Pyridinium oxime reactivators of cholinesterase inhibited by diisopropyl-fluorophosphate (DFP): predictive value of in-vitro testing for in-vivo efficacy.

摘要

Poisoning with organophosphorus cholinesterase inhibitors (OPCs) poses a serious global threat. Therapy comprises the use of atropine and pyridinium oximes to reactivate acetylcholinesterase (AChE). Clinical experience with established oximes (pralidoxime and obidoxime) is disappointing and several experimental potential alternatives (K oximes) have been developed. This review summarizes data on these oximes, when used in exposure to the OPC diisopropylfluorophosphate (DFP). In vitro testing includes determination of IC(50) (intrinsic oxime AChE inhibitory activity), of tan alpha (reactivation capacity) and in silico estimation of LogP (lipophilicity/hydrophilicity) of the individual oximes. In vivo approaches encompass determination of toxicity (LD(50)) and of protective efficacy (reduction of relative risk of death after DFP exposure in rats). Correlations between the different in vitro and in vivo data available reveal that an oxime with a low in vitro AChE inhibitory activity (high IC(50)) is rather non-toxic and reduces DFP-induced mortality (low cumulative relative risk). Oximes with a high in vitro AChE reactivation potency (high tan alpha) also have a high in vitro AChE inhibitory activity (low IC(50)) and have a low LD(50) in vivo, implying high toxicity. Less hydrophilic oximes have strong in vitro AChE inhibitory activity, are better in vitro AChE reactivators, but are also more toxic in vivo and are associated with a high cumulative risk of death after DFP exposure in rats, implying low in vivo efficacy. In vitro reactivation capacity of human red blood cell (RBC)-AChE has no predictive value for in vivo (rat) efficacy, at least in the case of DFP exposure.