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1.
Acta Pharmaceutica Sinica ; (12): 266-273, 2021.
Article in Chinese | WPRIM | ID: wpr-872628

ABSTRACT

Xianling Gubao is a common and effective medicine in the treatment of orthopedic diseases. In recent years, it has been reported to be associated with liver injury. However, through the analysis of the adverse drug reaction reports and key hospital cases, we found that there is considerable incomplete information in the reports of Xianling Gubao-related liver injury cases retrieved from the literature. Thus, it is difficult to accurately judge causality between the drug and liver injury. Six cases of liver injury related to Xianling Gubao were identified in key hospitals, two of which achieved the clinical diagnosis according to the assessment of the integrated evidence chain method. We further analyzed the public health data of all residents in Yinzhou. The gross incidence rate of Xianling Gubao-related liver injury was 0.034%, which corresponds to a level of rare incidence. This revealed that Xianling Gubao-related liver injury has significant divergence in individuals and an idiosyncratic nature. The gross incidence of liver injury related to Xianling Gubao was lower than that of other medicines for the treatment of orthopedic diseases. Based on the idiosyncratic drug-induced liver injury model mediated by immune stress, it was found that Epimedii Folium and Psoraleae Fructus were the major components that lead to liver injury, and the liver injury caused by a full prescription was less serious than that encountered with only Epimedii Folium and Psoraleae Fructus. This suggests that the other 4 herbs (Dipsaci Radix, Anemarrhenae Rhizoma, Rehmanniae Radix,Salviae Miltiorrhizae Radix et Rhizoma) can prevent/alleviate the liver injury. Through disassembled prescription analysis, we found that the attenuation efficacy of Salviae Miltiorrhizae Radix et Rhizoma was the most significant. In conclusion, Xianling Gubao may cause idiosyncratic liver injury in a tiny minority of susceptible individuals, but the incidence risk is lower than that of other commonly used drugs for orthopedic disease. Xianling Gubao should be discreetly applied to patients with immune stress. The major components that induced liver injury in Xianling Gubao were Epimedii Folium and Psoraleae Fructus, and Salviae Miltiorrhizae Radix et Rhizoma appears to attenuate this toxicity. This study provides a reference for the rational clinical medication with Xianling Gubao.

2.
Article in Chinese | WPRIM | ID: wpr-879160

ABSTRACT

Based on the heat-clearing and detoxifying effects of Gentianae Radix et Rhizoma, the network pharmacology is mainly used to predict the potential targets of Gentianae Radix et Rhizoma for anti-inflammatory activity and to perform the experimental verification. A method for detecting the biological potency of Gentianae Radix et Rhizoma based on verifiable targets has been established to provide a reference for improving the quality evaluation and control standards of Gentianae Radix et Rhizoma. High performance liquid chromatography can be used to construct chemical fingerprints of different batches of Gentianae Radix et Rhizoma. Constructing a component-target-disease network of Gentianae Radix et Rhizoma for its anti-inflammatory activity was applied to screen potential anti-inflammatory components and related targets of Gentianae Radix et Rhizoma, and to verify the target of Gentianae Radix et Rhizoma by using biological evaluation methods. Detecting the biological potency of different batches of Gentianae Radix et Rhizoma extracts was used to inhibit COX-2 enzyme activity based the verifiable target cyclooxygenase-2(COX-2). The results showed that different batches of Gentianae Radix et Rhizoma accorded with the pharmacopoeia testing regulations, and the chemical fingerprints have a high similarity(similarity>0.93), suggesting that there is no significant difference in the characteristics of the chemical components. Based on network pharmacology predictions, 18 candidate targets were found to have potential direct interactions with the ingredients in Gentianae Radix et Rhizoma. Among them, the most important target is COX-2. Based on the experimental verification of recombinant human COX-2 protease activity inhibition, Gentianae Radix et Rhizoma can inhibit the COX-2 enzyme activity in a dose-dependent manner. It can function with a low concentration(0.75 mg·mL~(-1)), which preliminarily confirmed the accuracy of network pharmacology prediction. The biological potency detection method of Gentianae Radix et Rhizoma based on COX-2 inhibitory activity was optimized and established. The qualitative response parallel line method was used to calculate the biological potency of anti-inflammatory activity, which ranged from 23.04 to 46.60 U·mg~(-1). For network pharmacology prediction, it can screen and clarify the possible targets of traditional Chinese medicine rapidly, which can guide the establishment of a biological evaluation method for the quality of medicinal materials with related activities. Compared with chemical fingerprints, the biological potency testing can better detect quality fluctuations of traditional Chinese medicine.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Biological Assay , Drugs, Chinese Herbal/pharmacology , Humans , Medicine, Chinese Traditional , Quality Control , Rhizome
3.
Acta Pharmaceutica Sinica ; (12): 276-282, 2020.
Article in Chinese | WPRIM | ID: wpr-789026

ABSTRACT

Recently, the hepatotoxicity issue regarding to Psoraleae Fructus (PF) has attracted remarkable concerns, which highlights the urgent need to explore the toxicity attenuation method for PF. In this study, we proposed an alcohol soaking and water rinsing method for pre-processing PF based on the record in the classics - "Lei Gong Pao Zhi Lun", aiming to attenuate the potential hepatotoxicity of PF. The optimal pre-processing methods and parameters were investigated by U*12(108) uniform design coupled with 3D-cultured human-derived liver organoids model and high-content imaging. The results showed that there were significant variations among the hepatotoxicity intensities of different pre-processed PF products. Four factors, including the concentration of alcohol, the ratio of material and alcohol in alcohol soaking, the time of alcohol soaking and the times of water rinsing, were found as independent significant factors (all P<0.01). The optimal pre-process parameters were further predicted and verified as follows: the alcohol concentration is 80%, the times of alcohol soaking is 3, the ratio of alcohol and material of alcohol soaking is 3, the time for alcohol soaking is 30 h, the ratio of water and material of water rinsing is 2, the times of water rinsing is 3, the time water rinsing is 12 h and the time of steaming is 5 h. This research demonstrated that the alcohol soaking and water rinsing method can effectively reduce the potential hepatotoxicity of PF. This method provides a reference for reducing the risk of PF liver injury from the perspective of Chinese medicinal materials pre-processing.

4.
Article in English | WPRIM | ID: wpr-827079

ABSTRACT

OBJECTIVES@#To develop a new Chinese medicine (CM)-based drug and to evaluate its safety and effect for suppressing acute respiratory distress syndrome (ARDS) in COVID-19 patients.@*METHODS@#A putative ARDS-suppressing drug Keguan-1 was first developed and then evaluated by a randomized, controlled two-arm trial. The two arms of the trial consist of a control therapy (alpha interferon inhalation, 50 µg twice daily; and lopinavir/ritonavir, 400 and 100 mg twice daily, respectively) and a testing therapy (control therapy plus Keguan-1 19.4 g twice daily) by random number table at 1:1 ratio with 24 cases each group. After 2-week treatment, adverse events, time to fever resolution, ARDS development, and lung injury on newly diagnosed COVID-19 patients were assessed.@*RESULTS@#An analysis of the data from the first 30 participants showed that the control arm and the testing arm did not exhibit any significant differences in terms of adverse events. Based on this result, the study was expanded to include a total of 48 participants (24 cases each arm). The results show that compared with the control arm, the testing arm exhibited a significant improvement in time to fever resolution (P=0.035), and a significant reduction in the development of ARDS (P=0.048).@*CONCLUSIONS@#Keguan-1-based integrative therapy was safe and superior to the standard therapy in suppressing the development of ARDS in COVID-19 patients. (Trial registration No. NCT04251871 at www.clinicaltrials.gov ).


Subject(s)
Administration, Inhalation , Adult , China , Coronavirus Infections , Diagnosis , Drug Therapy , Mortality , Dose-Response Relationship, Drug , Drug Administration Schedule , Drugs, Chinese Herbal , Female , Follow-Up Studies , Humans , Integrative Medicine , Interferon-alpha , Lopinavir , Male , Middle Aged , Pandemics , Pneumonia, Viral , Diagnosis , Drug Therapy , Mortality , Risk Assessment , Severe Acute Respiratory Syndrome , Diagnosis , Drug Therapy , Mortality , Severity of Illness Index , Survival Rate
5.
Article in Chinese | WPRIM | ID: wpr-828359

ABSTRACT

A total of 1 392 reports on liver injury associated adverse drug reaction(LI-ADR) related to bone diseases were retrospectively analyzed based on national ADR monitoring system [18.75% of the patients used traditional Chinese medicine(TCM) alone and 68.68% used Western medicine alone]. This kind of cases accounted for 2.5% of all drug-related liver injury adverse reactions, ranking top ten of all drug categories. The number of reported cases and the proportion of serious cases showed an increasing trend from 2012 to 2016. The average age of the patients was(54.2±15.8) years old, and there was little difference in overall gender(male-female 1.04∶1). However, the number of female patients with rheumatoid arthritis was significantly higher than that of male patients(male-female 1∶2.6), while the number of male patients with gout was significantly higher than that of female patients(male-female 7.16∶1). The overall prognosis was good, with the recovery and improvement rate of 85.27%. The time from medication to liver injury varied due to different medicines. The median time to liver injury was 27 days in TCM alone group, later than 11 days in Western me-dicine alone group(P<0.05). Drugs for bone diseases have been one of the important categories for clinical drug-induced liver injury, and the number of reported cases on liver injury caused by drugs for bone diseases is increasing, so we should pay close attention to the safe and rational use of them. The LI-ADRs of male and female were different due to their different diseases, and the latency of adverse reactions in TCM group was generally longer than that in Western medicine group. In clinical medication, liver function should be monitored according to different diseases and characteristics of drugs to prevent the risk of liver injury.


Subject(s)
Adult , Aged , Bone Diseases , Drug-Related Side Effects and Adverse Reactions , Drugs, Chinese Herbal , Female , Humans , Male , Medicine, Chinese Traditional , Middle Aged , Retrospective Studies
6.
Article in English | WPRIM | ID: wpr-827441

ABSTRACT

OBJECTIVES@#To develop a new Chinese medicine (CM)-based drug and to evaluate its safety and effect for suppressing acute respiratory distress syndrome (ARDS) in COVID-19 patients.@*METHODS@#A putative ARDS-suppressing drug Keguan-1 was first developed and then evaluated by a randomized, controlled two-arm trial. The two arms of the trial consist of a control therapy (alpha interferon inhalation, 50 µg twice daily; and lopinavir/ritonavir, 400 and 100 mg twice daily, respectively) and a testing therapy (control therapy plus Keguan-1 19.4 g twice daily) by random number table at 1:1 ratio with 24 cases each group. After 2-week treatment, adverse events, time to fever resolution, ARDS development, and lung injury on newly diagnosed COVID-19 patients were assessed.@*RESULTS@#An analysis of the data from the first 30 participants showed that the control arm and the testing arm did not exhibit any significant differences in terms of adverse events. Based on this result, the study was expanded to include a total of 48 participants (24 cases each arm). The results show that compared with the control arm, the testing arm exhibited a significant improvement in time to fever resolution (P=0.035), and a significant reduction in the development of ARDS (P=0.048).@*CONCLUSIONS@#Keguan-1-based integrative therapy was safe and superior to the standard therapy in suppressing the development of ARDS in COVID-19 patients. (Trial registration No. NCT04251871 at www.clinicaltrials.gov ).


Subject(s)
Administration, Inhalation , Adult , China , Coronavirus Infections , Diagnosis , Drug Therapy , Mortality , Dose-Response Relationship, Drug , Drug Administration Schedule , Drugs, Chinese Herbal , Female , Follow-Up Studies , Humans , Integrative Medicine , Interferon-alpha , Lopinavir , Male , Middle Aged , Pandemics , Pneumonia, Viral , Diagnosis , Drug Therapy , Mortality , Risk Assessment , Severe Acute Respiratory Syndrome , Diagnosis , Drug Therapy , Mortality , Severity of Illness Index , Survival Rate
7.
Article in Chinese | WPRIM | ID: wpr-773699

ABSTRACT

The aim of this paper was to investigate the anti-inflammatory effect of Tripterygium wilfordii processed with licorice on DSS-induced ulcerative colitis( UC) mice and its regulation on intestinal immune system. In this study,a DSS-induced animal model of UC mice was established,with mesalazine( Mes) as a positive drug. The pharmacodynamic effects of low( PT1) and high( PT2)doses of T. wilfordii processed with licorice were analyzed by disease activity index( DAI),colon length and colon histopathological score in mice. By detecting the expression levels of TNF-α and IL-6 cytokines in the serum of mice,immunohistochemical CD3+T and Fox P3+Treg staining in the colon of mice,the anti-inflammatory and immunoregulatory effects of T. wilfordii processed with licorice on UC mice were analyzed. The hepatotoxicity of each dose of T. wilfordii processed with licorice was also analyzed by HE staining in liver tissue of mice and ALT and AST levels in serum. The results showed that the colitis symptoms of the mice in the PT1 group and the PT2 group were alleviated,the inflammatory cell infiltration was reduced. And the expression of inflammatory factors was decreased,the difference was statistically significant compared with the model group( P<0. 05). The HE staining and ALT and AST levels in the high dose group and low dose group were not significantly different from those in the normal group. The results showed that T. wilfordii processed with licorice has the anti-inflammatory and immunomodulatory effects on UC mice,and the dose did not show significant hepatotoxicity.


Subject(s)
Animals , Anti-Inflammatory Agents , Pharmacology , Colitis, Ulcerative , Drug Therapy , Dextran Sulfate , Drugs, Chinese Herbal , Pharmacology , Glycyrrhiza , Chemistry , Mice , Plant Extracts , Pharmacology , Tripterygium , Chemistry
8.
Article in Chinese | WPRIM | ID: wpr-773696

ABSTRACT

The present study was aimed to explore the dose-toxicity-effect relationship of Tripterygium wilfordii Hook f( TW) processed by liquorice,to establish the safe and effective therapeutic window,and further to provide scientific reference for the clinical use of TW. The toxicity and anti-inflammatory effect of six doses of raw TW and TW processed by liquorice( 0. 78,1. 56,3. 12,6. 24,12. 48,15. 60 g·kg-1) in 1-fluoro-2,4-dinitrobenzene( DNFB)-induced allergic contact dermatitis( ACD) model were mainly examined by histopathology and serum biochemistry. The liver biochemical parameters including ALT and AST,related inflammatory factors including TNF-α and IL-2,together with liver index,kidney index and the other pharmacodynamic indicators,were examined and compared. The results showed that compared with the control group,the serum levels of TNF-α and IL-2 of the model group were significantly increased( P<0. 01),which proved that the ACD model was successful. The comprehensive analysis of liver biochemical indexes,serum inflammatory factors and the other indexes showed that the safe and effective therapeutic window of TW processed by liquorice was 3. 12-12. 48 g·kg-1. The results showed the therapeutic window of TW processed by liquorice was much broader than that of raw TW. And it could provide scientific reference for the clinical rational use of TW.


Subject(s)
Animals , Cytokines , Blood , Dermatitis, Allergic Contact , Drug Therapy , Drugs, Chinese Herbal , Pharmacology , Glycyrrhiza , Chemistry , Plant Extracts , Pharmacology , Tripterygium , Chemistry
9.
Article in Chinese | WPRIM | ID: wpr-773147

ABSTRACT

In the present study,non-targeted metabolomics technique was used to screen potentially susceptibility biomarkers in patients with mild liver function abnormalities during long-term use of Chinese herbal compound. According to the inclusion and exclusion criteria,we collected 7 cases of patients with abnormal liver function during the period of complete taking Chinese herbal medicine( 60 days),and 18 cases of patients with normal liver function in re-examination from the reproductive medicine center in our hospital. Ultra performance liquid chromatography coupled with time-of-flight mass spectrometry( UPLC-Q-TOF/MS~E) technique combined with Progenesis QI software was used to analyze the differential biomarkers in serum of patients with wild liver function abnormalities and normal liver function. 11 potential biomarkers such as bilirubin,pantothenic acid,hippuric acid,sphingomyelin,palmitic acid,and oleic acid were tentatively identified. Metabolic disorders in patients with herbal-induced mild liver abnormality were mainly related to two pathways: pantothenic acid and coenzyme A biosynthesis and linoleic acid metabolism. It could provide a reference for the early warning of mild liver function abnormalities of patients that may be caused by long-term use of Chinese medicine compound in clinical application,and will lay a foundation for further understanding the endogenous substance changes in different levels of liver injury.


Subject(s)
Biomarkers , Blood , Chromatography, High Pressure Liquid , Drugs, Chinese Herbal , Therapeutic Uses , Humans , Liver Diseases , Blood , Mass Spectrometry , Metabolomics
10.
Acta Pharmaceutica Sinica ; (12): 2141-2148, 2019.
Article in Chinese | WPRIM | ID: wpr-780352

ABSTRACT

To explore the application of an effect-constituents index (ECI) for the quality evaluation of rhubarb, we carried out the simultaneous determination of 12 chemical components by ultra-performance liquid chromatography and used the ICR mouse constipation model to determine the diarrhea biopotency of these 12 components. With the diarrhea biopotency of sennoside A as a reference, the diarrhea biopotency weight coefficient of each chemical component was obtained. A multi-component chemical quantitative analysis combined with the biopotency weight coefficients for rhubarb was developed, named the diarrhea ECI. Animal experiment ethics requirements were approved by the Animal Experimental Ethics Committee of the 302 Hospital of the People's Liberation Army (Grant Number: IACUC-2015-012). The results showed that there were significant differences in the content of the 12 chemical components in different batches of processed products of rhubarb. Especially worthy of attention was the content of aloe-emodin-8-O-β-D-glucoside in sample Rh03, nearly 40-fold higher than that in Rh07 (4.79 vs 0.12 mg·g-1), and the content of rhein-8-O-β-D-glucoside in sample Rh03, nearly 45 times higher than that in Rh07 (3.56 vs 0.08 mg·g-1). The actual measured diarrhea biopotencies of the 12 chemical components ranged from 61.65 ± 4.28 to 233.84 ± 5.58 U·mg-1. The calculated diarrhea effect-constituents indices of 16 rhubarb samples ranged from 1.07 (Rh15) to 19.38 (Rh03), and the actual measured diarrhea biopotencies of 16 rhubarb samples based the ICR mouse constipation model ranged from 23.84 U·g-1 (Rh16) to 310.94 U·g-1 (Rh05). The correlation between the diarrhea ECIs and the actual measured diarrhea biopotencies of 16 rhubarb samples was good (r = 0.969 5), suggesting that the diarrhea effect-constituents indices may be the most suitable for evaluating the quality of different rhubarbs with regard to diarrhea.

11.
Acta Pharmaceutica Sinica ; (12): 2169-2177, 2019.
Article in Chinese | WPRIM | ID: wpr-780349

ABSTRACT

There are many kinds of processed products of Aconiti Lateralis Radix Praeparata (ALRP), but their differences in toxicity and efficacy have not been identified. The minimum premature ventricular contraction (PVC) method was used to evaluate the biological toxicity of eight processed products. The results showed that the minimal toxic dose (MTD) of an ethanol extract of Shengfupian (SFP) was 0.16 g·kg-1, which was much lower than that of Heishunpian (HSP), Baifupian (BFP), Baofupian (BAP), Paofuzi (PFZ) or Zhengfupian (ZFP), with MTDs ranging from 2.64 to 5.75 g·kg-1. No cardiotoxicity was detected with Chaofupian (CFP) and Paotianxiong (PTX). A novel +dp/dtmax assay for acute heart failure in rats was developed to evaluate the cardiac activity. It was found that all eight processed products had cardiac effects, with Shengfupian showing the strongest cardiotonic effect and the ability to restore damaged cardiac function to normal within 15 minutes of injection. Heishunpian, Baifupian and the three other products displayed moderate activity, while Paofuzi and Paotianxiong were the weakest. An LC-MS/MS method was utilized to determine the content of 13 alkaloids in water extracts. The results demonstrated that hypertoxic aconitine, mesaconitine, and hypaconitine could not be detected, higenamine was only present in Shengfupian, and salsolinol was about 4-56 times higher in Shengfupian than in other products. A correlation analysis showed that salsolinol had the best correlation with the cardiotonic index, with a correlation coefficient as high as 0.817, while the three monoester alkaloids failed to correlate with the cardiotonic effect. Higenamine and salsolinol were cardiotonic, while the 11 other components had no cardiotonic activity. This study establishes methods for precise evaluation of cardiotoxicity and cardiac activity, reveals the toxicity and efficacy of common processed products, and identifies the key quality markers for cardiac activity, providing scientific support for the quality evaluation and clinical application of processed products of aconite.

12.
Acta Pharmaceutica Sinica ; (12): 2178-2183, 2019.
Article in Chinese | WPRIM | ID: wpr-780326

ABSTRACT

The objective of this work was to develop a bioassay to quantify the antiplatelet aggregation activity of hirudo for quality evaluation and control. Antithrombin activity of hirudo extracted by high temperature decoction was determined by thrombin titration. Antiplatelet aggregation activity of hirudo was determined through pharmacodynamic experiments in vitro and in vivo using a bioassay we developed for quantifying inhibition of platelet aggregation. Methodological investigation was carried out and the titers of 12 batches of hirudo samples were determined. During the experiment, the disposal of animals is in accordance with the ethical standards of animal experiments. The results showed that the antithrombin activity of hirudo decocted at high temperature decreased significantly and almost lost its activity. Hirudo inhibited platelet aggregation and results in vivo and in vitro were consistent. These assays were employed to test 12 batches of hirudo. The results demonstrated that the biopotency of 12 batches was 113.49, 96.13, 121.22, 127.33, 83.48, 108.72, 131.41, 127.95, 76.90, 126.27, 132.89 and 573.53 U·mg-1. The method was reliable and reproducible and can be used to assess the quality of hirudo.

13.
Acta Pharmaceutica Sinica ; (12): 1449-1456, 2019.
Article in Chinese | WPRIM | ID: wpr-780232

ABSTRACT

About 15%-20% of drug-induced liver injury (DILI) will progress to chronic manifestation (CH-DILI), which sometimes advances rapidly to liver cirrhosis (LC-DILI) within 0.5-1 year with deteriorative clinical prognosis. Therefore, it is important to find a non-invasive diagnosis for early detection of liver cirrhosis. In this study, the metabolomic profiles revealed significant differences in the metabolites from the plasma of LC-DILI versus CH-DILI. We found 35 differential metabolites through principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA). Through pathway enrichment analysis, some up-regulated metabolic pathways reflected impaired liver functions such as bile acid, lipid synthesis and decomposition during cirrhosis. Five biomarkers were found to exhibit effective diagnosis value (AUC > 0.6), including phosphatidylcholine, lysoPC (18:1 (9Z)), creatine, taurochenodeoxycholic acid and taurocholic acid. Furthermore, we found that the relative content ratio between phosphatidylcholine and lysoPC (18:1 (9Z)) had a better distinguishing ability (AUC = 0.867). The relative content ratio also had the feature to reduce systematic errors of sample processing and instrument detection, therefore having a greater value for clinical application.

14.
Article in Chinese | WPRIM | ID: wpr-777519

ABSTRACT

A retrospective study was performed in drug-induced liver injury(DILI) cases associated with Dictamni Cortex(Baixianpi,BXP) Preparations,which were treated at grade Ⅲ class A liver disease hospitals from 2008 to 2016 and spontaneously reported for adverse reactions between 2012 and 2016 at HILI Cloud(hilicloud.net). The results showed 25 DLII cases associated with BXP Preparations treated at grade Ⅲ class A liver disease hospitals during the 9 years,including only 14 cases in line with the clinical diagnostic criteria of Guidelines for the Diagnosis and Treatment of Herb-Induced Liver Injury. And 74 DILI cases associated with BXP Preparations spontaneously reports adverse reactions,and 18. 92% of them had unreasonable medication,including polypharmacy(21. 43%),overdose(28. 57%) and repeated dosage(50%). And 47 DILI cases used BXP Preparations to treat psoriasis and vitiligo(a total of59. 57%). The time range of taking BXP Preparations until liver injury occurred was 1-366 d,with the median of 18 d. The dose of BXP Preparations was estimated to be 0. 09-12 g·d-1. And the cumulative dosage of taking drugs until liver injury occurred was 1. 1-336 g. Obvious associations with time-toxicity as well as quantity-toxicity could not be found based on the wide range of time-toxicity relations and quantity-toxicity relations. On the basis of the study,we found that DILI cases associated with BXP Preparations commonly occurred in patients with immune diseases,such as psoriasis and vitiligo,indicating specific individual differences. The results suggested that DILI cases associated with BXP Preparations would be correlated with the property of idiosyncratic drug-induced liver injury. In conclusion,the risk of liver injury clinically caused by BXP Preparations should be paid more attention,and the studies on the mechanism of idiosyncratic drug-induced liver injury must be enhanced,and those on risk factors,like irrational drug use,should be strengthened. Moreover,the evaluation of the risk-to-benefit ratio is supposed to be performed for the sake of improving the risk prevention and control standards for BXP preparations,and ensuring safe and rational clinical application of BXP Preparations.


Subject(s)
Chemical and Drug Induced Liver Injury , Epidemiology , China , Dictamnus , Chemistry , Drugs, Chinese Herbal , Humans , Liver , Retrospective Studies , Risk Factors
15.
Article in Chinese | WPRIM | ID: wpr-689850

ABSTRACT

To investigate the hepatoprotective effect of Schisandrae Chinensis Fructus (SCF) on CCl₄-induced liver injury, observe its effect on serum metabolites, explore its scientific connotation in liver preservation and find the biomarkers for hepatoprotective effect of SCF. Liver injury model was established by using CCl₄. The pathological sections of liver tissues were observed and the contents of alanine transaminase (ALT) and aspartate transaminase (AST) in serum were determined. The metabolic skills were adopted based on ultra performance liquid chromatography time-of-flight mass spectrometry (UPLC-Q-TOF-MS), principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) for screening and identification of biomarkers related to liver injury. The results showed the metabolites in blank group, model group and administration group could be easily distinguished, 50 differential compounds were identified and 7 possible metabolic pathways of liver protection were enriched. In this experiment, the hepatoprotective effect of SCF was verified, and the related metabolic pathways such as amino acid metabolism, vitamin metabolism and glycerophospholipid metabolism were discussed.

17.
Acta Pharmaceutica Sinica ; (12): 1139-1147, 2018.
Article in Chinese | WPRIM | ID: wpr-779982

ABSTRACT

Focusing on the TCM-related adverse drug reactions, especially those conventionally non-toxic TCM induced hepatotoxicity, this paper has proposed and established the disease-syndrome-based toxicology evaluation pattern and approach for TCM, not only the normal rats, but the hepatic fibrosis model rat were studied hepatotoxic or hepatoprotective effects of rhubarb, meanwhile liver histopathology changes by histological tests such as HE and TUNEL staining. The metabolomics analysis method will be employed to screen the key metabolites and possible metabolic pathway of the dual effects of rhubarb in rats. The results showed that rhubarb could result in significant liver injury in normal rats, indicated by the elevation of plasma serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities (P L-arginine, creatine, L-valine, retinyl ester, and prostaglandin F2α were confirmed by multivariate statistical analysis and metabolic pathways enrichment analysis linked to six metabolic pathways, including taurine and hypotaurine metabolism, primary bile acid biosynthesis, arginine and proline metabolism, arachidonic acid metabolism, retinol metabolism and valine, leucine and isoleucine biosynthesis. In summary, the results suggested the dual effects of rhubarb screened by taurine and hypotaurine metabolism, primary bile acid biosynthesis and arginine and proline metabolism may be the key metabolic pathway related to You Gu Wu Yun phenomenon of rhubarb. This study will provide new vision and illustration of scientific evidences for the hepatotoxicity assessment and rational use of those drugs containing anthraquinones.

18.
Acta Pharmaceutica Sinica ; (12): 920-928, 2018.
Article in Chinese | WPRIM | ID: wpr-779952

ABSTRACT

Chinese medicines (CM)-induced liver injury is one of the severe adverse drug reactions (ADRs) in clinical application, which restricts new drug research and development (R&D), clinical safe usage and industry development of CM. The issue, to elucidate the causality between liver injury and CM, is either a globally challenging problem or the precondition of CM safety evaluation. However, owing to the complexicity of CM and various influencing factors to CM-induced liver injury, the causality assessment for CM is much difficult, compared to synthetic drugs. Besides, the current assessment methods, primarily designed for clinical diagnosis, are difficult to be used in new drug R&D of CM. Hereinto, we reviewed the current ADR causality methods and proposed a new strategy called integrated evidence chain-based causality assessment method for CM-induced liver injury. The new causality method is designed for new drug R&D based on the complexicity of CM, to provide methodology in scientific assessment of causality of CM-induced liver injury and to promote success rate of new drug R&D. The new method could also raise our ability to find, avoid and prevent the risk of CM-induced liver injury.

19.
Acta Pharmaceutica Sinica ; (12): 574-584, 2018.
Article in Chinese | WPRIM | ID: wpr-779910

ABSTRACT

In this study, we used a mathematic-based modeling system to screen the cytokines that are sensitive to Zhuangguguanjie wan (ZGW)-induced idiosyncratic liver injury. The values of 27 cytokines were used as the data source in rat liver of lipopolysaccharide (LPS) + ZGW group. The alanine aminotransferase (ALT) activity value of liver function indexes was used as the outcome evaluation index of liver injury. Cytokines of ZGW-induced idiosyncratic liver injury were screened using Logistic regression, random forest method, LASSO Logistics regression and method of combining rule discovery algorithm with LASSO, and cytokines filtered out were revalued in THP1 macrophage. Susceptible cytokine combinations:interleukin-1β (IL-1β), epidermal growth factor (EGF) and interleukin-18 (IL-18) closely related to ZGW-induced idiosyncratic liver injury were obtained after preliminary screening analysis. The result of revalued in THP1 showed that the ethanolic extract of ZGW (EtZ) combined with IL-1β or IL-18 synergistically enhanced tumor necrosis factor-α (TNF-α) secretion in THP1 macrophage, and EtZ combined with IL-1β significantly enhanced interleukin-6 (IL-6) secretion in THP1 macrophage, but EtZ combined with EGF markedly inhibited IL-6 secretion in THP1 macrophage. The results suggest that the sensitive cytokines that can be characterized in the ZGW-induced idiosyncratic liver injury are IL-1β and IL-18, which provides a basis for screening the ZGW-induced idiosyncratic liver injury patients, and a new experimental evidence for clinical safety medication and risk prevention of ZGW.

20.
Article in English | WPRIM | ID: wpr-691399

ABSTRACT

<p><b>OBJECTIVE</b>To investigate the possible mechanism of San-Cao Granule (SCG, ) mediating antiliver fibrosis.</p><p><b>METHODS</b>A total of 60 male Sprague-Dawley rats were randomly divided into the normal control group, porcine serum-treated group, ursodesoxycholic acid (UDCA, 60 mg/kg), SCG (3.6 g/kg) group, SCG (1.8 g/kg) group and SCG (0.9 g/kg) group, with 10 rats in each group. Liver fibrosis was induced with porcine serum by intraperitoneal injection for 8 weeks, except for the normal control group. Then, the rats in the three SCG-treated groups and UDCA group were administered SCG and UDCA respectively for 4 weeks. The serum levels of alanine transaminase (ALT), aspartate transaminase (AST), albumin (ALB), total bilirubin (TBIL), hyaluronic acid (HA), laminin (LN), and type IV collagen (IVC) were examined using commercial kits and hepatic histopathology was examined with hematoxylin and eosin and Masson staining. Moreover, the protein expression levels of high mobility group box-1 protein (HMGB1), transforming growth factor β1 (TGF-β1), phosphorylated mothers against decapentaplegic homolog 3 (p-Smad3), Smad7, toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), nuclear factor-kappa B (NF-κB) and α-smooth muscle actin (α-SMA) were determined by western blot, immunohistochemistry and real time quantitative-reverse transcription polymerase.</p><p><b>RESULTS</b>Both SCG (3.6 and 1.8 g/kg) and UDCA significantly ameliorated the liver fibrosis induced by porcine serum as indicated by retarding the serum levels increasing of ALT, AST, TBIL, HA, LN and IVC and preventing the serum level reducing of ALB compared with the model group (all P<0.01). Meanwhile, the collagen deposition was attenuated by SCG and UDCA treatment. Furthermore, SCG markedly reduced the expressions of HMGB1, TGF-β1, p-Smad3, TLR4, MyD88, NF-κB and α-SMA, and enhanced the expression of the Smad7 compared with the model group (all P<0.01).</p><p><b>CONCLUSION</b>SCG ameliorates hepatic fibrosis possibly through inhibiting HMGB1, TLR4/NF-κB and TGF-β1/Smad signaling pathway.</p>


Subject(s)
Animals , Disease Models, Animal , Drugs, Chinese Herbal , Therapeutic Uses , HMGB1 Protein , Metabolism , Liver , Metabolism , Pathology , Liver Cirrhosis , Drug Therapy , Metabolism , Pathology , Male , Rats , Rats, Sprague-Dawley , Signal Transduction , Smad Proteins , Metabolism
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