Journal of Chinese Pharmaceutical Sciences

Model-based meta-analysis of pharmacokinetics of direct-acting antiviral agents, ledipasvir and sofosbuvir, in healthy subjects and chronic HCV patients

Hechuan Wang, Liang Li, Yupeng Ren, Tianyan Zhou, Wei Lu

2015, 24(12): 773-779. DOI: 10.5246/jcps.2015.12.099

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A tablet consisting of direct-acting antiviral agents, ledipasvir (a NS5A protein inhibitor) and sofosbuvir (a NS5B polymerase inhibitor), is the first fixed-dose preparation used in the antiviral therapy of hepatitis C. A model-based meta-analysis of ledipasvir and GS331007, the primary metabolite of sofosbuvir, enabled the integration of pharmacokinetic (PK) information from separate clinical trials and the quantitative characterization of the population pharmacokinetics of these two drugs. A systematicpublication search was conducted for the clinical studies of ledipasvir and sofosbuvir. A total of 401 arm-level aggregate concentrations of GS331007 and 188 concentrations of ledipasvir were used for PK modeling. A two-compartment disposition model was used for both ledipasvir and GS331007. Zero-order absorption was applied for ledipasvir PK modeling, and a combined zero- and first-orderabsorption was used for the modeling of GS331007. Absorption lag was observed in concentration-time profiles of both ledipasvirand GS331007. To aid the development of direct-acting antiviral drugs, our established PK models provided a basis for the further PK-viral kinetic studies of ledipasvir and sofosbuvir.

Bioavailability of 10-hydroxycamptothecin-phospholipid complex loaded by solid dispersion and lipid-based formulations

Xianchuang Wu, Haijun Hao, Yuxin Liu, Xiaoyong Song, Yongzhou Zhang, Hongqin Zhang

2015, 24(12): 780-788. DOI: 10.5246/jcps.2015.12.100

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Previous study has shown that 10-hydroxycamptothecin (HCPT) has well-established pharmacological effectsin vitro. However, its in vivo bioavailability is very poor due to various problems, which severely restricts its clinical applications. In the present study, phospholipid complex (PC) technology was employed to improve the solubility and bioavailability of HCPT. XRD data confirmed the formation of HCPT-PC. However, our previously prepared HCPT-PC is too sticky, which may result in the slow dissolution rate and negative effects on its absorption. Therefore, we prepared HCPT-PC-solid dispersion (HCPT-PC-SD) and lipid-based formulations of HCPT-PC through simple preparation process. The results showed that the dissolution rate of HCPT-PC was effectively improved by solid dispersion technology, which reached 91.73% in 45 min. Pharmacokinetic study revealed that the AUC₀_–_tof HCPT-PC-SD and HCPT-PC lipid-based formulations was effectively further increased compared with HCPT-PC. Moreover, we found that the combination of SD technology and lipid-base formulations could be a promising drug-delivery system to improve the oral bioavailability of HCPT-PC. In addition, we showed that the bioavailability of HCPT-PC lipid-base formulations was even greater than that of HCPT-PC-SD. In particular, lipid-base formulations could be prepared just by a simple method, suggesting its feasibility of industrialization.

An Ac-SDKP analogue resistant to angiotensin converting enzyme exhibits anti-fibrosis effects and improves heart function in mice after myocardial infarction

Jianhui Chen, Xiaowen Ma, Zhao Zhang, Yingqi Zhang, Yuan Yuan, Meng Li

2015, 24(12): 789-800. DOI: 10.5246/jcps.2015.12.101

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To explore the effect of an Ac-SDKP analog on left ventricular remodeling after myocardial infarction, we synthesized the analog Ac-SD_DK_DP by replacing Asp and Lys with their D isomers. The biological activities of Ac-SD_DK_DP were conﬁrmed using ﬂow cytometry, qRT-PCR, Western blots and ﬂuorescence microscopy. The protective effects of Ac-SD_DK_DP on infarcted hearts were assessed in mice with myocardial infarction (MI). The half-life of Ac-SD_DK_DP was prolonged to over 2 h from a few minutes that Ac-SDKP has. Compared with Ac-SDKP, the analog exhibited stronger inhibition on the differentiation of macrophages, expression of arginase I (ARG I) and TGF-β1 in mature macrophages, proliferation and secretion of collagen type I in cardiac fibroblasts. In MI mice mode, Ac-SD_DK_DP decreased collagen deposition and TGF-β1 expression in myocardium, thus improvingthe FS (%) to 23.0±7.8 compared with 11.2±6.2 in untreated mice and 11.7±5.3 in Ac-SDKP treated mice (P<0.05). This work shows that the Ac-SDKP analogue is potentially useful for protective treatment for heart failure post-MI. In addition, the anti-fibrosis mechanism of Ac-SDKP was correlated with the alternative activation (M2) of macrophages by assessing ARG I and TGF-β1, two important fibrosis-related molecules secreted in M2 macrophages.

Design and synthesis of 1-substituted-β-carboline derivatives as potential anticancer agents

Liang Guo, Wenxi Fan, Ziyun Gan, Wei Chen, Qin Ma, Rihui Cao

2015, 24(12): 801-808. DOI: 10.5246/jcps.2015.12.102

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In the present study, we designed and synthesized a series of 1-substituted-β-carboline derivatives through modification of position-1, 2 and 9 of β-carboline nucleus in order to discover novel leading compounds with better antitumor activities and less toxicity. Their structures were confirmed by ¹H NMR, ¹³C NMR, MS, IR and elemental analyses. All the target compounds were tested for cytotoxic activity against six cancer cell lines, including Bel-7402, HepG2, A549, A375, 786-0 and HT-29 by methyl thiazolyl tetrazolium (MTT) method. Studies of structure-activity relationships indicated that the effects of substituents in position-1 on cytotoxic activities were in an order as follows: 2-thienyl >2-chlorophenyl >4-chlorophenyl >benzyl group.

Qualitative analysis of the chemical constituents of Lonicera japonica and its tetraploid cultivar Jiufengyihao

Xiao Zhang, Qing Guo, BoyangYu, Ming Li, Lixia Huo, Junjun Wang

2015, 24(12): 809-815. DOI: 10.5246/jcps.2015.12.103

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In the present study, we, for the first time, developed an UPLC-IT-TOF/MS method to compare the chemical constituentsof the flower buds of Lonicera japonicaThunb. (Jinyinhua, JYH, in Chinese) and its tetraploid cultivar Jiufengyihao (JFYH). The samples were separated on a C₁₈ ultra-column (100 mm×2.1 mm, 1.8 μm) eluted with a mixture of acetonitrile and 0.1% formic acid using a gradient program. Based on the accurate masses, fragmental MS² ions and fragmentation pathway, we unambiguously affirmed or tentatively identified 30 compounds, including 11 phenolic acids, 10 iridoid glycosides, 8 flavonoids and 1 saponin, from JYH and JFYH. Among them, all compounds were detected in Lonicera japonica, but only 21 compounds were detected in JFYH. In addition, the relative contents of the 21 common chemical constituents were also different in JYH and JFYH, suggesting an obvious chemical difference between JYH and JFYH.

Origin, development and current status of pharmaceutical education steering organizations in China

Qing Yang, Jing Wang, Yongze Zhang, Jing Chen, Mingli Shao

2015, 24(12): 816-820. DOI: 10.5246/jcps.2015.12.104

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Pharmaceutical education in China has evolved from the stages of scale expansion to quality improvement. In order to improve the quality and provide guidance for pharmaceutical education, the Ministry of Education has successively established several pharmaceutical education steering committees. The establishment and development of these committees are closely related to the current development of pharmaceutical education and industry in China. They have prompted the development of pharmaceutical education by providing guidance on related theories, policies, experience and information. This article is to present the establishment, development, current status and memberships of pharmaceutical education steering committees in China.

Institutional changes of China's drug regulation and improvement solutions

Lujia Chen, Guozhen Liu, Guo Huang, Dongsheng Yang, Bin Jiang

2015, 24(12): 821-825. DOI: 10.5246/jcps.2015.12.105

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Drug regulation is the most important policy to ensure drug safety. In this article, we analyzed institutional changes and problems in China’s drug regulation. In addition, suggestions were provided to enhance the capacity of drug regulation, including a clearer functional positioning for drug regulation, increased resource inputs in drug regulation at central level, a more rational allocation of vertical drug regulatory functions, and an improved supervision mechanism for regulatory departments.