Contrast-induced acute kidney injury (CI-AKI) continues to be an important complication of contrast administration, particularly in high risk patients. The utility of substituted cyclodextrins (SCD) for mitigating the renal toxicity of several classes of nephrotoxic agents including antibiotics, anticancer agents and contrast agents (CA) was recently discovered. This discovery is the basis for the development of Veropaque, a kidney sparing contrast agent containing iohexol and a SCD.
This report analyzes preclinical animal studies using two SCDs and several CAs administered at clinically relevant doses to evaluate kidney pathology and function, mortality, and cardiovascular effects.
The Differential Effect of Nembutal and Ketamine/Xylazine Anesthetic on QT In...CorDynamics
Nembutal and ketamine/xylazine were compared as anesthetics for guinea pigs tested with the QT-prolonging drug dofetilide. Dofetilide significantly increased the QTc interval in both anesthetic groups compared to controls. However, with Nembutal anesthesia, the QTc increased 22% at the highest dofetilide dose, versus 12% with ketamine/xylazine. No changes were seen in other ECG intervals or hemodynamics. Nembutal anesthetized guinea pigs were more sensitive to QT effects, making it the preferred choice for screening drugs' potential to prolong the QT interval.
Nonclinical Models of Heart Failure - Doxorubicin CardiomyopathyCorDynamics
C57BL/6NCrl mice received a single intraperitoneal injection of doxorubicin at 15 mg/kg to induce acute cardiomyopathy. Echocardiography was performed on day 5 and showed decreased systolic and diastolic function, increased heart weight and lung weight, and elevated circulating biomarkers in doxorubicin-treated mice compared to controls. This single-dose doxorubicin mouse model successfully induced heart failure features including cardiac dysfunction and remodeling within 5 days.
This document examines the effects of adenosine on septal coronary artery (SCA) blood flow velocity using Doppler echocardiography. It finds that adenosine increases SCA diastolic and systolic blood flow velocity in a dose-dependent manner. The systolic to diastolic velocity ratio and coronary flow velocity reserve - a measure of blood flow changes from baseline to hyperemia - also increase with higher adenosine doses.
Ischemic injury - nonclinical models of heart failureCorDynamics
The document discusses various animal models used to study heart failure, including models that induce heart failure through ischemic injury by temporarily or permanently ligating the left anterior descending coronary artery in rats and mice, as well as models that induce cardiac stress through transverse aortic constriction or isoproterenol administration. Details are provided on the surgical procedures, endpoints measured, and advantages and disadvantages of different models for studying heart failure with reduced ejection fraction.
Nonclinical Models of Heart Failure - Cardiomyopathy and Pressure OverloadCorDynamics
The document summarizes risk factors and current treatments for heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). It also describes various animal models that are used to study these conditions, including models induced by transverse aortic constriction (TAC) or isoproterenol administration. TAC reliably induces cardiac hypertrophy and dysfunction in mice or rats and mimics aspects of pressure overload on the heart. Isoproterenol administration also causes cardiac hypertrophy in mice and has been used to model toxic cardiomyopathy.
Vasoreactivity - Contraction and Relaxation Using Aortic RingsCorDynamics
Do you have test articles that cause changes in blood pressure? Would you like to screen your lead compounds or backups? Check out these slides describing our vasoreactivity assays. These are a perfect compliment to our cardiovascular toxicology and safety pharmacology assays.
Uses only milligrams of compound!
Rodent Models of Heart Failure and Cardiac Ischemic InjuryCorDynamics
1) The document describes several animal models used to study heart failure, including models that induce heart failure through myocardial infarction or pressure overload.
2) The left anterior descending coronary artery ligation model is commonly used in rats and mice to induce myocardial infarction, producing reductions in ejection fraction that mimic human heart failure.
3) Ischemia-reperfusion injury models, where the coronary artery is temporarily occluded then reperfused, are also used and can assess treatments administered prior to or after the ischemic event.
Sotatercept for Hypoxia Sugen PAH at CorDynamicsCorDynamics
CorDynamics conducted PAH studies on Sotatercept and Sildenafil for Acceleron. Sotatercept recently received FDA Breakthrough Therapy designation for PAH.
The Differential Effect of Nembutal and Ketamine/Xylazine Anesthetic on QT In...CorDynamics
Nembutal and ketamine/xylazine were compared as anesthetics for guinea pigs tested with the QT-prolonging drug dofetilide. Dofetilide significantly increased the QTc interval in both anesthetic groups compared to controls. However, with Nembutal anesthesia, the QTc increased 22% at the highest dofetilide dose, versus 12% with ketamine/xylazine. No changes were seen in other ECG intervals or hemodynamics. Nembutal anesthetized guinea pigs were more sensitive to QT effects, making it the preferred choice for screening drugs' potential to prolong the QT interval.
Nonclinical Models of Heart Failure - Doxorubicin CardiomyopathyCorDynamics
C57BL/6NCrl mice received a single intraperitoneal injection of doxorubicin at 15 mg/kg to induce acute cardiomyopathy. Echocardiography was performed on day 5 and showed decreased systolic and diastolic function, increased heart weight and lung weight, and elevated circulating biomarkers in doxorubicin-treated mice compared to controls. This single-dose doxorubicin mouse model successfully induced heart failure features including cardiac dysfunction and remodeling within 5 days.
This document examines the effects of adenosine on septal coronary artery (SCA) blood flow velocity using Doppler echocardiography. It finds that adenosine increases SCA diastolic and systolic blood flow velocity in a dose-dependent manner. The systolic to diastolic velocity ratio and coronary flow velocity reserve - a measure of blood flow changes from baseline to hyperemia - also increase with higher adenosine doses.
Ischemic injury - nonclinical models of heart failureCorDynamics
The document discusses various animal models used to study heart failure, including models that induce heart failure through ischemic injury by temporarily or permanently ligating the left anterior descending coronary artery in rats and mice, as well as models that induce cardiac stress through transverse aortic constriction or isoproterenol administration. Details are provided on the surgical procedures, endpoints measured, and advantages and disadvantages of different models for studying heart failure with reduced ejection fraction.
Nonclinical Models of Heart Failure - Cardiomyopathy and Pressure OverloadCorDynamics
The document summarizes risk factors and current treatments for heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). It also describes various animal models that are used to study these conditions, including models induced by transverse aortic constriction (TAC) or isoproterenol administration. TAC reliably induces cardiac hypertrophy and dysfunction in mice or rats and mimics aspects of pressure overload on the heart. Isoproterenol administration also causes cardiac hypertrophy in mice and has been used to model toxic cardiomyopathy.
Vasoreactivity - Contraction and Relaxation Using Aortic RingsCorDynamics
Do you have test articles that cause changes in blood pressure? Would you like to screen your lead compounds or backups? Check out these slides describing our vasoreactivity assays. These are a perfect compliment to our cardiovascular toxicology and safety pharmacology assays.
Uses only milligrams of compound!
Rodent Models of Heart Failure and Cardiac Ischemic InjuryCorDynamics
1) The document describes several animal models used to study heart failure, including models that induce heart failure through myocardial infarction or pressure overload.
2) The left anterior descending coronary artery ligation model is commonly used in rats and mice to induce myocardial infarction, producing reductions in ejection fraction that mimic human heart failure.
3) Ischemia-reperfusion injury models, where the coronary artery is temporarily occluded then reperfused, are also used and can assess treatments administered prior to or after the ischemic event.
Sotatercept for Hypoxia Sugen PAH at CorDynamicsCorDynamics
CorDynamics conducted PAH studies on Sotatercept and Sildenafil for Acceleron. Sotatercept recently received FDA Breakthrough Therapy designation for PAH.
Does Our Compound Show Efficacy in Heart Failure?CorDynamics
The document describes several rodent models of heart failure induced by myocardial infarction or pressure overload.
The left anterior descending coronary artery ligation model involves temporarily or permanently ligating the LAD in rats, inducing ischemia and infarction. Assessment endpoints include infarct size, echocardiography, and hemodynamic measurements up to 16 weeks later.
The isoproterenol model induces cardiac hypertrophy in mice by administering isoproterenol for 7 days. Echocardiography and tissue collection are performed on day 10 and 21.
Transverse aortic constriction in mice involves placing a clip around the aorta, inducing pressure overload-induced remodeling. Mice undergo echocardiography
Shifting Paradigms: Examining Pro-Thrombotic Activity from a Safety PerspectiveCorDynamics
CorDynamics conducts thrombosis experiments using small and large animals to examine pro-thrombotic activity from a safety perspective. Mouse models are used where ferric chloride is applied to the carotid artery to cause endothelial injury and monitor blood flow changes over time. Tests are done with various concentrations of ferric chloride to establish a pro-thrombotic window, showing that reducing the concentration reduces thrombosis as evidenced by increased occlusion times and incidence of non-occlusion.
This document discusses animal models used to study pulmonary arterial hypertension (PAH), including their advantages and limitations. The monocrotaline rat model induces PAH through injection of monocrotaline, which metabolizes into a toxin damaging the lungs. Antagonism of the 5HT2B receptor helps prevent PAH in this model. Hypoxia alone causes pulmonary vasoconstriction in animals but only moderate PAH. Combining chronic hypoxia with a cofactor like monocrotaline more closely mimics the human condition, resulting in thickened and muscularized pulmonary arteries and increased pressure similar to the effects seen in monocrotaline-induced PAH.
Time Course of Hypoxia/Sugen-Induced PAHCorDynamics
Additional data demonstrates the time course of pulmonary arterial hypertension (PAH) development in our most relevant preclinical model. This is important information in the effort to guide reversal therapy.
Leveraging the Langendorff Model to Detect ProarrhythmiaCorDynamics
Recognizing the nascent status of Comprehensive In Vitro Proarrhythmia Assay (CiPA), earlier this year we redesigned our standard rabbit Langendorff isolated heart assessments to be conducted with a much greater emphasis on proarrhythmia – while still capturing vital details on cardiac hemodynamics, electrocardiography, and electrophysiology.
Examining Drug Candidates for Pulmonary Arterial Hypertension: The Ups and Do...CorDynamics
Originally presented at the 2014 Safety Pharmacology Society Annual Meeting, this presentation offers a clear understanding of the differences as well as the benefits of monocrotaline, hypoxia with and without VEGF inhibition and immunodeficiency as preclinical initiators of PAH. A past SPS president, Dr. Gralinski will also provided insight on how your compounds may prevent or reverse PAH on the path to the clinic.
Recent publications detail a probabilistic method of correcting QT interval in canine and NHP using intensive telemetry interrogation. Our objective was to interrogate whether QTcH is appropriate for small animals, specifically the guinea pig.
Monitoring Pulmonary Arterial Hypertension with TelemetryCorDynamics
CorDynamics adds a powerful capability to its leading suite of pulmonary arterial hypertension models – the ability to record pulmonary artery pressures in the rat.
Validation for Anesthetized Models: Hemodynamics and ElectrocardiographyCorDynamics
This document discusses a comprehensive dataset that demonstrates the effect of multiple positive controls on hemodynamics and electrocardiography using limited quantities of test articles while maintaining throughput amenable for screening, allowing pharmacokinetic-pharmacodynamic relationships to be established.
CorDynamics introduces a new respiratory telemetry system that can simultaneously and continuously record respiratory parameters, blood pressure, and ECG in large animals like rabbits, dogs, pigs, and non-human primates. The system was validated using bethanechol, a cholinergic agonist, which increased heart rate, tidal volume, minute volume, and respiratory rate in conscious telemetrized rabbits. This allows researchers to combine assessments of cardiovascular and respiratory function within a single study.
Using dual pressure telemetry, systemic blood pressure AND either pulmonary artery pressure or left ventricular pressure can be measured in small species—simultaneously. Dual pressure telemetry also generates ECGs.
Computer in pharmaceutical research and development-Mpharm(Pharmaceutics)MuskanShingari
Statistics- Statistics is the science of collecting, organizing, presenting, analyzing and interpreting numerical data to assist in making more effective decisions.
A statistics is a measure which is used to estimate the population parameter
Parameters-It is used to describe the properties of an entire population.
Examples-Measures of central tendency Dispersion, Variance, Standard Deviation (SD), Absolute Error, Mean Absolute Error (MAE), Eigen Value
Discover the benefits of homeopathic medicine for irregular periods with our guide on 5 common remedies. Learn how these natural treatments can help regulate menstrual cycles and improve overall menstrual health.
Visit Us: https://drdeepikashomeopathy.com/service/irregular-periods-treatment/
Nutritional deficiency Disorder are problems in india.
It is very important to learn about Indian child's nutritional parameters as well the Disease related to alteration in their Nutrition.
How to Control Your Asthma Tips by gokuldas hospital.Gokuldas Hospital
Respiratory issues like asthma are the most sensitive issue that is affecting millions worldwide. It hampers the daily activities leaving the body tired and breathless.
The key to a good grip on asthma is proper knowledge and management strategies. Understanding the patient-specific symptoms and carving out an effective treatment likewise is the best way to keep asthma under control.
Breast cancer: Post menopausal endocrine therapyDr. Sumit KUMAR
Breast cancer in postmenopausal women with hormone receptor-positive (HR+) status is a common and complex condition that necessitates a multifaceted approach to management. HR+ breast cancer means that the cancer cells grow in response to hormones such as estrogen and progesterone. This subtype is prevalent among postmenopausal women and typically exhibits a more indolent course compared to other forms of breast cancer, which allows for a variety of treatment options.
Diagnosis and Staging
The diagnosis of HR+ breast cancer begins with clinical evaluation, imaging, and biopsy. Imaging modalities such as mammography, ultrasound, and MRI help in assessing the extent of the disease. Histopathological examination and immunohistochemical staining of the biopsy sample confirm the diagnosis and hormone receptor status by identifying the presence of estrogen receptors (ER) and progesterone receptors (PR) on the tumor cells.
Staging involves determining the size of the tumor (T), the involvement of regional lymph nodes (N), and the presence of distant metastasis (M). The American Joint Committee on Cancer (AJCC) staging system is commonly used. Accurate staging is critical as it guides treatment decisions.
Treatment Options
Endocrine Therapy
Endocrine therapy is the cornerstone of treatment for HR+ breast cancer in postmenopausal women. The primary goal is to reduce the levels of estrogen or block its effects on cancer cells. Commonly used agents include:
Selective Estrogen Receptor Modulators (SERMs): Tamoxifen is a SERM that binds to estrogen receptors, blocking estrogen from stimulating breast cancer cells. It is effective but may have side effects such as increased risk of endometrial cancer and thromboembolic events.
Aromatase Inhibitors (AIs): These drugs, including anastrozole, letrozole, and exemestane, lower estrogen levels by inhibiting the aromatase enzyme, which converts androgens to estrogen in peripheral tissues. AIs are generally preferred in postmenopausal women due to their efficacy and safety profile compared to tamoxifen.
Selective Estrogen Receptor Downregulators (SERDs): Fulvestrant is a SERD that degrades estrogen receptors and is used in cases where resistance to other endocrine therapies develops.
Combination Therapies
Combining endocrine therapy with other treatments enhances efficacy. Examples include:
Endocrine Therapy with CDK4/6 Inhibitors: Palbociclib, ribociclib, and abemaciclib are CDK4/6 inhibitors that, when combined with endocrine therapy, significantly improve progression-free survival in advanced HR+ breast cancer.
Endocrine Therapy with mTOR Inhibitors: Everolimus, an mTOR inhibitor, can be added to endocrine therapy for patients who have developed resistance to aromatase inhibitors.
Chemotherapy
Chemotherapy is generally reserved for patients with high-risk features, such as large tumor size, high-grade histology, or extensive lymph node involvement. Regimens often include anthracyclines and taxanes.
Spontaneous Bacterial Peritonitis - Pathogenesis , Clinical Features & Manage...Jim Jacob Roy
In this presentation , SBP ( spontaneous bacterial peritonitis ) , which is a common complication in patients with cirrhosis and ascites is described in detail.
The reference for this presentation is Sleisenger and Fordtran's Gastrointestinal and Liver Disease Textbook ( 11th edition ).
Does Our Compound Show Efficacy in Heart Failure?CorDynamics
The document describes several rodent models of heart failure induced by myocardial infarction or pressure overload.
The left anterior descending coronary artery ligation model involves temporarily or permanently ligating the LAD in rats, inducing ischemia and infarction. Assessment endpoints include infarct size, echocardiography, and hemodynamic measurements up to 16 weeks later.
The isoproterenol model induces cardiac hypertrophy in mice by administering isoproterenol for 7 days. Echocardiography and tissue collection are performed on day 10 and 21.
Transverse aortic constriction in mice involves placing a clip around the aorta, inducing pressure overload-induced remodeling. Mice undergo echocardiography
Shifting Paradigms: Examining Pro-Thrombotic Activity from a Safety PerspectiveCorDynamics
CorDynamics conducts thrombosis experiments using small and large animals to examine pro-thrombotic activity from a safety perspective. Mouse models are used where ferric chloride is applied to the carotid artery to cause endothelial injury and monitor blood flow changes over time. Tests are done with various concentrations of ferric chloride to establish a pro-thrombotic window, showing that reducing the concentration reduces thrombosis as evidenced by increased occlusion times and incidence of non-occlusion.
This document discusses animal models used to study pulmonary arterial hypertension (PAH), including their advantages and limitations. The monocrotaline rat model induces PAH through injection of monocrotaline, which metabolizes into a toxin damaging the lungs. Antagonism of the 5HT2B receptor helps prevent PAH in this model. Hypoxia alone causes pulmonary vasoconstriction in animals but only moderate PAH. Combining chronic hypoxia with a cofactor like monocrotaline more closely mimics the human condition, resulting in thickened and muscularized pulmonary arteries and increased pressure similar to the effects seen in monocrotaline-induced PAH.
Time Course of Hypoxia/Sugen-Induced PAHCorDynamics
Additional data demonstrates the time course of pulmonary arterial hypertension (PAH) development in our most relevant preclinical model. This is important information in the effort to guide reversal therapy.
Leveraging the Langendorff Model to Detect ProarrhythmiaCorDynamics
Recognizing the nascent status of Comprehensive In Vitro Proarrhythmia Assay (CiPA), earlier this year we redesigned our standard rabbit Langendorff isolated heart assessments to be conducted with a much greater emphasis on proarrhythmia – while still capturing vital details on cardiac hemodynamics, electrocardiography, and electrophysiology.
Examining Drug Candidates for Pulmonary Arterial Hypertension: The Ups and Do...CorDynamics
Originally presented at the 2014 Safety Pharmacology Society Annual Meeting, this presentation offers a clear understanding of the differences as well as the benefits of monocrotaline, hypoxia with and without VEGF inhibition and immunodeficiency as preclinical initiators of PAH. A past SPS president, Dr. Gralinski will also provided insight on how your compounds may prevent or reverse PAH on the path to the clinic.
Recent publications detail a probabilistic method of correcting QT interval in canine and NHP using intensive telemetry interrogation. Our objective was to interrogate whether QTcH is appropriate for small animals, specifically the guinea pig.
Monitoring Pulmonary Arterial Hypertension with TelemetryCorDynamics
CorDynamics adds a powerful capability to its leading suite of pulmonary arterial hypertension models – the ability to record pulmonary artery pressures in the rat.
Validation for Anesthetized Models: Hemodynamics and ElectrocardiographyCorDynamics
This document discusses a comprehensive dataset that demonstrates the effect of multiple positive controls on hemodynamics and electrocardiography using limited quantities of test articles while maintaining throughput amenable for screening, allowing pharmacokinetic-pharmacodynamic relationships to be established.
CorDynamics introduces a new respiratory telemetry system that can simultaneously and continuously record respiratory parameters, blood pressure, and ECG in large animals like rabbits, dogs, pigs, and non-human primates. The system was validated using bethanechol, a cholinergic agonist, which increased heart rate, tidal volume, minute volume, and respiratory rate in conscious telemetrized rabbits. This allows researchers to combine assessments of cardiovascular and respiratory function within a single study.
Using dual pressure telemetry, systemic blood pressure AND either pulmonary artery pressure or left ventricular pressure can be measured in small species—simultaneously. Dual pressure telemetry also generates ECGs.
Computer in pharmaceutical research and development-Mpharm(Pharmaceutics)MuskanShingari
Statistics- Statistics is the science of collecting, organizing, presenting, analyzing and interpreting numerical data to assist in making more effective decisions.
A statistics is a measure which is used to estimate the population parameter
Parameters-It is used to describe the properties of an entire population.
Examples-Measures of central tendency Dispersion, Variance, Standard Deviation (SD), Absolute Error, Mean Absolute Error (MAE), Eigen Value
Discover the benefits of homeopathic medicine for irregular periods with our guide on 5 common remedies. Learn how these natural treatments can help regulate menstrual cycles and improve overall menstrual health.
Visit Us: https://drdeepikashomeopathy.com/service/irregular-periods-treatment/
Nutritional deficiency Disorder are problems in india.
It is very important to learn about Indian child's nutritional parameters as well the Disease related to alteration in their Nutrition.
How to Control Your Asthma Tips by gokuldas hospital.Gokuldas Hospital
Respiratory issues like asthma are the most sensitive issue that is affecting millions worldwide. It hampers the daily activities leaving the body tired and breathless.
The key to a good grip on asthma is proper knowledge and management strategies. Understanding the patient-specific symptoms and carving out an effective treatment likewise is the best way to keep asthma under control.
Breast cancer: Post menopausal endocrine therapyDr. Sumit KUMAR
Breast cancer in postmenopausal women with hormone receptor-positive (HR+) status is a common and complex condition that necessitates a multifaceted approach to management. HR+ breast cancer means that the cancer cells grow in response to hormones such as estrogen and progesterone. This subtype is prevalent among postmenopausal women and typically exhibits a more indolent course compared to other forms of breast cancer, which allows for a variety of treatment options.
Diagnosis and Staging
The diagnosis of HR+ breast cancer begins with clinical evaluation, imaging, and biopsy. Imaging modalities such as mammography, ultrasound, and MRI help in assessing the extent of the disease. Histopathological examination and immunohistochemical staining of the biopsy sample confirm the diagnosis and hormone receptor status by identifying the presence of estrogen receptors (ER) and progesterone receptors (PR) on the tumor cells.
Staging involves determining the size of the tumor (T), the involvement of regional lymph nodes (N), and the presence of distant metastasis (M). The American Joint Committee on Cancer (AJCC) staging system is commonly used. Accurate staging is critical as it guides treatment decisions.
Treatment Options
Endocrine Therapy
Endocrine therapy is the cornerstone of treatment for HR+ breast cancer in postmenopausal women. The primary goal is to reduce the levels of estrogen or block its effects on cancer cells. Commonly used agents include:
Selective Estrogen Receptor Modulators (SERMs): Tamoxifen is a SERM that binds to estrogen receptors, blocking estrogen from stimulating breast cancer cells. It is effective but may have side effects such as increased risk of endometrial cancer and thromboembolic events.
Aromatase Inhibitors (AIs): These drugs, including anastrozole, letrozole, and exemestane, lower estrogen levels by inhibiting the aromatase enzyme, which converts androgens to estrogen in peripheral tissues. AIs are generally preferred in postmenopausal women due to their efficacy and safety profile compared to tamoxifen.
Selective Estrogen Receptor Downregulators (SERDs): Fulvestrant is a SERD that degrades estrogen receptors and is used in cases where resistance to other endocrine therapies develops.
Combination Therapies
Combining endocrine therapy with other treatments enhances efficacy. Examples include:
Endocrine Therapy with CDK4/6 Inhibitors: Palbociclib, ribociclib, and abemaciclib are CDK4/6 inhibitors that, when combined with endocrine therapy, significantly improve progression-free survival in advanced HR+ breast cancer.
Endocrine Therapy with mTOR Inhibitors: Everolimus, an mTOR inhibitor, can be added to endocrine therapy for patients who have developed resistance to aromatase inhibitors.
Chemotherapy
Chemotherapy is generally reserved for patients with high-risk features, such as large tumor size, high-grade histology, or extensive lymph node involvement. Regimens often include anthracyclines and taxanes.
Spontaneous Bacterial Peritonitis - Pathogenesis , Clinical Features & Manage...Jim Jacob Roy
In this presentation , SBP ( spontaneous bacterial peritonitis ) , which is a common complication in patients with cirrhosis and ascites is described in detail.
The reference for this presentation is Sleisenger and Fordtran's Gastrointestinal and Liver Disease Textbook ( 11th edition ).
Travel vaccination in Manchester offers comprehensive immunization services for individuals planning international trips. Expert healthcare providers administer vaccines tailored to your destination, ensuring you stay protected against various diseases. Conveniently located clinics and flexible appointment options make it easy to get the necessary shots before your journey. Stay healthy and travel with confidence by getting vaccinated in Manchester. Visit us: www.nxhealthcare.co.uk
- Video recording of this lecture in English language: https://youtu.be/Pt1nA32sdHQ
- Video recording of this lecture in Arabic language: https://youtu.be/uFdc9F0rlP0
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
STUDIES IN SUPPORT OF SPECIAL POPULATIONS: GERIATRICS E7shruti jagirdar
Unit 4: MRA 103T Regulatory affairs
This guideline is directed principally toward new Molecular Entities that are
likely to have significant use in the elderly, either because the disease intended
to be treated is characteristically a disease of aging ( e.g., Alzheimer's disease) or
because the population to be treated is known to include substantial numbers of
geriatric patients (e.g., hypertension).
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The biomechanics of running involves the study of the mechanical principles underlying running movements. It includes the analysis of the running gait cycle, which consists of the stance phase (foot contact to push-off) and the swing phase (foot lift-off to next contact). Key aspects include kinematics (joint angles and movements, stride length and frequency) and kinetics (forces involved in running, including ground reaction and muscle forces). Understanding these factors helps in improving running performance, optimizing technique, and preventing injuries.
1. TCT-138
Veropaque, A Novel Contrast Formulation, Mitigates Contrast Induced Acute Kidney Injury Verrow would like to acknowledge Dr.
S. Biswas, PhD1, ES Rowe, PhD MBA1,2, G Mosher, Ph.D.2, L Insisienmay1, MK Ozias, MS1, MR Gralinski, PhD3 and VD Rowe, MD1,2 Geoffrey O. Hartzler, a friend, investor,
1MidAmerica Neuroscience Research Foundation, 2Verrow Pharmaceuticals, Inc., 3CorDynamics, Inc.
Disclosures: G Mosher is an employee of Verrow Pharmaceuticals and ES Rowe and board member for his insightful
and VD Rowe have equity positions in Verrow Pharmaceuticals. input and support of this project.
RESULTS AND DISCUSSION
INTRODUCTION Kidney Pathology Kidney Functionality
Contrast-induced acute kidney injury (CI-AKI) continues to be an important A single dose of iohexol caused significant pathological changes to the kidneys of the RC rodents. The photomicro- The functionality of the kidney in terms of plasma creatinine levels, is also
complication of contrast administration, particularly in high risk patients. We've graph in Figure 1 illustrates the typical pathology seen at 24h in RC mice that received a single 1.5 g iodine/kg dose of maintained in both rats and mice in the presence of a SCD (Figure 7). Iohexol
recently discovered the utility of substituted cyclodextrins (SCD) for mitigating iohexol or Veropaque (iohexol:SBECD mole ratio of 1:0.025). Iohexol treated kidneys indicate pathological changes in dosed at 1.5g I/kg to RC rodents caused an increase in plasma creatinine
the renal toxicity of several classes of nephrotoxic agents including antibiotics, both the renal cortex (A) and medulla (C) such as tub- especially in the mouse model. No increase was observed when the SCD was
anticancer agents and contrast agents (CA). This discovery is the basis for the ular vacuolation, tubular dilatation (big arrow), cast present with the iohexol.
development of Veropaque, a kidney sparing contrast agent containing iohexol formation (thin arrow), loss of brush border (arrow 1.4 (13)(16)
Mouse
Creatinine [mg/dl]
and a SCD. heads) and focal edema (E). Concurrent SBECD 1.2
administration significantly attenuated the morph- Rat
Here we report on preclinical animal studies using two SCDs and several CAs
1.0
administered at clinically relevant doses to evaluate kidney pathology and func- ological changes in both cortex (B) and medulla (D). (N=67) (5) (8) (3) (12)(15) Figure 7. Plasma
0.8 creatinine levels at
tion, mortality, and cardiovascular effects.
The corresponding kidney pathology scores are 0.6 24h (mouse) or 48h
MATERIALS
presented in Figure 2 for the deep renal cortex/outer 0.4 (rat) post treatment in
Iopamidol & Iodixanol: Isovue-M 200 (Bracco Diagnostics) and Visipaque 320
medulla. The presence of the SBECD in Veropaque 0.2
RC rodents
(GE Healthcare) were diluted to 150mg Iodine/mL with phosphate buffered
provides dramatic reduction in the pathology at 24h.
saline (PBS) then solid SBECD (sulfobutylether β-cyclodextrin, CyDex Pharma- 0.0
Although not presented here, similar protection is also Predose RC RC-SBECD RC-Iohexol RC-Iohexol +
ceuticals) was added and dissolved in various mole ratios.
observed in the outer cortex and in both regions at SBECD
Iohexol (rodent studies): Omnipaque 300 (GE Healthcare) was diluted 1:1 (1:0.025 ratio)
48h, though the overall toxicity is reduced at 48h. The
with PBS then solid SBECD or HPCD (2-hydroxypropyl β-cyclodextrin, CTD, individual pathology scores can be added to give a Cardiovascular Assessment
Inc.) was added and dissolved in various mole ratios. total pathology score as shown in Figure 3, which The Veropaque formulation contains ~154mM sodium from the SBECD, and
Iohexol (dog studies): Aqueous formulations were prepared containing 350 shows the results for the outer renal cortex for both its effects on the cardiac electrophysiology was compared to iohexol after direct
mg iodine/mL iohexol (Hovione FarmaCiencia SA), 0 or 50 mg/mL SBECD, iohexol and iodixanol in the presence and absence of injection into the left coronary artery of instrumented dogs.
0.105 mg/mL edetate calcium disodium hydrate and 1.21 mg/mL TRIS buffer (pH Figure 1. Light microscopy of renal tissue of mouse (H&E, SBECD. There were no notable effects of intracoronary iohexol administration on most
6.8-7.7). The formulation containing SBECD is Veropaque. PAS, 200x)
measured cardiovascular parameters. Variables including LV contractility (Fig 8)
11
METHODS 3.0 (n=3) (n=3) and QTc interval (Fig 9) were notably, yet transiently, altered following both
Iohexol (n=3) 10 Iohexol
Rodent Pathology Model: Female C57BL/6 mice (8-10 weeks) and Sprague 2.5 9 iohexol and Veropaque, a finding consistent with the literature for iohexol†.
Total Pathology Score
Dawley male rats (9-11 weeks) were made renally compromised (RC) with a 10 Pathology Score Veropaque (n=3) 8 Iodixanol In addition to these transient quantitative changes, qualitative alterations in
mg/kg intraperitoneal (IP) injection of L-NAME (N-nitro-L-arginine methyl ester) 2.0 7 electrocardiographic morphology were observed for both formulations. These
followed in 10 min with 10 mg/kg indomethacin. The test formulations were 6 were generally concomitant with physical injection of the formulations into the
1.5 5
dosed 20 min later as single 10 mL/kg injections into the tail vein at 1.5g coronary artery, and likely associated with brief myocardial ischemia from inter-
4
iodine/kg. 1.0 (n=2) (n=3) ruption of arterial flow. The changes consisted of QRS complex widening along
3
The animals were sacrificed with rapid inhalation anesthesia at 24 or 48h post 2 with ST segment depression. Scattered premature ventricular contractions were
dosing and the kidneys removed and stored in buffered formalin. They were 0.5 also noted. Within 5 min after the end of each injection, ECG morphology
1
mounted in paraffin blocks, cut into 5 µM sections and stained with H&E and 0.0
0 returned to normal for each formulation.
periodic acid Schiff (PAS). The sections were examined by light microscopy and Tubular Tubular cast Vacuoles Loss of Edema Tubular RC/Contrast RC/Contrast + SBECD (†Jacobsen, et al, Repeated intracoronary injections of contrast media, additive hemodynamic and
dilatation brush border degeneration
(1:0.025 mole ratio) electrophysiologic effects in a dog model. Investigative radiology, 28(10) (1993) p. 917-924.)
scored for pathology in a blinded fashion.
Blood samples for creatinine determination were taken predose (iv) and at Figure 2. Pathology in the deep renal cortex and outer Figure 3. Total renal pathology scores in the outer renal 120
sacrifice (cardiac puncture). The plasma was isolated and stored at –70°C until renal medulla of mice at 24h cortex of mice at 48h
LV dP/dt max (% change from
100
assayed. Creatinine was measured colorimetrically with QuantiChrom Creatinine The nephroprotection can also be demonstrated in a rat model. Figure 4 illustrates the effects of the contrast agent: Iohexol
Assay Kit (BioAssay Systems, Hayward, CA). cyclodextrin mole ratio for iohexol and iopamidol. A dramatic reduction in pathology is observed in the presence of
80
Veropaque
Figure 8. Left
baseline)
Pathology Evaluation: Kidney sections were evaluated at 400x magnification. SBECD, and in a dose dependent manner. As mole ratios increase greater than about 1:0.05 (not shown), the pathol- 60
Five randomly selected fields in each section were assessed for the occurrence ogy score begins to increase due to the known effects of higher doses of the SCD on the kidney tissues. ventricular contractility
40
of: changes following
Several cyclodextrins have been evaluated and shown to provide nephroprotection of varying degrees. Figure 5
• dilated tubules • edema/mononuclear infiltration bolus dosing 20
illustrates the reduction in outer renal cortex pathology scores from iohexol in the presence of increasing amounts of a
• loss of brush border • vacuoles different cyclodextrin, HPCD. Veropaque (iohexol with SBECD) is shown for comparison. SBECD provides slightly 0
• tubular casts • tubular degradation greater efficacy than HPCD, generating a pathology score comparable to the RC control values. -20
and scored in a blinded manner on a scale of 0-4. A total of 4 sections were 0 50 100 150 200 250
10 7 (n=16)
(n=3) (n=4) Iohexol Iohexol + HPCD Time After First Administration (sec)
analyzed per kidney. The 20 assessments for each parameter were averaged 9 Total Pathology Score
Total Pathology Score
Iopamidol 6 Veropaque (SBECD)
and reported as an average score per field. Total pathology score, a summation 8
(n=4) 40
of the average scores for the six parameters, is used in some figures for 5
QTc (% change from baseline)
7
(n=4) Iohexol
efficiency of presentation. All error bars are SEM. 6 30
(n=4) (n=5) 4 Veropaque
5
Rodent Survival Model: Male Sprague Dawley rats (9-11 weeks, 8/group) (n=13) (n=10) 20
4 (n=5) 3
received IP L-NAME and indomethacin as above followed by IV placebo, iohexol 3 (n=12)
or Veropaque at 2.5 g I/kg. Their survival was then monitored for 14 days. 2 10 Figure 9. QTc interval
2
Instrumented Cardiovascular Dog Model: Male Beagle dogs were 1 (n=3) (n=1) 1
changes following
0
anesthetized with propofol, intubated, and placed on isoflurane gas anesthesia. 0 bolus dosing
Control RC/Contrast RC/Contrast + RC/Contrast + 0
Morphine (0.5mg/kg) was used for pain management in this open chest SBECD (1:0.025 SBECD (1:0.05 0:0 1:0 1:0.0125 1:0.0188 1:0.025 1:0.0375 -10
procedure. mole ratio) mole ratio) Iohexol:Cyclodextrin Mole Ratio -20
A Swan-Ganz catheter for measurement of right heart pressure was inserted Figure 4. Total renal pathology scores in the outer renal Figure 5. Effect of iohexol:cyclodextrin mole ratio on the 0 50 100 150 200 250
into the jugular vein, advanced to the pulmonary artery ‘wedge’ position. A solid- cortex of rats at 24h total pathology score in the outer renal cortex of rats at Time After First Administration (sec)
state high fidelity pressure catheter (Millar) for left ventricular pressure and aortic 48h CONCLUSIONS
pressure was inserted into the carotid artery. Both were secured with suture. 100
• Substituted cyclodextrins protect the kidney from the nephrotoxicity of
Survival (%)
The surface lead ECG was recorded continuously via electrodes placed on 80 contrast agents in two animal models, at clinically relevant doses of several
Control
the right arm, left leg and chest of the dog. ECGs were continuously recorded 14-Day Survival Study contrast agents including iohexol, iodixanol, and iopamidol.
60 Iohexol + SBECD
throughout the experiment, reporting PR, QRS, QT, QTc(VdW) and heart rate. The nephrotoxicity of contrast agents can lead to mor-
40 Iohexol • Direct intra-coronary injection of the Veropaque formulation into
Monophasic action potential was recorded (when possible) via left ventricular tality in rodents when larger doses are administered. Only instrumented dogs showed no differences from injection of iohexol alone.
epicardial probe. 20 half (4 of 8) survived a single dose of 2.5g I/kg iohexol as
• The kidney protection occurs at mole ratios below 1:1 suggesting a
Each formulation (iohexol or Veropaque) was bolused into the left main 0
shown in Figure 6. The presence of SBECD at an iohexol:
mechanism other than complexation of iohexol with cyclodextrin.
coronary artery as 5 doses of 4 mL each, administered at ~1mL/sec with 10 0 7 14 SBECD mole ratio of 1:0.025 reduced the nephrotoxicity
seconds between doses. Thirty minutes after the last dose, the procedure was Days Post Dosing and raised survival to 88% (7 of 8) Based on these and other data, we believe that Veropaque has the potential
repeated with the second formulation. The overall process was repeated in two Figure 6. Survival of RC rats receiving single IV 2.5g I/kg to markedly decrease the incidence of CI-AKI in high risk patients undergoing
additional animals. doses of iohexol or iohexol + SBECD. cardiology procedures. Development is in progress.