title: An in vivo drug screening model using glucose-6-phosphate dehydrogenase deficient mice to predict the hemolytic toxicity of 8-aminoquinolines.
abstract: 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.
authors.affiliation: Division of Experimental Therapeutics and Division of Pathology, Walter Reed Army Institute of Research, Silver Spring, MD, USA. peng.zhang@amedd.army.mil
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.forename: Xiugong
authors.initials: X
authors.lastname: Gao
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ishida
authors.forename: Jack
authors.initials: J
authors.lastname: Amnuaysirikul
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Weina
authors.forename: Max
authors.initials: M
authors.lastname: Grogl
authors.forename: Michael T
authors.initials: MT
authors.lastname: O'Neil
authors.forename: Qigui
authors.initials: Q
authors.lastname: Li
authors.forename: Diana
authors.initials: D
authors.lastname: Caridha
authors.forename: Colin
authors.initials: C
authors.lastname: Ohrt
authors.forename: Mark
authors.initials: M
authors.lastname: Hickman
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Magill
authors.forename: Prabhati
authors.initials: P
authors.lastname: Ray
mesh_terms: D000208:Acute Disease; D000634:Aminoquinolines / Q000008:administration & dosage / Q000009:adverse effects*; D000743:Anemia, Hemolytic / Q000209:etiology / Q000503:physiopathology*; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000009:adverse effects*; D002738:Chloroquine / Q000008:administration & dosage / Q000009:adverse effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005838:Genotype; D005955:Glucosephosphate Dehydrogenase Deficiency / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000097:blood; D006242:Haptoglobins / Q000032:analysis; D053878:Hemolytic Agents / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D015767:Mefloquine / Q000008:administration & dosage / Q000009:adverse effects; D051379:Mice; D010641:Phenotype; D011319:Primaquine / Q000008:administration & dosage / Q000009:adverse effects; D017701:Reticulocyte Count
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; D006242:Haptoglobins; D053878:Hemolytic Agents; D002738:Chloroquine; D005978:Glutathione; D011319:Primaquine; D015767:Mefloquine; C080436:8-aminoquinoline