Posts Tagged ‘Cardiovascular Preclinical Consulting’

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

ILSI/HESI Proarrhythmia Paradigm Raises More Questions Than Answers

Posted by CorDynamics on September 05th, 2013

At the end of July 2013, ILSI/HESI co-sponsored a meeting in Washington D.C. along with the Cardiac Safety Research Consortium / USFDA entitled “Rechanneling the Current Cardiac Risk Paradigm: Arrhythmia Risk Assessment during Drug Development without the Thorough QT Study”.

Essentially, the agenda was a discussion of the ‘paradigm shift’ and ‘proposed testing schema’ under consideration to improve the cardiovascular risk assessment of new chemical entities submitted for marketing licensing. The scheduling of the meeting indicates dissatisfaction, either perceived or real, with the current cardiovascular safety testing funnel.

I was not at the meeting due to a calendar conflict. Although I was frustrated as the topic is certainly germane to our business interests, the organizers posted the presentations and slides online. In hindsight, viewing the slides objectively unencumbered by discussions and sidebars gave me an unfiltered look.

After further view, I found the arguments to contradict one another. On one hand, the presentation highlighted potential consequences of not changing the current testing scheme as: the ‘perversion of lead selection’ and ‘NOT fulfilling the public health need.’ However, the presenters also stated there have been ‘no QT-related withdrawals’ and ‘reductions in post-marketing reports of arrhythmias’ as evidenced by E14 and S7B successes.

Frankly, which is it? Aren’t the reduction of QT-related withdrawals and reduction in post-marketing reports of arrhythmias fulfilling the public health need and informing drug developers who are making lead optimization decisions? Like most things it’s probably somewhere in the middle.

So, here are some questions:

1. If cardiovascular risk reduction has indeed improved – arguably the accurate metric of public health need – is the concern actually that the industry has become too conservative resulting in weak pipelines?

2. Where is the data demonstrating computer simulations of cardiac myocytes – or computer simulations of whole hearts–are more complex and integrative than in vitro or in vivo proarrhythmia models? With what information are these computer simulations being programmed? I would argue the animal models, when designed appropriately, likely contain the vulnerable substrate(s) similar to the susceptible population (the public) necessary to facilitate or induce triggered arrhythmias.

3. Speaking of proarrhythmia— what happened to the examination of in vivo proarrhythmia models? Is the database and methodology accrued over 30+ years just considered too complex with too few people to understand it?

4. The oft-used descriptor of the hERG assay’s potential as a red herring is that ‘many of the 100 most-prescribed drugs are hERG blockers’. Is somebody testing the 100 most-prescribed drugs in stem cells and in silico models? Are the results any different?

There are questions sure to be discussed vociferously in the months ahead.

The slide deck from the investment community representative makes the most sense at face value.

• Reduce uncertainly as far and as early as possible

• Make test batteries efficient and effective

• Create international benchmarks

Ironically, these were the exact same calls to arms for generating ICH S7A, S7B, and E14 in 2000 and 2005.

 

Filed under: Cardiac Ion Channels, Drug Safety Services, Electrophysiology, Langendorff Heart, Telemetry | 2 Comments

5 Signs Drug Development Outsourcing is In

Posted by Theresa Gralinski, Marketing Director at CorDynamics on November 14th, 2012

I spent most of last week at the American College of Toxicology meeting in Orlando taking the industry’s proverbial temperature.

Over the last four years this meeting’s attendees seemed concerned about feverishly downsizing, feverishly cutting budgets or feverishly outsourcing. People just didn’t feel well. This year attendees seemed to be “feeling” healthy and more optimistic.

Preclinical CRO Drug Development Outsourcing

I saw five clear signs that industry outsourcing is officially IN.

1. Back to Business—With mass waves of downsizing behind a number of our colleagues, clients and competitors, the focus of discussions turned to current programs and upcoming projects.

2. Changing Roles—Longtime  friends were embracing new positions, translating their pharma drug safety and drug discovery experience into success at virtual biotechs or contract research organizations.

3. New CROs and Consultants Join the Ranks—We welcomed new CROs to the “club” and I met with quite a few toxicologists who have decided to work as consultants to share their expertise to meet the anticipated demand.

4. Buzzwords—Collaboration. Customized. Experience. Responsive. Did I say collaboration?

5. Social Media…Really?—Admittedly the industry is still skeptical of the idea in a regulated industry. However with more drug developers looking for external services, vendors and CROs want to be easily found. (Shameless examples: cardiovascular CRO, prolonged QT interval, cardiovascular pharmacology.) Social media is a good way to get the message out.

I polled attendees on their comfort levels with the top social media platforms. Results: LinkedIn=Great; Blogging=Good; Twitter=So-So; Facebook=No Thanks.

Did you get a different temperature reading from the meeting? Or, did you sense a healthier optimism as well? Feel free to comment here or you can find me on Linkedin.

 

Filed under: Drug Discovery Services, Drug Safety Services, Preclinical Consulting Services | No Comments

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

How to Complete Two GLP Requirements in One Study: Respiratory Telemetry

Posted by Michael Gralinski, Chief Executive Officer at CorDynamics on October 17th, 2012

Clients with compounds poised for IND application are expected to conduct GLP (good laboratory practice) studies demonstrating drug safety in three areas.

Cardiovascular
• Respiratory
• Central Nervous System

With respiratory telemetry, we can now analyze two organ systems—cardiovascular and respiratory—with one large species study. Investing in this new technology is allowing us to help our clients meet their regulatory requirements within compressed timelines and finite budgets.

Our Telemetry Technology
Our Cardiopulmonary Transmitters (D70-PCTR developed by Data Sciences International) can be implemented in multiple large animal species. The telemetry system records respiratory parameters along with blood pressure and ECG simultaneously and continuously in conscious models.

Our Data
Our pharmacological validation data demonstrates the combined measurements captured with our respiratory telemetry. View data.

Measured, were the effects of bethanechol (a cholinergic agonist) on:
• Heart rate
• Tidal volume
• Minute volume
• Respiratory rate

In addition to saving our clients’ time and money, our telemetry studies also embrace the 3 R’s of animal welfare—replacement, refinement, reduction. This conservative approach is smart science and smart business.

Filed under: Drug Safety Services | No Comments

Cardiovascular Issues Hit Heart of Obesity Drug Development Debate

Posted by Michael Gralinski, Chief Executive Officer at CorDynamics on March 06th, 2012

The FDA is currently weighing the risk-benefit profile for a number of possible therapeutics targeting obesity.

Once again, potential cardiovascular issues are at the heart of the matter.

For years, the development of effective and safe obesity treatments for the target patient population, has stymied researchers. A generation ago, doctors were prescribing aminoxaphen. Patients were purchasing versions of products such as Dexatrim®. Both contained stimulant compounds that were indeed appetite suppressants, but also had very unfavorable cardiovascular side effects.

In the 1960s, aminoxaphen was associated with numerous cases of fatal pulmonary hypertension. Subsequently, phenylpropanolamine and ephedra, the active ingredients in older versions of Dexatrim® (also in many other OTC products including decongestants) were shown to raise risk of stroke and high blood pressure. Aminoxaphen was removed from the market, and all products containing either PPA or ephedra have been reformulated.

The simple fact is that many biological pathways involved in appetite control are also shared with the cardiovascular system.

The most recent demonstration of this conundrum occurred in the 1990s and involved the use of the no-longer-available fenfluramine.  Fenfluramine causes serotonin release from nerve terminals and prevents its re-uptake. The combination of this compound with phentermine (Fen-Phen) resulted in appetite suppression— an effective treatment for obesity. However, this pharmacology also caused a pathological change in both cardiac valves and pulmonary arterial function. As a result, there was again sufficient morbidity and mortality with an obesity treatment.

Obesity, clearly detrimental to cardiovascular health, is rising at an alarming rate. Current drug developers are working hard to bring forward effective compounds with a favorable safety profile. Regulatory agencies are being called on to facilitate some options for this prevalent health concern.

Hopefully, these new compounds and mechanisms of action will eventually help those who haven’t otherwise found a therapy that works.

 

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