Blood Pressure

Method of treatment of priapism without raising systemic blood pressure

Blood Pressure Abstract
Treatment or prophylaxis of persistent penile erection resulting from, for example, physiological dysfunction, trauma, surgical intervention, or chemical induction. The method of the present invention is practiced by the administration of an agent capable of inducing, promoting, or otherwise facilitating contraction of the cavernosum. Another aspect of the present invention provides a composition comprising a cavernosum contraction-inducing, -promoting, or -facilitating agent. In one embodiment, the agents of the present invention are prostaglandins or functional derivatives, homologous, analogues, agonists, mimetics, or metabolites thereof. This invention also provides a means for diagnosing the physiological basis behind penile dysfunction.

Blood Pressure Claims
What is claimed is:

1. A method for the treatment of priapism in a male subject suffering from priapism without raising the systemic blood pressure of said subject comprising

administering to said subject an amount of a pharmaceutical composition comprising a prostaglandin A1, prostaglandin B1, prostaglandin B2, or prostaglandin A2 in an amount which facilitates contraction of corpora cavernosa muscle in the cavernosum, without a concomitant rise in systemic blood pressure, whereby the subject experiences penile flaccidity.

2. The method of claim 1, wherein the prostaglandin is prostaglandin A2.

3. The method of claim 1, wherein the agent is intracavernously administered.

4. The method of claim 1, wherein the agent is administered at a dosage in the range of from 0.5 to 2.5 micrograms per kilogram of subject body weight.

5. A method for the treatment of priapism in a male subject suffering from priapism without raising the systemic blood pressure of said subject comprising

administering to said subject a composition comprising a prostaglandin A1, prostaglandin B1, prostaglandin B2, or prostaglandin A2 in an amount which facilitates contraction of corpora cavernosa muscle in the cavernosum, without a concomitant rise in systemic blood pressure, for a time and under conditions that induce penile flaccidity or reduce the intensity of an erection.

6. The method of claim 5, wherein the prostaglandin is prostaglandin A2.

Blood Pressure Description
FIELD OF THE INVENTION

The present invention relates generally to the treatment and prophylaxis of penile dysfunction. More particularly, the present invention contemplates the treatment and prophylaxis of persistent penile erection resulting from, for example, physiological dysfunction, trauma, surgical intervention, or chemical induction. The method of the present invention is practised by the administration of an agent capable of inducing, promoting or otherwise facilitating contraction of the cavernosum. Accordingly, another aspect of the present invention provides a composition comprising a cavernosum contraction-inducing, -promoting, or -facilitating agent. In one embodiment, the agents of the present invention are prostaglandins or functional derivatives, homologues, analogues, agonists, mimetics, or metabolites thereof. This invention also provides a means for diagnosing the physiological basis behind penile dysfunction.

BACKGROUND OF THE INVENTION

Priapism is defined as a prolonged, usually painful, penile erection generally not directly initiated by sexual stimulus. It results from a disturbance or other dysfunction in the normal regulatory mechanisms which initiate and maintain penile flaccidity. The treatment of this condition ranges from predominately surgical management to less invasive pharmacological therapies. Despite recent advances in the understanding of erectile mechanisms, the pathophysiology of priapism remains obscure in up to 50% of cases. See, e.g., Steers and Selby, J. Urol. 146(5): 1361-1363 (1991). Thus, in the absence of an identifiable aetiology, treatment has been essentially symptomatic. In at least 5% of patients treated for impotence, injection of vascoactive substances such as papaverine, prostagiandin E, and phenoxybenzamine (or phentolamine), an alpha-adrenergic blocking drug, into the corpora cavernosa muscle, is the most likely cause of priapism. Furthermore, the availability of sildenafil citrate (sold under the trademark "Viagra") as an anti-impotence drug, has resulted in its misuse as an aphrodisiac to improve male sexual performance. Reports indicate that sildenafil also has caused priapism. If left unattended, the abuse and misuse of erection-producing vasoactive agents is likely to lead to priapism and irreversible muscle damage. Other situations in which priapism is seen include disease states such as sickle cell anaemia and use of unrelated drugs such as antidepressants (e.g., trazodone).

Current antidotes for priapism are alpha-adrenoceptor agonists such as metaraminol, adrenaline, phenylephrine, noradrenaline, and ethylephrine. These alpha-mimetics are known to produce systemic side effects including a rise in systemic blood pressure. Hence, such agents are contraindicated for cardiovascular patients. Accordingly, there is a need to identify reliable, safe, and efficacious pharmacological agents for the treatment and prophylaxis of penile dysfunction characterized by prolonged penile erection.

SUMMARY OF THE INVENTION

The present invention is predicated in part on the identification of a group of compounds which induce, promote, or otherwise facilitate contraction of the cavernosum associated with penile tissue. An important feature of this invention is that the agents employed in accordance with the present invention do not cause a rise in systemic blood pressure. Particularly preferred agents include the prostaglandins such as, but not limited to, prostaglandin A2, prostaglandin A1, prostaglandin B1, and prostaglandin B2, as well as functional derivatives, homologues, analogues, agonists, mimetics, and metabolites thereof.

Accordingly, one aspect of the present invention contemplates a method for the treatment or prophylaxis of priapism in a male subject, said method comprising administering to said subject an effective amount of an agent which induces, promotes or otherwise facilitates contraction of corpora cavernosa muscle in the cavernosum, without a concomitant rise in systemic blood pressure, the administration of which agent leads to partial or complete penile flaccidity.

Another aspect of the present invention is directed to a method for the treatment or prophylaxis of priapism in a male subject said method comprising administering to said subject an effective amount of a prostaglandin or a functional derivative, homologue, analogue, agonist, mimetic, or metabolite thereof which induces, promotes, or otherwise facilitates contraction of corpora cavernosa muscle in the cavernosum, without a concomitant rise in systemic blood pressure, for a time and under conditions sufficient to lead to partial or complete penile flaccidity or to prevent or reduce the likelihood of an erection.

Yet another aspect of the present invention provides a composition for pharmaceutical use comprising an agent which induces, promotes, or otherwise facilitates contraction of corpora cavernosa muscle in the cavernosum in penile tissue, said composition further comprising one or more pharmaceutically acceptable carriers and/or diluents.

The preferred agents of the present invention are prostaglandins such as, but not limited to, prostaglandin A2, A1, B1, and B2.

The most preferred agent is prostaglandin A2 or functional derivatives, homologues, analogues, agonists, mimetics, or metabolites thereof. The terms "prostaglandin A2", "Adainus", "AS-8", and "priapres" may be used interchangeably to refer to "prostaglandin A2".

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graphical representation showing the effect of intravenous bolus dosages of prostaglandin A2 on blood pressure, heart rate, and respiratory rate in anaesthetised baboons.

FIG. 2 is a graphical representation showing contractile response of prostaglandin A2 on human corpus cavernosum smooth muscle.

FIG. 3 is a graphical representation showing cavernous pressure before and after saline and AS-8 administration.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, agents which are useful in the treatment of priapism have been identified. The agents of the present invention differ from known priapism-treating agents, such as alpha-adrenoceptor agonists, in that the present agents do not cause systemic side effects such as tachycardia or raised blood pressure. Such side effects render these known therapeutic contraindicated for cardiovascular patients.

The preferred agents of the present invention are prostaglandins including functional derivatives, homologues, analogues, agonists, mimetics, or metabolites thereof.

The preferred prostaglandins of the present invention are prostaglandin A2, prostaglandin A1, prostaglandin B1, and prostaglandin B2. The most preferred prostaglandin is prostaglandin A2.

Accordingly, one aspect of the present invention contemplates a method for the treatment or prophylaxis of priapism in a male subject, said method comprising administering to said subject an effective amount of an agent which induces, promotes, or otherwise facilitates contraction of corpora cavernosa muscle in the cavernosum, without a concomitant rise in systemic blood pressure, the administration of which agent leads to partial or complete penile flaccidity. Standard ED.sub.50 measurements, dose-response curves, bioassay methods, and the like can be used by those skilled in the art to evaluate contractile potency.

Reference herein to "priapism" includes and encompasses prolonged or sustained penile erection. Generally, priapism does not result from sexual stimulation. However, the present invention includes the treatment of prolonged penile erection following sexual stimulation. Priapism may result from surgical intervention, trauma, physiological dysfunction, or pharmacological intervention, such as following the ingestion or administration of drugs (e.g., sildenafil citrate, papaverine, or phenoxylbenzamine). Priapism may also result from disease states, from use of some drugs not related to erectile function/dysfunction, or may be spontaneous unexplained priapism.

The present invention extends to treating a subject having an erection or preventing or at least reducing the likelihood of a subject obtaining an erection. Accordingly, the present invention extends beyond priapism to the treatment of hypersexual stimulation. This may be useful in treating certain classes of habitual sex offenders.

Although the present invention is directed mainly at the treatment in human males, it also has an application in the veterinary field. For example, difficulties may arise for male stud animals such as stud bulls, horses, sheep, and pigs. Such animals may need to be chemically sexually aroused in order to produce semen or to service female animals. To induce a non-aroused state after service, the agents of the present invention may be administered to the male animal.

Another aspect of the present invention is directed to a method for the treatment or prophylaxis of priapism in a male subject, said method comprising administering to said subject an effective amount of a prostaglandin or a functional derivative, homologue, analogue, agonist, mimetic, or metabolite thereof which induces, promotes, or otherwise facilitates contraction of corpora cavernosa muscle in the cavernosum, without a concomitant rise in systemic blood pressure, for a time and under conditions sufficient to lead to partial or complete penile flaccidity or to prevent or reduce the likelihood of an erection.

Reference herein to "prostaglandin" and in particular prostaglandin A2, A1, B1, and/or B2 includes reference to functional derivatives, homologues, analogues, agonists, mimetics, or metabolites thereof. Derivatives and analogues will include those involving substitution at the 9 and 11 positions in the ring structure and those including changes in the degree of side chain unsaturation. Metabolites include, for instance, 15-oxo PGA2, 13,14-dihydro PGA2, and 13,14-dihydro-15-oxo PGA2, and the corresponding metabolites of PGA1, PGB1, and PGB2. The term "functional" means that the molecule behaves in substantially the same therapeutic manner, inducing flaccidity without inducing any substantial change in blood pressure, as the "parent" prostaglandin, i.e., the prostaglandin prior to modification.

The prostaglandin or other compound useful in the practice of the present invention is usefully formulated in the form of a pharmaceutical composition. Accordingly, another aspect of the present invention provides a composition for pharmaceutical use comprising an agent which induces, promotes, or otherwise facilitates contraction of corpora cavernosa muscle in the cavernosum in penile tissue. These compositions further comprise one or more pharmaceutically acceptable carriers and/or diluents. The compositions of the present invention may comprise the prostaglandin alone or it may be in combination with other therapeutic agents.

As indicated above, the preferred agent is a prostaglandin such as prostaglandin A2, A1, B1, or B2. The most preferred agent is prostaglandin A2 or its functional derivative, homologue, analogue, agonist, mimetic, or metabolite.

A preferred dosage range for these agents in accordance with this invention is from 1 to 10, more preferably 0.5 to 2.5, micrograms per kilogram of patient body weight.

The composition of the present invention may be administered in any convenient manner such as, but not limited to, intravenous injection, intramuscular injection, intrarectal, intranasal, subcutaneous injection, transdermal, transurethral, intraperitoneal, or oral administration. Administration may also be via patch, intravenous drip, spray, or during surgery or other invasive procedure. The most effective administration is via injection into the corpus cavernosa. This is referred to as intracavernous drug delivery.

The identification of prostaglandins as an effective treatment of priapism provides a means for identifying physiological causes for conditions such as impotence, hypersexuality, and priapism. For example, impotent males may produce excessive amounts of particular prostaglandins. Alternatively, reduced prostaglandin production or local levels may be indicated in priapism patients. The identification of levels of particular prostaglandins provides one level of diagnosis for penile dysfunction. Such methods of diagnosis are contemplated by the present invention.

Accordingly, another aspect of the present invention contemplates a method for diagnosing the physiological basis behind priapism in a male subject, said method comprising determining the level in said subject of prostaglandin A2, A1, B1, and/or B2 or derivatives and/or metabolites thereof, wherein low levels of one or more of said prostaglandin is indicative of a causative effect for priapism.

Yet another aspect of the present invention is directed to the use of a prostaglandin or a functional derivative, homologue, analogue, agonist, mimetic, or metabolite thereof in the treatment of priapism in a male subject.