Double-blind, placebo-controlled evaluation of the safety, pharmacokinetic properties and pharmacodynamic effects of intranasal PT-141, a melanocortin receptor agonist, in healthy males and patients with mild-to-moderate erectile dysfunction
Diamond LE, Earle DC, Rosen RC, Willett MS, Molinoff PB
International Journal of Impotence Research (2004)
First-in-human safety and efficacy study of intranasal PT-141 in healthy men and men with erectile dysfunction — established the central-mechanism erectile response, dose-related flushing and nausea profile, and the pharmacokinetic floor on which Palatin's male-indication development program was built before it was abandoned for the eventual female HSDD approval.
This is the Phase I dose-escalation study from Palatin Technologies that put PT-141 / bremelanotide on the clinical map and established the male erectile-response side of the program — the side that ultimately did not progress to FDA approval but that supplies essential context for the off-label male use case. Diamond and colleagues conducted two double-blind placebo-controlled studies of intranasal PT-141: one in healthy males assessed by RigiScan without visual sexual stimulation, and one in men with mild-to-moderate sildenafil-responsive erectile dysfunction assessed by RigiScan with visual sexual stimulation. PT-141 produced dose-related increases in Cmax and AUC with a median Tmax of 0.50 hours and a mean elimination half-life of 1.85-2.09 hours, supporting on-demand rather than chronic dosing. At doses above 7 mg intranasal, PT-141 produced statistically significant erectile responses versus placebo in both populations, with onset of first erection approximately 30 minutes post-administration. The most common adverse events were flushing and nausea, both dose-related and consistent with melanocortin agonism. No clinically significant changes were observed in vital signs, ECG, laboratory measures, or physical examination at the doses tested, and a maximum-tolerated dose was not reached in the studied range. The paper is the human-level proof-of-concept that PT-141 produces sexual response through a central mechanism — the RigiScan-without-visual-stimulation arm in healthy males specifically excludes the PDE5-inhibitor framework of "vasodilation given existing arousal" and demonstrates direct CNS-mediated arousal.
This is a Phase I study with the methodological limitations of that stage of development: small sample sizes, healthy-volunteer plus mild-to-moderate ED selection, short duration of treatment, and pharmacodynamic-surrogate endpoints (RigiScan-measured penile rigidity) rather than functional endpoints in real sexual activity. The intranasal formulation tested in this paper was subsequently abandoned in favor of subcutaneous administration for the eventual female HSDD approval; Palatin's male erectile-dysfunction program did not progress to FDA approval, in part because of dose-limiting blood-pressure increases observed in later trials at the dose range needed for robust erectile response in PDE5-non-responder populations. Industry involvement is direct: all five authors are Palatin Technologies employees or paid investigators, and the paper is part of the company's clinical-development dossier. The on-demand dose-response established here informed the eventual subcutaneous Vyleesi dose for the female indication, but it should not be read as evidence supporting any specific dose for male off-label use, which the data does not address in mature form. Subsequent studies — Safarinejad 2008 in sildenafil non-responders, the abandoned Phase II/III male trials — provide the rest of the male-indication context.
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