Posts Tagged ‘Telemetry’

Investigating Cardiotoxicity in Anti-Cancer TK Inhibitor Class

Posted by CorDynamics on June 10th, 2014

Last week a story entitled The Serious Heart Risks That Come With Chemo was published in Time. The case studies detailed cardiac issues faced by cancer patients during and after (sometime years after) chemotherapy. The recognition of this phenomenon has spawned a new branch of cancer doctor, the cardio-oncologist.

The observation that both traditional and newer chemotherapeutics agents may interfere with heart function is not a new one. Doxorubicin’s relationship to drug-induced cardiomyopathy was first described in the 1970s and more recent publications have detailed the left ventricular dysfunction that may arise from imatinib, a tyrosine kinase inhibitor. Direct cardiotoxicity is not exclusive to these two compounds.

It is well established that cancer medicines can affect:

  • cardiac function
  • hypertension
  • electrocardiographic changes (including QT interval prolongation)

Most of these effects can be modeled in a preclinical fashion.

The mechanism behind heart failure associated with imatinib has been detailed in the research laboratory–leading to increased clinical vigilance along with improvement in treatment regimens.

Our laboratories have also investigated the cardiovascular changes with newer anti-cancer agents, most notably the TK inhibitor class. This mechanism attacks targets having a role in cancer growth or progression, while attempting to leave non-cancer cells alone. Sometimes however, both normal and cancer cells express the molecular target. Using telemetry, we have demonstrated the strong hypertension with TK inhibitors in chronic animal models.

View Data

These experiments have helped clients in their attempt to reduce unwanted cardiovascular toxicity.

The more we know about the multi-faceted profile of these agents, the better chance we have to simultaneously treat the disease while working to mitigate any side effects.

Filed under: Drug Safety Services, Electrophysiology, Telemetry | No 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

How to Combine Two GLP Requirements in One Study

Posted by CorDynamics on February 10th, 2014

Telemetry Measures Cardiovascular and Respiratory Parameters

Respiratory Telemetry in Large Species

Some things sound too good to be true. But once in a while, they are actually are true—and there is data to support it.

Such is the case with our respiratory telemetry model designed to analyze two organ systems—cardiovascular and respiratory—with one large species study.

Our validated pharmacological data demonstrates how our respiratory telemetry captures the combined measurements. View Data.

 Measured, were the effects of bethanechol (a cholinergic agonist) on:

• Heart rate

• Tidal volume

• Minute volume

• Respiratory rate

Our Cardiopulmonary Transmitters 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.

We recommend these studies for clients with compounds poised for IND application to conduct GLP (good laboratory practice) studies demonstrating drug safety in three areas.

• Cardiovascular

• Respiratory

• Central Nervous System

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, Telemetry | 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

Expanding Telemetry Widens the Drug Development Picture

Posted by Michael Gralinski, Chief Executive Officer at CorDynamics on November 02nd, 2012

Highlighting our growing telemetry capabilities will be on our docket in booth #300 at the American College of Toxicology meeting in Orlando.

Cardiovascular Telemetry Drug Development

In an on-going effort to provide our clients with quality data addressing their specific scientific questions, we continue to expand our telemetry technology and our customized study designs.

Leverage GLP Studies and non-GLP Screening

It’s imperative to determine which lead compounds to put finite R&D dollars behind. Understanding this, our team has taken the telemetry models we use for GLP examinations of test articles and transformed the concept to create physiologically relevant screening models for lead compounds early in preclinical development.

Typical GLP canine or non-human primate telemetry studies average around six to eight subjects per interrogation and include a full protocol and report. Clients go back to their project teams with high fidelity assessments of effects on blood pressure, heart rate, ECG (including QT interval) and other parameters.

At the point of lead compound selection, however, project teams are trying to identify the most promising compound for advancement—thus we often compare one compound to another by rank order.

As a result, it’s often not necessary to invest in eight subjects on a screening study, nor have a full protocol or report.

Conserve Time and Money with Dual Capabilities

Simultaneously gathering data on two pressure measurements or analyzing two organ systems, helps project teams operating under tight budget constraints and ambitious timelines meet their regulatory requirements.

With dual pressure telemetry  we can now surgically instrument rats to measure systemic blood pressure AND either pulmonary artery pressure or left ventricular pressure —simultaneously. In addition, we can also provide ECG readings. Previously, this level of in vivo telemetry instrumentation was only available in large animal models.

Likewise with our respiratory telemetry capabilities, we can now analyze two organ systems—cardiovascular and respiratory—with one large species study.

In addition, these models are designed with the 3R’s in mind. Collecting multiple variables from the same subject reduces the need for redundant groups.

 

Filed under: Anesthetized Models, Drug Discovery Services, Drug Safety Services, Hemodynamics, Telemetry | 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

Timelines and Technology Drive Drug Development

Posted by Michael Gralinski, Chief Executive Officer at CorDynamics on October 05th, 2012

Safety Pharmacology Society 2012 Meeting Reveals the “New Normal”

I’m on my way back from a trade show exhibit at the Safety Pharmacology Society meeting in Phoenix. Four days in the desert were filled with sessions, events as well as many friends and colleagues stopping by the CorDynamics booth to say hello.

It didn’t hurt that my business partner Peter Senese once again claimed the prime booth space—as greeter to all—right inside the exhibit hall entrance. We opened up with a vendor show where we were airing Monday Night Football live. A consistent group enjoyed the game over a beer or two, and shared insight into the current state of their organizations.

New Normal

Attendance was down a bit from previous meetings. The continuing consolidations, mergers, and belt-tightening by nature reduced the size of representation from more than a few companies. Nevertheless, the topic seemed to pass as the ‘new normal’ instead of being the focus as years before.

Positive Signs, Rational Approach to Forward Progress

Clients stopped by to discuss their unique drug development projects. Overall, their questions came down to two general categories.

  1. Timelines—When can our new project be initiated? When can we expect results?
  2. New Technology—Are CorDynamics’ new technologies generating solid data? How can we incorporate small animal dual pressure telemetry into our studies? Can we screen for cardiovascular liability in guinea pigs?

Leaving the plus 100-degree weather for the tempered fall of Chicago, we’re coming back with good feelings for the remainder of 2012. Happily, new projects continued to flow into the labs during our absence.

We look forward to next years’ SPS meeting in Rotterdam, Netherlands. Word is that Peter already claimed our lead-in booth space. Hope to see you there.

Filed under: Drug Discovery Services, Drug Safety Services, Langendorff Heart, Telemetry | 2 Comments