Predicting clinical outcomes from off-target receptor interactions using Secondary Intelligence™.

Adverse effects due to off-target activity can be predicted by careful comparison of the relationship between expected plasma concentration and off-target activity of the test compound with that of reference drugs targeting that receptor for their therapeutic efficacy. The ratio between plasma concentration (unbound) and the K at the receptor is a surrogate measure reflecting receptor occupancy. Where data are available for reference drugs, we have curated and evaluated this at 100 receptors, 72 of which can involve both negative and positive modulations by drugs: a total of 172 'receptor modulations'.

Functional brain imaging in larval zebrafish for characterising the effects of seizurogenic compounds acting via a range of pharmacological mechanisms.

Background And Purpose: Functional brain imaging using genetically encoded Ca sensors in larval zebrafish is being developed for studying seizures and epilepsy as a more ethical alternative to rodent models. Despite this, few data have been generated on pharmacological mechanisms of action other than GABA antagonism. Assessing larval responsiveness across multiple mechanisms is vital to test the translational power of this approach, as well as assessing its validity for detecting unwanted drug-induced seizures and testing antiepileptic drug efficacy.

Applying the CiPA approach to evaluate cardiac proarrhythmia risk of some antimalarials used off-label in the first wave of COVID-19.

We applied a set of in silico and in vitro assays, compliant with the Comprehensive In Vitro Proarrhythmia Assay (CiPA) paradigm, to assess the risk of chloroquine (CLQ) or hydroxychloroquine (OH-CLQ)-mediated QT prolongation and Torsades de Pointes (TdP), alone and combined with erythromycin (ERT) and azithromycin (AZI), drugs repurposed during the first wave of coronavirus disease 2019 (COVID-19). Each drug or drug combination was tested in patch clamp assays on seven cardiac ion channels, in in silico models of human ventricular electrophysiology (Virtual Assay) using control (healthy) or high-risk cell populations, and in human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes. In each assay, concentration-response curves encompassing and exceeding therapeutic free plasma levels were generated.

Author Correction: 4-dimensional functional profiling in the convulsant-treated larval zebrafish brain.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

4-dimensional functional profiling in the convulsant-treated larval zebrafish brain.

Functional neuroimaging, using genetically-encoded Ca sensors in larval zebrafish, offers a powerful combination of high spatiotemporal resolution and higher vertebrate relevance for quantitative neuropharmacological profiling. Here we use zebrafish larvae with pan-neuronal expression of GCaMP6s, combined with light sheet microscopy and a novel image processing pipeline, for the 4D profiling of chemoconvulsant action in multiple brain regions. In untreated larvae, regions associated with autonomic functionality, sensory processing and stress-responsiveness, consistently exhibited elevated spontaneous activity.

Cardiovascular safety risk assessment for new candidate drugs from functional and pathological data: Conference report.

This is a report on a 2-day joint meeting between the British Society of Toxicological Pathology (BSTP) and the Safety Pharmacology Society (SPS) held in the UK in November 2013. Drug induced adverse effects on the cardiovascular system are associated with the attrition of more marketed and candidate drugs than any other safety issue. The objectives of this meeting were to foster inter-disciplinary approaches to address cardiovascular risk assessment, improve understanding of the respective disciplines, and increase awareness of new technologies.

Inclusion of Safety Pharmacology Endpoints in Repeat-Dose Toxicity Studies.

Whereas pharmacological responses tend to be fairly rapid in onset and are therefore detectable after a single dose, some diminish on repeated dosing, and others increase in magnitude and therefore can be missed or underestimated in single-dose safety pharmacology studies. Safety pharmacology measurements can be incorporated into repeat-dose toxicity studies, either routinely or on an ad hoc basis. Drivers for this are both scientific (see above) and regulatory (e.

The Diplomate in Safety Pharmacology (DSP) certification scheme.

As with other professional disciplines there is a growing need from within industry as well as global regulatory authorities for implementation of a certification process in order to assure that appropriate expertise is developed and quality standards are identified for professionals involved in the practice of Safety Pharmacology (SP). In order to meet this need, the Safety Pharmacology Society (SPS) has developed the Diplomate in Safety Pharmacology (DSP) certification process. There are many benefits to certification including authentication of the discipline within the overall pharmaceutical community and with regulatory authorities.

A multi-site comparison of in vivo safety pharmacology studies conducted to support ICH S7A & B regulatory submissions.

Introduction: Parts A and B of the ICH S7 guidelines on safety pharmacology describe the in vivo studies that must be conducted prior to first time in man administration of any new pharmaceutical. ICH S7A requires a consideration of the sensitivity and reproducibility of the test systems used. This could encompass maintaining a dataset of historical pre-dose values, power analyses, as well as a demonstration of acceptable model sensitivity and robust pharmacological validation.