Journal of Chinese Pharmaceutical Sciences

Design, synthesis and biological evaluation of novel quinoline [4,3-b]chromene derivatives as AChE inhibitors through an efficient one-pot, four-component microwave-mediated reaction

Ming He, Baohua Xie, Pei He, Haibing Zhou, Shengtang Huang, Chune Dong

2018, 27(11): 735-752. DOI: 10.5246/jcps.2018.11.075

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An efficient synthesis of chromeno[4,3-b]quinoline derivatives via one-pot, four-component reaction of 4-hydroxycoumarin, formaldehyde, cyclohexanedione, ammonium ceric nitrate under microwave irradiation was accomplished. The structures of these compounds were unambiguously confirmed by single crystal X-ray diffraction. Furthermore, the anti-AChE activities of these compounds in vitro were investigated at concentrations of 20 μM and 50 μM by using a standard Ellman’s method. The relationship of inhibitory activities and structures of these chromeno [4,3-b]quinolines was also systematically studied. Of all the compounds investigated, 4ag emerged as the most potent AChE inhibitor with IC₅₀ values of 5.63 µM, and it might be used as potent lead for the development anti-AChE agents. Moreover, molecular modelling was conducted to understand the optimal interaction of AChE with these types of compounds.

Synthesis of 4-aminoantipyrine Schiff bases and their antimicrobial activities

Olatunde S. Oladeji, Monisola I. Ikhile, Carine M. D. Fotsing, Messai Mamo, Patrick G. Ndungu, Derek T. Ndinteh

2018, 27(11): 753-766. DOI: 10.5246/jcps.2018.11.076

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Various compounds of 4-aminoantipyrine Schiff bases (M₁–M₁₂) were synthesized via a condensation reaction of 4-aminoantipyrine with different benzaldehydes through a conventional method of refluxing the mixture for 3–4 h. The synthesizedSchiff bases were characterized by using elemental analyses, FT-IR, UV-Vis, Mass, ¹H and ¹³C NMR spectroscopy. The antimicrobial activity of the synthesized Schiff bases was investigated against 12 bacterial strains(Mycobacterium smegmatis, Bacillus cereus, Bacillus subtilis, Enterococcus faecalis, Staphylococcus epidermidis, Klebsiella pneumonia, Escherichia coli, Enterobacter cloacae,Klebsiella oxytoca, Proteus vulgaris, Enterobacter aerogenes, and Pseudomonas aeruginosa), and antifungal activities were tested against seven fungal strains (Aspergillus flavus, Aspergillus carbonarious, Aspergillus parasiticus, Aspergillus fumigatus,Aspergillus niger, Fusarium verticillioides and Fusarium proliferatum). The antimicrobial activities of the synthesized compounds were compared with standard streptomycin and nalidixicacid. The results obtained from antibacterial assay indicated that M₁–M₁₂ inhibited potential growth of Proteus vulgaris with minimum inhibitory concentrations (MICs) ranging from 15.6–250 µg/mL compared with the standard nalidixic acid with an MIC of 500 µg/mL. Moreover, we could conclude that most of the tested compounds experienced mild to low activities at 15.6 µg/mL. Their activities could be attributed to their low concentrations.The antifungal analysis showed that the tested fungi were not sensitive to the prepared Schiff bases at the prepared concentration of 500 µg/mL. Therefore, we recommended further analysis on both cytotoxicity and minimum bactericidal concentration (MBC) to ascertain their potential effects against human cells.

Simulation-based simplification of target-mediated drug disposition model of denosumab

Yu Fu, Ye Yao, Peiming Ma, Xuan Zhou, Wei Lu, Tianyan Zhou

2018, 27(11): 767-776. DOI: 10.5246/jcps.2018.11.077

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Target-mediated drug disposition (TMDD) model is one of the main modeling theories for studying nonlinear pharmacokinetics (PK) of monoclonal antibodies. However, there are too many parameters in full TMDD model to be estimated based on limited clinical data, leading to instability of the final model. In the present study, we analyzed the predictive ability and applicability of a simplified quasi-steady state (QSS) model with the assumption that the total target concentration was a constant parameter during treatment with monoclonal antibody in clinical data modeling. Based on the parameters of a published TMDD model of denosumab, simulations were performed at population and individual levels. Then, a simplified TMDD model, QSS model, was used to examine the effects of hypotheses, in which the total receptor concentration was constant or variable on model fit and stability of parameter estimation. Both simulations at the population level and model fit results of simulated individual data showed that at the therapeutic doses, the total receptor concentration had little influence on changes in drug concentration, and the model with constant total receptor concentration had the same predictive power. The validated hypothesis could be applied to clinical trial design and selection of the optimal PK model in the development of monoclonal antibodies.

Pharmacokinetics, safety and bioequivalence of intravenous and oral formulations of the antiepileptic drug levetiracetam in healthy Chinese volunteers

Lanlan Hu, Juan Zhou, Huan Zou, Yue Zhang, Jianlin Tang

2018, 27(11): 777-786. DOI: 10.5246/jcps.2018.11.078

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The intravenous formulation of levetiracetam (LEV) has been available in clinical practice worldwide for several years, but not in China. In the present study, we aimed to evaluate the bioequivalence of intravenous and oral LEV (tablet), an antiepileptic drug, in healthy Chinese volunteers. Two randomized, single-dose (1500 mg), open-label, 2-period crossover trials were conducted as follows: study A, 15-min infusion; study B, 45-min infusion. A total of 22 healthy men participated in study A, and 24 healthy men and woman were enrolled in study B. In study A, blood samples were collected after termination of each treatment. In study B, samples were collected after oral or after the start of the intravenous administration. Safety and the ratio of intravenous/oral LEV for AUC_0–t and C_max were evaluated. The 90% confidence intervals of C_max and AUC_0–t ratios for LEV 1500-mg tablets versus 15-min intravenous administration were outside the bioequivalence limits (80.00%–125.00%). For LEV 45-min intravenous administration, bioequivalence versus 1500-mg tablets was within the range for C_max and AUC_0–t. The most frequently adverse event (AE) was somnolence. A total of eight subjects experienced nine mild AEs in study A, and 19 subjects experienced 29 mild AEs in study B. Intravenous infusions (15 and 45 min) of 1500-mg LEV were as well tolerated as the oral tablet. Bioequivalence was demonstrated by 45-min infusions. Therefore, direct conversion from oral to intravenous LEV 1500 mg (45-min infusion), or vice versa, was possible.

Design, preparation and activity evaluation of two novel proteins with thrombolysis or/and neuroprotection

Huan Chen, Danping Zheng, Xiaoyan Liu, Yuanjun Zhu, Yinye Wang

2018, 27(11): 787-798. DOI: 10.5246/jcps.2018.11.079

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We hypothesized that thrombolysis in combination with neuroprotection might have better therapeutic effects for ischemic stroke compared with thrombolysis alone. In order to verify such hypothesis, we designed a protein TBN by fusing NR6 and BH4, which possibly had dual functions of thrombolysis and neuroprotection. NR6 was obtained by introducingtwo RGD motifs to thrombolytic protein AcAP5 to target thrombus. BH4 is the key domain of anti-apoptotic protein Bcl-xL. The DNA fragments encoding TBN and NR6 were synthesized and cloned into pET30a and pET16b vectors, respectively. Both proteins were expressed in E. coli. BL21 (DE3), mainly in the form of inclusion bodies. With His-tag, NR6 was purified by nickel affinity chromatography, while TBN was purified by ion exchange chromatography. Purified proteins were refolded by dialysis assay. The thrombolytic activity of both proteins was evaluated by the rat arteriovenous bypass model. Both NR6 and TBN significantly reduced thrombus weight at higher dose (24 nmol/kg), TBN showed similar effect to NR6. These results suggested that NR6 was a thrombolytic protein, and fusion protein TBN reserved the thrombolytic activation of NR6. The effects of both proteins were also evaluated in thromboembolic middle cerebral artery occlusion (eMCAO) in mice. TBN exhibited better effect on reducing infarction volume and inhibiting apoptosis of cells than NR6, indicating that the introduction of BH4 increased the protective effect of NR6. The hemorrhagic side effects of the two proteins were evaluated by tail bleeding in mice, and it was found that NR6 and TBN showed shorter bleeding time compared with tPA. In conclusion, we designed and prepared the two novel proteins, and testified that they had significant thrombolytic effect and protective effect on cerebral IR injury. The protective effect of TBN was more potent than NR6. Their bleeding side reaction might be weaker than tPA. These results suggested that these two novel proteins deserved to be further investigated as new thrombolytic candidate agents.

Effects of drug procurement under cap price policy in Sanming

Ting Yin, Bin Jiang

2018, 27(11): 799-804. DOI: 10.5246/jcps.2018.11.080

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To study the effects of drug procurement under cap price policy (DPUCP) in Sanming, changes in drug category, price, availability and corporate structure were analyzed using purchasing data of the 7^th and 8^th centralized drug procurement in Fujian Province and the 1^st drug procurement under cap price in Sanming, and a field investigation was conducted. (1) The amounts of bid-winning drugs and pharmaceutical makers decreased sharply, leading to optimization of drug category and supplier structure. (2) The procurement could meet clinical demands, though a small percentage of drugs were out of stock. (3) Drug prices fell in general, with 10% decline in domestic drugs with a unit package price over RMB 5 yuan, a slight price reduction in imported drugs, and some price increase in cheap domestic drugs with a unit package price under RMB 3 yuan. DPUCP policy in Sanming optimized procurement drug category and supplier structure, reduced price, and improved industrial structure. However, problems still existed, such as shortage of some drugs and little price reduction in imported and brand-name drugs.

Brief introduction for search and determination of the comparator product for generic medicinal product application in the EU

Jianzhao Niu, Dongsheng Yang, Mingdi Xu

2018, 27(11): 805-812. DOI: 10.5246/jcps.2018.11.081

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It is vital segment to choose the right comparator product during the development and study of generic medicinal product, and this is also definitely specified in the relevant documents from the China Food and Drug Administration (CFDA) that the comparator product should be innovator product or internationally recognized same medicinal product, which is used in the re-evaluation of generic medicinal product or marketed authorization application of the generic medicinal product. To facilitate the domestic and foreign pharmaceutical enterprises to choose and determine comparator product, four medicinal product evaluation procedures, as well as the corresponding marketed medicinal product list, are detailed elaborated in this paper. At the same time, by taking the Mifepristone Tablet (200 mg) as example, the search and determination process of the comparator product for generic medicinal product application in the EU is illustrated with the combination of different marketed medicinal product lists.

Peking University School of Pharmaceutical Sciences finished the On-Site Review of International Peer Review Team

School of Pharmaceutical Sciences, Peking University Health Science Center

2018, 27(11): 813-814.

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