Evaluation of oral Ro70-0004/003, an alpha(1A)-adrenoceptor antagonist, inthe treatment of male erectile dysfunction

alpha -Adrenoceptor antagonists have been used for the treatment of male er ectile dysfunction (MED). Ro70-0004/003 (Ro70-0004) is a selective and oral ly active alpha (1A)-adrenoceptor antagonist. The objective of this study w as to: (1) pharmacologically elucidate the alpha (1)-adrenoceptor subtype m ediating norepinephrine-induced contraction of human isolated corpus cavern osal tissue and (2) conduct a clinical proof-of-concept study with Ro70-000 4 to test the hypothesis that selective alpha (1A)-Aadrenoceptor blockade w ould improve erectile function in patients with MED, In vitro organ bath st udies were conducted with strips of human isolated corpus cavernosal tissue obtained from patients undergoing penile prosthesis implantation. Prazosin , cyclazosin, RS-100329 and Ro70-0004/003 antagonized norepinephrine-induce d contractile responses with affinity estimates (pK(B) or pA(2)) of 8.4, 7. 3, 9.2 and 8.8, respectively, consistent with the singular involvement of a lpha (1A)-Aadrenoceptor subtype. A clinical study (single center, observer- blind, randomized, placebo-controlled, extended period Latin-Square crossov er design) was conducted in 24 male patients (mean age 44 y) with MED of no established organic cause to evaluate the efficacy of a 5-mg oral dose of Ro70-0004, The primary efficacy endpoint was the duration of rigidity > 60% at the base of the penis measured between 0.5 and 2.5 h post-dose. Rigidit y was assessed by penile plethysmography using the RigiScan Plus((R)) devic e during visual sexual stimulation, The safety and efficacy of Ro70-0004 wa s also assessed. A 50-mg dose of sildenafil was included as a positive cont rol, For the primary efficacy endpoint, the mean duration of erection was 9 .69 min following administration of placebo, 8.28 min following Ro70-0004, and 22.64 min following sildenafil, Only the difference between sildenafil and placebo reached statistical significance (P < 0.05). A similar pattern was observed when measuring a duration of rigidity > 80% at the base of the penis (secondary endpoint), Ro70-0004 was safe and generally well tolerate d (only two out of 20 patients reported at least one adverse event), The hi ghly selective ol,A-adrenoceptor antagonist, Ro70-0004, given at a single d ose of 5 mg, did not improve erectile function when compared to placebo.