Five oximes (K-27, K-33, K-48, BI-6 and methoxime) in comparison with pralidoxime: in vitro reactivation of red blood cell acetylcholinesterase inhibited by paraoxon.
Oximes are cholinesterase reactivators of use in poisoning with organophosphorus compounds. Pralidoxime (PRX) is used clinically as an adjunct to atropine in such exposure. Clinical experience with PRX (and other oximes) is, however, disappointing and routine use has been questioned. In addition it is known that oximes are not equally effective against all existing organophosphorus compounds. There is a clear demand for 'broad spectrum' cholinesterase reactivators with a higher efficacy than PRX. Over the years new reactivators of cholinesterase of potential clinical utility have been developed. Their chemical structures were derived from those of existing esterase reactivators, especially pralidoxime, obidoxime and HI-6. The purpose of the study was to quantify in vitro the extent of oxime (pralidoxime, K-27, K-33, K-48, methoxime and BI-6) conferred protection, using paraoxon as an inhibitor. Paraoxon (POX), the active metabolite of parathion (O,O-diethyl-O-p-nitro-phenyl phosphorothioate) is a non-neuropathic organophosphate. Red blood cell (RBC) acetylcholinesterase (AChE) activities in whole blood were measured photometrically in the presence of different POX concentrations and the IC50 was calculated. Determinations were repeated in the presence of increasing oxime concentrations. The IC50 of POX increases with the oxime concentration in a linear manner. The calculated IC50 values were plotted against the oxime concentrations to obtain an IC50 shift curve. The slope of the shift curve (tg alpha) was used to quantify the magnitude of the protective effect (nm IC50 increase per microm reactivator). Based on our determinations the new K series of reactivators is far superior to pralidoxime, methoxime and BI-6, K-27 being the outstanding compound with a tg alpha value of 3.7 (nm IC50 increase per microm reactivator) which is approximately 13 times the reactivator ability of PRX. In general there is an (expected) inverse relationship between the binding constant K and the slope of the IC50 shift curve (tg alpha) for all oximes examined. K-27 (the most protective substance judging by the tg alpha) has the lowest K value (highest affinity). In vivo testing of the new oximes as an organophosphate protective agent is necessary.
Petroianu
G A
GA
UAE University, Al Ain-UAE. georg.petroianu@uaeu.ac.ae
Arafat
K
K
Kuca
K
K
Kassa
J
J
D000110:Acetylcholinesterase / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000633:toxicity; D002801:Cholinesterase Reactivators / Q000494:pharmacology*; D004912:Erythrocytes / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D008297:Male; D010091:Oximes / Q000494:pharmacology*; D010261:Paraoxon / Q000633:toxicity
D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D010091:Oximes; D000110:Acetylcholinesterase; D010261:Paraoxon