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Supporting an integrated QTc risk assessment using the hERG margin distributions for three positive control agents derived from multiple laboratories and on multiple occasions

Derek J. Leishman, Jessica Brimecombe, William Crumb, Simon Hebeisen, Steve Jenkinson, Peter J. Kilfoil, Hiroshi Matsukawa, Karim Melliti, Yusheng Qu, Journal of Pharmacological and Toxicological Methods, Volume 128, 2024, 107524, ISSN 1056-8719. DOI: 10.1007/978-3-031-52197-3

Copyright prevents linking to the article.

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Development of TRPML1-4A assays across manual, automated patch-clamp, and fluorescence-based platforms

The development and validation of electrophysiological assays to study TRPML1 is important to understand the function and pharmacology of the channel. We used a TRPML1 variant that lacks the endo-lysosomal retention sequences (TRPML1-4A), enabling the channel to express at the plasma membrane3. As such channel behaviour can be characterised by means of whole-cell patch-clamp and fluorescence-based techniques.

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Development of TRPML1-4A assays across manual, automated patch-clamp, and fluorescence-based platforms

We developed a suite of screening assays using manual patch-clamp, automated patch-clamp and fluorescence-based platforms capable of identifying modulators of the TRPML1-4A channel.

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In Vitro Assessment of Cardiac Risk in Drug Discovery

Clear decision-making data for your project team is vital to ensure you avoid costly issues related to QTc and QRS cardiac liabilities in the clinic.

Hear from industry experts, Derek Leishman (VP Translational and Quantitative Toxicology, Eli Lilly and Company) and Steve Jenkinson (Metrion).

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Advanced in vitro screening of new drugs for proarrhythmic activity

Jenkinson, Steve Advanced In Vitro Screening of New Drugs for Proarrhythmic Activity, Genetic Engineering News. 2024 44:5, 48-50

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CHO-KV 1.3 and current clamp using Qube 384: another perspective of ion channel behaviour

Current clamp recordings provide more physiologically relevant measurements of ion channel activity (in comparison to voltage clamp), allowing the contribution of different ion channel sub-types to resting membrane potential to be evaluated.

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Ion channels as targets in drug discovery

Gary Stephens, Edwards Stevens (2024) Springer

DOI: 10.1007/978-3-031-52197-3

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GLP hERG testing assay validation following ICH E14/S7B 2022 Q&A best practice guidelines

The ICH E14/S7B 2022 Q&As stipulate that in vitro hERG assessments should be conducted in accordance with Good Laboratory Practice (GLP). We present a GLP compliant study using the conventional manual patch-clamp technique in accordance with the ICH E14/S7B Q&A best practice guidelines to establish in-house IC50 values for ondansetron, moxifloxacin and dofetilide.

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GLP hERG assay validation following ICH E14/ S7B 2022 Q&A best practice guidelines

The recently released ICH E14/S7B 2022 Q&As provides the best practice guidelines for evaluating the effect of preclinical compounds on the human ether-à-go-go-related gene (hERG) potassium channel1.

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Multi-assay high-throughput drug repurposing screen: KCNC1 case study

Eliana is a two-year-old from Canada with a de novo mutation (V434L) in her KCNC1 gene which encodes for the Kv3.1 channel in central nervous system neurons such as cerebellar neurons and GABAergic interneurons. The mutation manifests as a variety of neurological disorders which can include myoclonic epilepsy and ataxia due to K+ channel mutation, developmental epileptic encephalopathy (DEE), or hypotonia, depending on the specific variant. Although Eliana does not exhibit typical DEE, she suffers from hypotonia, cortical-visual impairment, vertical nystagmus, and global delays.

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