Eflornithine

Ornithine decarboxylase is a pyridoxal dependent enzyme. In its catalytic cycle, it normally converts ornithine (7) to putrisine by decarboxylation. If it starts the process with eflornithine instead, the key imine anion (11) produced by decarboxylation can either alkylate the enzyme directly by displacement of either fluorine atom or it can eject a fluorine atom to produce viny-logue 12 which can alkylate the enzyme by conjugate addidon. In either case, 13 results in which the active site of the enzyme is alkylated and unable to continue processing substrate. The net result is a downturn in the synthesis of cellular polyamine production and a decrease in growth rate. Eflornithine is described as being useful in the treatment of benign prostatic hyperplasia, as an antiprotozoal or an antineoplastic substance [3,4]. 

Eflornithine (difluoromethylornithine, DFMO) inhibits the ornithine decarboxylase of the polyamine pathway, in both the trypanosome and the mammalian cell, by acting as an irreversible competitor of the natural substrate ornithine. Inhibition of ornithine decarboxylase results in depletion of the polyamines, putrescine, spermidine and spermine, which are essential for cell proliferation. Eflornithine selectively harms the parasite and not the mammalian cells, despite acting as an ornithine decarboxylase inhibitor in both cell types. This selectivity is explained by the lower rate of ornithine decarboxylase production in the parasite, as compared to mammalian cells. Due to the high turnover rate, mammalian cells are capable of quickly replenishing inhibited ornithine decarboxylase by newly... 

Biosynthesis of polyamines is essential for growth and multiplication of T. brucei, hence discovery of drug candidates that inhibit enzymes in the polyamine biosynthesis pathway represent an attractive approach to development of trypanocides. The consequences of gene knockout of ornithine decarboxylase (ODC), the target of eflornithine (3), have been further characterized and suggest that new inhibitors of this enzyme may be particularly effective [18]. 

Eflornithine, DL-a-difluoromethylornithine Ornithine decarboxylase Suicide substrate... 

Eflornithine (difluoromethyl ornithine, Ornidyl) is a unique antiprotozoal agent in that its mode of action involves inhibition of a specific enzyme, ornifhine decarboxylase. In eukaryofes, decarboxylafion of ornifhine is required for biosynfhesis of polyamines, which are im-porfanf in cell division and differenfiafion. 

S.2.3.3 Treatment of Trypanosomiasis The difluoromethylornithine (DFMO), eflomithine is a mechanism-based inhibitor of ornithine decarboxylase— a pyridoxal-dependent key enzyme of the polyamine s biosynthesis from ornithine. Fluorine atoms are essential for the inhibition process (cf. Chapter 7). Eflornithine was first clinically developed for cancer, but its development has been abandoned for this indication. The activity of eflornithine on trypanosomes was then discovered. Now, despite its very low bioavailability, eflornithine is the best therapy for sleeeping sickness (trypanosomiasis)—in particular, at the cerebral stage—due to Trypanosoma brucei gambiense parasite. Eflornithine is registered with orphan drug status and is distributed by the WHO. 

Currently, production of eflornithine has been stopped because of industrial policy and environmental problems it involves the use of Ereon (CHF2CI) as a reagent in its synthesis (Eigure 8.27). However, production of eflornithine may start again in order to supply the WHO. Another reason is that a topical formulation for the treatment of female hirsutism has recently been launched (Vaniqa). Its synthesis has recently been improved by using the selective catalytic reduction of the cyano group without any cyclization into lactam. ... 

The most frequent, serious, toxic effect of eflornithine is myelosuppression, which maybe unavoidable if successful treatment is to be completed decisions to modify dosage or to interrupt or cease treatment depend on the severity of the observed adverse event(s) and the availability of support facilities... 

West African Early Pentamidine Suramin, eflornithine... 

Melarsoprol is a trivalent arsenical that has been available since 1949 and is first-line therapy for advanced central nervous system East African trypanosomiasis, and second-line therapy (after eflornithine) for advanced West African trypanosomiasis. 

Priotto G et al Nifurtimox-eflornithine combination therapy for second-stage Trypanosoma brucei gambiense sleeping sickness A randomized clinical trial in Congo. Clin Infect Dis 2007 45 1435. [PMID 17990225]... 

Eflornithine (Vaniqa) is an irreversible inhibitor of ornithine decarboxylase, which catalyzes the rate-limiting step in the biosynthesis of polyamines. Polyamines are required for cell division and differentiation, and inhibition of ornithine decarboxylase affects the rate of hair growth. Topical eflornithine has been shown to be effective in reducing facial hair growth in approximately 30% of women when applied twice daily for 6 months of therapy. Hair growth was observed to return to pretreatment levels 8 weeks after discontinuation. Local adverse effects include stinging, burning, and folliculitis. 

Facial hair reduction for women Eflornithine hydrochloride Vaniqa Ceteareth-20, cetearyl alcohol, glyceryl stearate, PEG-100 stearate, stearyl alcohol Methylparabens, propylparabens... 

Figure 17.35. Inactivation of ornithine decarboxylase by eflornithine. For clarity, substituents on the pyridine ring are omitted.

An .erican mclarsoprol should be used. Eflornithine is effective for both early and late stages. Expert advice is recommended. Prolonged (I 3 months) treatment with... 

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