PT-141 (Bremelanotide)
Bremelanotide or PT-141, a research chemical and peptide, belongs to the classification known as melanocyte stimulating hormones (MSH). It is a hexapeptide analog of alpha-MSH, and was originally developed from the MSH Melanotan II, a peptide agent that was reviewed in trials for sunless tanning but, unexpectedly, resulted in sexual arousal and sexual spontaneous erections in nine of ten test subjects. [1] Bremelanotide was developed as an agent to stimulate sexual arousal with the tanning “side effect;” it activates the melanocortin receptors MC1R and MC4R.[1]
Bremelanotide is effective in its potential to treat sexual desire disorders as well as disorders that affect physical arousal. Bremelanotide induces lordosis in animal subjects, a sign of physical preparation for copulation.[2] In males, it does not stimulate the vascular aspect of the penis, but instead acts to stimulate the central nervous system primarily via dopamine receptor activity to increase sexual desire and also demonstrates functionality in treating purely physical manifestations of ED/SAD, likely through improved signalling.
There are plans by the developer, Palatin Technologies, for a novel subcutaneous delivery system for the drug that makes the side effects more rare. In a double-blind placebo controlled study of 54 volunteers bremelanotide delivered with the novel system did not evoke hypertensive side effects as the nasal delivery system used in previous studies did, leading researchers to conclude "variability of uptake" due to intranasal administration of the research chemical resulted in "increases in blood pressure and gastrointestinal events...primarily related to high plasma levels in [only] a subset of patients."[3]
Palatin Technologies is now in discussion with the FDA to resume Phase II (human) studies utilizing subcutaneous administration exclusively.[3]
The research chemical also holds promise for treatment of acute hemmoraghic shock.[3] The activity at the M1CR and M4CR receptors has been demonstrated to specifically modulate inflammation and to limit ischemia (blood flow restriction). Of course, the blood pressure/hypertension "side effects" are not a concern in this patient population.[4]
The similarity in mechanisms-of-action of currently available (FDA-approved) medical treatments for ED means medical practitioners are often limited in treating patients who do not respond well to that class (PDE5 inhibitor) of drug. As Hellstrom writes:
Currently available agents for erectile dysfunction (ED) share the same mechanism of action and pharmacologic properties. Therefore, they share the same limitations, including a principal focus on erection as an end-organ process. One of the relatively unexplored areas of research has been the potential for centrally acting agents to improve male sexual response. A variety of neurohormones and neurotransmitter systems are involved in the male sexual response, including testosterone, dopamine, serotonin and the melanocortin systems. Investigations to determine the utility of centrally acting agents as monotherapy or adjunctive therapy in men with ED or other forms of sexual dysfunction are underway. Bremelanotide, a melanocortin agonist, has been tested in men with ED and may prove to be one of the first centrally acting agents to have clinical utility in male sexual dysfunction.[5]
Safarinejad and Hosseini explore the efficacy of bremelanotide where sildenafil (commercial name Viagra) fails:
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. RESULTS: 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).[6]
Bremelanotide also offers potential as a low-dose concurrent treatment with low-dose sildenafil:
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. CONCLUSIONS: 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.[7]
In conclusion, bremelanotide is a novel treatment that could potentially change the face of treating sexual disorders, not only because of its effectiveness due to a unique mode of action, but also due to its safety and the fact it works synergistically with other ED/SAD treatments:
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.[8]
Cititations:
[1]US 6,794,489 bremelanotide (PT-141) patent (Appl. No.:040547). (Available online:http://www.google.com/patents?q=6794489).
[2]Pfaus JG, Shadiack A, Van Soest T, Tse M, Molinoff P (July 2004). Selective facilitation of sexual solicitation in the female rat by a melanocortin receptor agonist. Proc. Natl. Acad. Sci. U.S.A. 101 (27): 10201–4.
[3]Press release: "Palatin Technologies Announces New Strategic Objectives and Reports Third Quarter 2008 Financial Results" 5/13/2008.
[4] Palatin Technologies: Bremelanotide Overview.
[5]Hellstrom WJ. Clinical applications of centrally acting agents in male sexual dysfunction. Int J Impot Res. 2008 Jul;20 Suppl 1:S17-23.
[6]Safarinejad MR, Hosseini SY. Salvage of sildenafil failures with bremelanotide: a randomized, double-blind, placebo controlled study. J Urol. 2008 Mar;179(3):1066-71.
[7]Diamond LE, Earle DC, Garcia WD, Spana C. Co-administration of low doses of intranasal PT-141, a melanocortin receptor agonist, and sildenafil to men with erectile dysfunction results in an enhanced erectile response. Urology. 2005 Apr;65(4):755-9.
[8] Shadiack AM, Sharma SD, Earle DC, Spana C, Hallam TJ. Melanocortins in the treatment of male and female sexual dysfunction. Curr Top Med Chem. 2007;7(11):1137-44.
*The latter article is intended for educational / informational purposes only. THIS PRODUCT IS INTENDED AS A RESEARCH CHEMICAL ONLY. This designation allows the use of research chemicals strictly for in vitro testing and laboratory experimentation only. Bodily introduction of any kind into humans or animals is strictly forbidden by law.
Bremelanotide or PT-141, a research chemical and peptide, belongs to the classification known as melanocyte stimulating hormones (MSH). It is a hexapeptide analog of alpha-MSH, and was originally developed from the MSH Melanotan II, a peptide agent that was reviewed in trials for sunless tanning but, unexpectedly, resulted in sexual arousal and sexual spontaneous erections in nine of ten test subjects. [1] Bremelanotide was developed as an agent to stimulate sexual arousal with the tanning “side effect;” it activates the melanocortin receptors MC1R and MC4R.[1]
Bremelanotide is effective in its potential to treat sexual desire disorders as well as disorders that affect physical arousal. Bremelanotide induces lordosis in animal subjects, a sign of physical preparation for copulation.[2] In males, it does not stimulate the vascular aspect of the penis, but instead acts to stimulate the central nervous system primarily via dopamine receptor activity to increase sexual desire and also demonstrates functionality in treating purely physical manifestations of ED/SAD, likely through improved signalling.
There are plans by the developer, Palatin Technologies, for a novel subcutaneous delivery system for the drug that makes the side effects more rare. In a double-blind placebo controlled study of 54 volunteers bremelanotide delivered with the novel system did not evoke hypertensive side effects as the nasal delivery system used in previous studies did, leading researchers to conclude "variability of uptake" due to intranasal administration of the research chemical resulted in "increases in blood pressure and gastrointestinal events...primarily related to high plasma levels in [only] a subset of patients."[3]
Palatin Technologies is now in discussion with the FDA to resume Phase II (human) studies utilizing subcutaneous administration exclusively.[3]
The research chemical also holds promise for treatment of acute hemmoraghic shock.[3] The activity at the M1CR and M4CR receptors has been demonstrated to specifically modulate inflammation and to limit ischemia (blood flow restriction). Of course, the blood pressure/hypertension "side effects" are not a concern in this patient population.[4]
The similarity in mechanisms-of-action of currently available (FDA-approved) medical treatments for ED means medical practitioners are often limited in treating patients who do not respond well to that class (PDE5 inhibitor) of drug. As Hellstrom writes:
Currently available agents for erectile dysfunction (ED) share the same mechanism of action and pharmacologic properties. Therefore, they share the same limitations, including a principal focus on erection as an end-organ process. One of the relatively unexplored areas of research has been the potential for centrally acting agents to improve male sexual response. A variety of neurohormones and neurotransmitter systems are involved in the male sexual response, including testosterone, dopamine, serotonin and the melanocortin systems. Investigations to determine the utility of centrally acting agents as monotherapy or adjunctive therapy in men with ED or other forms of sexual dysfunction are underway. Bremelanotide, a melanocortin agonist, has been tested in men with ED and may prove to be one of the first centrally acting agents to have clinical utility in male sexual dysfunction.[5]
Safarinejad and Hosseini explore the efficacy of bremelanotide where sildenafil (commercial name Viagra) fails:
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. RESULTS: 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).[6]
Bremelanotide also offers potential as a low-dose concurrent treatment with low-dose sildenafil:
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. CONCLUSIONS: 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.[7]
In conclusion, bremelanotide is a novel treatment that could potentially change the face of treating sexual disorders, not only because of its effectiveness due to a unique mode of action, but also due to its safety and the fact it works synergistically with other ED/SAD treatments:
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.[8]
Cititations:
[1]US 6,794,489 bremelanotide (PT-141) patent (Appl. No.:040547). (Available online:http://www.google.com/patents?q=6794489).
[2]Pfaus JG, Shadiack A, Van Soest T, Tse M, Molinoff P (July 2004). Selective facilitation of sexual solicitation in the female rat by a melanocortin receptor agonist. Proc. Natl. Acad. Sci. U.S.A. 101 (27): 10201–4.
[3]Press release: "Palatin Technologies Announces New Strategic Objectives and Reports Third Quarter 2008 Financial Results" 5/13/2008.
[4] Palatin Technologies: Bremelanotide Overview.
[5]Hellstrom WJ. Clinical applications of centrally acting agents in male sexual dysfunction. Int J Impot Res. 2008 Jul;20 Suppl 1:S17-23.
[6]Safarinejad MR, Hosseini SY. Salvage of sildenafil failures with bremelanotide: a randomized, double-blind, placebo controlled study. J Urol. 2008 Mar;179(3):1066-71.
[7]Diamond LE, Earle DC, Garcia WD, Spana C. Co-administration of low doses of intranasal PT-141, a melanocortin receptor agonist, and sildenafil to men with erectile dysfunction results in an enhanced erectile response. Urology. 2005 Apr;65(4):755-9.
[8] Shadiack AM, Sharma SD, Earle DC, Spana C, Hallam TJ. Melanocortins in the treatment of male and female sexual dysfunction. Curr Top Med Chem. 2007;7(11):1137-44.
*The latter article is intended for educational / informational purposes only. THIS PRODUCT IS INTENDED AS A RESEARCH CHEMICAL ONLY. This designation allows the use of research chemicals strictly for in vitro testing and laboratory experimentation only. Bodily introduction of any kind into humans or animals is strictly forbidden by law.
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