Amplification of Quinine Cardiac Effects by the Resistance-Reversing Agent Prochlorperazine in Falciparum Malaria

George WattDepartments of Medicine and Immunology, Armed Forces Research Institute of Medical Sciences (AFRIMS), Northern Regional Pharmacology Unit, Trade Provincial Hospital, Bangkok, Thailand

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Ampon Na-NakornDepartments of Medicine and Immunology, Armed Forces Research Institute of Medical Sciences (AFRIMS), Northern Regional Pharmacology Unit, Trade Provincial Hospital, Bangkok, Thailand

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D. N. BatemanDepartments of Medicine and Immunology, Armed Forces Research Institute of Medical Sciences (AFRIMS), Northern Regional Pharmacology Unit, Trade Provincial Hospital, Bangkok, Thailand

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Niyom PlubhaDepartments of Medicine and Immunology, Armed Forces Research Institute of Medical Sciences (AFRIMS), Northern Regional Pharmacology Unit, Trade Provincial Hospital, Bangkok, Thailand

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Preeda MothanaprakoonDepartments of Medicine and Immunology, Armed Forces Research Institute of Medical Sciences (AFRIMS), Northern Regional Pharmacology Unit, Trade Provincial Hospital, Bangkok, Thailand

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Michael EdsteinDepartments of Medicine and Immunology, Armed Forces Research Institute of Medical Sciences (AFRIMS), Northern Regional Pharmacology Unit, Trade Provincial Hospital, Bangkok, Thailand

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H. Kyle WebsterDepartments of Medicine and Immunology, Armed Forces Research Institute of Medical Sciences (AFRIMS), Northern Regional Pharmacology Unit, Trade Provincial Hospital, Bangkok, Thailand

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The use of reversing agents to overcome drug resistance is a potential new treatment strategy for both malaria and cancer. Laboratory studies have raised questions about the safety of this therapeutic approach, but data in humans are lacking. We therefore assessed the toxic potential of reversing agent therapy in Thai patients receiving quinine (17 mg/kg given over 4.5 hr) for falciparum malaria by serial measurements of the QTc interval, an electrocardiographic (ECG) marker of the effect of quinine. Six patients were randomly assigned to receive intravenous quinine alone while another six received one intramuscular injection of 12.5 mg of the reversing agent prochlorperazine (PC; compazine®, stemetil®) 2.5 hr after the quinine infusion had begun. Compared with baseline values at 2.5 hr, there was prolongation of the QTc interval 30, 60, 90, and 120 min after PC was injected (P < 0.05) but no further lengthening with quinine alone (P > 0.2). Prochlorperazine alone did not lengthen the QTc interval in six healthy volunteers. Neither total nor free quinine plasma levels increased after PC was injected, suggesting that ECG changes may have been due to PC-induced intracellular accumulation of quinine. Although only minor quinine ECG effects were amplified by the reversing agent PC in this study, resistance-reversing therapy could potentiate more serious drug effects. The possibility that more serious toxic effects could be produced by this therapeutic approach should be investigated further.

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