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Eflornithine

Basic information Pharmacology and mechanism of action Indications Side effects Contraindications and precautions Interactions Preparations References Safety Related Supplier

Eflornithine Basic information

Product Name:
Eflornithine
CAS:
67037-37-0
MF:
C6H12F2N2O2
MW:
182.17
Mol File:
67037-37-0.mol
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Eflornithine Chemical Properties

Density 
1.1800 (estimate)
storage temp. 
-15°C
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Eflornithine Usage And Synthesis

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.

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.

brand name

Ornidyl (Sanofi Aventis); Vaniqa (Skinmedica).

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.

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Pure Chemistry Scientific Inc.
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Richest Group Limited
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Hangzhou J&H Chemical Co., Ltd.
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Hubei Jusheng Technology Co.,Ltd
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027-59599241- ;027-59599240
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Basic information Pharmacology and mechanism of action Indications Side effects Contraindications and precautions Interactions Preparations References Safety Related Supplier