Study On The Mechanism Of Oxime's And Pyridazine's Antagonism To Respiratory Muscle Paralysis Caused By Acute Organophosphorus Pesticides Poisoning

Organophosphorus pesticides are responsible for a large number of severe intoxications . According to World Health Organization, there are more than 3 million cases of acute serious pesticide poisoning in the world annually, most of which caused by organophosphates pesticides especially in developing countries. Because of lacking of effective treatments, the mortality is up to 30%, even the lowest is 4%. It varies from country to country.Developed by the affiliated hospital of AMMS and the institute of pharmacology and toxicology of AMMS, the therapeutic project for the treatment to respiratory muscle paralysis (RMP) caused by AOPP has been popularized nationwide with good curative effects. However, the previous experiments suggested that pralidoxime was not the best drug in the treatment of RMP. The purpose of this experiment was to investigate the mechanism of oxime and the new compounds of pyridazine synthesized by the institute of pharmacology and toxicology of AMMS, to offer the theoretic foundation for the clinic therapy, and to find drugs more effective in antagonism of RMP.We observed the changes of diaphragm's tetanic contractions, the function of the nicotinic receptor and the structure of oxime. And we analyzed the direct and indirect mechanism of oxime and pyridazine in antagonism of RMP caused by AOPP.Results:1: HI-6 and L-1978 could affect the tetanic contraction of the normal diaphragm with the concentration of 10-4mol/L. L-1978's inhibitive effect was greater than that of oxime's.2:HI-6 and L-1978 could sustain tetanic contractions after inhibited by soman with higher concentration of 10-3mol/L.3:HI-6 , pralidoxime and L-1978 could sustain single contraction after inhibited by tubocurarine with high concentration(2 X 10-6mol/L), but there was no obvious recovery of tetanic contractions.4: HI-6, pralidoxime and L-1978 could sustain tetanic contraction after inhibited by tubocurarine at lower concentration (0.7 X 10-6mol/L). The efficacious concentration of L-1978 was 5X10~7mol/L, the best concentration was 1X10-5mol/L, but these tetanic single contraction of diaphragm would be inhibited again when the concentration was greater than 1 X 10-5mol/L. HI-6's efficacious concentration was 5 X 10-5mol/L, the best concentration was 4X10-3mol/L, tetanic single contraction of diaphragm would be inhibited at higher concentration. However, this efficacious concentration with pralidoxime to antagonize RMP caused by tubocurarine was higher than the other compounds. The order of effectiveness was L-1978>L-1655>HI-6>pralidoxime.5: This experiment also indicated that oxime had AchE-like activities, it could hydrolyze the ACh at physiological concentration. The order of the effectiveness of oxime was pralidoxime >obidoxime>HI-6. However, this effect was not found with the new compounds of pyridazine, L-1978.Clinical findings: we used the project of concentrative dose of pralidoxime to treat RMP caused by AOPP, Among 16 cases of RMP caused by AOPP-DDVP(dichlorvos), 13 recovered and three died. The average time of using mechanical ventilation and tracheal intubatton were 53+71h and 62+62h respectively. The two-sides Student's t test was used for statistical comparisons . compared to the the control group,values of P <0.05 , The difference was considered as statistically significant.The mortality of our research is 18.71%, but it was 31.38% in the control group. And this result in our research is consistent with the reports'.To sum up, the new method had good curative effects on the treatment of RMP caused by AOPP. The reason why pralidoxime had good effects on treating AOPP might be that it could affect the function of N2 receptor in neuromusclar junction and hydrolyze the ACh to decrease the accumulation of ACh in neuromusclar junction. Withits good effects on antagonizing of respiratory muscle paralysis, the new compound of pyridazine, L-1978, might be the new drug for the treatment of RMP caused by AOPP. This result is consistent with the fact that this project is so popular nationwide today.