Posts Tagged ‘Electrophysiology’

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

Investigating Cardiotoxicity in Anti-Cancer TK Inhibitor Class

Posted by CorDynamics on June 10th, 2014

Last week a story entitled The Serious Heart Risks That Come With Chemo was published in Time. The case studies detailed cardiac issues faced by cancer patients during and after (sometime years after) chemotherapy. The recognition of this phenomenon has spawned a new branch of cancer doctor, the cardio-oncologist.

The observation that both traditional and newer chemotherapeutics agents may interfere with heart function is not a new one. Doxorubicin’s relationship to drug-induced cardiomyopathy was first described in the 1970s and more recent publications have detailed the left ventricular dysfunction that may arise from imatinib, a tyrosine kinase inhibitor. Direct cardiotoxicity is not exclusive to these two compounds.

It is well established that cancer medicines can affect:

  • cardiac function
  • hypertension
  • electrocardiographic changes (including QT interval prolongation)

Most of these effects can be modeled in a preclinical fashion.

The mechanism behind heart failure associated with imatinib has been detailed in the research laboratory–leading to increased clinical vigilance along with improvement in treatment regimens.

Our laboratories have also investigated the cardiovascular changes with newer anti-cancer agents, most notably the TK inhibitor class. This mechanism attacks targets having a role in cancer growth or progression, while attempting to leave non-cancer cells alone. Sometimes however, both normal and cancer cells express the molecular target. Using telemetry, we have demonstrated the strong hypertension with TK inhibitors in chronic animal models.

View Data

These experiments have helped clients in their attempt to reduce unwanted cardiovascular toxicity.

The more we know about the multi-faceted profile of these agents, the better chance we have to simultaneously treat the disease while working to mitigate any side effects.

Filed under: Drug Safety Services, Electrophysiology, Telemetry | No Comments

CorDynamics to Showcase Cardiovascular Capabilities at SPS 2013

Posted by CorDynamics on September 10th, 2013

CorDynamics heads to Rotterdam for the Safety Pharmacology Society meeting next week, September 16-19th.

Peter Senese, CorDynamics co-founder and chief operating officer, along with Dr. Franz Hock, our European business developer will be on hand in The Netherlands to discuss cardiovascular safety assessments and capabilities:

• Telemetry—dual pressure, respiratory parameters, ECG

• Isolated Langendorff heart

• Electrophysiology, hemodynamics

Of special note, we will also be featuring the latest industry primer: Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays co-edited by Dr. Franz Hock.Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays

Among a number of hot topics, the book argues the days of sequential drug development should be a thing of the past, replaced instead with simultaneous data generation combining toxicological, pharmacodynamic and pharmacokinetic data both from a preclinical and clinical environment.

To discuss these topics and more, please stop by our booth. If you’re not attending this year, feel free to contact us for more information.

 

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

Cracking the Case on Sudden Cardiac Death and Domperidone

Posted by CorDynamics on April 18th, 2013

by Liomar Neves, Senior Scientist

Recently, the Journal of Cardiovascular Pharmacology published an original article investigating sudden cardiac death and QT interval prolongation associated with domperidone that caught the attention of our CorDynamics team.

The Report

Domperidone is a dopamine receptor antagonist not approved by FDA for sale in the US market, but is widely used in more than 100 countries. Its purported benefits are as a gastrointestinal prokinetic agent, an anti-nausea and vomiting therapeutic and more recently it has been used to promote lactation.

However, the compound has been associated with disturbances in ventricular electrophysiology. These include increases in QT interval and cardiac rhythm disturbances.

In this recent preclinical study, the authors confirm that domperidone prolongs action potential duration and suggests that the IC50 for blocking the hERG channel IKr may be lower than previously reported.

New Evidence

The study also involved the use of prolonged domperidone exposure times, longer cycle lengths to examine reverse-use dependence, and use of rabbit hearts that are naturally heightened for sensitivity to IKr antagonism.

  • Evidence demonstrated domperidone to have a high affinity to IKr and low safety margin, thus increasing risk of drug-induced long QT syndrome and potential proarrhythmogenesis.
  • Additionally, the report brings attention to the limited benefits of domperidone for gastrointestinal disturbances and highlights the risk of using a low safety margin drug for a non-threatening target such as promotion of lactation.

The authors concluded the report by urging other regulatory agencies to take the FDA’s approach and ban domperidone’s use.

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

Validated Anesthetized Model Screens Cardiovascular Effects Early

Posted by CorDynamics on January 31st, 2013

We have been getting a lot of communication lately from clients looking to outsource larger blocks of screening cardiovascular studies.

One frequently requested model is the anesthetized guinea pig assessment. We’ve been conducting this model for nearly ten years.  So we thought it was time to refresh the original validation dataset with the expertise we’ve gained to share with clients and colleagues interested in leveraging this model.

View Validation Data

The preparation uses a well-characterized method to screen for cardiovascular effects early.

  • Guinea pigs are anesthetized and instrumented for hemodynamics and electrocardiography.
  • Cardiovascular parameters such as blood pressure, heart rate, and ECG are measured.
  • Cardiac functional assessments can also be provided.

As such, we have conducted experiments with a number of ‘cardio-active’ compounds. Verapamil (primary effects on PR interval and blood pressure), pimobendan (heart rate), flecainide (QRS duration), and E-4031 (QT interval) were examined in the model.  We have posted the results to our website, the dataset is quite nice.

A benefit of the model is the ability to perform pharmacokinetic assessments to interrogate PK-PD relationships. The other plus is the aggressive timeline. In most cases, we can get full information on a compound to the client within 2-3 days.

Please take a look, and feel free to contact us with any questions.

Filed under: Anesthetized Models, Drug Safety Services, Electrophysiology, Hemodynamics | 1 Comment

Expanding Telemetry Widens the Drug Development Picture

Posted by Michael Gralinski, Chief Executive Officer at CorDynamics on November 02nd, 2012

Highlighting our growing telemetry capabilities will be on our docket in booth #300 at the American College of Toxicology meeting in Orlando.

Cardiovascular Telemetry Drug Development

In an on-going effort to provide our clients with quality data addressing their specific scientific questions, we continue to expand our telemetry technology and our customized study designs.

Leverage GLP Studies and non-GLP Screening

It’s imperative to determine which lead compounds to put finite R&D dollars behind. Understanding this, our team has taken the telemetry models we use for GLP examinations of test articles and transformed the concept to create physiologically relevant screening models for lead compounds early in preclinical development.

Typical GLP canine or non-human primate telemetry studies average around six to eight subjects per interrogation and include a full protocol and report. Clients go back to their project teams with high fidelity assessments of effects on blood pressure, heart rate, ECG (including QT interval) and other parameters.

At the point of lead compound selection, however, project teams are trying to identify the most promising compound for advancement—thus we often compare one compound to another by rank order.

As a result, it’s often not necessary to invest in eight subjects on a screening study, nor have a full protocol or report.

Conserve Time and Money with Dual Capabilities

Simultaneously gathering data on two pressure measurements or analyzing two organ systems, helps project teams operating under tight budget constraints and ambitious timelines meet their regulatory requirements.

With dual pressure telemetry  we can now surgically instrument rats to measure systemic blood pressure AND either pulmonary artery pressure or left ventricular pressure —simultaneously. In addition, we can also provide ECG readings. Previously, this level of in vivo telemetry instrumentation was only available in large animal models.

Likewise with our respiratory telemetry capabilities, we can now analyze two organ systems—cardiovascular and respiratory—with one large species study.

In addition, these models are designed with the 3R’s in mind. Collecting multiple variables from the same subject reduces the need for redundant groups.

 

Filed under: Anesthetized Models, Drug Discovery Services, Drug Safety Services, Hemodynamics, Telemetry | No Comments

How Preclinical Cardiovascular Anesthetized Data Translates into the Clinic

Posted by Michael Gralinski, Chief Executive Officer at CorDynamics on July 17th, 2012

Translating preclinical cardiovascular data into clinical success is the name of the R&D game.

Anesthetized models are some of the most sensitive assays researchers can use to investigate the cardiovascular effects of their lead candidates and back-up compounds.

The thoroughly validated research and a wealth of scientific publications demonstrate that anesthetized studies in several subject species (canine, rat, guinea pig, rabbit, NHP) are highly predictive and similar to those observed in humans.

This is imperative as 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.

Anesthetized studies can be designed with advanced hemodynamics and electrophysiological testing to assess a variety of cardiovascular effects.

• Advanced hemodynamics
• Heart rate
• Systemic blood pressures
• Pulmonary artery pressure
• Left ventricular pressures and derivatives
• Cardiac output
• Blood flow
• PK/PD relationships
• Electrocardiograms

Armed with this critical data, developers can translate their preclinical results into strategies for improved clinical performance.

Filed under: Anesthetized Models, Drug Safety Services, Electrophysiology, Hemodynamics | No Comments

Investigating the Truth About Afib

Posted by Michael Gralinski, Chief Executive Officer at CorDynamics on September 29th, 2011

AFib, AF, Atrial Fibrillation, — It’s the most common cardiac arrhythmia, affecting millions of individuals. Patients with AF rarely exhibit symptoms and are at a five-fold increased risk of stroke due to thrombosis from stagnant flow in the atrium. With such a target profile, the condition is a hot area for drug developers.

As with many disease states, the path toward targeted efficacy is fraught with hurdles. With AF, one of the long-standing 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.

One way of investigating test articles from both a safety and discovery perspective is to use an instrumented animal equipped to provide information on complete cardiac electrophysiology. These models are effective since they provide a detailed interrogation on these parameters, alongside tolerability and PK/PD information.

For a more in-depth look at how an in vivo model can provide a comprehensive safety and discovery investigation in one experiment, check out our abstract to be presented at the 2012 Safety Pharmacology Society meeting in Innsbruck. We used chronically instrumented dogs to demonstrate the doses of both flecainide and dronedarone that result in changes with atrial, but not ventricular, refractoriness.

Getting to the heart of atrial fibrillation will go a long way in helping researchers make good scientific decisions and drug companies make good business decisions so physicans can guide patients in making the best health decisions.

 

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