An In vivo Drug Screening Model Using Glucose-6-Phosphate Dehydrogenase Deficient Mice to Predict the Hemolytic Toxicity of 8-Aminoquinolines

Peng Zhang Division of Experimental Therapeutics and Division of Pathology, Walter Reed Army Institute of Research, Silver Spring, Maryland

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Xiugong Gao Division of Experimental Therapeutics and Division of Pathology, Walter Reed Army Institute of Research, Silver Spring, Maryland

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Hiroshi Ishida Division of Experimental Therapeutics and Division of Pathology, Walter Reed Army Institute of Research, Silver Spring, Maryland

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Jack Amnuaysirikul Division of Experimental Therapeutics and Division of Pathology, Walter Reed Army Institute of Research, Silver Spring, Maryland

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Peter J. Weina Division of Experimental Therapeutics and Division of Pathology, Walter Reed Army Institute of Research, Silver Spring, Maryland

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Max Grogl Division of Experimental Therapeutics and Division of Pathology, Walter Reed Army Institute of Research, Silver Spring, Maryland

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Michael T. O'Neil Division of Experimental Therapeutics and Division of Pathology, Walter Reed Army Institute of Research, Silver Spring, Maryland

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Qigui Li Division of Experimental Therapeutics and Division of Pathology, Walter Reed Army Institute of Research, Silver Spring, Maryland

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Diana Caridha Division of Experimental Therapeutics and Division of Pathology, Walter Reed Army Institute of Research, Silver Spring, Maryland

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Colin Ohrt Division of Experimental Therapeutics and Division of Pathology, Walter Reed Army Institute of Research, Silver Spring, Maryland

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Mark Hickman Division of Experimental Therapeutics and Division of Pathology, Walter Reed Army Institute of Research, Silver Spring, Maryland

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Alan J. Magill Division of Experimental Therapeutics and Division of Pathology, Walter Reed Army Institute of Research, Silver Spring, Maryland

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Prabhati Ray Division of Experimental Therapeutics and Division of Pathology, Walter Reed Army Institute of Research, Silver Spring, Maryland

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Anti-malarial 8-aminoquinolines drugs cause acute hemolytic anemia in individuals with glucose-6-phosphate dehydrogenase deficiency (G6PDD). Efforts to develop non-hemolytic 8-aminoquinolines have been severely limited caused by the lack of a predictive in vivo animal model of hemolytic potential that would allow screening of candidate compounds. This report describes a G6PDD mouse model with a phenotype closely resembling the G6PDD phenotype found in the African A-type G6PDD human. These G6PDD mice, given different doses of primaquine, which used as a reference hemolytic drug, display a full array of hemolytic anemia parameters, consistently and reproducibly. The hemolytic and therapeutic indexes were generated for evaluation of hemotoxicity of drugs. This model demonstrated a complete hemolytic toxicity response to another known hemolytic antimalarial drug, pamaquine, but no response to non-hemolytic drugs, chloroquine and mefloquine. These results suggest that this model is suitable for evaluation of selected 8-AQ type candidate antimalarial drugs for their hemolytic potential.

Author Notes

* Address correspondence to Prabhati Ray, Walter Reed Army Institute of Research, Silver Spring, MD. E-mail: prabhati.ray@us.army.mil

Financial support: This study was supported by the Military Infectious Diseases Research Program (MIDRP) Award #RQ0031_09_WR and the U.S. Army Medical Research & Materiel Command (USAMRMC) and the Telemedicine & Advanced Technology Research Center (TATRC), at Fort Detrick, MD, under award number: W81XWH-07-2-0095. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Authors' addresses: Peng Zhang, Xiugong Gao, Hiroshi Ishida, Jack Amnuaysirikul, Peter J. Weina, Max Grogl, Michael T. O'Neil, Qigui Li, Diana Caridha, Colin Ohrt, Mark Hickman, Alan J. Magill, and Prabhati Ray, Walter Reed Army Institute of Research - Experimental Therapeutics, Silver Spring, MD, E-mails: peng.zhang@amedd.army.mil, Xiugong.Gao@fda.hhs.gov, hiroshi.ishida@amedd.army.mil, Jack.Amnuaysirikul@us.army.mil, peter.weina@us.army.mil, Max.Grogl@amedd.army.mil, michael.t.oneil@us.army.mil, Qigui.Li@us.army.mil, Diana.Caridha2@us.army.mil, Colin.Ohrt@amedd.army.mil, Mark.Hickman@amedd.army.mil, Alan.Magill@us.army.mil, alan.magill@gatesfoundation.org, and prabhati.ray@us.army.mil.

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