Entry of two new asymmetric bispyridinium oximes (K‐27 and K‐48) into the rat brain: comparison with obidoxime

Abstract

In the search for new oximes with higher reactivation potency and a broader spectrum, K-27 and K-48, have recently been synthesized. To test if their superior efficacy was related to better penetration across the blood-brain barrier, their brain entry was compared with that of obidoxime, when administered either alone or after the organophosphate paraoxon (POX). Rats received 50 micromol obidoxime, K-27 or K-48, either alone or in addition to 1 micromol POX. Oxime concentrations at various points in time in brain and plasma were measured using HPLC. The obidoxime C(max) in brain was 1.3% of the plasma C(max) when injected alone, and 1.5% when injected following POX. The ratio of the area under the curve (AUC) brain to plasma for obidoxime was around 6%, irrespective of whether it was administered alone or after POX. For K-27, C(max) (brain) was 0.6% of C(max) (plasma) when injected alone, and 0.7% when injected after POX (no significant difference). The AUC (brain) was 2% of AUC (plasma) for both K-27 groups. K-48, when injected alone reached 1.4% of C(max) (plasma) in the brain and 1.2% of C(max) (plasma), when injected following POX. The AUC (brain) was 5% of the AUC (plasma), both when K-48 was administered alone and in combination with POX. Entry of all three oximes into the brain is minimal and cannot explain the better therapeutic efficacy of K-27 and K-48. As already observed for pralidoxime, injection of POX before oxime administration had no influence upon penetration across the blood-brain barrier.

Oxime K027: novel low-toxic candidate for the universal reactivator of nerve agent- and pesticide-inhibited acetylcholinesterase

“…In the case of pesticides, it was able to reactivate AChE inhibited by all tested members of this family. This is in very good agreement with results shown in former studies [24][25][26][27][28][29][30][31][32][33][34][35][36] . Oxime K027 was tested at two different concentrations, which had already been selected earlier in the study of Kuca and Cabal to capture the promising compounds 7,40 .…”

“…Moreover, if considering the lower concentration (10 −5 M), this is reachable also in the brain of an intoxicated organism. It is known that 1-10% of AChE reactivators, although they are quaternary compounds, can penetrate the blood-brain barrier and so act centrally 24,26,41 . The minimal reactivation activity needed for saving the life of an intoxicated organism is considered to be 10% 41 .…”

“…Subsequently, they confirmed their in vitro results using in vivo studies. According to this group, oxime K027 seems to be, at present, the most promising candidate to replace obidoxime ( Figure 1) in the treatment of organophosphorus pesticide poisonings [24][25][26][27][28][29][30][31][32][33][34][35][36] . As mentioned above, in the case of nerve-agent reactivation, the obtained results were not so promising.…”

Reactivation Potency of the Acetylcholinesterase Reactivator Obidoxime Is Limited

“…Obidoxime is the only accessible reactivator available for the civilian sector in the Czech Republic. Its reactivation potency is according to the literature not so good to think that it is a universal antidote [21][22][23][24] . In our in vitro experiment, we confirmed this statement.…”

Organophosphorus compounds as chemical warfare agents: a review

“…However, all of them have three great deficiencies: (i) the utilized oximes are generally quaternary ammonium ions and, as hydrophilic compounds, have many difficulties to cross the blood-brain barrier: their concentrations in the brain are only 1 to 10% of their plasma levels. [140][141][142] As a consequence, they can reactivate only a small fraction of the inhibited AChE in the CNS; (ii) oximes do not reactivate aged phosphyl-enzymes; and (iii) unlike atropine, oximes are not effective against all OPCs, having different activities for each one of them.…”