bremelanotide and Erectile-Dysfunction

Several centrally acting agents have shown potential to improve erectile function in men with ED. They still lack adequate data in efficacy and tolerability. Nasal formulations of apomorphine and bremelanotide seem to be the most likely candidates for future approval. They may play a role, specifically in men who fail phosphodiesterase 5 (PDE5) therapy, are unable to take PDE5 inhibitors because of side effects, or are on nitrate therapy. This article reviews the centrally acting agents and the data on their efficacy.

Topics: alpha-MSH; Amino Acids; Apomorphine; Central Nervous System Agents; Dopamine Agonists; Erectile Dysfunction; Humans; Male; Melanocortins; Nitric Oxide; Penile Erection; Peptides, Cyclic; Phosphodiesterase 5 Inhibitors; Selective Serotonin Reuptake Inhibitors

The development of pharmacologic therapy for erectile dysfunction (ED) has been possible because of incremental growth in our understanding of the physiology of normal erections and the complex pathophysiology of ED. Although the oral phosphodiesterase type 5 (PDE5) inhibitors have provided safe, effective treatment of ED for some men, a large proportion of men who have ED do not respond to PDE5 inhibitors or become less responsive or less satisfied as the duration of therapy increases. Also, men who are receiving organic nitrates and nitrates, such as amyl nitrate, cannot take PDE5 inhibitors because of nitrate interactions. The current options for treatment beyond PDE5 inhibitors are invasive, unappealing to some patients, and sometimes ineffective. The search for other options by which ED can be treated has branched out and now encompasses centrally acting mechanisms that control erectile function. Drugs available in Europe include apomorphine. This article focuses on the mechanism of centrally acting agents and reviews clinical data on potential new centrally acting drugs for men who have ED.

Topics: alpha-MSH; Animals; Apomorphine; Autonomic Nervous System; Dopamine; Dopamine Agonists; Erectile Dysfunction; Growth Hormone-Releasing Hormone; Humans; Male; Melanocortins; Muscle, Smooth; Nitric Oxide; Norepinephrine; Opioid Peptides; Penile Erection; Peptides, Cyclic; Phosphodiesterase Inhibitors; Serotonin; Treatment Outcome

Palatin, under license from Competitive Technology, is developing the peptide PT-141, a synthetically modified analog of PT-14, as a nasal spray for the potential treatment of erectile dysfunction (ED) and female sexual dysfunction. In September 2003, Palatin had completed a phase IIb trial in patients with ED and in February 2004, Palatin planned to start phase III trials in early 2005.

Topics: alpha-MSH; Animals; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Erectile Dysfunction; Humans; Male; Peptides, Cyclic; Receptors, Melanocortin; Structure-Activity Relationship

We evaluated the safety and efficacy of intranasal bremelanotide in men with erectile dysfunction who did not respond to sildenafil.. A total of 342 married men (28 to 59 years old) with erectile dysfunction who did not respond to sildenafil were randomly assigned to receive 10 mg bremelanotide as an intranasal spray (group 1, 172) 45 minutes to 2 hours prior to sexual stimulation, or a similar regimen of placebo (group 2, 170). Patients were asked to use at least 16 doses/attempts at home. They underwent preliminary assessment, including medical and sexual history, and self-administered International Index of Erectile Function. The efficacy of 2 treatments was assessed every 4 attempts during treatment and at the end of study, using responses to International Index of Erectile Function, and evaluation of mean intercourse satisfaction domain, mean weekly coitus episodes and adverse drug effects.. Positive clinical results were seen in 51 (33.5%) patients in the bremelanotide group compared with 13 (8.5%) patients in the placebo group (p = 0.03). Patients in the bremelanotide group reported significantly greater intercourse satisfaction than those in placebo group (p = 0.03). More drug related adverse effects occurred in the bremelanotide group (p = 0.01).. Bremelanotide can be an alternative treatment for erectile dysfunction with a potentially broad patient base. Further studies with different dosages and treatment regimens are necessary to draw final conclusions on the efficacy of this drug in erectile dysfunction.

Topics: Administration, Intranasal; Adult; alpha-MSH; Double-Blind Method; Erectile Dysfunction; Humans; Male; Middle Aged; Peptides; Peptides, Cyclic; Phosphodiesterase Inhibitors; Piperazines; Purines; Receptors, Melanocortin; Sildenafil Citrate; Sulfones; Treatment Failure; Treatment Outcome

To evaluate the safety and pharmacodynamic effect of co-administration of subtherapeutic doses of PT-141, a cyclic heptapeptide melanocortin analogue, and sildenafil to patients with erectile dysfunction.. Nineteen patients with erectile dysfunction who were responders to either Viagra or Levitra by self-report were given 25 mg sildenafil and 7.5 mg intranasal PT-141, 25 mg sildenafil and an intranasal placebo spray, and a placebo tablet and an intranasal placebo spray in a randomized cross-over design. Erectile activity in response to two 30-minute episodes of visual sexual stimulation was assessed by RigiScan during a 6-hour postdose period.. The erectile response induced by co-administration of PT-141 and sildenafil was significantly greater than the response elicited by administration of sildenafil alone. Co-administration of PT-141 and sildenafil was safe and well-tolerated and did not result in new adverse events or adverse events that were increased in frequency or severity compared with monotherapy.. Co-administration of intranasal PT-141 and a phosphodiesterase type 5 inhibitor may constitute a treatment alternative for patients in whom higher doses of a single therapy are not effective or well tolerated.

Topics: Administration, Intranasal; Adult; Aged; alpha-MSH; Drug Therapy, Combination; Erectile Dysfunction; Humans; Male; Middle Aged; Peptides, Cyclic; Pilot Projects; Piperazines; Purines; Remission Induction; Sildenafil Citrate; Sulfones

PT-141, a cyclic heptapeptide melanocortin analog, was evaluated following intranasal administration in healthy male subjects and in Viagra-responsive erectile dysfunction (ED) patients. Erectile response was assessed by RigiScan trade mark in healthy subjects without visual sexual stimulation (VSS) and in Viagra-responsive ED patients with VSS. In healthy subjects, mean C(max) and AUC((0-t)) increased in a dose-dependent manner. Median T(max) was 0.50 h and mean t(1/2) ranged from 1.85 to 2.09 h. In both studies, an erectile response induced by PT-141 administration was statistically significant, compared to placebo, at doses greater than 7 mg, with the onset of the first erection occurring in approximately 30 min. PT-141 was safely administered and well tolerated in both studies. A maximum-tolerated dose was not identified. Flushing and nausea were the most common adverse events reported in both studies and no clinically significant changes in vital signs, laboratory tests, ECGs, or physical exams were observed. Based upon its erectogenic potential and tolerability profile, PT-141 is a promising candidate for further evaluation as a treatment for male ED.

Topics: Administration, Intranasal; Adolescent; Adult; alpha-MSH; Double-Blind Method; Erectile Dysfunction; Humans; Male; Middle Aged; Penile Erection; Peptides, Cyclic; Placebos; Receptors, Melanocortin; Severity of Illness Index; Treatment Outcome

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. An inadequate response was defined for this study by patient report indicating that achievement of an erection suitable for vaginal penetration occurred < or =50% of the time while taking 100 mg Viagra. Erectile responses were assessed by RigiScan 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 10 mg 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 6 mg 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.

Topics: Adult; alpha-MSH; Cross-Over Studies; Dose-Response Relationship, Drug; Erectile Dysfunction; Headache; Humans; Injections, Subcutaneous; Male; Middle Aged; Nausea; Penile Erection; Peptides, Cyclic; Piperazines; Purines; Receptors, Melanocortin; Reference Values; Sildenafil Citrate; Sulfones; Time Factors; Vomiting

PT-141, a synthetic peptide analogue of alpha-MSH, is an agonist at melanocortin receptors including the MC3R and MC4R, which are expressed primarily in the central nervous system. Administration of PT-141 to rats and nonhuman primates results in penile erections. Systemic administration of PT-141 to rats activates neurons in the hypothalamus as shown by an increase in c-Fos immunoreactivity. Neurons in the same region of the central nervous system take up pseudorabies virus injected into the corpus cavernosum of the rat penis. Administration of PT-141 to normal men and to patients with erectile dysfunction resulted in a rapid dose-dependent increase in erectile activity. The results suggest that PT-141 holds promise as a new treatment for sexual dysfunction.

Topics: Administration, Intranasal; alpha-MSH; Animals; Cell Line; Cross-Over Studies; Double-Blind Method; Erectile Dysfunction; Genes, fos; Humans; Male; Neurons; Paraventricular Hypothalamic Nucleus; Penile Erection; Peptides, Cyclic; Photic Stimulation; Placebos; Rats; Rats, Sprague-Dawley; Receptor, Melanocortin, Type 3; Receptor, Melanocortin, Type 4; Receptors, Corticotropin