Time-Dependent Changes of Oxime K027 Concentrations in Different Parts of Rat Central Nervous System

Abstract

The blood-brain barrier plays a vital role in the protection of the central nervous system. It is composed of endothelial cells with tight-junctions to limit the penetration of many endogenous and exogenous compounds, particularly hydrophilic xenobiotics. Nerve agents and pesticides are groups of compounds with high penetration potential into the central nervous system. However, oxime type antidotes are known to penetrate blood-brain barrier only in low concentration. The aim of presented study is to describe the pharmacokinetic profile of oxime K027 a novel antidote candidate. The main focus is on penetration of tested substance into the selected brain regions following time-dependent manner. The maximum concentration of the oxime K027 was attaining 15 and 30 min after i.m. application in plasma and brain tissue, respectively. The perfused brain tissue concentration was relatively high (10(-7) M order of magnitude) and depending on the brain region it was constant 15-60 min after application. The highest concentration was found in the frontal cortex 15 min after application while the lowest measured concentration was determined in the basal ganglia. This study showed that oxime K027 is able to achieve high concentration level in perfused brain tissue relatively quickly, but also demonstrated rapid clearance from the central nervous system. These results are probably due to low overall uptake of oxime K027 into the brain.

Prophylactic administration of non‐organophosphate cholinesterase inhibitors before acute exposure to organophosphates: assessment using terbufos sulfone

“…Physostigmine (Blomqvist et al ., ; Triggle et al ., ; Tuovinen et al ., ) and tacrine (Sung et al ., ) readily pass into the brain. K‐27 only enters the brain to a relatively small extent (Karasova et al ., ; Lorke et al ., , ) and may be preferable if side effects from the central nervous system are not desirable.…”

“…Physostigmine (Blomqvist et al, 2001;Triggle et al, 1998;Tuovinen et al, 1999) and tacrine (Sung et al, 2005) readily pass into the brain. K-27 only enters the brain to a relatively small extent (Karasova et al, 2013;Lorke et al, 2007Lorke et al, , 2008c and Cox (1972) analysis in animals exposed to intraperitoneal (i.p.) injections of terbufos sulfone and adjusted for terbufos dose (high/low) for each of the time points examined (10, 30 min, 1, 2, 3, 4, 24 and 48 h).…”

HPLC determination of K027 in the body of pregnant mice

“…1), a bispyridinium monoaldoxime [7]. Considering lipophilicity of these compounds, K027, K048, and K203 show the upmost negative log P as well as the largest total polar surface area (TPSA) values [14][15][16]. Tekes et al [17,18] determined the level of K027 in serum, the brain, cerebrospinal fluid, and urine following i.m.…”

LC–MS/MS Approaches for The Assay of Bis -Quaternary Pyridinium Oximes Used as Ache Reactivators in Biological Matrices

“…The in vitro screening of penetration through biological barriers based on the chromatographic retention parameters and correlations with the molecular structure is also available [11,12]. LC-MS/MS approaches have been used for monitoring plasma levels of PAM and other active principles used during poisoning therapy (i.e., atropine and diazepam) [13], the study of blood-brain barrier penetration based on brain microdialysis [14], and partition after administration of therapeutic doses in different parts of the brain, liver, lungs and kidneys [15][16][17]. LC-diode array detection (DAD) was successfully used for the assay of PAM in urine in vivo collected samples in a pesticide poisoning scenario carried out on minipigs [18].…”

“…Applications referring to purity and stability control of oximes, as well as their assay in pharmaceutical formulations, are primarily based on the ion pair reversed-phase (IPRP) or reversed-phase (RP) separation mechanisms, although the aqueous normal-phase mechanism on bare silicagel stationary phase was also used [8]. For the IPRP mechanism, sodium octyl sulphonate is generally chosen as ion pairing agent [7,15,17]. Bile acids sodium salts have been also successfully used as ion pairing agents for quaternary ammonium oximes [19].…”