Original Article

International Journal of Impotence Research (2004) 16, 73–77. doi:10.1038/sj.ijir.3901145

Feline penile erection induced by topical glans penis application of combination alprostadil and SEPA (Topiglan)

M F Usta1, J Sanabriav1, T J Bivalacqua1 and W J G Hellstrom1

1Department of Urology, Tulane University Health Sciences Center, New Orleans, Louisiana, USA

Correspondence: WJG Hellstrom, Professor of Urology, Department of Urology SL-42, Tulane University, School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, USA. E-mail: whellst@tulane.edu

Received 24 March 2003; Revised 2 June 2003; Accepted 22 June 2003.

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Abstract

The objective of this study was to evaluate the efficacy of topically applied prostaglandin E1 (PGE1)+5% SEPA (soft enhancement of percutaneous absorption) on the glans penis in a feline erection model. Erectile response after glans penis administration of PGE1+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 mug phentolamine, and 0.5 mug PGE1). The placebo cream and increasing concentrations (0.25%, 2.5 mg/ml; 0.5%, 5 mg/ml; and 1%, 10 mg/ml) of PGE1+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+SEPA, and the triple-drug combination, changes in intracavernosal pressure and systemic blood pressure were continuously monitored. Topical application of PGE1+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+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.

Keywords:

topical treatment, erectile dysfunction, PGE1, cat

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Introduction

Erectile dysfunction (ED) is defined as the inability to attain or maintain an erection sufficient for satisfactory sexual intercourse.1 Though estimates vary, ED affects from 9 to 26% of the male population in the United States.2,3 Recent investigations using molecular biological techniques have given researchers new insights into the pathophysiology of ED in a number of systemic disorders, such as diabetes mellitus (DM), chronic renal failure, and cardiovascular disease. Vascular disease is recognized to be the most likely etiology for ED in older men, while psychogenic factors are common in younger men.2

Although many treatment options such as intracavernosal vasoactive drugs, medical devices, surgery, and psychotherapy have been used over the years for the treatment of ED, the introduction of an effective oral agent, sildenafil (Viagra, Pfizer, New York, NY, USA), has revolutionized the treatment of this condition.4,5 Efforts to develop minimally invasive local therapies for ED continue because they can conceivably circumvent many of the systemic side effects related to oral medications. In addition, local therapies may benefit patients who are unresponsive to current oral phosphodiesterase type 5 (PDE5) inhibitors or who have contraindications to using oral therapies, such as in men receiving oral nitrates and men with severe cardiovascular disease. Intracavernosal and transurethral alprostadil therapies are effective with high success rates, but have high rates of discontinuation because of discomfort, injection pain, or local fibrosis.6,7 Topical vasoactive drug delivery is a simple, safe, reversible, and relatively noninvasive alternative modality for the treatment of ED.8 Topiglan (PGE1+SEPA) is a topical agent applied to the glans penis, with SEPA acting as a transdermal penetration enhancer, improving the absorption of PGE1 through human epidermis.9

The present study examines the dose-dependent efficacy of a topical formulation of prostaglandin E1 and the penetration enhancer SEPA on cavernosal smooth muscle relaxation in vivo, and its effect on systemic arterial pressures using a well-established feline erection model.

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Materials and methods

Eight adult male cats weighing 3.2–4.5 kg were sedated with ketamine hydrochloride (10–15 mg/kg i.m.) and anesthetized with pentobarbital sodium (30 mg/kg i.v.). Supplemental doses of pentobarbital were administered to maintain a uniform level of anesthesia. The animals were maintained at 37°C body temperature with a heating blanket. The trachea of each animal was cannulated, and animals spontaneously breathed room air. Catheters were inserted into the femoral vein for i.v. administration of anesthesia and into the carotid artery for the measurements of mean systemic arterial pressure (MAP). A vertical, circumcision-like incision was made to expose the two ventral corpora cavernosa and the dorsal corpus spongiosum. A 25-gauge needle was placed midway into the left corpus cavernosum for the measurement of intracavernosal pressure (ICP, in mmHg). Systemic and intracavernosal pressures were measured with Statham P23 transducers (Viggo Spectramed, Oxnard, CA, USA) attached to a data-acquisition system (Biopac Systems, 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 peak of erectile response was calculated to normalize for variations in systemic blood pressure. These procedures have been previously described and approved by the Tulane University Animal Care and Use Committee.10,11

In all experiments, placebo and various concentrations of Topiglan (PGE1 in a cream formulation with 5% SEPA, 0.1 ml total volume) were applied to the glans penis when the cavernosal pressure was at baseline value. After dose–response curves for Topiglan were attained, the standard control combination of papaverine (1.65 mg), phentolamine (25 mug), and PGE1 (0.5 mug) was administered intracavernosally for comparative purposes. The study medications were creams composed of (0.25%, 2.5 mg/ml; 0.5%, 5 mg/ml; and 1%, 10 mg/ml) PGE1, ethanol, hydroxypropyl cellulose, water, and 5% SEPA. The placebo vehicle was identical except without PGE1. The medications were supplied in coded vials stored at 4°C. Each vial was removed from refrigeration 10 min before use and was applied using a plastic needle-less syringe on the glans penis. A small drape was made using a 2 times 2 cm2 latex material, and this was placed circumferentially around the sulcus coranarius of the glans penis to avoid contact of the gel with the instrumented shaft of the penis. The effect of each application of Topiglan on intracavernosal pressure was recorded until intracavernosal pressure had returned to the preapplication level. Each successive application 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, 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 total duration of erection were tabulated. In addition, after the application of Topiglan cream, the time to erectile response was also recorded.

Statistics

The data were expressed as meanplusminuss.e.m. and analyzed by a one-way analysis of variance (ANOVA) for multiple-group comparisons and by Students' t-test for individual group comparison. The value of P<0.05 was established as the criterion for statistical significance.

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Results

Erectile response to glans penis application of Topiglan

The effects of increasing concentrations (0.25, 0.5, and 1%) of PGE1+SEPA, the placebo, and the triple-drug combination on intracavernosal pressure were investigated in the cat, and the results of these experiments are summarized in Figure 1. Glans penis application of 0.25, 0.5, and 1% Topiglan induced dose-dependent increases in intracavernosal pressure when compared to baseline levels (P<0.05). Moreover, 1% Topiglan induced an increase in cavernosal pressure, which was comparable to the intracavernosal injection of the triple-drug combination. The placebo had no significant erectogenic effect on the resting intracavernosal pressure in any of the animals.

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Bar graph demonstrating dose-dependent increases on ICP/MAP ratios after topical administration of Topiglan and intracavernosal injection of the triple-drug combination. n=number of animals; *P<0.05, response is significantly different than placebo; **P<0.05, response is significantly different than Topiglan (0.25 and 0.5%).

Full figure and legend (14K)

The time to erection, as determined by the total time (min) required for an increase in intracavernosal pressure after application of Topiglan, is shown in Figure 2a. The total time to erectile response was dose-dependent for each of the doses of Topiglan in this model. In addition, the total time to erectile response for the triple-drug control combination was 28.6plusminus3 s, a value which was significantly lower when compared to 0.25, 0.5, and 1%PGE1 in Topiglan formulations (P<0.05).

Figure 2.
Figure 2 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Bar graph demonstrating the (a) time to erectile response (min) and (b) total duration of erectile response (min) after topical administration of Topiglan and intracavernosal injection of the triple-drug combination. n=number of animals.

Full figure and legend (27K)

The duration of erectile response (min) was compared for each of the Topiglan doses, and these data are summarized in Figure 2b. The total durations of erectile response induced by 0.25 and 0.5% Topiglan were similar (12plusminus8 and 22plusminus10 min, respectively), while the total duration of the erectile responses induced by 1% Topiglan (96plusminus21 min) was significantly higher than that of 0.25 and 0.5% Topiglan. The total duration of erectile response (99plusminus13 min) elicited by the triple-drug control combination was significantly longer than 0.25 and 0.5% Topiglan (P<0.05), but similar to 1% Topiglan. No priapism was encountered after treatment with PGE1 in any animal in this study.

The effects of the glans penis application of Topiglan formulations on systemic arterial pressure are shown in Table 1. Glans penis application of Topiglan formulations (0.25, 0.5, and 1%) and the triple-drug control combination induced significant decreases in systemic arterial pressure when compared with preinjection baseline values (Table 1). The decrease in systemic arterial pressure in response to the glans penis application of Topiglan was significantly (P<0.05) less than the decrease induced by the triple drug control combination (Table 1).


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Discussion

Penile erection is a neurovascular event. The accumulation of cAMP after exposure to PGE1, via modulation of the enzyme adenylate cyclase, causes a decrease in cytoplasmic free calcium and, ultimately, relaxation of the smooth muscle in the corpora cavernosa.7,12 Topiglan is a topical formation of alprostadil (PGE1) combined with the absorbtion enhancer/excipient SEPA.8,9 Topical vasoactive agents used for the treatment of ED must penetrate the epidermis and the tunica albuginea to gain access to the corpora cavernosal smooth muscle. SEPA is an amphiphilic molecule, which causes reversible alterations on the lipid structure of the stratum corneum. This alteration allows external agents to penetrate the lipid barrier in the skin. Once a drug enters the dermis, it can easily pass to the hypodermis. Application of PGE1+SEPA to the skin of the glans penis has the potential for a similar erectogenic effect to that of intraurethral application of PGE1. The topical application of PGE1 is absorbed through the skin of the glans penis and enters the corpus spongiosum. Anatomical studies have demonstrated that the corpus spongiosum is a direct extension of and continuous with the glans penis. Recently, it has been reported that PGE1 can diffuse from the corpus spongiosum to the corpora cavernosa via vascular communications between the spongious and cavernous compartments. Therefore, PGE1 has the potential for inducing an erectogenic effect similar to intraurethral application and may be more efficacious if enhanced absorption of PGE1 can be achieved by the transdermal route.8,13,14

The results of this study demonstrate that glans penis application of Topiglan induces dose-dependent increases in cavernosal pressure in cats. Moreover, the increases in cavernosal pressure in response to glans penis application of 1% PGE1 were comparable to the increases induced by intracavernosal injection of the standard triple-drug combination. The maximal duration of the erectile response to glans penis application of PGE1 1% and triple-drug combination were similar. However, the maximal duration of erectile response to PGE1 0.25 and 0.5% was significantly less than the triple-drug combination. The decrease in systemic arterial pressure following glans penis application of PGE1 was significantly less than with intracavernosal injections of the triple-drug combination.

An ostensible advantage of this topical approach is reduced systemic exposure as witnessed by minimal changes in systemic blood pressure compared to the triple-drug combination. Furthermore, because PGE1+SEPA is just applied to the glans penis and not to the entire penile urethra, it may be associated with less frequent local adverse effects. However, in clinical studies, the systemic effects of both intrauretheral PGE1 and topical administration of PGE1+SEPA were similar.8,15 Another long-term advantage of this method of application will be improved patient compliance because of absence of needles and simplicity of application to the glans penis.

The type 5 PDE inhibitors sildenafil, vardenafil, and tadalafil—are generally effective oral medications for the treatment of ED.4,5 The use of topical glans penis vasoactive agents may appeal to patients who do not respond to oral type 5 PDE inhibitors, patients who cannot tolerate the systemic side effects, or when type 5 PDE inhibitors are contraindicated. Topical application of PGE1 may circumvent the needle phobia anxiety observed in some patients. The present study demonstrates an erectile response caused by topical 1% PGE1, comparable, in terms of intracavernosal pressure and total duration of erection, to intracavernosal injection of the standard triple-drug combination. Additionally, there were no episodes of priapism in any of the cats.

Topical vasoactive agents are an attractive option for some men undergoing treatment of ED. Organic nitrates, minoxidil, aminophyilline, co-dergocrine mesylate, and vasoactive intestinal polypeptide have been previously described as topical cavernosal smooth muscle relaxants with different degrees of success and side-effect rates.16,17,18,19 Recently, McVary et al compared the systemic effects, local tolerance, and effectiveness of topical gel formulations of PGE1 and SEPA applied to the penile shaft and glans of men with spinal cord injuries. They reported that PGE1 gel generated an erectile response in 67–75% of men compared to 17% in controls. No serious side effects were reported in this study, except for minimal skin discomfort.12 Goldstein et al similarly reported that 38.9% of patients were able to achieve an erection sufficient for vaginal penetration after topical gel application without significant changes in systemic vital signs.8

In conclusion, the ideal treatment of ED needs to be simple to administer, noninvasive, and able to maintain a high success rate with minimal side effects. Topiglan meets these criteria. Since there is no data suggesting a risk of prolonged erection, priapism, or corporeal fibrosis, topical PGE1 application is a viable second-line agent for the treatment of ED, and may become an option for patients with moderate to severe ED who are unresponsive or contraindicated to take to oral type 5 PDE inhibitors. Additionally, this treatment modality may be useful for patients who are unable to perform local intracavernosal injection due to body inadequacy, such as in patients with Parkinson's disease and spinal injury as well as morbidly obese patients.

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References

  1. NIH Consensus Development Panel on Impotence. Impotence. JAMA 1993; 270: 83–90. | PubMed | ISI |
  2. Lue TF. Erectile dysfunction. N Engl J Med 2000; 342: 1802–1813. | Article | PubMed | ISI | ChemPort |
  3. Melman A, Rehman J. Pathophysiology of erectile dysfunction. Mol Urol 1999; 3: 87–102. | PubMed |
  4. Levine LA. Diagnosis and treatment of erectile dysfunction. Am J Med 2000; 109: 3S–30S. | Article | PubMed |
  5. Carson CC. Oral and injectable medications for the treatment of erectile dysfunction. Curr Urol Rep 2000; 1: 307–312. | PubMed |
  6. Yap RL, McVary KT. Topical agents and erectile dysfunction: is there a place? Curr Urol Rep 2002; 3: 471–476. | PubMed |
  7. Porst H. The rationale for prostaglandin E1 in erectile failure: a survey of worldwide experience. J Urol 1996; 155: 802–815. | Article | PubMed | ISI | ChemPort |
  8. Goldstein I, Payton TR, Scheichter PJ. A double-blind, placebo-controlled, efficacy and safety study of topical gel formulation of 1% alprostadil (Topiglan) for the in-office treatment of erectile dysfunction. Urology 2001; 57: 301–305. | Article | PubMed | ChemPort |
  9. McMahon CG. Topiglan MacroChem. Curr Opin Investig Drugs 2002; 3: 602–606. | PubMed |
  10. Bivalacqua TJ et al. Potentiation of erectile response and cAMP accumulation by combination of prostaglandin E1 and rolipram, a selective inhibitor of the type 4 phosphodiesterase (PDE4). J Urol 1999; 162: 1848–1855. | Article | PubMed |
  11. Bivalacqua TJ et al. Feline penile erection induced by transurethral administration of sodium nitroprusside. Urol Res 1999; 27: 432–436. | Article | PubMed |
  12. McVary KT, Polepalle S, Riggi S, Pelham RW. Topical prostaglandin E1 Sepa gel for the treatment of erectile dysfunction. J Urol 1999; 162: 726–731. | Article | PubMed | ISI | ChemPort |
  13. Berner B, John VA. Pharmacokinetic characterization of transdermal delivery systems. Clin Pharmacokinet 1994; 126: 121–134.
  14. Sharlip ID. Evaluation and nonsurgical management of erectile dysfunction. Urol Clin North Am 1998; 25: 647–659. | PubMed |
  15. Engel JD, McVary KT. Transurethral alprostadil as therapy for patients who withdrew from or failed prior intracavernous injection therapy. Urology 1998; 15: 687–692. | Article |
  16. Nunez BD, Anderson DC. Nitroglycerin ointment in the treatment of impotence. J Urol 1993; 150: 1241–1243. | PubMed |
  17. Cavallini G. Minoxidil versus nitroglycerin: a prospective double-blind conrolled trial in transcutaneous erection facilitation for organic impotence. J Urol 1991; 146: 50–53. | PubMed |
  18. Gomaa A et al. Topical treatment of erectile dysfunction: randomized double blind placebo controlled trial of cream containing aminophylline, isosorbide dinitrate, and co-dergocrine mesylate. Br J Med 1996; 312: 1512–1515.
  19. Gozes I, Fridkin M. A fatty neuropeptide. Potential drug for noninvasive impotence treatment in rat model. J Clin Invest 1992; 90: 810–814. | PubMed |
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Acknowledgements

This work was supported by an unrestricted educational grant by MacroChem Corporation, Lexington, MA.

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