Evaluation of the safety, pharmacokinetics and pharmacodynamic effects of subcutaneously administered PT-141, a melanocortin receptor agonist, in healthy male subjects and in patients with an inadequate response to Viagra s RC Rosen 1 *, LE Diamond 2 , DC Earle 2 , AM Shadiack 2 and PB Molinoff 2 1 Department of Psychiatry, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey, USA; and 2 Palatin Technologies, Inc., Cranbury, New Jersey, USA PT-141, a cyclic heptapeptide melanocortin analog, was evaluated following subcutaneous administration to healthy male subjects and to patients with erectile dysfunction (ED) who report an inadequate response to Viagra s . An inadequate response was defined for this study by patient report indicating that achievement of an erection suitable for vaginal penetration occurred r50% of the time while taking 100mg Viagra s . Erectile responses were assessed by RigiScant in healthy subjects in the absence of visual sexual stimulation (VSS) and in ED patients in the presence of VSS. Doses ranging from 0.3 to 10mg were administered to healthy male subjects, resulting in a statistically significant erectile response at doses greater than 1.0 mg. ED patients were treated with placebo, 4 or 6mg PT-141 in a crossover design in the presence of VSS. The erectile response induced by PT-141 was statistically significant at both doses. PT-141 was safe and well tolerated in both studies. The erectogenic potential of PT-141, its tolerability profile and its ability to cause significant erections in patients who do not have an adequate response to a PDE5 inhibitor suggest that PT-141 may provide an alternative treatment for ED with a potentially broad patient base. International Journal of Impotence Research (2004) 16, 135–142. doi:10.1038/sj.ijir.3901200 Published online 4 March 2004 Keywords: pharmacologic studies in sexual function; oral vasoactive agents Introduction Erectile dysfunction (ED) is associated with a variety of etiologies and/or risk factors, including age, depression, hypertension, diabetes, cardiac disease and benign prostatic hypertrophy. A limited range of medical and surgical treatments are currently available to treat ED. 1 Oral pharmacotherapies, in particular phosphodiesterase type 5 (PDE5) inhibi- tors, 2–4 are currently recognized as first-line treat- ments for ED. Sildenafil (Viagra s ), the first approved PDE5 inhibitor, has been shown to be effective in 40–80% of patients, depending upon the specific etiology and duration of ED. 5 Patients with a history of pelvic surgery or diabetes mellitus, for example, show a reduced level of response to sildenafil (eg 40–60%). 6–8 Approximately 50% of men who receive a prescription for sildenafil discontinue use of the drug over time. 9 Among other factors, side effects such as headache, flushing and changes in color vision are often cited as reasons for discontinuation of use. Because of the potentiation of hypotension following co-adminis- tration of PDE5 inhibitors and organic nitrates, sildenafil is contraindicated in patients taking organic nitrates. Centrally acting agents have potential as first-line treatments for ED, and might provide additive or synergistic effects given in combination with PDE5 inhibitors. 10 PT-141, a cyclic, heptapeptide melano- cortin analog, is an active metabolite of melanotan-II. 11 Results from pharmacological studies demonstrate PT-141 to be an agonist at the melanocortin receptors, including MC3-R and MC4-R, 12 which are primarily expressed in the central nervous system. 13,14 Received 21 August 2003; revised 19 November 2003; accepted 7 January 2003 *Correspondence: RC Rosen, PhD, University of Medicine and Dentistry, Robert Wood Johnson Medical School, Department of Psychiatry, 675 Hoes Lane, Piscataway, NJ 08554-5653, USA. E-mail: rosen@umdnj.edu International Journal of Impotence Research (2004) 16, 135–142 & 2004 Nature Publishing Group All rights reserved 0955-9930/04 $25.00 www.nature.com/ijir