Posts Tagged ‘Pulmonary Arterial Hypertension’

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

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

PAH Spotlight: Small Species with Dual Pressure Telemetry

Posted by CorDynamics on July 23rd, 2013

by Dr. Michael Gralinski, CorDynamics CEO

We continue to expand our capabilities in pulmonary arterial hypertension, and one thing is for certain: surgically instrumenting rats to measure systemic blood pressure AND pulmonary artery pressure—simultaneously—is an effective model for clients researching both prevention AND intervention of PAH.

To obtain continuous recording of pulmonary artery pressure, a telemetry catheter is placed into the pulmonary artery via the right ventricle. Post-recovery, the subjects are then exposed to classic PAH initiation agents such as monocrotaline or newer methods like hypoxia/semaxanib.

Measuring multiple pressures simultaneously allows our experts to differentiate test article effects on the pulmonary vasculature from those on the systemic circulation.

Up until recently, this level of in vivo telemetry instrumentation was only available in large animal models.

View Data Set #1

 View Data Set #2

Efficiency All-Around

At the risk of being obvious, the ability to measure multiple pressures clearly saves time and effort all around.

In addition, our low technical failure rate and clinical observations consistent with the development of robust pulmonary hypertension makes this an efficient option in terms of technician time as well as overall study deliverables.

As always, our models are designed with the 3R’s in mind. Collecting multiple variables from the same experimental subject reduces the need for redundant groups when separate pressures are interrogated.

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

Case Study: Targeting Reversal Therapy in Pulmonary Arterial Hypertension

Posted by CorDynamics on July 17th, 2013

Pulmonary Arterial Hypertension (PAH) is characterized by increased blood pressure in the arteries of lungs, causing dizziness, shortness of breath and can lead to heart failure.

reversal

PAH is an orphan disease that the CorDynamics team has studied extensively including generating terminal assessments of pulmonary arterial pressure to provide demonstration of efficacy.

In addition, measuring pulmonary artery pressure via single or dual channel telemetry to deliver daily readings of pulmonary artery pressures. These interim measurements of the PAH temporal course has been critical for clients interested in timing the initiation of reversal therapy.

View Data

Our daily data demonstrate that the variability associated with the model is small, even over six weeks of hypoxia. Animals progressed through development of PAH in a similar linear fashion. After six weeks in hypoxia, systolic pulmonary pressures increased greater than 400% versus baseline. In addition, right ventricular hypertrophy was robust. The low variability helps in the assessment of test article efficacy – and allows for better distribution of dose levels without having to add inordinate experimental numbers.

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

Pulmonary Arterial Hypertension Model Targets Disease Reversal

Posted by CorDynamics on February 13th, 2013

Finding Treatments for an Orphan Drug

We have added a powerful capability to our most requested small animal pulmonary arterial hypertension model – measuring pulmonary artery pressure via single or dual channel telemetry.

The hypoxia-semaxanib rat assessment has rapidly become the most requested assay among our Pulmonary Arterial Hypertension offerings. 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.

CorDynamics was the first laboratory to report the protective effects of bosentan and sildenafil in this model.

In an effort to refine the data, we have now added the option to include daily readings of pulmonary artery pressures.

 View Data

Why is this important in the discovery of new therapeutics for PAH?

While a terminal assessment of pulmonary pressure provides end-stage confirmation of efficacy, interim measurements of the PAH temporal course can be critical when timing the initiation of reversal therapy.

Our daily data demonstrate that the variability associated with the model is small, even over six weeks of hypoxia. Animals progressed through development of PAH in a similar linear fashion.  After six weeks in hypoxia, systolic pulmonary pressure increased greater than 400% versus baseline. In addition, right ventricular hypertrophy was robust. The low variability helps in the assessment of test article efficacy – and allows for better distribution of dose levels without having to add inordinate experimental numbers.

As we approach another celebration of World Rare Disease Day on February 28th it’s gratifying to have something new to report in the campaign to develop an orphan drug for PAH.

 

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

New Model for Investigating Orphan Drug PAH

Posted by Michael Gralinski, Chief Executive Officer at CorDynamics on May 09th, 2012

There is still a lot to learn and discover about Pulmonary Arterial Hypertension (PAH).

It’s something CorDynamics has been developing in our laboratories. We were pleased to share the resulting PAH model with fellow researchers in a poster presented at last month’s Experimental Biology 2012 conference.

Our poster: Bosentan and Sildenafil Reduce Pulmonary Arterial Hypertension in Rats Induced by Semaxanib and a Low Oxygen Environment.

What did we show?

Oral administration of bosentan and sildenafil reduce PAH induced by semaxanib and a low oxygen environment. We demonstrated that this is a clinically relevant model to evaluate efficacy of test articles.

How did we do it?

It occurred to us that a commercially available hypoxic tent could be turned into a low oxygen chamber that mimics PAH. It worked. From there, we were the first to use bosentan and sildenafil (two approved clinical treatments for pulmonary hypertension) to validate the reduction of PAH in this model.

The result is a new model that is predictive of the human PAH condition.

Continually moving toward finding treatments for PAH—one of the 6,000 orphan diseases—is the wave of the future.

Our belief was underscored this week with GBI Research predicting orphan drugs will represent a significant revenue increase over the next five years—increasing its market share from $2.3 billion in 2010 to $6 billion in 2018.

More importantly, the millions affected by these diseases will have hope for life-improving treatments.

 

Filed under: Pulmonary Arterial Hypertension | 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

World Rare Disease Day

Posted by Michael Gralinski, Chief Executive Officer at CorDynamics on February 29th, 2012

The Future Looks Bright

It’s World Rare Disease Day and supporters of all ages are coming together to raise awareness. From my point of view, the next generation makes the future look bright.

Today, I find myself back at the University of Michigan Medical School talking with pharmacology graduate students. Many of these future researchers will dedicate their careers to developing the very drugs and therapies needed to help those struggling with unmet medical needs.

My seminar is entitled World Rare Disease Day: Current Pharmacological Targets and Animal Models of Pulmonary Arterial Hypertension.”

I talk about my Michigan history and the career path that took me from grad student, to post doc, to industry researcher and ultimately entrepreneur. From the CorDynamics point of view, I discuss the extensive preclinical and discovery studies done for clients researching treatments for pulmonary arterial hypertension—an orphan disease.

Meanwhile, back in Illinois, kids at Spencer Loomis Elementary School are helping other kids in the hopes of eradicating some of these diseases in their lifetimes. For Dollar Denim Days, the students are purchasing denim ribbons as well as wearing their favorite pair of jeans in a nod to the Global Genes Project. The proceeds will go toward research on Rett Syndrome, a rare genetic disorder of the nervous system and the diagnosis given to the 3-year-old daughter of a former teacher at the school.

Inspired, CorDynamics pledged to match the funds raised by the Spencer Loomis Elementary students.

In the interest of full disclosure, the teacher was my oldest son’s kindergarten teacher and my youngest son still attends the school. Not to mention, Rett Syndrome is often associated with a dangerous heart condition that we regularly research—long QT syndrome.

Odds are, most of us are connected to one of the nearly 30 million Americans affected by a rare disease. From one generation to the next, I believe these connections will lead to solutions and cures.

Filed under: Press Releases, Pulmonary Arterial Hypertension | No Comments

FDA Orphan Drug Designation

Posted by Michael Gralinski, Chief Executive Officer at CorDynamics on January 30th, 2012

There are currently about 7,000 orphans out there waiting to be adopted, to be supported, to be cured. Many of us don’t even know their names: Kawasaki. Porphyria. Pulmonary Arterial Disease.

Orphan Status is a designation given by the FDA to identify rare diseases with unmet medical needs but with potentially promising compounds currently being researched. Orphan drugs receive expedited FDA reviews and fast tracks to clinical trials, providing hope for cures, treatments or comfort.

>>>>>  Nearly 2,400 experimental compounds have orphan drug designations.

>>>>>  So far, only 367 of these orphan drugs have been approved by the FDA.

Experts agree, coordinated collaboration and resources on all fronts will be the key to finding a potential drug therapy for these orphan drugs. Collaboration is also essential for the rare diseases still searching for enough answers to even begin the orphan drug development stage.

You may ask, what can I do to help? What can my organization do?

Adopt An Orphan

  • Pick an orphan disease with a compound in the works or a rare disease to adopt.
  • Show your support and learn more about the disease, follow related organizations on Facebook or in the news.  One that we follow on Facebook is Two Hearts Rock and Global Genes Project.
  • Donate your time, participate in a sponsored event, or fundraiser.
  • “Wear That You Care” on World Rare Disease Day, February 29th. Wear “jeans” for “genes” and encourage your workplace, schools, and sport teams to do so too to raise awareness for the Global Genes Project.

At CorDynamics, we sponsored a fundraising event for Hope4Bridget and Batten Disease (a rare disease) as well as continue to work with our clients on promising compounds for the potential treatment of Pulmonary Arterial Hypertension (an orphan designated rare disease).

Working together, we will continue to adopt more of these orphan diseases and meet more unmet medical needs. To learn more about this issue and how you can help, jump into today’s blog hop sponsored by the R.A.R.E Project.

 

Filed under: Drug Discovery Services, Drug Safety Services, Events, Pulmonary Arterial Hypertension | 4 Comments