Fexinidazole: a potential new drug candidate for Chagas disease
Maria Terezinha Bahia, Isabel Mayer de Andrade, Tassiane Assíria Fontes Martins, Álvaro Fernando da Silva do Nascimento, Lívia de Figueiredo Diniz, Ivo Santana Caldas, André Talvani, Bernadette Bourdin Trunz, Els Torreele, Isabela Ribeiro, Maria Terezinha Bahia, Isabel Mayer de Andrade, Tassiane Assíria Fontes Martins, Álvaro Fernando da Silva do Nascimento, Lívia de Figueiredo Diniz, Ivo Santana Caldas, André Talvani, Bernadette Bourdin Trunz, Els Torreele, Isabela Ribeiro
Abstract
Background: New safe and effective treatments for Chagas disease (CD) are urgently needed. Current chemotherapy options for CD have significant limitations, including failure to uniformly achieve parasitological cure or prevent the chronic phase of CD, and safety and tolerability concerns. Fexinidazole, a 2-subsituted 5-nitroimidazole drug candidate rediscovered following extensive compound mining by the Drugs for Neglected Diseases initiative and currently in Phase I clinical study for the treatment of human African trypanosomiasis, was evaluated in experimental models of acute and chronic CD caused by different strains of Trypanosoma cruzi.
Methods and findings: We investigated the in vivo activity of fexinidazole against T. cruzi, using mice as hosts. The T. cruzi strains used in the study were previously characterized in murine models as susceptible (CL strain), partially resistant (Y strain), and resistant (Colombian and VL-10 strains) to the drugs currently in clinical use, benznidazole and nifurtimox. Our results demonstrated that fexinidazole was effective in suppressing parasitemia and preventing death in infected animals for all strains tested. In addition, assessment of definitive parasite clearance (cure) through parasitological, PCR, and serological methods showed cure rates of 80.0% against CL and Y strains, 88.9% against VL-10 strain, and 77.8% against Colombian strain among animals treated during acute phase, and 70% (VL-10 strain) in those treated in chronic phase. Benznidazole had a similar effect against susceptible and partially resistant T. cruzi strains. Fexinidazole treatment was also shown to reduce myocarditis in all animals infected with VL-10 or Colombian resistant T. cruzi strains, although parasite eradication was not achieved in all treated animals at the tested doses.
Conclusions: Fexinidazole is an effective oral treatment of acute and chronic experimental CD caused by benznidazole-susceptible, partially resistant, and resistant T. cruzi. These findings illustrate the potential of fexinidazole as a drug candidate for the treatment of human CD.
Conflict of interest statement
The authors have declared that no competing interests exist.
Figures
References
- World Health Organization (2010) Media centre. Chagas disease (American trypanosomiasis). Fact sheet N°340, June 2010.
- Urbina JA (2009) New advances in the management of a long-neglected disease. Clin Infect Dis 49: 1685–1687.
- Diniz LF, Caldas IS, Guedes PM, Crepalde G, Lana M, et al. (2010) Effects of ravuconazole treatment on parasite load and immune response in dogs experimentally infected with Trypanosoma cruzi . Antimicrob Agents Chemother 54: 2979–2986.
- Guedes PM, Urbina JA, Lana M, Afonso LC, Veloso VM, et al. (2004) Activity of the new triazole derivative albaconazole against Trypanosoma (Schizotrypanum) cruzi in dog hosts. Antimicrob Agents Chemother 48: 4286–4292.
- Toledo MJ, Bahia MT, Carneiro CM, Martins-Filho OA, Tibayrenc M, et al. (2003) Chemotherapy with Benznidazole and Itraconazole for mice infected with different Trypanosoma cruzi clonal genotypes. Antimicrob Agents Chemother 47: 223–230.
- Molina J, Martins-Filho O, Brener Z, Romanha AJ, Loebenberg D, et al. (2000) Activities of the triazole derivative SCH 56592 (posaconazole) against drug-resistant strains of the protozoan parasite Trypanosoma (Schizotrypanum) cruzi in immunocompetent and immunosuppressed murine hosts. Antimicrob Agents Chemother 44: 150–155.
- Urbina JA (2009) Ergosterol biosynthesis and drug development for Chagas disease. Mem Inst Oswaldo Cruz 1: 311–8.
- Winkelmann E, Raether W, Hartung H, Wagner WH (1977) Chemotherapeutically effective nitro compounds. 3rd communication: nitropyridines, nitroimidazopyridines and related compounds. Arzneimittelforschung 27: 82–9.
- Freeman CD, Klutman NE, Lamp KC (1997) Metranidazole. A therapeutic review and update. Drugs 54: 679–708.
- Van den Boogaard J, Kibiki GS, Kisanga ER, Boeree MJ, Aarnoutse RE (2009) New drugs against tuberculosis: problems, progress, and evaluation of agents in clinical development. Antimicrob Agents Chemother 53: 849–62.
- Torreele E, Trunz BB, Tweats D, Kaiser M, Brun R, et al. (2010) Fexinidazole – A new oral nitroimidazole drug candidate entering clinical development for the treatment of sleeping sickness. PLoS Negl Trop Dis 4: e923.
- Raether W, Seidenath H (1983) The activity of Fexinidazole (HOE 239) against experimental infections with Trypanosoma cruzi, trichomonads and Entamoeba histolytica . Ann Trop Med Parasitol 77: 13–26.
- Moreno M, D'Avila DA, Silva MN, Galvão LMC, Macedo AM, et al. (2010) Trypanosoma cruzi Benznidazole susceptibility in vitro does not predict the therapeutic outcome of human Chagas disease. Mem Inst Oswaldo Cruz 105: 918–924.
- Filardi LS, Brener Z (1987) Susceptibility and natural resistance of Trypanosoma cruzi strains to drugs used clinically in Chagas disease. Trans R Soc Trop Med Hyg 81: 755–759.
- Coura JR, Borges-Pereira J (2011) Chronic Phase of Chagas Disease: Why should it be treated? A comprehensive review. Mem. Inst. Oswaldo Cruz 106: 641–645.
- Anonymous (1985) Reunião de Pesquisa Aplicada em Doença de Chagas: Validade do conceito de Forma Indeterminada. Ver Bras Med Trop 18: 46–49.
- Caldas S, Santos FM, Lana M, Diniz LF, Machado-Coelho GL, et al. (2008) Trypanosoma cruzi: acute and long-term infection in the vertebrate host can modify the response to Benznidazole. Exp Parasitol 118: 315–323.
- Gomes ML, Macedo AM, Vago AR, Pena SD, Galvão LM, et al. (1998) Trypanosoma cruzi: optimization of polymerase chain reaction for detection in human blood. Exp Parasitol 88: 28–33.
- Avila H, Gonçalves AM, Nehme NS, Morel CM, Simpson L (1990) Schizodeme analysis of Trypanosoma cruzi stocks from South and Central America by analysis of PCR-amplified minicircle variable region sequences. Mol Biochem Parasitol 42: 175–187.
- Cummings KL, Tarleton RL (2003) Rapid quantitation of Trypanosoma cruzi in host tissue by real-time PCR. Mol Biochem Parasitol 129: 53–59.
- Voller A, Bidwell DE, Bartlett A (1976) Enzyme immunoassays in diagnostic medicine. Theory and practice. Bull World Health Organ 53: 55–65.
- Maltos KL, Menezes GB, Caliari MV, Rocha OA, Santos JM, et al. (2004) Vascular and cellular responses to pro-inflammatory stimuli in rat dental pulp. Arch Oral Biol 49: 443–450.
- Barrett MP (2010) Potential new drugs for human African trypanosomiasis: some progress at last. Curr Opin Infect Dis 23: 603–608.
- Bustamante JM, Rivarola HW, Fernandez AR, Enders JE, Fretes R, et al. (2002) Trypanosoma cruzi reinfections in mice determine the severity of cardiac damage. Int J Parasitol 32: 889–896.
- Caldas IS, Talvani A, Caldas S, Carneiro CM, Lana M, et al. (2008) Benznidazole therapy during acute phase of Chagas disease reduces parasite load but does not prevent chronic cardiac lesions. Parasitol Res 103: 413–421.
- Garcia S, Ramos CO, Senra JF, Vilas-Boas F, Rodrigues MM, et al. (2005) Treatment with Benznidazole during the chronic phase of experimental Chagas' disease decreases cardiac alterations. Antimicrob Agents Chemother 49: 1521–1528.
- Sokolova AY, Wyllie S, Patterson S, Oza SL, Read KD, et al. (2010) Cross-resistance to nitro drugs and implications for treatment of human African trypanosomiasis. Antimicrob Agents Chemother 54: 2893–2900.
- Tweats D, Trunz BB, Torreele E (2012) Genotoxicity profile of fexinidazole—a drug candidate in clinical development for human African trypanomiasis (sleeping sickness). Mutagenesis 2012 [Epud ahead print].
Source: PubMed