Comparison of known sodium-channel blockers in DFP toxicity

Research on potential therapeutic agents for organophosphate toxicity has traditionally been directed toward blocking the action of acetylcholine on its muscarinic receptors or on reactivating the inhibited catalytic enzyme. Here, we used a whole-animal lethality paradigm to study another potential antidotal mechanism: pharmacological disruption of the sodium channel conductance associated with agonist action on cholinergic receptors. Mice were injected with several drugs which have in common the ability to block sodium-channels. Drugs tested were ketamine, phenobarbital, lidocaine, morphine, prednisolone, and lithium. All mice were injected with DFP (7.6 mg/kg) plus atropine; the treatment groups were simultaneously injected with the test drug, while controls received an equal volume of physiological saline. All the test drugs, at one or more doses, revealed protection, not only in terms of prolonging symptom onset but also in terms of mortality. The reduction in mortality was quantitatively similar for each drug. Although the various drugs could have protected by many different, coincidental mechanisms, a more parsimonious explanation is that the effect could have been due to one property which all had in common; namely, sodium-channel blockade.