Large dose means significant effect – dose and effect relationship of Chi-Dan-Tui-Huang decoction on alpha-naphthylisothiocyanate-induced cholestatic hepatitis in rats

Abstract

BackgroundLarge 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.MethodsThe 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.ResultIn 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.ConclusionsCDTHD 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.

Paeonia lactiflora Pall. regulates the NF-κB-NLRP3 inflammasome pathway to alleviate cholestasis in rats

“…In three PLP‐treated groups, different doses (20, 40 and 80 g/kg body weight, respectively) of PLP (dissolved in normal saline) were administered via intragastric gavage for five consecutive days and received 60 mg/kg ANIT on the third day. The doses of PLP used in this research were in line with previous experiments and were proved as no toxic reactions in rats …”

“…A genomewide microarray analysis revealed that paeonol shows the anti‐inflammation effects mediated by chemokine and cytokine signalling in LPS‐treated RAW264.7 macrophages . According to our previous study, the aqueous extract of PLP was clinically effective to cholestatic hepatitis and suggested that PLP played its role against cholestasis by its anti‐oxidation and free radical scavenger effect . That study also pointed out that the anticholestasis effect of PLP is closely associated with oxidative stress as well as other influencing factors, such as inflammation and imbalance of bile acid.…”

“…Traditionally, Chishao is the dried root of Paeonia lactiflora Pall. (PLP), which has been widely used as herbal medicine for treating hepatic disease over thousands of years, especially in China . Nevertheless, the involving mechanism of PLP on cholestasis is still not comprehensively researched.…”

“…(PLP), which has been widely used as herbal medicine for treating hepatic disease over thousands of years, especially in China. [17] Nevertheless, the involving mechanism of PLP on cholestasis is still not comprehensively researched. Particularly, the anti-inflammatory effect associated with the treatment of cholestasis still remains vastly unclear.…”

San-Huang-Xie-Xin-Tang Constituents Exert Drug-Drug Interaction of Mutual Reinforcement at Both Pharmacodynamics and Pharmacokinetic Level: A Review

“…RR as an example, the dosage to treat cholestasis in clinical is more than four times the regular dose recommended in the Chinese pharmacopeia (Zhang et al, 2016). For now, the widespread explanation is that drug should be administrated to the patient with the correct disorder indications, otherwise it will produce dosage variety and individual detrimental effect (Zhao et al, 2015). As displayed in Table 5, dosage of constituents from SHXXT has a big range with no obvious rule to follow, it is possibly due to different tested animals or cells may have different drug sensitivities, but still need further clarification.…”