47 Synergy Between Sildenafil and Topically Delivered Nitric-oxide in Eliciting an Erectile Response in a Rat Model of Radical Prostatectomy
Authors: Tar M , Draganaski A , Friedman J , Davies K 
Published: April 2022

ABSTRACT

Introduction
Sildenafil belongs to a group of phosphodiesterase-type-5-inhibitors (PDE5i) which represent the only class of FDA-approved oral treatments for erectile dysfunction (ED). However, because their mode of action is dependent on the production of nitric oxide (NO) from nerve endings, patients that undergo radical prostatectomy (RP), which results in cavernous nerve (CN) injury, are commonly refractory to these pharmacologic agents.

Objective
Our goal was to investigate the ability of topically applied microparticles capable of transdermal delivery of NO (NO-MP) to act synergistically with sildenafil in eliciting an erectile response in an animal model of RP.

Methods
As a model of RP, Sprague-Dawley rats underwent bi-lateral transection of the CN one-week prior to determining erectile response to treatment. Rats were treated by oral gavage of 0.05 and 0.005 mg sildenafil/kg, 30 minutes before being anesthetized for the determination of intracorporal pressure (ICP) and systemic blood pressure (BP). Baseline ICP and BP were recorded for 30 min, at which time 250 or 100 mg NO-MP (or control, blank-MP) were applied to the rat penile shaft. The ICP and systemic BP were used to determine the time to the first erectile response, duration of the erectile responses, the maximal and average ICP/BP responses and the number of spontaneous erections per hour.

Results
Although oral treatment with sildenafil by itself resulted in no observable erectile response, topical application of NO-MP in combination with sildenafil resulted in both a faster time to the first erectile response and greater numbers of spontaneous erections compared to NO-MP used alone. Combination of orally administered 0.05 sildenafil/kg with topical application of 250mg NO-MP, compared to 250 mg NO-MP by itself, resulted in significantly more spontaneous erections (4.6 compared to 2 erections per hour, t-test; p-value = 0.043), with a significantly faster onset for the first erectile response (11 compared to 22 minutes; t-test, p-value = 0.041).

Conclusions
Although knowledge of the molecular pathways that lead to an erection provide a rationale for a synergistic effect between PDE5i and NO in eliciting an erectile response, our results provide the first evidence of such synergy. When combined with the NO-MP, this synergy in eliciting an erectile response was seen with 0.05 mg sildenafil/kg, which would be equivalent to a clinical dose of approximately 2.5 mg sildenafil for an 80 kg patient. Our results suggest a novel treatment strategy for patients with ED following RP whereby an oral PDE5i is used in combination with therapeutics that topically deliver NO to corporal tissue and also the potential to lower the therapeutic dose of oral PDE5i in all patients where it is used for the treatment of ED.

Disclosure
Yes, this is sponsored by industry/sponsor: ZyloTherapeutics, Inc.

Clarification
Industry funding only - investigator initiated and executed study
Any of the authors act as a consultant, employee or shareholder of an industry for: ZyloTherapeutics, Inc