International Journal of Impotence Research (2004) 16, 73–77 & 2004 Nature Publishing Group All rights reserved 0955-9930/04 $25.00 www.nature.com/ijir Feline penile erection induced by topical glans penis application of combination alprostadil and SEPA (Topiglan) MF Usta, J Sanabriav, TJ Bivalacqua and WJG Hellstrom* Department of Urology, Tulane University Health Sciences Center, New Orleans, Louisiana, USA The objective of this study was to evaluate the efficacy of topically applied prostaglandin E1 (PGE1) þ 5% SEPA (soft enhancement of percutaneous absorption) on the glans penis in a feline erection model. Erectile response after glans penis administration of PGE1 þ 5% SEPA cream (Topiglan, MacroChem Co., Lexington, MA, USA) was compared to the erectile response after intracavernosal administration of the triple-drug combination (1.65 mg papaverine, 25 lg phentolamine, and 0.5 lgPGE1). The placebo cream and increasing concentrations (0.25%, 2.5 mg/ml; 0.5%, 5 mg/ml; and 1%, 10 mg/ml) of PGE1 þ 5% SEPA were applied in a total volume of 0.1 ml via a plastic needle-less syringe. The control triple-drug combination was administrated intracavernosally via a 30-gauge needle at the completion of each experiment to serve as a control reference. With each application of placebo, PGE1 þ SEPA, and the triple-drug combination, changes in intracavernosal pressure and systemic blood pressure were continuously monitored. Topical application of PGE1 þ SEPA induced increases in intracavernosal pressure in a dose- dependent manner, with minimal effects on systemic blood pressure. The increases obtained with 1% PGE1 Topiglan cream were similar to the intracavernosal pressure values elicited by the standard intracavernosal triple-drug combination. These data demonstrate that topical glans penis application of PGE1 þ SEPA can induce an erectile response in cats with minimal systemic adverse effects. Oral pharmacological agents are the first-line treatment for male ED. Studies investigating the effectiveness of noninvasive modalities such as topical therapy should continue, because these agents have the potential to avoid the systemic effects commonly seen with oral therapies. Additionally, topical therapy may also benefit patients who are unresponsive to oral agents or have explicit contraindications. Topical PGE1 application to the glans penis may become an important treatment option in selected patients suffering from erectile dysfunction. International Journal of Impotence Research (2004) 16, 73–77. doi:10.1038/sj.ijir.3901145 Keywords: topical treatment; erectile dysfunction; PGE1; cat Introduction older men, while psychogenic factors are common in younger men.2 Erectile dysfunction (ED) is defined as the inability Although many treatment options such as intra- to attain or maintain an erection sufficient for cavernosal vasoactive drugs, medical devices, sur- satisfactory sexual intercourse.1 Though estimates gery, and psychotherapy have been used over the vary, ED affects from 9 to 26% of the male years for the treatment of ED, the introduction of an population in the United States.2,3 Recent investiga- effective oral agent, sildenafil (Viagra, Pfizer, New tions using molecular biological techniques have York, NY, USA), has revolutionized the treatment of given researchers new insights into the pathophy- this condition.4,5 Efforts to develop minimally siology of ED in a number of systemic disorders, invasive local therapies for ED continue because such as diabetes mellitus (DM), chronic renal fail- they can conceivably circumvent many of the ure, and cardiovascular disease. Vascular disease is systemic side effects related to oral medications. In recognized to be the most likely etiology for ED in addition, local therapies may benefit patients who are unresponsive to current oral phosphodiesterase type 5 (PDE5) inhibitors or who have contraindica- tions to using oral therapies, such as in men receiving oral nitrates and men with severe cardio- *Correspondence: WJG Hellstrom, Professor of Urology, vascular disease. Intracavernosal and transurethral Department of Urology SL-42, Tulane University, School of Medicine, 1430 Tulane Avenue, New Orleans, LA alprostadil therapies are effective with high success rates, but have high rates of discontinuation because 70112, USA. 6,7 E-mail: [email protected] of discomfort, injection pain, or local fibrosis. Received 24 March 2003; revised 2 June 2003; accepted 22 Topical vasoactive drug delivery is a simple, safe, June 2003 reversible, and relatively noninvasive alternative Feline penile erection and Topiglan MF Usta et al 74 modality for the treatment of ED.8 Topiglan from refrigeration 10 min before use and was applied (PGE1 þ SEPA) is a topical agent applied to the glans using a plastic needle-less syringe on the glans penis, with SEPA acting as a transdermal penetra- penis. A small drape was made using a 2 Â 2cm2 tion enhancer, improving the absorption of PGE1 latex material, and this was placed circumferentially through human epidermis.9 around the sulcus coranarius of the glans penis to The present study examines the dose-dependent avoid contact of the gel with the instrumented shaft efficacy of a topical formulation of prostaglandin E1 of the penis. The effect of each application of and the penetration enhancer SEPA on cavernosal Topiglan on intracavernosal pressure was recorded smooth muscle relaxation in vivo, and its effect on until intracavernosal pressure had returned to the systemic arterial pressures using a well-established preapplication level. Each successive application feline erection model. was made after a period of at least 20–25 min from the completion of the preceding response to ensure a stable baseline. Before each application of Topiglan, Materials and methods the glans penis of animals was washed with soap and water. In all experiments, the effects of different doses of Topiglan on intracavernosal pressure and Eight adult male cats weighing 3.2–4.5 kg were total duration of erection were tabulated. In addi- sedated with ketamine hydrochloride (10–15 mg/kg tion, after the application of Topiglan cream, the i.m.) and anesthetized with pentobarbital sodium time to erectile response was also recorded. (30 mg/kg i.v.). Supplemental doses of pentobarbital were administered to maintain a uniform level of anesthesia. The animals were maintained at 371C Statistics body temperature with a heating blanket. The trachea of each animal was cannulated, and animals spontaneously breathed room air. Catheters were The data were expressed as mean7s.e.m. and inserted into the femoral vein for i.v. administration analyzed by a one-way analysis of variance (ANO- of anesthesia and into the carotid artery for the VA) for multiple-group comparisons and by Stu- measurements of mean systemic arterial pressure dents’ t-test for individual group comparison. The (MAP). A vertical, circumcision-like incision was value of Po0.05 was established as the criterion for made to expose the two ventral corpora cavernosa statistical significance. and the dorsal corpus spongiosum. A 25-gauge needle was placed midway into the left corpus cavernosum for the measurement of intracavernosal Results pressure (ICP, in mmHg). Systemic and intracaver- nosal pressures were measured with Statham P23 transducers (Viggo Spectramed, Oxnard, CA, USA) Erectile response to glans penis application of attached to a data-acquisition system (Biopac Sys- Topiglan tems, Santa Barbara, CA, USA), and connected to a computer for recording of mean pressures. The ratio between the maximal ICP and MAP obtained at the The effects of increasing concentrations (0.25, 0.5, peak of erectile response was calculated to normal- and 1%) of PGE1 þ SEPA, the placebo, and the triple- ize for variations in systemic blood pressure. These drug combination on intracavernosal pressure were procedures have been previously described and investigated in the cat, and the results of these approved by the Tulane University Animal Care experiments are summarized in Figure 1. Glans and Use Committee.10,11 penis application of 0.25, 0.5, and 1% Topiglan In all experiments, placebo and various concen- induced dose-dependent increases in intracaverno- trations of Topiglan (PGE1 in a cream formulation sal pressure when compared to baseline levels with 5% SEPA, 0.1 ml total volume) were applied to (Po0.05). Moreover, 1% Topiglan induced an the glans penis when the cavernosal pressure was at increase in cavernosal pressure, which was compar- baseline value. After dose–response curves for able to the intracavernosal injection of the triple- Topiglan were attained, the standard control combi- drug combination. The placebo had no significant nation of papaverine (1.65 mg), phentolamine erectogenic effect on the resting intracavernosal (25 mg), and PGE1 (0.5 mg) was administered intraca- pressure in any of the animals. vernosally for comparative purposes. The study The time to erection, as determined by the total medications were creams composed of (0.25%, time (min) required for an increase in intracaverno- 2.5 mg/ml; 0.5%, 5 mg/ml; and 1%, 10 mg/ml) sal pressure after application of Topiglan, is shown PGE1, ethanol, hydroxypropyl cellulose, water, and in Figure 2a. The total time to erectile response was 5% SEPA. The placebo vehicle was identical except dose-dependent for each of the doses of Topiglan in without PGE1. The medications were supplied in this model. In addition, the total time to erectile coded vials stored at 41C. Each vial was removed response for the triple-drug control combination was International Journal of Impotence Research Feline penile erection and Topiglan MF Usta et al 75 Figure 1 Bar graph demonstrating dose-dependent increases on ICP/MAP ratios after topical administration of Topiglan and intracavernosal injection of the triple-drug combination. n ¼ number of animals; *Po0.05, response is significantly different than placebo; **Po0.05, response is significantly different than Topiglan (0.25 and 0.5%). 28.673 s, a value which was significantly lower when compared to 0.25, 0.5, and 1%PGE1 in Topiglan formulations (Po0.05).