INTRACAVERNOSAL FORSKOLIN - ROLE IN MANAGEMENT OF VASCULOGENIC IMPOTENCE RESISTANT TO STANDARD 3-AGENT PHARMACOTHERAPY

Purpose: We investigated forskolin, a direct adenylate cyclase activat or, as an intracavernosal vasoactive agent in management of vasculogen ic impotence. Materials and Methods: Concentration responses for forsk olin and prostaglandin El induced relaxation of phenylephrine precontr acted strips of human corpus cavernosum smooth muscle were constructed in vitro. Cyclic adenosine monophosphate (cAMP) synthesis was determi ned with papaverine, phentolamine, prostaglandin El and forskolin in h uman corpus cavernosum smooth muscle cell cultures. Dose-dependent hem odynamic responses to intracavernosal forskolin (5 to 20 mu g.)were ev aluated in a New Zealand White rabbit model. Safety and efficacy outco me data were obtained in vasculogenically impotent patients who signed informed consent and met strict inclusion and exclusion criteria that included having had standard self-injection therapies fail. Results: In vitro forskolin and prostaglandin El alone caused concentration dep endent relaxation with an EC50 of approximately 200 nm, and 16 nm,, re spectively, When the 2 agents were combined, the concentration respons e curve for relaxation shifted to the left. cAMP production was highes t in cells treated with prostaglandin El and forskolin and was unaffec ted by papaverine or phentolamine. In 3 animals, equilibrium intracave rnosal pressure and duration of erection had a dose dependent increase . Clinical investigation in 31 patients showed no adverse events with a mean of 14 +/- 4, range 11 to 18 months of followup. Overall 61% rep orted improvement in rigidity and/or erection duration using intracave rnosal forskolin (98 mu g./ml.), papaverine (29 mg,/ml,), phentolamine (0.98 mg./ml,) and prostaglandin EB (9.8 mu g./ml.). Conclusions: For skolin is a United States Food and Drug Administration nonapproved vas oactive agent that acts in synergism with prostaglandin El to induce s mooth muscle relaxation. In combination with other vasoactive agents, forskolin has demonstrated preliminary safety and efficacy in patients with vasculogenic impotence resistant to standard 3-agent pharmacothe rapy.