A comprehensive evaluation of the efficacy of leading oxime therapies in guinea pigs exposed to organophosphorus chemical warfare agents or pesticides

Abstract

The currently fielded pre-hospital therapeutic regimen for the treatment of organophosphorus (OP) poisoning in the United States (U.S.) is the administration of atropine in combination with an oxime antidote (2-PAM Cl) to reactivate inhibited acetylcholinesterase (AChE). Depending on clinical symptoms, an anticonvulsant, e.g., diazepam, may also be administered. Unfortunately, 2-PAM Cl does not offer sufficient protection across the range of OP threat agents, and there is some question as to whether it is the most effective oxime compound available. The objective of the present study is to identify an oxime antidote, under standardized and comparable conditions, that offers protection at the FDA approved human equivalent dose (HED) of 2-PAM Cl against tabun (GA), sarin (GB), soman (GD), cyclosarin (GF), and VX, and the pesticides paraoxon, chlorpyrifos oxon, and phorate oxon. Male Hartley guinea pigs were subcutaneously challenged with a lethal level of OP and treated at approximately 1 min post challenge with atropine followed by equimolar oxime therapy (2-PAM Cl, HI-6 DMS, obidoxime Cl2, TMB-4, MMB4-DMS, HLö-7 DMS, MINA, and RS194B) or therapeutic-index (TI) level therapy (HI-6 DMS, MMB4-DMS, MINA, and RS194B). Clinical signs of toxicity were observed for 24 hours post challenge and blood cholinesterase [AChE and butyrylcholinesterase (BChE)] activity was analyzed utilizing a modified Ellman’s method. When the oxime is standardized against the HED of 2-PAM Cl for guinea pigs, the evidence from clinical observations, lethality, quality of life (QOL) scores, and cholinesterase reactivation rates across all OPs indicated that MMB4 DMS and HLö-7 DMS were the two most consistently efficacious oximes.

Toxicity and median effective doses of oxime therapies against percutaneous organophosphorus pesticide and nerve agent challenges in the Hartley guinea pig

“…Interestingly, while this same oxime completely prevented lethality against both percutaneously (Snider et al, 2015) or subcutaneously (Wilhelm et al, 2014) administered VX, it did not significantly promote overall survival against PHO in either previous reports. Efficacy in those studies was evaluated at 24-hr after a LD 85 challenge followed by a single administration of therapy that was given either 1 min or at onset of clinical toxic signs.…”

“…Although the mechanism of toxicosis via cholinolergic hyperstimulation is the same between OP insecticides/pesticides and OP CWNAs, the relative potencies can be radically different. In general, CWNAs such as sarin, soman, cyclosarin, VX and Russian VX (VR), have been shown to exhibit greater toxicity than bioactivated OP pesticides such as paraoxon, chlorpyrifos-oxon and phorate oxon or PHO (Balali-Mood and Shariat, 1998;Wilhelm et al, 2014;Snider et al, 2015;Misik et al, 2015).…”

A comparison of the reactivating and therapeutic efficacy of two novel bispyridinium oximes (K920, K923) with the oxime K203 and trimedoxime in tabun-poisoned rats and mice

“…Clinical opinions on the value of oximes as adjunct in the treatment of human poisoning with OPC remain divided. While some authors reported disappointing experiences with oximes (Eddleston et al, 2002;Peter et al, 2006), according to other authors, oximes are beneficial if used properly (Jokanovic, 2012;Wilhelm et al, 2014).…”

“…Unfortunately, currently available antidotal treatment consisting of atropine and commonly used reactivator of inhibited AChE (pralidoxime, obidoxime, trimedoxime, HI-6) is not able to sufficiently counteract acute toxic effects of tabun because of low ability of oximes to reactivate tabun-inhibited AChE Q3 (Jokanovic and Prostran, 2009;Jokanovic, 2012;Wilhelm et al, 2014). Therefore, the antidotal treatment of acute poisoning with tabun still remains a serious problem and the development of new and more effective AChE reactivator is still very important (Sharma et al, 2015).…”

Translation of in vitro to in vivo pyridinium oxime potential in tabun poisoning / Translacija učinkovitosti piridinijevih oksima kod trovanja tabunom iz in vitro sustava u in vivo primjenu

“…Current treatment relies on the use of anticholinergic drug atropine to reduce the effects of accumulating acetylcholine usually combined with oximes that reactivate phosphylated AChE (3)(4)(5). However, the potential of the oximes used in medical practice today, such as 2-PAM, HI-6, and obidoxime, is limited primarily due to the very specific properties of each of the enzyme-OP conjugates (6)(7)(8)(9).…”