Evaluating the broad-spectrum efficacy of the acetylcholinesterase oximes reactivators MMB4 DMS, HLö-7 DMS, and 2-PAM Cl against phorate oxon, sarin, and VX in the Hartley guinea pig

Abstract

Organophosphorus (OP) compounds, including pesticides and chemical warfare nerve agents (CWNA), are threats to the general population as possible weapons of terrorism or by accidental exposure whether through inadvertent release from manufacturing facilities or during transport. To mitigate the toxicities posed by these threats, a therapeutic regimen that is quick-acting and efficacious against a broad spectrum of OPs is highly desired. The work described herein sought to assess the protective ratio (PR), median effective doses (ED), and therapeutic index (TI = oxime 24-h LD/oxime ED) of MMB4 DMS, HLö-7 DMS, and 2-PAM Cl against the OPs sarin (GB), VX, and phorate-oxon (PHO). All OPs are representative of the broader classes of G and V chemical warfare nerve agents and persistent pesticides. MMB4 DMS and HLö-7 DMS were previously identified as comparative efficacy leads warranting further evaluations. 2-PAM Cl is the U.S. FDA-approved standard-of-care oxime therapy for OP intoxication. Briefly, PRs were determined in male guinea pigs by varying the subcutaneously (SC) delivered OP dose followed then by therapy with fixed levels of the oxime and atropine (0.4 mg/kg; administered intramuscularly [IM]). EDs were determined using a similar approach except the OP dose was held constant at twice the median lethal dose (2 × LD) while the oxime treatment levels were varied. The ED information was then used to calculate the TI for each OP/oxime combination. Both MMB4 DMS and HLö-7 DMS provided significant protection, i.e., higher PR against GB, VX, and PHO when compared to atropine controls, but significance was not readily demonstrated across the board when compared against 2-PAM Cl. The ED values of MMB4 DMS was consistently lower than that of the other oximes against all three OPs. Furthermore, based on those EDs, the TI trend of the various oximes against both GB and VX was MMB4 DMS > HLö-7 DMS > 2-PAM Cl, while against PHO, MMB4 DMS > 2-PAM Cl > HLö-7 DMS.

Positron emission tomography evaluation of oxime countermeasures in live rats using the tracer O‐(2‐[18F]fluoroethyl)‐O‐(p‐nitrophenyl)methylphosphonate [18F]‐VXS

“…2‐PAM is primarily used in the United States to treat OP exposures, but the ability of a given oxime to reactivate inhibited AChE is typically related to the structure of the OP–AChE adduct, 30,31 and whether or not adduct aging has occurred (Fig. 1).…”

Recent Advances on Detection of Insecticides Using Optical Sensors

“…They are similar to OPs insecticides in terms of how they act and what kind of harmful effects they cause [ 244 ]. Sarin is also known as GB [ 245 ]. Detection of sarin by using the AChE enzyme expanded with the detection of soman and paraoxon [ 140 ].…”