[Nle4-D-Phe7]-alpha-melanocyte-stimulating hormone significantly increased pigmentation and decreased UV damage in fair-skinned Caucasian volunteers.

Epidermal melanin reduces some effects of UV radiation, the major cause of skin cancer. To examine whether induced melanin can provide protection from sunburn injury, 65 subjects completed a trial with the potent synthetic melanotropin, [Nle4-D-Phe7]-alpha-melanocyte-stimulating hormone ([Nle4-D-Phe7]-alpha-MSH) delivered by subcutaneous injection into the abdomen at 0.16 mg/kg for three 10-day cycles over 3 months. Melanin density, measured by reflectance spectroscopy, increased significantly in all [Nle4-D-Phe7]-alpha-MSH-treated subjects. The highest increases were in volunteers with lowest baseline skin melanin levels. In subjects with low minimal erythemal dose (MED) skin type, melanin increased by an average of 41% (from 2.55 to 3.59, P < 0.0001 vs placebo) over eight separate skin sites compared with only 12% (from 4.18 to 4.70, P < 0.0001 vs placebo) in subjects with a high-MED skin type. Epidermal sunburn cells resulting from exposure to 3 MED of UV radiation were reduced by more than 50% after [Nle4-D-Phe7]-alpha-MSH treatment in the volunteers with low baseline MED. Thymine dimer formation was also shown to be reduced by 59% (P = 0.002) in the epidermal basal layer. This study has shown for the first time the potential ability of a synthetic hormone that augments melanin production to provide photoprotection to people who normally burn in direct sunlight.

Effect of MELANOTAN, [Nle(4), D-Phe(7)]-alpha-MSH, on melanin synthesis in humans with MC1R variant alleles.

MELANOTAN (NDP-MSH) binds the MC1 receptor to significantly increase the eumelanin content of human skin cells. In this study of 77 Caucasian individuals, we investigated the effects of MELANOTAN in individuals with variant MC1R genotypes, as it has been suggested through in vitro studies that variant alleles decrease MELANOTAN binding efficacy, which would subsequently affect the synthesis of melanin. Administration of MELANOTAN produced a significant (p<0.001) increase in melanin density in treated, compared to placebo, individuals. Importantly, MELANOTAN increased the melanin density to a greater extent in individuals carrying the variant alleles Val60Leu, Asp84Glu, Val92Met, Arg142His, Arg151Cys, and Arg160Trp than in individuals with no variant alleles. 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.

Effects of a superpotent melanotropic peptide in combination with solar UV radiation on tanning of the skin in human volunteers.

OBJECTIVE: Three phase 1 clinical trials of a superpotent melanotropic peptide, melanotan-1 (MT-1, or [Nle(4)-D-Phe(7)]alpha-melanocyte-stimulating hormone) were performed to demonstrate safety for MT-1 therapy combined with UV-B light or sunlight. DESIGN: Open-label studies at 2 dose levels of MT-1 combined with small doses of UV-B to the neck or buttock or full sunlight to half of the back. SETTING: Dermatology clinics at the Arizona Health Sciences Center, Tucson. INTERVENTIONS: The first study randomized 4 subjects to MT-1 (0.08 mg/kg per day subcutaneously) and 4 subjects to injections of isotonic sodium chloride (9%) solution for 10 days, followed by neck irradiation with 3 times the minimal erythema dose (MED) of UV-B light. In the next study (n = 12), the MT-1 dosage was increased to 0.16 mg/kg per day for 10 days, with UV-B radiation (0.25-0.75 MED) given to a buttock site for 5 days during (n = 7) or after (n = 5) MT-1 administration. A final study randomized 8 subjects to 3 to 5 days of sunlight to half of the back or to sunlight plus 0.16 mg/kg of MT-1 for 5 days per week for 4 weeks. RESULTS: Tanning in the first study was achieved in 3 of 4 subjects receiving MT-1, and these subjects also had 47% fewer sunburn cells at the irradiated neck site. More skin sites darkened with the higher dose of MT-1 in the second study. In the third study, there was significantly enhanced tanning of the back in the MT-1 group, and this was maintained at least 3 weeks longer than the tanning in the sunlight-only controls, who required 50% more sun-exposure time for equivalent tanning. MAIN OUTCOME MEASURE: There were no pathologic findings at any UV-B or sun-exposed sites in any subject. Toxic effects due to MT-1 were minor, consisting of nausea and transient facial flushing. CONCLUSION: Melanotan-1 can be safely combined with UV-B light or sunlight and appears to act synergistically in the tanning response to light.