Posts Tagged ‘Thrombosis’

Altering Anti-Thrombosis Discovery Models to Examine Pro-Thrombotic Activity from a Safety Perspective

Posted by CorDynamics on January 18th, 2016

Pro-Thrombotic Activity

Thrombosis, the process through which blood forms a clot, is a two-way street. It protects us from major bleeding following even minor injuries, yet is responsible for over ten million deaths globally every year via heart attacks and strokes.

Over the years we’ve conducted many preclinical thrombosis studies examining the effects of established and potential ANTI-thrombotic agents. Increasingly, a number of clients have asked for the development of slightly altered models to screen compounds for any PRO-thrombotic activity.

This new data set marks our evolution of anti-thrombosis discovery investigations into pro-thrombotic safety models, focusing on our ability to create a pro-thrombotic window. Clearly, pro-thrombotic activity is an undesirable property for drugs outside the cardiovascular arena.

See data.

Although our large animal anti-thrombotic models (including the electrolytic injury paradigms) are well characterized in a traditional efficacy mode, it is challenging from a resource perspective to scale those preparations to screen multiple compounds rapidly. As such we’ve been modifying our rodent models of arterial thrombosis – namely, the FeCl3 mouse – for a prothrombotic screening setting.

Briefly, we dose mice with either vehicle or active test article for the specified period prior to administration of reduced levels of FeCl3 to the external surface of the carotid artery. In most mice, the reduced levels of FeCl3 will cause instability in arterial blood flow – but not be associated with significant occlusion (formation of thrombus). Test article pro-thrombotic activity may be quantitated as reductions in arterial blood flow along with increasing incidence of occlusion.

More on thrombosis.

 

 

Filed under: Drug Discovery Services, Drug Safety Services, Thrombosis | No Comments

Drug Discovery: Models for Investigating Thrombosis

Posted by CorDynamics on August 25th, 2014

When clients approach us with our thoughts on investigating potential anti-thrombotic treatments we typically start by suggesting they consider our well-characterized mouse model.

The model, where we produce a carotid arterial thrombus using a process that can be interrupted by efficacious test articles,  provides a deeper understanding of the biological pathways associated with thrombosis.

Drug Discovery: Models for Investigating Thrombosis

 

View data.

Briefly, we dose mice with either vehicle or active test article prior to administration of FeCl3 to the external surface of the carotid artery. Following this exposure to FeCl3, thrombotic occlusion of the carotid artery occurs in a matter of minutes in the untreated animal. Test article efficacy can be quantitated as alterations in coronary artery blood flow along with time to occlusion.

Filed under: Drug Discovery Services, Thrombosis | No Comments

Thrombosis Models Provide Efficacy Assessment for Resurgent Therapeutic Area

Posted by CorDynamics on December 11th, 2013

Over the past 10 years, we’ve worked with clients to investigate potential anti-thrombotic treatments along with those interfering with the coagulation cascade.

Frankly, up until recently the requests for these types of experiments have been relatively infrequent. It was thought we had reached a new age of discovery in coagulation therapy, with the introduction of recent antiplatelet agents.

Recent challenges have arisen with these new modalities; most notably complications from excess bleeding. Some researchers have even suggested these compounds may not replace warfarin as first line therapy.

During 2013 our laboratories have experienced a notable uptick in the requests for thrombosis models.

Recently we released data demonstrating the ‘re-introduction’ of a well-characterized mouse model of arterial thrombosis. In these mice, we produce a carotid arterial thrombus using a process that can be interrupted by efficacious test articles.

Briefly, we dose mice with either vehicle or active test article prior to administration of FeCl3 to the external surface of the carotid artery. Following this exposure to FeCl3, thrombotic occlusion of the carotid artery occurs in a matter of minutes in the untreated animal. Test article efficacy can be quantitated as alterations in coronary artery blood flow along with time to occlusion.

Drug Discovery: Models for Investigating Thrombosis

View data.

Models like this provide a better understanding of the biological pathways associated with thrombosis. With this knowledge in hand, a number of our clients are taking a renewed look at the compounds in their arsenals in an effort to continue addressing this critical therapeutic area.

 

Filed under: Drug Discovery Services, Thrombosis | No Comments