Zhang Jiu-Liang, Wang Hui, Pi Hui-Fang, Ruan Han-Li, Zhang Peng, Wu Ji-Zhou
Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, PR China.
Steroids. 2009 Apr-May;74(4-5):424-34. doi: 10.1016/j.steroids.2008.12.007. Epub 2008 Dec 30.
Shedan-Chuanbei powder, a complex of traditional Chinese medicine preparation, which consists of Snake Bile (Chinese name "Shedan") and Fritillariae Cirrhosae (Chinese name "Chuanbei"), is the most popular antitussive and expectorant formulation in Chinese communities. However, the clinical application of Shedan-Chuanbei powder is now stringently limited because of the shortage of the two crude medicinal materials, especially for the sake of animal protection. In addition, the inherent defects of the most of the complex of traditional Chinese medicine such as the indistinct basal pharmacodynamic materials and the difficulties in quality control had blocked them heading into the international medicinal market. So we attempted to seek new substitute for Shedan-Chuanbei powder for antitussive drugs. In order to gain some new compounds with better bioactivity and attenuated toxicity, we tried to combine two kinds of drugs through ester bond. Enlightened with "combination principle" in drug discovery, we synthesized five novel esters of verticinone and bile acids, both of which are the major bioactive components in Shedan-Chuanbei powder. We then evaluated the antitussive activity and the acute toxicity of the five ester-linked compounds. The five ester-linked compounds had much more potent antitussive activity and expectorant activity than single bile acids at the same doses, and had equivalent antitussive activity and expectorant activity in comparison with about double moles dose of the monomer verticinone. Especially, cholic acid-verticinone ester had much more potent antitussive effects than the monomer verticinone or cholic acid at the same dose. A further acute toxicity study showed that the LD(50) values of the five ester-linked compounds exceeded 3.5g/kg by intraperitoneal injection in mice. Based on the studies of pharmacology and acute toxicity, the five ester-linked compounds have synergic pharmacodynamic action and attenuated toxicity compared with single verticinone and single bile acids.
蛇胆川贝散是一种中药复方制剂，由蛇胆（中药名“蛇胆”）和川贝母（中药名“川贝”）组成，是华人社区最常用的止咳祛痰制剂。然而，由于这两种药材短缺，特别是出于动物保护的考虑，蛇胆川贝散的临床应用目前受到严格限制。此外，大多数中药复方存在固有缺陷，如药效物质基础不明确、质量控制困难等，阻碍了它们进入国际医药市场。因此，我们试图寻找蛇胆川贝散的新型替代止咳药物。为了获得一些具有更好生物活性和更低毒性的新化合物，我们尝试通过酯键将两种药物结合起来。受药物发现中的“组合原理”启发，我们合成了五种新的浙贝母碱与胆汁酸的酯，它们都是蛇胆川贝散中的主要生物活性成分。然后，我们评估了这五种酯连接化合物的止咳活性和急性毒性。在相同剂量下，这五种酯连接化合物的止咳活性和祛痰活性比单一胆汁酸强得多，与约两倍摩尔剂量的单体浙贝母碱相比，具有相当的止咳活性和祛痰活性。特别是，胆酸 - 浙贝母碱酯在相同剂量下的止咳作用比单体浙贝母碱或胆酸强得多。进一步的急性毒性研究表明，这五种酯连接化合物经小鼠腹腔注射的半数致死量（LD50）值超过3.5g/kg。基于药理学和急性毒性研究，这五种酯连接化合物与单一浙贝母碱和单一胆汁酸相比，具有协同药效作用且毒性降低。
