Journal of Chinese Pharmaceutical Sciences

A synopsis on flavonoids from the roots of Scutellaria baicalensis with some insights on baicalein and its anti-cancer properties

Eric Wei Chiang Chan, Siu Kuin Wong, Joseph Tangah, Tomomi Inoue, Hung Tuck Chan

2019, 28(4): 217-228. DOI: 10.5246/jcps.2019.04.022

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Flavones are the most dominant type of flavonoids isolated from the roots of Scutellaria baicalensis (Radix Scutellariae),which is a traditional medicinal plant in East Asian countries, including China, Japan and Korea. Most of the flavones are derivativeswith methoxyl and hydroxyl groups, and they include baicalein, baicalin, chrysin, norwogonin, oroxylin A and wogonin. Baicalein possesses anti-cancer activities against a wide spectrum of human cancer cells by inducing apoptosis and cell cycle arrest, and by inhibiting angiogenesis, metastasis and inflammation. Some examples of the effects of baicalein on apoptosis, cell cycle arrest and metastasis are presented with discussion on the molecular targets and pathways. Studies on the structure-activity relationships of flavonoid cytotoxicity towards human cancer cells show that the potent cytotoxic activities of baicalein can be attributed to its -OH groupsat C5, C6 and C7 (triple hydroxylation) of ring A, carbonyl group at C4 of ring C, and C2–C3 double bond of ring C.Studies on structural modifications of baicalein have shown that the configurations at C6 of ring A are critical factors influencing its anti-proliferative activity. Considering the remarkable anti-cancer properties, the future prospects for developing baicalein into an anti-cancer drug are promising.

Inhibitory effect of the combination of notoginseng total saponins and safflower total flavonoids on UDP-glucuronosyltransferases 1A1, 1A4, and 2B7 in human liver microsomes

Yan Li, Yuqing Meng, Yingyuan Lu, Kun Chang, Peng Gao, Yong Jiang, Pengfei Tu, Xiaoyu Guo

2019, 28(4): 229-237. DOI: 10.5246/jcps.2019.04.023

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In the present study, the potential inhibition behaviors of notoginseng total saponins (NS), safflower total flavonoids (SF), and their combination (CNS) towards three major isoforms of UDP-glucuronosyltransferases (UGTs) in human liver microsomes (HLMs) were investigated to study the mechanism of the synergistic effect of CNS. Etoposide, trifluoperazine and azidothymidine were selected as the probe drugs to elucidate the activities of UGT1A1, 1A4 and 2B7 by UPLC-MS/MS method, respectively. The results showed that CNS, NS and SF significantly inhibited the activities of UGT1A1, 1A4 and 2B7 (P<0.05)with the IC₅₀values less than 30 mg/mL. Furthermore, the inhibitory effects of CNS towards UGT1A1, 1A4 and 2B7 were stronger than those of NS and SF (P<0.05). In conclusion, the combination of NS and SF could increase their inhibitory effects on UGT1A1, 1A4 and 2B7 activities in HLMs and might be conducive to reduce the phase II metabolism of the effective constituents in CNS. The potential herb-drug interactions of CNS based on UGT enzymes provided a useful experimental basis for its further research and development.

IMB-XH1 identified as a novel inhibitor of New Delhi metallo-β-lactamase-1

Jiangxue Han, Chunling Xiao, Maoluo Gan, Xinghua Li, Ying Wang, Jiayin Zheng, Dongsheng Li, Chennan Liu, Yan Guan, Jianzhou Meng, Shuchao Huang, Yishuang Liu

2019, 28(4): 238-246. DOI: 10.5246/jcps.2019.04.024

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The problem of drug resistance of Gram-negative bacteria has become increasingly serious and has aroused widespread public concern. The “super bacteria” producing New Delhi metallo-beta-lactamase (NDM-1) are resistant to almost all β-lactam antibiotics. However, clinically existing β-lactamase inhibitors are ineffective against metallo-β-lactamases (MBLs) including NDM-1. Therefore, effective NDM-1 inhibitors are urgently needed. In this study, a high-throughput screening model for NDM-1inhibitors was optimized and used to screen NDM-1 inhibitors. As a result, IMB-XH1 was screened out as a novel NDM-1 inhibitor from 52 100 compounds of different sources. The combined use of IMB-XH1 can increase the sensitivity of E. coli BL21(DE3) (pET-30a(+)-NDM-1) to β-lactam antibiotics. Enzymatic kinetic studies indicate that IMB-XH1 is a non-competitive inhibitor of NDM-1 and also has inhibitory activity against other MBLs such as IMP-4, ImiS and L1. As a novel NDM-1 inhibitor, its activity and mechanism of action need to be further explored.

Synthesis and antitumor, antityrosinase, and antiplatelet aggregation activities of xanthone

Beidou Zhou, Xin Wang, Zhimin Weng, Baocheng Huang, Zetong Ma, Bo Yu, Liqin Ruan, Dongbao Hu

2019, 28(4): 247-256. DOI: 10.5246/jcps.2019.04.025

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In the present study, five fluorine substituted and three chlorine substituted 1,3-dihydroxyxanthones were synthesized in one step.The yields ranged from 48% to 72%. Among them, compounds 12 and 15–18 were reported for the first time. The antitumor, antityrosinase and antiplatelet aggregation activities of all or part of compounds 1–19 were evaluated. Compounds 1, 2, 4, 6–7, 10–15 and 19 exhibited enhanced cytotoxicity against certain cancer cells. Compound 10,containing 2,4-difluorophenyl at the C7 position, particularly exhibited superior antitumor activity. The inhibition rate of compound 18 against tyrosinase was approximately 22%. Compounds 1–3, 6, 9, 12 and 18, 19 exhibited obvious inhibitory platelet aggregation induced by ADP in rats. Moreover, the effects of compounds 2 and 3 were more pronounced. These results demonstrated that compounds 1–4, 6–7, 9–15 and 19 were promising leads for further structural modification.

Pharmacokinetic interaction between glucocorticoids and tacrolimus after renal transplantation

Hui Yang, Xiaopeng Hu, Xiongyong Yang, Hang Liu, Liang Ren, Wei Wang, Lihong Liu, Xiaodong Zhang

2019, 28(4): 257-263. DOI: 10.5246/jcps.2019.04.026

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There is an interaction between tacrolimus (TAC) and glucocorticoids where glucocorticoids is a known CYP3A4 and P-gp inducer. However, the dose of glucocorticoids reported is low but not pulse therapy. We retrospectively studied 63 renal transplant recipients receiving TAC after transplantation. All the patients were classified as 500 mg (POD 1–3), 30 mg (POD 4–10), 25 mg (POD 11–17), 20 mg (POD 18–24), 15 mg (POD 25–31), 10 mg (POD 32–60) and 10 mg (POD 61–90). We recorded daily data for each patient from the day of transplantation until POD 90. There was no difference in TAC blood levels within the 3 months after transplantation in the glucocorticoids groups. However, the average daily dose of TAC was significantly lower by weekly reductions of 5 mg dose. The TAC daily dose was not changed from POD 1–4, but the blood concentrations of TAC were significantly lower after the glucocorticoid dose was changed from 500 mg to 30 mg. We demonstrated the induction effect of low-dose glucocorticoids on TAC in renal transplant recipients, and found that the high-dose of glucocorticoids might play a role in substrate competition. We proposed that monitoring of the blood concentrations of TAC was needed when the glucocorticoid dose was changed in the patient undergoing renal transplantation.

Cinobufacini injection for moderate and advanced primary liver cancer: A systematic review and meta-analysis

Zhiyong Dong, Xiantu Qiu, Stacy A. Kujawa, S.M. Shariful Islam, Jie Zhang

2019, 28(4): 264-275. DOI: 10.5246/jcps.2019.04.027

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Cinobufacini, a compound extracted from bufo toad, is a traditional Chinese medicine (TCM) that has been shown to have efficacy in cancer treatment. The cinobufacini injection is widely used in patients with moderate and advanced liver cancer in China. In the present study, we aimed to determine the effects of cinobufacini injection for this specific category of patients.A search for randomized control trials (RCTs) using cinobufacini was conducted in the PubMed, EMBASE, CENTRAL, and the other four major Chinese databases. The systematic review was performed according to the recommendations of the Cochrane collaboration, and the RevMan 5.3. software was used for statistical analysis. A random-effects model was used to perform the data. Risk ratios (RR) with corresponding 95% confidence interval were calculated according to Cochrane handbook.A total of 11 RCTs consisting of 728 patients were included. All of the trials demonstrated significantly improved total response rates, total response rates of Karnofsky Performance Score (KPS), 1- to 2-year survival rates, and quality of life in the intervention groups injected with cinobufacini. There was no statistically significant difference between the groups (cinobufacini versus no cinobufacini; cinobufacini plus transcatheter arterial chemoembolization (TACE) versus TACE only) in terms of the 6-month survival rate, clinical benefit rate and clinical benefit rate of KPS. This systematic review demonstrated the beneficial effects of cinobufacini injection in terms of total response rate and the 1- to 2-year survival rate in patients with moderate and advanced liver cancer. The efficacy for the cinobufacini injection group might be better than that of the control group for treatment of moderate and advanced liver cancer. Given that the majority of the trials were of low quality, more high-quality prospective RCTs with strict design in accordance with CONSORT for TCM are needed.

Design and implementation of mobile APP for medication guidance related to pharmacogenomic based on APICloud platform

Min Chen, Feng Jiang, Ming Zheng, Limei Yang, Hongjin Gao

2019, 28(4): 276-283. DOI: 10.5246/jcps.2019.04.028

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The mobile APP for medication guidance related to pharmacogenomic is developed to solve various practical problems, such as inconvenient reading of English database, slow updating of paper reference books and lack of shortcut for access. We extracted the medication guidance information related to the pharmacogenomic from ‘Dosing Guidelines’ (http://www.pharmgkb.com), ´Table of Pharmacogenomic Biomarkers in Drug Labeling´ (http://www.fda.gov/drugs/scienceresearch) and relevant authoritative books. SQLite was used to build the medication guidance information database. We designed and implemented a mobile APP for medication guidance by JavaScript programming language. The APP contained 197 drugs that have been extensively studied and have high levels of evidence. It covered 25 categories, such as anticoagulant and antiplatelet drugs, general antitumor, immunosuppressant drugs, targeted antitumor drugs, antipsychotic drugs, antiepileptic drugs, and proton pump inhibitors and so on. Users can obtain clinical significance and guidance information related to the genotype of the drug by entering the pinyin initials of the generic name of the drug. The mobile APP for medication guidance related to pharmacogenomic based on APICloud could provide practical and convenient pharmaceutical information service for clinical use.

Professor Yanxing Jia’s team has made continuous breakthroughs in the field of total synthesis of complex natural products

School of Pharmaceutical Sciences, Peking University Health Science Center

2019, 28(4): 284-286.

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