General information about the use of eflornithine.

Fråga: General information about the use of eflornithine.

Sammanfattning: The drugs available for the treatment of trypanosomiasis are either toxic or ineffective against the late stages of the disease. Thus we hope that eflornithine will be a major addition to the treatments for Trypanosoma brucei gambiense despite the absence of controlled clinical studies. However, the current dosage of 400 mg/kg/day delivered intravenously several times daily is cumbersome and requires certain skills and equipment. It also costs 140 US dollars per treatment.

Svar: Eflornithine, formerly known as DFMO (DL-alpha-difluoromethylornithine), is an antiprotozoal agent active in vitro against Trypanosoma brucei gambiense, exoerythrocytic forms of Plasmodium berghei, Giardia lamblia, Trichomonas vaginalis, and Pneumocystis carinii (1). The drug was originally developed as an anticancer agent. In November 1990, the US Food and Drug Administration (FDA) registered the drug under the name "Ornidyl" for the treatment of Trypanosoma brucei gambiense (2). Merrel-Dow Pharmaceuticals Inc, Cincinnati, OH, manufactures the drug; however, the company has offered WHO the rights, the patent and the technical know-how for manufacture of the drug on a royalty-free basis. Eflornithine irreversibly inhibits lower case ornithine decarboxylase (ODC) which catalyses the biosynthesis of polyamines. The common polyamines putrescine, spermidine and spermine are low-molecular weight molecules present in all living cells and are important for the cell growth, differentiation and replication of trypanosomes (3).

Pharmacokinetic studies of eflornithine are limited and there are no proper studies on patients with trypanosomiasis. In one study on healthy volunteers (4), a single oral dose of 10 mg/kg of eflornithine hydrochloride gave peak plasma levels of 39 umol/L four hours after the drug intake. The bioavailability of the drug was about 50 per cent that of the same dose given intravenously. More than 80 per cent of the drug was eliminated through the kidneys during the first 24 hours, of which half was accounted for as the parent drug. The elimination half-life is reported to be around 3-4 hours. The drug was analysed with a Kontron Liquimat II amino-acid analyser. However, more specific HPLC methods have been described (5,6). The access of eflornithine to the CSF increases proportionally with the degree of CNS involvement and CSF levels have been found to vary between 25 and 50 per cent those found in plasma (7,8).

The available clinical data on eflornithine are based on sporadic case reports and uncontrolled clinical observations from the Sudan, Italy, Belgium, the Ivory Coast, the United States of America, the Republic of Zaire, France, and the People´s Republic of the Congo (9-16). The patients were largely blacks suffering from late-stage (CNS involvement) Trypanosoma brucei gambiense and were living in Africa or had travelled to the west. Most of them had been treated previously with melarsoprol and were refractory to that treatment.

The dosages were 100 mg/kg given intravenously every six hours for 2-3 weeks, followed by 75 mg/kg given orally every six hours for a further 3 weeks. Most studies reported a rapid disappearance of trypanosomes from body fluids, in some cases within 24 hours after starting therapy, with a dramatic reversal of clinical signs and symptoms which led to complete recovery. Some of the patients were followed for more than two years without any relapse. Similar responses were reported from more than 600 patients treated in Gambia (2). The current recommended dosage regimen is 100 mg/kg/day intravenously for two weeks; however, the experience with this regimen is limited (2). There are no clinical studies on the efficacy of eflornithine against Trypanosoma brucei rhodesiense; however, there are some indications that the drug is not effective against this species (2).

Most studies reported the drug to be relatively well tolerated. In one study in the Ivory Coast (7), where 14 patients were given the drug, the following side-effects were reported: diarrhoea (11 persons), abdominal pain (6 persons), blood in the stools (two persons), anaemia (8 persons), thrombocytopenia (two persons), cutaneous eruptions (one person), seizures (two persons), and haematuria (one person). The diarrhoea accompanied with abdominal pain was usually encountered after oral intake of the drug. Anaemia developed several weeks after treatment. Side-effects are reported to be reversible after drug discontinuation. The teratogenic effects of eflornithine are unknown; however, it arrests embryonic development in animal models when the agent is present during early embryonic stages (17). 1 Tyms AS, Williamson JD, Bacchi CJ: Polyamine inhibitors in antimicrobial chemotherapy. J Antimicrob Chemother 1988; 22: 403-427 2 Tropical Diseases: progress in research 1989-1990. Tenth programme report UNDP/World bank/TDR. World Health Organization, Geneva, 1991 3 Bogaert I van, Haemers A: Eflornithine. A new drug in the treatment of sleeping sickness. Pharm Weekbl (Sci) 1989; 11: 69-75 4 Haegele KD, Alken RG, Grove J, Schechter PJ, Koch-Weser J: Kinetics of alpha-difluoromethylornithine: An irreversible inhibitor of ornithine decarboxylase. Clin Pharmacol Ther 1981; 30: 210-217 5 Smithers J: A precolumn derivatization high-performance liquid chromatographic (HPLC) procedure for the quantitation of difluoromethylornithine in plasma. Pharm Res 1988; 5: 684-686 6 Cohen JL, Ko RJ, Lo ATL, Shields MD, Gilman TM: High-pressure liquid chromatographic analysis of eflornithine in serum. J Pharm Sci 1989; 78: 114-116 7 Doua F, Bboa FY, Schechter PJ, Miezan TW, Diai D, Sanon SR, de Raad P, Haegele KD, Sjoerdsma A, Konian K: Treatment of human late stage gambiense trypanosomiasis with alpha-difluoromethylornithine (eflornithine): efficacy and tolerance in 14 cases in cote d´ivoire. Am J Trop Med Hyg 1987; 37: 525-533 8 Taelman H, Schechter PJ, Marcelis L, Sonnet J, Kazyumba G, Dasnoy J, Haegele KD, Sjoersdma A, Wery M: Difluoromethylornithine, an effective new treatment of gambian trypanosmiasis. Am J med 1987; 82: 607-614 9 van Nieuwenhove S, Schechter PJ, Declerqo J, Bone G, Burke J, Sjoersdma A: 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 1985; 79: 692-698 10 Eozenou P, Jannin J, Ngampo S, Carme B, Tell GP, Schechter PJ: Clinical trial of eflornnithine in human Trypanosoma brucei gambiensen trypanosmiasis in the Congo. Med Trop 1989; 49: 149-154 11 Hamon JF, Seri B, Doua F, Camara P, Aba L: Effects of Mel B Arsobal and alpha-difluoromethylornithine on the awakening electroencephalogram of humans with gambiense trypanisomiasos disease: preliminary report. Pharmacol Biochem Behav 1990; 36: 831-835 12 Di Bari C, Pastore G, Roscigno G, Schechter PJ, Sjoersdma A: Late-stage African trypanosomiasis and eflornithine. Ann Intern Med 1986; 105: 803-804 13 Petru AM, Azimi PH, Cummins SK, Sjoersdma A: African sleeping sickness in the United States. Successful treatment with eflornithine. Am J Dis Child 1988; 142: 224-226 14 Pepin J, Guern C, Milord F, Ethier L, Bokelo M, Schechter PJ: Utilization of difluoromethylornithine congenital Trypanosoma brucei gambiense trypanosomiasis. Med Trop 1989; 49: 83-85 15 Benhamou PH, Chandenier J, Schechter PJ, Epelbaum S, Tell GP, Haegele KD, Pautard JC, Piussan Ch: Childhood African trypanosomiasis treated with eflornithine. Presse Med 1989; 18: 1199-1202 16 Sjoerdsma A, Golden JA, Schechter PJ, Barlow JLR, Santi DV: Successful treatment of lethal protozoal infections with the ornithine decarboxylase inhibitor, alpha-difluoromethylornithine. Trans Assoc Am Physician 1984; 97: 70-79 17 Fozard JR, Part ML, Parakash NJ, Grove J, Schechter PJ, Sjoerdsma A, Koch-Weser J: L-Ornithine decarboxylase: An essential role in early mammalian embryogenesis. Science 1980; 208: 505-508