Potential herb-drug interactions between anti-COVID-19 drugs and traditional Chinese medicine

Coronavirus disease 2019(COVID-19), caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2), has spread worldwide. Effective treatments against COVID-19 remain urgently in need although vaccination significantly reduces the incidence, hospitalization, and mortality. At present, antiviral drugs including Nirmatrelvir/Ritonavir(Paxlovid^TM), Remdesivir, and Molnupiravir have been authorized to treat COVID-19 and become more globally available. On the other hand, traditional...     

Pharmacokinetic interactions of Mentat with carbamazepine and phenytoin.

In the present study, Mentat, a herbomineral psychotropic preparation, was studied for its pharmacokinetic interaction with the commonly used anti-epileptic drugs, carbamazepine and phenytoin. The interaction of carbamazepine and phenytoin with Mentat was studied in rabbits. Thirty two rabbits were divided into four groups of eight each. Animals of Group I were treated with carbamazepine (50 mg/kg b.wt. p.o.), Group II were treated with carbamazepine (50 mg/kg b.wt. p.o.) + Mentat (500 mg/kg b.wt. p.o.), Group III were treated with phenytoin (50 mg/kg b.wt. p.o.) and Group IV were treated with phenytoin (50 mg/kg b.wt. p.o.) + Mentat (500 mg/kg b.wt. p.o.) for a period of 8 days. On day 0 and day 8, plasma carbamazepine and phenytoin levels were estimated at different time intervals. A simultaneous treatment with Mentat resulted in a significant increase in plasma AUC of carbamazepine as well as phenytoin as compared to carbamazepine or phenytoin alone. Cmax and Tmax of carbamazepine and phenytoin also were evaluated. The results suggest that co-administration of Mentat could improve the effectiveness of anti-epileptic drugs due to the increased bioavailability of the latter. However, this has to be done with critical medical supervision to avoid any toxic reactions and preferably with therapeutic drug monitoring (TDM) which could also help in dose optimization.     

赤芍、白芍的LC-MS色谱峰与细胞抑制率的谱效关系研究

目的确定川赤芍、赤芍、白芍抑制脂多糖(LPS)诱导大鼠肺泡巨噬细胞NR8383过度激活的"药效成分组"。方法以川赤芍、赤芍、白芍不同提取物LC-MS图谱峰面积及其抑制LPS诱导的NR8383细胞活力增强为基础,采用偏最小二乘回归法,对LC-MS图谱和抑制细胞增殖的内在联系进行谱效分析。结果 LC-MS图上的X11、X6、X1、X2、X9、X3这6个成分组成的"药效成分组"对川赤芍、赤芍、白芍抑制NR8383细胞增殖药效的贡献较大。结论 "药效成分组"的研究显示,同基源的赤芍、白芍在抑制LPS诱导的NR8383细胞增殖方面具有相同的化学成分(X1、X2、X9、X3),但同时也有某些成分(X11、X6)仅能在赤芍中检测到,这提示不同的化学成分及含量差异可能是造成赤芍、白芍功效不同的物质基础。     

中药药剂学与方剂学关系研究

目的 对中药药剂学与方剂学之间的关系进行研究.方法 对两个学科之间的关系研究主要是从中药制剂学与方剂学的概念,中药药剂学是方剂学发生的条件以及方剂学是中药药剂学的发展的基础等几个方面进行分析.结果 中药药剂学的概念和方剂学的概念存在一定的区别和联系,同时中药药剂学则是方剂学发展的条件,然而方剂学又是中药制剂学进行发展的基础.结论 方剂学和药剂学存在着十分紧密的关系,其是相辅相成的关系,同时又是紧密联系和共同发展的两个重要学科.     

Pharmacokinetic interactions between Japanese traditional Kampo medicine and modern medicine (IV). Effect of Kamisyoyosan and Tokisyakuyakusan on the pharmacokinetics of etizolam in rats

Kamisyoyosan (KSS) and Tokisyakuyakusan (TSS) are widely used herbal formulas in Japanese traditional kampo medicine to relieve the symptoms occurred in climacteric disturbance. Since Japanese physicians frequently prescribe these formulas combined with etizolam, one of benzodiazepine anxiolytics, we evaluated the pharmacokinetic interaction between KSS or TSS and etizolam, and in vitro inhibitory effect of KSS and TSS on rat cytochrome P450 (CYP) 3A activity in rat microsomes, to obtain drug information to prevent from disadvantage or adverse effects by their combined therapy. In in vitro experiment, KSS and TSS inhibited CYP3A activity comparable to grapefruit juice. However in in vivo experiments, oral administration of KSS did not influence the plasma concentration profile of etizolam. The maximum concentration (Cmax) of etizolam was significantly reduced when TSS was co-administered at 20 times amount of human daily dosage. Since the double of human daily dose of TSS did not suppress the absorption of etizolam, TSS would not influence the pharmacokinetics of etizolam at the usual clinical dosage. Since both KSS and TSS did not influence the metabolism of etizolam, the result of in vitro experiment would not reflect to that of in vivo experiment or in clinic. The combination of etizolam with KSS or TSS at usual dosage would not cause drug interaction.     

Microscopic research on a multi-source traditional Chinese medicine,Astragali Radix

Astragali Radix is a widely and commonly used Chinese herbal medicine, which is derived from roots of Astragalus membranaceus var. mongholicus and Astragalus membranaceus. To find a quick and reliable method of distinguishing these two species of Astragali Radix and of determining the age of a sample, microscopic characteristics of the two species were compared using light microscopy. The results showed that the microscopic characteristics, such as number of layers of phellem, continuing lignified xylem bundles within spring wood and lignified parenchyma cells in the central part of the xylem could be used for the differentiation of the root of A. membranaceus from the root of A. membranaceus var. mongholicus. Growth rings (annual rings) were found for the first time in the roots of both species, and could determine the age of a sample. For the first time, radial fibers in both species of Astragali Radix and pipette-shaped fibers in A. membranaceus var. mongholicus were found. The structure of “rotten heart” cork tissue (decayed central xylem) and tubular cork tissue was carefully studied, and the arranged order of tissues in both “rotten heart” and tubular cork tissues is phelloderm and phellem from outside to inside, which is contrary to that in the periderm.     

Pharmacokinetic interaction between zolpidem and carbamazepine in healthy volunteers

The objective of this study was to evaluate the pharmacokinetic interaction between zolpidem and carbamazepine in healthy volunteers. The study consisted of 2 periods: period 1 (reference), when each volunteer received a single dose of 5 mg zolpidem, and period 2 (test), when each volunteer received a single dose of 5 mg zolpidem and 400 mg carbamazepine. Between the 2 periods, the participants were treated for 15 days with a single daily dose of 400 mg carbamazepine. Pharmacokinetic parameters of zolpidem administered in each treatment period were calculated using noncompartmental analysis. In the 2 periods of treatments, the mean peak plasma concentrations (C(max)) were 59 ng/mL (zolpidem alone) and 35 ng/mL (zolpidem after pretreatment with carbamazepine). The t(max), times taken to reach C(max), were 0.9 hours and 1.0 hour, respectively, and the total areas under the curve (AUC(0-∞)) were 234.9 ng·h/mL and 101.5 ng·h/mL, respectively. The half-life of zolpidem was 2.3 and 1.6 hours, respectively. Carbamazepine interacts with zolpidem in healthy volunteers and lowers its bioavailability by about 57%. The experimental data demonstrate the pharmacokinetic interaction between zolpidem and carbamazepine and suggest that the observed interaction may be clinically significant, but its relevance has to be confirmed.     

Pharmacokinetic interactions between Japanese traditional medicine (kampo) and modern medicine (III). Effect of Sho-seiryu-to on the pharmacokinetics of azelastine hydrochloride in rats

Sho-seiryu-to (SST) is widely used herbal formula in Japanese traditional medicine (kampo) to treat allergic diseases. Since Japanese physicians frequently prescribe this formula combined with azelastine hydrochloride, one of anti-histamine and anti-allergic medicines, we evaluated the pharmacokinetic interactions between SST and azelastine hydrochloride in rats to obtain the drug information for the prevention from disadvantage or adverse effects by their combined therapy. Oral administration of SST did not influence the plasma concentration profile of azelastine after its intravaneous injection, suggesting that SST would not change the activities of metabolic enzymes such as cytochrome P450s. However, maximum concentration (C(max)) of azelastine after oral administration of azelastine hydrochloride was significantly reduced and mean residence time (MRT) was significantly lengthened when SST was orally administered at 20 times amount of human daily dosage. There was not significant difference in the area under the plasma concentration-time curve (AUC), suggesting that SST might delay the absorption of azelastine without affecting the extent of bioavailability. Since this delay was independent of ephedrine that is a main constituent of SST and that a suppressor for gastric transit, SST might form unsoluble complex with azelastine to reduce its absorption. At the double of human daily dose, SST did not made the absorption of azelastine delay. The possibility that SST reduce the absorption of azelastine hydrochloride could not be denied completely, however, it is suggested that SST would not cause pharmacokinetic interaction with azelastine hydrochloride clinically.     

Pharmacokinetic interactions between felodipine and metoprolol

Summary This double-blind, cross-over study in healthy male subjects evaluated the pharmacokinetics of felodipine and metoprolol given both separately and in combination. During three, five-day study periods, felodipine 10 mg b.d., metoprolol 100 mg b.d. and a combination of the two, were given in random order. There was at least a 7-day washout period between each pharmacokinetic study day. Plasma levels of unchanged felodipine and metoprolol were measured for 24 h after the last dose, on the 5th day of each treatment period.Eight subjects, aged 19–22 years, completed the study. Both felodipine and metoprolol, given alone and in combination, were well tolerated.None of the felodipine pharmacokinetic variables (t_max, C_max, C_min, AUC (0–12) and t_1/2) changed significantly when felodipine and metoprolol were given in combination. C_max and AUC (0–12) for metoprolol increased significantly when metoprolol and felodipine were combined, although t_max, C_min and t_1/2 for metoprolol remained unchanged. The changes in metoprolol pharmacokinetics induced by felodipine are small and unlikely to be clinically important.     

Studies on interactions between traditional herbal and Western medicines. IV: lack of pharmacokinetic interactions between Saiko-ka-ryukotsu-borei-to and carbamazepine in rats.

The possibility of pharmacokinetic interactions between Saiko-ka-ryukotsu-borei-to extract powder (TJ-12), a widely used traditional Chinese herbal (Kampo) medicine, and carbamazepine (CBZ), an important anti-epileptic drug, was examined in rats. There were no significant differences in the serum protein binding of CBZ and carbamazepine- 10,11-epoxide (CBZ-E), its active metabolite, at two concentrations (1 and 10 Bg/ml) between twogroups pretreated orally with the vehicle andTJ-12 suspension (1 g/kg/d, p.o.) for 1 week. One-week repeated pretreatment with TJ- 12 (1 g/kg/d) did not influence liver weight, contents of cytochromes P450 and b5 in hepatic microsomes or the formation rate of CBZ-E from CBZ by its microsomes, while pretreatment with phenobarbital (80 mg/kg/d, i.p.) significantly increased these parameters. Neither a single nor 1-week repeated oral pretreatment with TJ-12 (1 g/kg/d) affected the plasma concentration-time profile and any pharmacokinetic parameter of CBZ or CBZ-E after oral administration of CBZ (50 mg/kg). These results indicated that oral co-administration of TJ-12 with CBZ has no effect ofthe pharmacokinetics of CBZ or CBZ-E in rats. Concomitant treatment with TJ- 12 and CBZ appears to be pharmacokinetically safe in humans.     

Pharmacokinetic interaction between imipramine and carbamazepine in patients with major depression

RATIONALE: Despite the fact that carbamazepine (CBZ) is frequently added to the existing tricyclic antidepressant (TCA) therapy, to date little is known about serum levels of pharmacologically active hydroxy metabolites of TCAs, as well as about possible changes in free (non-protein-bound) concentrations of these drugs and their metabolites during such combination treatment of depression. OBJECTIVE: The aim of this study was to evaluate the effect of CBZ on steady-state total and free serum concentrations of imipramine (IMI) and its metabolites, desipramine (DMI), 2-hydroxyimipramine and 2-hydroxydesipramnine, in depressed patients. In addition, the free and total serum concentrations of CBZ and 10,11-epoxycarbamazepine were measured. METHOD: Thirteen patients with DSM-III-R diagnosis of major depression were enrolled in the study. All patients hospitalised at the Department of Psychiatry, Collegium Medicum, Jagiellonian University were treated with IMI at a dose of 2 mg/kg per day for 3 weeks, after which CBZ at a dose of 400 mg/day was added. Steady-state serum concentrations of IMI, CBZ and their metabolites were assayed by HPLC. Free drug concentrations were measured by ultrafiltration. RESULTS: After 2 weeks of combination therapy a significant decrease in mean steady-state total serum concentrations of IMI (from 168.84 +/- 102.18 to 98.12 +/- 43.79 ng/ml) and DMI (from 293.89 +/- 171.93 to 221.85 +/- 153.21 ng/ml) was observed. Simultaneously, steady-state serum concentrations of total hydroxy metabolites and free IMI and its metabolites, measured just before and 2 weeks after CBZ were started, did not differ significantly. In consequence, a significant increase in free fraction of the parent drug was observed (3.36 +/- 3.24% vs 5.75 +/- 3.60%). Also free fraction of DMI tended to be higher after CBZ addition. CONCLUSION: CBZ affects not only the metabolism of IMI and its metabolites, but also their protein binding. Therefore, despite considerable reductions in total serum levels of IMI and DMI, but when the unchanged free fraction concentration of these compounds is maintained, a dosage elevation of IMI does not seem to be necessary after CBZ addition to TCA therapy.     

药物表型组学与传统中医药（英文）

In the post-genome era,different omics methods have been used to establish the relationship between clinical phenotypes and molecular characterizations.The combination of genomics,proteomics,and metabolomics has unraveled the etiology and pathophysiology of various diseases in a big-data fashion and the recent Genome-Wide Association Studies(GWAS)have provided a powerful systematic method to investigate the impact of common genomic variations on human cardiovascular pathophysiology and disease.But,these studies also revealed unmatched relationships between the genomic variability and the much narrower definition of various clinical phenotypes of cardiovascular diseases in individual patients.In the majority of GWAS a single targeted disease or a pre-defined and limited phenotype(trait)was studied and the accrual of such a large number of single gene variant-phenotype associations has led to the serendipitous identification of single loci associated with multiple diseases,or one gene being responsible or affecting more than one phenotypic characteristic(pleiotropy).Clearly,Western medicine is now facing the same challenges as traditional Chinese medicine(TCM)and newer approaches are needed for the redefinition of diseases using the underlying molecular causes and other factors in addition to traditional signs and symptoms.These are the same old questions for TCM for many years.A new method named″Phenome-Wide Association Study(PheWAS)″as an alternative approach that complements GWAS and utilizes phenomics and big-data technologies to analyze all genetic/proteomic variants and all available phenotypic information in the estimation of association between genome-phenome and detection of pleiotropy.Phenomics is a recently developed new transdiscipline that provides a suite of new technologies and platforms for the transition from focused phenotype-genotype study to a systematic phenome-genome approach,which can be used to redefine the clinical phenotypes of diseases.Accordingly,disease will be defined as a clinical phenome that is the sum total of a patient′s clinical characteristics or phenomic traits that signify the expression of the whole genome,proteome,and metabolome under specific environmental influence.With the fast advance and development of big-data technology and phenomics,we believe that the application of PheWAS in medicine opens important avenues to enhance systematically-integrated analysis of the genomic basis of human disease and responses to drug therapy and to reform our understanding and clinical treatment of diseases with a new concept of wholism.With well-defined clinical disease phenome,a new transdiscipline termed″pharmacophenomics″has been emerging.As a complement of pharmacogenomics,pharmacoproteomics,and pharmacometabolomics,pharmacophenomics offers a suite of new technologies and platforms for the transition from focused phenotype-genotype study to a systematic phenome-genome approach and refine drug research with systematically-defined drug response and therapeutic targets.Therefore,pharmacophenomics will provide a new paradigm for the study of drug response including effects and toxicities at the level of systems biology and will identify the corresponding therapeutic targets suitable for personalized medicine.     

白芍煎剂在大鼠体内的药物动力学

采用高效液相色谱法测定大鼠静脉注射芍药苷和灌胃给予白芍煎剂后血浆中芍药苷浓度,静脉注射后的数据经3P87处理,灌胃后的数据以非隔室模型处理.结果表明大鼠静脉注射芍药苷(15mg/kg)后,血药浓度时间曲线符合二室模型,药动学参数为T1/2α=26min,T1/2β=274min.大鼠灌胃白芍煎剂(相当于芍药苷850mg/kg)后,生物利用度为F=312%,Tmax=102min,Cmax=993mg/L.大鼠灌胃白芍煎剂后芍药苷的绝对生物利用度仅为3%,提示芍药苷有可能发生了生物转化.     

黄芩汤配伍使用白芍、赤芍抗溃疡性结肠炎作用比较

目的 基于网络药理学分析和动物实验比较黄芩汤配伍使用白芍、赤芍抗溃疡性结肠炎(ulcerative colitis,UC)的作用差异。方法 从TCMSP数据库和文献中检索白芍与赤芍活性成分,通过Swiss Target Prediction预测潜在靶点;以Ulcerative Colitis为关键词在DisGenet、OMIM、Genecard数据库检索疾病靶点;利用Venny 2.1.0获取交集靶点,Cytoscape 3.7.2软件构建“药物-成分”靶点网络,STRING平台进行蛋白质互作(protein-protein interaction,PPI)网络分析,Metascape数据库进行GO/WIKI分析。采用葡聚糖硫酸钠(dextran sulfate sodium,DSS)诱导建立UC小鼠模型,观察分别黄芩汤配伍使用白芍(HQT-BS)和赤芍(HQT-CS)对UC的防治作用,并比较异同。结果 HQT-BS、HQT-CS治疗UC的活性成分别有7,11个,其中共有成分5个;靶点分别有146,157个,其中共有靶点106个,HQT-BS核心靶点为SRC、HSP90AA1、PIK3...     

Pharmacokinetic interactions between indomethacin and paracetamol in the rat

The influence of concurrent administration of paracetamol with indomethacin on the plasma concentrations of these drugs was studied in rats. Orally administered paracetamol reduced the plasma levels of indomethacin during the first 2 hours after oral administration. Later, 16 and 24 hours after administration of indomethacin, the plasma levels exceeded the control values due to the concurrent oral administration of paracetamol. These data suggest that paracetamol delayed the absorption of indomethacin. In contrast the plasma concentrations of paracetamol were not influenced substantially by indomethacin. When paracetamol was co-administered subcutaneously with oral indomethacin, the plasma levels of the latter drug were not influenced. It is concluded that the protective effect of paracetamol against the gastric injuring side effect of indomethacin, which also occurs with subcutaneous administration of paracetamol, cannot be solely due to lowered plasma concentrations of indomethacin.     

中药防风抗肝癌作用及机制的网络药理学和细胞实验研究

目的: 应用网络药理学和细胞实验,探究中药防风提取液的抗肝癌效应及可能机制,为防风在抗肝癌的临床应用提供依据。方法: 应用网络药理学方法筛选防风抗肝癌的有效成分及相应靶点,并建立"药物-成分-靶点"可视化网络;采用富集分析筛选信号通路;利用Autodock Vina软件验证效应成分与肝癌相关靶点结合力,MTT法测定细胞增殖率,流式细胞术检测细胞凋亡率,Western blot检测相关蛋白表达。结果: 通过多种数据库共筛选得到防风抗肝癌的15种有效成分和AKT1、CASP3、TP53、JUN、IL-6前5个核心靶点基因。富集分析显示细胞凋亡通路尤为集中。前5位的有效成分与核心靶点对接,结果显示其结合能均小于-20.92 kJ·mol^-1。与空白对照组比较,24和48 h时防风提取液对HepG-2细胞的抑制率随浓度升高而增大;细胞凋亡率亦升高;同时促使Caspase-3蛋白磷酸化,提高Bax/Bcl-2比值。结论: 防风提取液可抑制人肝癌细胞 HepG-2 的增殖,诱导人肝癌细胞 HepG-2凋亡,且呈剂量、时间依赖性,其作用机制可能是通过上调HepG-2细胞内Bax蛋白表达、下调Bcl-2蛋白并促进Caspase-3蛋白磷酸化发挥作用。     

ICP-MS法比较矿物类中药在传统饮片和中药配方颗粒中微量元素的含量

本文采用电感耦合等离子体质谱(ICP-MS)结合微波消解的方法,比较煅龙骨、煅牡蛎、生石膏、滑石、芒硝、代赭石、琥珀、瓦楞子等8种矿物类中药传统饮片和其配方颗粒中微量元素铅、铜、锰、镍、铬、锌、砷、锑、镉的含量.结果表明矿物类中药和其配方颗粒的微量元素含量存在一定差异.     

赤芍与辛芍组方中没食子酸、芍药内酯苷在大鼠体内的药动学比较

目的建立UPLC-MS法,进行辛芍组方与单味赤芍提取物没食子酸、芍药内酯苷大鼠药动学研究,探讨中药复方对药效成分体内过程的影响。方法色谱采用Waters BEH C18柱,0.1%甲酸乙腈-0.1%甲酸水梯度洗脱,质谱采用电喷雾电离源(ESI),扫描方式为选择性离子监测(SIR)。实验大鼠分别灌胃辛芍组方、赤芍提取物,测定不同时间点大鼠血浆没食子酸和芍药内酯苷浓度,采用DAS2.0药动学软件对参数进行拟合。结果没食子酸和芍药内酯苷线性关系、精密度、准确度和稳定性良好。没食子酸、芍药内酯苷在大鼠体内符合二室药动学模型,赤芍和辛芍组方两组没食子酸T max和T1/2z差异无显著性,芍药内酯苷的各药动学参数均具有一定差异。结论中药组方与单味药材体内药动学之间存在差异,其产生的原因可能与复方间的相互配伍以及复方组成有关。     

Pharmacokinetic interaction between carbamazepine and neuroleptics after combined prolonged treatment in rats

Summary This study investigates how neuroleptics of phenothiazine or thioxanthene structure influence the pharmacokinetics of carbamazepine. Experiments were carried out on male Wistar rats. Carbamazepine and the neuroleptics were administered i.p., separately or together, for 2 weeks in the following daily doses (mg/kg): carbamazepine 15 during the 1st week of treatment and 20 during the 2nd week of treatment, promazine 10, chlorpromazine 2, perazine 10, chlorprothixene 2, flupenthixol 0.5. One hour after the last injection of carbamazepine and/or the neuroleptic, samples of blood plasma and brain were taken to determine the concentrations of carbamazepine and two of its metabolites: 10,11-epoxide and trans- 10,11-diol.The neuroleptics increased the concentration of carbamazepine in plasma and in brain, but tended to decrease (with the exception of chlorpromazine) the concentration of the epoxide and increased the concentration of trans-10,11-diol.Metabolic in vitro studies did not show any significant differences between rats treated with carbamazepine alone and those treated with carbamazepine plus neuroleptic in the rates of the carbamazepine epoxidation, of 10,11-epoxide hydrolysis or of 1-naphthol glucuronidation. Send offprint requests to W. Daniel, Polish Academy of Sciences, Institute of Pharmacology, 12 Smetna Street, PL-31-343 Krakow, Poland