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 1min 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 24h 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.
Highlights
Organophosphorus (OP) compounds, including pesticides and chemical warfare nerve agents (CWNAs), represent a threat to the general population, as possible weapons of terrorism (Okumura, 2005; Zurer, 1998; Hubbard et al, 2013; Baker, 2013; Dolgin, 2013), and as chemicals that could be released from transportation and storage facilities during industrial accidents
GB, GD, GF, and VX were diluted in 0.9 percent saline; GA and phorate oxon were diluted in multisol; and chlorpyrifos oxon and paraoxon were diluted in ethanol (99.96 percent), with the dosing solution concentration of each pesticide being limited to that which would allow the total volume of ethanol injected to be no more than 0.06 percent (v/w) of the body mass
Minor differences were observed in lethality and quality of life (QOL) for select agents when treated with a TI dose of MMB4 DMS, HI-6 DMS or MINA
Summary
Organophosphorus (OP) compounds, including pesticides and chemical warfare nerve agents (CWNAs), represent a threat to the general population, as possible weapons of terrorism (Okumura, 2005; Zurer, 1998; Hubbard et al, 2013; Baker, 2013; Dolgin, 2013), and as chemicals that could be released from transportation and storage facilities during industrial accidents. The current U.S therapy regimen includes the administration of atropine in combination with the oxime acetylcholinesterase (AChE) reactivator pralidoxime chloride (2-PAM Cl) (Inchem.org, 1989, 1999), followed by the anticonvulsant diazepam depending on whether convulsive symptoms are observed This approach is accomplished with the use of the DuoDote® autoinjector kit (Meridian Medical TechnologiesTM, Columbia, MD; https:// www.duodote.com/meridian.aspx#) by trained emergency medical services personnel. The DuoDote® is a two-chambered, self-propelled syringe used for the intramuscular (IM) injection of atropine (2.1 mg free base) and 2-PAM Cl (600 mg) through the same needle
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