Posts Tagged ‘Cardiac Arrhythmia’

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

American Heart Association Take-Away: Still Seeking Truth About AFib

Posted by Michael Gralinski, Chief Executive Officer at CorDynamics on November 17th, 2011

As we’ve discussed in a previous blog, Investigating the Truth About AFib, the path toward targeted efficacy is fraught with hurdles. The reports coming out of the American Heart Association’s Annual Meeting are confirming just that.

Clearly, AFib, AF, Atrial Fibrillation, while being the most common cardiac arrhythmia affecting millions of individuals, is still not commonly understood from a drug development standpoint. Dronedarone, one of the big AHA headliners, is a drug we have used in preclinical investigations as well. In fact, our abstract that was presented at the 2012 Safety Pharmacology Society meeting in Innsbruck featured the use of chronically instrumented dogs to demonstrate the doses of both flecainide and dronedarone that result in changes with atrial, but not ventricular, refractoriness.

Through these types of studies, we are finding one of the long-standing AF roadblocks has been the selectivity of compounds on atrial vs. ventricular electrophysiology. Usually, the goal is to specifically alter the electrical properties of the heart’s upper chambers (atria) while leaving the lower chambers (ventricles) alone. Not nearly enough new chemical entities have this property—thus, the limited good treatment options in this area.

I find much of drug development news features on the negative headlines of drugs that “fail.” As researchers, we learn important discoveries from each study. This ultimately leads us to more effective compounds and gives physicians, a better indication of which medications to prescribe to which patients on a case-by-case basis. Sometimes knowing what doesn’t work, is just as important as knowing what does.

Filed under: Atrial Fibrillation, Drug Discovery Services, Telemetry | No Comments