The overall goal of the current research is to develop a novel class of therapeutics that will mitigate mortality and morbidity caused by acute exposure to parathion, an organophosphate (OP) insecticide that is considered a high priority chemical threat. The toxicity of parathion is dependent on its metabolism by the cytochrome P450 system to an active metabolite, paraoxon. By inhibiting P450-mediated generation of paraoxon, progressive toxicity can be reduced. Ongoing research in our laboratory in the field of redox chemistry has led to the identification of a candidate therapeutic that is a highly effective inhibitor of the P450 system. This drug, which has very low toxicity, is currently undergoing advanced clinical trials for other diseases and has been approved by the FDA for other indications. In 'proof-of-concept' studies, we have generated strong data showing that our drug is highly effective in reducing parathion toxicity. We have partnered with a company that has a drug product containing our candidate therapeutic in phase 1/phase 2 clinical trials.
Our aims are to assess the ability of this drug product to inhibit bioactivation of parathion and reduce parathion toxicity in the rat model, conduct preclinical IND-enabling studies for the drug product for use in OP poisoning, and determine if the drug product can enhance the therapeutic actions of currently used drugs that are the standard of care in the treatment of OP toxicity. Success of this proposal may lead to the rapid development of a new agent to treat human exposure to a high priority chemical threat. Use of an FDA approved drug will greatly reduce the time required for regulatory approval.
There is increasing concern that toxic chemicals could be released by a deliberate terrorist attack, or by accident or natural disaster. One readily obtainable toxic chemical that is considered of particular risk is parathion, a highly toxic (LD50 ~2 mg/kg) organophosphate insecticide. Parathion is a restricted, but widely used agricultural chemical that becomes a toxic nerve agent once absorbed into the body where it is metabolized to a reactive metabolite called paraoxon. A major site of action for paraoxon is the enzyme acetylcholinesterase; proper functioning of this enzyme is crucial for normal nerve cell activity and its inhibition can be fatal. There are several treatments for organophosphate poisoning including atropine, a competitive antagonist of acetylcholine, and pralidoxime which binds to organophosphate-inactivated acetylcholinesterase and regenerates the enzyme. Both of these agents have limitations and there remains a pressing need to develop new more efficacious therapies for parathion poisoning. Success of this proposal will lead to the rapid development of a new agent to treat human exposure to a high priority chemical threat.
| Szilagyi, John T; Fussell, Karma C; Wang, Yun et al. (2018) Quinone and nitrofurantoin redox cycling by recombinant cytochrome b5 reductase. Toxicol Appl Pharmacol 359:102-107 |
