Pulmonary fibrosis(PF)is a chronic progressive lung disease caused by a variety of etiologies and is also a common outcome of various chronic inflammatory lung diseases.The incidence of pulmonary fibrosis is increasing year by year,with a high mortality rate that seriously threatens the life and health of patients.Although two drugs,pirfenidone and nintedanib,are already on the market for the treatment of pulmonary fibrosis,they can only slow down the progression of the disease but cannot reverse or stop the process of pulmonary fibrosis,and long-term use can produce a variety of adverse reactions.Therefore,it is highly necessary to develop new drugs for pulmonary fibrosis that are more targeted,effective,and well-tolerated by patients.The phosphatidylinositol-3-kinase(PI3K)signaling pathway plays an important role in the pathogenesis of pulmonary fibrosis.Targeted inhibition of the PI3K signaling pathway may be an important direction for the development of new drugs for pulmonary fibrosis.At present,some PI3K signaling pathway inhibitors have shown good effects in preventing and treating pulmonary fibrosis,but most of them are still in the research stage.This article reviews the role of the PI3K signaling pathway in PF,further summarizes promising PI3K pathway inhibitors with PF therapeutic effects,including inhibitors in clinical trials and preclinical studies,and discusses their mechanisms of action and development prospects.

With the increasing cost of drug development and clinical trials, it is of great value to make full use of all kinds of data to improve the efficiency of drug development and to provide valid information for medication guidelines. Model-based meta-analysis (MBMA) combines mathematical models with meta-analysis to integrate information from multiple sources (preclinical and clinical data, etc.) and multiple dimensions (targets/mechanisms, pharmacokinetics/pharmacodynamics, diseases/indications, populations, regimens, biomarkers/efficacy/safety, etc.), which not only provides decision-making for all key points of drug development, but also provides effective information for rational drug use and cost-effectiveness analysis. The classical meta-analysis requires high homogeneity of the data, while MBMA can combine and analyze the heterogeneous data of different doses, different time courses, and different populations through modeling, so as to quantify the dose-effect relationship, time-effect relationship, and the relevant impact factors, and thus the efficacy or safety features at the level of dose, time and covariable that have not been involved in previous studies. Although the modeling and simulation methods of MBMA are similar to population pharmacokinetics/pharmacodynamics (Pop PK/PD), compared with Pop PK/PD, the advantage of MBMA is that it can make full use of literature data, which not only improves the strength of evidence, but also can answer the questions that have not been proved or can not be answered by a single study. At present, MBMA has become one of the important methods in the strategy of model-informed drug development (MIDD). This paper will focus on the application value, data analysis plan, data acquisition and processing, data analysis and reporting of MBMA, in order to provide reference for the application of MBMA in drug development and clinical practice.

Objective To evaluate the effect of dexmedetomidine pretreatment on contents of glu-tamic acid and γ-aminobutyric acid during focal cerebral ischemia-reperfusion ( I∕R) in rats. Methods Thirty-six clean-grade healthy male Wistar rats, aged 10 months, weighing 250-300 g, were divided into 3 groups using a random number table method: sham operation group (group S), I∕R group, and dexme-detomidine group (group D). Focal cerebral I∕R was induced by occlusion of the left middle cerebral artery for 30 min followed by reperfusion in anesthetized rats. The left middle cerebral artery was only isolated but not occluded in group S. Sterile normal saline 1 ml was intraperitoneally injected, and 30 min later the model of focal cerebral I∕R was established in group I∕R. Rats were sacrificed at the end of reperfusion, and brains were removed for determination of contents of glutamic acid and γ-aminobutyric acid in brain tis-sues and for examination of ultrastructure (with an electron microscope). Results Compared with group S, the content of glutamic acid was significantly increased, and the content of γ-aminobutyric acid was de-creased in I∕R and D groups (P＜0. 05). Compared with group I∕R, the content of glutamic acid was signif-icantly decreased, and the content of γ-aminobutyric acid was increased in group D (P＜0. 05). The dam-age to the ultrastructure of brain tissues was significantly attenuated in group D when compared with group I∕R. Conclusion Dexmedetomidine pretreatment can reduce focal cerebral I∕R injury through decreasing the content of glutamic acid and increasing the content of γ-aminobutyric acid in rats.