半夏与钩藤生物总碱联合抗惊厥作用及毒性反应的定量评价

目的:利用已发表的半夏生物总碱(pinellia total alkaloid,PTA)与钩藤生物总碱(uncaria total alkaloid,UTA)联合抗惊厥和毒性作用数据,全面定量评价其相互作用和组方合理性。方法:采用等效图法(isobologram)和计算机模拟技术,定量评价不同强度(0%～99%)有效剂量(ED)和致死剂量(LD)的相互作用,并综合计算其获益指数(BI)和治疗指数(TI)。结果:3个配比(PTA∶UTA=1∶4,1∶1,4∶1)有协同作用趋势。由于最高剂量的有效率均低于70%,给参数计算和研究结论带来不确定性。PTA和UTA按4∶1联用的毒性呈现拮抗作用,其它2个配比毒性拮抗作用不明确。基于ED和LD参数的综合分析,3个配比的BI均大于1,其中4∶1配比的减毒增效作用明确,TI增大。结论:PTA和UTA按4∶1给药后安全性和有效性提高,呈现配伍优势。从方法学角度,本研究可对同类实验的设计和分析提供参考。

Synergistic effect of pinellia total alkaloids and uncaria total alkaloids on anticonvulsant action in mice and rats

Aim To investigate the synergistic effect of the combination of pinellia total alkaloid （PTA） and uncaria total alkaloid （UTA）, and explore the mechanism of anticonvulsant action. Methods Anticonvulsant and toxic effect profiles of combinations of PTA with UTA, alone and at three fixed ratios of 1：4, 1 ：1, 4：1, were evaluated in maximal electroshock （MES）-induced seizures and acute toxicity test in mice. Respective ED50 and LD50 were calculated with Bliss＇s method. Their synergistic effect were evaluated by isobolographic analysis and allowed the determination of benefit indices （BI） for respective combinations. The model of convulsive rats kindled by penicillin topically injected into cortex was used to investigated the content of Glu, Asp, Gly and GABA in hippocampus using high performance liquid chromatography （HPLC）. Results Combinations of PTA and UTA at the ratio of 4：1 were synergistic in MES test and antagonistic in acute toxicity test, showing the best profile for combinations of PTA with UTA. In contrast, the ratios of 1 ：4 and 1 ： 1, despite synergistic in MES test, were additive in acute toxicity test. The 4：1 combination and two drugs alone significantly decreased Glu level and increased GABA level in the hippocampus, but the GABA level in the 4：1 combination group was higher than that in the two drugs alone groups. They did not have significant influence on the levels of ASp and Gly. Conclusion Combinations of PTA and UTA at 4：1 ratio demonstrated synergistic effect in anticonvulsant action and antagonistic effect in toxicity. The anticonvulsant mechanism might be related to decreasing the excitability of Glutamatergic neurons and increasing the inhibition of GABAergic neurons.