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Chemotherapy against human African trypanosomiasis: Is there a road to success?

Published online by Cambridge University Press:  20 October 2010

CHRISTIAN BURRI
CHRISTIAN BURRI*
Affiliation:
Swiss Tropical and Public Health Institute, Department of Medicines Research, Basel, Switzerland; University of Basel, Basel, Switzerland
*
*Corresponding author: Christian Burri, MPharm. Ph.D., Head, Department of Medicines Research, Swiss Tropical & Public Health Institute, Socinstrasse 57, P.O. Box, CH-4002 Basel, Switzerland. Tel: +41 61 225 26 61. Fax: +41 61 225 26 78. E-mail: Christian.Burri@unibas.ch
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Summary

For over fifty years, human African trypanosomiasis (HAT, sleeping sickness) has been treated with suramin, pentamidine and the very toxic organo-arsenical melarsoprol that was the only drug available for effective treatment of the second stage of the disease. Recently there have been significant efforts using molecular and biochemical approaches to drug design, including high-throughput screening, but the number of lead compounds with promising activity against T. brucei spp. and an acceptable toxicity index has remained astonishingly small. Clinical research continues to be difficult due to the economic constraints and the complexity of trials on a low prevalence disease in remote and impoverished African regions. Despite those limitations the situation for the patients is improving thanks to the combination of a number of critical factors. By the late 1990s the disease had reached epidemic levels that triggered political support. WHO would sign a donation agreement with the manufacturers for all drugs to treat HAT. A result of this agreement was that eflornithine which is much safer than melarsoprol became available and widely used by non-governmental organizations. The Impamel I and II programmes demonstrated that against all odds the conduct of clinical trials on HAT was feasible. This allowed the initiation of trials on combination therapies which eventually resulted in the nifurtimox-eflornithine combination treatment (NECT). This combination is currently being introduced as first line treatment, and there is even the prospect of having a new compound, fexinidazole, in the development pipeline. This review summarizes the key information about the existing drugs and gives a comprehensive summary about the recent and currently ongoing efforts towards new drugs.

Keywords

Human African trypanosomiasissleeping sicknesstreatmentdrugspentamidinesuraminmelarsoproleflornithineNECTpafuramidine maleateDB289fexinidazole
Type
Research Article
Information
Parasitology , Volume 137 , Special Issue 14: African trypanosomiasis: New insights for disease control , December 2010 , pp. 1987 - 1994
Copyright
Copyright © Cambridge University Press 2010

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References

REFERENCES

Anonymous (2008). Pentacarinat®. In Arzneimittel-Kompendium der Schweiz (ed. DokumedA. G., Basel. A. G., Basel., Switzerland).Google Scholar
Anonymous (2009). Human African Trypanosomiasis: First in Man Clinical Trial of a New Medicinal Product, the Fexinidazole. ClinicalTrials.gov (Clinical Trials Registry) http://www.clinicaltrials.gov/ct2/show/NCT00982904?term=NCT00982904&rank=1 (Accessed 24 June 2010).Google Scholar
Balasegaram, M., Harris, S., Checchi, F., Ghorashian, S., Hamel, C. and Karunakara, U. (2006 a). Melarsoprol versus eflornithine for treating late-stage Gambian trypanosomiasis in the Republic of the Congo. Bulletin of the World Health Organization 84, 783–791.CrossRefGoogle ScholarPubMed
Balasegaram, M., Harris, S., Checchi, F., Hamel, C. and Karunakara, U. (2006 b). Treatment outcomes and risk factors for relapse in patients with early-stage human African trypanosomiasis (HAT) in the Republic of the Congo. Bulletin of the World Health Organization 84, 777–782.Google Scholar
Barrett, M. P., Boykin, D. W., Brun, R. and Tidwell, R. R. (2007). Human African trypanosomiasis: pharmacological re-engagement with a neglected disease. British Journal of Pharmacology 152, 1155–1171.CrossRefGoogle ScholarPubMed
Bayer (2002). Bayer sustainable development report 2004. Vol. 2008. http://www.bayer.com/en/sustainable_development_report_2004.pdfx (Accessed 29 July 2010).Google Scholar
Bisser, S., N'siesi, F. X., Lejon, V., Preux, P. M., Van Nieuwenhove, S., Miaka Mia Bilenge, C. and Buscher, P. (2007). Equivalence trial of melarsoprol and nifurtimox monotherapy and combination therapy for the treatment of second-stage Trypanosoma brucei gambiense sleeping sickness. Journal of Infectious Diseases 195, 322–329.CrossRefGoogle ScholarPubMed
Blum, J. A., Burri, C., Hatz, C., Kazumba, L., Mangoni, P. and Zellweger, M. J. (2007). Sleeping hearts: the role of the heart in sleeping sickness (human African trypanosomiasis). Tropical Medicine and International Health 12, 1422–1432.CrossRefGoogle ScholarPubMed
Bronner, U. (1994). Pharmacokinetics of pentamidine. Focus on treatment of Trypanosoma gambiense sleeping sickness. PhD Thesis, Karolinska Institute, Stockholm.Google Scholar
Bronner, U., Doua, F., Ericsson, O., Gustafsson, L., Miezan, T., Rais, M. and Rombo, L. (1991). Pentamidine concentrations in plasma, whole blood and cerebrospinal fluid during treatment of Trypanosoma gambiense infection in Côte d'Ivoire. Transactions of the Royal Society of Tropical Medicine and Hygiene 85, 608–611.CrossRefGoogle ScholarPubMed
Burri, C. and Brun, R. (2003). Eflornithine for treatment of human African trypanosomiasis. Parasitology Research 90 (Suppl), S49–S52.CrossRefGoogle ScholarPubMed
Burri, C. and Brun, R. (2008). Chapter 76: Human African trypanosomiasis. In Manson's Tropical Diseases (eds. Cook, G., and Zumla, A.), pp. 1307–1325. W.B. Saunders, London.Google Scholar
Burri, C., Nkunku, S., Merolle, A., Smith, T., Blum, J. and Brun, R. (2000). Efficacy of new, concise schedule for melarsoprol in treatment of sleeping sickness caused by Trypanosoma brucei gambiense: a randomised trial. Lancet 355, 1419–1425.Google Scholar
Burri, C., Stich, A. and Brun, R. (2004). Current chemotherapy of Human African sleeping sickness. In The Trypanosomiases (eds. Maudlin, I., Holmes, P., and Miles, M. A.), pp. 403–419. CABI, Wallingford.CrossRefGoogle Scholar
Chappuis, F. (2007). Melarsoprol-free drug combinations for second-stage Gambian sleeping sickness: the way to go. Clinical Infectious Diseases 45, 1443–1445.CrossRefGoogle ScholarPubMed
Chappuis, F., Udayraj, N., Stietenroth, K., Meussen, A. and Bovier, P. A. (2005). Eflornithine is safer than melarsoprol for the treatment of second-stage Trypanosoma brucei gambiense human African trypanosomiasis. Clinical Infectious Diseases 41, 748–751.Google Scholar
Checchi, F., Piola, P., Ayikoru, H., Thomas, F., Legros, D. and Priotto, G. (2007). Nifurtimox plus Eflornithine for late-Stage sleeping sickness in Uganda: A case series. PLoS Neglected Tropical Diseases 1, e64.CrossRefGoogle ScholarPubMed
DNDi (2008 a). NECT: Next steps. In DNDi Newsletter, 17.Google Scholar
DNDi (2008 b). Fexinidazole progresses into clinical development. DNDi Newsletter, 17.Google Scholar
DNDi (2009). NECT added to WHO essential medicines list as combination treatment against sleeping sickness. DNDi Press Release. http://www.dndi.org/press-releases/456-nect-added-to-who-essential-medicines-list-as-combination-treatment-against-sleeping-sickness.html (Accessed 24 June 2010)Google Scholar
DNDi (2010). NECT – Nifurtimox-Eflornithine: Co-Administration (HAT). http://www.dndi.org/portfolio/nect.html (Accessed 24 June 2010)Google Scholar
Dorlo, T. P. and Kager, P. A. (2008). Pentamidine dosage: a base/salt confusion. PLoS Neglected Tropical Diseases 2, e225.CrossRefGoogle ScholarPubMed
Doua, F., Miezan, T. W., Sanon Singaro, J. R., Boa Yapo, F. and Baltz, T. (1996). The efficacy of pentamidine in the treatment of early-late stage Trypanosoma brucei gambiense trypanosomiasis. American Journal of Tropical Medicine and Hygiene 55, 586–588.CrossRefGoogle ScholarPubMed
Doua, F. and Yapo, F. B. (1993). Human trypanosomiasis in the Ivory Coast - therapy and problems. Acta Tropica 54, 163–168.Google Scholar
Gustafsson, L. L., Beerman, B. and Aden Abdi, Y. (1987). Suramin. In Handbook of Drugs for Tropical Parasitic infections (eds. Gustafsson, L. L., Beerman, B., and Aden Abdi, Y.), pp. 160–163. Taylor & Francis, Basingstoke.Google Scholar
IFPMA and International Federation of Pharmaceutical Manufacturers & Associations (2008). Health Partnerships for the Developing World -Sanofi-Aventis Sleeping Sickness Program. Vol. 2008.Google Scholar
Iten, M., Mett, H., Evans, A., Enyaru, J. C., Brun, R. and Kaminsky, R. (1997). Alterations in ornithine decarboxylase characteristics account for tolerance of Trypanosoma brucei rhodesiense to D,L-alpha-difluoromethylornithine. Antimicrobial Agents and Chemotherapy 41, 1922–1925.Google Scholar
Jansson, R., Malm, M., Roth, C. and Ashton, M. (2008). Enantioselective and nonlinear intestinal absorption of eflornithine in the rat. Antimicrobial Agents and Chemotherapy 52, 2842–2848.CrossRefGoogle ScholarPubMed
Kansiime, F., Adibaku, S., Wanboga, C., Iddi, F., Matovu, E., Yamuah, L. and Kioy, D. (2009). Clinical study of nifurtimox-eflornithine combination treatment (NECT) of late stage Trypanosoma brucei gambiense patients in NW Uganda: Implications for the National sleeping sickness control programme. In 30th Meeting of the International Scientific Council for Trypanosomiasis Research and Control (ISCTRC) (ed. OAU/STRC, Nairobi), p.69, Kampala, Uganda.Google Scholar
Kuepfer, I. (2009). Impamel III - Improved melarsoprol application for the treatment of second stage T. b. rhodesiense sleeping sickness. In 30th Meeting of the International Scientific Council for Trypanosomiasis Research and Control (ISCTRC) (ed. OAU/STRC, Nairobi), p. 70. Kampala, Uganda.Google Scholar
Lejon, V., Legros, D., Savignoni, A., Etchegorry, M. G., Mbulamberi, D. and Buscher, P. (2003). Neuro-inflammatory risk factors for treatment failure in “early second stage” sleeping sickness patients treated with Pentamidine. Journal of Neuroimmunology 144, 132–138.Google Scholar
Médecins Sans Frontières (2007). Clinical Guidelines. http://www.refbooks.msf_docs/en/Clinical_Guide/CG_en.pdf (Accessed 29 July 2010).Google Scholar
Na-Bangchang, K., Doua, F., Konsil, J., Hanpitakpong, W., Kamanikom, B. and Kuzoe, F. (2004). The pharmacokinetics of eflornithine (alpha-difluoromethylornithine) in patients with late-stage T. b. gambiense sleeping sickness. European Journal of Clinical Pharmacology 60, 269–278.CrossRefGoogle ScholarPubMed
Pepin, J., Khonde, N., Maiso, F., Doua, F., Jaffar, S., Ngampo, S., Mpia, B., Mbulamberi, D. and Kuzoe, F. (2000). Short-course eflornithine in Gambian trypanosomiasis: a multicentre randomized controlled trial. Bulletin of the World Health Organization 78, 1284–1295.Google ScholarPubMed
Pepin, J., Milord, F., Meurice, F., Ethier, L., Loko, L. and Mpia, B. (1992). High-dose nifurtimox for arseno-resistant Trypanosoma brucei gambiense sleeping sickness: an open trial in central Zaire. Transactions of the Royal Society of Tropical Medicine and Hygiene 86, 254–256.CrossRefGoogle ScholarPubMed
Pohlig, G., Bernhard, S., Blum, J., Burri, C., Mpanya Kabeya, A., Fina Lubaki, J.-P., Mpoo Mpoto, A., Fungula Munungu, B., Kambau Manesa Deo, G., Nsele Mutantu, P., Mbo Kuikumbi, F., Fukinsia Mintwo, A., Kayeye Munungi, A., Dala, A., Macharia, S., Miaka Mia Bilenge, C., Kande Betu Ku Mesu, V., Ramon Franco, J., Dieyi Dituvanga, N. and Olson, C. (2008). Phase 3 trial of pafuramidine maleate (DB289), a novel, oral drug, for treatment of first stage sleeping sickness: Safety and Efficacy. In 57th Meeting of the American Society of Tropical Medicine and Hygiene pp. Abstract No. 542. New Orleans.Google Scholar
Priotto, G., Fogg, C., Balasegaram, M., Erphas, O., Louga, A., Checchi, F., Ghabri, S. and Piola, P. (2006). Three drug combinations for late-stage Trypanosoma brucei gambiense sleeping sickness: A randomized clinical trial in Uganda. PLoS Clinical Trials 1, e39: 31–38.Google Scholar
Priotto, G., Kasparian, S., Mutombo, W., Ngouama, D., Ghorashian, S., Arnold, U., Ghabri, S., Baudin, E., Buard, V., Kazadi-Kyanza, S., Ilunga, M., Mutangala, W., Pohlig, G., Schmid, C., Karunakara, U., Torreele, E. and Kande, V. (2009). Nifurtimox-eflornithine combination therapy for second-stage African Trypanosoma brucei gambiense trypanosomiasis: a multicentre, randomised, phase III, non-inferiority trial. Lancet 374, 56–64.CrossRefGoogle ScholarPubMed
Priotto, G., Kasparian, S., Ngouama, D., Ghorashian, S., Arnold, U., Ghabri, S. and Karunakara, U. (2007). Nifurtimox-Eflornithine combination therapy for second-stage Trypanosoma brucei gambiense sleeping sickness: A randomized clinical trial in Congo. Clinical Infectious Diseases 45, 1435–1442.Google Scholar
Priotto, G., Pinoges, L., Fursa, I. B., Burke, B., Nicolay, N., Grillet, G., Hewison, C. and Balasegaram, M. (2008). Safety and effectiveness of first line eflornithine for Trypanosoma brucei gambiense sleeping sickness in Sudan: cohort study. British Medical Journal 336, 705–708.Google Scholar
Rodgers, J., Bradley, B. and Kennedy, P. G. (2007). Combination chemotherapy with a substance P receptor antagonist (aprepitant) and melarsoprol in a mouse model of human African trypanosomiasis. Parasitology International 56, 321–324.CrossRefGoogle Scholar
Ruiz, J. A., Simarro, P. P. and Josenando, T. (2002). Control of human African trypanosomiasis in the Quicama focus, Angola. Bulletin of the World Health Organization 80, 738–745.Google Scholar
Schmid, C., Richer, M., Bilenge, C. M., Josenando, T., Chappuis, F., Manthelot, C. R., Nangouma, A., Doua, F., Asumu, P. N., Simarro, P. P. and Burri, C. (2005). Effectiveness of a 10-day melarsoprol schedule for the treatment of late-stage human African trypanosomiasis: Confirmation from a multinational study (Impamel II). Journal of Infectious Diseases 191, 1922–1931.Google Scholar
Seixas, J. (2004). Investigations on the encephalopathic syndrome during melarsoprol treatment of human African trypanosomiasis. PhD Thesis, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa.Google Scholar
Van Nieuwenhove, S. (1999). Present strategies in the treatment of human African trypanosomiasis. In Progress in Human African trypanosomiasis, Sleeping Sickness (eds. Dumas, M., Bouteille, B., and Buguet, A.), pp. 253–280. Springer, Paris.CrossRefGoogle Scholar
Waddy, B. B. (1970). Chemoprophylaxis of human trypanosomiasis. In The African Trypanosomiases (ed. Mulligan, H. W.), pp. 711. Allan & Unwin, London.Google Scholar
WHO (1986). Epidemiology and control of African trypanosomiasis. WHO Technical Report Series, 739.Google Scholar
WHO (1998). Control and surveillance of African trypanosomiasis, WHO, Geneva.Google Scholar
WHO (2006). Human African trypanosomiasis (sleeping sickness): epidemiological update. Weekly Epidemiological Report, 8, 71–80.Google Scholar
WHO (2007). Recommendations of the informal consultation on issues for clinical product development for human African trypanosomiasis. WHO/CDS/NTD/IDM/2007.1. Geneva, Switzerland.Google Scholar