Abstract
Poisoning with organophosphorus compounds (OPCs) is a major problem worldwide. Standard therapy with atropine and established oxime-type enzyme reactivators (pralidoxime, obidoxime) is unsatisfactory. In search of more efficacious broad-spectrum oximes, new bispyridinium (K-) oximes have been synthesized, with K027 being among the most promising. This review summarizes pharmacokinetic characteristics of K027, its toxicity and in vivo efficacy to protect from OPC toxicity and compares this oxime with another experimental bisquaternary asymmetric pyridinium aldoxime (K048) and two established oximes (pralidoxime, obidoxime). After intramuscular (i.m.) injection, K027 reaches maximum plasma concentration within ∼30 min; only ∼2% enter the brain. Its intrinsic cholinesterase inhibitory activity is low, making it relatively non-toxic. In vitro reactivation potency is high for ethyl-paraoxon-, methyl-paraoxon-, dichlorvos-, diisopropylfluorophosphate (DFP)- and tabun-inhibited cholinesterase. When administered in vivo after exposure to the same OPCs, K027 is comparable or more efficacious than pralidoxime and obidoxime. When given as a pretreatment before exposure to ethyl-paraoxon, methyl-paraoxon, DFP, or azinphos-methyl, it is superior to the Food and Drug Administration-approved compound pyridostigmine and comparable to physostigmine, which because of its entry into the brain may cause unwanted behavioral effects. Because of its low toxicity, K027 can be given in high dosages, making it a very efficacious oxime not only for postexposure treatment but also for prophylactic administration, especially when brain penetration is undesirable.
Highlights
Fatalities due to poisoning with organophosphorus compounds (OPCs) represent a major problem worldwide
When tested in rats exposed to the OPC pesticide dichlorvos, K027 was more efficacious in reducing the dichlorvos-induced lethal effects than the established oximes pralidoxime, trimedoxime, obidoxime, and HI-6, when given immediately after OPC administration (Antonijevic et al, 2016) and reactivated dichlorvos-inhibited AChE in vivo more efficiently than K203 (Antonijevic et al, 2018b)
In a standardized experimental setting, we have quantified in vivo the protection conferred by K027 to reduce mortality induced by DFP and the pesticides ethylparaoxon, methyl-paraoxon, and azinphos-methyl and compared it with established and experimental (K048, K053, K074, K075, K107, K108, K113) oximes (Lorke et al, 2008b; Nurulain et al, 2009; Petroianu et al, 2012; Lorke et al, 2013)
Summary
Fatalities due to poisoning with organophosphorus compounds (OPCs) represent a major problem worldwide. Their first series (Kuca et al, 2003) included bisquaternary asymmetric pyridinium aldoximes containing two pyridinium rings that are connected by a propylene (K027 = 1-(4-hydroxyiminomethyl–pyridinium)-3-(4-carbamoyl pyridinium) propane) or a butylene (K048 = [1-(4-hydroxy iminomethyl-pyridinium)-3-(4-carbamoylpyridinium) butane]) linker, one of the pyridinium rings carrying an oxime residue in position 4, the other one a carbamoyl residue in position 4 (Figure 1). The “Guiding principles in the Care of and Use of Laboratory Animals” (Council of The American Physiological Society) have been observed, and all experiments were performed with the approval of the Institutional Review Board (FMHS Animal Research Ethics Committee) We have tested these oximes, when administered immediately after the OPC diisopropylfluorophosphate (DFP), ethyl-paraoxon, methyl-paraoxon, and azinphos-methyl (Figure 1).
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