Table of Content

    22 January 2017, Volume 26 Issue 1
    Newly developed drugs invented to treat tuberculosis in clinical trial
    Mohammad Asif
    2017, 26(1):  1-22.  DOI: 10.5246/jcps.2017.01.001
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    Tuberculosis (TB) is a leading cause of morbidity and mortality in more than one-third of the world population. Its impact on global health is a result of decades of neglect for such an important infectious disease, lack of resources for national TB control programs, poor case detection, and inadequate/inappropriate therapy in high-burden countries. The worldwide dissemination of multidrug (MDR) and extensively drug resistant (XDR) Mycobacterium tuberculosis poses a serious threat to human health due to inadequacy of long and cumbersome tuberculosis (TB) therapy. Treatment regimens consist of at least four drugs with different mechanisms of action. Several new molecules in clinical development hasencouraged the scientific community to discover new drug targets and new drug candidates. Therefore, new drugs are urgently needed to shorten and improve the treatment course in drug resistant TB, and to minimize the occurrence of new infections and death. Nowadays, various new investigational drugs, such as bedaquine (TMC207), nitroimidazoles (PA-824, OPC-67683), diamines (SQ109), oxazolidinones (Linezolid, PNU-100480 (Sutezolid), ADZ5847), pyrroles (LL3858) and fluoroquinolones (moxifloxacin and gatifloxacin), have entered clinical trials and are in progress to be developed for the treatment of MDR-TB. In this perspectivearticle, an overview of the new anti-TB drugs with different structures that are either being clinically used or in advanced stages clinical stages as well as of preclinical development are presented. This review provides snapshots of the efforts that are being made in the development of new drugs as lead anti-TB agents. Finally, it is crucial to improve the connection between research and development institutes, industries, drug control authorities, and international policy-making bodies to deliver efficacious therapies for patients who are suffering from TB.

    Original articles
    Selective alkylation and bioactivity of phosphorothioated nucleolin aptamer AS1411
    Guangpu Zhang, Jiali Deng, Xiantao Yang, Yuejie Zhu, Zhu Guan, Lihe Zhang, Zhenjun Yang
    2017, 26(1):  23-30.  DOI: 10.5246/jcps.2017.01.002
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    An operationally simple and efficient method for the synthesis of a wide range of alkylated nucleotides under mild conditions was developed. This improved method furnishes alkylated nucleotides from both single nucleotides and oligonucleotides, and were prepared in high yields of 81% to 91%. Alkyl modified aptamer AS1411s were synthesized using this method and the biological activity screening results demonstrated that alkylation at the 1st P-S site on yielded stronger target protein binding capacity, greater growth suppression effects against K562 and HL-60 cell lines, and improved serum stability, as compared with AS1411. This modified aptamer may be useful in tumor detection and treatment.

    Design, synthesis and activity evaluation of novel pyridinone derivatives as anti-HIV-1 dual (RT/IN) inhibitors
    Quanzhi Yang, Tao Sheng, Ningning Fan, Yameng Hao, Yuanyuan Cao, Ying Guo, Zhili Zhang, Chao Tian, Junyi Liu, Xiaowei Wang
    2017, 26(1):  31-44.  DOI: 10.5246/jcps.2017.01.003
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    Three series of novel anti-immunodeficiency virus 1 (HIV-1) dual (RT/IN) inhibitors were rationally designed by introducing a functioning diketo acid (DKA) into pyridin-2-one scaffold. To efficiently analyze inhibitory activity, these compounds were screened against HIV-1 RT and IN respectively via surface plasmon resonance (SPR), and active compounds were subsequently evaluated by enzyme assay. It was noteworthy that compound A2 exhibited moderate activity against both HIV-1 RT and IN. This result provided information for further development of pyridinone analogues as potent dual HIV-1 inhibitors.

    Determination of mefunidone, a novel anti-fibrotic agent analogue of pirfenidone, in plasma by HPLC-UV and its pharmacokinetic application in rats
    Zhou Wen, Shan Ji, Feifan Xie, Gaoyun Hu, Zeneng Cheng
    2017, 26(1):  45-52.  DOI: 10.5246/jcps.2017.01.004
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    Mefunidone (MFD), a pirfenidone analogue, has been suggested as a novel anti-fibrotic agent in preclinical research stage. In this work, we developed a sensitive and specified HPLC-UV method and validated it for the determination of MFD in rat plasma. A cost-effective protein precipitation method using methanol was used to process the plasma samples, and pirfenidone was employed as the internal standard (IS). Chromatographic separation was performed on an Agilent ZORBAX SB-Aq column (4.6 mm×250 mm, 5 μm) with a mobile phase consisting of 10 mM ammonium formate solution (pH 3.0, adjusted by 1.5‰ formic acid)–acetonitrile–methanol (60:23:17, v/v/v) at a flow rate of 1.0 mL/min, and the samples were monitored at an ultraviolet wavelength of 245 nm. The retention times of MFD and IS were 5.5 and 7.8 min, respectively. The calibration curve was linear (r2 = 0.9997) between 0.1 and 20 μg/mL. The intra- and inter-day precisions were within 8.6%, and the bias of intra- and inter-accuracies of the method was between –4.2% and 6.5%. The method was successfully applied to pharmacokinetic study of MFD after i.g. and i.v. administration in rats. The elimination half-life was (3.41±0.81) h for i.g. administration and (2.26±0.87) h for i.v. administration. The absolute bioavailability of MFD in rat was 79.1%.  

    Berberine inhibits mRNA degradation by promoting the interaction between the poly A tail and its binding protein PABP
    Zhiyi Yuan, Xi Lu, Fan Lei, Jun Hu, Yugang Wang, Yushuang Chai, Jingfei Jiang, Huiyu Li, Dongming Xing, Lijun Du
    2017, 26(1):  53-62.  DOI: 10.5246/jcps.2017.01.005
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    Berberine (BBR) is a natural small molecule with various pharmacological activities and biological targets. BBR has been shown to inhibit mRNA decay in our previous studies, which is associated with its high binding affinity to the poly-adenine (poly A) tail at the 3′ end of mRNA. However, the exact mechanism remains unknown. In this research, we discovered that deficiency of cytoplasmic poly A binding protein (PABP), which protects mRNA from nucleolytic attack as a poly A-PABP complex, led to the loss of BBR’s effect on mRNA decay inhibition. We also demonstrated using fluorescence spectroscopy, RNA-EMSA (RNA-electrophoretic mobility shift assay) in vitro, and RIP (RNA immunoprecipitation) that BBR could significantly promote PABP binding to poly A. We might conclude that BBR could stabilize mRNA by enhancing the interaction between poly A and PABP. In addition, the HMBC (1H detected heteronuclear multiple bond correlation) studies demonstrated that BBR could bind to AMP, a monomer of poly A, directly and specifically. Further evidence of molecular docking suggested that BBR might act as a linker to stabilize the poly A-PABP, and elongate the half-life of mRNAs. This demonstrates that BBR might affect protein translation initiation and up-regulate protein expression.

    Drug administration and clinical pharmacy column
    Additive effect of α-ketoacids in chronic kidney disease: a systematic review and meta-analysis of randomized controlled trials
    Ru Han, Yajing An, Rongsheng Zhao
    2017, 26(1):  63-75.  DOI: 10.5246/jcps.2017.01.006
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    α-Ketoacids (KAs) are widely used in chronic kidney disease (CKD), but their efficacy is not clear. Therefore, we conducted a systematic review of the benefits of KAs. Two reviewers independently searched MEDLINE, EMBASE, the Cochrane library (http://www.cochrane.org), CNKI, and Wan Fang databases from inception to May 31, 2016 for randomized controlled trials (RCTs) comparing KAs plus low protein diet (LPD) with LPD only on CKD patients. Statistical analyses were performed using both a random effects model and a fixed effects model with Rev Man 5.3, followed by sensitivity analysis. We identified 21 randomized controlled trials that enrolled a total of 1448 patients. 726 had received LPD plus KAs and 722 had received only LPD. Compared with simply using of LPD, combining with KAs could decrease serum creatinine (95% CI, 0.46–0.96; P<0.00001), serum cholesterol (95% CI, 0.24–0.77; P = 0.02), serum LDL cholesterol (95% CI, 0.12–0.54; P = 0.31), and serum triglyceride (95% CI, 0.28–0.83; P = 0.02) while increasing serum HDL cholesterol (95% CI, -1.73–0.07; P<0.00001). Likewise, a decrease in P3– (95% CI, 0.90–1.26; P<0.00001) and PTH (95% CI, 0.70–1.21; P = 0.007) were observed. No hypercalcemia and other ARD or toxicity was reported, which indicated the safety of KAs. Nevertheless, the studies were pooled with considerable heterogeneity. In patients with CKD, there was low-quality evidence suggesting that KAs may perform an additive effect on the improvement of renal function, lipid profile, as well as the correction of calcium-phosphate metabolism disorders. On account of the considerable heterogeneity of the meta-analysis and the costly price and adherence of KAs administration, KAs’ roles in the management of mild or moderate CKD patients may need more RCTs of large scale and high quality to confirm.

    Information for Authors
    Journal of Chinese Pharmaceutical Sciences
    2017, 26(1):  76-85. 
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