Research Project
9621314
ABSTRACT Inhibition of AChE in the neuromuscular junction, peripheral autonomic and central neuron synapses, and on circulating red blood cells is associated with the toxicity for all organophosphate insecticides. Treatment typically involves the muscarinic antagonist (atropine) in combination with a pyridinium aldoxime, eg pralidoxime (2-PAM) and obidoxime, capable of reactivating the OP- inhibited AChE, with/without an anti-convulsant (diazepam) to control seizures. However, animal model studies and recent clinical trials using pesticide-poisoned individuals have shown uneven clinical bene?ts of these oximes and even harm so their true ef?cacy as antidotes has been debated. Currently used oximes either reactivate poorly, do not readily cross the BBB and are rapidly cleared from the circulation. Hence, they must be repeatedly administered. Recently, Dr. Palmer Taylor's lab at UCSD has developed zwitterionic oximes of simpli?ed structure eg RS194B, that efficiently cross the blood-brain-barrier (BBB) resulting in rapid reactivation of OP- inhibited AChE and dramatic reversal of severe clinical symptoms in mice and macaques exposed to OP insecticide or nerve agents. In a recent PlantVax macaque study, it was observed that a lethal dose of the OP insecticide paraoxon, delivered by inhalation, caused clinical symptoms very similar to those in insecticide poisoned people. This probably is a consequence of the unusual deposition of nebulized OP predominantly in the stomach in addition to the lungs in macaques and small children in contrast to that seen in adult humans. The challenges to understanding the acute and chronic effects of and treatments for different OP pesticides result from significant variability in their in vivo toxicokinetics and oxime responsiveness in the same or different animal species. In general, the inhibition and reactivation kinetics with swine, rat and guinea pig AChE exposed to a variety of OP insecticides (Px) or nerve agents (sarin, cyclosarin, VX) are slower than for humans and non-human primates. This Phase I proposal, is the first to evaluate the efficacy of a centrally acting oxime RS194B to reactivate phosphorothioate insecticides in vitro and in vivo. Initially, oxime reactivation of macaque and human rAChE inhibited by a panel of both diethyl- and dimethylphosphorothioate insecticides will be assessed and subsequently, RS194B efficacy to reactivate AChE and reverse clinical signs in macaques exposed to selected commonly used insecticides will be assessed. The similar biochemical/pharmacological properties and reactivation kinetics in macaques and humans and the shared clinical symptoms following insecticide poisoning should allow a reasonable animal-to- human extrapolation and provide support for the use of monkeys for in vivo evaluation of RS194B.
