Afamelanotide
Encyclopedia
- Note: this article describes afamelanotide which is also known by the name melanotan-1. afamelanotide should not be confused with melanotan IIMelanotan IIMelanotan II developed at the University of Arizona is a synthetic analog of the naturally occurring melanocortin peptide hormone alpha-melanocyte stimulating hormone that in usage has been shown to have melanogenesis and aphrodisiac effects in preliminary studies and clinical trials...
.
Afamelanotide developed at the University of Arizona
University of Arizona
The University of Arizona is a land-grant and space-grant public institution of higher education and research located in Tucson, Arizona, United States. The University of Arizona was the first university in the state of Arizona, founded in 1885...
is a synthetic
Peptide synthesis
In organic chemistry, peptide synthesis is the production of peptides, which are organic compounds in which multiple amino acids are linked via amide bonds which are also known as peptide bonds...
analog of the naturally-occurring
Natural product
A natural product is a chemical compound or substance produced by a living organism - found in nature that usually has a pharmacological or biological activity for use in pharmaceutical drug discovery and drug design...
melanocortin
Melanocortin
The melanocortins are a group of peptide hormones which include adrenocorticotropic hormone and the different forms of melanocyte-stimulating hormone . They can be synthetic . In humans they can be endogenously produced from proopiomelanocortin in the pituitary gland...
peptide hormone
Peptide hormone
Peptide hormones are a class of peptides that are secreted into the blood stream and have endocrine functions in living animals.Like other proteins, peptide hormones are synthesized in cells from amino acids according to an mRNA template, which is itself synthesized from a DNA template inside the...
alpha-melanocyte stimulating hormone
Melanocyte-stimulating hormone
The melanocyte-stimulating hormones are a class of peptide hormones that are produced by cells in the intermediate lobe of the pituitary gland...
(α-MSH) that has been shown to induce skin pigmentation
Biological pigment
Biological pigments, also known simply as pigments or biochromes are substances produced by living organisms that have a color resulting from selective color absorption. Biological pigments include plant pigments and flower pigments...
through melanogenesis and thereby subsequently reduce sun (UV) damage
Sunburn
A sunburn is a burn to living tissue, such as skin, which is produced by overexposure to ultraviolet radiation, commonly from the sun's rays. Usual mild symptoms in humans and other animals include red or reddish skin that is hot to the touch, general fatigue, and mild dizziness. An excess of UV...
to UV exposed skin in preliminary studies and clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s. Its amino acid sequence
Peptide sequence
Peptide sequence or amino acid sequence is the order in which amino acid residues, connected by peptide bonds, lie in the chain in peptides and proteins. The sequence is generally reported from the N-terminal end containing free amino group to the C-terminal end containing free carboxyl group...
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
International Nonproprietary Name
An International Nonproprietary Name is the official nonproprietary or generic name given to a pharmaceutical substance, as designated by the World Health Organization...
for the molecule [Nle4, D-Phe7]α-MSH initially researched and developed
Research and development
The phrase research and development , according to the Organization for Economic Co-operation and Development, refers to "creative work undertaken on a systematic basis in order to increase the stock of knowledge, including knowledge of man, culture and society, and the use of this stock of...
as melanotan-1 and later, CUV1647 [by Clinuvel]. A marketing trade name for one brand of afamelanotide was recently approved by the European Medicines Agency (EMA) Name Review Group (NRG) and the Agency's Committee for Human Medicinal Products (CHMP) as Scenesse . On May 5, 2010 the Italian Medicines Agency (AIFA - Agenzia Italiana del Farmaco) became the first governmental health organization ever (even before the drug received approval in Europe) to authorize afamelanotide as a medicine for therapeutic treatment of Italian citizens to reduce painful photosensitivity stemming from the orphan disease
Rare disease
A rare disease, also referred to as an orphan disease, is any disease that affects a small percentage of the population.Most rare diseases are genetic, and thus are present throughout the person's entire life, even if symptoms do not immediately appear...
erythropoietic protoporphyria
Erythropoietic protoporphyria
Erythropoietic protoporphyria is a relatively mild form of porphyria, although very painful, which arises from a deficiency in the enzyme ferrochelatase, leading to abnormally high levels of protoporphyrin in the tissue...
(EPP). Afamelanotide is currently being clinically trialled in the form of a "grain of rice" sized bioabsorbable subcutaneous implant as a potential therapeutic
Therapy
This is a list of types of therapy .* Adventure therapy* Animal-assisted therapy* Aquatic therapy* Aromatherapy* Art and dementia* Art therapy* Authentic Movement* Behavioral therapy* Bibliotherapy* Buteyko Method* Chemotherapy...
photoprotection
Photoprotection
Photoprotection is a group of mechanisms that nature has developed to minimize the damage that the human body suffers when exposed to UV radiation...
inducing agent for a series of light
Light
Light or visible light is electromagnetic radiation that is visible to the human eye, and is responsible for the sense of sight. Visible light has wavelength in a range from about 380 nanometres to about 740 nm, with a frequency range of about 405 THz to 790 THz...
related skin
Human skin
The human skin is the outer covering of the body. In humans, it is the largest organ of the integumentary system. The skin has multiple layers of ectodermal tissue and guards the underlying muscles, bones, ligaments and internal organs. Human skin is similar to that of most other mammals,...
indications
Indication (medicine)
In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. The opposite of indication is contraindication.-Drugs:...
. This approval allowed the drug to be immediately available for prescription in Italy and reimbursable under the country's national health system. The molecule [Nle4, D-Phe7]α-MSH has yet to be approved for use
Regulation of therapeutic goods
The regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction. In some countries, such as the United States, they are regulated at the national level by a single agency...
by additional governmental drug regulatory bodies outside of trials, but unlicensed and untested powders sold as "melanotan" are found on the Internet and are reported to be used by thousands of members of the general public.
Multiple regulatory bodies have warned consumers the peptides may be unsafe and ineffective in usage, with one regulatory agency warning that consumers who purchase any product labeled "melanotan" risk buying a counterfeit drug. Clinuvel Pharmaceuticals, the company developing afamelanotide, and medical researchers have warned consumers that counterfeit products sold using the names "melanotan I and II", "pose a hazard to public health". Clinuvel has stated publicly that products sold online as "melanotan" are not afamelanotide.
Historical development
[Nle4, D-Phe7]-α-MSH was first synthesized at the University of ArizonaUniversity of Arizona
The University of Arizona is a land-grant and space-grant public institution of higher education and research located in Tucson, Arizona, United States. The University of Arizona was the first university in the state of Arizona, founded in 1885...
. Researchers there knew that one of the best defenses against skin cancer
Skin cancer
Skin neoplasms are skin growths with differing causes and varying degrees of malignancy. The three most common malignant skin cancers are basal cell cancer, squamous cell cancer, and melanoma, each of which is named after the type of skin cell from which it arises...
was melanin activated in the skin, a tan. They hypothesized
Hypothesis
A hypothesis is a proposed explanation for a phenomenon. The term derives from the Greek, ὑποτιθέναι – hypotithenai meaning "to put under" or "to suppose". For a hypothesis to be put forward as a scientific hypothesis, the scientific method requires that one can test it...
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 (melanocyte
Melanocyte
-External links: - "Eye: fovea, RPE" - "Integument: pigmented skin"...
s) produce the skin's pigment (melanin
Melanin
Melanin is a pigment that is ubiquitous in nature, being found in most organisms . In animals melanin pigments are derivatives of the amino acid tyrosine. The most common form of biological melanin is eumelanin, a brown-black polymer of dihydroxyindole carboxylic acids, and their reduced forms...
). They tested to see if administering this endogenous hormone to the body directly could be an effective method to cause sunless tanning
Sunless tanning
Sunless tanning Sunless tanning Sunless tanning (also known as UV-free tanning, self tanning, spray tanning (when applied topical, or fake tanning) refers to the application of chemicals to the skin to produce an effect similar in appearance to a suntan...
. 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 J. Hruby and Mac E. Hadley, found a peptide, [Nle4, D-Phe7]-α-MSH, that was approximately 1,000 times more potent than natural α-MSH. They dubbed this new peptide molecule, "Melanotan" (later Melanotan-1, 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
Melanotan II
Melanotan II developed at the University of Arizona is a synthetic analog of the naturally occurring melanocortin peptide hormone alpha-melanocyte stimulating hormone that in usage has been shown to have melanogenesis and aphrodisiac effects in preliminary studies and clinical trials...
". The scientists hoped to use these peptides to combat melanoma
Melanoma
Melanoma is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye...
by stimulating the body's natural pigmentary mechanism to create a tan without first needing exposure to harmful levels of UV
Ultraviolet
Ultraviolet light is electromagnetic radiation with a wavelength shorter than that of visible light, but longer than X-rays, in the range 10 nm to 400 nm, and energies from 3 eV to 124 eV...
radiation. 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
Technology transfer
Technology Transfer, also called Transfer of Technology and Technology Commercialisation, is the process of skill transferring, knowledge, technologies, methods of manufacturing, samples of manufacturing and facilities among governments or universities and other institutions to ensure that...
company, to a number of biotechnology companies who intend to develop them into drugs. Afamelanotide (formerly the proprietary
Property
Property is any physical or intangible entity that is owned by a person or jointly by a group of people or a legal entity like a corporation...
CUV1647) is currently being tested, in an implant delivery formulation, and clinically trialed by the Australia
Australia
Australia , officially the Commonwealth of Australia, is a country in the Southern Hemisphere comprising the mainland of the Australian continent, the island of Tasmania, and numerous smaller islands in the Indian and Pacific Oceans. It is the world's sixth-largest country by total area...
n company Clinuvel Pharmaceuticals, for a series of conditions affecting the skin
Human skin
The human skin is the outer covering of the body. In humans, it is the largest organ of the integumentary system. The skin has multiple layers of ectodermal tissue and guards the underlying muscles, bones, ligaments and internal organs. Human skin is similar to that of most other mammals,...
including erythropoietic protoporphyria
Erythropoietic protoporphyria
Erythropoietic protoporphyria is a relatively mild form of porphyria, although very painful, which arises from a deficiency in the enzyme ferrochelatase, leading to abnormally high levels of protoporphyrin in the tissue...
(EPP), polymorphous light eruption
Polymorphous Light Eruption
Polymorphous light eruption , or polymorphic light eruption , is a skin condition caused by sunlight.- Types :Two subtypes have been described:*Juvenile spring eruption*Benign summer light eruption-Presentation:...
(PMLE), solar urticaria
Solar urticaria
Solar urticaria is a rare condition in which exposure to ultraviolet or UV radiation, or sometimes even visible light, induces a case of urticaria or hives that can appear in both covered and uncovered areas of the skin. It is classified as a type of physical urticaria. The classification of...
(SU), phototoxicity associated with systemic photodynamic therapy
Photodynamic therapy
Photodynamic therapy is used clinically to treat a wide range of medical conditions, including malignant cancers, and is recognised as a treatment strategy which is both minimally invasive and minimally toxic...
and actinic keratosis
Actinic keratosis
Actinic keratosis is a premalignant condition of thick, scaly, or crusty patches of skin. It is more common in fair-skinned people. It is associated with those who are frequently exposed to the sun, as it is usually accompanied by solar damage...
(AK) and squamous cell carcinoma
Squamous cell carcinoma
Squamous cell carcinoma , occasionally rendered as "squamous-cell carcinoma", is a histologically distinct form of cancer. It arises from the uncontrolled multiplication of malignant cells deriving from epithelium, or showing particular cytological or tissue architectural characteristics of...
skin cancer in patients who have received organ transplant
Organ transplant
Organ transplantation is the moving of an organ from one body to another or from a donor site on the patient's own body, for the purpose of replacing the recipient's damaged or absent organ. The emerging field of regenerative medicine is allowing scientists and engineers to create organs to be...
s.
Mechanism of action
Afamelanotide is a selectiveBinding selectivity
Binding selectivity refers to the differing affinities with which different ligands bind to a substrate forming a complex. A selectivity coefficient is the equilibrium constant for the reaction of displacement by one ligand of another ligand in a complex with the substrate...
agonist of the melanocortin 1 receptor
Melanocortin 1 receptor
The melanocortin 1 receptor , also known as melanocyte-stimulating hormone receptor , melanin-activating peptide receptor, or melanotropin receptor, is a G protein-coupled receptor which binds to a class of pituitary peptide hormones known as the melanocortins, of which include adrenocorticotropic...
(MC1R). As an analogue of α-MSH, its mechanism of action
Mechanism of action
In pharmacology, the term mechanism of action refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect...
is biomimicry
Biomimicry
Biomimicry or biomimetics is the examination of nature, its models, systems, processes, and elements to emulate or take inspiration from in order to solve human problems. The term biomimicry and biomimetics come from the Greek words bios, meaning life, and mimesis, meaning to imitate...
of the natural mammalian tanning process
Sun tanning
Sun tanning or simply tanning is the process whereby skin color is darkened or tanned. The process is most often a result of exposure to ultraviolet radiation from the sun or from artificial sources, such as a tanning bed, but can also be a result of windburn or reflected light...
.
Afamelanotide produces its photoprotective effects by triggering a 'signaling cascade' via its activation of the MC1R on melanin
Melanin
Melanin is a pigment that is ubiquitous in nature, being found in most organisms . In animals melanin pigments are derivatives of the amino acid tyrosine. The most common form of biological melanin is eumelanin, a brown-black polymer of dihydroxyindole carboxylic acids, and their reduced forms...
-producing cell
Cell
-Science and technology:*Cell , the functional basic unit of life*Cell , a term used in an electronic circuit design schematics*Cell , a three-dimensional element, part of a higher-dimensional object*Cell , a scientific journal...
s known as melanocyte
Melanocyte
-External links: - "Eye: fovea, RPE" - "Integument: pigmented skin"...
s.
Upon afamelanotide binding with the MC1R on the surface of melanocytes in the epidermal layer of the skin
Skin
-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...
, it begins a series of actions and reactions that result in melanocytes favoring the production of eumelanin (photoprotective black/brown pigment
Pigment
A pigment is a material that changes the color of reflected or transmitted light as the result of wavelength-selective absorption. This physical process differs from fluorescence, phosphorescence, and other forms of luminescence, in which a material emits light.Many materials selectively absorb...
) over pheomelanin (red/yellow pigment).
The initial binding activates the MC1R leading to the activation of adenylate cyclase
Adenylate cyclase
Adenylate cyclase is part of the G protein signalling cascade, which transmits chemical signals from outside the cell across the membrane to the inside of the cell ....
(AC) and stimulation of the production of cyclic adenosine monophosphate
Cyclic adenosine monophosphate
Cyclic adenosine monophosphate is a second messenger important in many biological processes...
(cAMP) from adenosine triphosphate
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
(ATP). cAMP in turn activates protein kinase A (PKA) resulting in the phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
of the cAMP response element-binding (CREB). Phosphorylated CREB will bind to the cAMP response element (CRE) on the microphthalmia-associated transcription factor
Microphthalmia-associated transcription factor
Microphthalmia-associated transcription factor is a basic helix-loop-helix leucine zipper transcription factor involved in melanocyte and osteoclast development.-Clinical significance:...
(MITF) gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
leading to the synthesis of the MITF protein. MITF has the ability to activate several genes by binding to them, including the MC1R gene and the genes involved in melanogenesis (tyrosinase
Tyrosinase
Tyrosinase also known as monophenol monooxygenase is an enzyme that catalyses the oxidation of phenols and is widespread in plants and animals...
, TYRP1
TYRP1
Tyrosinase-related protein 1, also known as TYRP1, is an enzyme which in humans is encoded by the TYRP1 gene- Function :Tyrp1 is a melanocyte-specific gene product involved in melanin synthesis. Mouse Tyrp1 possesses dihydroxyindole carboxylic acid oxidase activity, The function in human...
and DCT
Dopachrome tautomerase
Dopachrome tautomerase , also known as DCT, is a human gene. Its expression is regulated by the microphthalmia-associated transcription factor .-Further reading:...
, which encode enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s of the same names). This results in increased concentrations of the melanogenic enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s within the melanocyte. It is the levels of these enzymes within a melanocyte that determines whether the cell will create eumelanin instead of pheomelanin.
Production of eumelanin rather than pheomelanin by melanocytes, thereby increases pigmentation of the skin and thus provides photoprotection against harmful UV radiation from the sun. This is the intended therapeutic benefit from the medicinal administration of afamelanotide.
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 malignantMalignant
Malignancy is the tendency of a medical condition, especially tumors, to become progressively worse and to potentially result in death. Malignancy in cancers is characterized by anaplasia, invasiveness, and metastasis...
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 carcinogen
Carcinogen
A carcinogen is any substance, radionuclide, or radiation that is an agent directly involved in causing cancer. This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes...
ic potential that [Nle4, D-Phe7]α-MSH had in both in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
and in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
skin models
Pre-clinical development
In drug development, pre-clinical development is a stage of research that begins before clinical trials can begin, and during which important feasibility, iterative testing and drug safety data is collected....
. According to the researchers these studies established a, "lack of carcinogenic potential for melanotan". Further studies reported that [Nle4, D-Phe7]α-MSH did not enhance anchorage-independent clonogenic cell growth, a hallmark of malignancy, and it had no effect on tumor incidence, size or on metastatic
Metastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
spread in in vitro and animal model
Animal model
An animal model is a living, non-human animal used during the research and investigation of human disease, for the purpose of better understanding the disease without the added risk of causing harm to an actual human being during the process...
s. Instead, one study reported that [Nle4, D-Phe7]α-MSH actually inhibited melanoma cell proliferation in vitro.
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 melanotropinMelanocyte-stimulating hormone
The melanocyte-stimulating hormones are a class of peptide hormones that are produced by cells in the intermediate lobe of the pituitary gland...
given by subcutaneous injection
Injection (medicine)
An injection is an infusion method of putting fluid into the body, usually with a hollow needle and a syringe which is pierced through the skin to a sufficient depth for the material to be forced into the body...
. Skin tanning appears possible without potentially harmful exposure to ultraviolet radiation."
A 1997 pharmacokinetic
Pharmacokinetics
Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism...
trial to establish efficacy
Efficacy
Efficacy is the capacity to produce an effect. It has different specific meanings in different fields. In medicine, it is the ability of an intervention or drug to reproduce a desired effect in expert hands and under ideal circumstances.- Healthcare :...
of peptide administration compared intravenous, oral and subcutaneous routes. The study found that, "subcutaneous administration is an efficacious method of delivering melanotan".
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.
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."
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
Synergy
Synergy may be defined as two or more things functioning together to produce a result not independently obtainable.The term synergy comes from the Greek word from , , meaning "working together".-Definitions and usages:...
in the tanning response to light." This trial was funded by the National Cancer Institute
National Cancer Institute
The National Cancer Institute is part of the National Institutes of Health , which is one of 11 agencies that are part of the U.S. Department of Health and Human Services. The NCI coordinates the U.S...
.
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/IIFitzpatrick scale
The Fitzpatrick Scale is a numerical classification schema for the color of skin. It was developed in 1975 by Thomas B. Fitzpatrick, a Harvard dermatologist, as a way to classify the response of different types of skin to UV light...
) recorded increases in melanin of up to 100% in some areas and that their risk of sunburn injury was reduced by more than 50%.
A 2006 study Phase II clinical trial examined [Nle4, D-Phe7]α-MSH's effect on melanin synthesis in humans with MC1R
Melanocortin 1 receptor
The melanocortin 1 receptor , also known as melanocyte-stimulating hormone receptor , melanin-activating peptide receptor, or melanotropin receptor, is a G protein-coupled receptor which binds to a class of pituitary peptide hormones known as the melanocortins, of which include adrenocorticotropic...
variant allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
s. 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
Photoprotection
Photoprotection is a group of mechanisms that nature has developed to minimize the damage that the human body suffers when exposed to UV radiation...
."
Therapeutic clinical trials
Afamelanotide is being trialed by Clinuvel as a drug for photoprotectionPhotoprotection
Photoprotection is a group of mechanisms that nature has developed to minimize the damage that the human body suffers when exposed to UV radiation...
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
Erythropoietic protoporphyria
Phase II trials of afamelanotide in erythropoietic protoporphyria (EPP) were completed in February 2007. These results, published in the New England Journal of MedicineNew England Journal of Medicine
The New England Journal of Medicine is an English-language peer-reviewed medical journal published by the Massachusetts Medical Society. It describes itself as the oldest continuously published medical journal in the world.-History:...
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".
Phase III trials of afamelanotide as a treatment for EPP commenced in June 2007. 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
Zürich
Zurich is the largest city in Switzerland and the capital of the canton of Zurich. It is located in central Switzerland at the northwestern tip of Lake Zurich...
. These results showed that "the severity of phototoxic reaction for patients with the disease was significantly reduced".
The EMEA
European Medicines Agency
The European Medicines Agency is a European agency for the evaluation of medicinal products. From 1995 to 2004, the European Medicines Agency was known as European Agency for the Evaluation of Medicinal Products.Roughly parallel to the U.S...
, Swissmedic
Swissmedic
Swissmedic, the Swiss Agency for Therapeutic Products, is the Swiss surveillance authority for medicines and medical devices, registered in Berne. It started operations on 1 January 2002 as successor of Interkantonale Kontrollstelle für Heilmittel , which was itself the successor of Schweizerische...
and the U.S. Food and Drug Administration have recognized afamelanotide as an orphan drug
Orphan drug
An orphan drug is a pharmaceutical agent that has been developed specifically to treat a rare medical condition, the condition itself being referred to as an orphan disease...
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. Phase III trials commenced in January 2007.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.Phase II trials assessing afamelanotide as a preventative treatment in patients suffering solar urticaria commenced in September 2008.
Phase II trials are underway to assess afamelanotide's ability to prevent photosensitivity
Photosensitivity
Photosensitivity is the amount to which an object reacts upon receiving photons, especially visible light.- Human medicine :Sensitivity of the skin to a light source can take various forms. People with particular skin types are more sensitive to sunburn...
in patients who have undergone systemic photodynamic therapy (PDT), a cancer treatment where patients are given a light-sensitising drug.
General population usage of melanotan peptides
General public users of the melanotan peptides (including melanotan-1) have been reported to number into the thousands with one BBC report explaining that a January 2009 straw pollStraw poll
A straw poll or straw vote is a vote with nonbinding results. Straw polls provide dialogue among movements within large groups, reflecting trends like organization and motivation...
by the reporting journalist
Journalist
A journalist collects and distributes news and other information. A journalist's work is referred to as journalism.A reporter is a type of journalist who researchs, writes, and reports on information to be presented in mass media, including print media , electronic media , and digital media A...
of just 6 UK needle exchanges
Needle-exchange programme
A Needle & syringe programme or syringe-exchange programme is a social policy based on the philosophy of harm reduction where injecting drug users can obtain hypodermic needles and associated injection equipment at little or no cost. Many programmes are called "exchanges" because some require...
revealed, "nearly 500 people wanting the syringes [for peptide usage] or information about melanotan". Academic researchers have reported on a "thriving" internet community of users of the peptides at the site Melanotan.org where members discuss their experiences using the unlicensed and unregulated drugs. The site was reported to number more than 5,000 members as of February 2009. 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.
In May 2010 the Norwegian tabloid daily Verdens Gang
Verdens Gang
Verdens Gang , generally known under the abbreviation VG, is a Norwegian tabloid newspaper...
published a story based upon a report by the Norwegian Pharmacy Association stating that 10,000 syringes are sold annually to Norwegian users of melanotan-1 and melanotan II.
"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.comWired News
Wired News is an online technology news website, formerly known as HotWired, that split off from Wired magazine when the magazine was purchased by Condé Nast Publishing in the 1990s. Wired News was owned by Lycos not long after the split, until Condé Nast purchased Wired News on July 11, 2006...
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" and Clinuvel has stated that products sold as "melanotan" are "illegal" and "wholly unrelated to Clinuvel's proprietary afamelanotide". Chemicals sold as "melanotan" are not illegal to import
Import
The term import is derived from the conceptual meaning as to bring in the goods and services into the port of a country. The buyer of such goods and services is referred to an "importer" who is based in the country of import whereas the overseas based seller is referred to as an "exporter". Thus...
, use or own; however their domestic
Domestic policy
Domestic policy, also known as public policy, presents decisions, laws, and programs made by the government which are directly related to all issues and activity within the country....
sales (non-export
Export
The term export is derived from the conceptual meaning as to ship the goods and services out of the port of a country. The seller of such goods and services is referred to as an "exporter" who is based in the country of export whereas the overseas based buyer is referred to as an "importer"...
) and supply for human use outside of government sanctioned clinical trials is illegal within the boundaries of most jurisdictions, including the UK, USA, Europe and Australia.
A 2009 paper 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". Academic researchers
Academia
Academia is the community of students and scholars engaged in higher education and research.-Etymology:The word comes from the akademeia in ancient Greece. Outside the city walls of Athens, the gymnasium was made famous by Plato as a center of learning...
at Liverpool John Moores University
Liverpool John Moores University
Liverpool John Moores University is a British 'modern' university located in the city of Liverpool, England. The university is named after John Moores and was previously called Liverpool Mechanics' School of Arts and later Liverpool Polytechnic before gaining university status in 1992, thus...
specialized in performance-enhancing drugs
Performance-enhancing drugs
Performance-enhancing drugs are substances used by athletes to improve their performances in the sports in which they engage.- Types of performance-enhancing drugs :...
published an editorial
Editorial
An opinion piece is an article, published in a newspaper or magazine, that mainly reflects the author's opinion about the subject. Opinion pieces are featured in many periodicals.-Editorials:...
in the British Medical Journal
BMJ
BMJ is a partially open-access peer-reviewed medical journal. Originally called the British Medical Journal, the title was officially shortened to BMJ in 1988. The journal is published by the BMJ Group, a wholly owned subsidiary of the British Medical Association...
suggesting that use of 'melanotan I and II', "could damage the immune and cardiovascular systems as well as triggering other problems".
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.On August 8, 2008 the Danish Medicines Agency
Danish Medicines Agency
The Danish Medicines Agency is an agency under the Danish Ministry of Health and Prevention.The purpose of the agency is to ensure that medicinal products used in Denmark are of satisfactory quality, are safe to use and that they have the desired effect...
(DMA) issued a warning 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
Skin cancer
Skin neoplasms are skin growths with differing causes and varying degrees of malignancy. The three most common malignant skin cancers are basal cell cancer, squamous cell cancer, and melanoma, each of which is named after the type of skin cell from which it arises...
, "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
European Union
The European Union is an economic and political union of 27 independent member states which are located primarily in Europe. The EU traces its origins from the European Coal and Steel Community and the European Economic Community , formed by six countries in 1958...
or the USA.
The UK Medicines and Healthcare products Regulatory Agency
Medicines and Healthcare products Regulatory Agency
The Medicines and Healthcare products Regulatory Agency is the UK government agency which is responsible for ensuring that medicines and medical devices work and are acceptably safe....
issued a similar warning on November 17, 2008 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
FDA Warning Letter
The United States Food and Drug Adminstration defines a Warning Letter as "...a correspondence that notifies regulated industry about violations that FDA has documented during its inspections or investigations...
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
Federal Food, Drug, and Cosmetic Act
The United States Federal Food, Drug, and Cosmetic Act , is a set of laws passed by Congress in 1938 giving authority to the U.S. Food and Drug Administration to oversee the safety of food, drugs, and cosmetics. A principal author of this law was Royal S. Copeland, a three-term U.S. Senator from...
as the site was selling "new drug" products "intended for human use".
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." 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
Norwegian Medicines Agency
The Norwegian Medicines Agency is the national, regulatory authority for new and existing medicines and the supply chain. The Agency is responsible for supervising the production, trials and marketing of medicines. It approves medicines and monitors their use, and ensures cost-efficient, effective...
has issued warnings in 2007 and 2009 about the use of "Melanotan" sold online, while a spokesman for the Australian Therapeutic Goods Administration
Therapeutic Goods Administration
The Therapeutic Goods Administration is the regulatory body for therapeutic goods in Australia . It is a Division of the Australian Department of Health and Ageing established under the Therapeutic Goods Act 1989 ...
warned consumers to be "very wary" of using it.