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Validation of a larval zebrafish locomotor assay for assessing the seizure liability of early-stage development drugs.
TLDR
This assay offers potential as a medium throughput screen aimed at the early drug discovery detection of this complex safety pharmacological endpoint, particularly considering the potential for throughput and likely positioning within a safety pharmacology front-loading screening cascade. Expand
Approaches to seizure risk assessment in preclinical drug discovery.
TLDR
The current techniques available to assess seizure risk are reviewed and how they may be combined in a rational step-wise cascade allowing more effective assessment of seizure risk is described. Expand
Validation of the use of zebrafish larvae in visual safety assessment.
TLDR
The results suggest that the OMR assay in zebrafish could be useful in predicting the adverse effects of drugs on visual function in man and would support its potential as a screen for 'frontloading' safety pharmacology assessment of this endpoint in vivo. Expand
Cardiotoxicity associated with targeting kinase pathways in cancer.
TLDR
Cardiotoxicity, also referred to as drug-induced cardiac injury, is an issue associated with the use of some small-molecule kinase inhibitors and antibody-based therapies targeting signaling pathways in cancer and laboratory investigations into the underlying molecular mechanisms of heart toxicity induced by these molecules have identified potentially common themes. Expand
I(Ks) restricts excessive beat-to-beat variability of repolarization during beta-adrenergic receptor stimulation.
TLDR
Leaks of I(Ks) plus overriding of Ca(2+)-dependent membrane currents, including inward Na(+)-Ca(2)(+) exchange current, conspire to proarrhythmic BVR under these conditions. Expand
Nonclinical proarrhythmia models: predicting Torsades de Pointes.
TLDR
Standard assays are very good, although perhaps not infallible, at predicting the risk of QT interval prolongation in man they do not predict the proarrhythmic risk, and in this review, three in vitro and three in vivo models or methods are discussed. Expand
Evaluation of a convenient method of assessing rodent visual function in safety pharmacology studies: effects of sodium iodate on visual acuity and retinal morphology in albino and pigmented rats and
TLDR
The method proved to be very convenient, and the stability of visual acuity in vehicle control rats over a 6-week period also demonstrated its suitability for inclusion in long-term toxicity studies. Expand
On the relationship between block of the cardiac Na+ channel and drug‐induced prolongation of the QRS complex
TLDR
The safety implications of blocking hNav1.5 channels suggest the need to test for this activity early in drug discovery in order to design out any potential liability. Expand
A framework to assess the translation of safety pharmacology data to humans.
TLDR
This strategy should contribute to the reduction of candidate drug attrition and a more appropriate use of animals and more accurate comparisons of models e.g. pharmacokinetic/phamacodynamic relationships as well as non-clinical and clinical outcomes for determining concordance. Expand
Correction of QT values to allow for increases in heart rate in conscious Beagle dogs in toxicology assessment.
TLDR
The objective of this assessment was to identify a correction formula that adequately corrects QT over a wide range of HRs and it was independently demonstrated that sex did not influence the outcome of the evaluations. Expand
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