Jana Žďárová Karasová

A Comparison of the Neuroprotective Efficacy of Newly Developed Oximes (K156, K203) and Currently Available Oximes (Obidoxime, HI-6) in Cyclosarin-poisoned Rats

The neuroprotective effects of newly developed oximes (K156, K203) and currently available oximes (obidoxime, HI-6) in combination with atropine in rats poisoned with cyclosarin were studied. The cyclosarin-induced neurotoxicity was monitored using a functional observational battery 24 hours after cyclosarin challenge. The results indicate that a newly developed oxime K156 is able to counteract slightly cyclosarin-induced neurotoxicity while another newly developed oxime K203 is completely ineffective in reducing cyclosarin-induced neurotoxic signs and symptoms. The neuroprotective efficacy of K156 is comparable with commonly used obidoxime and oxime HI-6. Thus, none of the newly developed oximes achieves better neuroprotective efficacy than both commonly used oximes. They are therefore not suitable replacements for antidotal treatment of acute poisonings with cyclosarin.

A comparison of the potency of newly developed oximes (K347, K628) and currently available oximes (obidoxime, HI-6) to counteract acute neurotoxic effects of Tabun in rats.

The ability of newly developed oximes (K347, K628) to reduce tabun-induced acute neurotoxic signs and symptoms was compared with currently available oximes (obidoxime, HI-6) using a functional observational battery. The neuroprotective effects of the oximes studied (K347, K628, obidoxime, HI-6) combined with atropine on rats poisoned with tabun at a sublethal dose (220 microg/kg i.m.; 80% of LD50 value) were evaluated. Tabun-induced neurotoxicity was monitored by a functional observational battery and automatic measurement of motor activity at 24 hours following tabun challenge. The results indicate that all tested oximes combined with atropine enable tabun-poisoned rats to survive 24 hours following tabun challenge. Both newly developed oximes (K347, K628) combined with atropine are able to decrease tabun-induced neurotoxicity in the case of sublethal poisonings but they do not eliminate all tabun-induced acute neurotoxic signs and symptoms. Their ability to decrease the tabun-induced acute neurotoxicity is higher than that of the oxime HI-6 and it is slightly slower than the neuroprotective efficacy of obidoxime. As the neuroprotective potency of both newly developed oximes (K347, K628) is not as high as the potency of obidoxime, they are not a suitable replacement for obidoxime for the treatment of acute tabun poisonings.

Characterization of the Penetration of the Blood–Brain Barrier by High-Performance Liquid Chromatography (HPLC) Using a Stationary Phase with an Immobilized Artificial Membrane

ABSTRACT The biological activity of drugs on organisms is associated with the pharmacokinetic properties, such as the ability to penetrate through environments of varying polarity such as cellular organelles. In this area, particular attention is turned to the physicochemical properties that determine the potential of drugs to pass across the blood–brain barrier and thus to act on the central nervous system. In this study, special effort has been devoted to the simulation of passive diffusion of seven drugs (propranolol, ibuprofen, atenolol, promazine, chlorpromazine, imipramine, and desipramine) through the blood–brain barrier by high-performance liquid chromatography (HPLC) using a column with an immobilized artificial membrane. Gradient reverse elution was used to develop a linear correlation model for the capacity factors kIAM and the in vivo logarithmic values of brain-to-blood drug concentration ratios (log BB) with R of 0.9851. Eleven additional pharmaceuticals were determined by the same method to predict their potential to penetrate the blood–brain barrier. The reported analytical method represents an alternative tool for rapid and noninvasive assessment of the absorption properties of chemicals, especially for the development of novel drugs. The retention of the studied compounds on the immobilized artificial membrane column was also compared with three other C18-based stationary phases. Herein, the results of the HPLC determination of drugs using an immobilized artificial membrane are briefly discussed with respect to a general application of the method for evaluating a broader spectrum of pharmaceutical compounds.

The Evaluation of the Potency of Newly Developed Oximes (K727, K733) and Trimedoxime to Counteract Acute Neurotoxic Effects of Tabun in Rats.

AIM The ability of two newly developed oximes (K727, K733) to reduce tabun-induced acute neurotoxic signs and symptoms was evaluated and compared with currently available trimedoxime in rats. METHODS The neuroprotective effects of the oximes studied combined with atropine on Wistar rats poisoned with tabun at a lethal dose (380 µg/kg i.m.; 90% of LD50 value) were evaluated. Tabun-induced neurotoxicity was monitored by the functional observational battery consisting of 38 measurements of sensory, motor and autonomic nervous functions at 2 hours following tabun challenge. RESULTS All tested oximes combined with atropine enable tabun-poisoned rats to survive till the end of experiment. Both newly developed oximes (K727, K733) combined with atropine were able to decrease tabun-induced neurotoxicity in the case of lethal poisoning although they did not eliminate all tabun-induced acute neurotoxic signs and symptoms. CONCLUSION The ability of both novel bispyridinium oximes to decrease tabun-induced acute neurotoxicity was slightly lower than that of trimedoxime. Therefore, the newly developed oximes are not suitable for the replacement of commonly used oximes such as trimedoxime in the treatment of acute tabun poisonings.