Abstract
Individuals with glucose 6-phosphate dehydrogenase (G6PD) deficiency are at risk for the development of hemolytic anemia when given 8-aminoquinolines (8-AQs), an important class of antimalarial/antiinfective therapeutics. However, there is no suitable animal model that can predict the clinical hemolytic potential of drugs. We developed and validated a human (hu)RBC-SCID mouse model by giving nonobese diabetic/SCID mice daily transfusions of huRBCs from G6PD-deficient donors. Treatment of SCID mice engrafted with G6PD-deficient huRBCs with primaquine, an 8-AQ, resulted in a dose-dependent selective loss of huRBCs. To validate the specificity of this model, we tested known nonhemolytic antimalarial drugs: mefloquine, chloroquine, doxycycline, and pyrimethamine. No significant loss of G6PD-deficient huRBCs was observed. Treatment with drugs known to cause hemolytic toxicity (pamaquine, sitamaquine, tafenoquine, and dapsone) resulted in loss of G6PD-deficient huRBCs comparable to primaquine. This mouse model provides an important tool to test drugs for their potential to cause hemolytic toxicity in G6PD-deficient populations.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Aminoquinolines / adverse effects
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Aminoquinolines / therapeutic use
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Anemia, Hemolytic / blood
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Anemia, Hemolytic / chemically induced
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Anemia, Hemolytic / diagnosis*
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Animals
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Antimalarials / adverse effects
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Antimalarials / therapeutic use
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Chloroquine / adverse effects
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Chloroquine / therapeutic use
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Combined Modality Therapy
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Dapsone / adverse effects
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Dapsone / therapeutic use
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Dose-Response Relationship, Drug
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Doxycycline / adverse effects
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Doxycycline / therapeutic use
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Drug Evaluation, Preclinical / methods
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Erythrocyte Count
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Erythrocyte Transfusion / methods*
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Female
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Glucosephosphate Dehydrogenase Deficiency / blood
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Glucosephosphate Dehydrogenase Deficiency / therapy*
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Humans
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Mefloquine / adverse effects
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Mefloquine / therapeutic use
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Mice
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Mice, Inbred NOD
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Mice, SCID
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Primaquine / adverse effects
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Primaquine / therapeutic use*
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Pyrimethamine / adverse effects
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Pyrimethamine / therapeutic use
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Reproducibility of Results
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Sensitivity and Specificity
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Transplantation, Heterologous
Substances
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Aminoquinolines
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Antimalarials
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tafenoquine
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Chloroquine
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Dapsone
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pamaquine
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Primaquine
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Doxycycline
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Mefloquine
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8-aminoquinoline
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Pyrimethamine