Cardiotoxicity assessment using 3D vascularized cardiac tissue consisting of human iPSC-derived cardiomyocytes and fibroblasts.

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are used for cardiac safety assessment but have limitations for the evaluation of drug-induced contractility. Three-dimensional (3D) cardiac tissues are similar to native tissue and valuable for the assessment of contractility. However, a longer time and specialized equipment are required to generate 3D tissues.

Comprehensive Cardiac Safety Assessment using hiPS-cardiomyocytes (Consortium for Safety Assessment using Human iPS Cells: CSAHi).

Current cardiac safety assessment platforms (in vitro hERG-centric, APD, and/or in vivo animal QT assays) are not fully predictive of drug-induced Torsades de Pointes (TdP) and do not address other mechanism-based arrhythmia, including ventricular tachycardia or ventricular fibrillation, or cardiac safety liabilities such as contractile and structural cardiotoxicity which are another growing safety concerns. We organized the Consortium for Safety Assessment using Human iPS cells (CSAHi; http://csahi.org/en/) in 2013, based on the Japan Pharmaceutical Manufacturers Association (JPMA), to verify the application of human iPS/ES cell-derived cardiomyocytes for drug safety evaluation.

Effects of repeated restraint and blood sampling with needle injection on blood cardiac troponins in rats, dogs, and cynomolgus monkeys.

While cardiac troponins (cTnT and cTnI) have been used as blood biomarkers of myocardial injury such as myocardial infarction in both humans and animals, their high diagnostic sensitivity inevitably leads to decreased diagnostic specificity. For example, it is difficult to judge whether a slight increase of cardiac troponins in toxicological studies is a treatment-related response or not. Drawing an accurate conclusion requires reliable background data and definitive criteria based on that data.

Comprehensive in vitro cardiac safety assessment using human stem cell technology: Overview of CSAHi HEART initiative.

Recent increasing evidence suggests that the currently-used platforms in vitro I and APD, and/or in vivo QT assays are not fully predictive for TdP, and do not address potential arrhythmia (VT and/or VF) induced by diverse mechanisms of action. In addition, other cardiac safety liabilities such as functional dysfunction of excitation-contraction coupling (contractility) and structural damage (morphological damage to cardiomyocytes) are also major causes of drug attrition, but current in vitro assays do not cover all these liabilities. We organized the Consortium for Safety Assessment using Human iPS cells (CSAHi; http://csahi.

Effects of four-week feed restriction on toxicological parameters in beagle dogs.

This study was conducted to examine any changes caused by feed restriction in dogs to contribute to safety evaluation in toxicity studies. Two male 7-month-old beagle dogs/group were fed 300 (control), 150 (50% of control), or 70 g/animal of diet daily (23% of control) for 4 weeks. Effects of feed restriction, except for clinical signs, were noted depending on the feed dosage in almost all examinations.

Effects of pH on nifekalant-induced electrophysiological change assessed in the Langendorff heart model of guinea pigs.

Since information regarding the effects of pH on the extent of nifekalant-induced repolarization delay and torsades de pointes remains limited, we assessed it with a Langendorff heart model of guinea pigs. First, we investigated the effects of pH change from 7.4 to 6.

Quantitative trait loci analysis of heat stress resistance of spermatocytes in the MRL/MpJ mouse.

The MRL/MpJ mouse has previously been reported to possess an interesting phenotype in which spermatocytes are resistant to the abdominal temperature heat shock. In this study genetic analysis for it was performed. The phenotypes of F2 progenies produced by mating MRL/MpJ and control strain C57BL/6 mice were not segregated into two types as parental phenotypes, suggesting that the phenotype is controlled by multiple genetic loci.

Differences in spermatogenesis in cryptorchid testes among various strains of mice.

The purpose of the study reported here was to define strain differences in spermatogenesis in cryptorchid testes in mice. Mice of strains A/J, BALB/c, CBA/N, C3H/He, C57BL/6 (B6), ddY and ICR were found to be sensitive to heat stress attributable to experimentally induced cryptorchidism. In contrast, mice of strains AKR/N (AKR), MRL/MpJ-+/+ (M+) and MRL/MpJ-lpr/lpr (lpr) were resistant to heat stress.