Safety and Effectiveness of First Line Eflornithine for Trypanosoma Brucei Gambiense Sleeping Sickness in Sudan: Cohort Study

Overview

Journal BMJ

Specialty General Medicine

Date 2008 Mar 7

PMID 18321960

Citations 38

Authors

Gerardo Priotto

Loretxu Pinoges

Isaac Badi Fursa

Barbara Burke

Nathalie Nicolay

Guillaume Grillet

Cathy Hewison

Manica Balasegaram

Affiliations

Soon will be listed here.

Abstract

Objective: To assess the safety and effectiveness of eflornithine as first line treatment for human African trypanosomiasis.

Design: Cohort study.

Setting: Control programme in Ibba, southern Sudan.

Participants: 1055 adults and children newly diagnosed with second stage disease in a 16 month period.

Main Outcome Measures: Deaths, severe drug reactions, and cure at 24 months.

Results: 1055 patients received eflornithine for 14 days (400 mg/kg/day in adults and 600 mg/kg/day in a subgroup of 96 children). Overall, 2824 drug reactions (2.7 per patient) occurred during hospital stay, 1219 (43.2%) after the first week. Severe reactions affected 138 (13.1%) patients (mainly seizures, fever, diarrhoea, and bacterial infections), leading to 15 deaths. Risk factors for severe reactions included cerebrospinal fluid leucocyte counts > or =100x10(9)/l (adults: odds ratio 2.6, 95% confidence interval 1.5 to 4.6), seizures (adults: 5.9, 2.0 to 13.3), and stupor (children: 9.3, 2.5 to 34.2). Children receiving higher doses did not experience increased toxicity. Follow-up data were obtained for 924 (87.6%) patients at any follow-up but for only 533 (50.5%) at 24 months. Of 924 cases followed, 16 (1.7%) died during treatment, 70 (7.6%) relapsed, 15 (1.6%) died of disease, 403 (43.6%) were confirmed cured, and 420 (45.5%) were probably cured. The probability of event free survival at 24 months was 0.88 (0.86 to 0.91). Most (65.8%, 52/79) relapses and disease related deaths occurred after 12 months. Risk factors for relapse included being male (incidence rate ratio 2.42, 1.47 to 3.97) and cerebrospinal fluid leucocytosis: 20-99x10(9)/l (2.35, 1.36 to 4.06); > or =100x10(9)/l (1.87, 1.07 to 3.27). Higher doses did not yield better effectiveness among children (0.87 v 0.85, P=0.981). Conclusions Eflornithine shows acceptable safety and effectiveness as first line treatment for human African trypanosomiasis. Relapses did occur more than 12 months after treatment. Higher doses in children were well tolerated but showed no advantage in effectiveness.

Citing Articles

Cholesterol Efflux Decreases TLR4-Target Gene Expression in Cultured Macrophages Exposed to Ghosts.

Fernando L, Echesabal-Chen J, Miller M, Powell R, Bruce T, Paul A Microorganisms. 2024; 12(8).

PMID: 39203572 PMC: 11357207. DOI: 10.3390/microorganisms12081730.

Venturicidin A affects the mitochondrial membrane potential and induces kDNA loss in .

Hauser D, Kaiser M, Maser P, Albisetti A Antimicrob Agents Chemother. 2024; 68(7):e0167123.

PMID: 38869301 PMC: 11232411. DOI: 10.1128/aac.01671-23.

Phase 1 study of high-dose DFMO, celecoxib, cyclophosphamide and topotecan for patients with relapsed neuroblastoma: a New Approaches to Neuroblastoma Therapy trial.

Hogarty M, Ziegler D, Franson A, Chi Y, Tsao-Wei D, Liu K Br J Cancer. 2024; 130(5):788-797.

PMID: 38200233 PMC: 10912730. DOI: 10.1038/s41416-023-02525-2.

Inhibition of polyamine biosynthesis preserves β cell function in type 1 diabetes.

Sims E, Kulkarni A, Hull A, Woerner S, Cabrera S, Mastrandrea L Cell Rep Med. 2023; 4(11):101261.

PMID: 37918404 PMC: 10694631. DOI: 10.1016/j.xcrm.2023.101261.

Tackling Sleeping Sickness: Current and Promising Therapeutics and Treatment Strategies.

Jamabo M, Mahlalela M, Edkins A, Boshoff A Int J Mol Sci. 2023; 24(15).

PMID: 37569903 PMC: 10420020. DOI: 10.3390/ijms241512529.

References

Magnus E, Vervoort T, VAN MEIRVENNE N . A card-agglutination test with stained trypanosomes (C.A.T.T.) for the serological diagnosis of T. B. gambiense trypanosomiasis. Ann Soc Belg Med Trop. 1978; 58(3):169-76. View

Milord F, Pepin J, Loko L, Ethier L, Mpia B . Efficacy and toxicity of eflornithine for treatment of Trypanosoma brucei gambiense sleeping sickness. Lancet. 1992; 340(8820):652-5. DOI: 10.1016/0140-6736(92)92180-n. View

Schmid C, Richer M, Bilenge C, Josenando T, Chappuis F, Manthelot C . Effectiveness of a 10-day melarsoprol schedule for the treatment of late-stage human African trypanosomiasis: confirmation from a multinational study (IMPAMEL II). J Infect Dis. 2005; 191(11):1922-31. DOI: 10.1086/429929. View

Pepin J, Milord F, Khonde A, Niyonsenga T, Loko L, Mpia B . Risk factors for encephalopathy and mortality during melarsoprol treatment of Trypanosoma brucei gambiense sleeping sickness. Trans R Soc Trop Med Hyg. 1995; 89(1):92-7. DOI: 10.1016/0035-9203(95)90673-8. View

Stanghellini A, Josenando T . The situation of sleeping sickness in Angola: a calamity. Trop Med Int Health. 2001; 6(5):330-4. DOI: 10.1046/j.1365-3156.2001.00724.x. View

Haegele K, Alken R, Grove J, Schechter P, Koch-Weser J . Kinetics of alpha-difluoromethylornithine: an irreversible inhibitor of ornithine decarboxylase. Clin Pharmacol Ther. 1981; 30(2):210-7. DOI: 10.1038/clpt.1981.150. View

Pepin J, Khonde N, Maiso F, Doua F, Jaffar S, Ngampo S . Short-course eflornithine in Gambian trypanosomiasis: a multicentre randomized controlled trial. Bull World Health Organ. 2001; 78(11):1284-95. PMC: 2560627. View

Bacchi C, Garofalo J, Mockenhaupt D, McCann P, Diekema K, Pegg A . In vivo effects of alpha-DL-difluoromethylornithine on the metabolism and morphology of Trypanosoma brucei brucei. Mol Biochem Parasitol. 1983; 7(3):209-25. DOI: 10.1016/0166-6851(83)90022-1. View

Bacchi C, Nathan H, Hutner S, McCann P, SJOERDSMA A . Polyamine metabolism: a potential therapeutic target in trypanosomes. Science. 1980; 210(4467):332-4. DOI: 10.1126/science.6775372. View

10.

Chappuis F, Udayraj N, Stietenroth K, Meussen A, Bovier P . Eflornithine is safer than melarsoprol for the treatment of second-stage Trypanosoma brucei gambiense human African trypanosomiasis. Clin Infect Dis. 2005; 41(5):748-51. DOI: 10.1086/432576. View

11.

Abeloff M, Slavik M, Luk G, Griffin C, Hermann J, Blanc O . Phase I trial and pharmacokinetic studies of alpha-difluoromethylornithine--an inhibitor of polyamine biosynthesis. J Clin Oncol. 1984; 2(2):124-30. DOI: 10.1200/JCO.1984.2.2.124. View

12.

Griffin C, Slavik M, Chien S, Hermann J, Thompson G, Blanc O . Phase I trial and pharmacokinetic study of intravenous and oral alpha-difluoromethylornithine. Invest New Drugs. 1987; 5(2):177-86. DOI: 10.1007/BF00203544. View

13.

Bailey J, Smith D . The use of the acridine orange QBC technique in the diagnosis of African trypanosomiasis. Trans R Soc Trop Med Hyg. 1992; 86(6):630. DOI: 10.1016/0035-9203(92)90160-e. View

14.

Milord F, Loko L, Ethier L, Mpia B, Pepin J . Eflornithine concentrations in serum and cerebrospinal fluid of 63 patients treated for Trypanosoma brucei gambiense sleeping sickness. Trans R Soc Trop Med Hyg. 1993; 87(4):473-7. DOI: 10.1016/0035-9203(93)90044-q. View

15.

Van Nieuwenhove S . Advances in sleeping sickness therapy. Ann Soc Belg Med Trop. 1992; 72 Suppl 1:39-51. View

16.

. Control and surveillance of African trypanosomiasis. Report of a WHO Expert Committee. World Health Organ Tech Rep Ser. 1999; 881:I-VI, 1-114. View

17.

Burri C, Keiser J . Pharmacokinetic investigations in patients from northern Angola refractory to melarsoprol treatment. Trop Med Int Health. 2001; 6(5):412-20. DOI: 10.1046/j.1365-3156.2001.00725.x. View

18.

Legros D, Evans S, Maiso F, Enyaru J, Mbulamberi D . Risk factors for treatment failure after melarsoprol for Trypanosoma brucei gambiense trypanosomiasis in Uganda. Trans R Soc Trop Med Hyg. 2000; 93(4):439-42. DOI: 10.1016/s0035-9203(99)90151-7. View

19.

Woo P . The haematocrit centrifuge technique for the diagnosis of African trypanosomiasis. Acta Trop. 1970; 27(4):384-6. View

20.

Pepin J, Milord F . The treatment of human African trypanosomiasis. Adv Parasitol. 1994; 33:1-47. DOI: 10.1016/s0065-308x(08)60410-8. View