine
0.15 mg. and yohimbine 1.75 mg. into 50 patients, 35 (70%) achieved erections with rigidity of grades 4 to 5 and the other 15 (30%) had tumescence without rigidity (grade 3). The mean latency time between injection and erection was 9 minutes and the mean duration of erection was 86 minutes.
After the injection of milrinone 0.38 mg., papaverine 15 mg., chlorpromazine 5 mg., atropine 0.15 mg. and yohimbine 1.75 mg. into the same 50 patients, 48 (96%) achieved erections with rigidity of grades 4 to 5 and the other 2 (4%) had tumescence without rigidity (grade 3). The mean latency time between injection was 9 minutes and the mean duration of erection was 138 minutes.
Papaverine. Phentolamine. Atropine. Yohimbine versus Papaverine. Phentolamine. Atropine. Yohimbine. Milrinone:
After the injection of papaverine 15 mg., phentolamine 2 mg., atropine
0J5 mg. and yohimbine 1.75 mg. into 18 patients, 13 (72%) achieved erections with rigidity of grades 4 to 5 and the other 5 (28%) had tumescence without rigidity (grade 3). The mean latency time between injection and erection was 10 minutes and the mean duration of erection was 73 minutes.
After the injection of milrinone 0.38 mg., papaverine 15 mg., phentolamine 2 mg., atropine 0.15 mg. and yohimbine 1.75 mg. into the same 18 patients, 17 (94%) achieved erections with rigidity of grades 4 to 5 and the other 1 (6%) had tumescence without rigidity (grade 3). The mean latency time between injection and erection was 8 minutes and the mean duration of erection was 124 minutes. Papaverine. Chlorpromazine. Atropine. Prostaglandin E1 versus Papaverine. Chlorpromazine. Atropine. Prostaglandin E1. Milrinone:
After the injection of papaverine 11.25 mg., chlorpromazine 3.1 mg., atropine 0.12 mg. and prostaglandin E1 5 meg. into 9 patients, 6 (67%) achieved erections with rigidity of grades 4 to 5 and the other 3 (33%) had tumescence without rigidity (grade 3). The mean latency time between injection and erection was 10 minutes and the mean duration of erection was 92 minutes.
After the injection of milrinone 0.38 mg., papaverine 11.25 mg., chlorpromazine 3J mg., atropine 0.12 mg. and prostaglandin E1 5 meg. into the same 9 patients, 8 (89%) achieved erections with rigidity of grades 4 to 5 and the other 1 (11%) had tumescence without rigidity (grade 3). The mean latency time between injection and erection was 9 minutes and the mean duration of erection was 134 minutes.
Papaverine. Phentolamine. Atropine. Prostaglandin E1 versus Papaverine. Phentolamine. Atropine. Prostaglandin E1. Milrinone: After the injection of papaverine 18 mg., phentolamine 2 mg., atropine 0.2 mg. and prostaglandin E1 5 meg. into 14 patients, 10 (71%) achieved erections with rigidity of grades 4 to 5 and the other 4 (29%) had tumescence without rigidity (grade 3). The mean latency time between injection and erection was 11 minutes and the mean duration of erection was 82 minutes. After the injection of milrinone 0.38 mg., papaverine 18 mg., phentolamine 2 mg., atropine 0.2 mg. and prostaglandin E1 5 meg. into the same 14 patients, 13 (82%) achieved erections with rigidity of grades 4 to 5 and the other 1 (8%) had tumescence without rigidity (grade 3). The mean latency time between injection and erection was 9 minutes and the mean duration of erection was 143 minutes.
Papaverine. Chlorpromazine. Atropine. Yohimbine. Prostaglandin E1 versus Papaverine. Chlorpromazine. Atropine. Yohimbine. Prostaglandin E1. Milrinone: After the injection of papaverine 15 mg., chlorpromazine 5 mg., atropine 0J5 mg., yohimbine 1.75 mg. and prostaglandin E1 5 meg. into 18 patients, 14 (78%) achieved erections with rigidity of grades 4 to 5 and the other 4 (22%) had tumescence without rigidity (grade 3). The mean latency time between injection and erection was 11 minutes and the mean duration of erection was 76 minutes.
After the injection of milrinone 0.38 mg., papaverine 15 mg., chlorpromazine 5 mg., atropine 0J5 mg., yohimbine 1.75 mg. and prostaglandin E1 5 meg. into the same 18 patients, 17 (94%) achieved erections with rigidity of grades 4 to 5 and the other 1 (6%) had tumescence without rigidity (grade 3). The mean latency time between injection and erection was 10 minutes and the mean duration of erection was 143 minutes.
Papaverine. Phentolamine. Atropine. Yohimbine. Prostaglandin E1 versus Papaverine. Phentolamine. Atropine. Yohimbine. Prostaglandin E1. Milrinone: After the injection of papaverine 18 mg., phentolamine 2 mg., atropine 0.2 mg., yohimbine 1.75 mg. and prostaglandin E1 5 meg. into 11 patients, 8 (73%) achieved erections with rigidity of grades 4 to 5 and the other 3 (27%) had tumescence without rigidity (grade 3). The mean latency time between injection and erection was 8 minutes and the mean duration of erection was 84 minutes.
After the injection of milrinone 0.38 mg. papaverine 18 mg., phentolamine 2 mg., atropine 0.2 mg., yohimbine 1.75 mg. and prostaglandin E1 5 meg. into the same 11 patients, 10 (91%) achieved erections with rigidity of grades 4 to 5 and the other 1 (9%) had tumescence without rigidity (grade 3). The mean latency time between injection and erection was 8 minutes and the mean duration of erection was 132 minutes. Summary of study results
Milrinone alone produced erectogenic activity markedly lower than due to any combination of papaverine, chlorpromazine, phentolamine, atropine, yohimbine and prostaglandin E1 , both in terms of the rigidity and duration of responses. However, when combined with papaverine, chlorpromazine, phentolamine, atropine, yohimbine and prostaglandin E1 , milrinone proved to evoke erections similar to erections experienced by the patients during normal sexual intercourse. It is postulated that the combination of different mechanisms of action is a possible explanation for such a strong synergistic behaviour with milrinone. Together with papaverine and even more potent than papaverine, milrinone acts on a post-receptor level via the inhibition of phosphodiesterase (the consequent increase in cyclic adenosine monophosphate attenuates the α1 (alpha 1) receptor-mediated contraction of the smooth muscle cell, possibly by interfering with the calcium ion-mobilisation). Furthermore, the alpha blocking properties of yohimbine seem to be at least as effective as phentolamine if not more so, whereas prostaglandin E1 acts via a membrane- receptor. Atropine works by potentiating the action of the other active products on pathological erectile tissue by interfering with the mechanisms that trigger the relaxation of smooth muscle, especially the EDRF (Endothelium Releasing Factor).
It is concluded that a combination of milrinone with any combination of papaverine, chlorpromazine, phentolamine, atropine, yohimbine and prostaglandin E1 is significantly more effective than any combination of papaverine, chlorpromazine, phentolamine, atropine, yohimbine and prostaglandin E1 without milrinone.
Accordingly, it is believed that a strong synergistic effect has been demonstrated, so that milrinone included at a relatively low dose in a composition for the treatment of impotence enhances the effectiveness of the composition in a way which does not correlate with the activity of Milrinone alone or with the activity of the other components of the composition even when theses other components are used in combination.. A further advantage of the present invention is that it allows prostaglandin
E1 to be omitted from the therapeutic combination. For some patients, prostaglandin E1 produces significant side effects (pain at the site of the injection) while other patients have only a weak response to weak response to prostaglandin E1 (due to a low receptor density). It will be understood that analogues to the components described above may exhibit similar clinical activity to those particularly discussed, and that the present invention is not limited to the specific compounds discussed above in combination with Milrinone.
Effects of Clitoral Application of Milrinone Gel in Combination with Papaverine. Chlorpromazine. Phentolamine. Atropine and Yohimbine in Women with Orgasmic Dysfunction Clitoral Doppler ultrasonography was studied in 8 heterosexual active female volunteers with primary anorgasmia. Significant changes from baseline of all Doppler parameters was found before and after clitoral application of milrinone gel. The results obtained in this study showed a striking similarity between female clitoral vascular response and male eavernosal vascular response after intracavemosal injection of milrinone in combination with papaverine, chlorpromazine, phentolamine, atropine and yohimbine. After clitoral application of milrinone gel during the sexual excitement phase, all 8 women for the first time achieved full orgasm through intercourse or even during manual stimulation by the partner.

Claims

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:
1. A method of treating sexual dysfunction in mammals, which comprises of administering to said mammal an effective amount of milrinone.
2. The method according to claim 1 wherein the milrinone is used in combination with one or more therapeutically active agents selected from an alpha-adrenergic blocker, a phosphodiesterase inhibitor, a PGE prostaglandin type, an atropinic agent, with the alpha blocker itself being composed of one part alpha 1 and one part alpha 2.
3. The method according to claim 1 and 2,wherein the method of treating is by intracavemous injection, topical, transdermal, or intraurethral administration of the milrinone.
4. The use of milrinone in the manufacture of a medicament for the treatment of sexual dysfunction comprising an effective amount of milrinone and a pharmaceutically acceptable carrier or diluent.
5. The use according to claim 4 which further comprises one or more additional therapeutic agents which either facilitate, potentiate or are erectogenic.
6. The use according to claim 3 wherein the additional agents comprise one or more agents selected from the group comprising an alpha-adrenergic blocker, a phosphodiesterase inhibitor, a PGE prostaglandin type E, an atropinic agent, with the alpha blocker itself being composed of one part alpha 1 and one part alpha 2.
7. The use according to claim 6 wherein the composition is formulated so as to be administered by intracavernous injection, topically, transdermally, or intraurethraliy.
8. The use according to claims 4 to 7 wherein the composition further comprises a penetration-enhancing agent.
9. A composition for use in the treatment of sexual dysfunction, comprising an effective amount of milrinone, a pharmaceutically acceptable carrier or diluent, and one or more agents selected from the group comprising an alpha- adrenergic blocker, a phosphodiesterase inhibitor, a PGE prostaglandin type E, an atropinic agent, with the alpha blocker itself being composed of one part alpha 1 and one part alpha 2.
PCT/AU1998/000906 1997-10-30 1998-10-30 Method and composition for treatment of sexual dysfunction WO1999022731A1 (en)

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CA002315221A CA2315221A1 (en) 1997-10-30 1998-10-30 Method and composition for treatment of sexual dysfunction
EP98952416A EP1028726A1 (en) 1997-10-30 1998-10-30 Method and composition for treatment of sexual dysfunction
AU10116/99A AU1011699A (en) 1997-10-30 1998-10-30 Method and composition for treatment of sexual dysfunction

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AUPP0103 1997-10-30

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1097706A1 (en) * 1999-11-08 2001-05-09 Pfizer Limited Phosphodiesterase inhibitors for the treatment of female sexual dysfunction
WO2001041807A2 (en) * 1999-12-10 2001-06-14 Vivus, Inc. Transmucosal composition containing a phosphodiesterase inhibitors for the treatment of erectile dysfunction
US6331543B1 (en) 1996-11-01 2001-12-18 Nitromed, Inc. Nitrosated and nitrosylated phosphodiesterase inhibitors, compositions and methods of use
US6403597B1 (en) 1997-10-28 2002-06-11 Vivus, Inc. Administration of phosphodiesterase inhibitors for the treatment of premature ejaculation
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US6462044B2 (en) 1996-11-01 2002-10-08 Nitromed, Inc. Nitrosated and nitrosylated phosphodiesterase inhibitors, compositions and methods of use
US6930113B2 (en) 1996-11-01 2005-08-16 Nitromed, Inc. Nitrosated and nitrosylated phosphodiesterase inhibitors, compositions and methods of use
US6331543B1 (en) 1996-11-01 2001-12-18 Nitromed, Inc. Nitrosated and nitrosylated phosphodiesterase inhibitors, compositions and methods of use
US6548490B1 (en) 1997-10-28 2003-04-15 Vivus, Inc. Transmucosal administration of phosphodiesterase inhibitors for the treatment of erectile dysfunction
US6403597B1 (en) 1997-10-28 2002-06-11 Vivus, Inc. Administration of phosphodiesterase inhibitors for the treatment of premature ejaculation
US6472425B1 (en) 1997-10-31 2002-10-29 Nitromed, Inc. Methods for treating female sexual dysfunctions
US6825234B2 (en) 1998-12-10 2004-11-30 Nexmed (Holdings) , Inc. Compositions and methods for amelioration of human female sexual dysfunction
US7176238B1 (en) 1999-03-01 2007-02-13 Nitromed Inc. Nitrostated and nitrosylated prostaglandins, compositions and methods of use
US7772278B2 (en) 1999-03-01 2010-08-10 Nitromed, Inc. Nitrosated and nitrosylated prostaglandins, compositions and methods of use
US7449595B2 (en) 1999-03-01 2008-11-11 Nitromed, Inc. Nitrosated and nitrosylated prostaglandins, compositions and methods of use
USRE43372E1 (en) 1999-03-05 2012-05-08 Duke University C16 unsaturated FP-selective prostaglandins analogs
EP1097706A1 (en) * 1999-11-08 2001-05-09 Pfizer Limited Phosphodiesterase inhibitors for the treatment of female sexual dysfunction
EP1097707A1 (en) * 1999-11-08 2001-05-09 Pfizer Limited Treatment of female sexual dysfunction
US6734186B1 (en) 1999-11-08 2004-05-11 Pfizer Inc. Compounds for the treatment of female sexual dysfunction
WO2001041807A3 (en) * 1999-12-10 2002-02-14 Vivus Inc Transmucosal composition containing a phosphodiesterase inhibitors for the treatment of erectile dysfunction
WO2001041807A2 (en) * 1999-12-10 2001-06-14 Vivus, Inc. Transmucosal composition containing a phosphodiesterase inhibitors for the treatment of erectile dysfunction
US8906962B2 (en) 2000-03-31 2014-12-09 Duke University Compositions and methods for treating hair loss using non-naturally occurring prostaglandins
US9346837B2 (en) 2000-03-31 2016-05-24 Duke University Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives
US9579270B2 (en) 2000-03-31 2017-02-28 Duke University Compositions and methods for treating hair loss using non-naturally occurring prostaglandins
US9675539B2 (en) 2000-03-31 2017-06-13 Duke University Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives
CN100337629C (en) * 2004-04-07 2007-09-19 鲁南制药集团股份有限公司 Milrinone sodium chloride injection and production thereof
CN104739759A (en) * 2015-04-02 2015-07-01 海南合瑞制药股份有限公司 Pharmaceutical composition containing milrinone compound

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