Posts Tagged ‘Proarrhythmia Studies’

Leveraging the Langendorff Model to Detect Proarrhythmia

Posted by CorDynamics on November 20th, 2014
by Dr. Michael Gralinski, CorDynamics CEO

I spent last week with the CorDynamics team exhibiting at the American College of Toxicology meeting in Orlando.

A timely symposium on the ongoing CiPA (Comprehensive In Vitro Proarrhythmia Assay) initiative brought out a number of questions from attendees as they visited the CorDynamics booth. I enjoyed the lively discussion on various methods and approaches to tackle the concept of proarrhythmia prediction.

Recognizing the nascent status of CiPA, earlier this year we redesigned our standard rabbit Langendorff isolated heart assessments to be conducted with a much greater emphasis on proarrhythmia – while still capturing vital details on cardiac hemodynamics, electrocardiography, and electrophysiology. 

To do this, we perform Langendorff experiments amenable to a wide range of simulation frequencies.

First, we use advanced metrics:

  • instantaneous monophasic action potential variability
  • temporal characteristics of the electrocardiographic T wave
  • development of afterdepolarizations

We couple these data alongside hemodynamic parameters to afford a robust in vitro prediction of proarrhythmia – in a functioning heart.

Here are some data with E-4031 – a known proarrhythmic compound – vs. control.

Slide1

View Data

Using this paradigm, proarrrhythmia can be conclusively detected – or ruled out – in a concentration-response manner. We screen active test articles daily in the preparation, and have recommended advancing or deprioritizing interesting compounds based on these results.

As the pros and cons of the CiPA initiative clarify, an integrated approach to this area of drug safety has always been the prudent course.

Filed under: Drug Safety Services, Langendorff Heart | No Comments

How to Build a Relevant Bridge Between Ion Channel and In-Vivo Telemetry Studies: Langendorff Isolated Heart

Posted by Michael Gralinski, Chief Executive Officer at CorDynamics on November 27th, 2012

The potential to cause arrhythmias is a major concern during lead optimization and assessment of all potential drug candidates, regardless of their therapeutic target.

Why?

  • Potential to trigger lethal arrhythmias is a leading cause of removal of drugs from the market.
  • Regulatory agencies advocate preclinical and clinical testing for hemodynamic effects and proarrhythmic potential—for all new pharmaceutical compounds.

With this in mind, assessing the cardiovascular profile of novel compounds sooner rather than later is the name of the game.

In many cases the Langendorff isolated heart is an effective cardiovascular toxicity screen, and serves as a physiologically relevant bridge between the typical ion channel assay and in-vivo telemetry studies.

We’ve generated data demonstrating this model’s ability to effectively reproduce the known cardiovascular effects of compounds. View publication.

Unlike other experimental procedures such as those examining hERG channel binding and isolated Purkinje fiber assays, both hemodynamic AND electrophysiologic effects of compounds can be observed simultaneously with the Langendorff isolated heart. The model is also resource-sparing, an important consideration during compound selection.

Filed under: Anesthetized Models, Cardiac Ion Channels, Drug Safety Services, Electrophysiology, Hemodynamics, Langendorff Heart, Telemetry | No Comments

The Case for Cardiovascular Safety Studies

Posted by Michael Gralinski, Chief Executive Officer at CorDynamics on July 10th, 2012

What Drug Developers Need to Know….

Case for Cardiovascular Safety Studies

The FDA and the Committee for Proprietary and Medicinal Products (CPMP) firmly advocate that preclinical and clinical tests for adverse cardiovascular potential be performed for all new pharmaceutical compounds, regardless of the intended therapeutic application.

 

Why?

  • Over the past decade, several non-cardiac drugs have been under intense scrutiny due to unanticipated reports of morbidity and mortality associated with adverse cardiac events, namely an increased incidence of life-threatening arrhythmias.
  • Potential to trigger adverse cardiovascular events has become a leading cause for removal of drugs from the market.

What Should We Look For?

  • Of particular interest in cardiovascular safety assessment are the electrophysiologic effects of an agent, such as its consequences on QT interval.
  • In addition, the hemodynamic consequences of a compound are also important to investigate.

How Should We Investigate?

The key is to accurately, affordably and efficiently determine the cardiovascular effects of novel therapeutic compounds. It is important to screen the electrophysiologic and hemodynamic effects of test articles using a variety of applicable and validated methods.

Fulfilling this unique need and collaborating on this issue is what our team does best. We welcome your thoughts and discussions on the topic.

Filed under: Anesthetized Models, Cardiac Ion Channels, Drug Safety Services, Langendorff Heart, Telemetry | No Comments