Galangin delivered by retinoic acid-modified nanoparticles targeted hepatic stellate cells for the treatment of hepatic fibrosis.

Hepatic fibrosis (HF) is a chronic hepatic pathological process induced by various liver injuries, with few available therapies. Previous research studies revealed that HF is characterized by the accumulation of excess extracellular matrix in the liver, mainly overexpressed by activated hepatic stellate cells (HSC). Therefore, HSC have been targeted in clinical trials for the management of HF. The aim of the present study was to develop an anti-HF drug delivery system with acrylic resin (Eudragit® RS100, Eud RS100) nanoparticles (NPs) through modification by retinoic acid (RA), modified for binding the retinol-binding protein reporter (RBPR) in HSC. Galangin (GA), is a multiple effects flavonoid which has demonstrated an anti-HF effect in our previous studies. In this study, GA was utilized for the treatment of HF. The results revealed that the NPs were well formed (diameter: 70 nm), spherical in shape, and exhibited uniform distribution and a high encapsulation efficiency. Moreover, a prominent controlled release effect and a significant increase in bioavailability was observed following the encapsulation of GA in NPs. These findings indicated that the limitation of low bioavailability due to the hydrophobic feature of GA was overcome. Furthermore, the pharmacodynamics studies demonstrated that NPs could drastically influence the anti-HF effects of GA after modification with retinoic acid. The results of the present study suggested that retinoic acid-modified GA NPs represent a promising candidate in the development of an anti-HF drug delivery system for the treatment of HF.

Sacubitril-Valsartan Compared With Enalapril for the Treatment of Heart Failure: A Decision-Analytic Markov Model Simulation in China.

OBJECTIVES: Heart failure with reduced ejection fraction (HFrEF) is a major health concern globally due to high mortality rates, frequent hospitalization and considerable medical expenditure. The prevalence of HFrEF is steadily rising in Asian countries, and populous, developing countries like China are facing a significant socio-economic burden as a result. Sacubitril-valsartan (Sac-Val) is currently a class I recommendation for treating HFrEF in major guidelines, although it has not been pharmaco-economically evaluated in China. To this end, we compared the cost-effectiveness of Sac-Val and enalapril based on the negotiated prices in order to fully assess the expected costs and benefits of the clinical use of Sac-Val in China. METHOD: A Markov model was constructed to estimate long-term clinical and economic outcomes of Sac-Val versus enalapril for HFrEF patients in China over a 10-year horizon. Primary model outcomes were total costs and quality-adjusted life years (QALYs), and the incremental cost-effectiveness ratio (ICER). RESULTS: Treatment with Sac-Val resulted in 4.67 QALYs at the cost of $4,684.25, while enalapril yielded 4.40 QALYs at the cost of $4,014.47. Compared to enalapril, Sac-Val was associated with a gain of 0.27 QALYs, resulting in an ICER of $ 2,480.67 per QALY. Deterministic sensitivity analysis showed robust results. Probabilistic sensitivity analysis suggested that Sac-Val has a 99.99% probability of being cost-effective at the willingness-to-pay threshold of $10,276. CONCLUSION: From Chinese patients' perspective, Sac-Val is a cost-effective treatment option for HFrEF in China compared to enalapril. Our findings can aid clinicians plan the Sac-Val regimen, as well as decision makers to discuss the value and position of novel angiotensin receptor neprilysin inhibitors (ARNIs) in future.

Attitudes and perceptions regarding antimicrobial use and resistance among medical students in Central China.

OBJECTIVES: Senior medical students, who are future doctors, should be prepared to use antimicrobials appropriately and will be important partners in antimicrobial stewardship. This survey was designed to investigate the attitudes and perceptions of senior medical students regarding antimicrobial use and resistance. METHODOLOGY: We performed a multi-center survey involving a questionnaire handed out to all fourth year medical students from five representative teaching hospitals in Central China. The survey was completed within 1 month (October to November, 2015). Antimicrobial stewardship programs were taught in all of the teaching hospitals, yet only part of the respondents took part in it. RESULTS: A total of 611 out of 728 students completed our survey. The majority of the respondents (92 %) believed that inappropriate use of antimicrobials causes antimicrobial resistance and agreed with the importance of a strong knowledge of antimicrobials in their medical careers. Most students (67 %) rated their education concerning antimicrobial use and resistance as useful or very useful, but only 25 % recalled having courses on this subject. The overall mean number of correct answers on a section of 11 knowledge questions was 3.78 (standard deviation 1.57, P value for score between hospitals <0.001). CONCLUSIONS: We should make an effort to optimize curriculum system in Chinese institutions, and this may contribute to making our future doctors better prepared for antimicrobial stewardship and prudent antimicrobial prescribing.

In vitro and in vivo studies on ocular vitamin A palmitate cationic liposomal in situ gels.

N-trimethyl chitosan (TMC) with different degree of quaternization (DQ) as the coating materials, vitamin A palmitate (VAP)-loaded cationic liposomes dispersed in thermo-sensitive in situ gels (ISG) with poloxamer 407 (P407) as the base were prepared in this study. VAP-loaded liposomes (VAPL) were prepared using a film dispersion method followed by TMC-coating with DQ of 20%, 40% and 60% (TMC20, TMC40 and TMC60), respectively, then dispersed in P407 solution to obtain TMC-coated VAPL ISG. The in vitro properties of the system including morphology, size, zeta potential, entrapment efficiency, drug release and ocular retention were investigated. The ocular retention in vivo, eye irritation and pharmacokinetics in aqueous humor of the system were also studied in rabbits. VAPL revealed a spherical surface with mean size below 100 nm and negative zeta potential. After TMC-coating, the morphology and entrapment efficiency showed no significant changes, while the mean size was increased, zeta potential was changed into positive, and drug release was further sustained, and above all was influenced by DQ of TMC. TMC-coated VAPL exhibited little effect on the gelation temperature of P407 solution, and at the P407 concentration of 25% (w/v), TMC-coated VAPL ISG had the gelation temperature closest to the eye surface (34 °C) after diluted by the artificial tears. Compared with uncoated VAPL ISG and the marketed Oculotect gels, TMC-coated VAPL ISG displayed more retarded drug release and gel corrosion with a good linear relationship between them, and the higher DQ was, the slower drug release and gel corrosion. The ocular retention time in vitro and in vivo of TMC-coated VAPL ISG were both notable prolonged with a positive correlation with DQ of TMC. Compared with the marketed gels, TMC60-coated VAPL ISG showed delayed Tmax, improved Cmax and AUC(0­24) in rabbit aqueous humor, suggesting the sustained drug release and better corneal penetration and absorption. The local irritation of TMC-coated VAPL ISG was proved to be negligible. TMC-coated VAPL ISG with the properties of sustained drug release, prolonged ocular retention, improved corneal penetration and promising bio-safety is valuable to be studied further.

Study on the mechanisms of chitosan and its derivatives used as transdermal penetration enhancers.

The efficacy of chitosan (CS) and its derivatives used as transdermal penetration enhancers has been confirmed in our previous research. This study investigated the mechanisms of penetration enhancement by CS and its derivatives, i.e., N-trimethyl chitosan (TMC) with different degree of quaternization (DQ) and mono-N-carboxylmethyl chitosan (MCC). After treatment with CS, TMCs or MCC, the secondary structure changes of keratin in stratum corneum (SC) from mice were examined by an Attenuated Total Reflection-Fourier Transform Infrared (ATR-FTIR) combined with the application of the second-order derivative, deconvolution and curve-fitting. The water content in the SC was also studied by ATR-FTIR. HaCaT cell lines were employed as the cell models in the study. HaCaT cells were first treated with blank D-Hanks solution, CS or its derivatives, and were then fluorescent labeled with DiBAC(4) (3). The change of membrane potential was measured by a flow cytometer (FCM). Alternatively, the treated HaCaT cells were labeled with NBD-C(6)-HPC and the change of membrane fluidity was examined under a Confocal Laser Scanning Microscope (CLSM). It was found that CS, TMCs and MCC could significantly affect the secondary structure of keratin in SC in different ways. Although the amide II absorption peak of keratin moved to a lower wave number following treatment with CS, TMCs, or MCC, the beta-turning structure of keratin was converted to beta-sheeting and random coiling after treatment with TMCs and was converted to beta-sheeting and alpha-helix following treatment with MCC and CS. At the same time, CS and its derivatives all could increase the water content of SC, decrease HaCaT cells membrane potentials and enhance HaCaT cells membrane fluidity significantly. The effect of TMCs appeared to be independent of their DQ. The results suggest that the mechanisms of transdermal enhancement of CS, TMCs and MCC are closely related to their effects on the secondary structure of keratin and water content in SC, cell membrane potential and fluidity.

Transdermal permeation enhancement of N-trimethyl chitosan for testosterone.

The aim of this study was to evaluate the transdermal permeation enhancement of N-trimethyl chitosan (TMC) with different degrees of quaternization (DQ). TMCs with DQ of 40 and 60% (TMC40 and TMC60) were synthesized and characterized by (1)H NMR. Testosterone (TS) used as an effective drug, four different gels were prepared without enhancer, with 5% TMC40, 5% TMC60 or 2% Azone, respectively as enhancer. The effect of TMC60 on the stratum corneum was studied by Attenuated Total Reflection-Fourier Transform Infrared Spectroscopy (ATR-FTIR) combined with the technique of deconvolution. The results showed that TMC60 could significantly affect the secondary structure of keratin in stratum corneum. In vitro permeation studies were carried out using Franz-diffusion cells and in vivo studies were performed in rabbits. Both in vitro and in vivo permeation studies suggested the transdermal permeation enhancement of TMCs. Compared to the TS gel without enhancer, TS gels with enhancers all showed significant enhancing effect on transdermal permeation of TS (P<0.05). Meanwhile, compared to 2% Azone, 5% TMC60 had a stronger enhancement (P<0.05) while 5% TMC40 had a similar effect (P>0.05). The results suggested that the enhancement of TMCs increased with the increase of DQ.

[Study on the pharmacokinetics and bioavailability of syringic acid in rabbits].

OBJECTIVE: To study the pharmacokinetics and bioavailability of syringic acid(SA) in rabbits by HPLC. METHOD: After the rabbits were injected SA injection via ear vein and peritoneal cavity, blood was collected also via ear vein at different time-point. Then the concentration of SA in blood was determined by HPLC and the concentration-time curve was mapped to simulate a compartment model. So the pharmacokinetic parameters were calculated out. Several days after this injection, the drug was administered to the rabbits via i.p. and using the same method, another concentration-time curve was obtained. By comparing the AUC of the two curves, bioavailability was obtained. RESULTS: The concentration-time curve of SA in rabbits after i.v. fitted in a two-compartment open model and the absolute bioavailability was 86.27%. CONCLUSION: The results were valuable for the clinical application of new anti-endotoxic drug from Radix Isatidis.