Posts Tagged ‘Dr. Liomar Neves’

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

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

Producing PAH Results: Elaborating on Collaborating

Posted by Theresa Gralinski, Marketing Director at CorDynamics on December 02nd, 2011

Drug development researchers have been putting a lot of emphasis on collaborating in the effort to produce safe and effective drugs as quickly as possible. This is especially true in the area of rare disease research.

The CorDynamics team collaborates day in and day out—with each other, with colleagues, with our clients and their project teams. But collaborating is kind of like parenting, you think and hope you are doing it well but there isn’t a definitive gauge to tell you if you are making progress.

Well lo and behold, a tangible affirmation of collaboration was recently celebrated in our lab. CorDynamics Senior Scientist Dr. Liomar Neves, with our colleagues at Corridor Pharmaceuticals, demonstrated the novel serotonin receptor antagonist C-122 prevents monocrotaline induced pulmonary arterial hypertension (PAH) in rats in a paper published in the European Journal of Pharmacology.

PAH—an orphan disease, with unmet medical treatment—is characterized by increased blood pressure in the arteries of lungs, causing dizziness, shortness of breath and can lead to heart failure. Current therapies for pulmonary artery hypertension (PAH) improve longevity and performance of daily activities in the lives of PAH patients, but do not notably affect the disease processes that lead to morbidity and mortality. Since serotonin has a definitive role in the development of PAH, the authors hypothesized that interfering with serotonin function may reduce the vascular remodeling and hemodynamic changes that occur in this preclinical model.

With the industry continuing to embrace a collaborative environment, I look forward to more research results that will ultimately provide more treatment options for patients in the future. As far as my kids and my parenting skills go, I guess I’ll have to assume no coal in their stockings means I’m doing something right and continue to believe.

 

Filed under: Drug Discovery Services, Publications, Pulmonary Arterial Hypertension, Uncategorized | No Comments