Antitrypanosomal activity of fexinidazole metabolites, potential new drug candidates for Chagas disease

Maria Terezinha Bahia, Alvaro F S Nascimento, Ana Lia Mazzeti, Luiz F Marques, Karolina Ribeiro Goncalves, Ludmilla W R Mota, Livia de F Diniz, Ivo Santana Caldas, Andre Talvani, David Shackleford, Maria Koltun, Jessica Saunders, Karen Louise White, Ivan Scandale, Susan Ann Charman, Eric Chatelain

Research output: Contribution to journalArticleResearchpeer-review

Abstract

This study was designed to verify the in vivo efficacy of sulfoxide and sulfone fexinidazole metabolites following oral administration in a murine model of Chagas disease. Female Swiss mice infected with the Y strain of Trypanosoma cruzi were treated orally once per day with each metabolite at doses of 10 to 100 mg/kg of body weight for a period of 20 days. Parasitemia was monitored throughout, and cures were detected by parasitological and PCR assays. The results were compared with those achieved with benznidazole treatment at the same doses. Fexinidazole metabolites were effective in reducing the numbers of circulating parasites and protecting mice against death, compared with untreated mice, but without providing cures at daily doses of 10 and 25 mg/kg. Both metabolites were effective in curing mice at 50 mg/kg/day (30 to 40 ) and 100 mg/kg/day (100 ). In the benznidazoletreated group, parasitological cure was detected only in animals treated with the higher dose of 100 mg/kg/day (80 ). Single-dose pharmacokinetic parameters for each metabolite were obtained from a parallel group of uninfected mice and were used to estimate the profiles following repeated doses. Pharmacokinetic data suggested that biological efficacy most likely resides with the sulfone metabolite (or subsequent reactive metabolites formed following reduction of the nitro group) following administration of either the sulfoxide or the sulfone and that prolonged plasma exposure over the 24-h dosing window is required to achieve high cure rates. Fexinidazole metabolites were effective in treating T. cruzi in a mouse model of acute infection, with cure rates superior to those achieved with either fexinidazole itself or benznidazole.
Original languageEnglish
Pages (from-to)4362 - 4370
Number of pages9
JournalAntimicrobial Agents and Chemotherapy
Volume58
Issue number8
DOIs
Publication statusPublished - 2014

Cite this

Bahia, M. T., Nascimento, A. F. S., Mazzeti, A. L., Marques, L. F., Goncalves, K. R., Mota, L. W. R., ... Chatelain, E. (2014). Antitrypanosomal activity of fexinidazole metabolites, potential new drug candidates for Chagas disease. Antimicrobial Agents and Chemotherapy, 58(8), 4362 - 4370. https://doi.org/10.1128/AAC.02754-13
Bahia, Maria Terezinha ; Nascimento, Alvaro F S ; Mazzeti, Ana Lia ; Marques, Luiz F ; Goncalves, Karolina Ribeiro ; Mota, Ludmilla W R ; Diniz, Livia de F ; Caldas, Ivo Santana ; Talvani, Andre ; Shackleford, David ; Koltun, Maria ; Saunders, Jessica ; White, Karen Louise ; Scandale, Ivan ; Charman, Susan Ann ; Chatelain, Eric. / Antitrypanosomal activity of fexinidazole metabolites, potential new drug candidates for Chagas disease. In: Antimicrobial Agents and Chemotherapy. 2014 ; Vol. 58, No. 8. pp. 4362 - 4370.
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title = "Antitrypanosomal activity of fexinidazole metabolites, potential new drug candidates for Chagas disease",
abstract = "This study was designed to verify the in vivo efficacy of sulfoxide and sulfone fexinidazole metabolites following oral administration in a murine model of Chagas disease. Female Swiss mice infected with the Y strain of Trypanosoma cruzi were treated orally once per day with each metabolite at doses of 10 to 100 mg/kg of body weight for a period of 20 days. Parasitemia was monitored throughout, and cures were detected by parasitological and PCR assays. The results were compared with those achieved with benznidazole treatment at the same doses. Fexinidazole metabolites were effective in reducing the numbers of circulating parasites and protecting mice against death, compared with untreated mice, but without providing cures at daily doses of 10 and 25 mg/kg. Both metabolites were effective in curing mice at 50 mg/kg/day (30 to 40 ) and 100 mg/kg/day (100 ). In the benznidazoletreated group, parasitological cure was detected only in animals treated with the higher dose of 100 mg/kg/day (80 ). Single-dose pharmacokinetic parameters for each metabolite were obtained from a parallel group of uninfected mice and were used to estimate the profiles following repeated doses. Pharmacokinetic data suggested that biological efficacy most likely resides with the sulfone metabolite (or subsequent reactive metabolites formed following reduction of the nitro group) following administration of either the sulfoxide or the sulfone and that prolonged plasma exposure over the 24-h dosing window is required to achieve high cure rates. Fexinidazole metabolites were effective in treating T. cruzi in a mouse model of acute infection, with cure rates superior to those achieved with either fexinidazole itself or benznidazole.",
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year = "2014",
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Bahia, MT, Nascimento, AFS, Mazzeti, AL, Marques, LF, Goncalves, KR, Mota, LWR, Diniz, LDF, Caldas, IS, Talvani, A, Shackleford, D, Koltun, M, Saunders, J, White, KL, Scandale, I, Charman, SA & Chatelain, E 2014, 'Antitrypanosomal activity of fexinidazole metabolites, potential new drug candidates for Chagas disease' Antimicrobial Agents and Chemotherapy, vol. 58, no. 8, pp. 4362 - 4370. https://doi.org/10.1128/AAC.02754-13

Antitrypanosomal activity of fexinidazole metabolites, potential new drug candidates for Chagas disease. / Bahia, Maria Terezinha; Nascimento, Alvaro F S; Mazzeti, Ana Lia; Marques, Luiz F; Goncalves, Karolina Ribeiro; Mota, Ludmilla W R; Diniz, Livia de F; Caldas, Ivo Santana; Talvani, Andre; Shackleford, David; Koltun, Maria; Saunders, Jessica; White, Karen Louise; Scandale, Ivan; Charman, Susan Ann; Chatelain, Eric.

In: Antimicrobial Agents and Chemotherapy, Vol. 58, No. 8, 2014, p. 4362 - 4370.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Antitrypanosomal activity of fexinidazole metabolites, potential new drug candidates for Chagas disease

AU - Bahia, Maria Terezinha

AU - Nascimento, Alvaro F S

AU - Mazzeti, Ana Lia

AU - Marques, Luiz F

AU - Goncalves, Karolina Ribeiro

AU - Mota, Ludmilla W R

AU - Diniz, Livia de F

AU - Caldas, Ivo Santana

AU - Talvani, Andre

AU - Shackleford, David

AU - Koltun, Maria

AU - Saunders, Jessica

AU - White, Karen Louise

AU - Scandale, Ivan

AU - Charman, Susan Ann

AU - Chatelain, Eric

PY - 2014

Y1 - 2014

N2 - This study was designed to verify the in vivo efficacy of sulfoxide and sulfone fexinidazole metabolites following oral administration in a murine model of Chagas disease. Female Swiss mice infected with the Y strain of Trypanosoma cruzi were treated orally once per day with each metabolite at doses of 10 to 100 mg/kg of body weight for a period of 20 days. Parasitemia was monitored throughout, and cures were detected by parasitological and PCR assays. The results were compared with those achieved with benznidazole treatment at the same doses. Fexinidazole metabolites were effective in reducing the numbers of circulating parasites and protecting mice against death, compared with untreated mice, but without providing cures at daily doses of 10 and 25 mg/kg. Both metabolites were effective in curing mice at 50 mg/kg/day (30 to 40 ) and 100 mg/kg/day (100 ). In the benznidazoletreated group, parasitological cure was detected only in animals treated with the higher dose of 100 mg/kg/day (80 ). Single-dose pharmacokinetic parameters for each metabolite were obtained from a parallel group of uninfected mice and were used to estimate the profiles following repeated doses. Pharmacokinetic data suggested that biological efficacy most likely resides with the sulfone metabolite (or subsequent reactive metabolites formed following reduction of the nitro group) following administration of either the sulfoxide or the sulfone and that prolonged plasma exposure over the 24-h dosing window is required to achieve high cure rates. Fexinidazole metabolites were effective in treating T. cruzi in a mouse model of acute infection, with cure rates superior to those achieved with either fexinidazole itself or benznidazole.

AB - This study was designed to verify the in vivo efficacy of sulfoxide and sulfone fexinidazole metabolites following oral administration in a murine model of Chagas disease. Female Swiss mice infected with the Y strain of Trypanosoma cruzi were treated orally once per day with each metabolite at doses of 10 to 100 mg/kg of body weight for a period of 20 days. Parasitemia was monitored throughout, and cures were detected by parasitological and PCR assays. The results were compared with those achieved with benznidazole treatment at the same doses. Fexinidazole metabolites were effective in reducing the numbers of circulating parasites and protecting mice against death, compared with untreated mice, but without providing cures at daily doses of 10 and 25 mg/kg. Both metabolites were effective in curing mice at 50 mg/kg/day (30 to 40 ) and 100 mg/kg/day (100 ). In the benznidazoletreated group, parasitological cure was detected only in animals treated with the higher dose of 100 mg/kg/day (80 ). Single-dose pharmacokinetic parameters for each metabolite were obtained from a parallel group of uninfected mice and were used to estimate the profiles following repeated doses. Pharmacokinetic data suggested that biological efficacy most likely resides with the sulfone metabolite (or subsequent reactive metabolites formed following reduction of the nitro group) following administration of either the sulfoxide or the sulfone and that prolonged plasma exposure over the 24-h dosing window is required to achieve high cure rates. Fexinidazole metabolites were effective in treating T. cruzi in a mouse model of acute infection, with cure rates superior to those achieved with either fexinidazole itself or benznidazole.

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