Cytochrome P450 2D-mediated metabolism is not necessary for tafenoquine and primaquine to eradicate the erythrocytic stages of Plasmodium berghei.

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.

Reduced effectiveness of permethrin-treated military uniforms after prolonged wear measured by contact irritancy and toxicity bioassays with Ixodes scapularis (Acari: Ixodidae) nymphs.

Factory-treated permethrin uniforms are the primary method used by the US Army to prevent arthropod bites and transmission of arthropod-borne diseases. In this study previously worn uniforms were collected from cadets at the United States Military Academy in West Point, NY to determine the amount of permethrin remaining after prolonged wear and subsequent effects on ticks. Six trousers were collected from cadets in the sophomore, junior, and senior classes. A new, unwashed uniform served as a positive control and an untreated maternity uniform served as a negative control. Fabric samples were removed from each trouser and used in bioassays with laboratory-reared Ixodes scapularis Say nymphs. Contact irritancy bioassays measured the nymphs' ability to remain in contact with fabric for a period of 5 min. Toxicity bioassays measured tick survival at 1 and 24 h after contacting uniform samples. liquid chromatography-mass spectrometry was used to quantify the permethrin content (mg/cm2) in each uniform after the bioassays were complete. The results showed significant amounts of permethrin were lost after extended wear and it was related to the cadet year group. The contact irritancy assays found uniforms with less permethrin did not irritate ticks and cause them to dislodge. Mortality was also affected by permethrin levels, with less ticks dying at 24 h on older uniforms. The results from this study show older uniforms lose most of their permethrin and no longer provide the same levels of protection.

Synthesis and biological evaluation of the first pentafluorosulfanyl analogs of mefloquine.

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.

Concepts of Operations (CONOPS) for Biodosimetry Tools Employed in Operational Environments.

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.