Comprehensive in vitro Proarrhythmia Assay (CiPA): Pending issues for successful validation and implementation

International audienceIntroduction: The Comprehensive in vitro Proarrhythmia Assay (CiPA) is a nonclinical Safety Pharmacology paradigm for discovering electrophysiological mechanisms that are likely to confer proarrhythmic liability to drug candidates intended for human use.Topics covered: Key talks delivered at the ‘CiPA on my mind’ session, held during the 2015 Annual Meeting of the Safety Pharmacology Society (SPS), are summarized. Issues and potential solutions relating to crucial constituents [e.g., biological materials (ion channels and pluripotent stem cell-derived cardiomyocytes), study platforms, drug solutions, and data analysis] of CiPA core assays are critically examined.Discussion: In order to advance the CiPA paradigm from the current testing and validation stages to a research and regulatory drug development strategy, systematic guidance by CiPA stakeholders is necessary to expedite solutions to pending and newly arising issues. Once a study protocol is proved to yield robust and reproducible results within and across laboratories, it can be implemented as qualified regulatory procedure

Trace Metals Content Of The Sewage From The Sewer Network Of Abidjan (Côte d’Ivoire)

Many studies have incriminated the effluents of the sewer network of Abidjan as major trace metal contamination sources in the Ebrié Lagoon. However, no data are available on wastewater regarding trace metal contaminations in Cote d’Ivoire. Thus, this study aimed at assessing the level of contamination of wastewater by metals copper, iron, cadmium, lead and Zinc. To achieve this objective, six campaigns were carried out from december 2013 to november 2014 in eight specific sites. The samples were analyzed using an atomic absorption spectrophotometer AA20 Varian, after mineralization. The results showed a significant contamination of effluents from the sewer network. The order of metals concentrations was Fe >Zn > Cu> Pb>Cd. Total metal concentrations (μg/L) ranged from 313.4 to 881.5 for Fe, 144 to 240 for Zn, 132 to 318 for Cu, 10 to 30 for Cd and 114.3 to 263 for Pb. Among these values only Cd concentrations considerably exceeded WHO guideline value (10 μg/L)

The oral Ca/calmodulin‐dependent kinase II inhibitor RA608 improves contractile function and prevents arrhythmias in heart failure

Aims Excessive activation of Ca/calmodulin-dependent kinase II (CaMKII) is of critical importance in heart failure (HF) and atrial fibrillation. Unfortunately, lack of selectivity, specificity, and bioavailability have slowed down development of inhibitors for clinical use. We investigated a novel CaMKII delta/CaMKII-selective, ATP-competitive, orally available CaMKII inhibitor (RA608) on right atrial biopsies of 119 patients undergoing heart surgery. Furthermore, we evaluated its oral efficacy to prevent deterioration of HF in mice after transverse aortic constriction (TAC). Methods and results In human atrial cardiomyocytes and trabeculae, respectively, RA608 significantly reduced sarcoplasmic reticulum Ca leak, reduced diastolic tension, and increased sarcoplasmic reticulum Ca content. Patch-clamp recordings confirmed the safety of RA608 in human cardiomyocytes. C57BL6/J mice were subjected to TAC, and left ventricular function was monitored by echocardiography. Two weeks after TAC, RA608 was administered by oral gavage for 7 days. Oral RA608 treatment prevented deterioration of ejection fraction. At 3 weeks after TAC, ejection fraction was 46.1 +/- 3.7% (RA608) vs. 34.9 +/- 2.6% (vehicle), n = 9 vs.n = 12, P < 0.05, ANOVA, which correlated with significantly less CaMKII autophosphorylation at threonine 287. Moreover, a single oral dose significantly reduced inducibility of atrial and ventricular arrhythmias in CaMKII delta transgenic mice 4 h after administration. Atrial fibrillation was induced in 6/6 mice for vehicle vs. 1/7 for RA608,P < 0.05, 'n - 1' chi(2) test. Ventricular tachycardia was induced in 6/7 for vehicle vs. 2/7 for RA608,P < 0.05, 'n - 1' chi(2) test. Conclusions RA608 is the first orally administrable CaMKII inhibitor with potent efficacy in human myocytes. Moreover, oral administration potently inhibits arrhythmogenesis and attenuates HF development in micein vivo