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Eflornithine
Systematic (IUPAC) name
2,5-diamino-2-(difluoromethyl)pentanoic acid
Identifiers
CAS number 70052-12-9
ATC code D11AX16 P01CX03
PubChem 3009
ChemSpider 2902
Chemical data
Formula C6H12F2N2O2 
Mol. mass 182.2 g/mol
Pharmacokinetic data
Bioavailability 100% (Intravenous)
13% (Dermal)
Metabolism Not metabolised
Half life 8 hours
Excretion Renal
Therapeutic considerations
Licence data

US FDA:link

Pregnancy cat. Category C for dermal cream
Legal status Prescription only
Routes Intravenous (discontinued)
Dermal

Eflornithine (α-difluoromethylornithine or DFMO) is a drug manufactured by Sanofi-Aventis that has various uses. It was initially developed for cancer treatment, but, while having little use in treating malignancies, it was found to be highly effective in African trypanosomiasis (sleeping sickness), especially the West African form (Trypanosoma brucei gambiense).[1] In the United States it is known by the brand name Ornidyl.[2] A recent study (reported 2008 [3]) conducted by UC Irvine researchers indicates that, when combined with sulindac (an anti-inflammatory drug), DFMO significantly reduces the risk of recurring colorectal polyps.

Contents

Sleeping sickness treatment

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 relatively 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.[4] 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.[5]

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.[6]

Chemical mechanism for irreversible inhibition of ornithine decarboxylase by DFMO. Pyridoxal 5'-phosphate (Py) and enzyme (E) are not shown. Adapted from[7]

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.[8] 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.[9] 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 re-start the manufacture of eflornithine, and which allowed it to once again become available for use in sleeping sickness.

References

  1. ^ 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. http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(87)91131-7. 
  2. ^ Ornidyl advanced consumer information | Drugs.com
  3. ^ An effective colon cancer prevention treatment
  4. ^ IFPMA Health Initiatives: Sleeping Sickness
  5. ^ (Spanish) http://www.dndi.org.br/Espanhol/doenca_sono.aspx
  6. ^ 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. 
  7. ^ 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. http://www.jbc.org/cgi/reprint/267/1/150. 
  8. ^ Vaniqa package insert
  9. ^ 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. http://openurl.ingenta.com/content/nlm?genre=article&issn=0300-7995&volume=16&issue=4&spage=235&aulast=Hickman. 

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