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Neurochemical, receptor and biotransport mechanisms of antiepileptic action of propoxazepam in the general strategy of development of an innovative drug

Work number - M 16 FILED

Presented the A. V. Bogatsky Physico-Chemical Institute of the National Academy of Sciences of Ukraine

VALIVODZ Iryna Petrivna, candidate of biological sciences, junior researcher of the laboratory of molecular pharmacology and medicine, department of biomedicine of the A. V. Bogatsky Physico-Chemical Institute of the National Academy of Sciences of Ukraine

The purpose of the work is to create scientific approaches to the development and introduction into medical practice of an innovative drug with antiepileptic mechanisms of action, which meets national and international standards, and is registered for the first time on the basis of a complete set of documents regarding its quality, safety and effectiveness (full registration information). Prepare the appropriate dossier for the drug, obtain permission from the Ministry of Health of Ukraine for clinical research and conduct the first phase of clinical trials.

Mean weighted effective doses (ED50) of propoxazepam in antagonism with picrotoxin, corazol, strychnine, semicarbazide, bemegrid, 4-aminopyridine and maximum electric shock were determined on the seizure-induced models, which indicate high antiepileptic activity of the compound. On the basis of these «dose-effect» curves, it was proved that the anti-elliptic effect of propoxazepam is mainly realized by the GABA-ergic mechanism. Glycine - ergic components involved in the administration of propocasazepam in doses exceeding ED50 are an additional means of protection against convulsions. This was confirmed by the results of the docking analysis of the interaction of the drug with GAMKA-R.

To evaluate the pharmacokinetic parameters of propoxazepam, its 14C analogue was synthesized, with the help of which the bioavailability, absorption constant and volumes of distribution in the body of animals were determined. Analytical methods were used to determine the structures of propoxazepam metabolites and their quantitative correlation. On the basis of the obtained results, the main indicators (therapeutic index, therapeutic width, therapeutic interval and reliable safety factor) were calculated, characterizing the safety of propoxazepam use and made it possible to conduct a single-center open clinical study to assess the safety and pharmacokinetic profiles of propoxazepam in volunteers. Propoxazepam tablets of 5 mg TDV «Interchem» (batch №600719) were used in the study.

Number of publications: 3 collective monographs, 8 articles in magazines included in category "A" (including 7 foreign editions) and 14 articles in magazines included in category "B", 25 abstracts of reports. The total number of references to authors' publications/h-index by work according to the databases is, respectively: Web of Science __/__, Scopus 3/2, Google Scholar 94/4.