Pharmacological and toxicological in vitro and in vivo effect of higher doses of oxime reactivators.

Pharmacological and toxicological in vitro and in vivo effect of higher doses of oxime reactivators. Toxicol Appl Pharmacol. 2019 Oct 17;:114776 Authors: Hepnarova V, Muckova L, Ring A, Pejchal J, Herman D, Misik J, Hrabinova M, Jun D, Soukup O Abstract The major function of compounds with an oxime moiety attached to a quarternary nitrogen pyridinium ring is to reactivate acetylcholinesterase inhibited by organophosphorus agent (OP). However, other oxime mechanisms (e.g. modulation of cholinergic or glutamatergic receptor) may be involved in the recovery. The main disadvantage of positively charged reactivators is their low ability to penetrate into the brain although crossing the blood brain barrier could be supported via increasing the dose of administered oxime. Thus, this study presents maximal tolerated doses (MTD) for marketed oximes (TMB-4, MMB-4, LüH-6, HI-6, 2-PAM) and the most promising K-oximes (K027, K048, K203) which can be used in OP therapy in the future. No signs of sarin intoxication were observed in mice treated with 100% MTD of HI-6 in contrast to those treated with atropine and only 5% LD50 of HI-6. 100% MTD of HI-6 resulted in levels of 500 μM and 12 μM in plasma and brain, respectively. This concentration is by a far margin safe with respect to direct effects on neuronal cell viability and, on the other hand, does not have any effects on central NMDA receptors or central nACh receptors. However, a weak an...
Source: Toxicology and Applied Pharmacology - Category: Toxicology Authors: Tags: Toxicol Appl Pharmacol Source Type: research