Journal of Chinese Pharmaceutical Sciences

The relationship between structural parameters and antibacterial biofilm activity for alkyl rhamnoside as a novel amphiphilic material

Guanghua Peng, Wenxi Zhang, Maoyuan Song, Mengya Yin, Jiaxing Wang, Jiajia Li, Yajie Liu, Yuanyuan Zhang, Xinru Li, Guiling Li

2018, 27(12): 817-823. DOI: 10.5246/jcps.2018.12.082

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In the present study, we aimed to explore the structure-activity relationship for the new amphiphilic material rhamnoside with antibacterial biofilm activity, and provide the basis for selecting rhamnoside with the optimum antibacterial biofilm activity. A series of alkyl rhamnosides with different carbon chain lengths were obtained by a simple and effective synthesis method. The structure was characterized by ¹H NMR spectrum, and their critical micelle concentration (CMC) was measured by fluorescence probe method. The hydrophilic and lipophilic balance (HLB) value was obtained by calculation. The minimal inhibitory concentration (MIC) of Staphylococcus aureus was determined by the broth double dilution method. The effect of biofilm inhibition and biofilm disruption was assayed by crystal violet method. The results showed that with the increase of carbon chain length, the CMC and HLB of alkyl rhamnosides displayed a linear downward trend, indicating that the lipophilicity and surface activityof the alkyl rhamnoside were increased. At the same time, the antibacterial activity in vitro produced the maximum, ie, 12-hydroxydecanoyl rhamnoside had the strongest antibacterial activity in vitro. Similarly, this material also exhibited the strongest antibacterial biofilm activity in vitro. The results of this study demonstrated that the most potent active material was obtained through the structure-activity relationship and it could be applied antibacterial biofilms in clinical practice.

Dose optimization of piperacillin/tazobactam in patients with renal dysfunction based on population pharmacokinetic and pharmacodynamic simulations

Chao Zhang, Ruohan Xie, Chuhui Wang, Chenchen Xi, Mengjia Ge

2018, 27(12): 824-831. DOI: 10.5246/jcps.2018.12.083

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In the present study, we aimed to investigate the optimal dosage regimens of piperacillin/tazobactam in patients with chronic kidney disease according to their different classes of renal function based on bacterial resistance. A total of 2700 simulationswere applied based on a published population pharmacokinetic and pharmacodynamic model using nonlinear mixed effects modeling (NONMEM) software. Permissible optimal dosage regimens were defined as those associated with a less than 10% of patients whose probabilities of target attainment (PTA) were not attain target. For patients with mild to moderate renal injury, 4/0.5 g of piperacillin/tazobactam every 12 h in 30 min intermittent infusion could attain the target. If the MIC (minimum inhibitory concentration) for the pathogen was 8 mg/L or 16 mg/L, either an 8-h or 6-h dosing interval or extended 2–6 h infusion regimen had to be used to achieve the outcome of the therapy. Regarding MIC was up to above 32 mg/L, a high dose of piperacillin (12–24 g/d) in continuous infusion was the only approach that could achieve the effective target in patients with renal dysfunction. A low dose with extended 4–6 h infusion regimen was recommended for patients with severe renal injury. Our study identified permissible optimal piperacillin/tazobactam dosage regimens for patients with renal dysfunction with an MIC up to 64 mg/L. The findings of this study would be helpful for precise administration of piperacillin/tazobactam in clinical practice.

Development of a simple and rapid method to measure the free fraction of lamotrigine in plasma using HPLC: applications for therapeutic drug monitoring

Huanxin Wang, Yaxin Sun, Shansen Xu, Tong Lu, Yanan Chen, Limei Zhao

2018, 27(12): 832-839. DOI: 10.5246/jcps.2018.12.084

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Lamotrigine (LTG) is a widely used antiepileptic drug (AED) for the treatment of new-onset, as well as refractory epilepsy. Due to the narrow treatment window and large individual variability in the pharmacokinetics and pharmacodynamics of LTG, therapeutic drug monitoring (TDM) is necessary in clinical practice to guide dose adjustments. Individual differences and drug combinations can also affect protein binding rate, which further affects the unbound concentration of LTG. The unbound fraction is more closely related to adverse reactions and therapeutic efficacy than total concentration. Therefore, it may be more meaningful to determine the unbound LTG concentration in plasma than the total concentration.Unbound LTG in plasma was extracted by ultrafiltration. High-performance liquid chromatography (HPLC) was used to measure unbound LTG concentration. This method was validated by studies of its selectivity, linearity, lower limit of quantification (LLOQ), accuracy, precision, recovery, and stability.The method was validated over a linear range of 0.2 to 10.0 μg·mL^–¹, and its LLOQ was 0.2 μg·mL^–¹. The method’s relative standard deviations (RSDs) for intra-day and inter-day precision were less than 15%, and its accuracy (RE) was ±4.69%. The recoveries of unbound LTG at three different concentrations satisfied the requirements for the analysis of biological samples, and no significant degradation of LTG was observed under different storage conditions.A simple HPLC method showed good performance when used to measure unbound LTG concentration. This method might be used to study the relationship between unboundLTG concentrations and its effectiveness according to TDM.

Anti-hyperlipidaemic assay and LC-MS/MS determination of piperinic ester in rat

Bo Surina, Dan Mu, Ochir Sarangua, Chunjie Ma

2018, 27(12): 840-846. DOI: 10.5246/jcps.2018.12.085

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In the present study, we aimed to establish high-fat diet model for evaluating anti-hyperlipidaemic activity of GBA and to establish the HPLC-MS method for measuring the pharmacokinetics of GBA in rat blood plasma and liver after oral administration. Rats were orally administrated with GBA at the dose of 50mg/kg body weight. GBA concentrations in blood plasma and liver were detected by HPLC from 0.5–10 h post administrations. The pharmacokinetic parameters were analyzed by the DAS1.0Software. The concentration-time curves of the plasma GBA and liver GBA wereconformed to two-compartment model. GBA was rapidly absorbed in the gastrointestinal tract and could be detected in plasma and liver 0.5 h after oral administration.

The effect of curcumin as an antioxidant on cochlea fibroblasts in ototoxic rat models

Tengku Siti Hajar Haryuna, Agustinus Hamonangan Winston Purba, Farhat Farhat, Soehartono Taat Putra

2018, 27(12): 847-854. DOI: 10.5246/jcps.2018.12.086

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Aminoglycosides (e.g. Gentamicin) are ototoxic drugs and widely prescribed due to their effective antimicrobial actions and affordable prices. This study focused on determining protective effect of curcumin against the damage caused by aminoglycosides. We aimed to demonstrate the potential of curcumin as an antioxidant to increase the expressions of superoxide dismutase (SOD) in fibroblasts of cochlea lateral wall in ototoxic rat models. The experiment was conducted with randomized post test-only control group design by using 32 male Rattusnorvegicus adults which received a combination of gentamicin and curcumin with different durations and doses. Then, the rats underwent terminations and immunohistochemical assay to determine the expression of SOD. The rats receiving gentamicin injection showed significantly decreased expression of SOD (P<0.05), and the administration of curcumin before and after the gentamicin injection showed significantly increased expression of SOD (P<0.05). Collectively, we showed that curcumin was an antioxidant against oxidative stress due to ototoxicity evidenced by the expression of SOD.

Chemical constituents and analgesic activity of Aconitum kusnezoffii Reichb.

Qian Li, Shuding Sun, Meiying Wang, Caifeng Li, Dan Yuan, Hongzheng Fu

2018, 27(12): 855-863. DOI: 10.5246/jcps.2018.12.087

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In the present study,we aimed to investigate the chemical constituents and analgesic activity of Aconitum kusnezoffii Reichb. The isolation and purification of components were achieved by a series of chromatography, including silica gel, Sephadex LH-20 and HPLC. By using spectroscopic analysis, their structures were identified. Using PDE-4A as analgesic target, moleculardocking was conducted between isolated compounds by using Schrodinger software. Neoline is a typical non-ester diterpene alkaloid. It was studied by using the mouse torsion body method and hot plate method. A total of 12 diterpene alkaloids were obtainedand identified as Mesaconitine(1), Bewutine (2), Bewudine (3), Songoramine (4), Songorine (5), Neoline (6), Talasamine (7), isotalatizidine (8), Hokbusine A (9), Mesaconine (10), 8-OEt-14-benzoylmesaconine (11), 8-Methoxy-14-benzoyl-beiwutinine (12).Compounds 9 and 12 were isolated from Aconitum kusnezoffii Reichb. for the first time. Twelve diterpenealkaloids could act on the analgesic target. Neoline is a typical non-ester diterpene alkaloid. It had significant analgesic effect. Diterpene alkaloids were the main components of Aconitum kusnezoffiiReichb., and they had good analgesic activity.

Chemical constituents from the the twigs and leaves of Caesalpinia enneaphylla

Lanjun Zhang, Dewen Bi, Jihua Wang, Guanghui Xia, Liqin Wang

2018, 27(12): 864-870. DOI: 10.5246/jcps.2018.12.088

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Fifteen compounds were isolated from the twigs and leaves of Caesalpiniaenneaphylla. Their structures were identified to be: (E)-3-(4-hydroxybenzylidene)- 5,7-dihydroxychroman-4-one (1), 8-methoxybonducellin (2), (E)-3-(3,4- dihydroxybenzylidene)-5,7-hydroxychroman-4-one (3), 2′,4′-dihydroxychalcone (4), oxyfadichalcone B (5), 7-hydroxyflavonone (6), pinocembrin (7), kaempferol (8), quercitrin (9), kaempferol 3-O-α-L-rhamnopyranoside (10), quercetin 3-O-α-D-arabinoside (11), trans-2,3-diacetoxy-1-[(benzoyloxy)methyl]-cyclohexa-4,6-diene (12), 3-hydroxybenzyl benzoate (13), 2-acetoxybenzyl benzoate (14), and glutinol (15). All the compounds were isolated from C. enneaphylla for the first time.