bremelanotide and Sexual-Dysfunction--Physiological

Melanocortinergic agents are currently being investigated for a possible therapeutic role in male and female sexual dysfunction. These investigations were sparked by findings that systemic administration of a synthetic analog of alpha-MSH, MT-II, causes penile erections in a variety of species, including humans. Several other melanocortinergic agents including HP-228, THIQ, and bremelanotide (PT-141) have since been shown to have erectogenic properties thought to be due to binding to melanocortin receptors in the central nervous system, particularly the hypothalamus. Bremelanotide, a nasally administered synthetic peptide, is the only melanocortinergic agent that has been clinically studied in both males and females. Data from Phase II clinical trials of bremelanotide support the use of melanocortin-based therapy for erectile dysfunction. Studies using animal models have demonstrated that pre-copulatory behaviors in female rats analogous to sexual arousal are evoked, and preliminary clinical data also suggest a role in promoting sexual desire and arousal in women. Based on bremelanotide clinical experience, administration of a melanocortin agonist is well tolerated and not associated the hypotension observed with phosphodiesterase-5 inhibitors currently used to treat erectile dysfunction. This review discusses investigations of melanocortin agonists for the treatment of sexual dysfunction with emphasis on proposed sites and mechanisms of action in the central nervous system that appear to be involved in melanocortinergic modulation of sexual function. Current research validates use of melanocortinergic agents for the treatment of both male and female sexual dysfunction.

Topics: alpha-MSH; Animals; Disease Models, Animal; Humans; Melanocortins; Peptides, Cyclic; Receptors, Melanocortin; Sexual Dysfunction, Physiological

Human sexual response involves a complex sequencing of interrelated mind/body processes. Few treatment options exist that address the complex multilayered etiological determinants of female sexual dysfunction (FSD).. Review and evaluate the clinical application of centrally acting agents for the treatment of FSD, with particular emphasis on recently released data on bremelanotide.. Review of literature on the treatment of FSD.. Approaches to FSD treatment have ranged from psychological counseling through a variety of medical interventions along the physiological pathways of sexual function and dysfunction. Despite a great deal of research, especially into hormonal and vasoactive substances, few therapeutics have broad consistent applicability and have withstood scientific scrutiny. Recent clinical trials have investigated the potential role of agents which act on the central nervous system for the treatment of FSD.. While the recent data supporting the therapeutic use of centrally acting agents as a monotherapy for FSD are cautiously encouraging, there would seem to be tremendous promise for these centrally acting compounds to be integrated with treatment approaches that utilize other pathways in a multilayered, individualized approach to care.

Topics: alpha-MSH; Central Nervous System Agents; Evidence-Based Medicine; Female; Humans; Peptides, Cyclic; Randomized Controlled Trials as Topic; Research Design; Sexual Dysfunction, Physiological; Sexual Dysfunctions, Psychological; Treatment Outcome; Women's Health

Responder analyses are used to determine whether changes that occur during a clinical trial are clinically meaningful; for subjective endpoints such as those based on patient-reported outcomes (PROs), responder analyses are particularly useful.. To identify the minimal clinically important difference (MCID) for selected scores on questionnaires assessing female sexual functioning and to use these differences to analyze the response in a large, controlled, phase 2b, dose-finding study of bremelanotide in premenopausal women with hypoactive sexual desire disorder (HSDD) and mixed HSDD/female sexual arousal disorder (FSAD).. The responder analyses were performed for the change from baseline to end of study for a total of 7 endpoints. Each PRO endpoint was assessed using at least 1 of 4 types of responder analyses: a planned analysis anchored to MCIDs based on expert estimates (historical anchors); post hoc analyses based on self-reported global benefit; receiver operating characteristic (ROC) curves; and cumulative distribution function. The prespecified analysis groups were all female sexual dysfunction (FSD)-based diagnoses (all study participants), those with HSDD alone, and a combined group of those with FSAD alone plus those with mixed HSDD/FSAD. Post hoc analyses were also performed for subjects with mixed HSDD/FSAD with a primary diagnosis of HSDD.. MCIDs based on the ROC curves for changes in Female Sexual Function Index-desire domain, Female Sexual Distress Scale-Desire/Arousal/Orgasm (FSDS-DAO) total score, FSDS-DAO item 13 and 14 scores, and number of satisfying sexual events.. Outcomes matched those based on input from clinical experts. For all 7 endpoints, responder rates at the 1.75 mg dose in the overall modified intention-to-treat population achieved statistical significance compared with placebo (P ≤ .03).. These responder definitions were subsequently used in the bremelanotide phase 3 registration studies (RECONNECT) that evaluated the safety and efficacy of the bremelanotide 1.75 mg subcutaneous dose in premenopausal women with HSDD.. MCIDs for this study were based on changes from a single-blind phase to account for changes due to the placebo effect. These analyses were restricted to a study population composed only of premenopausal women with a clinical diagnosis of HSDD and/or FSAD and were based on data from the same clinical trial.. Bremelanotide was safe and well tolerated and demonstrated significant improvement in efficacy vs placebo in the phase 2b trial. The multiple responder analyses offer a valuable approach for determining clinically important effects of bremelanotide for HSDD and FSAD. Althof S, Derogatis LR, Greenberg S, et al. Responder Analyses from a Phase 2b Dose-Ranging Study of Bremelanotide. J Sex Med 2019;16:1226-1235.

Topics: Adult; alpha-MSH; Double-Blind Method; Female; Humans; Libido; Peptides, Cyclic; Premenopause; Sexual Dysfunction, Physiological; Sexual Dysfunctions, Psychological; Single-Blind Method; Surveys and Questionnaires

Evaluate efficacy/safety of bremelanotide (BMT), a melanocortin-receptor-4 agonist, to treat female sexual dysfunctions in premenopausal women.. Patients randomized to receive placebo or BMT 0.75, 1.25 or 1.75 mg self-administered subcutaneously, as desired, over 12 weeks. Primary end point was change in satisfying sexual events/month. Secondary end points included total score changes on female sexual function index and female sexual distress scale-desire/arousal/orgasm.. Efficacy data, n = 327. For 1.25/1.75-mg pooled versus placebo, mean changes from baseline to study end were +0.7 versus +0.2 satisfying sexual events/month (p = 0.0180), +3.6 versus +1.9 female sexual function index total score (p = 0.0017), -11.1 versus -6.8 female sexual distress scale-desire/arousal/orgasm total score (p = 0.0014). Adverse events: nausea, flushing, headache.. In premenopausal women with female sexual dysfunctions, self-administered, as desired, subcutaneous BMT was safe, effective, and well tolerated (NCT01382719).

Topics: alpha-MSH; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Libido; Middle Aged; Peptides, Cyclic; Sexual Dysfunction, Physiological; Sexual Dysfunctions, Psychological; Treatment Outcome; Women's Health

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal).\ This article has been retracted at the request of the Editor-in-Chief. Following the retraction of Dr. Safarinejad's work by other journals, The Journal of Sexual Medicine has undertaken an extensive re-review of all papers Dr. Safarinejad published with the journal. Following an intensive re-evaluation and close scrutiny of the manuscripts, our expert reviewers raised multiple concerning questions about the methodology, results, and statistical interpretation as presented in this article. Dr. Safarinejad was contacted to provide his original data and offer explanations to address the concerns expressed by the reviewers. Dr Safarinejad chose not to respond. Consequently, we can no longer verify the results or methods as presented and therefore retract the article.

Topics: Administration, Intranasal; Adult; alpha-MSH; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Libido; Peptides, Cyclic; Receptor, Melanocortin, Type 3; Receptor, Melanocortin, Type 4; Sexual Dysfunction, Physiological; Sexual Dysfunctions, Psychological; Statistics, Nonparametric; Surveys and Questionnaires; Treatment Outcome; Women's Health

Melanocortins affect multiple physiological responses, including sexual behaviors. Bremelanotide is a synthetic peptide melanocortin analog of alpha-melanocyte-stimulating hormone that is an agonist at melanocortin receptors MC3R and MC4R.. To evaluate a single intranasal dose of bremelanotide for potential effects on physiological and subjective measurements of sexual arousal and desire in premenopausal women with sexual arousal disorder.. Change in vaginal pulse amplitude during neutral and erotic videos after treatment with bremelanotide or placebo and subjects' perceptions of physiological and sexual response within 24 hours of treatment with bremelanotide or placebo.. Eighteen premenopausal women with a primary diagnosis of female sexual arousal disorder were randomly assigned to receive a single intranasal dose of 20 mg bremelanotide or matching placebo in a double-blind manner during the first in-clinic treatment session, and the alternate medication during the second in-clinic treatment session. During each session, subjects viewed a 20-minute neutral video followed by a 20-minute sexually explicit video. Vaginal photoplethysmography was used to monitor vaginal vasocongestion and questionnaires were used to evaluate perceptions of sexual response within the following 24-hour period.. More women reported moderate or high sexual desire following bremelanotide treatment vs. placebo (P = 0.0114), and a trend toward more positive responses regarding feelings of genital arousal occurred after bremelanotide compared with placebo (P = 0.0833). Among women who attempted sexual intercourse within 24 hours after treatment, significantly more were satisfied with their level of sexual arousal following bremelanotide, compared with placebo (P = 0.0256). Vaginal vasocongestion did not change significantly while viewing erotic videos following bremelanotide administration compared with placebo.. This preliminary evaluation suggests the potential for bremelanotide to positively affect desire and arousal in women with female sexual arousal disorder and indicates that bremelanotide is a promising candidate for further evaluation in an at-home study.

Topics: Adult; alpha-MSH; Arousal; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Libido; Patient Satisfaction; Peptides, Cyclic; Premenopause; Receptor, Melanocortin, Type 3; Receptor, Melanocortin, Type 4; Sexual Dysfunction, Physiological; Sexual Dysfunctions, Psychological; Statistics, Nonparametric; Surveys and Questionnaires; Treatment Outcome; Women's Health

Topics: alpha-MSH; Animals; Aphrodisiacs; Female; Humans; Male; Peptides, Cyclic; Sexual Dysfunction, Physiological

Bremelanotide is an analogue of the naturally occurring peptide alpha-melanocyte-stimulating hormone (alpha-MSH). It stimulates erection in men and male rats, and is currently in clinical trials for the treatment of erectile dysfunction.. To review the effects of bremelanotide, an analogue of the naturally occurring peptide alpha-MSH, on the preclinical indices of sexual desire in female rats, and where in the brain these actions may occur.. Appetitive sexual behaviors, such as solicitations, hops and darts, and pacing, were assessed along with consummatory behaviors such as lordosis. The involvement of brain regions was assessed following direct administration to the region, by the stimulation of molecular markers of neural activation, and using microdialysis to examine extracellular fluid for different neurotransmitters.. Using a model that allows ovariectomized, hormone-primed female rats to control the timing of sexual encounters with males, we tested the ability of bremelanotide to increase appetitive (proceptive) and/or consummatory sexual behaviors.. Bremelanotide dramatically and selectively increased measures of solicitation in female rats, without altering pacing or lordosis, following both peripheral (subcutaneous) administration or infusions directly into the lateral ventricles or medial preoptic area (mPOA), but not the ventromedial hypothalamus. The mPOA is critical for the display of appetitive sexual behaviors in females and males of a variety of species. Peripheral administration of bremelanotide activates the mPOA and other hypothalamic and limbic regions of the brain involved in sexual behavior, and may work by activating dopamine terminals in the mPOA.. To the extent that solicitations indicate the desire of female rats to engage in sexual activity, bremelanotide appears to possess the behavioral, pharmacological, and neuroanatomical specificity required of a drug in the treatment of hypoactive sexual desire disorders.

Topics: alpha-MSH; Animals; Copulation; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Male; Orgasm; Peptides, Cyclic; Rats; Rats, Long-Evans; Sexual Dysfunction, Physiological