The Experimental Oxime K027-A Promising Protector From Organophosphate Pesticide Poisoning. A Review Comparing K027, K048, Pralidoxime, and Obidoxime

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.

Keywords: Cox analysis; carbamates; cholinesterase; obidoxime; paraoxon; pralidoxime; prophylaxis; pyridostigmine.

FIGURE 1

Chemical formulas of the experimental K-oximes K027 and K048, the established oximes pralidoxime and obidoxime, the organophosphorus compounds (OPCs) diisopropylfluorophosphate (DFP), ethyl-paraoxon, methyl-paraoxon, and azinphos-methyl, and the reversible acetylcholinesterase (AChE) inhibitors physostigmine, pyridostigmine, tacrine, and ranitidine.

FIGURE 2

Time course of concentrations of experimental K-oximes K027 (A,B) and K048 (C,D) and the established oxime obidoxime (E,F) in plasma (A,C,E) and brain (B,D,F) after intramuscular (i.m.) injections of 50 μmol of oxime into rats. Depicted are concentrations, when oxime was injected alone (black) or in combination with paraoxon (POX, blue), which did not significantly influence plasma or brain concentrations of K027, K048, or obidoxime. Data from Lorke et al. (2007) and Petroianu et al. (2007b). Image reproduced with permission of “JOHN WILEY AND SONS,” License Number: 4450270092893.