Posts Tagged ‘Hemodynamics’
Posted by CorDynamics on April 22nd, 2015
The answer is: sometimes.
A few months ago I attended an excellent Safety Pharmacology Society webinar (Nov 2014, “Cardiac Safety Testing Models”) where the non-clinical examination of cardiac contractility was discussed.
Dr. Philip Gatti, from the US FDA, concluded that compounds with putative inotropic effects should undergo “better utilization of in vitro systems (Langendorff or wedge preps) or use of animal models of heart failure which would enhance sensitivity to such drug effects.”
Our labs have interrogated the cardiovascular effects of test articles in a variety of underlying pathophysiological states, including subjects with hypertension to those with impaired respiratory capacity.
One of the more frequent drug safety conditions we are asked to model is the compromised or failing heart. Many project teams need to know if their compounds affect left ventricular hemodynamics in the presence of pre-existing cardiac dysfunction. Sometimes these properties may not exist in the normal subject. However, they may be present in the target population.
We have conducted these studies using multiple models, including the post-infarcted heart, hypertrophy following hemodynamic overload (such as transverse aortic constriction), and tachypaced-induced cardiomyopathy.
Similar questions are usually asked:
- Is it appropriate to examine drug safety in animals with ‘disease-state’?
- Is this a current regulatory expectation?
- Is there a differential effect compared to ‘normal’ animals?
Using these approaches, we have uncovered substantive areas of concern while also mitigating issues that previously appeared insurmountable.
We know there is an important role for using the ‘disease-state’ subject in cardiovascular safety pharmacology assessments.
While most preclinical studies will continue to use normal animals for risk assessment, the inclusion of disease models where appropriate can help unmask notable toxicities that may only occur in the target patient population.
Filed under: Drug Safety Services, Heart Failure, Hemodynamics, Langendorff Heart |
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.
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 |
Posted by CorDynamics on September 09th, 2014
The recent heart failure announcement of the PARADIGM-HF lit up the news sites, and for good reason.
PARADIGM-HF is a clinical trial designed to assess the composite outcome of death or hospitalization in >8000 AHA Class II-IV heart failure patients assigned to receive either enalapril or a novel combined angiotensin receptor antagonist–neprilysin inhibitor. The trial, detailed in The New England Journal of Medicine, was stopped early due to an “overwhelming” benefit from receiving the angiotensin receptor antagonist–neprilysin inhibitor.
Angiotensin receptor antagonists and angiotensin-converting enzyme (ACE) inhibitors have been used in the treatment of heart failure for many years. So what was special about this new method of attacking the disease? The neprilysin inhibitor aspect appears to be critical for the superior efficacy.
Neprilysin inhibition causes an increase in circulating levels of natriuretic peptides. Natriuretic peptides are a family of moieties that cause increased levels of sodium to be excreted by the kidneys. In addition they are vasodilators, inhibit renin-angiotensin-aldosterone axis function and have anti-hypertrophic properties among other effects. One can see why this approach may be beneficial to the failing heart.
Going beyond simply relieving hemodynamic load, increasing our understanding of the complex pathophysiology involving cardiac dysfunction and failure will lead to improved treatments for the > 20 million patients with this condition.
Filed under: Drug Discovery Services, Heart Failure, Hemodynamics |
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.
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 |
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
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 |