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Intraurethral prostaglandin E-2 cream: A possible alternative treatment for erectile dysfunction
PREUMlXMnr
CQWMJNICATION
INTRAURETHRAL PROSTAGLANDIN E-2 CREAM: A POSSIBLE ALTERNATIVE TREATMENT FOR ERECTILE DYSFUNCTION BRADWOLFSON, M.D. STEVEN PICKETT, M.D. NATHAN E. SCOTT. M.D.
JEAN B. DEKERNION,M.D. JACOB RAJFER,M.D.
From the Division of Urology, Department of Surgery, Harbor-UCLA Medical Center, UCLA School of Medicine, Torrance, California
ABSTRACT-Prostaglandin E-2 (PGE-2) is an oxytocic agent in suppository form with vasodilatory effects similar to prostaglandin E-l (PGE-1). Because some men find intracavernosal injections disagreeable, we investigated whether intraurethral PGE-2 may provide an alternative method for treating erectile dysfunction. A PGE-2 cream was made using PGE-2 suppositories (20 mg or 40 mg), 10 cc of 2% lidocaine (Xylocaine) jelly, and 40 cc of surgical lubrication. Two cc of the cream was instilled into the urethral meatus using a syringe, the cream was massaged down the urethra, and the urethra was occluded for five minutes. Treatment response was rated as no penile tumescence, partial tumescence, and full tumescence. Overall, 70 percent showed a response and 30 percent had full penile tumescence. Two of 4 men who had no tumescence using PGE-2 had a subsequent full tumescence using intracavernosal PGE-1 (15 mg), while 3 of 4 men with a partial tumescence with PGE-2 had a subsequent full tumescence using intracavernosal PGE-1 (15 mg). These data demonstrate that full penile tumescence may be achieved in impotent men using intraurethral PGE-2 cream. This pilot study supports the necessity for further investigations in a randomized double-blind manner in the use of intraurethral PGE2 cream as a less invasive treatment alternative for erectile dysfunction.
The use of injectable intracavemosal agents to induce erection has become routine in urologic practice. 1-6Many men with erectile dysfunction can achieve normal erections with this therapy, but some choose not to proceed with self-injection because of the discomfort involved or because of a generalized “needlephobia.“3*4 Furthermore, side effects including corporeal scarring, penile hematoma, priapism, and penile pain have been described using this modality1,2 Prostin E-2 (Upjohn, Kalamazoo) is an oxytocic agent which contains dinoprostone as the naturally occurring prostaglandin E-2 (PGE-2).’ PGE2 has vasodilatory effects similar to prostaglandin E-l (PGE-1) which has been studied extensively as an intracavemosal injection therapy PGE-2 is Submitted (Rapid Communication): (with revisions): March 29, 1993
UROLOGY I
JULY 1993
I
March 23, 1993, accepted
VOLUME 42, NLWBER 1
processed as a suppository which can be easily crushed into surgical lubrication to form a PGE-2 cream. We investigated the efficacy of two doses of an intraurethral instillation of PGE-2 cream on induction of penile erection. MATERIAL AND METHODS A PGE-2 cream was made by hand in the clinic using Prostin E-2 vaginal suppositories (20 or 40 mg), 10 cc of 2% lidocaine (Xylocaine) jelly, and 40 cc of surgical lubricant. Using a syringe, 2 mL of the cream (67 J.tgor 134 J.tg>of PGE-2 was instilled into the urethral meatus; the cream was massaged down the urethra, and the distal urethra was occluded for five minutes with an occlusive clamp. Treatment response was evaluated at twenty minutes postinstillation, and was rated as no penile tumescence, partial tumescence, or full tumescence. If full tumescence was not achieved, 73
patients were offered intracavemosal injection of PGE-1 solution (15 pg) at a subsequent visit. Manual or visual stimulation was not performed by any of the patients. A total of 20 men presenting to our urologic clinic with erectile dysfunction participated in the study after verbal informed consent was obtained. The mean age of these patients was fifty-seven years. Medical history associated with erectile dysfunction was variable (Table I). RESULTS A serum testosterone was normal in each of these patients. For various reasons, the etiology of the impotence was not determined in most of these 20 patients. Ten men received 2 mL (67 pg) of the 20 mg PGE-2 cream. No tumescence was achieved in 4, partial tumescence in 2, and full tumescence in 4. Two of the men with full tumescence described erections lasting three hours. The medical conditions associated with erectile dysfunction in the full responders included hypertension and diabetes mellitus. Ten men received 2 mL (134 pg) of the 40 mg PGE-2 cream: 2 had no tumescence, 6 partial tumescence, and 2 achieved full tumescence. Both men who fully responded described a history of hypertension. Overall, 14 of 20 men (70%) receiving PGE-2 cream showed a response to treatment, and 30 percent had full penile tumescence. All men experienced a transient mild urethral burning sensation with instillation of the cream. In none did persistent dysuria develop, and there were no cardiovascular side effects. Of the 14 me< who failed to achieve a full tumescence with the PGE-2 cream, 8 elected to undergo an intracavernosal injection of PGE-1 (15 pg). Two of 4 men who had no response with intraurethral PGE-2 had a subsequent full tumescence with intracavernosal PGE-1, and 3 of 4 men with a partial tumescence with PGE-2 cream achieved a full tumescence with intracavernosal PGE-1. Thus, 5 of 8 men (62%) who did not demonstrate a full tumescence with PGE-2 cream subsequently achieved a full tumescence with intracavemosal PGE-1. COMMENT The physiologic mechanism of penile erection requires an increase in penile arterial inflow, relaxation of cavemosal smooth muscle sinusoids, and increased penile venous resistance.2 Intracavemosal agents such as papaverine, phentolamine, and prostaglandin E-l have been shown to be useful in eliciting penile erection by increasing arter74
TABLEI. Factors associated with dysfunction (n = 20)
erectile Number
Medical History Hypertension Diabetes mellitus Hypertension and diabetes Post surgical Other
6 3 7 2 2
ial inflow and/or relaxing cavemosal smooth muscle.l** Up to 80 percent of men with erectile dysfunction can achieve an erection sufficient for sexual intercourse with the use of these agents.4 Unfortunately, many men find self-injection undesirable, and up to 50 percent of men who respond adequately with use of these agents subsequently discontinue their use for various reasons.3J Papaverine therapy has been associated with development of corporeal plaques at the injection site, priapism, and systemic cardiovascular side effects including vasovagal episodes and syncope.’ PGE-1 has been associated with priapism and painful erection with penile pain and burning.’ Prostin E2 is an oxytocic agent in suppository form which contains the naturally occurring prostaglandin E2 dinoprostone.’ It is water soluble and can easily be crushed into a cream form when mixed with surgical lubricant. PGE-2 has been noted to lower blood pressure in laboratory animals as well as in man, likely due to its effect on the smooth muscle of the vascular system. Adverse reactions associated with the use of PGE-2 as a vaginal suppository in the treatment of termination of pregnancy or evacuation of the uterine contents in missed abortion include nausea/vomiting, elevated temperature, headaches, shivering/chills, and transient hypotension. In our study, instillation of a PGE-2 cream resulted in full penile tumescence in 30 percent of the subjects. No significant side effects were demonstrated except for mild transient burning with instillation of the cream. In addition, another 40 percent of subjects achieved partial tumescence. The mechanism of the translocation of the PGE2 from the urethra into the corporeal bodies remains to be discerned. The drug may be effective through a local absorptive effect or passage of the drug through corporeal spongiosal channels. The mechanism of local transdermal absorption has been postulated as a potential mode of therapy for erectile dysfunction. ’ However, there are no data to confirm whether or not these drugs actually reach their target tissue via the systemic circulation rather than these two aforementioned routes. UROLOGY
I JULY1993 / VOLUME 42, NUMBER 1
Whether other vasodilatory compounds incorporated into a cream form could elicit an erectile response or enhance the response of PGE-2 remains to be investigated. Of the subjects who did not achieve a full tumescence with PGE-2 cream, 8 subsequently received intracavernosal injection with PGE-1 and 5 (62%) achieved a full tumescence. Whether or not further elevation of the dose of PGE-2 cream would have elicited a full tumescence in these men remains to be investigated. In summary, PGE-2 cream can elicit a full penile tumescence in men with erectile dysfunction. It can be administered with minimal discomfort and displays no major adverse reactions. The mechanism of action, optimal dosage, and longterm effects require further investigation. Since the completion of this pilot study, a request to perform a randomized, placebo controlled, double-blind study to test the true efficacy of this compound has been denied by the FDA until animal toxicologic studies are submitted.
UROLOGY
/
JULY
1993 / VOLUME42, NLMBER 1
Jacob Rajfer,M.D. Torrance, Cal@7tia 90502 REFERENCES 1. Krane R, Goldstein I, and Saenz de Tejada I: Impotence. N Engl J Med 321: 1648-1659,1989. 2. Lue T, and Tanagho E: Physiology of erection and pharmacological management of impotence. J Urol 137: 829-836,1987. 3. Lakin M, Montague D, Medendorp S, Tesar L, and Schover L: Intracavemous injection therapy: analysis of results and complication. J Urol 143: 1138-1141, 1990. 4. Schramek P, Dominger R, Waldhouser M, Konecny P and Porpaczy P: Prostaglandin El in erectile dysfunction efiiciency and incidence of priapism. Br J Urol65: 68-71,199O. 5. Gerber G, and Levine L: Pharmacological erection program using prostaglandin El. J Urol 146:786-789, 1991. 6. Sarosdy M, Hudnall C, Erickson D, Hardin T, and Novicki D: A prospective double-blind trial of intracorpoteal papaverine versus prostaglandin El in the treatment of impotence. J Uro1141: 551-553, 1989. 7. Prostin E2 package insert, The Upjohn Company, Kalamazoo, MI, revised May 1991. 8. Owen J, Saunders E Harris C, Fenemore J, Reid K, Surridge D, Condra M, and Morales A: Topical nitroglycerin: a potential treatment for impotence. J Uroll41: 546-548,1989.
75
CQWMJNICATION
INTRAURETHRAL PROSTAGLANDIN E-2 CREAM: A POSSIBLE ALTERNATIVE TREATMENT FOR ERECTILE DYSFUNCTION BRADWOLFSON, M.D. STEVEN PICKETT, M.D. NATHAN E. SCOTT. M.D.
JEAN B. DEKERNION,M.D. JACOB RAJFER,M.D.
From the Division of Urology, Department of Surgery, Harbor-UCLA Medical Center, UCLA School of Medicine, Torrance, California
ABSTRACT-Prostaglandin E-2 (PGE-2) is an oxytocic agent in suppository form with vasodilatory effects similar to prostaglandin E-l (PGE-1). Because some men find intracavernosal injections disagreeable, we investigated whether intraurethral PGE-2 may provide an alternative method for treating erectile dysfunction. A PGE-2 cream was made using PGE-2 suppositories (20 mg or 40 mg), 10 cc of 2% lidocaine (Xylocaine) jelly, and 40 cc of surgical lubrication. Two cc of the cream was instilled into the urethral meatus using a syringe, the cream was massaged down the urethra, and the urethra was occluded for five minutes. Treatment response was rated as no penile tumescence, partial tumescence, and full tumescence. Overall, 70 percent showed a response and 30 percent had full penile tumescence. Two of 4 men who had no tumescence using PGE-2 had a subsequent full tumescence using intracavernosal PGE-1 (15 mg), while 3 of 4 men with a partial tumescence with PGE-2 had a subsequent full tumescence using intracavernosal PGE-1 (15 mg). These data demonstrate that full penile tumescence may be achieved in impotent men using intraurethral PGE-2 cream. This pilot study supports the necessity for further investigations in a randomized double-blind manner in the use of intraurethral PGE2 cream as a less invasive treatment alternative for erectile dysfunction.
The use of injectable intracavemosal agents to induce erection has become routine in urologic practice. 1-6Many men with erectile dysfunction can achieve normal erections with this therapy, but some choose not to proceed with self-injection because of the discomfort involved or because of a generalized “needlephobia.“3*4 Furthermore, side effects including corporeal scarring, penile hematoma, priapism, and penile pain have been described using this modality1,2 Prostin E-2 (Upjohn, Kalamazoo) is an oxytocic agent which contains dinoprostone as the naturally occurring prostaglandin E-2 (PGE-2).’ PGE2 has vasodilatory effects similar to prostaglandin E-l (PGE-1) which has been studied extensively as an intracavemosal injection therapy PGE-2 is Submitted (Rapid Communication): (with revisions): March 29, 1993
UROLOGY I
JULY 1993
I
March 23, 1993, accepted
VOLUME 42, NLWBER 1
processed as a suppository which can be easily crushed into surgical lubrication to form a PGE-2 cream. We investigated the efficacy of two doses of an intraurethral instillation of PGE-2 cream on induction of penile erection. MATERIAL AND METHODS A PGE-2 cream was made by hand in the clinic using Prostin E-2 vaginal suppositories (20 or 40 mg), 10 cc of 2% lidocaine (Xylocaine) jelly, and 40 cc of surgical lubricant. Using a syringe, 2 mL of the cream (67 J.tgor 134 J.tg>of PGE-2 was instilled into the urethral meatus; the cream was massaged down the urethra, and the distal urethra was occluded for five minutes with an occlusive clamp. Treatment response was evaluated at twenty minutes postinstillation, and was rated as no penile tumescence, partial tumescence, or full tumescence. If full tumescence was not achieved, 73
patients were offered intracavemosal injection of PGE-1 solution (15 pg) at a subsequent visit. Manual or visual stimulation was not performed by any of the patients. A total of 20 men presenting to our urologic clinic with erectile dysfunction participated in the study after verbal informed consent was obtained. The mean age of these patients was fifty-seven years. Medical history associated with erectile dysfunction was variable (Table I). RESULTS A serum testosterone was normal in each of these patients. For various reasons, the etiology of the impotence was not determined in most of these 20 patients. Ten men received 2 mL (67 pg) of the 20 mg PGE-2 cream. No tumescence was achieved in 4, partial tumescence in 2, and full tumescence in 4. Two of the men with full tumescence described erections lasting three hours. The medical conditions associated with erectile dysfunction in the full responders included hypertension and diabetes mellitus. Ten men received 2 mL (134 pg) of the 40 mg PGE-2 cream: 2 had no tumescence, 6 partial tumescence, and 2 achieved full tumescence. Both men who fully responded described a history of hypertension. Overall, 14 of 20 men (70%) receiving PGE-2 cream showed a response to treatment, and 30 percent had full penile tumescence. All men experienced a transient mild urethral burning sensation with instillation of the cream. In none did persistent dysuria develop, and there were no cardiovascular side effects. Of the 14 me< who failed to achieve a full tumescence with the PGE-2 cream, 8 elected to undergo an intracavernosal injection of PGE-1 (15 pg). Two of 4 men who had no response with intraurethral PGE-2 had a subsequent full tumescence with intracavernosal PGE-1, and 3 of 4 men with a partial tumescence with PGE-2 cream achieved a full tumescence with intracavernosal PGE-1. Thus, 5 of 8 men (62%) who did not demonstrate a full tumescence with PGE-2 cream subsequently achieved a full tumescence with intracavemosal PGE-1. COMMENT The physiologic mechanism of penile erection requires an increase in penile arterial inflow, relaxation of cavemosal smooth muscle sinusoids, and increased penile venous resistance.2 Intracavemosal agents such as papaverine, phentolamine, and prostaglandin E-l have been shown to be useful in eliciting penile erection by increasing arter74
TABLEI. Factors associated with dysfunction (n = 20)
erectile Number
Medical History Hypertension Diabetes mellitus Hypertension and diabetes Post surgical Other
6 3 7 2 2
ial inflow and/or relaxing cavemosal smooth muscle.l** Up to 80 percent of men with erectile dysfunction can achieve an erection sufficient for sexual intercourse with the use of these agents.4 Unfortunately, many men find self-injection undesirable, and up to 50 percent of men who respond adequately with use of these agents subsequently discontinue their use for various reasons.3J Papaverine therapy has been associated with development of corporeal plaques at the injection site, priapism, and systemic cardiovascular side effects including vasovagal episodes and syncope.’ PGE-1 has been associated with priapism and painful erection with penile pain and burning.’ Prostin E2 is an oxytocic agent in suppository form which contains the naturally occurring prostaglandin E2 dinoprostone.’ It is water soluble and can easily be crushed into a cream form when mixed with surgical lubricant. PGE-2 has been noted to lower blood pressure in laboratory animals as well as in man, likely due to its effect on the smooth muscle of the vascular system. Adverse reactions associated with the use of PGE-2 as a vaginal suppository in the treatment of termination of pregnancy or evacuation of the uterine contents in missed abortion include nausea/vomiting, elevated temperature, headaches, shivering/chills, and transient hypotension. In our study, instillation of a PGE-2 cream resulted in full penile tumescence in 30 percent of the subjects. No significant side effects were demonstrated except for mild transient burning with instillation of the cream. In addition, another 40 percent of subjects achieved partial tumescence. The mechanism of the translocation of the PGE2 from the urethra into the corporeal bodies remains to be discerned. The drug may be effective through a local absorptive effect or passage of the drug through corporeal spongiosal channels. The mechanism of local transdermal absorption has been postulated as a potential mode of therapy for erectile dysfunction. ’ However, there are no data to confirm whether or not these drugs actually reach their target tissue via the systemic circulation rather than these two aforementioned routes. UROLOGY
I JULY1993 / VOLUME 42, NUMBER 1
Whether other vasodilatory compounds incorporated into a cream form could elicit an erectile response or enhance the response of PGE-2 remains to be investigated. Of the subjects who did not achieve a full tumescence with PGE-2 cream, 8 subsequently received intracavernosal injection with PGE-1 and 5 (62%) achieved a full tumescence. Whether or not further elevation of the dose of PGE-2 cream would have elicited a full tumescence in these men remains to be investigated. In summary, PGE-2 cream can elicit a full penile tumescence in men with erectile dysfunction. It can be administered with minimal discomfort and displays no major adverse reactions. The mechanism of action, optimal dosage, and longterm effects require further investigation. Since the completion of this pilot study, a request to perform a randomized, placebo controlled, double-blind study to test the true efficacy of this compound has been denied by the FDA until animal toxicologic studies are submitted.
UROLOGY
/
JULY
1993 / VOLUME42, NLMBER 1
Jacob Rajfer,M.D. Torrance, Cal@7tia 90502 REFERENCES 1. Krane R, Goldstein I, and Saenz de Tejada I: Impotence. N Engl J Med 321: 1648-1659,1989. 2. Lue T, and Tanagho E: Physiology of erection and pharmacological management of impotence. J Urol 137: 829-836,1987. 3. Lakin M, Montague D, Medendorp S, Tesar L, and Schover L: Intracavemous injection therapy: analysis of results and complication. J Urol 143: 1138-1141, 1990. 4. Schramek P, Dominger R, Waldhouser M, Konecny P and Porpaczy P: Prostaglandin El in erectile dysfunction efiiciency and incidence of priapism. Br J Urol65: 68-71,199O. 5. Gerber G, and Levine L: Pharmacological erection program using prostaglandin El. J Urol 146:786-789, 1991. 6. Sarosdy M, Hudnall C, Erickson D, Hardin T, and Novicki D: A prospective double-blind trial of intracorpoteal papaverine versus prostaglandin El in the treatment of impotence. J Uro1141: 551-553, 1989. 7. Prostin E2 package insert, The Upjohn Company, Kalamazoo, MI, revised May 1991. 8. Owen J, Saunders E Harris C, Fenemore J, Reid K, Surridge D, Condra M, and Morales A: Topical nitroglycerin: a potential treatment for impotence. J Uroll41: 546-548,1989.
75