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.
A new simple, sensitive, rapid, accurate,
precise and economical Derivative
Spectrophotometric method for the
simultaneous determination of Quinapril
HCl
A new simple, sensitive, rapid, accurate,
precise and economical Derivative
Spectrophotometric method for the
simultaneous determination of Quinapril
HCl
Effects of eugenol on resting tension of rat atriaRobson Olivoto
Artigo para analise do Eugenol, um óleo essencial, como uma possível ferramenta biológica para experimentos com células musculares. Os resultados indicaram ou sugerem que existe uma via de ativação da maquinaria contrátil que ativa as proteínas contrateis (promovendo a contração) mesmo na ausência de íons cálcio.
Analytical method Development and Validation for the estimation of Pioglitazo...SriramNagarajan15
This paper describes the analytical method suitable for validation of Pioglitazone hydrochloride by UV Spectrophotometric method. The method utilized UV spectroscopy and the solvent system was consists of 6 N Glacial acetic acid at wave length 270 nm. Validation experiments were performed to demonstrate Specificity, Precision, Linearity, Accuracy, ruggedness. The method was linear over the concentration range of 10-50 µg/ml. The Proposed method was simple, sensitive & reliable with good Precise, Accurate, and Reproducible and rapid for the determination of Pioglitazone. The commercial formulations are estimated without interference. Hence this method can be used for routine determination of Pioglitazone hydrochloride in bulk and their pharmaceutical dosage forms.
Expt. 4 DRC of acetylcholine using frog rectus abdominis muscleVISHALJADHAV100
Objective
Principle
Requirements
Experimental specifications (conditions)
Preparation of ACh stock and standard solutions
Preparation of frog ringer solution (PSS)
Procedure
Kymograph recording of contractions
Observation table
Calculation of magnification value (Mf)
Graphical presentation of CRC/ DRC
Result and interpretation
Spectrophotometric Determination of Cardiovascular DrugsIJMER
International Journal of Modern Engineering Research (IJMER) is Peer reviewed, online Journal. It serves as an international archival forum of scholarly research related to engineering and science education.
Association between polymorphisms of the DNA repair gene (OGG1) in Iraqi pati...iosrjce
IOSR Journal of Pharmacy and Biological Sciences(IOSR-JPBS) is a double blind peer reviewed International Journal that provides rapid publication (within a month) of articles in all areas of Pharmacy and Biological Science. The journal welcomes publications of high quality papers on theoretical developments and practical applications in Pharmacy and Biological Science. Original research papers, state-of-the-art reviews, and high quality technical notes are invited for publications.
Effects of eugenol on resting tension of rat atriaRobson Olivoto
Artigo para analise do Eugenol, um óleo essencial, como uma possível ferramenta biológica para experimentos com células musculares. Os resultados indicaram ou sugerem que existe uma via de ativação da maquinaria contrátil que ativa as proteínas contrateis (promovendo a contração) mesmo na ausência de íons cálcio.
Analytical method Development and Validation for the estimation of Pioglitazo...SriramNagarajan15
This paper describes the analytical method suitable for validation of Pioglitazone hydrochloride by UV Spectrophotometric method. The method utilized UV spectroscopy and the solvent system was consists of 6 N Glacial acetic acid at wave length 270 nm. Validation experiments were performed to demonstrate Specificity, Precision, Linearity, Accuracy, ruggedness. The method was linear over the concentration range of 10-50 µg/ml. The Proposed method was simple, sensitive & reliable with good Precise, Accurate, and Reproducible and rapid for the determination of Pioglitazone. The commercial formulations are estimated without interference. Hence this method can be used for routine determination of Pioglitazone hydrochloride in bulk and their pharmaceutical dosage forms.
Expt. 4 DRC of acetylcholine using frog rectus abdominis muscleVISHALJADHAV100
Objective
Principle
Requirements
Experimental specifications (conditions)
Preparation of ACh stock and standard solutions
Preparation of frog ringer solution (PSS)
Procedure
Kymograph recording of contractions
Observation table
Calculation of magnification value (Mf)
Graphical presentation of CRC/ DRC
Result and interpretation
Spectrophotometric Determination of Cardiovascular DrugsIJMER
International Journal of Modern Engineering Research (IJMER) is Peer reviewed, online Journal. It serves as an international archival forum of scholarly research related to engineering and science education.
Association between polymorphisms of the DNA repair gene (OGG1) in Iraqi pati...iosrjce
IOSR Journal of Pharmacy and Biological Sciences(IOSR-JPBS) is a double blind peer reviewed International Journal that provides rapid publication (within a month) of articles in all areas of Pharmacy and Biological Science. The journal welcomes publications of high quality papers on theoretical developments and practical applications in Pharmacy and Biological Science. Original research papers, state-of-the-art reviews, and high quality technical notes are invited for publications.
Effects of two anaesthetic combinations (xylazine ketamine and xylazine-propo...Pravin Mishra
The research was conducted to evaluate the effects of two anaesthetic combinations (Xylazine-Ketamine and Xylazine-Propofol) on clinical and hemato-biochemical profile in dogs. A total of 12 dogs, apparently healthy, age 2-3 years and weighing 12-17 kg were used and randomly grouped into two; X-K (Xylazine @1.1mg/kg IM-Ketamine @10mg/kg IM) and X-P (Xylazine @1.1mg/kg IM-Propofol 2mg/kg IV). Animals were permitted for the anaesthetic procedure after 2-3 days of acclimatization. Clinical parameters such as body temperature (C), pulse rate (beats/min), respiratory rate (breaths/min.), oxygen saturation (SpO2, %), hematological profile; hemoglobin (Hb, %), total erythrocyte count (TEC, 106/mm3), total leucocyte count (TLC, 103mm3), packed cell volume (PCV, %) and, serum biochemical profile; aspartate aminotransferase (AST, IU/L), alanine aminotransferase (ALT, IU/L), bilirubin (mg/dL), creatinine (mg/dL), blood urea nitrogen (BUN, mg/dL), triglyceride (TG, mg/dL) and cholesterol (mg/dL) were recorded and evaluated before 0 minute and after 10, 20, 30, 40 minutes after anesthesia in individual animal. Rectal temperature, Respiratory rate and SpO2 decreased initially at 10 min after induction. It then increased towards the pre-anaesthetics level in both groups. Pulse rate increased initially, and this was decreased gradually towards baseline in both groups. In both groups, haematological values altered after induction with both the combinations and returned to near the baseline when the animal recovered utterly (12 hrs post-induction). Serum biochemical analysis showed that ALT, AST, bilirubin, creatinine, BUN, TG and cholesterol level seriously altered initially after 10 min of induction. In some instances (ALT, AST and TG) the changes continued up to the wake up of animals. They then gradually returned to the initial value. Results of the study reveal that the anaesthetics combination of Xylazine-Ketamine and Xylazine-Propofol exert some systemic effect in body compromising vital organs at a certain level.
The IOSR Journal of Pharmacy (IOSRPHR) is an open access online & offline peer reviewed international journal, which publishes innovative research papers, reviews, mini-reviews, short communications and notes dealing with Pharmaceutical Sciences( Pharmaceutical Technology, Pharmaceutics, Biopharmaceutics, Pharmacokinetics, Pharmaceutical/Medicinal Chemistry, Computational Chemistry and Molecular Drug Design, Pharmacognosy & Phytochemistry, Pharmacology, Pharmaceutical Analysis, Pharmacy Practice, Clinical and Hospital Pharmacy, Cell Biology, Genomics and Proteomics, Pharmacogenomics, Bioinformatics and Biotechnology of Pharmaceutical Interest........more details on Aim & Scope).
All manuscripts are subject to rapid peer review. Those of high quality (not previously published and not under consideration for publication in another journal) will be published without delay
Bosentan Ameliorates Diabetic Angiopathy and Nephropathy in Streptozotocin-In...iosrjce
Angiopathy and nephropathy are serious problems encountered in management of diabetes mellitus.
Angiotensin II (AII) and endothelins (ETs) receptors play an important role in the pathogenesis of diabetic
complications. The purpose of this study was to investigate the possible renoprotective and antiangiopathic
effects of the non-selective endothelin (ET) receptor blocker bosentan in type 1 diabetic model of albino wister
rats. These rats were divided into four groups ( each group , N= 12 rats): control group (1), control group (2)
treated with bosentan (50 mg/kg/day), untreated diabetic group (3) and diabetic group (4) treated with
bosentan. Induction of type 1 diabetes mellitus in tested rats was performed by a single injection, in the tail vein,
of 35 mg/kg streptozotozin after overnight fast. Treatment with bosentan was continued for 12 weeks during
which the 24h urine volume, urinary albumin content, urine and plasma levels of creatinine as well as mean
non-invasive blood pressure (mean BP) were assessed at the end of each 4 weeks. At the end of the 12
th week
rats were sacrificed then the thoracic aortae were dissected for assessment of the vasorelaxant effect of
acetylcholine. Diabetic rats showed hyperglycemia, polyuria, albuminuria, elevated mean BP, reduced
response to vasorelaxant effect of ACh. Bosentan significantly reduced albuminuria and lowered elevated mean
BP. In addition the drug restored the normal values of creatinine clearance and improved vascular reactivity to
ACh. The present study suggested a possible renoprotective and aortic vasorelaxant effects by bosentan without
a significant effect on the control of blood glucose. The results of the present study was directed towards a
possible role of bosentan, as a drug acting on Endothelin receptors, in the improvement of diabetic angiopathy and nephropathy.
Awake Fiberoptic Intubation with Sedation in Cardiac (High-Risk) Patients – O...info622939
Embark on a compelling exploration of anesthesia innovation with our presentation on 'Awake Fiberoptic Intubation with Sedation in Cardiac (High-Risk) Patients – Our Experience.' Delve into the intricacies of this specialized technique, tailored for high-risk cardiac patients, as we share our unique insights and experiences.
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!
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.
Shifting Paradigms: Examining Pro-Thrombotic Activity from a Safety PerspectiveCorDynamics
This research marks the evolution of anti-thrombosis discovery investigations into pro-thrombotic safety models. Clearly, pro-thrombotic activity is an undesirable property for drugs outside the cardiovascular arena. The ability to create a pro-thrombotic window provides safety intel on lead candidates.
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.
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.
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
The Gram stain is a fundamental technique in microbiology used to classify bacteria based on their cell wall structure. It provides a quick and simple method to distinguish between Gram-positive and Gram-negative bacteria, which have different susceptibilities to antibiotics
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
CDSCO and Phamacovigilance {Regulatory body in India}NEHA GUPTA
The Central Drugs Standard Control Organization (CDSCO) is India's national regulatory body for pharmaceuticals and medical devices. Operating under the Directorate General of Health Services, Ministry of Health & Family Welfare, Government of India, the CDSCO is responsible for approving new drugs, conducting clinical trials, setting standards for drugs, controlling the quality of imported drugs, and coordinating the activities of State Drug Control Organizations by providing expert advice.
Pharmacovigilance, on the other hand, is the science and activities related to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problems. The primary aim of pharmacovigilance is to ensure the safety and efficacy of medicines, thereby protecting public health.
In India, pharmacovigilance activities are monitored by the Pharmacovigilance Programme of India (PvPI), which works closely with CDSCO to collect, analyze, and act upon data regarding adverse drug reactions (ADRs). Together, they play a critical role in ensuring that the benefits of drugs outweigh their risks, maintaining high standards of patient safety, and promoting the rational use of medicines.
Basavarajeeyam is an important text for ayurvedic physician belonging to andhra pradehs. It is a popular compendium in various parts of our country as well as in andhra pradesh. The content of the text was presented in sanskrit and telugu language (Bilingual). One of the most famous book in ayurvedic pharmaceutics and therapeutics. This book contains 25 chapters called as prakaranas. Many rasaoushadis were explained, pioneer of dhatu druti, nadi pareeksha, mutra pareeksha etc. Belongs to the period of 15-16 century. New diseases like upadamsha, phiranga rogas are explained.
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
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The Differential Effect of Nembutal and Ketamine/Xylazine Anesthetic on QT Interval Prolongation
1. Abstract #902
Objectives
Summary
The Differential Effect of Nembutal and Ketamine/Xylazine
Anesthetic on Dofetilide-Induced QT Interval Prolongation
Liomar A. A. Neves, Hongjian Wang, Olga Tiniakova, Jinbao Huang, Peter B. Senese, Michael R. Gralinski
CorDynamics, Inc., Chicago, IL - www.cordynamics.com
Methods
Conclusion
Introduction
Effects of Anesthetic on QT Interval
in the Guinea Pig
The anesthetized guinea pig is a widely used model for early
screening of drug-candidate effects on cardiovascular function.
They are excellent for predicting the potential of a test article to
delay ventricular repolarization in humans as they have similar
cardiac action potential and ECG characteristics. Many
anesthetics have been studied in this model but sodium
pentobarbital is the most widely used. Studies have documented
that sodium pentobarbital is an antagonist of the inward rectifying
cardiac potassium channel IKs. Since the IKs is a component of
the guinea pig cardiac repolarization sequence, this species can be
exquisitely sensitive to IKs blockade. Because anesthetics can alter
the sensitivity of a preparation to test articles it is necessary to
assess its vulnerability in the guinea pig QT model. In this study
we assessed the hemodynamic effects of increasing doses of
dofetilide in the Nembutal and ketamine/xylazine anesthetized
guinea pig model. Dofetilide is a Class III antiarrhythmic drug that
increases refractoriness by antagonizing IKr. It has been associated
with QTc prolongation and TdP arrhythmias in humans.
Anesthesia - Nembutal (60 mg/kg IP, maintenance dose continuous IV infusion 6mg/kg/h)
Group 1 Dose 2-Dose 7 - Vehicle 0.5 mL/kg
Group 2 Dose 2-Dose 7 - Dofetilide (0.0025, 0.005, 0.01, 0.02, 0.04, and 0.08 mg/kg)
Anesthesia - ketamine/xylazine (87/5 mg/kg IP, maintenance dose ketamine 44 mg/kg IP)
Group 3 Dose 2-Dose 7 - Vehicle 2.5 mL/kg
Group 4 Dose 2-Dose 7 - Dofetilide (0.0125, 0.025, 0.05, 0.1, 0.2, and 0.4 mg/kg)
5
min
Dose 1
Vehicle Dose 2 Dose 3 Dose 5Dose 4 Dose 6 Dose 7
10min
5
min
10min
5
min
10min
5
min
10min
5
min
10min
5
min
10min
5
min
10min
Assess vulnerability of the Nembutal and
ketamine/xylazine anesthetized guinea pig for safety
pharmacology screening of drugs with potential to
prolong the QT interval.
The Differential Effect of Nembutal and Ketamine/Xylazine Anesthetic on Dofetilide-
Induced QT Interval Prolongation. Liomar A. A. Neves, Hongjian Wang, Olga Tiniakova, Jinbao
Huang, Peter B. Senese, Michael R. Gralinski. CorDynamics, Inc., Chicago, IL
Previous work from our group has suggested that anesthetics with additional inherent IKs
blockade such as sodium pentobarbital may sensitize the animal to agents that prolong the
electrocardiographic QT interval. In the present work, we used dofetilide to assess the
vulnerability of both the Nembutal and ketamine/xylazine anesthetized guinea pig. Male guinea
pigs (400-550g) were anesthetized with Nembutal (60 mg/kg IP, maintenance dose continuous IV
infusion 6 mg/kg/h) or ketamine/xylazine (87/5 mg/kg IP, maintenance dose 44 mg/kg IP) and
surgically instrumented with a Millar pressure catheter to measure arterial pressure and heart
rate. PR interval, QRS duration, QT/QTc interval and arrhythmogenesis were determined from
continuous surface electrocardiograms. Animals anesthetized with Nembutal received vehicle
(10% hydroxypropyl beta cyclodextrin in saline) or dofetilide (0, 0.0025, 0.005, 0.01, 0.02, 0.04,
and 0.08 mg/kg; 0.5 mL/kg), and animals anesthetized with ketamine/xylazine received vehicle
(10% hydroxypropyl beta cyclodextrin in saline) or dofetilide (0, 0.0125, 0.025, 0.05, 0.1, 0.2, and
0.4 mg/kg; 2.5 mL/kg) over a period of 5 minutes followed by 10 minute-recovery period.
Administration of dofetilide to either Nembutal or ketamine/xylazine anesthetized guinea pigs
significantly increased QTcB interval at all doses studied compared to time-matched vehicle
control (p< 0.05). QTcB interval maximally increased 22% at a dofetilide dose of 0.08 mg/kg in
the Nembutal group. In ketamine/xylazine guinea pigs, a dose of dofetilide five times higher
(0.4mg/kg) increased QTcB by only 12% maximally. No changes in mean arterial pressure, HR,
QRS interval or PR interval were observed in Nembutal or ketamine/xylazine groups treated with
dofetilide compared with each respective vehicle control. Our results demonstrate that sodium
pentobarbital anesthetized guinea pigs are more sensitive to QTc interval prolongation; this
should be the anesthetic of choice when screening agents for the potential to prolong QTc
interval.
Experimental Design
Surgical Preparation: Male Dunkin Hartley guinea pigs (400-550g) were
anesthetized with ketamine/xylazine (87/5 mg/kg IP, maintenance dose
44 mg/kg IP) or Nembutal (60 mg/kg IP, maintenance dose continuous
IV infusion 6mg/kg/h). Once consciousness was lost the trachea was
isolated and an endotracheal tube was inserted for mechanical
ventilation (~60 breaths/min with a tidal volume of ~7-8 mL/kg). A
Millar pressure catheter was placed in the carotid artery to measure
arterial pressure. A lead II electrocardiogram was monitored throughout
the experiment via electrodes placed in the skin of the right arm, left leg
and chest of the animal. Body temperature was also monitored
throughout the experiment. The jugular vein was cannulated for test
compound administration.
Experimental Plan: ECG and blood pressure were continuously
monitored throughout the experiment with the NOTOCORD-Hem
(Software 4.3 NOTOCORD Inc., Croissy sur Seine, France) data capture
system. Individual animals were deemed acceptable for use in the study
if they exhibited acceptable hemodynamic parameters during the
approximate 15-30 minutes equilibration period. Baseline hemodynamic
and electrocardiographic parameters were obtained for 15 minutes
followed by escalating doses of vehicle or dofetilide administered into a
jugular vein. Guinea pigs anesthetized with Nembutal received vehicle
(10% hydroxypropyl beta cyclodextrin in saline) or dofetilide (0, 0.0025,
0.005, 0.01, 0.02, 0.04, and 0.08 mg/kg; 0.5 mL/kg) and animals
anesthetized with ketamine/xylazine received vehicle (10% hydroxypropyl
beta cyclodextrin in saline) or dofetilide (0, 0.0125, 0.025, 0.05, 0.1, 0.2,
and 0.4 mg/kg; 2.5 mL/kg) over a period of 5 minutes followed by 10
minute-recovery period.
Hemodynamic and Electrocardiographic Measurements: Average
values taken from 20 second blocks of consecutive cardiac cycles
uninterrupted by interference of ectopic beats were used for analysis.
Measurements were taken at baseline, and every 1 minute during the
monitoring period. The monitoring period began at the initiation of that
test period’s respective dose. Values from each individual animal were
pooled to determine an average for each variable for each group.
Statistical Methods: Hemodynamic parameters were analyzed using an
analysis of variance (ANOVA) model at each timepoint. Baseline data
were analyzed with an ANOVA model with an effect for treatment. The
model for each subsequent timepoint included baseline as a covariate
and an effect for treatment. Baseline was defined as the value at time 0.
Comparisons were considered significant at the 0.05 level. All statistical
analyses were conducted with SAS® version 9.2.
Effects of Anesthetic on Mean Arterial Pressure
And Heart Rate in the Guinea Pig
Administration of dofetilide to either Nembutal or
ketamine/xylazine anesthetized guinea pigs significantly
increased QTcB interval at all doses tested compared to time-
matched vehicle control (p< 0.05).
In the Nembutal group, QTcB interval (Δ-Δ% vs Vehicle)
maximally increased by 22% at a dofetilide dose of 0.08 mg/kg.
In ketamine/xylazine group, QTcB interval (Δ-Δ% vs Vehicle)
maximally increased by 12% at a dofetilide dose of 0.1 mg/kg.
No further increase in QTcB was observed at 0.2 and 0.4 mg/kg
of Dofetilide.
No changes in mean arterial pressure, HR, QRS interval or PR
interval were observed in Nembutal or ketamine/xylazine groups
treated with dofetilide compared with each respective vehicle
control.
No changes in any of the parameters evaluated were observed in
Nembutal vehicle group compared to ketamine/xylazine vehicle
group.
Effects of Anesthetic on PR Interval and
QRS Duration in the Guinea Pig
Figure 1. A- Effects of dofetilide on QTcB duration in ketamine and Nembutal anesthetized guinea pigs. Values
are expressed as mean±SEM. Data were analyzed by using an analysis of variance (ANOVA) model at each
timepoint. Comparisons were considered significant at the 0.05 level. All statistical analyses were conducted
with SAS® version 9.2. B- QT versus RR interval plot of dofetilide treated ketamine and Nembutal anesthetized
guinea pigs. Each data point is an average values taken from 20 second blocks of consecutive cardiac cycles
uninterrupted by interference of ectopic beats, measurements were taken at baseline, and every 1 minute during
the monitoring period.
In summary, the choice of anesthetic appears to influence the
maximum QTc increase in anesthetized guinea. Sodium
pentobarbital anesthetized guinea pigs are more sensitive to
QTc interval prolongation; and this should be the anesthetic of
choice when screening agents for the potential to prolong QTc
interval.
Figure 3. Effects of dofetilide on mean arterial pressure and heart rate in ketamine and Nembutal anesthetized
guinea pigs. Values are expressed as mean±SEM. Data were analyzed by using an analysis of variance
(ANOVA) model at each timepoint. Comparisons were considered significant at the 0.05 level. All statistical
analyses were conducted with SAS® version 9.2.
Figure 2. Effects of dofetilide on PR interval and QRS duration in ketamine and Nembutal anesthetized guinea
pigs. Values are expressed as mean±SEM. Data were analyzed by using an analysis of variance (ANOVA)
model at each timepoint. Comparisons were considered significant at the 0.05 level. All statistical analyses
were conducted with SAS® version 9.2.