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IPS Therapeutique

Sherbrooke, QC, CA

IPST : Building collaborative relationships one customized study at a time.

IPS Therapeutique (IPST) is a Contract Research Organization dedicated to the preclinical evaluation of the efficacy and safety of new drugs using validated and highly predictive models – with a strong cardiovascular focus.

At IPST we believe each study is worthy of tailored protocols designed to maximize the scientific and strategic value of the data generated. We believe in taking ownership of the studies entrusted to IPST while ensuring mutual collaboration for developing and agreeing to overall project plans.

Our senior management team is fully engaged on every project. We invite our clients to talk through challenges, business requirements and quantitative expectations for each project. Our team understands the linkages between tasks, projects costs and schedules.

Established in 1999, we have conducted more than 650 preclinical... Show more »

IPST : Building collaborative relationships one customized study at a time.

IPS Therapeutique (IPST) is a Contract Research Organization dedicated to the preclinical evaluation of the efficacy and safety of new drugs using validated and highly predictive models – with a strong cardiovascular focus.

At IPST we believe each study is worthy of tailored protocols designed to maximize the scientific and strategic value of the data generated. We believe in taking ownership of the studies entrusted to IPST while ensuring mutual collaboration for developing and agreeing to overall project plans.

Our senior management team is fully engaged on every project. We invite our clients to talk through challenges, business requirements and quantitative expectations for each project. Our team understands the linkages between tasks, projects costs and schedules.

Established in 1999, we have conducted more than 650 preclinical cardiac safety and efficacy studies and over 100 GLP-compliant studies in support of FDA, EMEA, Health Canada and MoHW.

We have a well-earned reputation for the sustained delivery of accurate results at a reasonable cost. IPST is proud of our applied science approach to addressing the needs of both start-up and mature biopharmaceutical and nutraceutical companies.

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IPS Therapeutique has not listed any services.

Metabolic Animal Models
Price on request

The focus of IPST’s cardiometabolic lab, under the direction of Senior Research Scientist Dr. Sébastien Labbé, is to inform pre-clinical drug development in diabetes, obesity and metabolic disease.

Service offering:

Metabolic profiles

Metabolic screening

Animal models

Type 2 Diabetes Cardiomyopathy

Acute and... Show more »

The focus of IPST’s cardiometabolic lab, under the direction of Senior Research Scientist Dr. Sébastien Labbé, is to inform pre-clinical drug development in diabetes, obesity and metabolic disease.

Service offering:

Metabolic profiles

Metabolic screening

Animal models

Type 2 Diabetes Cardiomyopathy

Acute and chronic studies

Customized protocol development

Measurements available:

food intake and food choice
energy expenditure and RQ
thermic response to food
basal metabolic rate at thermoneutrality
metabolic parameters such as glucose, lactate, lipids
hormones such as insulin, glucagon, active and total GLP-1, and adipokines
glucose tolerance, insulin tolerance and pyruvate tolerance
euglycemic hyperinsulinemic clamps
hepatic glucose output and tissue glucose uptake rates
isolated hepatocytes and adipocytes
isolated muscle
microarrays, RNA analysis and Western blots
liver and muscle toxicology markers
real time inflammatory markers
bioinformatics; automated imaging tools
cell culture
central administration
immunohistochemistry

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Cardiovascular Disease Animal Models
Price on request

Cardiometabolic Studies

The focus of IPST’s cardiometabolic lab, under the direction of Senior Research Scientist Dr. Sébastien Labbé, is to inform pre-clinical drug development in diabetes, obesity and metabolic disease.

Service offering:

Metabolic profiles

Metabolic screening

Animal models

Type 2 Diabetes... Show more »

Cardiometabolic Studies

The focus of IPST’s cardiometabolic lab, under the direction of Senior Research Scientist Dr. Sébastien Labbé, is to inform pre-clinical drug development in diabetes, obesity and metabolic disease.

Service offering:

Metabolic profiles

Metabolic screening

Animal models

Type 2 Diabetes Cardiomyopathy

Acute and chronic studies

Customized protocol development

Measurements available:

food intake and food choice
energy expenditure and RQ
thermic response to food
basal metabolic rate at thermoneutrality
metabolic parameters such as glucose, lactate, lipids
hormones such as insulin, glucagon, active and total GLP-1, and adipokines
glucose tolerance, insulin tolerance and pyruvate tolerance
euglycemic hyperinsulinemic clamps
hepatic glucose output and tissue glucose uptake rates
isolated hepatocytes and adipocytes
isolated muscle
microarrays, RNA analysis and Western blots
liver and muscle toxicology markers
real time inflammatory markers
bioinformatics; automated imaging tools
cell culture
central administration
immunohistochemistry

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Hamster
Guinea pig
Mouse
Rat
Hypertension
Diabetes Type 1
Diabetes Type 2
Liver
Obesity
Cardiomyopathy
Atherosclerosis
Cognitive decline
cardiometabolism
metabolism
Bleeding Disorder Animal Models
Price on request

Bleeding disorders affect the blood clotting process, called coagulation. In a normal blood clotting process, blood cell platelets rush to an injured blood vessel and form a clot to slow and stop any bleeding.

Bleeding disorders cause an inability to form blood clots normally, which can cause prolonged bleeding after injury,... Show more »

Bleeding disorders affect the blood clotting process, called coagulation. In a normal blood clotting process, blood cell platelets rush to an injured blood vessel and form a clot to slow and stop any bleeding.

Bleeding disorders cause an inability to form blood clots normally, which can cause prolonged bleeding after injury, menstruation, etc. Cuts and injury are of particular concern for those living with bleeding disorders due to potential for internal bleeding and damage to joints, organs, and tissues.

Bleeding disorders range in severity from mild to severe and are usually inherited, though some can be developed.

Blood clotting most often involves blood cells known as platelets and proteins known as clotting factors. For individuals with bleeding disorders, these factors are produced at a lower level or can even be missing.

Hemophilia is an inherited condition and occurs in families, however in one-third of cases it appears in families with no previous history of the disorder. The genetic alteration causing hemophilia is passed down from parent to child through generations. Men with hemophilia will pass the gene on to their daughters but not their sons. Women who carry the gene can pass the gene on to their sons and daughters. Sons with the gene will have hemophilia. Some women and girls who carry the gene may also experience bleeding problems.

Von Willebrand disorder (VWD) is an inherited bleeding disorder. This disorder is caused by when there is not enough von Willebrand factor in the blood or it does not work the way it should. It takes longer for blood to clot and for bleeding to stop.

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Pulmonary Disease Animal Models
Price on request

Respiratory disease causes an immense worldwide health burden.

It is estimated that 235 million people suffer from asthma, more than 200 million people have chronic obstructive pulmonary disease (COPD), 65 million endure moderate-to-severe COPD, 1-6% of the adult population (more than 100 million people) experience sleep... Show more »

Respiratory disease causes an immense worldwide health burden.

It is estimated that 235 million people suffer from asthma, more than 200 million people have chronic obstructive pulmonary disease (COPD), 65 million endure moderate-to-severe COPD, 1-6% of the adult population (more than 100 million people) experience sleep disordered breathing, 8.7 million people develop tuberculosis (TB) annually, millions live with pulmonary hypertension and more than 50 million people struggle with occupational lung diseases, totaling more than 1 billion persons suffering from chronic respiratory conditions.

COPD affects more than 200 million people and is the fourth leading cause of death in the world. COPD is the only major disease that is increasing in prevalence worldwide and on all continents.

Asthma afflicts about 235 million people worldwide and it has been increasing during the past three decades in both developed and developing countries. Although it strikes all ages, races and ethnicities, wide variation exists in different countries and in different groups within the same country. It is the most common chronic disease in children and is more severe in children in non-affluent countries. In these settings, under-diagnosis and under-treatment are common, and effective medicines may not be available or affordable. The burden of asthma is also greater in urban settings. It is one of the most frequent reasons for preventable hospital admissions among children.

Respiratory infections account for more than 4 million deaths annually and are the leading cause of death in developing countries. Since these deaths are preventable with adequate medical care, a much higher proportion of them occur in low-income countries. Pneumonia is the most common serious respiratory infection. In children under 5 years of age, pneumonia accounts for 18% of all deaths, or more than 1.3 million annually; pneumonia kills far more than HIVor malaria.

Listed below are selected respiratory models used by IPST:

Allergic Rhinitis

Bleomycin-induced Lung Injury

Chronic Obstructive Lung Disease (COPD)

LPS-induced Acute Lung Injury

Acute hypoxia-induced pulmonary arterial hypertension (PAH)

Monocrotaline-induced PAH

Chronic hypoxia-induced PAH

Chronic hypoxia with Sugen PAH

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Ischemia Animal Models
Price on request

Death from myocardial infarction and related cardiovascular events remains the number one cause of death in the Western world. Proper preclinical models are essential in order to study the efficacy of potential pharmacological agents which may have novel potential for treatment and/or prevention of ischemic heart disease.

The... Show more »

Death from myocardial infarction and related cardiovascular events remains the number one cause of death in the Western world. Proper preclinical models are essential in order to study the efficacy of potential pharmacological agents which may have novel potential for treatment and/or prevention of ischemic heart disease.

The canine model of infarction resembles the diseased human heart in terms of size and the development of coronary collateral blood vessels. The canine heart’s size and circulation are suitable not only for assessment of infarct size, but also for catheterization of the major coronary arteries for localized administration of test compounds.

The rabbit and rat models of infarction present the advantages of being less expensive and can accommodate larger cohorts of animals. Properly designed, these models can be used to test sparse collateral circulation to isolate drug effects to the ischemic region of interest – preventing confounding cardioprotective effects resulting from increasing coronary collateral blood flow.

End points:

  • Measurement of the myocardial segment shortening (%SS)
  • Regional myocardial blood flow
  • Release of Troponin C from the ischemic area
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Rabbit
Rat
Dog
Pulmonary Hypertension Animal Models
Price on request

iPST employs four preclinical models of induced pulmonary arterial hypertension. Each is characterized by defined underlying phenomena, and is best suited to specific pathologies and associated treatments:

Monocrotaline-induced PAH

Monocrotaline (MCT) is a toxin injected once which causes a remodeling of the pulmonary... Show more »

iPST employs four preclinical models of induced pulmonary arterial hypertension. Each is characterized by defined underlying phenomena, and is best suited to specific pathologies and associated treatments:

Monocrotaline-induced PAH

Monocrotaline (MCT) is a toxin injected once which causes a remodeling of the pulmonary vasculature through a combination of endothelial damage, tissue inflammation, cytokine migration, and resulting increased vasoconstriction. Morphometric analysis of MCT-exposed pulmonary vasculature conducted in this lab and elsewhere reveals a decreased lumen size due to increased muscular layer thickening, hyperplasia of the endothelium, infiltration of monocytes and various signs of inflammation.

MCT causes an irreversible decline of the animal’s pulmonary vasculature, which becomes practical to work with at Day 21 (post-injection) and critical at Day 28, with 65-75% death by Day 30. Physiologically, saturation goes down, gas-exchanges become inefficient, and pulmonary arterial pressure goes up by more than 15 mmHg. Contrary to some literature reports, the condition is irreversible, and treatment with test articles can only slow down the rate of decline of the vascular/respiratory parameters. iPST’s MCT study designs allow simultaneous treatment of approximately 100 animals at a time. Typical experimental group size is 10 animals.

Chronic hypoxia with Sugen PAH

The more recent model of Sugen5416 combined with chronic hypoxia SU/CH is associated with tissue restructuration involving formation of occlusive neointimal (plexiform) lesions in small pulmonary arteries and arterioles often seen in human with severe pulmonary hypertension. The progression of the disease continues and worsens even after the animals had been removed from hypoxic stimulus.

The absence of endothelial damage in chronic hypoxia PAH is a limitation of the model, as pertains to its direct relevance to adult pulmonary arterial hypertension. A model was developed using Sugen reagent SU5416, which is injected once (rodent) or repeatedly (other species) over three weeks combined with chronic hypoxia.

This results in endothelial damage and inflammation, along with the expected hypertrophy/hyperplasia of the smooth muscle layer to cause pulmonary arterial hypertension with both inflammation and vasoconstriction.

As for the chronic hypoxia model above, physiological parameters are monitored to ascribe various functional changes to the correct anatomical systems of the animal. The functional parameter assessment is complemented by histopathological examination and morphometric analysis of the vasculature.

iPST’s chronic hypoxia systems are used for the Sugen Model and allow simultaneous treatment of approximately 100 animals at a time. Typical experimental group size is 10 animals.

Acute hypoxia-induced pulmonary arterial hypertension (PAH)

Acute hypoxia was first developed to mimic and study the pathology of persistent pulmonary hypertension of the newborn PPHN. The rapid pulmonary vessel constriction response to the hypoxic stimulus without tissue remodeling allows us to monitor and observe the rapid effect of antihypertensive agents such as nitric oxide (see figure below) on pulmonary arterial pressure.

Acute hypoxia is used under anesthesia to increase pulmonary arterial pressure while continuously monitoring a series of physiological parameters to assess the condition of every system in the animal.

The hypoxia causes pulmonary vasoconstriction without remodeling, similar to the situation faced by newborn infants with acute pulmonary hypertension.

The increase in pulmonary pressure is reversible, and dialed to the level prescribed by changing FiO2.

The model is best suited to small animals (rats, guinea pigs are commonly used), and is a particularly useful model for efficacy assessment.

Acute hypoxia experiments are surgically intensive, and have a throughput at iPST of two (2) animals per day (typical experimental group size is 4-6 animals).

Chronic hypoxia-induced PAH

Chronic hypoxia involves maintaining the animals in low-FiO2 conditions for 14-21 days to induce pulmonary arterial hypertension.

The remodelling is smooth-muscle based, characterized by chronic vasoconstriction leading to hypertrophy and hyperplasia of the vascular smooth muscle cells.

Unlike Monocrotaline, there is no endothelial damage or inflammatory component in chronic hypoxia-induced pulmonary arterial hypertension. The remodeling is reversible, can be dialed-in to a desired severity, and is in itself non-lethal, unless pushed to extremes.

The functional parameters measured on the animals monitor all the systems within the animal, and are complemented by a full-scale histopathological examination of the lung’s vasculature.

iPST’s chronic hypoxia systems allow simultaneous treatment of approximately 100 animals at a time. Typical experimental group size is 10 animals.

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Bleomycin-Induced Lung Injury Animal Models
Price on request

The progression of fibrosis may lead to respiratory failure combined with pulmonary arterial hypertension, giving a poor prognosis in patients with various types of interstitial lung disorders.

Bleomycin (BLM) is a glycopeptide antibiotic commonly used as an anticancer agent. It is widely used in research for its association... Show more »

The progression of fibrosis may lead to respiratory failure combined with pulmonary arterial hypertension, giving a poor prognosis in patients with various types of interstitial lung disorders.

Bleomycin (BLM) is a glycopeptide antibiotic commonly used as an anticancer agent. It is widely used in research for its association with development of pulmonary fibrosis in animals which has great similarities with histological and functional fibrotic lung disease in humans.

This study model investigates the functional, anatomical, and biochemical consequences of the onset of BLM-induced lung fibrosis, as well as the full range of changes resulting from any test compound treatment.

The cellular content and the enzymatic activities measured from the bronchoalveolar lavage fluid (BALF) have been valuable to determine the pulmonary toxicity caused by various gaseous or nongaseous compounds. It is well recognized that the cellular and non-cellular components have important value to identify specific interstitial lung diseases.

Lung and heart tissues are fixed, stained/sliced, and examined by a team of pulmonary histopathologists on-site. Tissue fibrosis and inflammatory cells are all documented in our complete report. This model of lung fibrosis exhibits various increases in DNA and protein expression which can also be determined by PCR on site by our molecular biology expert, depending on the sponsor’s interest.

Specific protein contents can also be assessed by ELISA if necessary. IPS Therapeutique is able to conduct the analysis of the lung histopathological/ morphometric changes.

In addition, other functional parameters such as respiratory rate and resistance can be assessed to evaluate the severity of lung fibrosis.

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Custom Cell-Based Assays
Price on request
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In vitro Safety Evaluation
Price on request

IPST’s in vitro studies are developed by an experienced team of scientists trained in biochemistry, pharmacology, cellular and molecular biology. Whether GLP-compliant or Discovery-stage, all protocols are customized to fit your needs and to answer any questions you might have on compound efficacy, safety, and toxicity.

With... Show more »

IPST’s in vitro studies are developed by an experienced team of scientists trained in biochemistry, pharmacology, cellular and molecular biology. Whether GLP-compliant or Discovery-stage, all protocols are customized to fit your needs and to answer any questions you might have on compound efficacy, safety, and toxicity.

With ample cell and tissue culture experience, IPST scientists can isolate sub-cellular components such as mitochondria and various enzymes to monitor an assortment of activities in cell extracts. Methods used include ELISA, mass spectrometry, RT-QPCR, histology and immune-histochemistry (IHC).

IPST’s experts can measure the effect or identify the mechanism of action of your compound by reproducing physiopathologies in vitro. By submitting selected cell types to specific conditions (examples include: inflammation stimulus, metabolic deficit, or hypoxia), an economical, higher-throughput efficacy model can be validated within a week or two to accelerate your early-phase drug development.

Listed below are a few in vitro models used routinely at IPST:

  • hERG-expressing cells lines
  • Heterologous ion channel expression systems
  • Stem Cells (IPS cell) differentiated into various phenotypes
  • Normoxic, hypoxic cardiac and vascular tissues
  • Isolated cardiomyocytes (dog, rabbit, rats)
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In vitro Toxicity Testing
Price on request

IPST’s in vitro studies are developed by an experienced team of scientists trained in biochemistry, pharmacology, cellular and molecular biology. Whether GLP-compliant or Discovery-stage, all protocols are customized to fit your needs and to answer any questions you might have on compound efficacy, safety, and toxicity.

With... Show more »

IPST’s in vitro studies are developed by an experienced team of scientists trained in biochemistry, pharmacology, cellular and molecular biology. Whether GLP-compliant or Discovery-stage, all protocols are customized to fit your needs and to answer any questions you might have on compound efficacy, safety, and toxicity.

With ample cell and tissue culture experience, IPST scientists can isolate sub-cellular components such as mitochondria and various enzymes to monitor an assortment of activities in cell extracts. Methods used include ELISA, mass spectrometry, RT-QPCR, histology and immune-histochemistry (IHC).

IPST’s experts can measure the effect or identify the mechanism of action of your compound by reproducing physiopathologies in vitro. By submitting selected cell types to specific conditions (examples include: inflammation stimulus, metabolic deficit, or hypoxia), an economical, higher-throughput efficacy model can be validated within a week or two to accelerate your early-phase drug development.

Listed below are a few in vitro models used routinely at IPST:

  • hERG-expressing cells lines
  • Heterologous ion channel expression systems
  • Stem Cells (IPS cell) differentiated into various phenotypes
  • Normoxic, hypoxic cardiac and vascular tissues
  • Isolated cardiomyocytes (dog, rabbit, rats)
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Animal Fibrinogen Assay
Price on request

Understanding the relative contribution of fibrinogen and platelets to clot strength can provide additional insights into the causes of bleeding. The Functional Fibrinogen assay can help determine if the origin of the coagulopathy is platelets or fibrinogen.

The Functional Fibrinogen assay is a rapid whole blood test which... Show more »

Understanding the relative contribution of fibrinogen and platelets to clot strength can provide additional insights into the causes of bleeding. The Functional Fibrinogen assay can help determine if the origin of the coagulopathy is platelets or fibrinogen.

The Functional Fibrinogen assay is a rapid whole blood test which measures the fibrinogen that actually contributes to the structure and strength of the clot. Platelet function is blocked by a potent inhibitor and the resulting MA-FF reflects the fibrin component of the clot.

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Thrombosis Animal Models
Price on request

Cardiovascular diseases associated with intravascular thrombosis are among the most common causes of death in both developed and developing countries. Arterial thrombosis leads to myocardial infarction while venous thrombosis is a frequent side-effect of oncology drugs.

The stasis-induced thrombosis model (aka the Wessler... Show more »

Cardiovascular diseases associated with intravascular thrombosis are among the most common causes of death in both developed and developing countries. Arterial thrombosis leads to myocardial infarction while venous thrombosis is a frequent side-effect of oncology drugs.

The stasis-induced thrombosis model (aka the Wessler Model) is a classical method to evaluate potential effective antithrombotic agents. It combines local arterial or venous stasis with hypercoagulability produced by the injection of thromboplastin into the systemic circulation of rabbits or rats.

IPST currently runs several thrombosis and homeostasis models including the Wessler (venous stasis) model, which involves the occlusion of a segment of the rabbit jugular vein. Our venous stasis models include vessel clamp (stasis), with or without clotting agent, followed by reperfusion, thrombus examination, etc. Bleeding time is also measured from a standard incision made on the ventral part of the rabbit’s ear.

The potential antithrombotic agent is administered and the carotid artery or jugular vein (vena cava in rats) is occluded by clamp one (1) minute after the injection of the hypercoagulant into the circulation.

Over the years, IPST has used several coagulation factors as reference compounds to induce thrombosis, such as NovoSeven and human FXIa. Our experience with the model includes various endpoints aimed at evaluating thromboembolitic propensity in the rabbit venous stasis model.

Synthetic molecules, naturally occurring peptides, IVIGs, have all been tested here. IVIGs also require precautious infusion to reduce thromboembolic events – and as such, we have had to develop special protocols for those.

Other assays such as aPTT/PT, platelets aggregation and TEG5000 are also available if they can support or refine the findings of a study.

IPST has recently completed the validation of a TEG5000 thromboelastograph for IVIG bath quality control. The test is added to the standard Wessler assay produced for IVIG batch clearance, and the North American regulators, in the United States and Canada, have been very pleased with the refinement it brings to the assay.

Thromboelastography (TEG) is yet another method of assessing the coagulation cascade in blood. While preclinical methods often rely on optical platelet aggregation assays using platelet-rich plasma, clinical procedures work directly with whole blood from a patient. This allows less fluid handling, supposedly more rapid results which can be useful immediately in the context of surgical procedures, or belatedly during diagnostics.

TEG relies on the “thickening” of whole blood once the coagulation cascade is activated; a paddled-shaft measures the resistance of the blood to motor-driven torsion, giving a direct readout of the consistence of the coagulated blood. The method uses 250 µL of whole blood, and is a perfect complement to whole-animal Wessler assays, in which in-situ coagulation/thrombus formation is measured after a short stasis period. Combined with bleeding time and optical (Chronolog) platelet aggregation assessments, also on the same Wessler animal, one gets a very thorough examination of coagulation, thrombogenicity, and platelet aggregation.

All in all, it’s probably a good idea – and definitely economically viable – to work TEG into your testing strategy.

End points:

  • Blood sample analysis: CBC
  • Thrombus weight
  • Thrombus score
  • Bleeding time
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Rabbit
Rat
Animal Cardiac Test Panel
Price on request

The Cardiac and Vascular Muscle Tension Measurement Assay

Highlights:

  • Isolated atrial/ventricular trabeculae & papillary muscles as well as thoracic/abdominal aorta & coronary arteries
  • Isometric tension measurements performed on vertically-mounted tissues
  • Pre-IND (GLP-compliant ) or exploratory designs... Show more »

The Cardiac and Vascular Muscle Tension Measurement Assay

Highlights:

  • Isolated atrial/ventricular trabeculae & papillary muscles as well as thoracic/abdominal aorta & coronary arteries
  • Isometric tension measurements performed on vertically-mounted tissues
  • Pre-IND (GLP-compliant ) or exploratory designs (non-GLP compliant)
  • Rat, guinea pig, rabbit, dog

Cardiac Muscle Tension measurement : Ventricular and papillary muscle contraction results from a transient depolarization of the myocytes in the heart (action potential). The alteration of the cardiac action potential not only affects the electrophysiology of the organ, but also its mechanical properties. By using contraction-relaxation parameters as an integrated phenomenon, the measurement of the time-course of the contraction-repolarisation cycle in cardiac tissues verifies the effects of a test article on the electrogenic (ion currents) and protein structures involved in its contraction.

Vascular Muscle Measurement : Changes in arterial blood pressure result from variations in the elasticity and tension components of the arterial tree, controlled by exogenous and endogenous factors which fine-tune the tissue’s contractile machinery. By using contraction-relaxation parameters as an integrated phenomenon, the analysis of the amplitude and time-course of the contractile cycle in aortic muscle allows the quantification of the effects of a test article on the structures involved in vascular tension, and, indirectly, on arterial blood pressure.

Study outline:

  • Number of tissues exposed to the test article: 5 tissues
  • Number of concentrations of test article tested: 4
  • Stimulation: single or multiple frequencies, electric field stimulation
  • A study includes positive, negative, and vehicle controls

Study outcome:

  • A quantitative assessment A quantitative assessment of the effects of increasing concentrations of a test article on parameters such as amplitude, rates of contraction / relaxation
  • Determination of the EC50 value (if applicable)
  • FDA-ready hard copy and e-report for electronic IND submission
  • Holistic interpretation of a positive signal, considering all other data generated

Recommended reading:

  1. Allen DG. Kentish JC., The cellular basis of the length-tension relation in cardiac muscle., Journal of Molecular & Cellular Cardiology., 1985; 17(9):821-40.
  2. Manring A. Anderson PA., The contractility of cardiac muscle., Critical Reviews
  3. Lucchesi BR., Role of calcium on excitation-contraction coupling in cardiac and vascular smooth muscle., Circulation., 1989; 80(6 Suppl):IV1-13.
  4. McCall D., Excitation-contraction coupling in cardiac and vascular smooth muscle: modification by calcium-entry blockade., Circulation 1987; 75(6 Pt 2):V3-14
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Rabbit
Guinea pig
Rat
Dog
hERG Channel Inhibition Assay
Price on request

Whole-cell current amplitude and kinetics measurements verify the result of potential interactions of a test article with the product of the hERG gene, a human ion channel responsible for the IKr repolarizing current. IKr current inhibition has been shown to prolong the cardiac action potential, a phenomenon associated with... Show more »

Whole-cell current amplitude and kinetics measurements verify the result of potential interactions of a test article with the product of the hERG gene, a human ion channel responsible for the IKr repolarizing current. IKr current inhibition has been shown to prolong the cardiac action potential, a phenomenon associated with increased risk of arrhythmia. IKr inhibition accounts for the vast majority of known cases of drug-induced QT-prolongation.

Highlights:

  • GLP-compliant manual patch-clamp
  • Conducted at physiological temperature
  • Part of the core battery of Safety Pharmacology tests required for IND submission
  • Screens (non-GLP, faster study design) also available

Assay description: Rapid delayed rectifying potassium (IKr) current inhibition assay

Cell line type: HEK293 or CHO cells stably transfected with the human ERG (hERG) gene

Technique: Manual patch-clamp, whole-cell configuration

GLP compliance: Pre-IND (GLP-compliant) or exploratory designs (screen = non-GLP compliant)

Rationale: Part of the core battery of Safety Pharmacology tests required for IND submission Whole-cell current amplitude and kinetics measurements verify the results of the interactions of a test article with the product of the hERG gene, a K+-selective ion channel responsible for the IKr repolarizing current. IKr current inhibition has been shown to prolong the cardiac action potential, a phenomenon associated with increased risk of arrhythmia. IKr current inhibition accounts for the vast majority of known cases of drug-induced QT- prolongation.

Study Outline:

  • Number of cells exposed to the test article: 7 (screens: 3)
  • Number of concentrations of test article: 4 (screens: 3)
  • Method of test article exposure: cumulative concentrations in closed-circuit perfusion, or constant perfusion of individual concentrations
  • Voltage pulse: partial current-voltage relationship
  • A study includes positive and vehicle controls as well as a reference article

Study Outcome:

  • A quantitative assessment of IKr current inhibition
  • Determination of the IC50 value (if applicable)
  • Analysis of both amplitude and current kinetics as indicators of inhibition
  • FDA-ready hard copy and e-report for electronic IND submission
  • Holistic interpretation of a positive signal, considering all other data generated

Recommended reading:

  1. Shah RR., Drug-induced QT interval prolongation-regulatory guidance and perspectives on hERG channels studies., Novartis Foundation Symp., 2005; 266:251-80.
  2. Sanguinetti MC. Mitcheson JS., Predicting drug-hERG channel interactions that cause acquired long QT syndrome., Trends in Pharmacological Sciences., 2005; 26(3): 119-24.
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hERG
patch-clamp
Cardiac Safety Assays
Price on request

Compound attrition and drug development costs have increased considerably since the advent of the clinical Thorough QT studies, supporting the need to reconsider the current cardiovascular liability assessment strategy.

The Comprehensive In Vitro ProArrhythmia Assay (CiPA) represents a paradigm shift towards a more complete... Show more »

Compound attrition and drug development costs have increased considerably since the advent of the clinical Thorough QT studies, supporting the need to reconsider the current cardiovascular liability assessment strategy.

The Comprehensive In Vitro ProArrhythmia Assay (CiPA) represents a paradigm shift towards a more complete assessment of proarrhythmic risk rather than QT prolongation alone.

The CiPA approach includes evaluating drug effects on multiple cardiac ionic currents, then integrating the data into in silico modeling, and finally confirming the data through the use of human stem cell-derived cardiomyocytes (Sager et al, 2014).

The higher specificity of the CiPA strategy will produce less false positives than those based purely on functional hERG studies. According to Kramer et al, 2013, patch-clamp results on three ionic currents predict proarrhythmia better than hERG assessment alone. CiPA recognizes that hERG represents only one of multiple ion currents which define cardiac electrophysiology.

The CIPA strategy is based on patch-clamp assessment of inhibition on the following channels:

Cardiac Ion Channels Function
Cav1.2/β2/α2δ1 L-type calcium current
Cav3.2 T-type calcium current
HCN2 pacemaker current
HCN4 pacemaker current
hERG delayed rectifier potassium current
Kir2.1 inward rectifier potassium current
Kir3.1/3.4 inward rectifier potassium current
Kir6.2/SUR2A inward rectifier potassium current
Kv1.5 delayed rectifier potassium current
Kv4.3 transient outward potassium current
KvLQT1/minK delayed rectifier potassium current
Nav1.5 sodium current

Ahead of the regulatory acceptance of CIPA (planned for early 2016), it has become common practice to estimate cardiovascular liability from patch-clamp inhibition data involving INa, ICa-L, IKr (hERG), and ITo, as a “mini comprehensive in-vitro panel”.

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CiPA
Veterinary Laboratory Services
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Safety Pharmacology & Efficacy Testing
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Cardiovascular Animal Models
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Veterinary Research & Diagnostic Services
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Cardiovascular Toxicology
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Cell-Based Assays
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Pharmacology & Toxicology
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Respiratory Disease Animal Models
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Hematology Animal Models
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Toxicology
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Specialized Cell-Based Assays
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Animal Models and Studies
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Animal Models of Disease
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Biology
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Experimental Design
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Project Management & Consulting Services
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Project Management & Consulting Services

Project Management & Consulting Services

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Veterinary Pathology
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3D Printing
Three dimensional printing
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Engineering & Devices
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2018-01-22 16:24:42 +0200

Net Promoter Score of 7 received for In vitro Toxicity Testing.

Additional Ratings: satisfaction with deliverable: 8, satisfaction with timeliness: 3.
November 27, 2017

Positive review received for In vitro Toxicity Testing:

"Very good lab and quality capabilities. Also easy going personnel able to adapt to change as needed. Would have wished that communication was more frequent and effective - maybe something that develops over longer periods of time rather than a single project."

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