Tuesday, April 30, 2024
4/30/2024
7. Abstract Organophosphate (OP) anticholinesterases, e.g., nerve agents and some insecticides, present a threat to the civilian population via terrorist activity or accidents. These OP compounds or metabolites are potent and persistent inhibitors of central and peripheral nervous system acetylcholinesterase (AChE). High dose OP exposures can lead to seizures, respiratory failure and death. Survivors may suffer from brain damage and behavioral deficits. One of these OP insecticides, phorate, is very acutely toxic making it a potential threat. Unlike the nerve agents, phorate requires bioactivation to its anticholinesterase metabolites (oxons) which results in a delay (4-5 h) in toxic signs (tremors, salivation, and seizure-like behavior). The current therapy (US) for severe OP poisoning includes atropine plus the oxime AChE reactivator 2-PAM. A major limitation of 2- PAM is its relatively short plasma half-life and inability to cross the blood-brain barrier (BBB) and protect the brain. Our laboratories have invented and patented a series of oximes that have shown survival efficacy and attenuation of seizure-like behavior and neuropathology following exposure of rats to high levels of nerve agent surrogates and one OP insecticidal metabolite (paraoxon). The delay in toxic signs following phorate challenge makes the timing of oxime administration and oxime plasma half-life important in establishing an effective therapeutic regimen. Our lead novel oximes have demonstrated longer plasma half-lives compared to 2-PAM which should be beneficial combating OPs that have delays in initiation of the cholinergic crisis. Some of our novel oximes can also effectively reactivate butyrylcholinesterase (BChE) inhibited by the anticholinesterase metabolites of OPs including phorate. BChE is prominent in serum and is inhibited by circulating oxons. An oxime that can effectively reactivate BChE, creating a pseudo-catalytic bio-scavenger of circulating oxons, could prevent or attenuate OP-induced toxicity. The Aims of this project are: 1) Characterize the temporal relationship between ChE inhibition and the phorate toxidrome, and the survival efficacy provided by 3 novel oximes; 2) Demonstrate in vitro (rat and human) and in vivo (male and female rats) with a down- selected lead novel oxime the ability to reactivate phorate inhibited BChE and enhance survival. The challenge dosage of phorate will be lethal (LD99) to rats receiving atropine only. A novel oxime or 2-PAM will be administered at the initiation of seizure-like behavior and at one earlier time point prior to initiation of cholinergic crisis. In addition, oxime-mediated reactivation of OP-inhibited BChE will allow a demonstration that pseudo-catalytic BChE-mediated destruction of OP can attenuate toxicity. A selective BChE inhibitor will be used to confirm the significance of BChE reactivation, as evidenced by a reduction of AChE inhibition and lethality in oxime-treated rats having functional BChE (rats not receiving the BChE inhibitor). The data from this translational project will be used to further develop an oxime into a more effective therapeutic for poisoning by insecticidal OPs, like phorate, that display a delayed toxidrome because they require bioactivation.
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