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Preclinical Cardiac Safety Assessment

Approximately one third of compounds in pre-clinical development exhibit some levels of cardiac risks. Unfortunately, many of these compounds are not identified until they are in clinical trials after millions of dollars and years of effort have been invested. As a result, the vast majority of investigational products that enter clinical trials fail. Therefore, for the sake of saving time and money, it is critical to assess the preclinical cardiac safety of these investigational products before they enter clinical trials.

The hERG channel plays a significant role in cardiac repolarization and acute hERG block alone will prolong QT and induce Torsades de Pointes. Compounds routinely affect The hERG channel influencing the effect of hERG block. AddexBio provides a fast, comprehensive preclinical cardiac safety assessment for full resolution of potential cardiac risk prior to IND submission. Multiple assays are employed to assess a compound's effect on preclinical cardiac safety at molecular, cellular, tissue and system levels. We enable you to achieve nearly 100% predictivity of cardiac risk with our preclinical cardiac safety assessment. AddexBio provides the most complete preclinical cardiac safety package presently available.

Drug-induced delayed cardiac repolarization has associated with hERG channel block that is linked to cardiac proarrhythmia. However, routine hERG screening in early discovery efforts should be supplemented with additional studies to avoid unduly discarding hERG blocking drugs not affecting delayed repolarization and to ensure overall cardiac safety. Addexbio uses manual patch clamp (a gold standard) to assess hERG channel inhibition of your compounds on HEK293 cells or CHO cells stably transfected with hERG channel. Protocols include exploratory non-GLP screening of single high concentration or IC50. A number of agents known to affect the hERG current are validated and used as positive controls, including terfenadine, cisapride and E-4031.

    2) In vitro QT Service Using Langendorff Perfused Hearts

If your drug has a positive effect on hERG channel, does it have a QT risk? The follow-up studies to the heart models in vitro can provide greater depth of understanding or additional knowledge regarding the potential of test substance for delayed ventricular repolarization and QT interval prolongation in humans. AddexBio offers a heart model in vitro QT service to characterize a drug's potential to affect ventricular repolarization and contractility. Early testing for multiple effects on key cardiac ion channels fully resolves discordances and prevents advancement of cardiotoxic drug candidates. Using isolated rat or rabbit hearts, AddexBio offers Langendorff perfused heart ECG and contractility assessment so that drugs can be tested on isolated animal hearts. We can identify effects of your compounds on the ECG (QT interval, QRS), heart contractility (LVDP, dP/dt) and coronary flow. Three hearts will be used per concentration. Final reports of the in vitro QT service include drug effects on the study parameters including a summary of the results, description of methods used, statement of quality standard, and any amendments or deviations included as an appendix.

    3) In vivo QT Service Using Whole Animals

The in vivo QT Service is a component of AddexBios preclinical cardiac safety assessment, a comprehensive cardiac safety assessment package for full resolution of potential cardiac risk prior to IND submission. Using rat, rabbit or dog, AddexBio can determine the effects of drugs on ECG in vivo, such as QT/QTc interval, QRS duration, RR interval, PR interval. Three animals will be used per concentration. Final reports of the in vivo QT service include drug effects on the study parameters including a summary of the results, description of methods used, statement of quality standard, and any amendments or deviations included as an appendix.

    4) Cardiac Hemodynamic Assessment on Whole Animals

Cardiac hemodynamic assessment is another component of AddexBios preclinical cardiac safety assessment. Using rat, rabbit or dog, AddexBio can determine the effects of drugs on cardiac hemodynamic parameters, such as heart rate, arterial blood pressure (including systolic, diastolic and mean arterial blood pressure), heart contractility (LVDP, dP/dt) and coronary flow. Three animals will be used per concentration. Final reports of the cardiac hemodynamic assessment include drug effects on the study parameters including a summary of the results, description of methods used, statement of quality standard, and any amendments or deviations included as an appendix.

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