Development of the Complement C5 Assay by LC-MS/MS in Monkey Serum and Comparison with Enzyme-Linked Immunosorbent Assay.

Complement C5 (C5) is the key component for the complement activation pathway, which is important for innate immunity, and inhibition of C5 is considered to be effective in antibody-mediated rejection in organ transplantation. Thus determination of C5 levels in systemic circulation is a simple way to understand efficacy of drugs that aim to inhibit C5 production. We have developed a simple liquid chromatography with tandem mass spectrometry (LC-MS/MS) assay for C5 in cynomolgus monkey serum.

In Vitro Metabolism of 2-Methoxy-N-[3-[4-[3-methyl-4-[(6-methyl- 3-pyridinyl)oxy]anilino]-6-quinazolinyl]prop-2-enyl]acetamide (CP-724,714) by Aldehyde Oxidase and Predicting Its Percent Contribution Relative to CYP-Mediated Metabolism.

2-methoxy-N-[3-[4-[3-methyl-4-[(6-methyl-3-pyridinyl)oxy]anilino]-6-quinazolinyl]prop-2-enyl]acetamide (CP-724,714) is an anticancer drug that was discontinued due to hepatotoxicity found in clinical studies. Metabolite analysis of CP-724,714 was conducted using human hepatocytes, in which twelve oxidative metabolites and one hydrolyzed metabolite were formed. Among the three mono-oxidative metabolites, the formation of two was inhibited by adding 1-aminobenzotriazole, a pan-CYP inhibitor.

Eribulin penetrates brain tumor tissue and prolongs survival of mice harboring intracerebral glioblastoma xenografts.

Glioblastoma is one of the most devastating human malignancies for which a novel efficient treatment is urgently required. This pre-clinical study shows that eribulin, a specific inhibitor of telomerase reverse transcriptase (TERT)-RNA-dependent RNA polymerase, is an effective anticancer agent against glioblastoma. Eribulin inhibited the growth of 4 TERT promoter mutation-harboring glioblastoma cell lines in vitro at subnanomolar concentrations.

A new paradigm for drug-induced torsadogenic risk assessment using human iPS cell-derived cardiomyocytes.

Introduction: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are anticipated to be a useful tool for conducting proarrhythmia risk assessments of drug candidates. However, a torsadogenic risk prediction paradigm using hiPSC-CMs has not yet been fully established.

Methods: Extracellular field potentials (FPs) were recorded from hiPSC-CMs using the multi-electrode array (MEA) system.

Generation of metabolically functioning hepatocytes from human pluripotent stem cells by FOXA2 and HNF1α transduction.

Background & Aims: Hepatocyte-like cells differentiated from human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) can be utilized as a tool for screening for hepatotoxicity in the early phase of pharmaceutical development. We have recently reported that hepatic differentiation is promoted by sequential transduction of SOX17, HEX, and HNF4α into hESC- or hiPSC-derived cells, but further maturation of hepatocyte-like cells is required for widespread use of drug screening.

Methods: To screen for hepatic differentiation-promoting factors, we tested the seven candidate genes related to liver development.