(094) Synergy Between Orally Administered Phosphodiesterase-type-5-inhibitors and Topically Delivered Nitric-oxide in Eliciting Erectile Responses

Abstract

Abstract Introduction Phosphodiesterase-type-5-inhibitors (PDE5i) represent first-line 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 suffer neurogenic ED (for example, following the procedures for radical prostatectomy (RP) or resulting from diabetes) are commonly refractory to PDE5i treatment. We recently demonstrated proof-of-principle for increased efficacy of topically applied NO-releasing microparticles (NO-MP) in eliciting an erectile response when used in combination with the orally administered PDE5i, sildenafil. However, there are several other FDA approved PDE5i used to treat ED, which, although acting through the common mechanism of PDE5 inhibition, exhibit several characteristics that potentially could impact clinical and commercial translation of combination therapy. Objective The goal of the present studies was to determine if other commercially available PDE5i besides sildenafil (avanafil, tadalafil and vardenafil) also act cooperatively when used in combination with NO-MP to elicit an erectile response. Methods Sprague-Dawley rats underwent bi-lateral transection of the cavernous nerve (CN), as a model of RP, one-week prior to determining erectile response to treatment. We investigated the effect of oral administration of 0.05mg sildenafil/kg, 0.005mg tadalafil/kg, 0.01mg vardenafil/kg and 0.1mg avanafil/kg (approximately equivalent to clinical doses of 2.5mg, 0.25mg, 0.5mg and 5mg, respectively, administered to an 80 kg patient) 30 minutes prior to being anesthetized for the determination of erectile response by intracorporal pressure (ICP) and systemic blood pressure (BP). Baseline ICP and BP were recorded for 30 minutes, at which time 100 mg of 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 by PDE5i alone resulted in no observable erectile response, topical application of NO-MP resulted in spontaneous erectile responses. When NO-MP were applied in combination with oral PDE5i treatment, all PDE5i resulted in faster times to the first erectile response (on average 11 minutes compared to 22 minutes when NO-MP were used alone; P-value=0.041) and greater numbers of spontaneous erections (on average 4.6 erections per hour compared to 2.0 when NO-MP were used alone, P-value=0.043). Although there were no significant differences between any of the PDE5i when used in combination with NO-MP with respect to the average erectile responses per hour, duration of erectile response, and maximal ICP/BP, there was a trend in the vardenafil and avanafil treated animals for a more rapid onset of the erectile responses than observed with sildenafil and tadalafil. 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. Our results suggest a novel treatment strategy for patients with ED refractory to PDE5i, namely any of the FDA-approved oral PDE5 inhibitors used in combination with formulations that topically deliver NO to corporal tissue. Disclosure Yes, this is sponsored by industry/sponsor: Zylo Therapeutics, 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: Zylo Therapeutics, Inc