Eflornithine

Pharmacology and mechanism of action

Eflornithine, formerly known as DFMO (a-difluoromethylornithine), is a recent product deliberately designed to inhibit polyamine synthesis. The drug was originally intended for tumour chemotherapy but was later found unsatisfactory. The drug has demonstrated antiprotozoal activity in vitro, particularly against Trypanosoma brucei gambiense^[1] and Pneumocystis carinii^[2]. The efficacy of the drug in human trypanosomes has been confirmed both in animal models ^[3]and in humans ^[4]. In 1990 the US Food and Drug Administration approved eflornithine for the treatment of Trypanosoma brucei gambiense. The mechanism of action of eflornithine is due to its irreversible inhibition of ornithine decarboxylase (ODC) which catalyses the biosynthesis of polyamines. Common polyamines such as putrescine, spermidine and spermine are low-molecular weight molecules present in all living cells. They are important for cell growth, differentiation and replication of trypanosomes. Trypanosomes are more susceptible to the drug than human cells, possibly due to their slow turnover of this enzyme ^[1].

Indications

Because of its high cost, need of repeated intravenous administration and the relatively large quantities of the drug needed for each patient eflornithine use will be associated with major difficulties in rural Africa. Currently it is only recommended in patients with late-stage Trypanosoma brucei gambiense sleeping sickness refractory to melarsoprol.

Side effects

Eflornithine is generally better tolerated than melarsoprol. In one study in Zaire^[5], where 207 patients were given the drug the following side effects were reported: leucopenia (53%), anaemia (43%), diarrhoea (13%), convulsions (4%), abdominal pain (3%). Four patients (2%), who were already in a severe condition before treatment, died during treatment. Diarrhoea accompanied with abdominal pain was usually encountered after oral administration of the drug. Anaemia developed several weeks after treatment.
Other side effects reported include alopecia, hearing loss, blood in stool, thrombocytopenia, haematuria and alterations in liver function and skin rashes ^[5,6]. All side effects are reported to be reversible after drug discontinuation.

Contraindications and precautions

Patients with cardiac diseases, epilepsy or with anaemia must be treated with extra caution. White blood cell counts and haemoglobin levels must be monitored during eflornithine treatment. In patients with kidney failure dosage reduction has to be made.

Interactions

Drugs such as melarsoprol, suramin, and antimonial compounds have been reported to potentiate the clinical effects of eflornithine ^[7-9]. Combination between melarsoprol and eflornithine seems rational since both drugs have effects on trypanathione.

Preparations

Available as eflornithine hydrochloride.
• Ornidyl® (Marion Merrel Dow) Solution for injection, 100 mg per ml. Ornidyl is not available in all countries.
The drug may be obtained from the World Health Organization, Geneva, Switzerland (attention: Dr Kuzoe).

References

1. Bacchi CJ, Nathan HC, Hunter SH (1980). Polyamine metabolism: a potential therapeutic target in trypanosomes. Science, 210, 332–334.
2. Cushion MT, Stanforth D, Linke MJ, Walzer PD (1985). Method of testing the susceptibility of Pneumocystis carinii to antimicrobial agents in vitro. Antimicrob Agents Chemother, 28, 796–801.
3. McCann PP, Bachi CJ, Clarkson AB Jr, Seed JR, Nathan HC, Amole BO, Hutner SH, Sjoerdsma A (1981). Further studies on difluoromethylornithine in African trypanosomes. Med Biol, 59, 434–440.
4. Van Nieuwenhove S, Schechter PJ, Declercq J, Burke J, Sjoerdsma A (1985). Treatment of gambiense sleeping sickness in the Sudan with oral DFMO (DL-alfa-difluoromethylornithine) an inhibitor of ornithine decarboxylase; first field trial. Trans R Soc Trop Med Hyg, 79, 692–698.
5. Milord F, Pepin J, Loko L. Mpia B (1992). Efficacy and toxicity of eflornithine for treatment of Trypanosoma brucei gambiense sleeping sickness. Lancet, 340, 652–655.
6. Doua F, Boa FY, Schechter PJ, Miezan TW, Haegele KD, Sjoerdsma A, Konian K (1987). Treatment of human late stage gambiense trypanosomiasis with alfa-difluoromethylornithine (eflornithine): Efficacy and tolerance in 14 cases in C?te D’Ivoire. Am J Trop Med Hyg, 37, 525–533.
7. Jennings FW (1988). Chemotherapy of trypanosomiasis: the potentiation of melarsoprol by concurrent difluoromethylornithine (DFMO) treatment. Trans R Soc Trop Med Hyg, 82, 572–573.
8. Jennings FW (1991). Chemotherapy of trypanosomiasis: the potentiation of antimonial compounds by difluoromethylornithine (DFMO). Trop Med Parasitol, 42, 135–138.
9. Clarkson AB, Bienen EJ, Bacchi CJ, McCann PP, Nathan HC, Hunter SH, Sjoerdsma A (1984). New drug combination for experimental late-stage African trypanosomiasis: DL-alfadifluoromethylornithine (DFMO) with suramin. Am J Trop Med Hyg, 33, 1073–1077.

Description

Metcalf et al.reported the synthesis of eflornithine (difluoromethyl ornithine [DFMO]) in 1978. Their interest arose from the desire to prepare ornithine decarboxylase (ODC) inhibitors as tools for studying the role of polyamines as regulators of growth processes. Ornithine decarboxylase catalyzes the conversion of ornithine to putrescine (1,4-diaminobutane), which in turn leads to the formation of the polyamines, spermine, and spermidine. It was not until 1980 that Bacchi et al. demonstrated the potential of DFMO in the treatment of trypanosomiasis.

Uses

Eflornithine is an irreversible inhibitor of ornithine decarboxylase that blocks putrescine biosynthesis in T. brucei in vitro and inhibits the growth and multiplication of the parasite in vivo. The drug, administered orally or parenterally, is relatively nontoxic and is effective in eliminating the parasite T. b. rhodesiense and, to a greater extent, T. b. gambiense. Eflornithine was approved for human use by the FDA in late 1990. Side effects associated with oral administration are diarrhea, nausea, and vomiting. There is a significant relapse rate. A mixture of eflornithine (5) and nifurtimox (6, C10H13N3O5S, Lampit, Bayer 2502) shows good activity against T. b. gambiense. The former compound is also reported to potentiate the effect of melarsoprol in infected mice.

Uses

Labelled Eflornithine. Irreversible inhibitor of ornithine decarboxylase, an enzyme involved in polyamine biosynthesis. Antineoplastic; antipneumocystic; antiprotozoal (Trypanosoma). Used in the treatment of hirsutism.

Indications

Eflornithine (difluoromethyl ornithine, Ornidyl) is a unique antiprotozoal agent in that its mode of action involves inhibition of a specific enzyme, ornithine decarboxylase. In eukaryotes, decarboxylation of ornithine is required for biosynthesis of polyamines, which are important in cell division and differentiation.
Eflornithine is given intravenously, and about 80% of the drug is excreted in the urine within 24 hours. It does not bind significantly to plasma proteins and has a terminal plasma half-life of about 3 hours. It crosses the blood-brain barrier and is one of the drugs of choice for treating the hemolymphatic and meningoencephalitic stage of T. brucei-gambiense. The most significant side effects are anemia and leukopenia. Oral therapy is associated with considerable gastrointestinal toxicity. Diarrhea, thrombocytopenia, and seizures are occasionally reported.

Definition

ChEBI: Eflornithine is a fluoroamino acid that is ornithine substituted by a difluoromethyl group at position 2. It has a role as a trypanocidal drug. It is a fluoroamino acid and an alpha-amino acid. It is functionally related to an ornithine.

brand name

Ornidyl (Sanofi Aventis); Vaniqa (Skinmedica).

Mechanism of action

Difluoromethyl ornithine is a suicide inhibitor of ODC, a pyridoxal phosphate–dependent enzyme. Evidence suggests that cysteine-360 in ODC is the site of eflornithine alkylation. Alkylation of ODC blocks the synthesis of putrescine, the rate-determining step in the synthesis of polyamines. Mammalian ODC also may be inhibited, but because the turnover of ODC is so rapid in mammals, eflornithine does not produce serious side effects.

Clinical Use

Eflornithine is used for the treatment of West African sleepingsickness, caused by Trypanosoma brucei gambiense.It is specifically indicated for the meningoencephaliticstage of the disease. Eflornithine is a myelosuppressivedrug that causes high incidences of anemia, leukopenia,and thrombocytopenia. Complete blood cell counts must bemonitored during the course of therapy.The irreversible inactivation of ornithine decarboxylaseby eflornithine is accompanied by decarboxylation andrelease of fluoride ion from the inhibitor, suggesting enzyme-catalyzed activation of the inhibitor. Only the (—) isomer,stereochemically related to L-ornithine, is active.
Eflornithine is supplied as the hydrochloride salt. It may beadministered either intravenously or orally. Approximately80% of the unchanged drug is excreted in the urine.Penetration of eflornithine into the CSF is facilitated by inflammationof the meninges.

Side effects

Side effects reported for eflornithine consist of anemia, diarrhea, and leukopenia.