Current treatment of acute pesticide or organophosphate (OP) poisoning includes a combined administration of a cholinesterase reactivator (oxime), a muscarinic receptor antagonist (atropine) and an anticonvulsant (diazepam). Since the oxime does not penetrate the blood brain barrier (BBS), removal of excessive accumulation of acetylcholine (ACh) is not accomplished by acetylcholinesterase (AChE). Pesticides and OPs are significant terrorist threats to civilian populations. The chemical agent sarin was used in the Tokyo subway terrorist event in 1995 and resulted in long-term neuronal sequelae. Clearly, a new formulation of oxime is required to improve CNS therapy. Because of their chemical structure, the positively charged small molecule oximes do not penetrate the BBB and therefore can not treat pesticide- and OP- induced toxicity in the brain. Our long term goal is to transport oxime (2-PAM, MMB-4) quickly and non-invasively into the CNS. CNS-penetrating oxime therapy will reactivate the brain AChE in a timely manner, reduce the requirement for anticonvulsant drug regimens, and improve the long term recovery of the exposed individual by reducing or eliminating CNS neuronal damage, (a) We will synthesize and evaluate more lipoidal forms (pro-oximes), that can be converted to their active (charged) form in the brain, (b) In addition, we will develop carrier(s) of oximes that will come from a class of FDA approved/phase 1 trial Pharmaceuticals that pass the BBB for treatment of CNS dancers, including Stealth liposomes, nanoparticles, or cyclodextrins. (c) Two additional advantages to the carriers: should permit a sustained delivery of oxime into the systemic circulation through the skin (via skin patch) and prolong the circulatory time of the oxime(s), which are rapidly cleared by the renal system (T1/2<2 hr). (d) For formulations that are successful in in vitro BBB tissue culture and pig skin penetration models, we will determine reactivation kinetics of the encapsulated oximes with pesticide- and OP-inhibited AChE and BuChE, the release rates of the oxime from the carrier in the peripheral and CNS of our animal model (guinea pig), and the pharmacokinetics of the pro-oxime and oxime carrier and distribution in diaphragm, blood, and brain, (d) The most efficacious formulation will be validated in our status epilepticus guinea pig model as a therapy for CNS chemical agent OP-induced toxicity of DFP, GB, GD, and VX using EEC radiotelemetry probe techniques. This program will address an important and potential threat to civilian populations, for post-exposure CNS treatment in response to exposure to chemical threat agents. Further, the outcome of this work could provide a non-invasive means of administrating appropriate therapeutics for deleterious effects of OP poisoning, directly relevant to emergency and preparedness response to chemical threats for Public Health.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZNS1-SRB-R (22))
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Jett, David A
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Geneva Foundation
United States
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Khan, Farhat A; Campbell, Amy J; Hoyt, Benjamin et al. (2011) Oxidative mechanisms for the biotransformation of 1-methyl-1,6-dihydropyridine-2-carbaldoxime to pralidoxime chloride. Life Sci 89:911-7
Demar, James C; Clarkson, Edward D; Ratcliffe, Ruthie H et al. (2010) Pro-2-PAM therapy for central and peripheral cholinesterases. Chem Biol Interact 187:191-8