Archive for the ‘Drug Discovery Services’ 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

Efficacy with PAH Clinical Drugs in Modified Gold Standard Preclinical Assessment

Posted by CorDynamics on January 13th, 2015

Riociguat Reduces Pulmonary Arterial Hypertension in Hypoxia-Semaxanib Intervention Model

Our laboratories recently conducted experiments examining whether riociguat – approved by the FDA for PAH in 2013 – along with sildenafil could intervene against established hypoxia-semaxanib mediated pulmonary arterial hypertension (PAH) in the rat.

Our research team has already reported on the effects of numerous positive controls including sildenafil, bosentan, bestatin and tadalafil using a prevention mode.

These intervention-focused experiments were novel since riociguat or sildenafil were dosed daily beginning 4 weeks after the initiation of PAH.

Riociguat Reduce Pulmonary Arterial Hypertension in Hypoxia-Semaxanib Intervention Model

View Data

The data demonstrate a 21% reduction in pulmonary artery pressure following 4 weeks of intervention with riociguat (42% decrease with sildenafil). In addition, right ventricular hypertrophy was decreased 20% in the riociguat cohort vs. vehicle (sildenafil – 22% reduction).

Examining these clinically utilized compounds in both prevention and intervention modes provides clients with an enhanced, translatable model of pulmonary arterial hypertension.

 

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

Multiple Models for Researching the Complexities of PAH

Posted by CorDynamics on November 06th, 2014

To state it simply, pulmonary arterial hypertension is a complex disease.

Our labs have generated substantive data, and after numerous conversations with colleagues, it is clear that researching this disease from multiple aspects is likely the most efficient way to help find new treatments.

We recently presented a comprehensive overview of our PAH findings at a Lunch and Learn at the 2014 Safety Pharmacology Society Annual meeting and again for a client project team.

new_therapies_for_PAH

VIEW PRESENTATION

Over the past several years, companies were focused on providing benefit to PAH patients primarily through a hemodynamic mechanism such as selective pulmonary arterial vasodilation. Recently, the paradigm has shifted to focus more on the remodeling and inflammatory processes associated with the development of PAH.

Although the hypoxia / VEGF antagonist treated rat continues to be the gold standard animal model of this disease, increasingly we have been conducting experiments using a T-cell deficient rat co-treated with VEGF antagonist. This model is dependent on dysregulated immunity contributing to increased inflammation that exacerbates PAH.

Our results showing a protective effect with the LTA4 hydrolase inhibitor bestatin are consistent with the literature. In addition, we now have data demonstrating that sildenafil (PDE5 inhibitor – hemodynamic effect) shows efficacy in this ‘inflammatory’ model as well. A recent article has also shown that sildenafil has an anti-inflammatory effect in monocrotaline treated rats.

Research into developing additional and better treatments for PAH continues at a rapid and growing rate. We are also discovering new mechanisms by which current options exert efficacy. By continuing to refine the animal models of this disease, we stack the odds of success in our favor.

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

PAH Data Download: The Ins and Outs of Multiple Models

Posted by CorDynamics on October 15th, 2014

Over the past 5 years our laboratories have conducted numerous studies with various models of pulmonary hypertension.

We are looking forward to sharing some our findings next week at the Safety Pharmacology Society Annual meeting in Washington, D.C. in a lunch and learn on Monday, October 20th.

We will be discussing results from our monocrotaline and hypoxia experiments as well as sharing our large datasets generated from clinical treatments in our gold standard model–the hypoxia/VEGF receptor antagonist exposed rat.  These results are very compelling – and show differential effects of sildenafil at 3, 4, 6 and 12 weeks into the hypoxia/VEGF model.

Slide2

Over the past year, our labs have also conducted studies with an alternative preclinical model of PAH – the athymic nude rat treated with VEGF receptor antagonist. This model may be applicable to a certain subset of PAH patients where inflammation appears to play a major pathogenic role.

If you are at SPS – stop over for some lunch accompanied by an in depth data dissection from various models of pulmonary arterial hypertension.

For those that are not attending – check our website after the SPS meeting where you’ll be able to download the slide deck from our presentation.

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

Burgeoning Heart Failure Treatment Goes Beyond Relieving Hemodynamic Load

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.

crackingheart

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 | 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

Cardiac Stem Cell Science on Thin Ice

Posted by CorDynamics on May 21st, 2014

Solid Data Needed to Strengthen Case

by Dr. Michael Gralinski

thin ice 2

Every day I scan a variety of news outlets for the latest developments in the biotech field. Recently, a piece published online in Forbes grabbed my attention.

The article, “Stem Cell Therapy To Fix The Heart: A House Of Cards About To Fall?” discussed a scientific paper (BMJ) which concluded that many of the most exciting developments in clinical cardiac stem cell research are not true. In addition,  the purported benefits to patients with cardiovascular disease are at best very modest and likely non-existent. The authors call into question the recent reports of high profile stem cell research, citing the recent withdrawals of ‘landmark’ publications in prestigious journals such as Circulation and The Lancet.

What took me by surprise was this concise, yet elegant dissection of cutting-edge research was published in Forbes – a business journal. The Forbes authors did a fantastic job of explaining the detailed methods and rigor of analysis in the original BMJ article. (Both are compelling reads.) It also underscored a conversation I had with a colleague at a recent scientific conference. He too was struggling with how to incorporate cardiac stem cells into their offering. He told me his business development team loved the idea so they invested in building this into their services. However, the clients are not jumping on board and asking for it. Why? They aren’t will to spend finite R&D resources on a safety study without solid, validated data.

In the same vein, I recently attended the 2014 Society of Toxicology-Midwest Regional Chapter meeting at a venue outside of Chicago. The theme of this years’ symposium was “The Use of Stem Cells in Toxicology Evaluation”.

Most of the speakers were associated with companies offering stem cell technology as a fee-for-service/product. A few academicians also detailed their research in the field. In the main, the presentations were interesting yet felt commercial in nature. Again, from a business development side, it is an exciting prospect. However, after a few talks detailing how beneficial and predictive this technology is, I asked a simple question.

“What are the pitfalls and potential downside of using stem cells for drug safety screening?”

The answer was frankly very disappointing and even described as ‘wishy-washy’ from the apologetic speaker I was addressing – a leader in the field.

Many of us believe this technology has some interesting characteristics and the potential to streamline drug safety screening. It is clear the regulators are also moving in this direction. However, those of us who have seen these ‘transformative technologies’ come with a vengeance and disappear with a whimper are still looking for answers to questions and solid scientific data to help guide our opinions and ultimately our research. Good science will always lead to good business.

 

Filed under: Drug Discovery Services, Drug Safety Services | 4 Comments

How to Conserve Test Article, Time and Money with Telemetry

Posted by CorDynamics on March 11th, 2014

Here’s a familiar dilemma. Your research team detects unanticipated cardiovascular activity in your lead candidate but there is limited test article for follow-up discovery and safety studies.

In these cases, we often suggest either conscious telemetry or an anesthetized preparation in the guinea pig as an effective model for cardiovascular testing, when appropriate. Since they are smaller in size, guinea pigs can serve as a viable species when compound supply is limited.

In some cases, the guinea pig can use five times less compound to conduct studies than amounts needed for their larger counterparts, such as rabbits.

The Conscious Model

Using telemetry to deliver quasi beat-to-beat data, this guinea pig model generates ultra high fidelity QT interval correction. View Conscious Validation Data

The Anesthetized Model

In this preparation, we employ a well-characterized anesthetized method to screen for cardiovascular effects early. Cardiovascular parameters such as blood pressure, heart rate, as well as ECG are measured and cardiac functional assessments can also be provided. View Anesthetized Validation Data

While a plus in terms of compound conservation, the guinea pig’s small size and inherent anatomical obstacles do pose potential roadblocks. This is especially true in the hands of less experienced technical personnel. Guinea pigs have rather obscure vascular access due to the lack of a tail and their orogastric structure can make orally dosing somewhat challenging.

Although the guinea pig is not appropriate for every situation, with careful planning and expert execution, this species does indeed play a valuable role in the successful de-risking funnels employed by a number of our biopharmaceutical clients.

Filed under: Drug Discovery Services, Drug Safety Services, Telemetry | 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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New Model Measures Time Course of Pulmonary Artery Pressure Increases

Posted by CorDynamics on November 20th, 2013

November is pulmonary hypertension month, shedding needed attention on the rare disease.

Pulmonary arterial hypertension is an orphan disease, characterized by increased blood pressure in the arteries of lungs, causing dizziness, shortness of breath and can lead to heart failure.

CorDynamics has developed several discovery research models for PAH.

We recently published a poster at ACT 2013 sharing our findings: PAH Induced by Semaxanib and Low Oxygen Environment: Time Course Pulmonary Artery Pressure Increases Measured by Telemetry.

The study built on our previous data set which showed a robust increase in pulmonary arterial pressure (PAP) between Day 1 and Day 42 in untreated rats. In our latest study, we conducted additional validation of the model by evaluating the daily progressive increase in pulmonary artery pressures using telemetry.

In this investigation, instead of only interrogating PAP at the end of study, in the current assessment we used telemetry to provide daily readings of PAP. The data demonstrate a linear increase in PAP between Day 1 (~35 mm Hg) to approximately Day 28 (~120 mm Hg). After this time, PAP increases tended to plateau when examined out to Day 42.

This data was intriguing for a number of reasons.

  • It suggested that an optimal interval for intervention exists, as opposed to prevention mode when we start dosing on Day 1. In our labs we recommend considering to initiate treatment between Days 10 and 14 to reverse or mitigate further PAP increases.
  • Starting reversal therapy later than that has diminishing returns, as PAP levels become very high toward Day 21.
  • There were no substantive increases in PAP between Days 28 and 42.

This suggests a nominal difference between 4 and 6 weeks of treatment – saving test article and getting efficacy issues resolved quicker.

Conclusions
Oral administration of sildenafil reduces PAH induced by semaxanib and a low oxygen environment. The increase in pulmonary artery pressure reaches a plateau after approximately 4 weeks. Putative reversal therapy should be started between two and three weeks after initiation of PAH.

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