BACKGROUND:Intracerebral administration of selective drugsviathe carotid artery is currently one of the effective methods to enhance the drug concentration in the brain and reduce the influence of drugs on other system functions. OBJECTIVE:To establish the muscle-relaxation rabbit models by infusing propofol continuously in the internal carotid artery and analyze the variations of propofol concentration. METHODS: The muscle-relaxation rabbit models were established by continuously infusing propofol at a constant speedviacatheterization in the internal carotid artery. The pharmacokinetic characteristics could be analyzed by the methods of obtaining arterial and venous blood on both sides of neck and samples of brain tissue on both sides in different points, detecting drug concentration using high pressure liquid assay, and then mathematicaly conversing the resulting data for fitting processing and statistical regression. RESULTS AND CONCLUSION:The method of determining the concentration of propofol using high pressure liquid assay is feasible, stable and reliable. Through investigating the concentration of propofol infused via the carotid artery at different time points, we discovered that the growth rate distribution of propofol concentration and data distribution are in log-normal distribution profile which belong to non-exponential kinetics model,i.e., modified log-normal distribution model,??)(ln x μ 2 1 fx ()=e 2σ2 , whereσ is the range of drug concentration growth indicating stability xk 2πσ of concentration changes, which is an integrated variable related to various factors, such as brain tissue uptake of drugs and brain circulation. The pharmacokinetic model of continuously infusing propofol in the internal carotid artery belongs to log-normal distribution function, i.e., a non-exponential function kinetics model. The brain concentration variations on both sides changing over time folow log-normal distribution function law.

Objective:To evaluate the security of recombinant human brain natriuretic peptide (rhBNP)in the treatment of acute decompensated heart failure (ADHF ), and to provide the basis for its application.Methods:Both foreign language databases including PubMed,The Cochrane Library (Issue 1,2015),EMBase and Chinese databases involving CNKI,VIP and Wanfang Data were searched.Two reviewers independently extracted the data,and assessed the quality;then the Meta-analysis was performed by using RevMan 5.1 software and Stata 12.0 software.Results:A total of 35 randomized controlled trials (RCTs)involving 12 143 patients were included. The results of Meta-analysis showed that compared with control group the 1-month mortality (RR=1.01,95%CI:0.85-1.21,P =0.88),3-month mortality (RR=0.89,95%CI:0.63-1.27,P =0.53)and 6-month mortality (RR = 0.97, 95% CI: 0.87 - 1.08,P = 0.59 )in rhBNP group had no statistical differences;no statistical difference was found in the incidence of side effects (RR=1.01,95%CI:0.71-1.43,P =0.97).The incidence of hypotension in rhBNP group was significantly higher than that in control group (RR= 1.42,95%CI:0.99 -2.03,P =0.06).Conclusion:Compared with dobutamine,vasodilator drugs and placebo,rhBNP doesn’t change the mortality and incidence of adverse reactions of the patients with ADHF,but increases the risk of hypotension.Clinical application of rhBNP should be reasonable and its effectiveness should be exerted sufficiently,meanwhile,as much as possible to avoid hypotension,etc.

OBJECTIVE： To design and optimize the formulation and technology of Theophylline hydrophilic gel matrix sustained-release tablets （self-made sustained-release tablets for short） based on the concept of “Quality by Design” （QbD）. METHODS： Diluent type， tablet diameter， the property of adhesive （ratio of different adhesive types）， the amount of adhesive were regarded as critical process parameters （CPPs）. Similarity factor of dissolution curves of self-made Theophylline sustained-release tablets and reference preparation and its accumulative release rate at different time points were regarded as critical quality attributes （CQAs）. L18（34） orthogonal tablet was adopted for design and trial， and secondary polynomial regression model was established. By using Modde 12.0 software， the design space and its acceptable range （PAR） were calculated through the optimal model. The optimal formulation and technology of Theophylline sustained-release tablets was determined， and validation test and Monte Carlo simulation verification were conducted. RESULTS： The optimal model with good coincidence， accuracy， validity and reproducibility was obtained， which could better fit the relationship between CQAs and CPPs. The design space and PAR value were obtained by further calculation （The optimum value of diluent was lactose； tablet diameter was 9.07-9.33 mm， and the optimal value was 9.20 mm； ratio of HPMC K4M to HPMC was 0.50-0.83， and the optimal value was 0.80； total amount of HPMC was 0.036 0-0.041 3 g per tablet， and the optimal value was 0.038 g per tablet）. The optimal formulation and technology included that ratio of theophylline， HPMC K4M and HPMC K100M were 50％， 15.48％ and 3.87％， respectively； the rest was filled with lactose and the diameter of the tablet was 9.20 mm. The results of validation confirmed that self-made Theophylline sustained-release tablets had similar in vitro release behavior compared with reference preparation. CONCLUSIONS： Based on the concept of QbD， the formulation and technology of Theophylline sustained-release tablets can meet the requirements of design， and the CPPs can be adjusted within the PAR range to meet the requirements of CQAs. This shows that the QbD concept is scientific and effective in the design and optimization of the formulation and technology of sustained and controlled release preparations.