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

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