Radical curative efficacy of tafenoquine combination regimens in Plasmodium cynomolgi-infected Rhesus monkeys (Macaca mulatta)

Dow, Geoffrey S.; Gettayacamin, Montip; Hansukjariya, P; Im-Erbsin, Rawiwan; Komcharoen, Srawuth; Sattabongkot, Jetsumon; Kyle, Dennis E.; Milhous, Wilbur K.; Cozens, Simon; Kenworthy, David; Miller, Anne; Veazey, Jim; Ohrt, Colin

doi:10.1186/1475-2875-10-212

Cited by 57 publications

(46 citation statements)

References 19 publications

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“…For the P. cynomolgi malaria radical cure study, 10 rhesus macaques were allocated to 5 groups of 2 animals each to receive 7 daily doses of (ϩ)-or (Ϫ)-PQ base at 1.3 or 0.6 mg/kg/day in combination with the chloroquine base at 10 mg/kg/day, with two of the animals receiving chloroquine alone as negative controls. Animals were infected with P. cynomolgi and treated to prevent relapse using a previously described method (14,15). Animals received 1 ϫ 10 6 P. cynomolgi sporozoites intravenously on study day 0 and were treated when parasitemia reached Ն5,000 blood-stage parasites on peripheral blood film.…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of (+)-Primaquine and (−)-Primaquine Enantiomers in Rhesus Macaques (Macaca mulatta)

Saunders

Vanachayangkul

Im-Erbsin

et al. 2014

Antimicrob Agents Chemother

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e Primaquine (PQ) remains the sole available drug to prevent relapse of Plasmodium vivax malaria more than 60 years after licensure. While this drug was administered as a racemic mixture, prior studies suggested a pharmacodynamic advantage based on differential antirelapse activity and/or toxicities of its enantiomers. Oral primaquine enantiomers prepared using a novel, easily scalable method were given for 7 days to healthy rhesus macaques in a dose-rising fashion to evaluate their effects on the blood, liver, and kidneys. The enantiomers were then administered to Plasmodium cynomolgi-infected rhesus macaques at doses of 1.3 and 0.6 mg/kg of body weight/day in combination with chloroquine. The (؊)-PQ enantiomer had higher clearance and apparent volume of distribution than did (؉)-PQ and was more extensively converted to the carboxy metabolite. There is evidence for differential oxidative stress with a concentration-dependent rise in methemoglobin (MetHgb) with increasing doses of (؉)-PQ greater than that seen for (؊)-PQ. There was a marked, reversible hepatotoxicity in 2 of 3 animals dosed with (؊)-PQ at 4.5 mg/ kg. (؊)-PQ in combination with chloroquine was successful in preventing P. cynomolgi disease relapse at doses of 0.6 and 1.3 mg/kg/day, while 1 of 2 animals receiving (؉)-PQ at 0.6 mg/kg/day relapsed. While (؊)-PQ was also associated with hepatotoxicity at higher doses as seen previously, this has not been identified as a clinical concern in humans during >60 years of use. Limited evidence for increased MetHgb generation with the (؉) form in the rhesus macaque model suggests that it may be possible to improve the therapeutic window for hematologic toxicity in the clinic by separating primaquine into its enantiomers.

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Section: Methodsmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of (+)-Primaquine and (−)-Primaquine Enantiomers in Rhesus Macaques (Macaca mulatta)

Saunders

Vanachayangkul

Im-Erbsin

et al. 2014

Antimicrob Agents Chemother

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“…T he 8-aminoquinoline class of antimalarial compounds is the only molecular scaffold with proven efficacy against relapsing strains of malaria (1)(2)(3)(4)(5). Currently, the only FDA-approved drug from this class that is available for clinical use is primaquine.…”

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confidence: 99%

Differential Cytochrome P450 2D Metabolism Alters Tafenoquine Pharmacokinetics

Vuong

Xie

Potter

et al. 2015

Antimicrob Agents Chemother

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dCytochrome P450 (CYP) 2D metabolism is required for the liver-stage antimalarial efficacy of the 8-aminoquinoline molecule tafenoquine in mice. This could be problematic for Plasmodium vivax radical cure, as the human CYP 2D ortholog (2D6) is highly polymorphic. Diminished CYP 2D6 enzyme activity, as in the poor-metabolizer phenotype, could compromise radical curative efficacy in humans. Despite the importance of CYP 2D metabolism for tafenoquine liver-stage efficacy, the exact role that CYP 2D metabolism plays in the metabolism and pharmacokinetics of tafenoquine and other 8-aminoquinoline molecules has not been extensively studied. In this study, a series of tafenoquine pharmacokinetic experiments were conducted in mice with different CYP 2D metabolism statuses, including wild-type (WT) (reflecting extensive metabolizers for CYP 2D6 substrates) and CYP mouse 2D knockout (KO) (reflecting poor metabolizers for CYP 2D6 substrates) mice. Plasma and liver pharmacokinetic profiles from a single 20-mg/kg of body weight dose of tafenoquine differed between the strains; however, the differences were less striking than previous results obtained for primaquine in the same model. Additionally, the presence of a 5,6-ortho-quinone tafenoquine metabolite was examined in both mouse strains. The 5,6-ortho-quinone species of tafenoquine was observed, and concentrations of the metabolite were highest in the WT extensive-metabolizer phenotype. Altogether, this study indicates that CYP 2D metabolism in mice affects tafenoquine pharmacokinetics and could have implications for human tafenoquine pharmacokinetics in polymorphic CYP 2D6 human populations.T he 8-aminoquinoline class of antimalarial compounds is the only molecular scaffold with proven efficacy against relapsing strains of malaria (1-5). Currently, the only FDA-approved drug from this class that is available for clinical use is primaquine. Primaquine has been utilized for over 6 decades in treating malaria (6). Despite the long history of primaquine therapy for malaria treatment, primaquine has several disadvantages, including the hemolytic toxicity associated with glucose-6-phosphate dehydrogenase (G6PD) deficiency; its relatively short elimination half-life in humans, which requires daily administration; and the potential requirement for cytochrome P450 (CYP) 2D6-mediated activation for radical curative activity (7-11). The 8-aminoquinoline molecule tafenoquine, currently under late-stage clinical development, has a significantly longer elimination half-life than primaquine (12-16) and has single-dose radical curative activity in humans (3). Tafenoquine is also being developed as a chemoprophylactic agent and has demonstrated efficacy against Plasmodium vivax and Plasmodium falciparum (17)(18)(19)(20)(21). Despite the pharmacological advantages of tafenoquine over primaquine, both molecules seem to have the same pharmacogenomic liability of CYP 2D6-mediated activation for liver-stage antimalarial activity (7,10,22,23) and are not free of hemolytic liability in G6PD def...

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“…En el caso de P. vivax la situación es más notoria (24); aunque se están estudiando nuevos medicamentos con buenos resultados (25), por el momento sólo contamos con primaquina disponible en el mercado para eliminar los gametocitos e hipnozoítos (2,26). Debido a esta limitación en medicamentos gametocidas, es importante mejorar los tiempos entre el acceso al diagnóstico y el tratamiento.…”

Section: Discussionunclassified

Factors that delay malaria diagnosis and treatment in the municipality of Riberalta in Bolivia

Añez¹,

Suárez²,

Cuba³

2012

biomedica

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Introducción. Se publican pocos estudios sobre las causas del retardo del diagnóstico y el tratamiento de la malaria en Bolivia. Objetivo. Conocer los factores que retardan el diagnóstico y el tratamiento de la malaria en el servicio público del municipio de Riberalta, Bolivia. Materiales y métodos. Se calcularon los tiempos transcurridos entre el inicio de los síntomas y el tratamiento, entre el inicio de los síntomas y el diagnóstico, y entre el diagnóstico y el inicio del tratamiento; se compararon las medias de los tiempos calculados con el lugar de infección, la especie parasitaria, el nivel de atención, el lugar y el método de diagnóstico, y la edad se correlacionó con los tiempos calculados. Resultados. De 2.482 casos positivos válidos evaluados entre enero y diciembre de 2010, se encontró una media de 4,16 días entre el inicio de los síntomas y el inicio del tratamiento, de 4,07 días entre el inicio de los síntomas y el diagnóstico, y de 0,10 días entre el diagnóstico y el tratamiento. El retardo del diagnóstico y los factores, lugar de diagnóstico, lugar de infección, nivel de atención, especie parasitaria y método de diagnóstico, mostraron una diferencia estadística significativa (p<0,05). En el análisis de la covarianza se observó una asociación estadística con el nivel de atención y la especie parasitaria (p<0,05) Conclusión. Existe un retardo en el diagnóstico de la malaria, lo cual es influenciado por factores como el lugar de infección, lugar del diagnóstico, nivel de atención, especie parasitaria y método de diagnóstico.Palabras clave: malaria/diagnóstico, signos y síntomas, tratamiento, Plasmodium, Bolivia. Factors that delay malaria diagnosis and treatment in the municipality of Riberalta in BoliviaIntroduction. Few studies on the causes of the delay of malaria diagnosis and treatment in Bolivia are published. Objective. To know the factors that delay malaria diagnosis and treatment of malaria in the public service of the town of Riberalta, Bolivia. Materials and methods. The times between the onset of symptoms and treatment, between the onset of symptoms and diagnosis and between the diagnosis and the start of treatment were calculated. The averages of the calculated times were compared with respect to the site of infection, parasite species, level of care, place of diagnosis and diagnostic method and th patient's age was correlated with the calculated times. Results. Between January and December 2010, 2,482 positive valid cases were studied. An average of 4.16 days was found between the onset of symptoms and the start of treatment, the average time between the onset of symptoms and diagnosis was 4.07 days, and between diagnosis and the start of treatment 0.10 days. Statistically significant (p<0.05) differences were found for factors related to the delay of diagnosis such as place of diagnosis, site of infection, level of care, parasite species and diagnostic method. The analysis of covariance showed a statistical association with the level of care and the parasite species (p<0.05). Conclusio...

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Radical curative efficacy of tafenoquine combination regimens in Plasmodium cynomolgi-infected Rhesus monkeys (Macaca mulatta)

Cited by 57 publications

References 19 publications

Pharmacokinetics and Pharmacodynamics of (+)-Primaquine and (−)-Primaquine Enantiomers in Rhesus Macaques (Macaca mulatta)

Pharmacokinetics and Pharmacodynamics of (+)-Primaquine and (−)-Primaquine Enantiomers in Rhesus Macaques (Macaca mulatta)

Differential Cytochrome P450 2D Metabolism Alters Tafenoquine Pharmacokinetics

Factors that delay malaria diagnosis and treatment in the municipality of Riberalta in Bolivia

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