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Malar J ; 10: 212, 2011 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-21801400

RESUMO

BACKGROUND: Tafenoquine is an 8-aminoquinoline being developed for radical cure (blood and liver stage elimination) of Plasmodium vivax. During monotherapy treatment, the compound exhibits slow parasite and fever clearance times, and toxicity in glucose-6-phosphate dehydrogenase (G6PD) deficiency is a concern. Combination with other antimalarials may mitigate these concerns. METHODS: In 2005, the radical curative efficacy of tafenoquine combinations was investigated in Plasmodium cynomolgi-infected naïve Indian-origin Rhesus monkeys. In the first cohort, groups of two monkeys were treated with a three-day regimen of tafenoquine at different doses alone and in combination with a three-day chloroquine regimen to determine the minimum curative dose (MCD). In the second cohort, the radical curative efficacy of a single-day regimen of tafenoquine-mefloquine was compared to that of two three-day regimens comprising tafenoquine at its MCD with chloroquine or artemether-lumefantrine in groups of six monkeys. In a final cohort, the efficacy of the MCD of tafenoquine against hypnozoites alone and in combination with chloroquine was investigated in groups of six monkeys after quinine pre-treatment to eliminate asexual parasites. Plasma tafenoquine, chloroquine and desethylchloroquine concentrations were determined by LC-MS in order to compare doses of the drugs to those used clinically in humans. RESULTS: The total MCD of tafenoquine required in combination regimens for radical cure was ten-fold lower (1.8 mg/kg versus 18 mg/kg) than for monotherapy. This regimen (1.8 mg/kg) was equally efficacious as monotherapy or in combination with chloroquine after quinine pre-treatment to eliminate asexual stages. The same dose of (1.8 mg/kg) was radically curative in combination with artemether-lumefantrine. Tafenoquine was also radically curative when combined with mefloquine. The MCD of tafenoquine monotherapy for radical cure (18 mg/kg) appears to be biologically equivalent to a 600-1200 mg dose in humans. At its MCD in combination with blood schizonticidal drugs (1.8 mg/kg), the maximum observed plasma concentrations were substantially lower than (20-84 versus 550-1,100 ng/ml) after administration of 1, 200 mg in clinical studies. CONCLUSIONS: Ten-fold lower clinical doses of tafenoquine than used in prior studies may be effective against P. vivax hypnozoites if the drug is deployed in combination with effective blood-schizonticidal drugs.


Assuntos
Aminoquinolinas/administração & dosagem , Antimaláricos/administração & dosagem , Macaca mulatta/parasitologia , Malária/tratamento farmacológico , Doenças dos Primatas/tratamento farmacológico , Aminoquinolinas/farmacocinética , Animais , Antimaláricos/farmacocinética , Combinação Arteméter e Lumefantrina , Artemisininas/administração & dosagem , Artemisininas/farmacocinética , Cloroquina/administração & dosagem , Cloroquina/farmacocinética , Cromatografia Líquida , Modelos Animais de Doenças , Combinação de Medicamentos , Quimioterapia Combinada/métodos , Etanolaminas/administração & dosagem , Etanolaminas/farmacocinética , Fluorenos/administração & dosagem , Fluorenos/farmacocinética , Humanos , Masculino , Espectrometria de Massas , Mefloquina/administração & dosagem , Mefloquina/farmacocinética , Plasma/química , Plasmodium cynomolgi , Quinina/administração & dosagem , Quinina/farmacocinética , Resultado do Tratamento
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