Posts Tagged ‘Anesthetized Studies’

Questioning QT Interval Measurements? Look at the Anesthetic: Part 2

Posted by CorDynamics on March 16th, 2015

QT Questions Look at Anesthetic

CorDynamics will be presenting a poster at the upcoming 2015 Society of Toxicology meeting in San Diego entitled: The Differential Effect of Nembutal and Ketamine/Xylazine Anesthetic on Dofetilide-Induced QT Interval Prolongation. 

The objective was to advance upon our previous findings presented at SOT last year. (Read Part I: When Questioning QT Interval Measurements: Look at the Anesthetic.) This model examines the effects of dofetilide, an IKr antagonist known to prolong QT interval, on guinea pigs anesthetized with either Nembutal or ketamine/xylazine.

The anesthetized guinea pig is a widely used model for early screening of drug-candidate effects on cardiovascular function. This species also continues to gain traction for use in conscious telemetry screening.

In this study, we found that administration of dofetilide to either Nembutal or ketamine/xylazine anesthetized guinea pigs significantly increased QTcB interval at all doses tested compared to time-matched vehicle control. QTcB interval increased up to 22% in the Nembutal group, yet only reached 12% in the ketamine/xylazine group even though the dose was increased 5-fold in the latter cohort. There were no effects on mean arterial pressure, heart rate, or other ECG parameters in either group.

View Poster

Our data demonstrate that sodium pentobarbital anesthetized guinea pigs are more sensitive to QTc interval prolongation than ketamine/xylazine animals.

Our Conclusion

Consideration should be taken when selecting anesthetics for the guinea pig cardiovascular model. Sodium pentobarbital should be the anesthetic of choice when screening compounds for the potential to prolong QTc interval.

Filed under: Anesthetized Models, Telemetry | No Comments

When Questioning QT Interval Measurements: Look at the Anesthetic

Posted by CorDynamics on April 09th, 2014

QT Questions Look at Anesthetic

CorDynamics recently presented a poster at the 2014 Society of toxicology meeting in Phoenix entitled: Effect of Anesthetic on QT Interval Measurements in Guinea Pigs.

Our objective was to investigate the baseline vulnerability of the anesthetized guinea pig for safety pharmacology screening of drugs with the potential to prolong the QT interval.

The anesthetized guinea pig is a widely used model for early screening of drug-candidate effects on cardiovascular function. This species also continues to gain traction for use in conscious telemetry screening.

The vast majority of these cardiac safety studies are performed in anesthetized guinea pigs with sodium pentobarbital as the anesthetic of choice. However, it’s well documented that sodium pentobarbital is an antagonist of the inward rectifying cardiac potassium channel IKs. Since the IKs is a robust component of the guinea pig cardiac repolarization sequence, this species can be particularly sensitive to IKs blockade.

In this study we investigated the baseline vulnerability of the guinea pig anesthetized with ketamine and Nembutal for safety pharmacology screening of drugs with potential to prolong the QT interval.

View Poster

Our data demonstrated that the choice of anesthetic appears to influence the QT interval in anesthetized guinea pigs compared to conscious animals.

Our Conclusion

It is possible that anesthetics with additional inherent IKs blockade such as sodium pentobarbital may overly sensitize the animal to agents that prolong the electrocardiographic QT interval. Consideration should be taken when selecting anesthetics for this model.

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

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

Preclinical Case Study: How to Investigate Hemodynamics and Cardiac Electrophysiology In Vivo

Posted by Michael Gralinski, Chief Executive Officer at CorDynamics on October 24th, 2012

The Case Study

Verrow Pharmaceuticals came to CorDynamics with an interesting cardiovascular safety question regarding their compound Veropaque. We came up with a customized study design leveraging our in vivo anesthetized canine model to generate answers.

The Question

Contrast products can cause significant kidney injury in about 10% of cardiology patients, resulting in contrast induced nephropathy. With Veropaque, Verrow hypothesized that the use of substituted cyclodextrins (SCD) in the formulation would mitigate the renal toxicity of a contrast agent (CA).

CorDynamics was enlisted to determine if Veropaque exhibited a hemodynamic and electrocardiographic profile similar to a marketed comparator in a relevant species.

The Answers

In our laboratories, we conducted in vivo anesthetized canine studies uniquely designed to monitor the cardiac hemodynamic and electrocardiographic effects of Veropaque.

View Data

Intracoronary artery injections in the dog revealed no significant differences between iohexol and Veropaque and no notable effects on most measured cardiovascular parameters other than transient changes in left ventricular contractility and QTc interval as previously described in the literature.

The resulting abstract, exhibiting at this week’s Transcatheter Cardiovascular Therapeutics Conference in Miami, illustrates that including substituted cyclodextrins in the formulation of a novel contrast agent is nephroprotective against contrast-induced acute kidney injury, functional changes, and mortality in rodent models without altering their cardiovascular profile.

 

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

Catching Cardiotoxicity: Physiological Changes Can Precede Pathology

Posted by Michael Gralinski, Chief Executive Officer at CorDynamics on August 29th, 2012

Time and again, we hear of compounds exhibiting cardiotoxicity well into the clinical stage of R&D and ultimately being pulled from the pipeline.

1. Were cardiovascular effects noticed early and not vetted properly?
2. Were there insufficient preclinical studies to find these indicators?
3. Or, did they not show up at all?

Any one of these three scenarios means millions if not billions of dollars wasted, not to mention the untold time spent advancing a doomed to fail compound through drug development. In case #’s 1 and 2, investing in a comprehensive battery of preclinical cardiovascular studies and following up on possible red flags can allow a sponsor to make critical go/no-go decisions early.

An example of this is outlined in a paper we recently co-published with Hoffman-La Roche in the British Journal of Pharmacology.

In standard two week toxicology studies, the compound RO5657- a CCR5 antagonist -had induced treatment related myocardial degeneration in previously normal animals. Employing a variety of preclinical models, the article demonstrated that the compound exhibited cardiovascular side effects and life threatening arrhythmias before the development of pathological findings. Thus, the change in cardiovascular physiology served as a harbinger of downstream histopathological events.

In fact, the ion channel and isolated heart interrogations conducted on RO5657 ultimately predicted the anesthetized, telemetry and toxicology study results. The sponsor was then able to use good scientific rationale to help make good business decisions on this compound.

Filed under: Anesthetized Models, Cardiac Ion Channels, Drug Safety Services, Langendorff Heart | 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

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