PRO-2-PAM: The First Therapeutic Drug for Reactivation of Organo-Phosphate-Inhibited Central (Brain) and Peripheral Cholinesterases

Due to the documented use of organophosphorus OP chemical agents in warfare and by terrorists around the globe, Federal, State, and local authorities need novel therapeutics to overcome their deleterious effects. OPs inhibit cholinesterases ChE, leading to accumulation of the neurotransmitter acetylcholine ACh. Potentially lethal effects begin with secretion, muscle fasciculation, and paralysis in the peripheral nervous system PNS. Central nervous system CNS perturbations include epileptic seizures leading to neuronal damage and long-term structural changes. Therapy for OP exposure is a combination of atropine sulfate to block the overload of cholinergic muscarinic receptors, the FDA approved cholinesterase reactivator oxime pralidoxime chloride 2-PAM, and a benzodiazepine diazepam anticonvulsant to ameliorate seizures. However, current therapies for acute pesticide or organophosphate poisoning do not provide treatment for centrally inhibited cholinesterases because quaternary nitrogen charged oximes, including 2- PAM, do not cross the blood brain barrier.