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==="Melanotan" products sold for human use===
==="Melanotan" products sold for human use===
A number of products are sold online and in gyms and beauty salons as "melanotan" or "melanotan-1" which purport to have the same chemical make up as afamelanotide, of which the visual effect resulting from usage has been noted in an article by [[Wired News|Wired.com]] as being "eerily similar to results obtained in trials at the University of Arizona or by Clinuvel". The Wired.com article explained that these products were Melanotan II, "a similar (but not identical) compound"<ref name=Wired-01-09 /> and Clinuvel has stated that products sold as "melanotan" are "illegal" and "wholly unrelated to Clinuvel's proprietary afamelanotide".<ref name="PosStat"/> Chemicals sold as "melanotan" are not illegal to import, use or own, however their sales and supply for human use outside of government sanctioned clinical trials is illegal within the boundaries of most jurisdictions, including the UK<ref name="Inside-Out" />, USA, Europe and Australia <ref name="HeraldSun">{{Cite web|url=http://www.heraldsun.com.au/news/tanning-drug-a-health-risk/story-e6frf7jo-1225792923321|title=Tanning drug a health risk|accessdate=2009-10-31|publisher=[[Herald Sun]]|date=2009-10-31}}</ref>
A number of products are sold online and in gyms and beauty salons as "melanotan" or "melanotan-1" which purport to have the same chemical make up as afamelanotide, of which the visual effect resulting from usage has been noted in an article by [[Wired News|Wired.com]] as being "eerily similar to results obtained in trials at the University of Arizona or by Clinuvel". The Wired.com article explained that these products were Melanotan II, "a similar (but not identical) compound"<ref name=Wired-01-09 /> and Clinuvel has stated that products sold as "melanotan" are "illegal" and "wholly unrelated to Clinuvel's proprietary afamelanotide".<ref name="PosStat"/> Chemicals sold as "melanotan" are not illegal to import, use or own, however their sales and supply for human use outside of government sanctioned clinical trials is illegal within the boundaries of most jurisdictions, including the UK<ref name="Inside-Out" />, USA, Europe and Australia. <ref name="HeraldSun">{{Cite web|url=http://www.heraldsun.com.au/news/tanning-drug-a-health-risk/story-e6frf7jo-1225792923321|title=Tanning drug a health risk|accessdate=2009-10-31|publisher=[[Herald Sun]]|date=2009-10-31}}</ref>


A 2009 article on unlicensed "melanotan" products, sold on the internet, has reported that the products caused moles to darken and increase in size over a short period, "an early warning sign of skin cancer".<ref>{{Cite web|url=http://news.bbc.co.uk/2/hi/health/7852833.stm|title=Worry over tan jab mole changes |accessdate=2009-03-04|publisher=[[BBC]]|date=2009-01-28}}</ref><ref>{{Cite web|url=http://www.telegraph.co.uk/health/healthnews/4360594/Illegal-tanning-drug-can-change-appearance-of-moles-scientists-warn.html|title=Illegal tanning drug can change appearance of moles, scientists warn|accessdate=2009-03-04|publisher=[[The Daily Telegraph]]|date=2009-01-27}}</ref> [[Academia|Academic researchers]] at [[Liverpool John Moores University]] specialized in [[performance-enhancing drugs]] published an [[editorial]] in the [[BMJ|British Medical Journal]] suggesting that use of 'melanotan I and II', "could damage the immune and cardiovascular systems as well as triggering other problems".<ref>{{Cite web|url=http://news.bbc.co.uk/2/hi/health/7895366.stm|title=Risky tan jab warnings 'ignored' |accessdate=2009-03-04|publisher=[[BBC]]|date=2009-02-18}}</ref>
A 2009 article on unlicensed "melanotan" products, sold on the internet, has reported that the products caused moles to darken and increase in size over a short period, "an early warning sign of skin cancer".<ref>{{Cite web|url=http://news.bbc.co.uk/2/hi/health/7852833.stm|title=Worry over tan jab mole changes |accessdate=2009-03-04|publisher=[[BBC]]|date=2009-01-28}}</ref><ref>{{Cite web|url=http://www.telegraph.co.uk/health/healthnews/4360594/Illegal-tanning-drug-can-change-appearance-of-moles-scientists-warn.html|title=Illegal tanning drug can change appearance of moles, scientists warn|accessdate=2009-03-04|publisher=[[The Daily Telegraph]]|date=2009-01-27}}</ref> [[Academia|Academic researchers]] at [[Liverpool John Moores University]] specialized in [[performance-enhancing drugs]] published an [[editorial]] in the [[BMJ|British Medical Journal]] suggesting that use of 'melanotan I and II', "could damage the immune and cardiovascular systems as well as triggering other problems".<ref>{{Cite web|url=http://news.bbc.co.uk/2/hi/health/7895366.stm|title=Risky tan jab warnings 'ignored' |accessdate=2009-03-04|publisher=[[BBC]]|date=2009-02-18}}</ref>

Revision as of 17:17, 21 November 2009

Afamelanotide
Names
Other names
  • Melanotan
  • Melanotan 1
  • Melanotan-1
  • Melanotan I
  • Melanotan-I
  • [Nle4, D-Phe7]α-MSH,
  • NDP-MSH
  • CUV1647
Identifiers
MeSH Melanotan-1
Properties
C78H111N21O19
Molar mass 1646.84524
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
3D rendered animation of the structure of the afamelanotide peptide molecule.
(Full size)

Afamelanotide (Template:Pron-en) is a synthetic analog of the naturally occurring melanocortin peptide hormone alpha-melanocyte stimulating hormone (α-MSH) that has been shown to induce skin pigmentation through melanogenesis and thereby subsequently reduce sun (UV) damage to UV exposed skin in preliminary studies and clinical trials. Its amino acid sequence is Ac-Ser-Tyr-Ser-Nle-Glu-His-D-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2 or [Nle4, D-Phe7]-α-MSH.

Afamelanotide is the International Nonproprietary Name given to the molecule [Nle4, D-Phe7]α-MSH [1] initially researched and developed under the names melanotan 1 (Template:Pron-en) and CUV1647. It is currently being clinically trialled in the form of a "grain of rice" sized bioabsorbable subcutaneous implant as a potential therapeutic photoprotection inducing agent for a series of light related skin indications. As of 2009, no drug containing the molecule [Nle4, D-Phe7]α-MSH has been approved for use by any governmental drug regulatory bodies outside of trials, but unlicensed and untested powders sold as "melanotan" are found on the Internet[2] and are reported to be used by thousands of members of the general public. One regulatory agency has warned that consumers purchasing "melanotan" risk buying a counterfeit drug[3] while Clinuvel Pharmaceuticals, the company developing afamelanotide, has warned consumers that counterfeit products sold using the names "melanotan I and II", "pose a hazard to public health".[4] Clinuvel has stated publicly that products sold online as "melanotan" are not afamelanotide.[5]

Historical development

[Nle4, D-Phe7]-α-MSH was first synthesized at the University of Arizona. Researchers there knew that one of the best defenses against skin cancer was melanin activated in the skin, a tan. They hypothesized that an effective way to reduce skin cancer rates in people would be to induce the body's natural pigmentary system to produce a protective tan prior to UV exposure. The body's naturally occurring hormone α-MSH causes melanogenesis, a process by which the skin's pigment cells (melanocytes) produce the skin's pigment (melanin). They tested to see if administering this endogenous 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 α-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 Victor Hruby, found a peptide, [Nle4, D-Phe7]-α-MSH, that was approximately 1,000 times more potent than natural α-MSH. [6] They dubbed this new peptide molecule, "Melanotan" (later Melanotan I, now known as afamelanotide). They subsequently developed another analog, Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-NH2), which they called "Melanotan II". The scientists hoped to use these peptides to combat melanoma by stimulating the body's natural pigmentary mechanism to create a tan without first needing exposure to harmful levels of UV radiation. [7] This in turn, they hypothesized, could reduce the potential for skin damage[8][9] 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.[10] Afamelanotide (formerly the proprietary CUV1647) is currently being tested, in an implant delivery formulation, and clinically trialed by the Australian company Clinuvel Pharmaceuticals, for a series of conditions affecting the skin including erythropoietic protoporphyria (EPP)[11], polymorphous light eruption (PMLE), solar urticaria (SU), phototoxicity associated with systemic photodynamic therapy and actinic keratosis (AK) and squamous cell carcinoma skin cancer in patients who have received organ transplants.

Preclinical studies relative to carcinogenicity

Owing to [Nle4, D-Phe7]α-MSH being a superpotent synthetic form of a-MSH concerns were present in the minds of the original researchers as to it possibly having the potential to cause melanocytes to turn malignant or to enhance the proliferation of pre-existing melanomas and possibly other skin cancer types. These concerns led the researchers to conduct a series of preclinical studies to examine the carcinogenic potential that [Nle4, D-Phe7]α-MSH had in both in vivo and in vitro skin models. According to the researchers these studies established a, "lack of carcinogenic potential for melanotan".[12] Further studies reported that [Nle4, D-Phe7]α-MSH did not enhance anchorage-independent clonogenic cell growth, a hallmark of malignancy, [13] and it had no effect on tumor incidence, size or on metastatic spread in in vitro and animal models.[14][15] Instead, one study reported that [Nle4, D-Phe7]α-MSH actually inhibited melanoma cell proliferation in vitro. [16]

Human pigmentation clinical trials

Arizona

A 1991 study of [Nle4, D-Phe7]α-MSH in 28 "healthy white men" who used a "high-potency sunscreen during the trial" concluded that "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." [17]

A 1997 pharmacokinetic trial to establish efficacy of peptide administration compared intravenous, oral and subcutaneous routes. The study found that, "subcutaneous administration is an efficacious method of delivering melanotan". [18]

A 1999 clinical dose ranging study in "eight male volunteers with 'tannable' skin types III-IV" given [Nle4, D-Phe7]α-MSH (Melanotan-I) determined that an optimal dose for ten daily subcutaneous injections is 0.16 mg/kg per day. [19]

A 2000 study to determine increases of eumelanin expression in seven, "normal volunteers" administered [Nle4, D-Phe7]α-MSH 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." [20]

Three 2004 Phase I clinical trials sought to establish the safety of [Nle4, D-Phe7]α-MSH therapy combined with UV-B light or sunlight exposure. 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." This trial was funded by the National Cancer Institute. [21]

Australia

A 2003 Phase IIb clinical human trial demonstrated in a group of seventy-nine volunteers that those who were administered [Nle4, D-Phe7]α-MSH 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) recorded increases in melanin of up to 100% in some areas and that their risk of sunburn injury was reduced by more than 50%. [22][23]

A 2006 study Phase II clinical trial examined [Nle4, D-Phe7]α-MSH's effect on melanin synthesis in humans with MC1R variant alleles. Researchers found that "MELANOTAN effectively increases the melanin content of skin in those individuals with MC1R variant alleles and therefore, those most in need of photoprotection." [24]

Therapeutic clinical trials

Afamelanotide is being trialed by Clinuvel as a drug for photoprotection for five indications:

  • Erythropoietic protoporphyria
  • Polymorphous light eruption
  • Phototoxicity associated with systemic photodynamic therapy
  • Solar urticaria
  • Actinic keratosis and squamous cell carcinoma skin cancer in patients who have received an organ tranplant[25]

Erythropoietic protoporphyria

Phase II trials of afamelanotide in erythropoietic protoporphyria (EPP) were completed in February 2007 [26]. These results, published in the New England Journal of Medicine in 2009, showed that EPP patient's "tolerance to artificial light and melanin density increased significantly by day 120 after the start of afamelanotide, to 11 times and 1.3 times the baseline values". [27]

Phase III trials of afamelanotide as a treatment for EPP commenced in June 2007.[28] These trials were to determine if afamelanotide "could reduce the number and severity of phototoxic reactions in patients with erythropoietic protoporphyria" and "increase the duration of exposure to sunlight that can be tolerated by EPP patients".

In January 2009, interim results were released from the Phase III trial involving 14 patients from a clinic in Zurich. These results showed that "the severity of phototoxic reaction for patients with the disease was significantly reduced".[29]

The EMEA[30], Swissmedic[31] and the U.S. Food and Drug Administration[32] have recognized afamelanotide as an orphan drug for the treatment of EPP and congenital erythropoietic porphyria.

Polymorphous light eruption

Phase II trials of afamelanotide in polymorphous light eruption (PLE) were completed in August 2006. The trials reported that patients treated with the drug "used significantly less systemic corticosteroids" and reported "fewer episodes of PLE" compared to those treated with a placebo.[33]. Phase III trials commenced in January 2007.[34]

Skin cancer, solar urticaria and phototoxicity with photodynamic therapy

Phase II trials are underway to assess afamelanotide's ability to reduce the prevalence of actinic keratoses and squamous cell carcinoma skin cancers in patients who have received organ transplants. These patients suffer greater numbers of skin cancers as they are immunosuppressed. Trials commenced in November 2007.[35]

Phase II trials assessing afamelanotide as a preventative treatment in patients suffering solar urticaria commenced in September 2008.[36]

Phase II trials are underway to assess afamelanotide's ability to prevent photosensitivity in patients who have undergone systemic photodynamic therapy (PDT), a cancer treatment where patients are given a light-sensitising drug.[37]

General population usage of melanotan peptides

General public users of the melanotan peptides (including melanotan I) have been reported to number into the thousands with one BBC report explaining that a January 2009 straw poll by the reporting journalist of just 6 UK needle exchanges revealed, "nearly 500 people wanting the syringes [for peptide usage] or information about melanotan". [38][39][40] Academic researchers have reported on a "thriving" internet community of users of the peptides at the site Melanotan.org[41] where members discuss their experiences using the unlicensed and unregulated drugs. [42] The site was reported to number more than 5,000 members as of February 2009. [43] A January 2009 report in Wired Science described the site's forum as having more than 50,000 posts primarily covering "Usage and Experimentation" by members with many covering detailed regimens on how to attain skin darkening and/or sexual function [with Melanotan II] improvements. [44]

"Melanotan" products sold for human use

A number of products are sold online and in gyms and beauty salons as "melanotan" or "melanotan-1" which purport to have the same chemical make up as afamelanotide, of which the visual effect resulting from usage has been noted in an article by Wired.com as being "eerily similar to results obtained in trials at the University of Arizona or by Clinuvel". The Wired.com article explained that these products were Melanotan II, "a similar (but not identical) compound"[44] and Clinuvel has stated that products sold as "melanotan" are "illegal" and "wholly unrelated to Clinuvel's proprietary afamelanotide".[4] Chemicals sold as "melanotan" are not illegal to import, use or own, however their sales and supply for human use outside of government sanctioned clinical trials is illegal within the boundaries of most jurisdictions, including the UK[38], USA, Europe and Australia. [45]

A 2009 article on unlicensed "melanotan" products, sold on the internet, has reported that the products caused moles to darken and increase in size over a short period, "an early warning sign of skin cancer".[46][47] Academic researchers at Liverpool John Moores University specialized in performance-enhancing drugs published an editorial in the British Medical Journal suggesting that use of 'melanotan I and II', "could damage the immune and cardiovascular systems as well as triggering other problems".[48]

Health warnings on "melanotan" products sold for human use

Clinuvel has warned consumers against the use of what it terms are "counterfeit", "illegal" drugs sold as "melanotan I and II" that are promoted by citing research on afamelanotide. [4]

On August 8, 2008 the Danish Medicines Agency (DMA) issued a warning[49] against the usage of any product called "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 is an "illegal medicinal product" that it is not licensed for usage in the EU or the USA.

The UK Medicines and Healthcare products Regulatory Agency issued a similar warning on November 17, 2008[50] stating that "We are warning people not to use this product. Don’t be fooled into thinking that Melanotan offers a shortcut to a safer and more even tan. The safety of these products is unknown and they are unlicensed in the UK. The side effects could be extremely serious. If you have used either of these products do not use them again and if you have any concerns you should seek advice from your doctor.”

The FDA issued a warning letter to an online vendor in January 2009 selling "Melanotan ONE" as advertisements of the products on their website were in breach of the Federal Food, Drug, and Cosmetic Act as the site was selling "new drug" products "intended for human use".[51]

The Irish Medicines Board (IMB) issued a precautionary safety alert on February 27, 2009 regarding the use of "the unauthorised medicine Melanotan (I and II)", sold as a powder for injection, stating that "Melanotan is not authorised in Ireland and therefore the IMB cannot guarantee the efficacy, safety or quality of this product."[2] In its release, the IMB announced that its tests had found the presence of microbial contamination in a vial of water sold together with melanotan powder which "would expose recipients to a risk of serious infection".

The Norwegian Medicines Agency has issued warnings in 2007[52] and 2009[3] about the use of "Melanotan" sold online, while a spokesman for the Australian Therapeutic Goods Administration warned consumers to be "very wary" of using it.[45]

See also

References

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  2. ^ a b "Melanotan Powder for Injection". Notice Information: - Warning - 27/02/2009. Irish Medicines Board. 2009. Retrieved 2009-02-02.
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  18. ^ Ugwu SO, Blanchard J, Dorr RT; et al. (1997). "Skin pigmentation and pharmacokinetics of melanotan-I in humans". Biopharm Drug Dispos. 18 (3): 259–69. doi:10.1002/(SICI)1099-081X(199704)18:3<259::AID-BDD20>3.0.CO;2-X. PMID 9113347. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  19. ^ Levine N, Dorr R, Ertl G, Brooks C, Alberts D (1999). "Effects of a potent synthetic melanotropin, Nle4-D-Phe7-α-MSH (Melanotan-I) on tanning: a dose-ranging study". Journal of Dermatological Treatment. 10 (2): 127–32. doi:10.3109/09546639909056014. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  20. ^ Dorr RT, Dvorakova K, Brooks C; et al. (2000). "Increased eumelanin expression and tanning is induced by a superpotent melanotropin [[Nle4, D-Phe7]-α-MSH in humans". Photochem Photobiol. 72 (4): 526–32. doi:10.1562/0031-8655(2000)072<0526:IEEATI>2.0.CO;2. PMID 11045725. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  21. ^ Dorr RT, Ertl G, Levine N; et al. (2004). "Effects of a superpotent melanotropic peptide in combination with solar UV radiation on tanning of the skin in human volunteers". Archives of Dermatology (Arch Dermatol). 140 (7): 827–35. doi:10.1001/archderm.140.7.827. PMID 15262693. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  22. ^ "Suntan could come 'in an implant'". BBC News. 2003. Retrieved 2008-10-12.
  23. ^ "Sunburn Trial Results Show Drug Can Reduce Sun Damage by 50% for Fair-Skinned People, says Trial Head". innovations report. 2003. Retrieved 2008-08-22.
  24. ^ Fitzgerald LM, Fryer JL, Dwyer T, Humphrey SM (2006). "Effect of MELANOTAN, [Nle(4), D-Phe(7)]-alpha-MSH, on melanin synthesis in humans with MC1R variant alleles". Peptides. 27 (2): 388–94. doi:10.1016/j.peptides.2004.12.038. PMID 16293341. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
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  28. ^ "Clinuvel gets early nod on sun drug". Australian Life Scientist. 2007-06-12. Retrieved 2009-03-04.
  29. ^ "Positive results for Clinuvel's drug trial". The Australian. 2009-01-22. Retrieved 2009-03-04.
  30. ^ "EMEA grants Clinuvel two orphan drug designations". Biospectrum Asia. 2008-03-12. Retrieved 2009-03-04.
  31. ^ "US orphan designation for Clinuvel". Biospectrum Asia. 2008-04-29. Retrieved 2009-03-04.
  32. ^ "US orphan designation for Clinuvel". BioTechnologyNews.Net. 2008-07-29. Retrieved 2009-03-04.
  33. ^ "Clinuvel positive Phase 2". BioTechnologyNews.Net. 2008-08-29. Retrieved 2009-03-04.
  34. ^ "Clinuvel moves to phase III for PLE". Australian Life Scientist. 2007-01-25. Retrieved 2009-03-04.
  35. ^ "New trial target for Clinuvel's suntan drug". BiotechnologyNews.net. 2007-11-01. Retrieved 2009-03-04.
  36. ^ "Ethics approval for sun drug in sunny Manchester". BiotechnologyNews.net. 2008-06-12. Retrieved 2009-03-04.
  37. ^ "Clinuvel launches new Phase 2". BiotechnologyNews.net. 2008-09-23. Retrieved 2009-03-04.
  38. ^ a b "Illegal Tanning drugs sold" (Windows Media Video). Inside Out, BBC. 2009-01-14. Retrieved 2009-07-23.
  39. ^ "Believe It Or Not 'Tanorexia' A Very Real Problem" (Flash Video). WCBS-TV, CBS. 2009-05-20. Retrieved 2009-07-23.
  40. ^ "Fools Gold". Cosmopolitan (Australia). 2009-06-14. Retrieved 2009-07-25.
  41. ^ "Melanotan.org". Melanotan.org. Retrieved 2009-08-29.
  42. ^ Dr. Kim Mulvihill (2009-03-05). "'Barbie drug' promises instant tan without sun damage" (Flash Video). KSL-TV, NBC. Retrieved 2009-07-23.
  43. ^ "People risking health with internet 'tan jabs', warns expert". The Daily Telegraph. 2009-02-17. Retrieved 2009-07-23.
  44. ^ a b "Suntan Drug Greenlighted for Trials". Wired. 2009-01-29. Retrieved 2009-04-11.
  45. ^ a b "Tanning drug a health risk". Herald Sun. 2009-10-31. Retrieved 2009-10-31.
  46. ^ "Worry over tan jab mole changes". BBC. 2009-01-28. Retrieved 2009-03-04.
  47. ^ "Illegal tanning drug can change appearance of moles, scientists warn". The Daily Telegraph. 2009-01-27. Retrieved 2009-03-04.
  48. ^ "Risky tan jab warnings 'ignored'". BBC. 2009-02-18. Retrieved 2009-03-04.
  49. ^ "Warning against the product Melanotan". Danish Medicines Agency. 2008. Retrieved 2008-08-11.
  50. ^ ""Tan jab" is an unlicensed medicine and may not be safe". MHRA. 2008. Retrieved 2008-11-17.
  51. ^ "US Lab Research Inc Warning letter". U.S. Food and Drug Administration. 2009-01-29. Retrieved 2009-07-23.
  52. ^ "Legemiddelverket advarer mot bruk av Melanotan". Norwegian Medicines Agency. 2007-12-13. Retrieved 2009-03-11.

Template:Peptide hormone agonists and antagonists

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