engleski

Molecular mechanisms underlying the toxicity of antidotes and potential drugs

In organophosphorus poisoning (OP) antidote research, the lead candidates are selected mostly based on in vitro kinetic studies and are further tested in vivo without any of cell toxicity studies performed previously. This way, adverse effects of oximes as xenobiotics can be masked by a stronger system response to the applied in vivo treatment. This becomes visible in the next steps of drug development process and due to negative effects on the cell level, previously designated lead oximes cannot be further considered for use as antidotes. Therefore, to overcome this shortcoming, the here presented work focuses on the implementation of an adequate cell-based preclinical screening or cell-based early safety evaluation in antidote discovery prior to any in vivo testing. We try to define the exact mechanism of cell chemosensitivity to potential antidotes and define the possible structural features/moieties of the tested compounds triggering certain effects. This will ensure more efficient feedback to researchers designing these drugs and aid the challenging development of a more effective treatment for OP poisoning.

apoptosis ; cell-based preclinical screening ; cell chemosensitivity ; oxidative stress

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