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Related Concept Videos

Electrocardiogram01:29

Electrocardiogram

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An electrocardiogram (ECG or EKG) is a critical diagnostic tool that records the electrical signals produced by the heart during each heartbeat. This recording is achieved through electrodes placed strategically on the arms, legs, and chest. The electrocardiograph amplifies these signals and produces 12 distinct tracings, offering a comprehensive understanding of the heart's electrical activity.
Three major waveforms are present in a typical ECG recording: the P wave, the QRS complex, and...
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Pharmacodynamic Models: Linear Concentration–Effect Model01:15

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The linear concentration–effect model, underpinned by the principle that pharmacological effect (E) is directly proportional to plasma drug concentration (C), emerges as a pivotal simplification of the Emax model for conditions where C is significantly less than EC50. This model portrays a linear trajectory of the concentration–effect relationship when drug levels are markedly below the EC50 threshold.Despite its inherent assumption of continuous effect augmentation with increasing...
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Related Experiment Video

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Electrocardiogram Recordings in Anesthetized Mice using Lead II
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Predicting QRS and PR interval prolongations in humans using nonclinical data.

L Bergenholm1,2, J Parkinson3, J Mettetal4

  • 1Biomedical and Biological Systems Laboratory, School of Engineering, University of Warwick, Coventry, UK.

British Journal of Pharmacology
|July 5, 2017
PubMed
Summary
This summary is machine-generated.

Predicting human cardiac conduction slowing (QRS/PR prolongation) from preclinical studies is now possible. Small in vitro and in vivo effects reliably forecast meaningful clinical outcomes, improving drug safety assessments.

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Area of Science:

  • Pharmacology
  • Cardiovascular Safety
  • Drug Development

Background:

  • Cardiac conduction slowing, indicated by QRS/PR prolongations, is a key safety concern assessed pre-clinically.
  • Quantitative translation of in vitro and in vivo data to clinical outcomes is crucial for accurate risk assessment in nonclinical drug development phases.

Purpose of the Study:

  • To establish quantitative translational relationships between in vitro, in vivo, and clinical data for cardiac conduction parameters.
  • To enable improved prediction of human QRS/PR effects from nonclinical study findings.

Main Methods:

  • Characterization of four compounds (AZD1305, flecainide, quinidine, verapamil) with known QRS/PR effects using in vitro (ion channel assays) and in vivo (guinea pig, dog) models.
  • Development of concentration-matched translational models and quantification of in vitro to clinical translation using AZD1305.

Main Results:

  • Meaningful human QRS/PR effects (≥10%) correlated with low in vitro Nav1.5 block (3-7%) and Cav1.2 binding (13-21%).
  • An in vitro model successfully predicted QRS/PR effects for all tested compounds.
  • Human QRS/PR changes correlated with small effects in animal models, suggesting a 4x amplification factor for predicting worst-case human outcomes from dog/guinea pig data.

Conclusions:

  • Preclinical in vitro and in vivo findings consistently translate to significant human PR/QRS changes.
  • This predictive approach enhances cardiovascular safety risk assessment for non-arrhythmic drugs.
  • The study provides a validated method for predicting human QRS/PR effects based on nonclinical data.