Archive for the ‘Thrombosis’ Category

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.

 

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Several Models Shed Light on Potential Pulmonary Hypertension Therapies

Posted by Michael Gralinski, Chief Executive Officer at CorDynamics on March 24th, 2010

This week I’ve been in both Southern California and Western Europe – visiting exclusively with current clients to discuss their ongoing work in our laboratories. What’s interesting was the amount of renewed interest and discussion around very early-stage programs, including those nowhere near ready for GLP safety studies. What a difference from a year ago.

Overall, we’ve seen a promising uptick in the number and scope of typical IND-enabling CV safety studies along with their associated screening endeavors and mechanistic follow-ups. The supply of capital is loosening up for a number of biotechs, and larger Pharma companies continue to hone their pipelines via acquisition and the revisiting of projects previously placed on hold.

The demand for our discovery services has swelled noticeably since the start of 4Q’09 as well. You may recall a recent writing detailing our experimental offerings in pulmonary arterial hypertension. What started as a methods development expedition for one client more than two years ago has now blossomed into critical outsourcing relationships with multiple biopharmaceutical companies using several well-established paradigms in this therapeutic area.

But we’ve not been content with only PAH Discovery work; as of this writing, our laboratories are also actively conducting efficacy experiments in ischemia/reperfusion injury, thrombosis, congestive heart failure, and atrial fibrillation  — with the latter two areas strongly leveraging our expertise in advanced conscious instrumented models.

I had the pleasure of attending the 2009 American Heart Association Scientific Sessions in Orlando during November. While sitting down with a current small biotech client – they also noted the window of progress opening again. For them, this meant the ability to finally start vetting promising compounds across therapeutic platforms rather than just focusing on a single area that’s been successful. For the industry as a whole, the ability to have multiple backup strategies in the case of primary failure will be critical as we navigate toward recovery.

I look forward to the 2010 Western Pharmacology Society meeting in San Diego during February. We exhibited at this meeting when it was held in Honolulu a few years ago, and the organizers use a brilliant tactic to break up the agenda and maximize the attendance. There are sessions during the morning and evening, with free time during the day to enjoy the locale. I hope to see you there.

 

Filed under: Atrial Fibrillation, Drug Discovery Services, Heart Failure, Ischemia Reperfusion Models, Pulmonary Arterial Hypertension, Thrombosis | No Comments