Comparative determination of the efficacy of bispyridinium oximes in paraoxon poisoning / Usporedno određivanje učinkovitosti bispiridinijevih oksima pri trovanju paraoksonom

Abstract

The inability of standard therapy to provide adequate protection against poisoning by organophosphorus compounds (pesticides and nerve agents) motivated us to search for new, more effective oximes. We investigated the pharmacotoxicological properties of six experimental K-oximes (K027, K033, K048, K074, K075, and K203) in vivo. The therapeutic efficacy of K-oximes (at doses of 5 or 25 % of their LD 50 ) combined with atropine was assessed in paraoxon-poisoned mice and compared with conventionally used oximes HI-6 and TMB-4. The bisoxime K074 was the most toxic (LD 50 =21.4 mg kg -1 ) to mice, while monoxime K027 was the least toxic (LD 50 =672.8 mg kg -1 ). With the exception of K033, all of the tested K-oximes showed better therapeutic efficiency than HI-6 and TMB-4. K027 and K048 stood out by demonstrating low acute toxicities and ensuring protective indices ranging from 60.0 to 100.0 LD 50 of paraoxon. Taking into account that these two oximes showed a similar therapeutic efficacy regardless of the applied doses, our results suggest that K027 and K048 could be antidotes for paraoxon intoxication.

Reversible cholinesterase inhibitors as pretreatment for exposure to organophosphates. A review

“…Tacrine comes third, but in four of five studies, tacrine did not perform as well as K-27. Another selling point for K-27 is its comparatively low toxicity demonstrated in vitro (Muckova et al, 2018;Prado, Petroianu, Lorke, & Chambers, 2015) and in vivo (Zunec, Radic, Kuca, Musilek, & Lucic Vrdoljak, 2015).…”

Synthesis,in vitroscreening and molecular docking of isoquinolinium-5-carbaldoximes as acetylcholinesterase and butyrylcholinesterase reactivators

“…OPs are a heterogeneous group of organic compounds that are a serious toxicological problem. These synthetic compounds have been discovered since the first half of 20th century 6 . To date, they were misused in several military conflicts or terrorist attacks.…”

“…The second group, referred to as the "V-series," contains e.g. VX (5), CVX -the Chinese isomer (6) and RVX -the Russian isomer (7) ( Figure 1) 5 . This group of agents is relatively non-volatile, has high persistence in the environment and enhanced toxicity 8 .…”

“…chlorpyriphos, paraoxon (8), or methyl paraoxon, which might pose a threat to civilians due to their extensive agricultural use 9 . The pesticides annually cause about 3 million of acute intoxications, with over 260,000 of them end fatally 6 . Some of these cases are deliberate suicides 4 .…”

“…This pathological condition is referred to as "cholinergic crisis," which is characterised by: sweating, saliva, diarrhoea, tremors, muscle twitching, or increased gastrointestinal effects. Death is caused by respiratory failure 6 . The current antidotal treatment of OPs poisoning involves the administration of an anticholinergic agent atropine that blocks excessive stimulation of muscarinic receptors, and oximes that are capable of reactivating irreversibly inhibited AChE.…”