ABSTRACT
BACKGROUND: Due to the ability of the 8-aminoquinolines (8AQs) to kill different stages of the malaria parasite, primaquine (PQ) and tafenoquine (TQ) are vital for causal prophylaxis and the eradication of erythrocytic Plasmodium sp. parasites. Recognizing the potential role of cytochrome (CYP) 450 2D6 in the metabolism and subsequent hepatic efficacy of 8-aminoquinolines, studies were designed to explore whether CYP2D-mediated metabolism was related to the ability of single-dose PQ and TQ to eliminate the asexual and sexual erythrocytic stages of Plasmodium berghei. METHODS: An IV P. berghei sporozoite murine challenge model was utilized to directly compare causal prophylactic and erythrocytic activity (asexual and sexual parasite stages) dose-response relationships in C57BL/6 wild-type (WT) mice and subsequently compare the erythrocytic activity of PQ and TQ in WT and CYP2D knock-out (KO) mice. RESULTS: Single-dose administration of either 25 mg/kg TQ or 40 mg/kg PQ eradicated the erythrocytic stages (asexual and sexual) of P. berghei in C57BL WT and CYP2D KO mice. In WT animals, the apparent elimination of hepatic infections occurs at lower doses of PQ than are required to eliminate erythrocytic infections. In contrast, the minimally effective dose of TQ needed to achieve causal prophylaxis and to eradicate erythrocytic parasites was analogous. CONCLUSION: The genetic deletion of the CYP2D cluster does not affect the ability of PQ or TQ to eradicate the blood stages (asexual and sexual) of P. berghei after single-dose administration.
Subject(s)
Aminoquinolines/pharmacology , Antimalarials/pharmacology , Cytochrome P-450 CYP2D6/metabolism , Malaria/drug therapy , Plasmodium berghei/drug effects , Primaquine/pharmacology , Aminoquinolines/administration & dosage , Animals , Antimalarials/administration & dosage , Chemoprevention/methods , Cytochrome P-450 CYP2D6/deficiency , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Therapy/methods , Female , Male , Mice, Inbred C57BL , Mice, Knockout , Primaquine/administration & dosage , Treatment OutcomeABSTRACT
It is essential to identify improved capabilities to accurately identify, confirm, and/or quantify radiological exposure and injury in order to inform critical triage, diagnosis, and treatment decisions. Herein the authors report characteristic requirements and potential Concepts of Operations (CONOPS) for biodosimetry tools employed in operational environments. While similar significant efforts have been completed in this area for the U.S. civilian sector, limited perspectives are published in the peer-reviewed literature regarding the use of radiological diagnostic technologies in deployed military medical treatment settings. Two radiological exposure scenarios were developed to clarify the diagnostic performance criteria and identify capability gaps. The emerging technology areas associated with radiation exposure diagnostics were reviewed and assessed to gauge their suitability in supporting triage, treatment, and return to duty decisions within the military medical support system.
Subject(s)
Radiation Exposure , Radiation Injuries/diagnosis , Gene Expression/radiation effects , Humans , MicroRNAs/radiation effects , Military Medicine , Models, Theoretical , Proteomics , Radiation Dosage , Radiation Exposure/analysis , Radiation Injuries/blood , Radioactive Hazard ReleaseABSTRACT
Two novel SF5 analogs of the antimalarial agent mefloquine were synthesized in 5 steps and 10-23% overall yields and found to have improved activity and selectivity against malaria parasites. This work also represents the first report of SF5-substituted quinolines.
