title: Large dose means significant effect--dose and effect relationship of Chi-Dan-Tui-Huang decoction on alpha-naphthylisothiocyanate-induced cholestatic hepatitis in rats.
abstract: BACKGROUND
  Large dose application of traditional Chinese medicines has attracted more and more attentions in recent years. However, the scientific connotation of large dose application has not been clarified so far. The present study was designed to investigate the protective effects of Chi-Dan-Tui-Huang decoction (CDTHD) against Alpha-naphthylisothiocyanate (ANIT) induced acute cholestatic hepatitis in rats and explore the dose-effect relationship of CDTHD as a reference for clinical application.
  
  
  METHODS
  The administration of CDTHD at a series of doses was performed twice each day for 5 days. The acute cholestasic hepatitis models were induced by intragastric administration of ANIT on the third day of CDTHD administration. Then, the protective effects on cholestatic hepatitis were investigated by examining the following parameters: body weights of rats, morphological and histopathological liver changes, the levels of serum biomarkers including alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, direct bilirubin and γ-glutamyltranspeptidase. Furthermore, the dose-effect relationship was investigated with the application of correspondence analysis.
  
  
  RESULTS
  In the tested range of doses, CDTHD at the maximum tolerance dose did not show any toxicity as time went on. The efficacy result showed that CDTHD from 21.6 g/kg⋅d to 86.4 g/kg⋅d exhibited significant hepatoprotective effect against ANIT-induced acute cholestatic hepatitis. It alleviated liver injury and reversed adverse biochemical and histopathological changes in a dose-dependent manner. Correspondence analysis showed that Radix Paeoniae Rubra in CDTHD was the main effective component and CDTHD could enhance the integrated efficacy in dose-dependent manner.
  
  
  CONCLUSIONS
  CDTHD is beneficial to liver protection in a dose-dependent manner. Especially large dose demonstrates potent efficacy and Radix Paeoniae Rubra in the formula contributes the main effect on ANIT-induced acute cholestatic hepatitis without toxicity.
authors.affiliation: China Military Institute of Chinese Medicine, 302 Military Hospital of China,100#, the 4th Ring Road, Beijing, 100039, P R China. zhaoyl2855@126.com.
authors.forename: Yanling
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: China Military Institute of Chinese Medicine, 302 Military Hospital of China,100#, the 4th Ring Road, Beijing, 100039, P R China. tobymaxiao@163.com.|Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China. tobymaxiao@163.com.
authors.forename: Xiao
authors.initials: X
authors.lastname: Ma
authors.affiliation: China Military Institute of Chinese Medicine, 302 Military Hospital of China,100#, the 4th Ring Road, Beijing, 100039, P R China. JiaboWang302@163.com.
authors.forename: Jiabo
authors.initials: J
authors.lastname: Wang
authors.affiliation: Beijing Haidian District Institute for Drug Control, Beijing, 100083, P R China. wrq302@163.com.
authors.forename: Ruiqing
authors.initials: R
authors.lastname: Wen
authors.affiliation: School of Chinese Medicine, The University of Hong Kong, Estates Building, 10 Sassoon Road, 999077, Hong Kong, 100039, P R China. jialei0101@163.com.
authors.forename: Lei
authors.initials: L
authors.lastname: Jia
authors.affiliation: Department of Integrative Medical Center, 302 Military Hospital of China, 100#, the 4th Ring Road, Beijing, 100039, P R China. ZYun0813@126.com.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Research and Technology Service Center, 302 Military Hospital of China, 100#, the 4th Ring Road, Beijing, 100039, P R China. Liruisheng302@163.com.
authors.forename: Ruisheng
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Integrative Medical Center, 302 Military Hospital of China, 100#, the 4th Ring Road, Beijing, 100039, P R China. wangruilin302302@163.com.
authors.forename: Ruilin
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Integrative Medical Center, 302 Military Hospital of China, 100#, the 4th Ring Road, Beijing, 100039, P R China. ljy630812@163.com.
authors.forename: Jianyu
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Integrative Medical Center, 302 Military Hospital of China, 100#, the 4th Ring Road, Beijing, 100039, P R China. wlf3022011@163.com.
authors.forename: Lifu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Integrative Medical Center, 302 Military Hospital of China, 100#, the 4th Ring Road, Beijing, 100039, P R China. liyg302@126.com.
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Li
authors.affiliation: China Military Institute of Chinese Medicine, 302 Military Hospital of China,100#, the 4th Ring Road, Beijing, 100039, P R China. xiaoxiaohe302@126.com.
authors.forename: Xiaohe
authors.initials: X
authors.lastname: Xiao
mesh_terms: D015058:1-Naphthylisothiocyanate; D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001663:Bilirubin / Q000097:blood; D015415:Biomarkers / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000188:drug therapy*; D002779:Cholestasis / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D006505:Hepatitis / Q000097:blood / Q000188:drug therapy*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D029596:Paeonia; D008517:Phytotherapy; D029908:Pueraria; D051381:Rats; D027561:Salvia miltiorrhiza; D005723:gamma-Glutamyltransferase / Q000097:blood
chemical_list: D015415:Biomarkers; D004365:Drugs, Chinese Herbal; D015058:1-Naphthylisothiocyanate; D005723:gamma-Glutamyltransferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D001663:Bilirubin