Comparison of two pre-exposure treatment regimens in acute organophosphate (paraoxon) poisoning in rats: Tiapride vs. pyridostigmine

Recently, the FDA approved the medical use of oral pyridostigmine as prophylactic treatment of possible nerve agent exposure: the concept is to block the cholinesterase transitorily using the carbamate (pyridostigmine) in order to deny access to the active site of the enzyme to the irreversible inhibitor (nerve agent) on subsequent exposure. We have shown previously that tiapride is in vitro a weak inhibitor of acetylcholinesterase and that in rats administration of tiapride before the organophosphate paraoxon significantly decreases mortality. The purpose of the present study was to compare tiapride- and pyridostigmine-based pretreatment strategies, either alone or in combination with pralidoxime reactivation, by using a prospective, non-blinded study in a rat model of acute high-dose paraoxon exposure. Groups 1-6 received 1 μMol paraoxon (≈ LD₇₅) groups 2-6 received in addition:G₂50 μMol tiapride 30 min before paraoxonG₃50 μMol tiapride 30 min before paraoxon and 50 μMol pralidoxime 1 min after paraoxonG₄1 μMol pyridostigmine 30 min before paraoxonG₅1 μMol pyridostigmine 30 min before paraoxon and 50 μMol pralidoxime 1 min after paraoxonG₆50 μMol pralidoxime 1 min after paraoxon. Mortality data were compared using Kaplan-Meier plots and logrank tests. Mortality is statistically significantly influenced by all treatment strategies. Tiapride pretreatment followed by pralidoxime treatment (G₃) is aux par with pyridostigmine pretreatment followed by pralidoxime treatment (G₅). Tiapride pretreatment only (G₂) is inferior to pyridostigmine pretreatment only (G₄). The best results are achieved with pyridostigmine pretreatment only or pralidoxime treatment only (G₄ and G₆).