Talampanel

Intrahepatic cholestasis of pregnancy (ICP) was the most common liver disease specific to pregnancy. The symptoms of ICP were maternal pruritus and increased bile acid level in serum which was related to preterm birth, fetal distress, meconium-stained amniotic fluid and stillbirth. However, the mechanism of ICP progression on fetal development remained obscure. Sequencing data of 2 normal placenta samples and 4 intrahepatic cholestasis samples during pregnancy was analyzed by GEO2R. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used for analysis of differentially expressed genes. MCODE - A plug-in of Cytoscape was used for molecular complex detection. STRING, Cytoscape, GeneMANIA, NetworkAnalyst, TransmiR, JASPAR, DGIdb and DrugBank were used in this study. Furthermore, histopathological and cell experiments were used to verify our results. Our study identified the key KEGG pathway and four MCODEs which were closely with ICP development, further, sorted by degree centrality, we showed top 30 genes from 7209 differential genes, such as TP53, SRC, EGFR, ESR1, IL10, CD8A, MAPK3, PTPRC, EGF, KIT, ITGAM, LEP and CSF2, etc. Moreover, these hub genes participated in JAK-STAT3 signaling pathway and STAT1/3 regulated these genes expression in a direct way or miRNA-mediated manner. Drug-target analysis about up-regulated genes among hub genes showed that these genes contained multiple drug action site. Furthermore, hub gene-EGFR was associated with destroyed autophagy and ferroptosis. In conclusion, our study analyzed key genes and pathways in ICP development. JAK-STAT3 pathway and EGFR might be a potential target for ICP therapy.

The success rate from first time in man to regulatory approval of central nervous system (CNS) drugs is lower than the overall success rate across all therapeutic indications (eg, cardiovascular, infectious diseases). To understand the reasons for drug‐candidate failure and to capture trends in antiseizure drug (ASD) design, we have analyzed the physicochemical and biopharmaceutical properties of marketed ASDs in comparison with new ASDs in development. Our comparative analysis included molecular weight (MW), logP, polar surface area (PSA), the “Lipinski rule of five,” and the CNS Multiparameter Optimization (MPO) score. LogP is the logarithm of a drug‐partition coefficient (P) between n‐octanol and water. PSA is the molecule's surface sum of its polar atoms. ASDs' biopharmaceutical properties were classified according to their water solubility, permeability, and route of elimination as outlined by the Biopharmaceutics Classification System (BCS) and Biopharmaceutics Drug Disposition Classification System (BDDCS). For old ASDs (1912‐1990), logP, PSA, and CNS MPO values ranged between 0.4 and 2.8, 37 and 87 Å2, and 4.4 and 6.0, respectively. For second‐generation ASDs (1990‐2008), PSA values ranged between 39 and 116 Å2. However, logP values showed a difference between the lipophilic (logP = 0.3‐3.21) and hydrophilic (logP = −0.6 to −2.16) ASDs. For third‐generation ASDs (2008‐2020), logP and PSA ranged between 0.3 and 3.5 and between 57 and 76 Å2, respectively. The mean CNS MPO scores of all marketed ASDs were similar, ranging between 4.9 and 5.4, and were similar to those of the ASDs in development (3.5‐5.8). Most ASDs belong to BCS and BDDCS classes 1 and 2. MW, logP, CNS MPO score, and PSA assess lipophilicity and correlate with antiseizure activity. To succeed, a new small‐molecule ASD must have MW < 375 and PSA < 140Å2, belong to BCS and/or BDDCS class 1 or 2, and obey the Lipinski rule of five: logP < 5, MW < 500, and <5 and <10 of hydrogen‐bond donors and acceptors, respectively. The similarity in the MW, logP, and PSA values of marketed and new drugs in development indicates a conservative trend in ASD design.