Pharmacological Study Of New Derivants And Pharmacokinetics Of Benthiactzine

There are about 100,000 victims caused by organophosphate insecticides every year in China. Most victims are died from circulatory failure, respiratory failure or convulsion. Up to now, the last two symptoms have been deal quite well clinically, while circulatory failure is still the main cause of death. Accordingly, it is of significant virtual importance to search for innovative and effective medicine against circulatory failure caused by ChEI.Recent studies show that neuronal nicotinic acetylcholine receptors play a role in the process of cholinesterase inhibitors poisoning. Based on the theory, our lab synthesized benthiactzine, a derivant of benzilic acid, which has antagonism of both muscarinic and nicotinic acetylcholine receptors. It's confirmed its favourable effect on circulatory failure caused by ChEI.To facilitate the following development of benthiactzine, we further investigated the concentration-time curve of benthiactzine in rat plasma and its distribution among different tissues with the method of HPLC. The pharmacokinetical data indicates that the distribution of benthiactzine follows the two-compartment model and we also found out that it distributed mainly in lungs.It's investigated the effect of other 18 derivants of benzilic acid, compared by benthiactzine on the circulatory failure caused by DDVP. Furthermore , it's analyzed some important pharmacological parameters about benthiactzine and 18 derivants, such as arecoline-induced tremor and salivation in mice,nicotine-induced convulsion in mice,DDVP-induced death of mice and acetylcholine-induced contraction of guinea-pig ileum.Our study shows that benthiactzine,the 1st and the 18th derivant have satisfactory effect on circulatory failure. Benthiactzine and the 1st derivant have favourable effect on mice death induced by DDVP. Benthiactzine, the 1st and the 18th derivant have equally stronger antagonism against central M and peripheral M receptors. Benthiactzine has stronger antagonism against central N. In the M and N antagonism of these derivants on guinea-pig ileum, it's found that benthiactzine and the 1st derivant have stronger antagonism against M receptor than others. Among all these derivants, benthiactzine,the 5th and the 10th derivant has stronger antagonism against N receptor.