Table of Content

26 November 2016, Volume 25 Issue 11

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Review

Influence of voriconazole on pharmacokinetics and safety of combined drugs: a systematic review

Yuanyuan Liu, Shuyao Liang, Ken Chen, Fan Zhang, Fang Liu

2016, 25(11):  785-798.  DOI: 10.5246/jcps.2016.11.088

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We performed a systematic review to evaluate pharmacokinetics changes of drugs when concomitantly used with voriconazole, including randomized controlled trials (RCTs), randomized cross-over trials, self-controlled before-and-after studies, cohort studies and case reports. Literature databases, including Medline, Embase, Cochrane library, were searched to identify eligible studies (until Jan, 2016). A modified risk of bias tool specially developed in this research was used to evaluate the quality of pharmacokinetic randomized crossover trials and self-controlled before-and-after studies. Cochrane risk of bias tool provided by Cochrane Library and Cochrane Reviewer’s handbook was used to evaluate the quality of RCTs and non-randomized controlled studies. Pharmacokinetic parameters, such as area under curve (AUC), C_min, and C_max before and after using voriconalzole were collected. Meta-analysis was conducted to synthesize results if possible. Among 41 studies included in our search, 17 were randomized crossover trials, 3 were RCTs, 13 were self-controlled before-and-after study (SBAs), 1 was cohort studies and 7 were case reports. A total of 12 classes of drugs were involved, including opiates, non-steroidal anti-inflammatory drugs (NSAIDs), psychopathic drugs, anti-HIV drugs, immunosuppressors, oral contraceptive, digoxin, warfarin, oral hypoglycemic agents, antihypertensive agents, lipid regulating agents and cytotoxic agents. According to our results, the impacts of voriconazole on tilidine, buprenorphine, etoricoxib, meloxicam, venlafaxine, midazolam, zolpidem, etravirine and sirolimus were different from the package insert. Our systematic review provided comprehensive data on the pharmacokinetics changes of drugs when used in combination with voriconazole.



Original articles

Cabozantinib enhances the response of NSCLC cells with wild-type EGFR to erlotinib and pharmacodynamic modeling of their sequential combinations

Zhenzhen Mou, Siyuan Wang, Qinghong Su, Yin Yuan, Jingyun Li, Lijie Wang, Qingyu Yao, Shuangmin Ji, Wei Lu, Tianyan Zhou

2016, 25(11):  799-813.  DOI: 10.5246/jcps.2016.11.089

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The epidermal growth factor receptor (EGFR)—tyrosine kinase inhibitors (TKIs) monotherapies have limited efficacy in the treatment of EGFR mutation-negative non-small cell lung cancers (NSCLCs). In the present study, we aimed to investigate the combined effect of erlotinib (ER) and cabozantinib (CAB) on NSCLC cell lines harboring wild-type EGFR and to optimize the dosage regimens using pharmacodynamic (PD) modeling and simulation. Therefore, we examined the combined effect of ER and CAB on cell viability, cloning, apoptosis induction, migration and growth dynamics in H1299 and A549 cells. PD modeling and simulation were also performed to quantitatively describe the H1299 cells growth dynamics and to optimize the dosage regimens as well. Our results showed that CAB effectively enhanced the sensitivity of both cell lines to ER. The PD models fitted the data well, and some important parameters were obtained. The exponential (λ₀) and linear (λ₁) growth rates of H1299 cells were 0.0241 h^–1 and 360 cells·h^–1, respectively. The E_max of ER and CAB was 0.0091 h^–1 and 0.0085 h^–1, and the EC₅₀ was 0.812 μM and 1.16 μM, respectively. The synergistic effect observed in the experiments was further confirmed by the estimated combination index φ (1.37), (95% confidence interval: 1.24–1.50), obtained from PD modeling. Furthermore, the dosage regimens were optimized using simulations. In summary, both the experimental and modeling results demonstrated the synergistic interaction between ER and CAB in NSCLCs without EGFR mutations. Sequential combinations of ER and CAB provided an option for the therapy of the NSCLCs with wild-type EGFR, which would provide some references for preclinical study and translational research as well.



Bis(acetylacetonato)-oxidovanadium(IV) inhibits isoproterenol-induced lipolysis in insulin-resistant 3T3-L1 adipocytes by reducing phosphorylation of perilipin and hormone-sensitive lipase

Xia Hu, Jingcheng Liu, You Yu, Weixia Bian, Xiaogai Yang

2016, 25(11):  814-820.  DOI: 10.5246/jcps.2016.11.090

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Insulin resistance is characterized as one of crucial pathological changes in type 2 diabetes mellitus (T2DM), and dyslipidaemia is frequently detected in T2DM. A variety of vanadium compounds have been studied as drug candidates for diabetes based on their insulin-like action. However, few studies focus on their antilipolytic effect. In the present study, we established an insulin-resistant model in 3T3-L1 adipocytes to mimic pathological conditions of T2DM according to a well-established method by the treatment of high concentrations of glucose and insulin, which was validated by oil red O staining and the decreased levels of phosphorylated Akt, AS160 and GSK3 after insulin treatment. The results demonstrated that bis(acetylacetonato)-oxidovanadium (IV) (VO(acac)₂) could inhibit isoproterenol-stimulated lipolysis through the reduction of the phosphorylated HSL and perilipin levels in both insulin-sensitive and insulin-resistant 3T3-L1 adipocytes. Moreover, although the levels of phosphorylated Akt induced by VO(acac)₂ were decreased, the rates of lipolytic inhibition were not significantly altered compared with those under insulin-sensitive condition, indicating that the anti-lipolytic effect of VO(acac)₂ might also function in an Akt-independent way in insulin-resistant adipocytes. Our work here help elucidate the anti-diabetic effects of vanadium compounds. It may not only shed light on the utility of vanadium-based compounds as potential anti-diabetic drugs but also serve as a useful screening model for new anti-diabetic drugs.



A new method of immobilizing HEK293 cells on the inner wall of a capillary column as stationary phase for drug screening

Xiaodan Zhang, Chen Li, Kai Zhu, Yanmeng Liu, Ruijun Wu, Jinyu Ren, Xiaomei Ling

2016, 25(11):  821-825.  DOI: 10.5246/jcps.2016.11.091

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It is a new strategy to immobilize cells on the inner wall of a capillary column and use affinity capillary electrophoresis (ACE) to study receptor-ligand interactions or to screen natural products and compounds synthesized by combinatorial chemistry. In this paper, we developed a new method of immobilizing HEK293 cells on the inner wall of a capillary column. Four important experimental conditions were optimized, including cell injection density, PLL concentration, cell culturing time and sterile processing method. Immobilized cell-coated capillary columns prepared under the optimized experimental conditions exhibited good uniformity, stability and durability, which were suitable for capillary electrophoresis. The method could also be used to immobilize HEK293 cells over-expressing certain membrane receptors on the inner wall of a capillary. In this way, cell-coated capillary columns could be applied to ACE drug screening targeting certain membrane proteins.



Chemical constituents from Croton crassifolius Geisel

Junli Liu, Yanping Hao, Jianbin Wang, Wentong Dou, Chen Chen, Yan Guo, Dan Yuan, Hongzheng Fu

2016, 25(11):  826-831.  DOI: 10.5246/jcps.2016.11.092

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Croton crassifolius Geisel belongs to the genus croton of the family euphorbiaceae. By means of solvent extraction and repeated chromatorgraphy on silica gel, Sephadex LH-20 and HPLC, the ethanol extract of the roots of Croton crassifolius Geisel was chemically investigated, which led to the isolation of nine diterpenoids. By using spectroscopic analysis, their structures were identified as follows: Crassifolin P (1), Crassifolin J (2), 1,5,6-trimethyl-5-(2-(5-oxo-2,5-dihydrofuran-3-yl)ethyl)-1,2,3,4,5,6,7,8-octahydronaphthalene-1-carboxylate (3), Penduliflaworosin (4), isoteucvin (5), Crassifolin G (6), teucvin (7), Chettaphanin I (8), mallotucin D (9). Among of them compound 1 was a new compound.



Study of parameters affecting infection risk from contaminated injectable products using multiple spot contamination model: a case study of insulin vials

Mostafa Essam Eissa

2016, 25(11):  832-837.  DOI: 10.5246/jcps.2016.11.093

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Infections of patients from consumption of contaminated pharmaceutical products constituted major health risk problems. Medicinal products are liable to microbial intrusion during in-use application. The current study focused on repeated contamination with constant level of microbiological burden by two bacteria viz. Staphylococcus aureus and Pseudomonas aeruginosa were used as dose-response models for infection through two different routes of administration. Nine different forms of insulin vials were subjected to this type of simulation study at constant assumed level of contaminations, preservative efficacy test (PET) and dose potency. Multi-spot contamination imitation study showed that initial fast rise in contamination, followed shortly by longer but steeper slope which finally turned into higher rate of contamination during the few last doses of the unit dosage forms, where the volume of the product became increasingly and progressively very small. When the probability of infection curves was constructed, both S. aureus and P. aeruginosa showed same pattern, with notably higher risk from septicemia route of the latter rather than subcutaneous route of the former. The present simulation study showed that continuous use of the same contaminated syringe progressively increased the risk of infection, especially at final few doses (between 3^th and 10^th last doses depending on the dosage form sizes in the vials and the administration volumes) of the product. Small volume parenterals (SVP) are especially products at higher risk than the larger volume ones.



Drug administration and clinical pharmacy column

The correlation and consistency of light transmission aggregometry and thrombelastography in identifying high clopidogrel on-treatment platelet reactivity in patients with acute coronary syndrome

Xiaoyan Nie, Yang Xu, Yu Fu, Junlei Li, Guangkai Liang, Yong Zhang, Yun Lu, Jian Liu, Luwen Shi

2016, 25(11):  838-845.  DOI: 10.5246/jcps.2016.11.094

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Various platelet function tests are currently used to identify responsiveness to antiplatelet therapy. 176 ACS patients were enrolled and Linear regression and Kappa consistency analysis showed there was a significant but moderate correlation between platelet inhibition rate and a significant but fair agreement between high clopidogrel on-treatment platelet reactivity tested by light transmission aggregometry and thrombelastography.  



Research on the construction of a pharmacist competency model in China

Qi Zhao, Xiaoyuan Xu, Jiehan Zhang

2016, 25(11):  846-854.  DOI: 10.5246/jcps.2016.11.095

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Based on the competency model building theory, a literature review, a behavioral event interview and statistical analysis were used in this study to build a competency model for pharmacists in China. The competency model framework for pharmacists included five dimensions of characteristics, consisting of 25 competency elements of pharmacists, such as the general competency elements that all pharmacists should possess and outstanding competency elements that community pharmacists and hospital pharmacists should possess. This newly constructed competency model for pharmacists helped develop and cultivate the abilities of future Chinese pharmacists.



Other

Information from US FDA

http://www.fda.gov

2016, 25(11):  855-858. 

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Here at FDA, we work diligently to be part of our nation’s solution to the opioid abuse epidemic. While there is no single solution to this complex problem, we continue to encourage efforts to develop new opioid formulations with abuse-deterrent properties that make it harder to abuse these powerful medications.

Knowing there are some 100 million Americans with significant pain each year, we need to help ensure that patients in need continue to have appropriate access to pain medications, including opioids. At the same time we must work to ensure that these powerful medications are used as safely as possible.