All the Facts About Bremelanotide

Hypoactive Sexual Desire Disorder, or simply HSDD, is not an uncommon condition found in humans mostly due to excessive stress, or even due to interpersonal issues. HSDD is mainly categorized into two types: (1) Acquired, meaning that this condition prevails after a certain period of time of normal functions; and (2) Generalized, meaning that it prevails all (or most) of the times regardless of the environment or partners (1).

Several approaches to treat HSDD are currently available, which includes therapy such as behavioral therapy and couples’ therapy, and many medications are being prescribed to treat this condition.

With the advancement of science technology and the booming development of peptides, a known peptide that has proven to show improved results in treating HSDD is Bremelanotide, or commonly named PT-141 peptide (1).

Introduction

Bremelanotide, which is also commonly known by its investigational code PT-141, is a synthetic peptide composed of 7 amino acids (2).

This peptide is analogous to alpha-MSH hormone found in humans (3). Initially studied for treatment in both men and women, this peptide is now primarily prescribed to women, mostly in premenopausal age (2).

History

PT-141 synthetic peptide is agonistic to melanocortin receptors, which is similar to the natural hormone called alpha-MSH (3).

Initial studies had shown that melanocortin hormone regulates various physiological functions in the human body. When animals were administered with this isolated hormone, it elevated the sexual functions in them, which is indicative of the fact that Melanotan II leads to erectile activity in men while PT-141 leads to sexual arousal in women (4).

Two analogs of this hormone were patented by two different companies for further studies – one, Melanotan I, which is a linear peptide (patented by Competitive Technologies) and second, Melanotan II, which is a cyclic peptide (patented by Palatin Technologies) (5). Further studies led Palatin to be the first developer of the synthetic peptide (6) PT-141, identical to alpha-MSH and likely a metabolite of Melanotan II.

How does PT-141 work?

Studies (3) have shown that PT-141 shows agonistic properties towards melanocortin receptors, namely MC3R and MC4R, which primarily results in elevated reactions in the central nervous system in the human body.

In these studies (3), it was observed that after binding with the MC3R and MC4R receptors, the peptide leads to the activation of the neurons found in the hypothalamus leading to increased immunoreactivity. Neurons in the surrounding region of the central nervous system also get stimulated as they intake the chemicals which then leads to sexual arousal in the study animals. This study suggested the mechanism by which the peptide works in rats, which is expected to be similar in humans. Analogous reactions were observed in human volunteers, as described later in this article.

Benefits of PT-141

The key benefit of PT-141 peptide is that it is used to treat hypoactive sexual desire disorder in premenopausal women.

It should be noted that this medication should only be used by women who are naturally experiencing low sexual desire – and not by women in whom the condition is induced by preexisting medical conditions, mental problems, or problems in relationships (7).

Also, this medication is not recommended for postmenopausal women and also not for men. This medication does not improve their sexual performance at all (7).

Research and Clinical Studies

In vitro studies on female rats

This early 2000 study (8) was conducted to understand the effects of PT-141 peptide on the female rats. Female rat model was used as the subject in this study to determine how the peptide impacts their sexual behavior.

After administration, it was determined that the female rats showed elevated sexual desire without effecting the sexual pace, lumbar lordosis, or any other behaviors. After analysis, it was determined that the peptide did not cause a generalized motor activation, instead it has a highly selective pharmacological effect that stimulates the central nervous system, mainly the melanocortin receptor activities, which results in elevated sexual arousal.

This study demonstrated that PT-141 was a promising candidate to treat low sexual desire, mainly in females.

Preclinical studies in female rats – determination of CNS effects

In this study (9), the main focus was to understand the functioning of the peptide in the central nervous system (CNS) and potentially the brain regions. The study was carried out in prime age female rats with rich levels of the female sexual hormones. Researchers mainly focused on both the sexual behaviors of the rats i.e., appetitive behaviors such as increased pace and agitation and consummatory behaviors such as lordosis.

In this study, the rats were administered with the peptide via two routes of administration including subcutaneous route and direct infusion into the medial preoptic area mPOA.

The outcome of this study was that both routes of administration induced increased levels of appetitive behavior of solicitation, but there was no impact on the sexual pace or lordosis. The primary reason for this display of behavior was induced mPOA, which led to the activation of the hypothalamic and other regions of the brain causing increased sexual behavior.

This study indicated that PT-141 not only has pharmacological, but also behavioral and neuroanatomical effects in the body, which are key promising factors of the peptide for its potential use in treating HSDD in females.

Meta-analysis – Study in Female Volunteers

This study(10) was carried out to quantify the effects of various pharmacological medications on the females suffering from HSDD, arousal disorder and female sexual dysfunction.

24 randomized clinical studies were conducted where 1723 women with the mentioned clinical conditions were treated with placebo and 2236 women were treated with the ‘treatment drug’, including Bremelanotide.

After this meta-analysis, it was determined that the women treated with placebo reported a 3.62% increase in sexual function index, whereas women treated with the medication reported a 5.35% increment. This medication, thus, proved its potential benefits in treating the female sexual dysfunction disorder.

Phase I Clinical Trials to establish Bremelanotide efficacy in presence of alcohol

The main goal of this study(11) was to determine the safety, efficacy, and pharmacokinetic effects of Bremelanotide peptide in healthy males and females, when co-administered with alcohol, more specifically, with ethanol (also called ethyl alcohol).

This was a randomized double blind 3 cross over study where a total of 24 participants were enrolled, 12 males and 12 females. Volunteers were divided into groups that were administered with either Bremelanotide or placebo, with or without ethanol. The peptide was administered intranasally in single doses of 20mg, for 7 consecutive days.

After the study, physical and clinical examination was carried out, including analysis of blood and urine samples.

Upon analysis, it was determined that there was no drug interaction between the peptide and ethanol, indicating an overall safe and tolerated profile, even when administered with up to a maximum amount of 80 mg/dL ethanol in females. There was no peptide induced hypotension or orthostatic reactions, and no adverse reactions were reported at the time of the study.

This phase I trial proved that Bremelanotide is a well-tolerated medication that can potentially be used to treat female sexual dysfunction disorder with negligible negative impact.

Phase II Clinical Trials on female volunteers with HSDD and FSAD

This study (12) was conducted based on the ‘responder analyses’ phenomenon, the process that helps to determine whether results or changes seen during a clinical trial are clinically meaningful upon application.

This was a controlled dose finding study where the patient reported outcomes were monitored throughout the study. The volunteers for this study were premenopausal women suffering from either HSDD – hypoactive sexual desire disorder or mixed HSDD/FSAD – female sexual arousal disorder.

The result of this study was satisfactory amongst all women in terms of patient reported outcomes – indicating safety and well tolerability amongst all the volunteers. Based on the responses, it was determined that the overall patient outcomes were significant at 1.75mg dose when compared to other doses and the placebo.

Succeeding phase III clinical trials were conducted based on the above dose determination for drug approval and registration purposes.

Phase III Clinical Trials establishing Bremelanotide drug dosing in Females with HSDD

This study (13)(14) was carried out in premenopausal women suffering from HSDD. Two randomized, double blind studies (RECONNECT studies) (13)(14) were carried out in 1202 women who were administered with a 1.75mg dose of Bremelanotide via subcutaneous route. This study lasted for a total of 24 weeks.

1202 women participated in this study, who were initially treated with the placebo and monitored. Out of all the volunteers, 80% women progressed with the next phase, which was the administration of the peptide, which would be 45 minutes prior to the anticipated sexual event. All 856 women completed the course of this study with no reported major adverse effects.

After the study, it was examined that the women treated with Bremelanotide showed significantly higher sexual desire than those treated with placebo. The female sexual function index was 1.2 times or more amongst the peptide treated women compared to the rest. While the numbers of sexual events did not increase with the administration of the peptide, the number of satisfactory events did increase.

With such promising results and no reported events of the adverse reactions, this study demonstrated that the peptide was highly tolerated in females with highly potential use in the medical field to treat HSDD in females.

PT-141 Side Effects

As with all medications, there are some side effects associated with this peptide. Though no major side effects have been reported, below listed are common, manageable contraindications of this peptide (7):

• Nausea (common)
• Vomiting (less common)
• Headaches
• Dizziness
• Blurred vision
• Anxiety, nervousness
• Irregular heartbeats
• Ear pounding

Bremelanotide Drug Profile

Pharmacokinetics

The bioavailability of the Bremelanotide peptide is 100% (11), (15) with 21% protein binding rate. The average half-life of this peptide is 2.7 hours, ranging anywhere between 1.9 to 4 hours.

The peptide is metabolized in the body via several hydrolyses phenomenon on the amide bond of this peptide. Once metabolized, almost 65% of the peptide is eliminated via urine whereas 23% is excreted via feces (15).

Bremelanotide Contraindications

This peptide is not recommended to be used by patients suffering from high blood pressure or any known cardiovascular disease (15).

This peptide should not be co-administered with Naltrexone (15) as the peptide may decrease the absorptivity of the orally administered drugs. Naltrexone is mainly used to treat alcohol and opioid addiction, and failure of Naltrexone treatment leads to severe consequences. Hence, it is recommended to avoid intake of the two medications at the same time.

Recommended Dosage

While the effective dose and dosage form of this peptide may vary amongst different individuals, studies (12), (13) have shown that a dose of 1.75 mg solution injected via subcutaneous route is the optimal dose to treat HSDD. This medication was administered 45 minutes prior to the intended sexual activity (13) and only one dose per day (not more than 8 doses per month) is recommended (7).

Summary

Bremelanotide, aka PT-141, is a synthetic cyclic peptide composed of 7 amino acids, which is highly analogous to the alpha MSH hormones found in humans.

Similar to the alpha MSH and melanocortin, this peptide binds with the melanocortin receptors, namely MC3R and MC4R, found in the central nervous system of the body. Upon binding, it stimulates the hypothalamus and other regions in the brain which leads to elevated sexual desire.

While initially thought to be used to treat sexual disorders in both men and women, studies have provided significantly positive results in premenopausal women. As an FDA approved medication (14), this medication is universally used in women naturally suffering from sexual disorders such as hypoactive sexual desire and female sexual arousal disorder. Multiple studies have demonstrated a highly safe and tolerated profile of this medication. Currently, studies are ongoing till date to explore further benefits and full utilization of this peptide in the medicinal world.