SBIR/STTR Award attributes
ABSTRACTInhibition of AChE in the neuromuscular junctionperipheral autonomic and central neuron synapsesand on circulating red blood cells is associated with the toxicity for all organophosphate insecticidesTreatment typically involves the muscarinic antagonistatropinein combination with a pyridinium aldoximeeg pralidoximePAMand obidoximecapable of reactivating the OPinhibited AChEwith without an anti convulsantdiazepamto control seizuresHoweveranimal 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 debatedCurrently used oximes either reactivate poorlydo not readily cross the BBB and are rapidly cleared from the circulationHencethey must be repeatedly administeredRecentlyDrPalmer Taylorandapos s lab at UCSD has developed zwitterionic oximes of simpli ed structure eg RSBthat efficiently cross the blood brain barrierBBBresulting in rapid reactivation of OPinhibited AChE and dramatic reversal of severe clinical symptoms in mice and macaques exposed to OP insecticide or nerve agentsIn a recent PlantVax macaque studyit was observed that a lethal dose of the OP insecticide paraoxondelivered by inhalationcaused clinical symptoms very similar to those in insecticide poisoned peopleThis 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 humansThe 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 speciesIn generalthe inhibition and reactivation kinetics with swinerat and guinea pig AChE exposed to a variety of OP insecticidesPxor nerve agentssarincyclosarinVXare slower than for humans and non human primatesThis Phase I proposalis the first to evaluate the efficacy of a centrally acting oxime RSB to reactivate phosphorothioate insecticides in vitro and in vivoInitiallyoxime reactivation of macaque and human rAChE inhibited by a panel of both diethyland dimethylphosphorothioate insecticides will be assessed and subsequentlyRSB efficacy to reactivate AChE and reverse clinical signs in macaques exposed to selected commonly used insecticides will be assessedThe similar biochemical pharmacological properties and reactivation kinetics in macaques and humans and the shared clinical symptoms following insecticide poisoning should allow a reasonable animal tohuman extrapolation and provide support for the use of monkeys for in vivo evaluation of RSB Project NarrativeWhile organophosphateOPinsecticides greatly increase yields of agricultural cropsthey can also cause neurotoxicity and even death in humansdue to inhibition of acetylcholinesteraseAChEin the brainThe current post exposure treatment in poisoned humans involves administration of atropine and an oxime which reactivates the inhibited AChEHowever the value of these oxime treatments is being debated since in since cases they appear to provide no benefitA recently developed oximeRSwhich can cross into the brainhas been shown to readily reverse clinical symptoms after OP exposure and reactivate AChE in the brain of animalsHere it is being tested in a new macaque model as an antidote for protection against insecticide poisoning
