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Melanotan

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Note: this article describes both melanotan and melanotan II: although their names are similar, they have different chemical and biological properties and different clinical histories. Also note that the familiar supplement melatonin is an entirely different hormone.

Melanotan 1 and melanotan II (Template:Pron-en melanotanⓘ) are both synthetic analogs of the naturally occurring peptide hormone alpha-melanocyte stimulating hormone (α-MSH) that have been shown to induce skin tanning through melanogenesis and in the case of melanotan I, reduce sun (UV) damage in preliminary studies and clinical trials. Melanotan II has the additional effect of increasing libido in both sexes[1] and has been clinically demonstrated to overcome both organic and psychogenic erectile dysfunction. The first peptide unchanged and a derivative of the second are in development by pharmaceutical companies, but as of 2008 no melanotan I or II based compound has been approved for use by any governmental drug regulatory bodies outside of clinical trials. Unlicensed and untested melanotan products are sold through the Internet [2] however, regulatory bodies have warned consumers they may be unsafe and ineffective.

Historical development

Both peptides were first synthesized at the University of Arizona. Researchers there knew that one of the best defenses against skin cancer was a natural tan which has been slowly developed over weeks. They hypothesized that an effective way to reduce skin cancer rates in people would be to induce the body's natural tanning system to produce a protective tan prior to UV exposure. The body's naturally occurring hormone alpha-melanocyte stimulating hormone (α-MSH) causes melanogenesis, a process by which the skin's tanning cells (melanocytes) produce the skin's tanning pigment (melanin). With that knowledge they tested to see if administering this hormone to the body directly could be an effective method to cause sunless tanning. What they found was that while it appeared to work, natural alpha-MSH had too short a half life in the body to be practical as a therapeutic drug. So they decided to find a more potent and stable alternative, one that would be more practical.

After synthesizing and screening hundreds of molecules, the researchers headed by Dr. Victor Hruby, found a peptide that after trials and testing seemed to be approximately 1,000 times more potent than natural α-MSH. [3] They dubbed this new peptide, "Melanotan". Since their discovery, numerous studies dating back to the mid-1980s have shown no obvious toxic effects of the Melanotan peptides (then known by their amino acid formulas: [Nle4, D-Phe7]-α-MSH and Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-NH2). The scientists hoped to use Melanotan peptides to combat melanoma by stimulating the body's natural tanning mechanism to create a tan without first needing exposure to harmful levels of UV radiation. [4] This in turn, they hypothesized, could reduce the potential for skin damage that can eventually lead to skin cancer.

The scientists licensed their patented peptides, via a technology transfer company, to a number of biotechnology companies who intend to develop them into drugs.[5]

Peptide properties and clinical trial information

Melanotan 1

Melanotan 1 has the amino acid sequence Ac-Ser-Tyr-Ser-Nle-Glu-His-D-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2 or [Nle4, D-Phe7]-α-MSH ( [Nle4, D-Phe7]-alpha-MSH ).

A 1991 clinical Investigational new drug trial conducted at the Department of Internal Medicine, University of Arizona Health Sciences Center with Melanotan (then known by its chemical constituents [Nle4, D-Phe7] (NDP)-alpha-melanocyte-stimulating hormone) with 28, "healthy white men" who used a, "high-potency sunscreen during the trial" and concluded, "Human skin darkens as a response to a synthetic melanotropin given by subcutaneous injection. Skin tanning appears possible without potentially harmful exposure to ultraviolet radiation." [6]

The Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona performed a comparative pharmacokinetic trial in three male volunteers to begin to establish efficacy of peptide administration via intravenous, oral and subcutaneous routes. Their study published in 1997 found that, "subcutaneous administration is an efficacious method of delivering melanotan". [7]

A Section of Dermatology, Department of Medicine, College of Medicine, University of Arizona clinical dose ranging study published in 1999 on tanning effects in, "eight male volunteers with 'tannable' skin types III-IV" given melanotan determined that an optimal dose for ten daily subcutaneous injections is 0.16 mg/kg per day. [8]

A clinical trial by the Department of Pharmacology and Arizona Cancer Center to determine increases of eumelanin expression in seven, "normal volunteers" administered Melanotan published in 2000 concluded that, "the tanning induced by Melanotan in the face and forearm is associated with a significant increase in the eumelanin content of the human skin." [9]

A Phase IIb clinical human trial study conducted in 2003 at the University of Sydney demonstrated in a group of seventy-nine volunteers that those who were administered Melanotan daily for a period of three months had highly significant increases in skin-melanin while those who were not, did not. It found fairer-skin people (Fitzpatrick Types I/II, those who never tan and only burn and those who can tan in a limited fashion) recorded increases in melanin of up to 100% in some areas and that sunburn injury was reduced by more than 50% in fair skinned volunteers. [10][11]

Three phase I clinical trials by the Department of Medicine, Cancer Center Division, University of Arizona, Tucson published in 2004 sought to establish the safety of melanotan therapy combined with UV-B light or sunlight. The first trial was conducted with 8 volunteers the second trial with 12 and the final with 8. The researchers determined, "Melanotan-1 can be safely combined with UV-B light or sunlight and appears to act synergistically in the tanning response to light." [12]

To examine Melanotan's effect on melanin synthesis in humans with MC1R variant alleles researchers at the Genetic Epidemiology Unit, Menzies Research Institute, Hobart, Tasmania, Australia conducted human trials on, "77 Caucasian individuals" with variant MC1R genotypes and in a published report from 2006 stated that, "This study demonstrates that MELANOTAN effectively increases the melanin content of skin in those individuals with MC1R variant alleles and therefore, those most in need of photoprotection." [13]

Melanotan is currently being tested, developed, and clinically trialed under the International Nonproprietary Name afamelanotide (formerly the proprietary CUV1647)[14] by the Australian company Clinuvel Pharmaceuticals, for a series of skin related diseases including polymorphous light eruption (PMLE) and actinic keratosis (AK).

Melanotan II

Melanotan II has tanning and aphrodisiac properties. [1][15][16]

It is a cyclic lactam analog of alpha-MSH with the amino acid sequence Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-NH2.

A pilot Phase I clinical trial conducted on three males by the College of Medicine, Pharmacology Department, University of Arizona in Tucson, Arizona published in 1996 demonstrated that, "Melanotan II has tanning activity in humans given only 5 low doses every other day by subcutaneous injection." The side effects reported were mild nausea and a "stretching and yawning complex" that correlated with spontaneous penile erections. [17]

The Department of Pharmacology, University of Arizona College of Medicine published a study in 1998 that involved ten men who suffered from psychogenic erectile dysfunction. Their trial concluded that, "Melanotan-II is a potent initiator of erections in men with psychogenic erectile dysfunction and has manageable side effects at a dose of 0.025 mg./kg." [18]

A clinical study published in 2000 of 20 men with psychogenic and organic erectile dysfunction conducted at the Section of Urology of The University of Arizona College of Medicine concluded, "that Melanotan II is a potent initiator of penile erection in men with erectile dysfunction." [19]

Bremelanotide

Main article: Bremelanotide

Palatin Technologies developed another hormone originally targeted towards sexual dysfunction based upon melanotan II called bremelanotide (formerly PT-141). Bremelanotide is a metabolite of melanotan II that lacks the C-terminal amide function. In 2008, development for sexual dysfunction was discontinued after concerns were raised by the U.S. Food and Drug Administration (FDA) about the adverse side effect of increased blood pressure found in Phase II clinical trials. Concurrently the company announced plans to develop it as a treatment for hemorrhagic shock instead. [20]

Drug agency warnings

In 2007, the FDA issued a warning to an American vendor illegally marketing melanotan II on the internet as a drug that prevents skin cancer and assists tanning. The FDA has not licensed melanotan II, and explained: "There is no evidence that the product is generally recognized as safe and effective [GRAS/E] for its labeled uses." [21]

On August 8, 2008 the Danish Medicines Agency (DMA) issued a warning[22] against the usage of Melanotan purchased on the internet, noting that claims that imply that it has an, "effect" for protection against skin cancer, "has not been documented". The DMA further warned that Melanotan has not undergone tests for its effect and possible side effects, and that it is not licensed for usage in the EU or the USA.

References

  1. ^ a b Mac E. Hadley (2005). "Discovery that a melanocortin regulates sexual functions in male and female humans" (HTML). Volume 26, Issue 10, October 2005, Pages 1687-1689. Peptides. Retrieved 2008-10-21.
  2. ^ Nicole O'Neil (2008). "The Dark Side of Beauty Pills" (HTML). life & style / Fashion & Beauty / Be Beautiful. UK MSN. Retrieved 2008-08-21.
  3. ^ "UA-developed synthetic hormones speed a tan" (HTML). Arizona Daily Star. 2006. Retrieved 2007-09-22.
  4. ^ "The Barbie Drug" (HTML,WMV). Campbell Live, TV3. 2007. Retrieved 2007-09-16.
  5. ^ "Competitive Technologies Licenses Additional Patent to Melanotan Corporation, Receives Additional Shares of Epitan" (HTML). Business Wire. 2005. Retrieved 2008-08-22.
  6. ^ "Induction of skin tanning by subcutaneous administration of a potent synthetic melanotropin" (HTML). Vol. 266 No. 19, November 20, 1991. Journal of the American Medical Association. 1991. Retrieved 2008-10-13.
  7. ^ "Skin pigmentation and pharmacokinetics of melanotan-I in humans" (HTML). 1997 Apr;18(3):259-69. Biopharmaceutics & Drug Disposition. 1997. Retrieved 2008-10-13.
  8. ^ "Effects of a potent synthetic melanotropin, Nle4-D-Phe7-α-MSH (Melanotan-I) on tanning: a dose-ranging study" (HTML). Volume 10, Issue 2 June 1999 , pages 127 - 132. Journal of Dermatological Treatment. 1999. Retrieved 2008-10-14.
  9. ^ "Increased eumelanin expression and tanning is induced by a superpotent melanotropin [Nle4-D-Phe7]-alpha-MSH in humans" (HTML). Volume 72 Issue 4, Pages 526 - 532. Photochemistry and Photobiology. 2000. Retrieved 2008-10-13.
  10. ^ "Suntan could come 'in an implant'" (HTML). BBC News. 2003. Retrieved 2008-10-12.
  11. ^ "Sunburn Trial Results Show Drug Can Reduce Sun Damage by 50% for Fair-Skinned People, says Trial Head" (HTML). innovations report. 2003. Retrieved 2008-08-22.
  12. ^ "Effects of a superpotent melanotropic peptide in combination with solar UV radiation on tanning of the skin in human volunteers" (HTML). 2004;140:827-835. Archives of Dermatology. 2004. Retrieved 2008-10-13.
  13. ^ "Effect of MELANOTAN, [Nle(4), D-Phe(7)]-alpha-MSH, on melanin synthesis in humans with MC1R variant alleles" (HTML). Volume 27, Issue 2, February 2006, Pages 388-394. Peptides. 2006. Retrieved 2008-10-23.
  14. ^ "World Health Organisation assigns CUV1647 generic name" (PDF). Clinuvel. 2008. Retrieved 2008-06-17.
  15. ^ "CNN.com "Tanning drug may find new life as Viagra alternative"" (HTML). CNN. 1999. Retrieved 2008-06-12.
  16. ^ "Tanning Bonus" (HTML). Time. 1999. Retrieved 2008-09-17.
  17. ^ "Evaluation of melanotan-II, a superpotent cyclic melanotropic peptide in a pilot phase-I clinical study" (HTML). Life Sciences, Volume 58, Issue 20, 12 April 1996, Pages 1777-1784. Elsevier Science Inc. 1996.
  18. ^ "Synthetic melanotropic peptide initiates erections in men with psychogenic erectile dysfunction: double-blind, placebo controlled crossover study" (HTML). Volume 160 , Issue 2 , Pages 389 - 393. The Journal of Urology. 1998. Retrieved 2008-10-20.
  19. ^ "Melanocortin receptor agonists, penile erection, and sexual motivation: human studies with Melanotan II" (HTML). 12, Suppl 4, S74-S79. International Journal of Impotence Research. 2000.
  20. ^ "Palatin Technologies announces new strategic objectives and reports third quarter 2008 financial results" (HTML). Palatin Technologies. 2008. Retrieved 2008-08-21.
  21. ^ "FDA Warns About Unapproved Product, Melanotan II" (HTML). U.S. Food and Drug Administration. 2007. Retrieved 2008-08-21.
  22. ^ "Warning against the product Melanotan" (HTML). Danish Medicines Agency. 2008. Retrieved 2008-08-11.
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