WO2004069167A2

WO2004069167A2 - Method and compositions for treating male infertility

Info

Publication number: WO2004069167A2
Application number: PCT/US2004/002400
Authority: WO
Inventors: Steven C. Quay
Original assignee: Nastech Pharmaceutical Company Inc.
Priority date: 2003-01-31
Filing date: 2004-01-27
Publication date: 2004-08-19
Also published as: WO2004069167A3

Abstract

The use of ejaculatory-enhancing agents to treat males having low sperm counts to promote fertilization of an ovum. The ejaculatory-enhancing agents are used to promote more frequent ejaculations, thus producing more sperm, thus increasing the chance for the ovum to be fertilized because more sperm are available. The fertilization of the ovum can be by sexual intercourse with a female, or by in vitro or artificial insemination fertilization. Examples of ejaculatory enhancing agents are dopamine receptor agonists, specific phosphodiesterase-5 (PDE-V) inhibitors, organic nitrates, L-arginine and combinations thereof. The dopamine receptor agonists include apomorphine, a pharmaceutically acceptable addition salt of apomorphine, a derivative of apomorphine, bromocriptine, ropinirole, cabergoline, pramipexole, roxindole and lisuride. Examples of PDE-V inhibitors include sildenafil, tadalafil and vardenafil. Examples of organic nitrates include glycerol trinitrate, amyl nitrite, isosorbide dinitrate, isosorbide-5-mononitrate and erythrityl tetranitrate.

Description

METHOD AND COMPOSITIONS FOR TREATING MALE INFERTILITY

Background of the Invention

The teachings of all of the references cited herein are incorporated in their entirety by reference.

Known causes of male infertility include primary testicular disease, disorders of sperm transport, and hypothalamic-pituitary disease resulting in hypogonadism. However, the etiology is not ascertained in up to half of men with suspected male factor infertility. The key initial diagnostic test is a semen analysis. Studies suggest that sperm counts of less than 20 million per milliliter of ejaculate, with a motility of less than 40%, are associated with an increased risk of infertility. However, if a man were able to produce more ejaculate or ejaculate more frequently to compensate for the low sperm count, the chances would be better that he would produce enough sperm to induce fertilization of an ovum either in an in vivo or in vitro setting. Thus, there is a need for a therapy to promote more frequent ejaculations in a man having low sperm count to obtain an increased number of sperm to increase the chances that an ovum can be fertilized either by in vivo or in vitro means.

Description of the Invention

The present invention fills this need by providing for a method for promoting fertilization of an ovum by a male having a low sperm count comprising administering to the male an ejaculatory-enhancing agent.

The present invention further comprises determining the sperm count in a male, administering to the male an ejaculatory-enhancing agent male if the male has a sperm count lower than about 20 million spermatozoa per milliliter of ejaculate so as to produce the opportunity for the male to have an increase number of ejaculations thus obtaining an increased number of sperm.

An ejaculatory-enhancing agent is a pharmaceutical agent that when administered promotes sexual arousal or an erection in a male, which can lead to an ejaculation. Examples of ejaculatory-enhancing agents are dopamine receptor agonists, cyclic GMP-specific phosphodiesterase-5 (PDE-V) inhibitors, organic nitrates and L-arginine. According to the present invention^ a male who is having difficulty impregnating a female is first tested to determine if he has a low sperm count. The semen analysis is the major test for evaluating the sperm count of the male. The analysis should be performed after 2 to 3 days of sexual abstinence. At least two to three ejaculates obtained at intervals of not less than 1 week should be examined because the sperm count of a male varies. Each ejaculate is obtained by masturbation into a clean glass jar, preferable a the laboratory site. For men who have difficulty with this method, special condoms free of lubricants and chemicals toxic to sperm can be used.

The ejaculate is then liquefied at room temperature for 20 -30 minutes and the following parameters are evaluated: ejaculate volume (normal being 2 to 6 mL), viscosity (normally it liquefies within 1 hour), gross and microscopic appearance (normally it is opaque, cream colored, and has 1 to 3 white blood cells per high power field), pH (normal is 7 to 8), and sperm count (normal is a quantity greater than 20 million per mL).

If the sperm count is less than 20 million, an ejaculatory-enhancing agent is administered to the male to promote more frequent ejaculations for more frequent sexual intercourse with the female whom the male is trying to impregnate.

Alternatively, the ejaculates can be collected for in vitro fertilization or artificial insemination.

If the ejaculate is collected either for in vitro fertilization or artificial insemination, the ejaculates can be collected and the sperm concentrated using standard centrifugation techniques so that the concentration of the sperm is greater than 20 million per mL. An example of a centrifuge-like device for the concentration of sperm in ejaculate is the CENTRIMOT® centrifuge sold by Andrology Laboratory Services, Inc., Chicago, IL. For a more detailed explanation of sperm collection and analysis see 'Sperm Collection and Processing Methods' (2001) Editor Jeyendran, R.S. (Cambridge University Press, Cambridge, England).

The dopamine receptor agonist is preferably apomorphine or its functional equivalents including pharmaceutical salts and chemically modified equivalents thereof, including for example pro-drug forms of apomorphine. Apomorphine is designated chemically as a 4H-dibenzo[de,g]quinoline-10,ll-diol, 5, 6, 6a, 7- tetrahydro-6-methyl-, hydrochloride, hemihydrate or (R)-(6a, R)-5, 6, 6a, 7- tetrahydro-6-methyl-4H-dibenzo [de,g] quinoline-10, 11-diol and has the molecular formula: Cι₇Hι₇NO₂ΗCl-¹/2 H₂O. Methods for producing apomorphine are described in U.S. Patent No. 4,162,361 and in JOrg. Client. 5: 344 (1940). Apomorphine has the chemical structure shown below.

For purposes of the present invention apomorphine is preferred; however, other pharmacologically acceptable moieties thereof can be used as well. The term "apomorphine" as used herein includes the free base for of this compound as well as the pharmacologicaly acceptable acid addition salts thereof. In addition to the hydrochloride salt, other acceptable acid addition salts are the hydrobromide, the hydroiodide, the bisulfate, the phosphate, the acid phosphate, the lactate, the citrate, the tartrate, the salicylate, the succinate, the maleate, the gluconate and the like.

Examples of derivatives of apomorphine include but are not limited to apomorphine N-glucuronide, apomorphine O-glucuronide, apomorphine O-sulfate, apomorphine N-sulfate, norapomorphine, norapomorphine O-glucuronide, norapomorphine N-glucuronide, norapomorphine O-sulfate and norapomorphine N- sulfate as disclosed in U.S. Patent No. 6,506,765, diacylapmorphines including diacetylapomorphine, diisobutrylapomorphine, dicyclohexanoylapomorphine, divaleroylapomorphine, dipivaloylapomorphine, di-n-butyrylapomorphine, dicyclopropanoylapomorphine, dicyclobutanoylapomorphine and dicyclopentanoylapomorphine as disclosed in U.S. Patent No. 4,080,456.

Other dopamine receptor agonists that could be administered according to the process of the present invention include bromocriptine, ropinirole, cabergoline, pramipexole, roxindole and lisuride.

Apomorphine or its variants can be administered orally, sublingually, subcutaneously or intranasally. It should be administered at a concentration high enough to promote an erection but at a low enough dose so that vomiting or nausea is not induced. A sublingual or oral dose of an apomorphine should be about 2-10 mg. However, it the apomorphine is administered intranasally the dose should range from about 0.25 to 2 mg (See U.S. Patent No. 6,436,950). Other dopamine receptor agonists can be administered at the following doses: bromocriptine mesylate (Geneva Pharmaceuticals, Broomfield, CO) 2.5-10mg, ropinirole

(REQUIP®,GlaxoSmithKline, Research Triangle Park, NC) 0.25-5 mg, cabergoline (DOSTINEX®, Pharmacia & Upjohn, Peapack, New Jersey) 0.5-7 mg, and pramipexole dihydrochloride (MIRAPEX®, Pharmacia & Upjohn) 0.125-1.5 mg.

A preferred apomorphine hydrochloride hemihydrate nasal formulation is comprised of the following as percent of total weight (% w/w):

Apomorphine Solution Apomorphine HCI, USP 1

Citric Acid Anhydrous, USP 0.69

Sodium Citrate Dihydrate, USP 0.42 Propylene Glycol, USP 7

Glycerin, USP 4.98

Ascorbic Acid, USP 0.012

Sodium etabisulfite, NF 0.088

Edetate Disodium, USP 0.02

Benzalkonium Chloride, USP 0.04

Sodium Hydroxide, NF (1 N) TAP

Hydrochloric Acid, NF (1 N) TAP

Purified water q.s. 100

If a cyclic GMP-specific phosphodiesterase-5 inhibitor such as sildenafil, tadalafil or vardenafil is administered, the dose should be according to the recommended manufacturer's recommendations. For example, the dosage of sildenafil (VIAGRA®, Pfizer, New York, New York) is 25 - 100 mg.

If an organic nitrate is administered, a cyclic GMP-specific phosphodiesterase-5 inhibitor should not be administered. However, organic nitrates can be administered in conjunction with a dopamine receptor agonist to promote firmer and more frequent erections. As was stated above, examples of organic nitrates are glycerol trinitrate, amyl nitrite, isosorbide dinitrate, isosorbide-5- mononitrate and erythrityl tetranitrate.

Example 1

Use of Apomorphine Hydrochloride for Treatment of Infertility in Men Caused by

Infertility Title: To assess the effects of apomorphine hydrochloride delivered as a nasal spray for the treatment of infertility in men caused by hypospermia.

Objective of the Study: To compare the baseline and post administration of nasal apomorphine seminal fluid samples for ejaculate volume, spermatozoa density, spermatozoa motility and percentage of morphological normal spermatozoa in men diagnosed with hypospermia.

Spermatozoa availability comprises the product of the daily testicular production rate and those stored in the extra-gonadal reserve. Hypospermia is defined as a decrease in the seminal fructose, asthenospermia (loss or reduction in motility of the spermatozoa, which causes infertility) and oligospermia (subnormal concentration of spermatozoa). Increase in the number of ejaculations in men with hypospermia, may increase the number of mobile spermatozoa available for fertility that are stored in the extra- gonadal reserve.

Analyses of seminal fluid samples will be obtained after masturbation, 48 hours after abstinence from ejaculation. This analysis will include ejaculate volume, spermatozoa density, spermatozoa motility and percentage of morphological normal spermatozoa. Since sperm counts exhibit extreme variability, a reasonable estimate of mean sperm production requires at least three seminal fluid analyses over a 2 month period.

Once a diagnosis of hypospermia is confirmed with baseline analysis over a two month period, nasal apomorphine will be given in an in-clinic setting once a week for two months. Patients would be required to attempt multiple ejaculations while masturbating. They must refrain from sexual activity 48 hours before admission into the clinic. Analyses of seminal fluid samples will be obtained and compared to baseline values for ejaculate volume, spermatozoa density, spermatozoa motility and percentage of morphological normal spermatozoa.

Study Population: 50 males, age 18 years or over, diagnosed with hypospermia and who have been in a heterosexual relationship for at least the past six months.

Study Design: This study will be an open label, in-clinic study involving 50 male patients diagnosed with hypospermia. After a two month baseline analysis of seminal fluid, the patients will take nasal apomorphine in an in-clinic setting once weekly and attempt to achieve multiple ejaculations while performing masturbation. The seminal fluid will be analyzed and compared to the two month baseline values.

Study Treatments: Apomorphine hydrochloride nasal spray 1.0 mg; n=50

Study Methodology:

Inclusion Criteria for Patients:

• The patient is a heterosexual male in good health and age 18 years or over;

• The patient has been in a monogamous heterosexual relationship for at least the past six months;

• The patient has a diagnosis of hypospermia based on seminal fluid analysis over a two month period; o The patient has normal nasal mucosa;

Exclusion Criteria for Patients:

• Males with erectile dysfunction of psychogenic or organic origin;

• Evaluation of patient' s baseline International Index of Erectile Function Questionnaire (IIEF). Exclusion defined as a score of 1 to 18 inclusive following summation of IIEF Erectile Domain Scores (Questions 1,2, 3, 4, 5, and 15)

• Genital anatomical deformities that would significantly impair erection (e.g. severe penile fibrosis)

• Presence of penile prosthesis or penile implants;

• Presence of neurological disease of significant severity or a likelihood of the disease state significantly deteriorating during the course of the study; o Other sexual disorders (e.g. hypoactive sexual desire); o History of alcoholism or substance abuse within the past five years; o History of major hematological, renal or hepatic abnormalities o Established diagnosis of hypogondasm or hyperprolactiniemia o Recent (less than six months) history of stroke, transient ischemic attack or myocardial infarction;

• Chronic heart failure; • Hypotension ( a resting sitting blood pressure < 90/50 mmHg) or a history of malignant hypertension and/or resting systolic blood pressure > 170 mmHg and/or a resting diastolic blood pressure > 100 mmHg.

• History of Prostate cancer with the last five years

Visit 1: Screening The study procedures will be explained to each patient and each patient will be required to sign an Informed Consent Form. The patient will undergo the following screening assessments:

• Physical examination and medical history

Assessment of nasal mucosa 12 lead EKG and vital signs Chest X-Ray • Blood Chemistry, Hematology and Urinalyis

If patient satisfies the eligibility criteria, he will then come back within four weeks into the clinic.

Visit 2-9: In-clinic Baseline Evaluations: A total of eight visits, one visit per week for two months. Following confirmation of the patient's eligibility, the following procedures/assessment will be performed in-clinic:

• Patient must have refrained from sexual intercourse, or ejaculation within 48 hours before each visit; • Seminal fluid will be collected after attempts at multiple ejaculations during masturbation, while watching explicit sexual videos for two hours.

Visits 2-17: Nasal Apomorphine: A total of sixteen visits, one visit per week for two months. Following confirmation of the patient's eligibility, the following procedures/assessment will be performed in-clinic:

o Patient must have refrained from sexual intercourse, or ejaculation within 48 hours before the visit; o The patient will be instructed that study drug should be administered 15 minutes prior to planned masturbation.

• Seminal fluid will be collected after attempts at multiple ejaculations during masturbation, while watching explicit sexual videos for two hours. Visit 18: Study Completion Visit: The patient will undergo the following completion assessments:

• Physical examination and any change in medical history • Assessment of nasal mucosa

• 12 lead EKG and vital signs

• Blood Chemistry, Hematology and Urinalyis

Measurement of Efficacy:

The primary efficacy endpoint would be the change from baseline in ejaculate volume, spermatozoa density, spermatozoa motility and percentage of morphological normal spermatozoa.

The secondary efficacy endpoint would be the following:

• Improvement in erection duration during treatment

• Improvement in time to erection during treatment

Example 2

Title: An at-home study to assess the effects of apomorphine hydrochloride delivered as a nasal spray for the treatment of infertility in men caused by hypospermia.

Objective of the Study: To compare the rate of fertility of males diagnosed with hypospermia when given nasal apomorphine versus placebo.

Spermatozoa availability comprises the product of the daily testicular production rate and those stored in the extra-gonadal reserve. Hypospermia is defined as a decrease in the seminal fructose, asthenospermia (loss or reduction in motility of the spermatozoa, which causes infertility) and oligospermia (subnormal concentration of spermatozoa). Increase in the number of ejaculations in men with hypospermia, may increase the number of mobile spermatozoa available for fertility that are stored in the extra- gonadal reserve. Diagnosis of hypospermia is confirmed with baseline analysis over a two month period. Since sperm count exhibit extreme variability, a reasonable estimate of mean sperm production requires at least three seminal fluid analyses over 2 months. Analyses of seminal fluid samples will be obtained after masturbation, 48 hours after abstinence from ejaculation. Analyses of seminal fluid samples will include ejaculate volume, spermatozoa density, spermatozoa motility and percentage of morphological normal spermatozoa

Peak age of fertility in the female is 25 years. There is a decline in both female and male reproductive performance after age 25 years. This study will recruit patients in the height of their sexual and reproductive performance in both study groups. For nulliparous women of this age the average time during which unprotected intercourse occurs until conception is 5.3 months.

Once a diagnosis of hypospermia is confirmed, nasal apomorphine or placebo will be given in an at-home setting for a six month period. The average patients would be required to attempt sexual intercourse frequently during the partner's ovulation period.

Study Population: 150 males, age 20-30 years, diagnosed with hypospermia and who have been in a heterosexual relationship for at least the past six months and are trying to conceive.

Study Design: This study will be an double blind, parallel, placebo controlled, at- home study involving 150 male patients diagnosed with hypospermia who are seeking medical assistance for infertility. After a two month baseline analysis of seminal fluid, the patients will take nasal apomorphine or placebo in an at-home setting once weekly for six months.

Study Treatments: Apomorphine hydrochloride nasal spray 1.0 mg; n=75 Nasal spray placebo, n=75

Study Methodology:

Inclusion Criteria for Patients:

• The patient is a heterosexual male in good health and age 20 to 30. • Female partners in good health and age 20 to 30.

• Female partner has no infertility problems;

• The patient has been in a monogamous heterosexual relationship for at least the past six months; • The couple has been seeking medical attention for infertility and trying to conceive;

• The patient has a diagnosis of hypospermia based on seminal fluid analysis over a two month period;

• The patient has normal nasal mucosa; • The patient has read, signed and received a copy of the Informed Consent

Form prior to initiation of any study procedure.

Exclusion Criteria for Patients:

o Males with erectile dysfunction of psychogenic or organic origin; β Female partners with infertility problems; β Evaluation of patient's baseline International Index of Erectile Function Questionnaire (IIEF). Exclusion defined as a score of 1 to 18 inclusive following summation of IIEF Erectile Domain Scores (Questions 1,2, 3, 4, 5, and 15)

• Presence of penile prosthesis or penile implants;

• Presence of neurological disease of significant severity or a likelihood of the disease state significantly deteriorating during the course of the study;

• Other sexual disorders (e.g. hypoactive sexual desire);

• History of alcoholism or substance abuse within the past five years;

• History of major hematological, renal or hepatic abnormalities

• Established diagnosis of hypogondasm or hyperprolactiniemia © Recent (less than six months) history of stroke, transient ischemic attack or myocardial infarction; o Chronic heart failure; o Hypotension (a resting sitting blood pressure < 90/50 mmHg) or a history of malignant hypertension and/or resting systolic blood pressure > 170 mmHg and/or a resting diastolic blood pressure > 100 mmHg.

• History of Prostate cancer with the last five years Visit 1: Screening The study procedures will be explained to each patient and partner. The patient and partner will be required to sign an Informed Consent Form. The patient and partner will undergo the following screening assessments:

• Physical examination and medical history of both partners

• The standard evaluation of infertility of both partners

• Collection of seminal fluid over a two month period, (at least three).

• Assessment of nasal mucosa for the patient

• 12 lead EKG and vital signs of both partners • Chest X-Ray for the patient

• Blood Chemistry including analysis (prolactin, testosterone and thyroid hormones), Hematology and Urinalysis of both partners

If patient and partner satisfies the eligibility criteria, he will then come back within eight weeks into the clinic.

Visit 2: In-clinic: Following confirmation of the patient's eligibility, the following procedures/assessment will be performed in-clinic:

• Ability to self administer the drug.

• Conformation of diagnosis of hypospermia based on the analysis of the seminal fluid.

• Three bottles of study drug (18 nasal doses) dispensed to the patient. The patient will be instructed that the study drug should be administered 15 minutes prior to planned sexual intercourse.

• An appointment for Visit 3 will be scheduled in four weeks time.

Visits 3-8: Nasal Apomorphine: A total of 6 visits, one visit per month for six months. Following confirmation of the patient's eligibility, the following procedures/assessment will be performed in-clinic for each visit:

o Ability to self administer the drug. o Three bottles of study drug (18 nasal doses) dispensed to the patient. The patient will be instructed that the study drug should be administered 15 minutes prior to planned sexual intercourse.

• An appointment for the next visit will be scheduled in four weeks time.

• If the partner becomes pregnant, they return all study drug and they are considered completing the study. Visit 9: Study Completion Visit: The patient will undergo the following completion assessments:

• Physical examination and any change in medical history

• Assessment of nasal mucosa

• 12 lead EKG and vital signs

• Blood Chemistry, Hematology and Urinalyis

Measurement of Efficacy:

The primary efficacy endpoint would be the rate of conception of the nasal apomorphine group versus the placebo.

The secondary efficacy endpoint would be the following:

* Improvement in the ability to have multiple ejaculation during treatment.

• Improvement in erection duration during treatment • Improvement in time to erection during treatment

Claims

WHAT IS CLAIMED IS:

1. A method for promoting fertilization of an ovum by a male having a low sperm count comprising administering an ejaculatory-enhancing agent to the male.

2. The method of claim 1 wherein the ejaculatory-enhancing agent is selected from the group consisting of dopamine receptor agonists, cyclic GMP-specific phosphodiesterase-5 (PDE-V) inhibitors, organic nitrates, and combinations thereof.

3. The method of claim 1 wherein the ejaculatory-enhancing agent is administered under conditions so as to enable the male to have multiple ejaculations so as to produce a greater number of sperm to promote fertilization of the ovum.

4. The method of claim 1 wherein the fertilization of the ovum occurs through sexual intercourse with a female.

5. The method of claim 1 wherein the fertilization occurs by means of artificial insemination.

6. The method of claim 1 wherein the ejaculate-enhancing agent is a dopamine receptor agonist.

7. The method of claim 6 wherein the dopamine receptor agonist is selected from the group consisting of apomorphine, a pharmaceutically acceptable addition salt of apomorphine, a derivative of apomorphine, bromocriptine, ropinirole, cabergoline, pramipexole, roxindole and lisuride.

8. The method of claim 7 wherein the dopamine receptor agonist is selected from the group consisting of apomorphine, a pharmaceutically acceptable addition salt of apomorphine and a derivative of apomorphine.

9. The method of claim 8 wherein the pharmaceutically acceptable addition salt of apomorphine is apomorphine hydrochloride.

10. The method of claim 1 wherein ejaculate-enhancing agent is a PDE-V inhibitor.

11. The method of claim 10 wherein the ejaculate-enhancing agent is selected from the group consisting of sildenafil, tadalafil and vardenafil.

12. The method of claim 1 wherein the ejaculate-enhancing agent is an organic nitrate.

13. The method of claim 1 wherein the organic nitrate is selected from the group consisting of glycerol trinitrate, amyl nitrite, isosorbide dinitrate, isosorbide-5- mononitrate and erythrityl tetranitrate.

14. The method of claim 1 wherein the prior to administration of the ejaculate- enhancing agent sperm-containing ejaculate is obtained from the male, the sperm count per milliliter (mL) of ejaculate is determined, and an ejaculate-enhancing agent is administered to males having a sperm count of lower than 20 million sperm per mL of ejaculate.

15. The method of claim 14 further comprising collecting multiple ejaculates from the male, concentrating the sperm in the ejaculate so that the sperm count is greater than 20 million sperm per mL of ejaculate, and bringing the ejaculate into contact with the ovum to produce fertilization of the ovum.

16. The method of claim 14 wherein the ejaculate-containing the concentrated number of sperm is brought into contact with the ovum through in vitro fertilization.

17. The method of claim 1 wherein the ejaculate-enhancing agent is L-arginine.

18. A method for promoting fertilization of an ovum by a male having a low sperm count comprising: collecting sperm-containing ejaculate from the male; determining the sperm count per milliliter (mL) of ejaculate; administering an ejaculatory-enhancing agent to the male, if the male has a sperm count lower than 20 million sperm per mL of ejaculate so as to enable the male to have multiple ejaculations so as to produce a greater number of sperm to promote fertilization of the ovum.

19. The method of claim 18 wherein the ejaculatory-enhancing agent is selected from the group consisting of dopamine receptor agonists, cyclic GMP-specific phosphodiesterase-5 (PDE-V) inhibitors, organic nitrates, L-arginine and combinations thereof.

20. The method of claim 18 wherein the fertilization of the ovum occurs by means of sexual intercourse with a female.

21. The method of claim 18 wherein the fertilization of the ovum occurs by means of artificial insemination.

22. The method of claim 18 wherein the ejaculatory-enhancing agent is a dopamine receptor agonist.

23. The method of claim 23 wherein the dopamine receptor agonist is selected from the group consisting of apomorphine, a pharmaceutically acceptable addition salt of apomorphine, a derivative of apbmorphine, bromocriptine, ropinirole, cabergoline, pramipexple, roxindole and lisuride.

24. The method of claim 24 wherein the dopamine.receptor agonist is selected from the group consisting of apomorphine, a pharmaceutically acceptable addition salt of apomorphine and a derivative of apomorphine.

25. The method of claim 25 wherein the dopamine receptor agonist is apomorphine hydrochloride.

26. The method of claim 19 wherein the PDE-V inhibitor is selected from the, group consisting of sildenafil, tadalafil and vardenafil.

27. The method of claim 19 wherein the organic nitrate is selected from the group consisting of glycerol trinitrate, amyl nitrite, isosorbide dinitrate, isosorbide-5- mononitrate and erythrityl tetranitrate.

28. The method of claim 19 wherein the ejaculatory-enhancing agent is L-arginine.