Potential Mechanism of Herb-Drug Interaction Mediated by Angelica dahurica: Inhibition on CYP3A Enzymes in Rats

Angelica dahurica is commonly referred to as ‘Baizhi’ in China and has been noted for its therapeutic significance. The major active ingredients of Angelica dahurica is coumarin, which is reported as a kind of potent inhibitor of cytochrome P450 enzymes (CYP450s). The aim of this study was to investigate the inhibition of CYP3A enzymes by total coumarin extract (TCE) obtained from dried root of Angelica dahurica by using in situ single pass intestinal perfusion (SPIP) and in situ liver perfusion in rats. When midazolam (MDZ) which is a substrate of CYP3A co-perfused with TCE (198 μg/mL) from Baizhi in duodenum and ileum segments, the Peff of MDZ has increased significantly compared with the MDZ single perfused group (p 0.05) (n = 6). During in situ liver perfusion study, the results demonstrated that, 3 days oral administration of TCE obtained from Baizhi could significantly reduce the elimination rate of MDZ in the perfusate (p Angelica dahurica extract co-administrated with drugs which are the substrates of CYP3A, much more attention should be paid rather than that of other CYP450 enzymes. These findings may facilitate in predicting possible herb-drug interactions (HDIs) when Angelica dahurica is used in combination with other drugs, and decrease the incidence of the CYP450-mediated HDIs.

Drug and herb induced liver injury: Council for International Organizations of Medical Sciences scale for causality assessment

Causality assessment of suspected drug induced liver injury(DILI) and herb induced liver injury(HILI) is hampered by the lack of a standardized approach to be used by attending physicians and at various subsequent evaluating levels. The aim of this review was to analyze the suitability of the liver specific Council for International Organizations of Medical Sciences(CIOMS) scale as a standard tool for causality assessment in DILI and HILI cases. PubMed database was searched for the following terms: drug induced liver injury; herb induced liver injury; DILI causality assessment; and HILI causality assessment. The strength of the CIOMS lies in its potential as a standardized scale for DILI and HILI causality assessment. Other advantages include its liver specificity and its validation for hepatotoxicity with excellent sensitivity, specificity and predictive validity, based on cases with a positive reexposure test. This scale allows prospective collection of all relevant data required for a valid causality assessment. It does not require expert knowledge in hepatotoxicity and its results may subsequently be refined. Weaknesses of the CIOMS scale include the limited exclusion of alternative causes and qualitatively graded risk factors. In conclusion, CIOMS appears to be suitable as a standard scale for attending physicians, regulatory agencies, expert panels and other scientists to provide a standardized, reproducible causality assessment in suspected DILI and HILI cases, applicable primarily at all assessing levels involved. 2014 Baishideng Publishing Group Co., Limited. All

Perspectives and challenges of tropical medicinal herbs and modern drug discovery in the current scenario

Tropical diseases such as malaria, tuberculosis, trypanosomiasis, and leishmaniasis, account for a large number of deaths annually. Herbs are an excellent source of tropical medicines. Many advancements and discoveries have taken place in the field of drug discovery but still, a major population of tropical diseases relies on herbal traditional medicine. There are some challenges related to policy implementation, efficacy, resistance and toxicity of tropical medicines. There are many tropical diseases such as such as schistosomiasis, leishmaniasis, African sleeping sickness, filariasis and chagas disease which are neglected because very few pharmaceutical companies have shown their interest in developing therapeutics against these diseases of poor people. There are many benefits associated with herbal medicine such as the cost of production, patient tolerance, large scale availability, efficacy, safety, potency, recyclability, and environment friendly. A large number of natural extracts such as curcumin, artemisinin, morphine, reserpine, and hypericin, are in use for treatment of different tropical diseases for a long time. The current review is to discuss the overview of tropical medicinal herbs, its scope and limitations in the modern drug discovery process.

Critical Evaluation for Alternative Causes of Drug Induced and Herbal Induced (DILI/HILI) Hepatotoxicity

The objective of this review is to highlight the continued exclusion of discussion in the literature regarding alternative causes and proper causality assessment of cases of hepatotoxicity when use of dietary supplements is reported. Though independent experts are working diligently to advance the discussion related to alternative causes of hepatotoxicity resulting in idiosyncratic drug-induced liver injury/herb-induced liver injury (DILI/HILI), the literature continues to recite the same cases, such as those presented here, to reiterate potentially biased positions and ignore current, standardized and valid evaluations utilizing the Roussel Uclaf Causality Assessment Method (RUCAM). Several historical cases purporting hepatotoxicity induced by use of dietary supplements are presented in this review to demonstrate how such cases may be improperly assessed due to bias, inconsistent use of causality assessment methods, as well as use of causality assessment methods deemed obsolete. This in essence, delays any true progress in establishing sound criteria to determine and address the actual cause(s) of DILI/HILI.

Herbal hepatotoxicity:Challenges and pitfalls of causality assessment methods

The diagnosis of herbal hepatotoxicity or herb induced liver injury(HILI) represents a particular clinical and regulatory challenge with major pitfalls for the causality evaluation.At the day HILI is suspected in a patient,physicians should start assessing the quality of the used herbal product,optimizing the clinical data for completeness,and applying the Council for International Organizations of Medical Sciences(CIOMS) scale for initial causality assessment.This scale is structured,quantitative,liver specific,and validated for hepatotoxicity cases.Its items provide individual scores,which together yield causality levels of highly probable,probable,possible,unlikely,and excluded.After completion by additional information including raw data,this scale with all items should be reported to regulatory agencies and manufacturers for further evaluation.The CIOMS scale is preferred as tool for assessing causality in hepatotoxicity cases,compared to numerous other causality assessment methods,which are inferior on various grounds.Among these disputed methods are the Maria and Victorino scale,an insufficiently qualified,shortened version of the CIOMS scale,as well as various liver unspecific methods such as thead hoc causality approach,the Naranjo scale,the World Health Organization(WHO) method,and the Karch and Lasagna method.An expert panel is required for the Drug Induced Liver Injury Network method,the WHO method,and other approaches based on expert opinion,which provide retrospective analyses with a long delay and thereby prevent a timely assessment of the illness in question by the physician.In conclusion,HILI causality assessment is challenging and is best achieved by the liver specific CIOMS scale,avoiding pitfalls commonly observed with other approaches.

Comprehensive review of hepatotoxicity associated with traditional Indian Ayurvedic herbs

With growing antipathy toward conventional prescription drugs due to the fear of adverse events,the general and patient populations have been increasingly using complementary and alternative medications(CAMs)for managing acute and chronic diseases.The general misconception is that natural herbal-based preparations are devoid of toxicity,and hence short-and long-term use remain justified among people as well as the CAM practitioners who prescribe these medicines.In this regard,Ayurvedic herbal medications have become one of the most utilized in the East,specifically the Indian sub-continent,with increasing use in the West.Recent well-performed observational studies have confirmed the hepatotoxic potential of Ayurvedic drugs.Toxicity stems from direct effects or from indirect effects through herbal metabolites,unknown herb-herb and herbdrug interactions,adulteration of Ayurvedic drugs with other prescription medicines,and contamination due to poor manufacturing practices.In this exhaustive review,we present details on their hepatotoxic potential,discuss the mechanisms,clinical presentation,liver histology and patient outcomes of certain commonly used Ayurvedic herbs which will serve as a knowledge bank for physicians caring for liver disease patients,to support early identification and treatment of those who present with CAM-induced liver injury.

Radix Polygoni Multiflori Praeparata and Dioscorea Bulbifera Rhizome Decoctions Display Combined Effects Detected by a Three-Probe Drug Cocktail with Substrates of Rat Hepatic Cytochrome P450 Enzymes

Objectives: Radix Polygoni Multiflori Praeparata (RPMP) and Dioscorea Bulbifera Rhizomes (DBR) are used in Chinese herbal medicine and have been frequently reported for adverse reactions on liver. In this research, we aimed to evaluate in vivo effects of RPMP and DBR on rat cytochrome P450 enzymes (CYP1A2, CYP2E1 and CYP3A2) with their respective substrates as probes. Methods: Rats were orally administered RPMP, DBR and RPMP/DBR combination at 12, 10 and (12 + 10) g/kg, respectively, or saline as a control, once daily for 7 days. Thereafter, a cocktail containing 10 mg/kg caffeine, 20 mg/kg chlorzoxazone and 10 mg/kg dapsone was tail vein injected to rats. At defined time points, plasma drug concentrations were simultaneously evaluated by HPLC. Pharmacokinetic parameters simulated by DAS software were used to assess RPMP and/or DBR effects on cytochrome P450 enzymes activity. ANOVA and Dunnett’s test were used for data analysis. Results: Caffeine metabolism was enhanced in RPMP animals and reduced after pretreatment with DBR, but no effect was observed in RPMP/DBR combination group. Chlorzoxazone and dapsone metabolism was enhanced in both RPMP and DBR groups and consequently in combination group. The data suggested that RPMP independently induces rat CYP1A2, CYP2E1 and CYP3A2 activity, while DBR independently inhibits activity of rat CYP1A2 and induces that of CYP2E1 and CYP3A2. RPMP/DBR combination showed no significant benefit compared with the two drugs alone and even showed a neutralized effect in CYP1A2 activity. Conclusions: Caution is needed when RPMP and/or DBR are co-administered with drugs metabolized by human CYP1A2, CYP2E1 and CYP3A4.

7576张含丹参-当归药对的门诊中药饮片处方回顾性分析

目的:了解江苏省中西医结合医院南部院区/南京市溧水区中医院(以下简称“该院”)含丹参-当归药对的门诊中药饮片处方情况,探究该药对的临床配伍应用规律,为该药对的合理使用提供参考。方法:采用回顾性分析方法,统计2020—2022年该院使用丹参-当归药对的7576张门诊中药饮片处方,对患者的性别、年龄、处方药味数、金额、疗程、涉及科室及病症、使用剂量、常用的配伍比例及配伍饮片等相关内容进行统计分析。结果:7576张含丹参-当归药对的门诊中药饮片处方中,女性患者处方数约为男性患者处方数的3.21倍(5776张vs.1800张),>30~40岁患者居多。单张处方的中药饮片味数多集中在16~20味,开具的疗程均<30 d。丹参的使用剂量为《中华人民共和国药典》规定的10~15 g的处方有6490张,占85.67%;当归的使用剂量为《中华人民共和国药典》规定的6~12 g的处方有6608张,占87.22%。处方数排序居前3位的科室依次为国医堂、妇科及脑病科,治疗的病证以冲任失调、心脾两虚及气滞血瘀证为主。单张处方中丹参用量大于等于当归用量,丹参与当归的配伍比例以1∶1为多,高频配伍饮片为茯苓、川芎、炒白芍。结论:基于处方用药分析,该院含丹参-当归药对的门诊中药饮片处方基本合理,为丹参-当归药对的使用剂量范围及配伍规律研究提供了数据支持,有利于促进临床合理用药。

基于中药特色技术传承概述广东芸香科道地药材

基于中药传统特色技术,文章通过现场观摩调研与文献检索,概述在十大广药中占有1/3的芸香科药物的药用历史、产地采收加工、性状鉴别特点。芸香科药物多含挥发油,具有芳香气,大部分具有宽中理气的功效,临床应用广泛。据考证,柚类橘红始自清代,此前使用橘类橘红;广陈皮主产区在新会地区,也称新会陈皮,药用时间至今约有600年;广佛手以肇庆高要地区产量多且质优,“佛手柑”的记载最早见于元朝。化橘红的传统加工方法是将化州柚的外层果皮切成角状,加工成7角的毛橘红药材,称为“毛七爪”;新会陈皮需在新会地区内陈化三年,方可称为“新会陈皮”。化橘红鉴别特点为表面密被柔软毡状细绒毛,有油点,气清香;新会陈皮“鬃眼”明显,对光照视呈半透明状,香气浓郁。广佛手切面的外皮呈黄色,肉呈白色,俗称“金边白肉”。文章基于中药传统理论、技术对广东地区芸香科道地药材进行概述,以期守正创新,使中药的传统特色技术得到传承发展。

从单味中药的剂量选择探讨随证施量与临床用药安全

“随证施量”是“辨证论治”之后重要的一环,考虑患者体质、年龄、病程等个体化差异,是中医个体化治疗的体现。总结现代医家关于附子、大黄、水蛭、天花粉、淫羊藿五味常用中药在“随证施量”过程中超剂量用药情况,不同剂量针对疾病的轻重程度和相关指标的改善情况,希望能够拓宽药物临床剂量使用范围,为临床提供理论依据。

基于问卷调研的中药材质量监测机制优化探索

目的:为进一步优化完善中药材质量监测机制,探索建立国家与省级中药材质量监测统筹模式提供参考。方法:基于国家药品抽检协作网络,在国家药品抽检信息系统内,采用在线问卷调研的方式,面向国家药品抽检承检机构以及省级药品监督管理部门征集意见建议。结果:共有46家承检机构与32家药品监督管理部门作答问卷,汇总分析显示,中药材质量监测逐步建立相互衔接、各有侧重的国家与省级协作体系,适当扩大监测品种范围,对药材市场与种植基地、饮片和中成药生产企业重点监测,建立风险分级管理制度,并与国家药品抽检协同发布监测结果。结论:中药材质量监测应当基于国家药品抽检协作网络,进一步优化品种遴选流程与范围,围绕药品生产企业、药材市场与种植基地,完善风险处置机制。

4种单一中草药及其配伍用药对动物肠道益生菌乳杆菌的促进作用

试验旨在探究4种单一中草药五味子、山楂、木香、白术及其配伍用药对益生菌乳杆菌的激活增殖作用。试验测定添加不同单一和联合配伍中草药前后乳杆菌培养液OD值、菌落数变化情况,探究其激活益生菌乳杆菌增殖的最佳剂量浓度。建立阿莫西林型肠道菌群失衡模型,考察单一中草药及联合配伍中草药对小鼠肠道内乳杆菌的影响。结果显示,五味子、山楂和白术对乳杆菌的最佳激活增殖浓度均为0.250 g/mL,木香最佳激活增殖浓度为0.500 g/mL;五味子+山楂、五味子+白术、五味子+木香的最佳激活增殖浓度均为0.125 g/mL;白术+山楂、木香+山楂的最佳激活增殖浓度均为0.250 g/mL;白术+木香的最佳激活增殖浓度为0.450 g/mL。研究表明,在畜牧生产中,建议添加五味子与山楂水提液的最佳浓度为0.250 g/mL,五味子+山楂、五味子+白术、五味子+木香的最佳添加浓度均为0.125 g/mL,能够最大限度地发挥中草药对动物肠道乳杆菌的促进作用。

Efficacy of integrating short-course chemotherapy with Chinese herbs to treat multi-drug resistant pulmonary tuberculosis in China: a study protocol

Background:Tuberculosis(TB)causedMycobacterium tuberculosis(M.tb)is one of infectious disease that lead a large number of morbidity and mortality all over the world.Although no reliable evidence has been found,it is considered that combining chemotherapeutic drugs with Chinese herbs can significantly improves the cure rate and the clinical therapeutic effect.Methods:Multi-drug resistant pulmonary tuberculosis(MDR-PTB,n=258)patients with Qi-yin deficiency syndrome will be randomly assigned into a treatment group(n=172)or control/placebo group(n=86).The treatment group will receive the chemotherapeutic drugs combined with Chinese herbs granules(1+3 granules),while the control group will receive the chemotherapeutic drugs combined with Chinese herbs placebo(1+3 placebo granules).In addition,MDR-PTB(n=312)patients with Yin deficiency lung heat syndrome will be randomly assigned to a treatment(n=208)or control/placebo(n=104)group.The treatment group will receive the chemotherapeutic regimen combined with Chinese herbs granules(2+4 granules),while the control group will receive the chemotherapeutic drugs and Chinese herbs placebo(2+4 placebo granules).The primary outcome is cure rate,the secondary outcomes included time to sputum culture conversion,lesion absorption rate and cavity closure rate.BACTEC^(TM)MGIT^(TM)automated mycobacterial detection system will be used to evaluate theM.tb infection and drug resistance.Chi-square test and Cox regression will be conducted with SAS 9.4 Statistical software to analyze the data.Discussion:The treatment cycle for MDR-PTB using standardized modern medicine could cause lengthy substantial side effects.Chinese herbs have been used for many years to treat MDR-PTB,but are without high-quality evidence.Hence,it is unknown whether Chinese herbs enhances the clinical therapeutic effect of synthetic drugs for treating MDR-PTB.Therefore,this study will be conducted to evaluate the clinical therapeutic effect of combining Chinese herbs and chemotherapeutic drugs to treat MDR-PTB cases.It will assist in screening new therapeutic drugs and establishing treatment plan that aims to improve the clinical therapeutic effect for MDR-PTB patients.Trial registration This trial was registered at ClinicalTrials.gov(ChiCTR1900027720)on 24 November 2019(prospective registered).

Chinese herb pollen derived micromotors as active oral drug delivery system for gastric ulcer treatment

Considerable efforts have been devoted to treating gastric ulcers.Attempts in this field tend to develop drug delivery systems with prolonged gastric retention time.Herein,we develop novel Chinese herb pollen-derived micromotors as active oral drug delivery system for treating gastric ulcer.Such Chinese herb pollen-derived micromotors are simply produced by asymmetrically sputtering Mg layer onto one side of pollen grains.When exposed to gastric juice,the Mg layer can react with the hydrogen ions,resulting in intensive generation of hydrogen bubbles to propel the micromotors.Benefiting from the autonomous motion and unique spiny structure,our micromotors can move actively in the stomach and adhere to the surrounding tissues.Besides,their special architecture endows the micromotors with salient capacity of drug loading and releasing.Based on these features,we have demonstrated that our Chinese herb pollen-derived micromotors could effective deliver berberine hydrochloride and show desirable curative effect on the gastric ulcer model of mice.Therefore,these Chinese herb pollen-derived micromotors are anticipated to serve as promising oral drug delivery carriers for clinical applications.

腹泻奶牛源大肠杆菌的分离鉴定及中药的体外抑菌效果

为了研究贵州毕节某奶牛场荷斯坦奶牛发生腹泻的原因,从该奶牛场采集50份新鲜粪便样本,通过平板划线法对大肠杆菌进行分离纯化和PCR鉴定,采用K-B纸片法进行药物敏感试验,并对多种耐药基因进行PCR检测。针对多重耐药菌,选取虎耳草和杜鹃花2种中草药进行体外抑菌效果研究。结果显示:从腹泻奶牛粪便中分离出31株细菌,其菌落形态和生化特性与大肠杆菌相符;16S rRNA基因测序比对发现该牛场分离的菌株与NCBI数据库中大肠杆菌参考菌株的同源性达到99.65%~99.86%,确定该奶牛场的腹泻病原为大肠杆菌;药敏试验发现该牛场来源的大肠杆菌对多种抗生素(强力霉素、红霉素、青霉素G和四环素)耐药,而对磺胺异恶唑、头孢曲松、环丙沙星、庆大霉素、多黏菌素B、磷霉素等10种抗生素敏感;PCR扩增相关耐药基因发现,导致该牛场腹泻的大肠杆菌携带2种β-内酰胺类(blaCTX-M、blaTEM),4种四环素类(TetD、TetB、TetK、TetD、TetA),2种氨基糖苷类(ant(3″)-Ia、rmtB)和3种喹诺酮类(qnrS、qepA、oqxA)耐药基因。体外抑菌研究发现,杜鹃花(3.125 mg/mL)的水提物有显著的抑菌效果。试验结果可为该奶牛场防治大肠杆菌性腹泻提供用药指导,同时为开发替抗中草药产品提供了依据。

Potential Herb-Drug Interaction in the Prevention of Cardiovascular Diseases during Integrated Traditional and Western Medicine Treatment

The combination of herbs and drugs is one of the most important approaches in the prevention and treatment of diseases in the integrated traditional and Western medicine （ITWM）. While most medical practices have proved that the combination of herbs and drugs led to a clinical efficacy that was often superior to merely using only one of them; results from some studies have triggered adverse reactions to such an approach. Since few herb-drug interaction studies were carried out during treatments combining herbs and drugs, it really restricts the development of treatment and treatment theory of the combination of herbs and drugs. Given that herb-drug interactions may occur through the main pathway of cytochrome P450 enzymes and transporters; then to exhaustively study the role and impact of herbs in drug metabolism, as well as to establish a corresponding database, is of greatsignificance for guiding the rational combination of herbs and drugs. When the herb-drug interaction information platform is implemented, we would get at ease a reasonable herb-drug prescription to achieve a better outcome, reduce dosage of some expensive drugs preserving the same efficacy, or even reduce some side effects of particular drugs; which might also promote the dynamic combination of Chinese and Western medicine, and accelerate the theory development of ITWM.

荭草苷对UGT1A1代谢伊立替康的抑制作用

目的探究荭草苷对野生型尿苷二磷酸葡萄糖醛酸转移酶1A1(UGT1A1)及其常见突变体UGT1A1*6酶活性的影响,定量预测含有荭草苷的中草药与伊立替康同时服用时发生草药-药物相互作用的风险。方法建立体外孵育体系,将系列浓度的荭草苷与SN-38共同孵育,用超高效液相色谱-串联质谱法(UPLC-MS/MS)测定SN-38代谢产物SN-38葡萄糖醛酸酯(SN-38G)的生成速率,考察荭草苷对SN-38葡萄糖醛酸化的影响。结果荭草苷对UGT1A1*1和UGT1A1*6的半抑制浓度(IC50)分别为19.04、34.35μmol/L,计算得到的Ki值分别为9.32、19.63μmol/L。利用体外-体内外推法(IVIVE)定量预测表明口服含有荭草苷的中草药与伊立替康联合使用时,会导致SN-38的血浆浓度-时间曲线下面积(AUC)至少增加87%。结论荭草苷有可能抑制UGT1A1的活性而引发伊立替康的不良反应,为合理使用含荭草苷的中草药与伊立替康提供了理论指导。

矿物药琥珀的本草考证

琥珀为我国传统常用药材,距今已有1400余年的药用历史。历代本草关于琥珀来源说法不一,多有关于琥珀真伪鉴别的记载,目前市售琥珀品质亦存在质量参差不齐等问题。经考证,古代本草大多将琥珀列入寓木部或寓木类,然本品实为松脂化石,而产地、品质、采收、加工、炮制及功效等方面古今差异不大。通过本草文献学研究方法,对矿物药琥珀进行系统的本草考证,明确了历代本草中药用琥珀的正品来源及产地,以期规范琥珀药材的流通及应用,合理开发和利用琥珀药材资源。

特应性皮炎治疗的新进展

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