Eflornithine: Difference between revisions
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Eflornithine (α-difluoromethylornithine or DFMO) is a [[medication|drug]] found to be effective in the treatment of facial [[hirsutism]] <ref>{{Wolf JE, Shander D, Huber F, Jackson J, Lin CS, Mathes BM, Schrode K, and the Eflornithine Study Group. Randomized, double-blind clinical evaluation of the efficacy and safety of topical eflornithine HCI 13.9% cream in the treatment of women with facial hair. Int J Dermatol 2007 Jan; 46(1): 94-8.}}</ref> (excessive hair growth) as well as in [[African trypanosomiasis]] (sleeping sickness) <ref>{{Pepin J, Milord F, Guern C, Schechter PJ (1987). "Difluoromethylornithine for arseno-resistant Trypanosoma brucei gambiense sleeping sickness". Lancet 2 (8573): 1431–3. doi:10.1016/S0140-6736(87)91131-7. PMID 2891995. |
Eflornithine (α-difluoromethylornithine or DFMO) is a [[medication|drug]] found to be effective in the treatment of facial [[hirsutism]] <ref>{{1. Wolf JE, Shander D, Huber F, Jackson J, Lin CS, Mathes BM, Schrode K, and the Eflornithine Study Group. Randomized, double-blind clinical evaluation of the efficacy and safety of topical eflornithine HCI 13.9% cream in the treatment of women with facial hair. Int J Dermatol 2007 Jan; 46(1): 94-8.}}</ref> (excessive hair growth) as well as in [[African trypanosomiasis]] (sleeping sickness) <ref>{{Pepin J, Milord F, Guern C, Schechter PJ (1987). "Difluoromethylornithine for arseno-resistant Trypanosoma brucei gambiense sleeping sickness".|url=http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(87)91131-7 Lancet 2 (8573): 1431–3. [[Digital_object_identifier|doi]]:10.1016/S0140-6736(87)91131-7.|url=http://dx.doi.org/10.1016%2FS0140-6736%2887%2991131-7 [[PubMed_Identifier|PMID]] 2891995.|url=http://www.ncbi.nlm.nih.gov/pubmed/2891995}}</ref>. Eflornithine hydrochloride cream, which is for topical administration in women suffering from facial hirsutism, is marketed under the brand name Vaniqa by Almirall in Europe, CSL in Australia, Triton in Canada, Medison in Israel and SkinMedica in the USA. <ref>{{Vaniqa US Patient Information Leaflet|url=http://www.vaniqa.com/files/Vaniqa_Prescription_Info.pdf}}</ref> Eflornithine for injection against sleeping sickness is manufactured by Sanofi Aventis and sold under the brand name Ornidyl in the USA. <ref>{{Ornidyl advanced consumer information | Drugs.com|url=http://www.drugs.com/cons/Ornidyl.html}}</ref> Both are prescription drugs. |
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==History== |
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Eflornithine was initially developed for cancer treatment at Merrell Dow Research Institute in the late 1970s, but, while having little use in treating malignancies, it was found to be highly effective in reducing hair growth <ref>{{Wolf JE, Shander D, Huber F, Jackson J, Lin CS, Mathes BM, Schrode K, and the Eflornithine Study Group. Randomized, double-blind clinical evaluation of the efficacy and safety of topical eflornithine HCI 13.9% cream in the treatment of women with facial hair. Int J Dermatol 2007 Jan; 46(1): 94-8.}}</ref>, as well as in treatment of [[African trypanosomiasis]] (sleeping sickness) <ref>{{Pepin J, Milord F, Guern C, Schechter PJ (1987). "Difluoromethylornithine for arseno-resistant Trypanosoma brucei gambiense sleeping sickness".|url=http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(87)91131-7 Lancet 2 (8573): 1431–3. [[Digital_object_identifier|doi]]:10.1016/S0140-6736(87)91131-7.|url=http://dx.doi.org/10.1016%2FS0140-6736%2887%2991131-7 [[PubMed_Identifier|PMID]] 2891995.|url=http://www.ncbi.nlm.nih.gov/pubmed/2891995}}</ref>, especially the West African form (Trypanosoma brucei gambiense). |
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==Hirsutism== |
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In the 1980s, Gillette was awarded a patent for the discovery that topical application of eflornithine HCl cream inhibits hair growth. In the 1990s, Gillette conducted dose-ranging studies with eflornithine in hirsute women that demonstrated that the drug slows the rate of facial hair growth. Gillette then filed a patent for the formulation of eflornithine cream. In July 2000, the [[FDA]] granted a U.S. [[New_Drug_Application|NDA]] for Vaniqa. The following year, the European Commission issued its Marketing Authorisation. Today, Vaniqa is marketed by Almirall in Europe, CSL in Australia, Triton in Canada, Medison in Israel and SkinMedica in the USA. <ref>{{Vaniqa Training Programme Module 5}}</ref> |
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==Sleeping sickness treatment== |
==Sleeping sickness treatment== |
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In 2001, Aventis (now Sanofi-Aventis) and the WHO formed a five-year partnership, during which more than 320,000 vials of pentamidine, over 420,000 vials of melarsoprol, and over 200,000 bottles of eflornithine were produced by Sanofi-Aventis, to be given to the WHO and distributed by the association Doctors Without Borders (aka MSF - Médecins sans Frontières) <ref>{{IFPMA Health Initiatives: Sleeping Sickness|url=http://www.ifpma.org/Health/other_infect/health_sleep.aspx}}</ref> <ref>{{Sanofi-Aventis Access to Medicines Brochure|url=http://en.sanofi-aventis.com/binaries/brochure_aam_en_tcm28-18133.pdf}}</ref> in countries where the sleeping sickness is endemic. |
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From 2001 through 2006, 14 million diagnoses were made. This greatly contributed to stemming the spread of sleeping sickness, and to saving nearly 110,000 lives. This changed the epidemiological profile of the disease, meaning that eliminating it altogether can now be envisaged. <ref>{{Sanofi-Aventis Access to Medicines Brochure|url=http://en.sanofi-aventis.com/binaries/brochure_aam_en_tcm28-18133.pdf}}</ref> |
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===Function=== |
===Function=== |
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Eflornithine appears to kill [[trypanosomes]] by acting as a [[suicide inhibitor]] of the enzyme [[ornithine decarboxylase]] ({{EC number|4.1.1.17}}); this enzyme regulates [[cell division]] by catalysing the first step in [[polyamine]] biosynthesis. As the inhibitor has a low half-life in humans, it is broken down quickly, while the parasite cannot [[metabolise]] it quickly enough. This means that it preferentially harms the parasite. |
Eflornithine appears to kill [[trypanosomes]] by acting as a [[suicide inhibitor]] of the enzyme [[ornithine decarboxylase]] ({{EC number|4.1.1.17}}); this enzyme regulates [[cell division]] by catalysing the first step in [[polyamine]] biosynthesis. As the inhibitor has a low half-life in humans, it is broken down quickly, while the parasite cannot [[metabolise]] it quickly enough. This means that it preferentially harms the parasite. |
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Revision as of 09:16, 19 May 2010
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| Routes of administration | Intravenous (discontinued) Dermal |
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| Pharmacokinetic data | |
| Bioavailability | 100% (Intravenous) Negligible (Dermal) |
| Metabolism | Not metabolised |
| Elimination half-life | 8 hours |
| Excretion | Renal |
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| Chemical and physical data | |
| Formula | C6H12F2N2O2 |
| Molar mass | 182.2 g/mol g·mol−1 |
Eflornithine (α-difluoromethylornithine or DFMO) is a drug found to be effective in the treatment of facial hirsutism [1] (excessive hair growth) as well as in African trypanosomiasis (sleeping sickness) [2]. Eflornithine hydrochloride cream, which is for topical administration in women suffering from facial hirsutism, is marketed under the brand name Vaniqa by Almirall in Europe, CSL in Australia, Triton in Canada, Medison in Israel and SkinMedica in the USA. [3] Eflornithine for injection against sleeping sickness is manufactured by Sanofi Aventis and sold under the brand name Ornidyl in the USA. [4] Both are prescription drugs.
History
Eflornithine was initially developed for cancer treatment at Merrell Dow Research Institute in the late 1970s, but, while having little use in treating malignancies, it was found to be highly effective in reducing hair growth [5], as well as in treatment of African trypanosomiasis (sleeping sickness) [6], especially the West African form (Trypanosoma brucei gambiense).
Hirsutism
In the 1980s, Gillette was awarded a patent for the discovery that topical application of eflornithine HCl cream inhibits hair growth. In the 1990s, Gillette conducted dose-ranging studies with eflornithine in hirsute women that demonstrated that the drug slows the rate of facial hair growth. Gillette then filed a patent for the formulation of eflornithine cream. In July 2000, the FDA granted a U.S. NDA for Vaniqa. The following year, the European Commission issued its Marketing Authorisation. Today, Vaniqa is marketed by Almirall in Europe, CSL in Australia, Triton in Canada, Medison in Israel and SkinMedica in the USA. [7]
Sleeping sickness treatment
In 2001, Aventis (now Sanofi-Aventis) and the WHO formed a five-year partnership, during which more than 320,000 vials of pentamidine, over 420,000 vials of melarsoprol, and over 200,000 bottles of eflornithine were produced by Sanofi-Aventis, to be given to the WHO and distributed by the association Doctors Without Borders (aka MSF - Médecins sans Frontières) [8] [9] in countries where the sleeping sickness is endemic.
From 2001 through 2006, 14 million diagnoses were made. This greatly contributed to stemming the spread of sleeping sickness, and to saving nearly 110,000 lives. This changed the epidemiological profile of the disease, meaning that eliminating it altogether can now be envisaged. [10]
Function
Eflornithine appears to kill trypanosomes by acting as a suicide inhibitor of the enzyme ornithine decarboxylase (EC 4.1.1.17); this enzyme regulates cell division by catalysing the first step in polyamine biosynthesis. As the inhibitor has a low half-life in humans, it is broken down quickly, while the parasite cannot metabolise it quickly enough. This means that it preferentially harms the parasite.
Eflornithine's effects against Trypanosoma brucei gambiense were discovered by chance, and because of its ability to bring patients back from coma, it became known as "Resurrection Drug."
It is hoped that eflornithine will replace the more toxic melarsoprol.
Production
Supplies of eflornithine are limited, as its manufacturer does not consider it cost effective.
Its production was halted by its manufacturer, Aventis, in 1995 because the company did not consider it a profitable drug. The disease mainly affects poor people unable to pay for any sort of treatment.
In 2001, after lobbying at the WHO World Health Organization by Médecins Sans Frontières ("Doctors Without Borders"), the manufacturer resumed production of eflornithine, melarsoprol, and pentamidine in sufficient amounts to cover existing needs. This 5-year agreement with the WHO also envisaged MSF's working on the distribution of the drugs. The yearly value of the drugs donated by Aventis under this agreement is US$5 million. In addition, under the agreement, Bristol-Myers Squibb, the manufacturer of Vaniqa, will pay for part of the eflornithine. The 5-year agreement expired in 2006.[11] The trade name of eflornithine as manufactured for the treatment of sleeping sickness is Ornidyl.
Once the five-year period is over, Sanofi-Aventis (its new name after merging with another drugs company, Sanofi-Synthélabo) would start transferring technology and giving technical assistance to any possible manufacturer willing to continue production on their own.[12]
As of September 2005, the World Health Organization reports that the India Institute of Chemical Technology in Hyderabad, India and ILEX Oncology in Texas, United States are both working on new ways of making eflornithine more cheaply. The WHO goes on to say that ILEX is experimenting with an oral formulation of the drug as a treatment for cancer and that trials of the new oral formulation for efficacy against sleeping sickness are underway.
Dosing
When used for sleeping sickness, eflornithine is given intravenously, 50 mg/kg every six hours for 14 days.[13]
Hair growth inhibitor cream
Eflornithine is also an effective hair growth inhibiting agent. As a topical application, the drug has been shown to be an effective hair growth retardant in some patients, and is sold under the brand name Vaniqa (eflornithine hydrochloride 13.9%). Efficacy data submitted to Food and Drug Administration (FDA) observed about 58% of women using it on facial hair had improvement.[15] This study suggested it may be particularly effective in postmenopausal women. One large published study on safety found the product rarely caused significant side effects such as acne, follicle irritation, itching or dryness.[16] This corroborates unpublished data submitted to FDA showing about 2% of subjects discontinued use due to adverse reactions.
It is partly the development of the hair removal market that encouraged Aventis to restart the manufacture of eflornithine, and which allowed it to once again become available for use in sleeping sickness.
References
- ^ {{1. Wolf JE, Shander D, Huber F, Jackson J, Lin CS, Mathes BM, Schrode K, and the Eflornithine Study Group. Randomized, double-blind clinical evaluation of the efficacy and safety of topical eflornithine HCI 13.9% cream in the treatment of women with facial hair. Int J Dermatol 2007 Jan; 46(1): 94-8.}}
- ^ Template:Pepin J, Milord F, Guern C, Schechter PJ (1987). "Difluoromethylornithine for arseno-resistant Trypanosoma brucei gambiense sleeping sickness".
- ^ Template:Vaniqa US Patient Information Leaflet
- ^ Template:Ornidyl advanced consumer information
- ^ {{Wolf JE, Shander D, Huber F, Jackson J, Lin CS, Mathes BM, Schrode K, and the Eflornithine Study Group. Randomized, double-blind clinical evaluation of the efficacy and safety of topical eflornithine HCI 13.9% cream in the treatment of women with facial hair. Int J Dermatol 2007 Jan; 46(1): 94-8.}}
- ^ Template:Pepin J, Milord F, Guern C, Schechter PJ (1987). "Difluoromethylornithine for arseno-resistant Trypanosoma brucei gambiense sleeping sickness".
- ^ Template:Vaniqa Training Programme Module 5
- ^ Template:IFPMA Health Initiatives: Sleeping Sickness
- ^ Template:Sanofi-Aventis Access to Medicines Brochure
- ^ Template:Sanofi-Aventis Access to Medicines Brochure
- ^ IFPMA Health Initiatives: Sleeping Sickness
- ^ Template:Es icon http://www.dndi.org.br/Espanhol/doenca_sono.aspx
- ^ Van Nieuwenhove S, Schechter PJ, Declercq J, Boné G, Burke J, Sjoerdsma A (1985). "Treatment of gambiense sleeping sickness in the Sudan with oral DFMO (DL-alpha-difluoromethylornithine), an inhibitor of ornithine decarboxylase; first field trial". Trans. R. Soc. Trop. Med. Hyg. 79 (5): 692–8. doi:0.1016/0035-9203(85)90195-6. PMID 3938090.
{{cite journal}}: Check|doi=value (help)CS1 maint: multiple names: authors list (link) - ^ Poulin R, Lu L, Ackermann B, Bey P, Pegg AE (1992). "Mechanism of the irreversible inactivation of mouse ornithine decarboxylase by alpha-difluoromethylornithine. Characterization of sequences at the inhibitor and coenzyme binding sites". J. Biol. Chem. 267 (1): 150–8. PMID 1730582.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Vaniqa package insert
- ^ Hickman JG, Huber F, Palmisano M (2001). "Human dermal safety studies with eflornithine HCl 13.9% cream (Vaniqa), a novel treatment for excessive facial hair". Curr Med Res Opin. 16 (4): 235–44. doi:10.1185/030079901750176735. PMID 11268707.
{{cite journal}}: CS1 maint: multiple names: authors list (link)