Screening of Candidate Pretreatment and Therapeutic Compounds against Vesicant and Nerve Agents Using In Vitro Models

摘要

The Drug Assessment Division of the U.S. Army Medical Research Institute of Chemical Defense (USAMRICD) has the mission of identifying and evaluating candidate pretreatment and therapeutic compounds which are safe and effective in preventing or reversing the effects of chemical warfare agents. Medical Research and Evaluation Facility (MREF) Task 92-32 was initiated in 1993 to assist the identification of pretreatment and treatment (P&T) compounds efficacious in countering the effects of nerve agents and sulfur mustard (HE). Screening assays were initially established and validated under MREF Task 88-36, 'Development of In Vitro Screening Assays for Candidate Pretreatment and Treatment Compounds'. The evaluations developed included four nerve agent assays and four vesicant assays. The four nerve agent assays were developed to assess: Direct inhibitory effects on acetylcholinesterase (AChE) activity produced P&T compounds P&T compound efficacy in reactivating Tabun (GA)-inhibited AChE P&T compound efficacy in reactivating VX-inhibited AChE Candidate P&T compound efficacy in decreasing the aging rate of the Soman (GD)- AChE complex The four vesicant assays were designed to measure: Candidate P&T compound solubility in an aqueous solution Candidate P&T compound cytotoxicity against human peripheral blood mononuclear cells (PBMC) Protection against HD-induced human PBMC toxicity Protection against HD-induced nicotinamide adenine dinucleotide (NAD+) depletion in human epidermal keratinocytes (HEK).