Given that cardiovascular safety liabilities remain a major cause of drug attrition during preclinical and clinical development, adverse drug reactions, and post‐approval withdrawal of medicines, the Medical Research Council Centre for Drug Safety Science hosted a workshop to discuss current challenges in determining, understanding and addressing ‘Cardiovascular Toxicity of Medicines’. This article summarizes the key discussions from the workshop that aimed to address three major questions: (i) what are the key cardiovascular safety liabilities in drug discovery, drug development and clinical practice? (ii) how good are preclinical and clinical strategies for detecting cardiovascular liabilities? and (iii) do we have a mechanistic understanding of these liabilities? It was concluded that in order to understand, address and ultimately reduce cardiovascular safety liabilities of new therapeutic agents there is an urgent need to: Fully characterize the incidence, prevalence and impact of drug‐induced cardiovascular issues at all stages of the drug development process. Ascertain the predictive value of existing non‐clinical models and assays towards the clinical outcome. Understand the mechanistic basis of cardiovascular liabilities; by addressing areas where it is currently not possible to predict clinical outcome based on preclinical safety data. Provide scientists in all disciplines with additional skills to enable them to better integrate preclinical and clinical data and to better understand the biological and clinical significance of observed changes. Develop more appropriate, highly relevant and predictive tools and assays to identify and wherever feasible to eliminate cardiovascular safety liabilities from molecules and wherever appropriate to develop clinically relevant and reliable safety biomarkers.

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The effect of quindoxin on the synthesis of deoxyribonucleic acid (DNA), ribonucleic acid, and protein in Escherichia coli KL 399 was examined under aerobic and anaerobic conditions. In the absence of oxygen the synthesis of DNA was completely inhibited by 10 ppm of quindoxin, whereas the syntheses of ribonucleic acid and protein were not affected. Quinoxalin-di-N-oxides (QdNO) induce degradation of DNA in both proliferating and non-proliferating cells.polA, recA, recB, recC, exrA, and uvrA mutants were more susceptible than the corresponding repair-proficient strains. All strains were more resistant in the presence of oxygen. The potent in vivo activity of various quinoxaline-1,4-di-N-oxides (QdNO) against diverse bacteria, Entamoeba histolytica, and Chlamydiae of the psittacosis-lymphogranuloma venereum group has been known for more than two decades (9,24,29,35,50). Like many antibiotics (e.g., penicillin or tetracyclines) and chemotherapeutics (e.g., nitrofuran or sulfonamide), QdNO increase the live weight gain in young chickens, pigs, and calves when added to the diet (5,12,16,37). At present two QdNO, carbadox and olaquindox, are on the market as growth promoters in various countries; a third, quindoxin, has been withdrawn.QdNO were first prepared as potential antagonists of vitamin K activity, but such antagonism has never been demonstrated (24,35). Only a few further reports on the mode of action have been published. Studies on the effect of 2,3-dihydroximethyl-quinoxaline-1,4-di-N-oxide on the incorporation of radioactive precursors into deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and protein in Escherichia coli revealed a specific inhibition of DNA synthesis (15). Morphological changes in cells of E. coli and Staphylococcus aureus treated with 2,3-dihydroxit Present address:

It is widely accepted that more needs to be done to bring new, safe, and efficacious drugs to the market. Cardiovascular toxicity detected both in early drug discovery as well as in the clinic, is a major contributor to the high failure rate of new molecules. The growth of translational safety offers a promising approach to improve the probability of success for new molecules. Here we describe a cross-company initiative to determine the concordance between the conscious telemetered dog and phase I outcome for 3 cardiovascular parameters. The data indicate that, in the context of the methods applied in this analysis, the ability to detect compounds that affect the corrected QT interval (QTc) was good within the 10-30x exposure range but the predictive or detective value for heart rate and diastolic blood pressure was poor. These findings may highlight opportunities to refine both the animal and the clinical study designs, as well as refocusing the assessment of value of dog cardiovascular assessments beyond phase 1. This investigation has also highlighted key considerations for cross-company data sharing and presents a unique learning opportunity to improve future translational projects.