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Melatonin-Wessells1.Pdf ADULT UROLOGY EFFECT OF AN ALPHA-MELANOCYTE STIMULATING HORMONE ANALOG ON PENILE ERECTION AND SEXUAL DESIRE IN MEN WITH ORGANIC ERECTILE DYSFUNCTION HUNTER WESSELLS, DAN GRALNEK, ROBERT DORR, VICTOR J. HRUBY, MAC E. HADLEY, AND NORMAN LEVINE ABSTRACT Objectives. To assess the safety, erectogenic properties, and effect on sexual desire of Melanotan II, a synthetic melanotropic initiator of erection, in men with erectile dysfunction and organic risk factors. Methods. Ten subjects were enrolled in a double-blind, placebo-controlled, crossover study. Melanotan II (0.025 mg/kg) and vehicle were each administered twice by subcutaneous injection; real-time RigiScan monitoring and a visual analog were used to quantify the erections during a 6-hour period. The level of sexual desire and side effects were recorded with a questionnaire. Results. Melanotan II initiated subjectively reported erections in 12 of 19 injections versus only 1 of 21 doses of placebo. The mean rigidity score of the responders was 6.9 on a scale of 0 to 10. The mean duration of tip rigidity greater than 80% was 45.3 minutes with Melanotan II versus 1.9 for placebo (P ϭ 0.047). The level of sexual desire after injection was significantly higher after Melanotan II administration than after placebo. Nausea and stretching/yawning occurred more frequently with Melanotan II, and 4 of 19 injections were associated with severe nausea. Conclusions. The erectogenic properties of Melanotan II are not limited to cases of psychogenic erectile dysfunction; men with a variety of organic risk factors developed penile erections. The finding of increased sexual desire warrants further investigation of centrally acting agents on disorders of sexual desire. UROLOGY 56: 641–646, 2000. © 2000, Elsevier Science Inc. he central initiators of erection represent a has been implicated in the facilitation of partner Tnew class of agents for the treatment of erectile preferences in certain species, and alpha-MSH in- dysfunction (ED).1 Apomorphine, a dopamine ag- creases sexual behavior in rats.4,5 onist, has been studied extensively and has been Melanotan II, a superpotent cyclic alpha-MSH shown to improve sexual function in men with analog, initiates erections in normal men and pa- ED.2 Oxytocin, alpha-melanocyte-stimulating hor- tients with psychogenic ED.6,7 No studies have mone (alpha-MSH), and adrenocorticotropin act evaluated the effects of melanotropic peptides on centrally to induce penile erections in experimen- sexual desire in humans nor assessed their erecto- tal animals.3 These neuropeptides have also been genic properties in men with organic ED. The ra- shown to modulate sexual motivation in animals, tionale for the use of central initiators includes the but the results have been inconsistent. Oxytocin rapidity of onset, reduced side-effect profile, and potentially synergistic interaction with peripher- This study was supported by the University of Arizona Founda- ally acting agents. We report the effects of Melano- tion and the Office of the Vice President for Research (H.W.) and tan II on penile erection and sexual desire in a U.S. Public Health Service Grant DK 17420 (V.J.H.). double-blind, placebo-controlled, crossover study From the Sections of Urology and Dermatology, and Depart- of 10 men with ED and organic risk factors. ment of Pharmacology, University of Arizona College of Medi- cine; and Departments of Chemistry, Cell Biology, and Anatomy, University of Arizona, Tucson, Arizona MATERIAL AND METHODS Reprint requests: Hunter Wessells, M.D., Section of Urology, University of Arizona College of Medicine, P.O. Box 245077, SUBJECTS Tucson, AZ 85724 Men 18 to 75 years of age presenting to our Sexual Dysfunc- Submitted: August 10, 1999, accepted (with revisions): April tion Clinic with a chief complaint of ED were considered for 13, 2000 inclusion in this study. ED was defined as the persistent in- © 2000, ELSEVIER SCIENCE INC. 0090-4295/00/$20.00 ALL RIGHTS RESERVED PII S0090-4295(00)00680-4 641 any symptoms, the duration, and any measures taken to re- TABLE I. Organic risk factors in 10 subjects lieve them. Antiemetics were not routinely prescribed. Risk Factor n Hypercholesterolemia 5 STATISTICAL ANALYSIS Obesity 4 Visual analog scales were measured (range 0 to 10) and Hypertension 3 treated as continuous variables. RigiScan results were con- Peripheral neuropathic injury 2 verted using RigiScan Plus software and exported into SigmaPlot 4.0 (SPSS, San Rafael, Calif). The parameters exam- Diabetes mellitus 2 ined during the 6-hour experimental session included the Cigarette smoking 2 number and duration of erectile events, duration of tip rigidity Heart disease 2 between 60% and 79% and between 80% and 100%, latency to Venoocclusive dysfunction 1 the first event, and tip rigidity and tumescence activity units. Pudendal arterial insufficiency 1 The mean values of the RigiScan parameters after Melanotan II and placebo administration were compared using the one- tailed Student t test. Regression analysis was used to compare two continuous variables. ability to obtain and maintain an erection sufficient for sexual Side-effect responses were transformed into categories for satisfaction.8 Exclusion criteria included concurrent use of analysis: the presence of side effects (mild, moderate, or se- erectogenic medications, radical prostatectomy, cancer che- vere) versus an absence of side effects. A similar transforma- motherapy, Peyronie’s disease, or other genital anomalies. A tion was carried out for the sexual desire question. Nausea was history and physical examination identified men likely to have categorized as “severe” or “not severe” (none, mild, or mod- organic etiologies; subjects had a mean of 2.2 organic risk erate). Side effects due to Melanotan II and placebo were com- factors (Table I). Each individual completed the International pared with Fisher’s exact test (categorical variables) or one- Index of Erectile Function (IIEF)9; the mean values for ques- way analysis of variance (continuous variables) with Statview tions 3 and 4 were 0.77 (range 0 to 2) and 0.22 (range 0 to 1), (Abacus Concepts, Berkeley, Calif). The level of significance respectively. A serum biochemical and hormonal profile was was P ϭ 0.05. obtained before entry into the study. The renal function was normal and the mean serum testosterone level was 362 mg/mL (normal 280 to 1100) in all subjects, including 3 men receiv- RESULTS ing testosterone replacement therapy for hypogonadism. To further characterize ED, subjects underwent 1 night of noc- Ten subjects 37 to 67 years old (mean 56.2) com- turnal penile tumescence (NPT) monitoring with the RigiScan pleted the study between January and December of (Timm, Eden Prairie, Minn).10 The pre-study NPT study 1998. Nineteen total injections of Melanotan II (mean values) documented 2.7 erectile events per night, 29.5 minutes of base rigidity greater than 60%, and 9.3 minutes of were given and 21 of placebo (1 subject received tip rigidity greater than 80%. Nine of the 10 subjects had tried three placebo injections and one Melanotan II in- other treatments for ED, including intracavernous injection jection due to an erroneous administration of vials (n ϭ 7), sildenafil (n ϭ 5), and intraurethral prostaglandin E1 discovered after completion of the study). No pa- ϭ (n 1). Of these 9 men, 3 used sildenafil and 1 used prosta- tient withdrew because of side effects. glandin E1 on an ongoing basis. The Human Subjects Com- mittee of the University of Arizona approved the study; writ- Of the 10 subjects, 9 reported a subjectively ap- ten informed consent was obtained from all subjects. parent erection on at least one of two injections of Melanotan II. Overall, erectile activity was re- EXPERIMENTAL DESIGN ported with 12 (63%) of 19 Melanotan II injections A double-blind, placebo-controlled, crossover study was and 1 of 21 placebo injections (P ϭ 0.0001). Five performed. Drug synthesis and purification were carried out, subjects responded to each Melanotan II injection, as previously described.11 Melanotan II (0.025 mg/kg) and four responded to only one of two doses, and one vehicle were each administered twice by subcutaneous injec- tion for a total of four injections; the order of administration man reported no subjective erections with Melano- was unknown to both the subject and the investigator. The tan II. The subject-reported duration of erection study drug doses were separated by at least 48 hours. Confir- after Melanotan II administration averaged 64.1 mation of the identity of the study drug, when indicated, was minutes, ranging from 2 minutes to 4 hours of in- performed by measuring the protein content of the fluid in the termittent erectile activity. Two patients reported vial with a Bio-Rad Protein Assay (Bio-Rad, Hercules, Calif). The experimental protocol is shown in Figure 1. Erectile erections outside of the 6-hour observation period. activity was measured with real-time RigiScan monitoring in No subject reported a painful erection or a single the home situation. Subjects were asked to avoid all erotic sustained erection longer than 3 hours. The vial stimuli and to remain awake for the duration of the 6-hour used for the subject who reported erection after session. A questionnaire was used to document the number placebo administration contained no protein, con- and duration of erectile events and any side effects noted dur- ing the observation period. A visual analog scale allowed the firming that no error in blinding or labeling had subject to quantify the rigidity of erection by drawing a line occurred. through the 10-cm scale. Subjects were instructed to rate their RigiScan erectile activity showed statistically sig- level of sexual desire for the 6 hours after the injection of the nificant differences in response to Melanotan II drug, using a modification of question 12 on the IIEF.9 and placebo (Table II).
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