engleski

An insight into the principles of oxime bioactivity: Example of experimental oxime K048

Pyridinium oximes are an essential part of antidotal therapy used in organophosphorous (OP) compound poisoning. Through the reactivation of phosphorylated acetylcholinesterase (AChE), oximes ameliorate symptoms arising from acute OP poisoning. However, survivors of OP exposures often have delayed neurologic symptoms of memory loss and cognitive dysfunction. Recent studies have shown that oxidative stress mediates secondary OP injury so long-term neurological consequences may be amenable to antioxidant therapy. Pyridiunium oximes have incorporated iminium and oxime moieties that are electron-affinic which enables them various physiological properties and might contribute to their overall therapeutic efficacy. However, currently none of the four conventional oximes (2-PAM, TMB-4, HI-6 and obidoxime) promote the recovery of OP intoxicated patients to a satisfactory extent. Another issue are their low blood–brain barrier permeability and relatively high toxicity in mammals. During the last decade, great efforts have been done to evaluate the biological activity of a new generation of pyridinium oximes called K-oximes. From the group of new oximes, K048 stood out by showing excellent antidotal properties in the case of OP nerve agent tabun poisoning and it seems to be effective against OP pesticides ; it showed no cytotoxic effect on several cell lines and it has low acute toxicity in rodents. By applying a simultaneous approach, our research group studied the biochemical properties of oxime K048 together with an evaluation of its cyto-/genotoxicity on human white blood cells in vitro as well as in somatic cells of rats in vivo. In this chapter, we will elucidate results on K048's safety profile and bioactivity as well show results of an assessment of effects of K048 on AChE activity and oxidative response in tabun-exposed rats. A better understanding of the mechanism of action of OP compounds, as well as new knowledge of oxime biological properties, could help set guidelines for new therapeutic possibilities.

organophosphorous compounds, oximes, oxidative stress, therapy

nije evidentirano