不同醚类药物对胆囊结石的溶石效果及其生物安全性

Litholysis Effect and Biological Safety of Different Ethers for Gallbladder Stones

背景:对于存在手术禁忌证的胆囊结石患者,溶石治疗是一种可选方法,因此寻找合适的低毒性溶石药物具有重要临床意义。目的:比较不同醚类药物对胆囊结石的溶石效果及其生物安全性。方法:分别以相对分子质量依次增加的醚类药物甲基叔丁基醚(MTBE)、乙基叔丁基醚(ETBE)、乙二醇单叔丁基醚(ETB)和二乙二醇单叔丁基醚(DETB)行体外溶石实验,并以CCK-8实验检测四者对人正常肝细胞株LO2的增殖毒性。分别予30只SpragueDawley大鼠上述药物灌胃2周,观察血清生化指标和肝、肺、肾、胃、十二指肠、空肠组织病理学改变。结果:MTBE的体外溶石效果最为显著(P<0.05),ETB和DETB的溶石效果虽弱于ETBE(P<0.05),但仍较显著。CCK-8实验显示ETBE增殖毒性最强(P<0.05),ETB与DETB增殖毒性无明显差异(P>0.05)。除MTBE、ETBE和ETB可略升高血清AST水平(P<0.05)外,四种药物对模型大鼠血清生化指标和各脏器组织病理学均无明显影响。结论:相对分子质量的增加虽会部分降低醚类药物的溶石效果,但同时极大地提高了药物的生物安全性。

Background： Dissolution therapy is used as an alternative to surgery in patients with gallbladder stone and contraindication for surgery. Finding medicines with optimal litholysis effect and low cytotoxicity is of great importance in clinical practice. Aims： To study the litholysis effect and biological safety of different ethers for gallbladder stones.Methods： Methyl tertiary-butyl ether（ MTBE）,ethyl tertiary-butyl ether（ ETBE）,ethylene glycol mono-tert-butyl ether（ ETB）,and di（ ethylene glycol） tert-butyl ether（ DETB）,arranged by the order of relative molecular weight,were used to dissolve the gallbladder stones in vitro. Normal human liver cell line LO2 was treated with the above mentioned four ethers,and the cell viability was assessed by CCK-8 assay for analyzing the proliferative toxicity. Thirty Sprague-Dawley rats were administered intragastrically with the four ethers for 2 weeks,and then the serum biochemical indices and histopathology of liver,lung,kidney,stomach,duodenum and jejunum were examined. Results： The litholysis effect of MTBE was the most prominent（ P 0. 05）; that of ETB and DETB were weaker than ETBE（ P 0. 05） but still had a substantial effect. CCK-8 assay showed that ETBE was the most toxic ether（ P 0. 05）,and the proliferative toxicity of ETB and DETB was similar（ P 0. 05）. Except for the slightly increased serum AST in MTBE,ETBE and ETB groups（ P 0. 05）,the four ethers had no significant impact on serum biochemical indices and histopathology of multiple organs of the model rats. Conclusions： The increase of relative molecular weight of ether may reduce its litholysis effect,but meanwhile its biological safety is increased.