ABSTRACT
Objective:To study the genotype distribution of drug-related gene polymorphism of methotrexate (MTX) and leflunomide (LEF) in patients with rheumatoid arthritis (RA).Methods:The genotyping results of RA patients' MTX and LEF related genes(MTHFR677C/T, MTHFR1298A/C, ABCB13435T/C, DHODH19C/A and CYP1A2734C/A) detected in Shanghai Guanghua Hospital from December 2018 to May2019 and drug-related adverse effect were statisticallyanalyzed. The independence of allele distribution was tested by Hardy-Weinberg test. Counting data of genotypes and allele frequencies among the groups were analyzed by the chi-square test. Measurement data were showed as Mean±SD deviation. The network between incidence of adverse events and genotypes of patients was analyzed by cytoscape software. Results:Genotype distribution in 151 patients was consistent with Hardy-Weinberg genetic balance ( P>0.05), and genotype and allele distribution of each gene showed no statistical difference in gender ( P>0.05). The results showed that the most common genotype in RA were that genotypes of the good response with moderate resistance to MTX (MTHFR677CC/MTHFR1298AA/ABCB13435CT) (16 cases, 13.5%) and the good response with moderate side effect risk to LEF(DHODH19CC/CYP1A2734AC) (25 cases, 28.4%). According to the distribution frequency of alleles, the incidence of high side effects caused by MTX combined with LEF was predicted to be 2.9%, which was close to 1.8% of the actual genotypes of patients. The types and proportion of clinical adverse reactions in patients were retrospectively analyzed and the correlation network analysis was conducted with the genotype analysis results. It was found that the incidence rates of adverse reactions were liver injury (35.4%, 35/99), leukopenia (14.1%, 14/99), thrombocytopenia (2.0%, 2/99), and skin rash (1.0%, 1/99) from the top to the bottom. The top two genotypes that were related to the occurence of adverse events were MTHFR677CT/MTHFR1298AA/ABCB13435CT and DHODH19CA/CYP1A2734AC, respectively, which verified the consistency between drug-related genotype and clinical manifestations in RA patients. Conclusion:Our results suggested that genotype in RA patients is closely related to drug efficacy and adverse events. 2.9% of RA patients need to stop taking MTX and LEF due to high MTX resistance and poor MTX response and increased toxicity when combined with LEF, in which the proportion of liver injury is the highest.
ABSTRACT
To investigate the effects of three classical anti-jaundice formulas Yinchenhao Decoction (YCHD). Yinchen Wuling San (YCWLS) and Zhizi Baipi Decoction (ZZBPD) on liver fibrosis induced by dimethylnitrosamine (DMN) in rats and explore the formula-syndrome relationship.
ABSTRACT
Objective: To investigate the different efficacy of Yinchenhao Decoction (YCHD), a compound traditional Chinese herbal medicine, for liver cirrhosis induced by dimethylnitrosamine (DMN) or carbon tetrachloride (CCl(4)) in rats. Methods: To induce liver fibrosis, 0.5% DMN solution (2mL/kg body weight, i.p.) was given three consecutive days a week to male Wistar rats for 4 weeks. Cirrhotic rats were randomly divided into DMN group, YCHD group, Xiaochaihu decoction group by the end of the fourth week to accomplish a 2-week recipe treatment course. In CCl(4)-induced liver fibrosis model, 50% CCl(4)-olive solution was injected subcutaneously to rats at a dose of 2 mL/kg body weight twice a week to duplicate rat cirrhosis model. After 8 weeks, rats were divided into CCl(4) group, CCl(4) plus YCHD group and Xiaochaihu decoction group. For the YCHD group, YCHD was administered intragastrically once a day for 4 weeks. For DMN or CCl(4) model, by the end of 6 or 12 weeks respectively, rats were sacrificed for sampling to detect liver function, hepatic histological changes, hydroxyproline (Hyp) content and apoptosis-related gene expressions. Results: In DMN liver fibrosis model, hepatic fibrosis was obvious at week 2 and cirrhosis was evident at week 4 in DMN-treated rats. Compared to 6-week DMN group, hepatic pathological changes and liver function were improved significantly and content of Hyp decreased remarkably in YCHD group. In CCl(4)-induced liver fibrosis model, hepatic fibrosis was obvious at 8 weeks and cirrhosis was evident at 12 weeks in CCl(4)-treated rats. Compared to 12-week CCl(4) group, hepatic pathological changes and liver function were not obviously improvement in YCHD group. The results of gene chip showed that YCHD significantly decreased Fas, Bax and caspase-3 gene expressions, and increased Bcl-xL gene expression in the liver of DMN model. However, in the model induced by CCl(4), YCHD did not inhibit hepatocyte apoptosis induced by CCl(4), but increased tyrosine kinase receptor gene expression by 4.8 times. Conclusion: YCHD exerts more significant therapeutic effects on DMN-induced than CCl(4)-induced cirrhosis in rats in Hyp content and pathological change in liver tissue.