engleski

Novel insight into the principles of oxime bioactivity

Pyridinium oximes are an essential part of antidotal therapy used in organophosphorous (OP) compounds poisoning. Through 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 amendable 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. Currently non of the four conventional oximes (2-PAM, TMB-4, HI-6 and obidoxime) promotes the recovery of OP intoxicated patients to a satisfactory extent. Another issues are their low blood–brain barrier permeability and relatively high toxicity in mammals. Our research group has recently adopted a simultaneous approach for studying the biochemical properties of oximes together with evaluation of their cyto-/genotoxicity on human white blood cells in vitro as well as in somatic cells of rats in vivo. Our results have shown weak antioxidant potential of the conventional oxime HI-6 and experimental oxime K048. Taking into account that genotoxicity studies on oxime compounds have thus far been rare, our results provide insight into the toxicity of HI-6 and K048 toward human non- target cells. Since this compounds should provide pharmacological protection by minimizing the adverse effects it is important to elucidate their safety profile. Our studies have shown taht HI-6 and K048 applied at concentrations/doses relevant for therapeutic interventions did not possess DNA-damaging potential.

antidotal therapy ; antioxidative potential ; genotoxicity ; oximes

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