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Izquierdo M, de Souto Barreto P, Arai H, Bischoff-Ferrari HA, Cadore EL, Cesari M, Chen LK, Coen PM, Courneya KS, Duque G, Ferrucci L, Fielding RA, García-Hermoso A, Gutiérrez-Robledo LM, Harridge SDR, Kirk B, Kritchevsky S, Landi F, Lazarus N, Liu-Ambrose T, Marzetti E, Merchant RA, Morley JE, Pitkälä KH, Ramírez-Vélez R, Rodriguez-Mañas L, Rolland Y, Ruiz JG, Sáez de Asteasu ML, Villareal DT, Waters DL, Won Won C, Vellas B, Fiatarone Singh MA. Global consensus on optimal exercise recommendations for enhancing healthy longevity in older adults (ICFSR). J Nutr Health Aging 2025; 29:100401. [PMID: 39743381 PMCID: PMC11812118 DOI: 10.1016/j.jnha.2024.100401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 10/14/2024] [Accepted: 10/15/2024] [Indexed: 01/04/2025]
Abstract
Aging, a universal and inevitable process, is characterized by a progressive accumulation of physiological alterations and functional decline over time, leading to increased vulnerability to diseases and ultimately mortality as age advances. Lifestyle factors, notably physical activity (PA) and exercise, significantly modulate aging phenotypes. Physical activity and exercise can prevent or ameliorate lifestyle-related diseases, extend health span, enhance physical function, and reduce the burden of non-communicable chronic diseases including cardiometabolic disease, cancer, musculoskeletal and neurological conditions, and chronic respiratory diseases as well as premature mortality. Physical activity influences the cellular and molecular drivers of biological aging, slowing aging rates-a foundational aspect of geroscience. Thus, PA serves both as preventive medicine and therapeutic agent in pathological states. Sub-optimal PA levels correlate with increased disease prevalence in aging populations. Structured exercise prescriptions should therefore be customized and monitored like any other medical treatment, considering the dose-response relationships and specific adaptations necessary for intended outcomes. Current guidelines recommend a multifaceted exercise regimen that includes aerobic, resistance, balance, and flexibility training through structured and incidental (integrated lifestyle) activities. Tailored exercise programs have proven effective in helping older adults maintain their functional capacities, extending their health span, and enhancing their quality of life. Particularly important are anabolic exercises, such as Progressive resistance training (PRT), which are indispensable for maintaining or improving functional capacity in older adults, particularly those with frailty, sarcopenia or osteoporosis, or those hospitalized or in residential aged care. Multicomponent exercise interventions that include cognitive tasks significantly enhance the hallmarks of frailty (low body mass, strength, mobility, PA level, and energy) and cognitive function, thus preventing falls and optimizing functional capacity during aging. Importantly, PA/exercise displays dose-response characteristics and varies between individuals, necessitating personalized modalities tailored to specific medical conditions. Precision in exercise prescriptions remains a significant area of further research, given the global impact of aging and broad effects of PA. Economic analyses underscore the cost benefits of exercise programs, justifying broader integration into health care for older adults. However, despite these benefits, exercise is far from fully integrated into medical practice for older people. Many healthcare professionals, including geriatricians, need more training to incorporate exercise directly into patient care, whether in settings including hospitals, outpatient clinics, or residential care. Education about the use of exercise as isolated or adjunctive treatment for geriatric syndromes and chronic diseases would do much to ease the problems of polypharmacy and widespread prescription of potentially inappropriate medications. This intersection of prescriptive practices and PA/exercise offers a promising approach to enhance the well-being of older adults. An integrated strategy that combines exercise prescriptions with pharmacotherapy would optimize the vitality and functional independence of older people whilst minimizing adverse drug reactions. This consensus provides the rationale for the integration of PA into health promotion, disease prevention, and management strategies for older adults. Guidelines are included for specific modalities and dosages of exercise with proven efficacy in randomized controlled trials. Descriptions of the beneficial physiological changes, attenuation of aging phenotypes, and role of exercise in chronic disease and disability management in older adults are provided. The use of exercise in cardiometabolic disease, cancer, musculoskeletal conditions, frailty, sarcopenia, and neuropsychological health is emphasized. Recommendations to bridge existing knowledge and implementation gaps and fully integrate PA into the mainstream of geriatric care are provided. Particular attention is paid to the need for personalized medicine as it applies to exercise and geroscience, given the inter-individual variability in adaptation to exercise demonstrated in older adult cohorts. Overall, this consensus provides a foundation for applying and extending the current knowledge base of exercise as medicine for an aging population to optimize health span and quality of life.
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Affiliation(s)
- Mikel Izquierdo
- Navarrabiomed, Hospital Universitario de Navarra (CHN)-Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain; CIBER of Frailty and Healthy Ageing (CIBERFES), Instituto de Salud Carlos III Madrid, Spain.
| | - Philipe de Souto Barreto
- IHU HealthAge, Gérontopôle de Toulouse, Institut du Vieillissement, Centre Hospitalo-Universitaire de Toulouse, Toulouse, France; CERPOP, UPS/Inserm 1295, Toulouse, France
| | - Hidenori Arai
- National Center for Geriatrics and Gerontology, Obu, Japan
| | - Heike A Bischoff-Ferrari
- Department of Geriatrics and Aging Research, Research Centre on Aging and Mobility, University of Zurich, Zurich, Switzerland
| | - Eduardo L Cadore
- Exercise Research Laboratory, School of Physical Education, Physiotherapy and Dance, Universidade Federal do Rio Grande do Sul, Brazil
| | - Matteo Cesari
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Liang-Kung Chen
- Center for Healthy Longevity and Aging Sciences, National Yang Ming Chiao Tung University, Center for Geriatrics and Gerontology, Taipei Veterans General Hospital, Taipei Municipal Gab-Dau Hospital, Taipei, Taiwan
| | - Paul M Coen
- AdventHealth Orlando, Translational Research Institute, Orlando, Florida, United States
| | - Kerry S Courneya
- Faculty of Kinesiology, Sport, and Recreation, College of Health Sciences, University of Alberta, Edmonton, Alberta T6G 2H9, Canada
| | - Gustavo Duque
- Bone, Muscle & Geroscience Group, Research Institute of the McGill University Health Centre, Montreal, QC, Canada
| | - Luigi Ferrucci
- National Institute on Aging, Baltimore, MD, United States
| | - Roger A Fielding
- Nutrition, Exercise Physiology, and Sarcopenia Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, United States
| | - Antonio García-Hermoso
- Navarrabiomed, Hospital Universitario de Navarra (CHN)-Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain; CIBER of Frailty and Healthy Ageing (CIBERFES), Instituto de Salud Carlos III Madrid, Spain
| | | | - Stephen D R Harridge
- Centre for Human and Applied Physiological Sciences, King's College London, United Kingdom
| | - Ben Kirk
- Department of Medicine-Western Health, Melbourne Medical School, University of Melbourne, St. Albans, Melbourne, VIC, Australia
| | - Stephen Kritchevsky
- Sticht Center for Healthy Aging and Alzheimer's Prevention, Wake Forest University School of Medicine, Winston-Salem, NC, United States
| | - Francesco Landi
- Department of Geriatrics, Orthopedics and Rheumatology, Università Cattolica del Sacro Cuore, Rome, Italy; Fondazione Policlinico Universitario "Agostino Gemelli" IRCCS, Rome, Italy
| | - Norman Lazarus
- Centre for Human and Applied Physiological Sciences, King's College London, United Kingdom
| | - Teresa Liu-Ambrose
- Aging, Mobility, and Cognitive Health Laboratory, Department of Physical Therapy, Faculty of Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Centre for Aging SMART at Vancouver Coastal Health, Vancouver Coastal Health Research Institute,Vancouver, BC, Canada
| | - Emanuele Marzetti
- Department of Geriatrics, Orthopedics and Rheumatology, Università Cattolica del Sacro Cuore, Rome, Italy; Fondazione Policlinico Universitario "Agostino Gemelli" IRCCS, Rome, Italy
| | - Reshma A Merchant
- Division of Geriatric Medicine, Department of Medicine, National University Hospital, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University Singapore, Singapore
| | - John E Morley
- Saint Louis University School of Medicine, St. Louis, MO, United States
| | - Kaisu H Pitkälä
- University of Helsinki and Helsinki University Hospital, PO Box 20, 00029 Helsinki, Finland
| | - Robinson Ramírez-Vélez
- Navarrabiomed, Hospital Universitario de Navarra (CHN)-Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain; CIBER of Frailty and Healthy Ageing (CIBERFES), Instituto de Salud Carlos III Madrid, Spain
| | - Leocadio Rodriguez-Mañas
- CIBER of Frailty and Healthy Ageing (CIBERFES), Instituto de Salud Carlos III Madrid, Spain; Geriatric Service, University Hospital of Getafe, Getafe, Spain
| | - Yves Rolland
- IHU HealthAge, Gérontopôle de Toulouse, Institut du Vieillissement, Centre Hospitalo-Universitaire de Toulouse, Toulouse, France; CERPOP, UPS/Inserm 1295, Toulouse, France
| | - Jorge G Ruiz
- Memorial Healthcare System, Hollywood, Florida and Florida Atlantic University Charles E. Schmidt College of Medicine, Boca Raton, Florida, United States
| | - Mikel L Sáez de Asteasu
- Navarrabiomed, Hospital Universitario de Navarra (CHN)-Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain; CIBER of Frailty and Healthy Ageing (CIBERFES), Instituto de Salud Carlos III Madrid, Spain
| | - Dennis T Villareal
- Baylor College of Medicine, and Center for Translational Research on Inflammatory Diseases, Michael E DeBakey VA Medical Center, Houston, Texas, United States
| | - Debra L Waters
- Department of Medicine, School of Physiotherapy, University of Otago, Dunedin; Department of Internal Medicine/Geriatrics, University of New Mexico, Albuquerque, Mexico
| | - Chang Won Won
- Elderly Frailty Research Center, Department of Family Medicine, College of Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Bruno Vellas
- IHU HealthAge, Gérontopôle de Toulouse, Institut du Vieillissement, Centre Hospitalo-Universitaire de Toulouse, Toulouse, France; CERPOP, UPS/Inserm 1295, Toulouse, France
| | - Maria A Fiatarone Singh
- Faculty of Medicine and Health, School of Health Sciences and Sydney Medical School, University of Sydney, New South Wales, Australia, and Hinda and Arthur Marcus Institute for Aging Research, Hebrew SeniorLife, Roslindale, MA, United States
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Moiz A, Zolotarova T, Eisenberg MJ. Outpatient management of essential hypertension: a review based on the latest clinical guidelines. Ann Med 2024; 56:2338242. [PMID: 38604225 PMCID: PMC11011233 DOI: 10.1080/07853890.2024.2338242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 03/15/2024] [Indexed: 04/13/2024] Open
Abstract
Background: Essential hypertension, a prevalent cardiovascular condition, poses a significant health burden worldwide. Based on the latest American clinical guidelines, half of adults in the United States have hypertension. Of these, only about a half are treated and about a quarter are adequately controlled for hypertension. Given its impact on morbidity and mortality, ensuring effective management of high blood pressure is crucial to reduce associated risks and improve patient outcomes.Objective: This review aims to provide a comprehensive and up-to-date summary of the latest cardiology guidelines and evidence-based research on essential hypertension, with a focus on guiding outpatient clinical practice.Methods: The review evaluates both non-pharmacological approaches and pharmacological interventions to offer clinicians practical insights. Notably, it emphasizes the importance of individualized treatment plans tailored to patients' specific risk profiles and comorbidities.Results: By consolidating the latest advancements in hypertension management, this review provides clinicians with an up-to-date reference, offering a nuanced understanding of treatment goals and strategies.Conclusion: Through the incorporation of evidence-based recommendations, healthcare practitioners can optimize patient care, mitigate potential complications, and improve overall outcomes in essential hypertension.
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Affiliation(s)
- Areesha Moiz
- Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Canada
| | - Tetiana Zolotarova
- Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Canada
| | - Mark J. Eisenberg
- Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Canada
- Department of Medicine and Health Sciences, McGill University, Montreal, Canada
- Departments of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Canada
- Division of Cardiology, Jewish General Hospital, McGill University, Montreal, Canada
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Arrokhman S, Luo YH, Lin P. Additive cardiotoxicity of a bisphenol mixture in zebrafish embryos: The involvement of calcium channel and pump. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2023; 263:115225. [PMID: 37418940 DOI: 10.1016/j.ecoenv.2023.115225] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 06/28/2023] [Accepted: 07/01/2023] [Indexed: 07/09/2023]
Abstract
Bisphenol A (BPA) and its analogs, such as bisphenol F (BPF), bisphenol AF (BPAF), and bisphenol B (BPB), are often simultaneously detected in environmental and human specimens. Thus, assessing the toxicity of bisphenol (BP) mixtures is more relevant than assessing that of each BP type. Here, we found that BPs, individually or in a mixture, concentration-dependently and additively increased the mortality of zebrafish embryos (ZFEs) at 96 h post fertilization (hpf) and induced bradycardia (i.e., reduced heart rate) at 48 hpf, indicating their cardiotoxic potency. BPAF was the most potent, followed by BPB, BPA, and BPF. We then explored the mechanism underlying BP-induced bradycardia in ZFEs. Although BPs increased the mRNA expression of the estrogen-responsive gene, treatment with the estrogen receptor inhibitor ICI 182780 did not prevent BP-induced bradycardia. Because they did not change cardiomyocyte counts or heart development-related gene expression, BPs might not affect cardiomyocyte development. By contrast, BPs might impair calcium homeostasis during cardiac contraction and relaxation through the downregulation of the expression of the mRNAs for the pore-forming subunit of L-type Ca2+ channel (LTCC; cacna1c) and sarco/endoplasmic reticulum Ca2+-ATPase (SERCA; atp2a2a). BPs reduced SERCA activity significantly. BPs also potentiated the cardiotoxicity induced by the LTCC blocker nisoldipine, conceivably by inhibiting SERCA activity. In conclusion, BPs additively induced bradycardia in ZFEs, possibly by impeding calcium homeostasis during cardiac contraction and relaxation. BPs also potentiated the cardiotoxicity of calcium channel blockers.
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Affiliation(s)
- Salim Arrokhman
- National Institute of Environmental Health Sciences, National Health Research Institutes, Zhunan, Miaoli County 35053, Taiwan; Department of Life Sciences, National Central University, Taoyuan 320317, Taiwan
| | - Yueh-Hsia Luo
- Department of Life Sciences, National Central University, Taoyuan 320317, Taiwan
| | - Pinpin Lin
- National Institute of Environmental Health Sciences, National Health Research Institutes, Zhunan, Miaoli County 35053, Taiwan.
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Audisio K, Halbreiner MS, Chadow D, Gaudino M. Radial artery or saphenous vein for Coronary artery bypass grafitng. Trends Cardiovasc Med 2021; 32:479-484. [PMID: 34562573 DOI: 10.1016/j.tcm.2021.09.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 09/15/2021] [Accepted: 09/18/2021] [Indexed: 11/16/2022]
Abstract
Coronary artery disease (CAD) is the most common cardiovascular disease worldwide, affecting over 18 million American adults. Coronary artery bypass grafting (CABG) is the standard of care for patients with left main or triple vessel CAD. Historically, the saphenous vein (SV) has been utilized to bypass the majority of the coronary vessels in patients undergoing CABG, but more recent data suggest that the use of the radial artery (RA), rather than the SV, is associated with improved cardiac outcomes and better survival. The aim of this review is to summarize the current literature on the use of RA and SV for CABG in patients with multivessel CAD.
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Affiliation(s)
- Katia Audisio
- Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, USA
| | - M Scott Halbreiner
- Department of Thoracic and Cardiovascular Surgery, Allegheny General Hospital, Pittsburgh, PA, USA
| | - David Chadow
- Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, USA
| | - Mario Gaudino
- Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, USA.
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5
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Shahsavani N, Kataria H, Karimi-Abdolrezaee S. Mechanisms and repair strategies for white matter degeneration in CNS injury and diseases. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166117. [PMID: 33667627 DOI: 10.1016/j.bbadis.2021.166117] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 02/22/2021] [Accepted: 02/23/2021] [Indexed: 12/14/2022]
Abstract
White matter degeneration is an important pathophysiological event of the central nervous system that is collectively characterized by demyelination, oligodendrocyte loss, axonal degeneration and parenchymal changes that can result in sensory, motor, autonomic and cognitive impairments. White matter degeneration can occur due to a variety of causes including trauma, neurotoxic exposure, insufficient blood flow, neuroinflammation, and developmental and inherited neuropathies. Regardless of the etiology, the degeneration processes share similar pathologic features. In recent years, a plethora of cellular and molecular mechanisms have been identified for axon and oligodendrocyte degeneration including oxidative damage, calcium overload, neuroinflammatory events, activation of proteases, depletion of adenosine triphosphate and energy supply. Extensive efforts have been also made to develop neuroprotective and neuroregenerative approaches for white matter repair. However, less progress has been achieved in this area mainly due to the complexity and multifactorial nature of the degeneration processes. Here, we will provide a timely review on the current understanding of the cellular and molecular mechanisms of white matter degeneration and will also discuss recent pharmacological and cellular therapeutic approaches for white matter protection as well as axonal regeneration, oligodendrogenesis and remyelination.
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Affiliation(s)
- Narjes Shahsavani
- Department of Physiology and Pathophysiology, Regenerative Medicine Program, Spinal Cord Research Centre, Children's Hospital Research Institute of Manitoba, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Hardeep Kataria
- Department of Physiology and Pathophysiology, Regenerative Medicine Program, Spinal Cord Research Centre, Children's Hospital Research Institute of Manitoba, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Soheila Karimi-Abdolrezaee
- Department of Physiology and Pathophysiology, Regenerative Medicine Program, Spinal Cord Research Centre, Children's Hospital Research Institute of Manitoba, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
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Cipriani A, Saunders K, Attenburrow MJ, Stefaniak J, Panchal P, Stockton S, Lane TA, Tunbridge EM, Geddes JR, Harrison PJ. A systematic review of calcium channel antagonists in bipolar disorder and some considerations for their future development. Mol Psychiatry 2016; 21:1324-32. [PMID: 27240535 PMCID: PMC5030455 DOI: 10.1038/mp.2016.86] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Revised: 03/01/2016] [Accepted: 04/15/2016] [Indexed: 12/17/2022]
Abstract
l-type calcium channel (LTCC) antagonists have been used in bipolar disorder for over 30 years, without becoming an established therapeutic approach. Interest in this class of drugs has been rekindled by the discovery that LTCC genes are part of the genetic aetiology of bipolar disorder and related phenotypes. We have therefore conducted a systematic review of LTCC antagonists in the treatment and prophylaxis of bipolar disorder. We identified 23 eligible studies, with six randomised, double-blind, controlled clinical trials, all of which investigated verapamil in acute mania, and finding no evidence that it is effective. Data for other LTCC antagonists (diltiazem, nimodipine, nifedipine, methyoxyverapamil and isradipine) and for other phases of the illness are limited to observational studies, and therefore no robust conclusions can be drawn. Given the increasingly strong evidence for calcium signalling dysfunction in bipolar disorder, the therapeutic candidacy of this class of drugs has become stronger, and hence we also discuss issues relevant to their future development and evaluation. In particular, we consider how genetic, molecular and pharmacological data can be used to improve the selectivity, efficacy and tolerability of LTCC antagonists. We suggest that a renewed focus on LTCCs as targets, and the development of 'brain-selective' LTCC ligands, could be one fruitful approach to innovative pharmacotherapy for bipolar disorder and related phenotypes.
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Affiliation(s)
- A Cipriani
- Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK
- Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, UK
| | - K Saunders
- Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK
- Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, UK
| | - M-J Attenburrow
- Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK
- Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, UK
| | - J Stefaniak
- Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK
| | - P Panchal
- Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK
- Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, UK
| | - S Stockton
- Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK
- Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, UK
| | - T A Lane
- Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK
| | - E M Tunbridge
- Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK
- Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, UK
| | - J R Geddes
- Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK
- Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, UK
| | - P J Harrison
- Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK
- Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, UK
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Kahlon A, Gnanabakthan N, Dhillon A, Subedi D. A rare case of bilateral lower extremity edema due to low dose gabapentin therapy in a young male patient. J Basic Clin Pharm 2015; 6:117-8. [PMID: 26692738 PMCID: PMC4660483 DOI: 10.4103/0976-0105.168053] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
46 year old male with past medical history of schizoaffective disorder and chronic lower back pain, was admitted for management of worsening depression and anxiety. He was started on gabapentin, 300mg twice daily for his back pain and anxiety symptoms. His only other medication was hydrocodone. Over next few days, he started developing worsening bilateral lower extremity edema. He did not have any cardiovascular related symptoms. Physical exam was only significant for 3+ pitting edema with all laboratory values and imaging being unremarkable. Gabapentin was discontinued and his lower extremity swelling improved over subsequent days. Incidence of pedal edema with gabapentin use is approximately 7 to 7.5% with all studies being in elderly patients receiving doses above 1200 mg/day. This case illustrates that lower doses of gabapentin can also cause this adverse effect. It is important to recognize this adverse effect because gabapentin is used in conditions like diabetic neuropathy, which is associated with multiple co-morbidities that can give rise to bilateral leg swelling. Presence of gabapentin induced leg swelling can thus confound the clinical picture.
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Affiliation(s)
- Arunpreet Kahlon
- Department of Medicine, State University of New York Upstate Medical University, Syracuse, New York, USA
| | - Naveen Gnanabakthan
- Department of Medicine, State University of New York Upstate Medical University, Syracuse, New York, USA
| | - Amrita Dhillon
- Department of Medicine, State University of New York Upstate Medical University, Syracuse, New York, USA
| | - Dinesh Subedi
- Department of Medicine, State University of New York Upstate Medical University, Syracuse, New York, USA
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Oliveto A, Mancino M, Sanders N, Cargile C, Benjamin Guise J, Bickel W, Brooks Gentry W. Effects of prototypic calcium channel blockers in methadone-maintained humans responding under a naloxone discrimination procedure. Eur J Pharmacol 2013; 715:424-35. [PMID: 23524089 DOI: 10.1016/j.ejphar.2013.03.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2012] [Revised: 03/07/2013] [Accepted: 03/07/2013] [Indexed: 11/28/2022]
Abstract
Accumulating evidence suggests that L-type calcium channel blockers (CCBs) attenuate the expression of opioid withdrawal and the dihydropyridine L-type CCB isradipine has been shown to block the behavioral effects of naloxone in opioid-maintained humans. This study determined whether two prototypic L-type CCBs with differing chemical structures, the benzothiazepine diltiazem and the phenylalkamine verapamil, attenuate the behavioral effects of naloxone in methadone-maintained humans trained to distinguish between low-dose naloxone (0.15 mg/70 kg, i.m.) and placebo under an instructed novel-response drug discrimination procedure. Once discrimination was acquired, diltiazem (0, 30, 60, 120 mg) and verapamil (0, 30, 60, 120 mg), alone and combined with the training dose of naloxone, were tested. Diltiazem alone produced 33-50% naloxone- and novel-appropriate responding at 30 and 60 mg and essentially placebo-appropriate responding at 120 mg. Verapamil alone produced 20-40% naloxone- and 0% novel-appropriate responding. Diltiazem at 60 mg decreased several ratings associated with positive mood and increased VAS ratings of "Bad Drug Effects" relative to placebo, whereas verapamil increased ratings associated with euphoria. When administered with naloxone, diltiazem produced 94-100% naloxone-appropriate-responding with 6% novel-appropriate responding at 60 mg (n=3). When administered with naloxone, verapamil produced 60-80% naloxone- and 0% novel-appropriate responding (n=5). Diltiazem decreased diastolic blood pressure and heart rate whereas verapamil decreased ratings of arousal relative to placebo. These results suggest that CCBs with different chemical structures can be differentiated behaviorally, and that diltiazem and verapamil do not attenuate the discriminative stimulus effects of naloxone in humans at the doses tested.
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Affiliation(s)
- Alison Oliveto
- Department of Psychiatry and Behavioral Sciences, University of Arkansas for Medical Sciences, 4301 W Markham St., Little Rock, AR 72205, USA.
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Levy B, Rosenberg L, Colasante D, Deitch M. A Comparison of Two Structurally Distinct Types of Calcium Channel Blockers in the Treatment of Patients with Mild to Moderate Hypertension. ACTA ACUST UNITED AC 2012. [DOI: 10.1007/bf03259233] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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10
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Abstract
Blood pressure (BP) plays an important role in the development and progression of cardiovascular disease. Moreover, hypertensive patients often have additional cardiovascular risk factors. Despite the abundance of antihypertensive drug categories, satisfactory BP regulation is often difficult to achieve. A major cause of this difficulty to properly manage BP is the less than optimal adherence of subjects to treatment. This is often due to the various adverse effects of the antihypertensive drugs. Calcium channel blockers (CCB) have an established efficacy for reducing BP. However, their side effect of peripheral edema is often a cause for the discontinuation of treatment. Manidipine holds some unique properties differentiating it from the rest of the CCB class. It has a better safety profile with a lower incidence of peripheral edema. Moreover, there are indications that manidipine holds additional beneficial attributes, such as improvement of renal function and decrease of insulin resistance.
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Fogari R, Zoppi A, Mugellini A, Maffioli P, Lazzari P, Monti C, Derosa G. Effect of aliskiren addition to amlodipine on ankle edema in hypertensive patients: a three-way crossover study. Expert Opin Pharmacother 2011; 12:1351-8. [PMID: 21510830 DOI: 10.1517/14656566.2011.580276] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVE The aim of this study was to assess the effect of aliskiren and amlopidine on ankle-foot volume (AFV) and pretibial subcutaneous tissue pressure (PSTP). RESEARCH DESIGN AND METHODS After 4-week placebo, 120 outpatients with grade 1 - 2 hypertension were randomized to amlodipine 10 mg or aliskiren 300 mg or their combination for 8 weeks in three crossover periods. At the end of each treatment, blood pressure, AFV, PSTP, plasma renin activity (PRA) and norepinephrine were assessed. RESULTS Both monotherapies similarly reduced systolic blood pressure (SBP; p < 0.001) and diastolic blood pressure (DBP; p < 0.001), but the reduction was greater with amlodipine/aliskiren combination (SBP: - 24.6 mmHg, p < 0.001 vs monotherapy; DBP: -20.9 mmHg, p < 0.01 vs monotherapy). Amlodipine increased both AFV (+ 28.4%, p < 0.01) and PSTP (+ 80.4%, p < 0.01), while the combination produced a less marked increase in AFV (+ 6.6%, p < 0.01 vs amlodipine) and PSTP (+ 20.1%, p < 0.01 vs amlodipine). Plasma norepinephrine increased with amlodipine (+ 53.5%, p < 0.01) and this increase was not reduced by aliskiren addition. PRA was unaffected by amlodipine, while it was reduced by both aliskiren monotherapy (- 77.7%, p < 0.01) and aliskiren/amlodipine combination (- 75.7%, p < 0.01). CONCLUSIONS Direct renin inhibition by aliskiren partially counteracts the microcirculatory changes responsible for calcium-channel-induced edema formation, possibly through preferential vasodilation of venous capacitance vessels.
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Affiliation(s)
- Roberto Fogari
- Clinica Medica II, University of Pavia, Centro Ipertensione e Fisiopatologia Cardiovascolare, Department of Internal Medicine and Therapeutics , Pavia , Italy.
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12
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Richy FF, Laurent S. Efficacy and safety profiles of manidipine compared with amlodipine: a meta-analysis of head-to-head trials. Blood Press 2011; 20:54-9. [PMID: 20945994 PMCID: PMC3026391 DOI: 10.3109/08037051.2010.518670] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2010] [Accepted: 08/09/2010] [Indexed: 01/05/2023]
Abstract
Abstract The aim of this meta-analysis was to compare the efficacy and safety profile of manidipine 20 mg with that of amlodipine 10 mg. A systematic research of quantitative data produced or published between 1995 and 2009 was performed. Head-to-head randomized controlled trials (RCTs) of 12 months minimum duration reporting comparative efficacy (changes in systolic and diastolic blood pressure) and safety (total adverse events and ankle oedema), were included. Four high-quality RCTs, accounting for 838 patients (436 received manidipine and 402 received amlodipine) were included. The efficacy of manidipine and amlodipine was statistically equivalent: effect size for DBP = -0.08 (p = 0.22) and SBP = -0.01 (p = 0.83). The global safety of manidipine was significantly better than amlodipine: the relative risk (RR) for adverse event was 0.69 (0.56-0.85), and particularly for ankle oedema RR was 0.35 (0.22-0.54). Publication bias was not significant and the robustness of the analyses was good. These data suggest a better efficacy/safety ratio of manidipine over amlodipine.
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Affiliation(s)
- Florent F Richy
- Department of Public Health, Epidemiology and Health Economics, University of Liege Faculty of Medicine, Belgium.
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13
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Abstract
The objective of this article is to describe adverse drug events related to the liver and gastrointestinal tract in critically ill patients. PubMed and other resources were used to identify information related to drug-induced acute liver failure, gastrointestinal hypomotility, constipation, diarrhea, gastrointestinal bleeding, and pancreatitis in critically ill patients. This information was reviewed, and data regarding pathophysiology, common drug causes, and guidelines for prevention and management were collected and summarized. In cases in which data in critically ill patients were unavailable, data were extrapolated from other patient populations. Drug-induced acute liver failure can be caused by many drugs routinely used in the intensive care unit and may be associated with significant morbidity and mortality. Drug-related hypomotility and constipation and drug-related diarrhea are reported with many drugs, and these are common adverse drug events in critically ill patients that can substantially complicate the care of these patients. Drug-induced gastrointestinal bleeding and drug-induced pancreatitis occur less frequently, can range in disease severity, and can be associated with morbidity and mortality. Many drugs used in critically ill patients are associated with adverse drug events related to the liver and gastrointestinal tract. Critical care clinicians should be aware of common drug causes of drug-induced acute liver failure, gastrointestinal hypomotility, constipation, diarrhea, gastrointestinal bleeding, and pancreatitis, and should be familiar with the prevention and management of these diverse conditions.
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14
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Thakali KM, Kharade SV, Sonkusare SK, Rhee SW, Stimers JR, Rusch NJ. Intracellular Ca2+ silences L-type Ca2+ channels in mesenteric veins: mechanism of venous smooth muscle resistance to calcium channel blockers. Circ Res 2009; 106:739-47. [PMID: 20044515 DOI: 10.1161/circresaha.109.206763] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
RATIONALE Calcium channel blockers (CCBs) exert their antihypertensive effect by reducing cardiac afterload but not preload, suggesting that Ca(2+) influx through L-type Ca(2+) channels (LTCC) mediates arterial but not venous tone. OBJECTIVE The object of this study was to resolve the mechanism of venous resistance to CCBs. METHODS AND RESULTS We compared the sensitivity of depolarization (KCl)-induced constriction of rat small mesenteric arteries (MAs) and veins (MVs) to the dilator effect of CCBs. Initial findings confirmed that nifedipine progressively dilated depolarization-induced constrictions in MAs but not MVs. However, Western blots showed a similar expression of the alpha(1C) pore-forming subunit of the LTCC in both vessels. Patch-clamp studies revealed a similar density of whole-cell Ca(2+) channel current between single smooth muscle cells (SMCs) of MAs and MVs. Based on these findings, we hypothesized that LTCCs are expressed but "silenced" by intracellular Ca(2+) in venous SMCs. After depletion of intracellular Ca(2+) stores by the SERCA pump inhibitor thapsigargin, depolarization-induced constrictions in MVs were blocked 80% by nifedipine suggesting restoration of Ca(2+) influx through LTCCs. Similarly, KCl-induced constrictions were sensitive to block by nifedipine after depletion of intracellular Ca(2+) stores by caffeine, ryanodine, or 2-aminoethoxydiphenyl borate. Cell-attached patch recordings of unitary LTCC currents confirmed rare channel openings during depolarization of venous compared to arterial SMCs, but chelating intracellular Ca(2+) significantly increased the open-state probability of venous LTCCs. CONCLUSIONS We report that intracellular Ca(2+) inactivates LTCCs in venous SMCs to confer venous resistance to CCB-induced dilation, a fundamental drug property that was previously unexplained.
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Affiliation(s)
- Keshari M Thakali
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Little Rock, AR 72205, USA.
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15
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Abstract
Ankle oedema is a common adverse event during treatment with dihydropyridine (DHP) calcium channel antagonist therapy, the incidence of which is dose related. The three mechanisms put forward to explain the formation of oedema during calcium channel antagonist therapy are arteriolar vasodilation, impairment of the local vascular autoregulation of blood flow and impaired protection against hydrostatic load. The importance of differential arteriolar-venular dilation has been demonstrated in numerous clinical studies. In particular, differences in sympathetic overactivation after arterial vasodilation have been shown to be related to differences in ankle oedema rates. If these results are confirmed, calcium channel antagonists that activate the sympathetic nervous system to a lesser extent, such as manidipine, may become first-choice calcium channel antagonists because of their more favourable adverse event profile.
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Affiliation(s)
- Roberto Fogari
- Department of Internal Medicine, University of Pavia, Pavia, Italy.
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Zhou H, Parks V, Patat A, Le Coz F, Simcoe D, Korth-Bradley J. Absence of a clinically relevant interaction between etanercept and digoxin. J Clin Pharmacol 2005; 44:1244-51. [PMID: 15496642 DOI: 10.1177/0091270004268050] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Etanercept, a soluble recombinant human tumor necrosis factor receptor (TNFr), is effective and well tolerated in the treatment of rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and psoriasis. The primary objective of this study was to investigate the potential pharmacokinetic and pharmacodynamic interaction between digoxin and etanercept at steady state. In a crossover, open-label, nonrandomized, 3-period study, 12 healthy male subjects received loading oral doses of digoxin 0.5 mg every 12 hours on day 1 and 0.25 mg every 12 hours on day 2, followed by a daily maintenance dose of 0.25 mg for a total of 27 days. Etanercept was administered as a twice-weekly 25-mg subcutaneous dose beginning on day 9 and continuing up to day 37 for a total of 9 doses. All ratios of maximum plasma concentration (C(max)) and area under the plasma concentration versus time curve (AUC) for pharmacokinetics of digoxin fell within the confidence interval of 0.8 to 1.25. Although not considered clinically relevant, the mean C(max) and AUC of etanercept were 4.2% and 12.5% lower, respectively, when etanercept was given with digoxin than when administered alone. There were no clinically relevant changes in the electrocardiogram (ECG) parameters, and adverse events did not increase when both drugs were combined. In conclusion, there is no clinically relevant interaction between etanercept and digoxin, and both drugs can be safely coadministered without the need for a dosage adjustment.
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Affiliation(s)
- Honghui Zhou
- Clinical Pharmacology, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA
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17
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Pedrinelli R, Dell'Omo G, Nuti M, Menegato A, Balbarini A, Mariani M. Heterogeneous effect of calcium antagonists on leg oedema: a comparison of amlodipine versus lercanidipine in hypertensive patients. J Hypertens 2004; 21:1969-73. [PMID: 14508205 DOI: 10.1097/00004872-200310000-00026] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
AIMS To compare the effect of amlodipine, a prototype dihydropyridine calcium-channel blocker with lercanidipine, a newer dihydropyridine compound with lipophilic properties, on dependent oedema generation and interference with skin blood flow vasomotion in hypertensive patients. DESIGN Single-blind, sequence-randomized, cross-over comparison of amlodipine and lercanidipine. Drugs were given at equipotent doses (10 mg daily and 20 mg daily, respectively) in 22 never-treated mild-to-moderate hypertensive men (age: 48 +/- 5 years). Each treatment was administered for 2 weeks with a 2-week intervening period to restore baseline values. MAIN OUTCOME MEASURES Dependent oedema formation was quantified through leg weight changes (water displacement method). Blood pressure (the mean of at least 10 determinations) was recorded by an automated oscillometric device and skin blood flow (laser Doppler flowmetry) measured at the dorsum of the foot, both supine and with the limb passively placed 50 cm below the heart level, to evaluate the behaviour of cutaneous postural vasoconstriction, an autoregulatory mechanism that minimizes gravitational increases in capillary pressure and avoids fluid extravasation when standing. RESULTS Leg weight was increased by both drugs, but the increase was significantly greater during treatment with amlodipine than with lercanidipine. Blood pressure decreased to a similar extent and postural vasoconstriction was antagonized comparably during both treatments. CONCLUSIONS The oedema-forming potential of amlodipine is greater than that induced by lercanidipine, a difference which emerged in the presence of a comparable drop in blood pressure and could not be attributed to interference with postural vasoconstrictor mechanisms.
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18
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O'Brien KD, Zhao XQ, Shavelle DM, Caulfield MT, Letterer RA, Kapadia SR, Probstfield JL, Otto CM. Hemodynamic Effects of the Angiotensin-Converting Enzyme Inhibitor, Ramipril, in Patients with Mild to Moderate Aortic Stenosis and Preserved Left Ventricular Function. J Investig Med 2004. [DOI: 10.1177/108155890405200334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Background Angiotensin-converting enzyme (ACE) inhibitor use is presumed to be contraindicated in patients with aortic stenosis (AS). We determined the hemodynamic effects of ACE inhibitors in patients with mild to moderate aortic stenosis (AS) and preserved left ventricular function. Methods Thirteen elderly patients (mean [SD] age = 65 [17] years), with mild to moderate AS (aortic jet velocity 2.5–4.0 m/s), normal left ventricular and renal function, and no clinical coronary artery disease, were enrolled in a single-center, open-label trial comparing the hemodynamic effects at baseline and following titration of ramipril to a maximum dose of 7.5 mg twice daily. Patients were identified from echocardiography laboratory logs. Despite a presumed contraindication to ACE inhibitor use in AS patients, 30% (71 of 235) of patients otherwise meeting inclusion or exclusion criteria were excluded owing to current ACE inhibitor use. Patients were monitored with weekly clinic visits, biweekly laboratory tests, and monthly echocardiograms. Results There were no significant changes from baseline to week 8 in echocardiographic parameters, including mean (SD) aortic jet velocity [2.9 (0.4) vs 2.9 (0.4) m/s], calculated aortic transvalvular gradient [18 (6) vs 18 (6) mm Hg], or cardiac output [5.5 (1.2) vs 6.0 (2.1) L/min], or significant changes in blood pressure or heart rate. Early discontinuations were for asymptomatic low blood pressure (one patient) or a reversible creatinine increase of 0.3 mg/dL (one patient). Conclusions Short-term treatment with up to 7.5 mg twice daily of ramipril was well tolerated in patients with mild to moderate AS and preserved left ventricular function. A surprisingly high proportion of patients with documented AS were already receiving ACE inhibitors.
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Affiliation(s)
| | - Xue-Qiao Zhao
- Division of Cardiology, University of Washington, Seattle, WA
| | - David M. Shavelle
- Division of Cardiology, University of Washington, Seattle, WA
- Currently Division of Cardiology, Harbor-UCLA Medical Center, Torrance, CA
| | - Michael T. Caulfield
- Division of Cardiology, University of Washington, Seattle, WA
- Division of Cardiology, Massachusetts General Hospital, Boston, MA
| | | | - Samir R. Kapadia
- Division of Cardiology, University of Washington, Seattle, WA
- Department of Cardiology, Cleveland Clinic, Cleveland, OH
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19
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Unger T, Kaschina E. Drug interactions with angiotensin receptor blockers: a comparison with other antihypertensives. Drug Saf 2003; 26:707-20. [PMID: 12862505 DOI: 10.2165/00002018-200326100-00004] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
The ever-increasing introduction of new therapeutic agents means that the potential for drug interactions is likely to escalate. Numerous different classes of drugs are currently used to treat hypertension. The angiotensin receptor blockers offer one of the newest approaches to the management of patients with high blood pressure. Compared with other classes of antihypertensive agents, the angiotensin receptor blockers appear overall to have a low potential for drug interactions, but variations within the class have been detected. Losartan and irbesartan have a greater affinity for cytochrome p450 (CYP) isoenzymes and, thus, are more likely to be implicated in drug interactions. There is pharmacokinetic evidence to suggest that such interactions could have a clinical impact. Candesartan cilexetil, valsartan and eprosartan have variable but generally modest affinity and telmisartan has no affinity for any of the CYP isoenzymes. In vitro studies and pharmacokinetic/pharmacodynamic evaluation can provide evidence for some interactions, but only a relatively small number of drug combinations are usually studied in this way. The absence of any pharmacokinetic evidence of drug interaction, however, should not lead to complacency. Patients should be made aware of possible interactions, especially involving the concurrent use of over-the-counter products, and it may be prudent for all patients receiving antihypertensive treatment to be monitored for possible drug interactions at their regular check-ups. The physician can help by prescribing agents with a low potential for interaction, such as angiotensin receptor blockers.
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Affiliation(s)
- Thomas Unger
- Institute of Pharmacology and Toxicology, Charité Hospital, Humboldt University at Berlin, Berlin, Germany
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20
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Abstract
Typically, old patients scheduled to undergo a surgical procedure take many medications for various disorders. The anaesthetist must consider the benefits and/or risks of continuation or withdrawal of such chronic medications. This chapter reviews these issues in respect of cardiovascular drugs (calcium channel blockers, beta adrenoreceptor antagonists, angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists) and of psychotropic and antiparkinson medications and insulin. Focus is put on the few scientific studies available and on the recommendations given by experts in the field.
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Affiliation(s)
- Thomas Bruessel
- Department of Anaesthesia and Pain Management, Canberra Clinical School, University of Sydney, The Canberra Hospital, Yamba Drive, Garran ACT 2605, Australia.
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21
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Pedrinelli R, Dell'Omo G, Mariani M. Calcium channel blockers, postural vasoconstriction and dependent oedema in essential hypertension. J Hum Hypertens 2001; 15:455-61. [PMID: 11464254 DOI: 10.1038/sj.jhh.1001201] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2000] [Revised: 01/15/2001] [Accepted: 01/31/2001] [Indexed: 11/09/2022]
Abstract
Treatment with calcium channel blocker (CCB)s, dihydropyridines and others, is frequently complicated by dependent oedema in the absence of sodium retention or cardiac failure, a bothersome side effect of unclear aetiology. The present paper reviews our own and other work dealing with the antagonism exerted by such drugs on postural vasoconstriction, a mechanism triggered by limb venous congestion during orthostasis and controlled through a local sympathetic axo-axonic reflex and increased myogenic tone in response to changes in transmural pressure. By stabilising capillary pressure, postural vasoconstriction counteracts fluid hyperfiltration consequent to gravitational stimuli, and consistent evidence shows attenuation of this response by L-type calcium channel blockers. Interference with the postural reflex control of skin blood flow may therefore contribute to dependent oedema, although cannot entirely explain its development. Attenuation of postural vasoconstriction may amplify the fluid hyperfiltration induced by CCBs through other mechanisms, such as imbalanced intracapillary pressure or enhanced vascular permeability, which are the main factors determining net fluid filtration into the interstitial compartment.
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Affiliation(s)
- R Pedrinelli
- Dipartimento Cardiotoracico, Universita' di Pisa, Italy.
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Fogari R, Malamani GD, Zoppi A, Preti P, Vanasia A, Fogari E, Mugellini A. Comparative effect of lercanidipine and nifedipine gastrointestinal therapeutic system on ankle volume and subcutaneous interstitial pressure in hypertensive patients: a double-blind, randomized, parallel-group study. Curr Ther Res Clin Exp 2000. [DOI: 10.1016/s0011-393x(00)90012-2] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
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23
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Fischberg GM, Lozano E, Rajamani K, Ameriso S, Fisher MJ. Stroke precipitated by moderate blood pressure reduction. J Emerg Med 2000; 19:339-46. [PMID: 11074327 DOI: 10.1016/s0736-4679(00)00267-5] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Rapid lowering of blood pressure can precipitate or worsen ischemic strokes. This usually has been observed in the setting of profoundly lowered pressure and hypotension. We report on six patients in whom ischemic neurologic injury ensued or worsened after moderate reduction of blood pressure by pharmacological treatment. The 6 patients suffered new or worsened ischemic neurologic deficits after receiving oral or intravenous antihypertensive medications, mostly after relatively small doses. Mean arterial blood pressure in these patients was decreased by 25 +/- 7.7%, or 37 +/- 16 mm Hg (mean +/- SD) without resultant hypotension. These cases emphasize the potential hazards of moderate blood pressure reduction by antihypertensive medications in the setting of an acute ischemic stroke or transient ischemic attack (TIA), as well as rapidly treated hypertension even in those who have not yet manifested ischemic symptoms.
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Affiliation(s)
- G M Fischberg
- University of Southern California, Los Angeles, California, USA
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Pedrinelli R, Dell'Omo G, Melillo E, Mariani M. Amlodipine, enalapril, and dependent leg edema in essential hypertension. Hypertension 2000; 35:621-5. [PMID: 10679507 DOI: 10.1161/01.hyp.35.2.621] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Calcium channel blockers (CCBs) blunt postural skin vasoconstriction, an autoregulatory mechanism that minimizes gravitational increases in capillary pressure and avoids fluid extravasation when standing. To evaluate the dose-response relation between this pharmacological interference and dependent edema, a frequent side effect of CCBs during antihypertensive treatment, skin blood flow (laser Doppler flowmetry) at the dorsum of the foot, both supine and with the limb passively placed 50 cm below the heart level, and leg weight (Archimedes principle) were measured at baseline, during increasing doses of the dihydropyridine amlodipine (5 and 10 mg UID each for 2 weeks), and after drug withdrawal in 10 hypertensive men. Because angiotensin-converting enzyme inhibitors may attenuate ankle swelling by CCBs, those parameters were evaluated according to a similar design during amlodipine (10 mg UID) and enalapril (20 mg UID) combined (n=10). As a control, the effect of enalapril monotherapy (10 and 20 mg UID for 2 weeks each) was evaluated in a third series of patients (n=8). Amlodipine (5 mg UID) increased leg weight without modifying postural vasoconstriction (the percent skin blood flow decrease from horizontal to dependent position), which indicates that extravascular fluid shift was independent of postural skin vasoconstriction. At 10 mg UID, however, amlodipine blunted postural vasoconstriction and increased leg weight further, which suggests that skin blood flow autoregulation limited additional fluid transfer. Both parameters normalized after drug withdrawal. Enalapril per se did not affect cutaneous vasomotion or leg weight but reduced the amount of dependent fluid extravasation by the CCB despite a persistent antagonism for postural vasoconstrictor responses.
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Affiliation(s)
- R Pedrinelli
- Dipartimento Cardiotoracico, Medicina Interna, Azienda Ospedaliera, Universita' di Pisa, Italy.
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Sandmann S, Spitznagel H, Chung O, Xia QG, Illner S, Jänichen G, Rossius B, Daemen MJ, Unger T. Effects of the calcium channel antagonist mibefradil on haemodynamic and morphological parameters in myocardial infarction-induced cardiac failure in rats. Cardiovasc Res 1998; 39:339-50. [PMID: 9798519 DOI: 10.1016/s0008-6363(98)00087-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/09/2023] Open
Abstract
OBJECTIVE Calcium channel antagonists (CCA) have been proposed for the prevention of cardiac events after myocardial infarction (MI). Mibefradil is a CCA featuring a selective blockade of T-type Ca2(+)-channels. The aim of the study was to characterize the effects of mibefradil on haemodynamic and morphological parameters in a model of postMI chronic heart failure and to establish the "therapeutic window" for the start of therapy. METHODS MI was induced by permanent ligation of the left coronary artery in male normotensive Wistar rats. Animals were assigned to placebo- or mibefradil-treated (10 mg/kg/day p.o.) groups as follows: (1) sham operation; (2) MI placebo treatment; (3) 7 days preMI start of treatment; (4) 3 h postMI start of treatment; (5) 24 h postMI start of treatment; (6) 3 days postMI start of treatment; (7) 7 days postMI start of treatment. Treatment was continued for 6 weeks postMI. At this time point, mean arterial blood pressure (MAP), heart rate, left ventricular enddiastolic pressure (LVEDP) and contraction force (dP/dtmax) were measured in conscious rats at baseline and after methoxamine (MEX; 0.5-1.0 mg/h i.v.) stimulation to increase afterload. The hearts were subjected to histological determination of infarct size (IS), infarct length (IL), noninfarcted length (NL), left ventricular circumference (LVC), inner LV-diameter (LVD) and septal thickness (ST). RESULTS Six weeks after MI, MAP was lowered, LVEDP increased and dP/dtmax reduced. Mibefradil treatment increased basal MAP in groups 3-5 compared to the placebo-treated MI group. Under mibefradil, LVEDP was reduced at baseline in groups 3-6 and, after MEX, in all groups. dP/dtmax was increased in groups 3-4 at baseline and after MEX. In the placebo-treated MI group, the infarcted area was 39% of the LV and heart weight, LVD and LVC were increased. Heart weights of mibefradil-treated rats (groups 3-6) did not differ from those of the placebo-treated group. Early onset of treatment with mibefradil reduced IS and IL and increased NL in groups 3-4. LVD and LVC were decreased in group 3 only. ST was increased in groups 3-5. CONCLUSION Chronic treatment with mibefradil exerts beneficial actions on cardiac structure and performance in postMI cardiac failure in rats, especially when the onset of treatment is either prior to or within hours after the acute ischemic event.
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Affiliation(s)
- S Sandmann
- Institute of Pharmacology, Christian-Albrechts-University of Kiel, Germany
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26
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Hoischen S, Brixius K, Schwinger RH. T- and L-type Ca2+-channel antagonists reduce contractility in guinea pig cardiac myocytes. J Cardiovasc Pharmacol 1998; 32:323-30. [PMID: 9700997 DOI: 10.1097/00005344-199808000-00022] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
The aim of this study was to investigate the influence of L- and T-type Ca2+-channel blockade on myocardial contractility in guinea pig cardiomyocytes. Left ventricular myocardium from guinea pig contains both L- and T-type Ca2+ channels. The T-type Ca2+ influx was inhibited with mibefradil (1-100 microM), a novel compound with a threefold higher affinity for T- compared with L-type Ca2+ channels. In comparison, L-type Ca2+ influx was reduced by the benzodiazepine diltiazem (1-100 microM). The effect of mibefradil and diltiazem on electrically driven (0.5 Hz) isolated cardiomyocytes (n = 12) was studied in a concentration-dependent manner. The change of the contraction amplitude (percentage of cell shortening) was continuously recorded with an one-dimensional high-speed camera. Both mibefradil and diltiazem concentration-dependently reduced (p < 0.05 vs. control) the contraction amplitude in isolated myocytes from guinea pig. The concentration at which the contraction amplitude of guinea pig cardiomyocytes was reduced by 50% (EC50) was 31.6 microM for diltiazem and 6.3 microM for mibefradil, indicating that the T-type Ca2+-channel blocker mibefradil is more potent in reducing contractility in guinea pig cardiac myocytes in comparison with the L-type Ca2+-channel antagonist diltiazem. Mean values for cell shortening in percentage +/- SEM for mibefradil (0, 1, 10, 100 microM) were 100%, 78 +/- 9.2%, 36 +/- 5.4%, and 24 +/- 3.6%. The corresponding values for diltiazem were 100%, 92 +/- 12.5%, 79 +/- 8.9%, and 35 +/- 2.6%. In contrast, the increase of the extracellular Ca2+ concentration (2-7.5 mM) resulted in a significant increase of the contraction amplitude (+213 +/- 14%). Therefore, blockade of the Ca2+ influx through voltage-dependent T- or L-type Ca2+ channels decreases contraction in isolated cardiac myocytes from guinea pigs containing L- and T-type Ca2+ channels.
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Affiliation(s)
- S Hoischen
- Klink III für Innere Medizin der Universität zu Köln, Germany
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Walker JM, Curry PV, Bailey AE, Steare SE. A comparison of nifedipine once daily (Adalat LA), isosorbide mononitrate once daily, and isosorbide dinitrate twice daily in patients with chronic stable angina. Int J Cardiol 1996; 53:117-26. [PMID: 8682597 DOI: 10.1016/0167-5273(95)02531-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
The efficacy of nifedipine gastrointestinal therapeutic system (GITS), 60-90 mg o.d., isosorbide dinitrate, 40-60 mg b.d., and isosorbide mononitrate slow-release, 50-100 mg o.d. was assessed in a six week double-blind, parallel-group study in patients with stable angina on chronic beta-blocker treatment. Of 339 patients who entered the study, 229 were eligible for the valid case analysis of efficacy and 335 for the safety analysis. Nifedipine GITS was significantly better than isosorbide dinitrate (P < or = 0.025) in prolonging time to 1 mm ST-segment depression, time to maximum ST-segment depression, time to occurrence of angina and total exercise duration, in addition to reducing the number of angina attacks and glyceryl trinitrate consumption after six weeks therapy. Nifedipine GITS was also significantly better than isosorbide mononitrate (P < or = 0.025) in prolonging time to occurrence of angina and time to 1 mm ST-segment depression after six weeks therapy. The incidence of headache was considerably higher in both the isosorbide dinitrate and isosorbide mononitrate groups (40% and 41%, respectively) than in the nifedipine GITS group (9.5%, P < or = 0.001), and was the main reason for withdrawal from the study (isosorbide dinitrate 18/99, isosorbide mononitrate 17/99, nifedipine GITS 2/95). Peripheral oedema was more common in patients treated with nifedipine GITS (12.5%) compared to nitrates (2% in both groups, P < or = 0.01), but resulted in withdrawal of only one patient (treated with nifedipine GITS). This study suggests that the efficacy and tolerability of nifedipine GITS is superior to long acting nitrates as second-line therapy to beta-blockade in the treatment of chronic stable angina.
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Affiliation(s)
- J M Walker
- Department of Cardiology, University College London Hospitals, UK
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29
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Opie LH. Calcium channel antagonists in the treatment of coronary artery disease: fundamental pharmacological properties relevant to clinical use. Prog Cardiovasc Dis 1996; 38:273-90. [PMID: 8552787 DOI: 10.1016/s0033-0620(96)80014-4] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Calcium channel antagonists are a diverse group of drugs with clinical antianginal and antihypertensive properties. They have as a common property the capacity to lessen the rate of calcium ion entry through a specific type of calcium channel, namely the voltage-gated L-type channel. They do not bind to all the pore molecules; therefore, there is still some residual entry of calcium ions. Variables determining the clinical efficacy of the different drugs include the binding sites involved, the tissue specificity of the drug, the duration of action, and (closely related) the degree of counter-regulatory neurohumoral activation. Inhibitory effects on the calcium channels of vascular smooth muscle explain the antihypertensive effect and the reduction of afterload, one of the antianginal mechanisms common to all of the drugs. In general, the dihydropyridines, such as nifedipine, are more vascular-selective than the non-dihydropyridines, such as verapamil and diltiazem. The latter owe part of their antianginal activity to more prominent effects on the calcium channels in the sinoatrial node (decreased heart rate) and the myocardium (negative inotropic effect). In addition, calcium channel antagonists are coronary artery vasodilators. Whether the latter effect confers on these drugs any specific advantage in the therapy of anginal syndromes is controversial.
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Affiliation(s)
- L H Opie
- Heart Research Unit of the Medical Research Council, University of Cape Town Medical School, South Africa
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30
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Zidek W, Spiecker C, Knaup G, Steindl L, Breuer HW. Comparison of the efficacy and safety of nifedipine coat-core versus amlodipine in the treatment of patients with mild-to-moderate essential hypertension. Hypertension Study Group. Clin Ther 1995; 17:686-700. [PMID: 8565032 DOI: 10.1016/0149-2918(95)80045-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The antihypertensive efficacy and safety of once-daily nifedipine coat-core was compared with that of once-daily amlodipine in a multicenter, prospective, double-blind, randomized, parallel-group study in which titration was based on response. The study consisted of a 2-week, single-blind, placebo run-in period followed by an 8-week double-blind treatment period. Double-blind treatment began with nifedipine coat-core 30 mg or amlodipine 5 mg. After 4 weeks of double-blind therapy, patients with a trough seated diastolic blood pressure (DBP) > or = 90 mm Hg received an increased dose of nifedipine coat-core (60 mg) or amlodipine (10 mg). A total of 207 patients received the study medication at 12 private-practice medical centers. Ambulatory blood pressure monitoring (ABPM) was performed at six medical centers with 38 nifedipine coat-core and 37 amlodipine patients. Data from 176 patients were valid for the primary efficacy analysis. Treatment groups were well matched with respect to baseline demographic and disease characteristics. During the study period, 59 (65.6%) nifedipine coat-core patients remained on their original 30-mg dose of study medication compared with 52 (60.5%) amlodipine patients who remained on the 5-mg starting dose. Mean trough blood pressure at baseline was 160.9/101.9 mm Hg in the nifedipine coat-core patients compared with 160.5/101.8 mm Hg in the amlodipine patients. Mean trough blood pressures at end point were 141.3/85.5 mm Hg and 140.7/85.9 mm Hg in the nifedipine coat-core and amlodipine groups, respectively. Equivalence between the two treatment groups was demonstrated based on the difference between amlodipine and nifedipine coat-core in the change from baseline in trough seated DBP (90% confidence interval, -0.50 to 2.59). Systolic blood pressure and 24-hour ABPM data supported the equivalent antihypertensive efficacy of the two treatments. Both drugs were well tolerated and had similar safety profiles. Nineteen patients in the amlodipine group experienced at least one adverse event compared with 12 in the nifedipine coat-core group. The amlodipine patients tended toward a later occurrence of adverse events plus a greater number of events, particularly edema and gastrointestinal symptoms. More patients in the nifedipine coat-core group (n = 3) than in the amlodipine group (n = 1) discontinued treatment because of adverse events.(ABSTRACT TRUNCATED AT 400 WORDS)
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Affiliation(s)
- W Zidek
- Westfälische Wilhelms-Universität, Münster, Germany
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31
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Ekelund LG, Ulvenstam G, Walldius G, Aberg A. Effects of felodipine versus nifedipine on exercise tolerance in stable angina pectoris. Am J Cardiol 1994; 73:658-60. [PMID: 8166061 DOI: 10.1016/0002-9149(94)90929-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
The effects of single doses of felodipine (5 and 10 mg) and nifedipine (10 and 20 mg) on chronic stable effort angina pectoris were assessed in a placebo-controlled, double-blind, crossover study of 24 patients receiving beta blockers and short-acting nitroglycerin. The effects were measured by repeated bicycle ergometer tests. The total work, and time until 1 mm of ST depression increased significantly by 9 to 31% after both active drugs at both dose levels in comparison with placebo. The differences were not significant between drugs or doses. At rest, blood pressure decreased (10 to 15%) and heart rate increased (5 to 10%) significantly after both active drugs. During exercise at the highest comparable work load, systolic blood pressure decreased significantly (23 to 26%), whereas heart rate was not affected after felodipine and nifedipine compared with placebo. The 2 drugs were well tolerated, and side effects were mild. Therefore, single doses of 5 and 10 mg of felodipine, and 10 and 20 mg of nifedipine have similar antianginal and anti-ischemic properties. However, felodipine has a longer duration of action, which may improve compliance.
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Affiliation(s)
- L G Ekelund
- Diet and Fitness Center, Duke University Medical Center, Durham, North Carolina 27710
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32
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DiBianco R, Schoomaker FW, Singh JB, Awan NA, Bennett T, Canosa FL, Kawanishi DT, Bamrah VS, Glasser SP, Barry W. Amlodipine combined with beta blockade for chronic angina: Results of a multicenter, placebo-controlled, randomized double-blind study. Clin Cardiol 1992; 15:519-24. [PMID: 1354085 DOI: 10.1002/clc.4960150709] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Amlodipine, a potent long-acting dihydropyridine calcium antagonist, was compared with placebo in a parallel, randomized, double-blind study in 134 patients with chronic stable angina pectoris maintained on beta-adrenergic blocking agents. After a single-blind, two-week placebo period, patients were randomized to receive either amlodipine (2.5, 5, and 10 mg) or placebo once daily for four weeks. The effects of amlodipine on maximal exercise time, work, time to angina onset, and subjective indices including angina frequency, nitroglycerin tablet consumption, and patient and investigator ratings were assessed. Each dose of amlodipine produced increases in exercise time and calculated total work accomplished compared to baseline. Improvements at 5 and 10 mg were significantly greater than placebo which produced no significant change (p less than 0.05). Qualitative improvements in the severity of angina were produced by amlodipine at 5 and 10 mg daily assessed by patient-rating questionnaires (p less than 0.05). Reductions in angina frequency attacks per week and weekly nitroglycerin tablet consumption occurred but were not statistically significant when compared with placebo. Adverse effects observed during amlodipine treatment prompted discontinuation of treatment in only 2 out of 100 patients. Three patients discontinued treatment for reported lack of efficacy. No laboratory abnormalities prompted treatment discontinuation and minor side effects of dizziness, nausea, headache, and fatigue were observed infrequently. The results of this controlled, large-scale multicenter trial suggest that amlodipine significantly increased exercise capacity and was well tolerated when added to the antianginal regimen of patients remaining symptomatic while receiving beta-blocking agents.
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Affiliation(s)
- R DiBianco
- Cardiology Department, Washington Adventist Hospital, Takoma Park, Maryland 20912
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33
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Clozel JP, Osterrieder W, Kleinbloesem CH, Welker HA, Schläppi B, Tudor R, Hefti F, Schmitt R, Eggers H. Ro 40?5967: A New Nondihydropyridine Calcium Antagonist. ACTA ACUST UNITED AC 1991. [DOI: 10.1111/j.1527-3466.1991.tb00539.x] [Citation(s) in RCA: 76] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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34
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Dimenäs E, Wallander MA, Svärdsudd K, Wiklund I. Aspects of quality of life on treatment with felodipine. Eur J Clin Pharmacol 1991; 40:141-7. [PMID: 2065695 DOI: 10.1007/bf00280068] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Quality of life has been assessed in a double-blind four week study comparing felodipine 5, 10, 20 mg and placebo added to metoprolol by adding two self-administered questionnaires to the conventional procedure for the evaluation of adverse events. None of the aspects related to general well-being was affected by felodipine. The subjective symptoms reported were mostly dose-related and so here mainly observed at the highest dose. Some of them, e.g. headache, were transient. It is concluded that felodipine in combination with metoprolol CR did not negatively influence the feeling of well-being of the patients. When the drug was given in low, individually adjusted doses, the symptoms normally associated with Ca antagonists were likely to be minimised.
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Affiliation(s)
- E Dimenäs
- Research Laboratories, AB Hässle, Mölndal, Sweden
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35
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Yoneyama F, Yamada H, Satoh K, Taira N. Cardiac versus coronary dilator effects of SD-3211, a new nondihydropyridine calcium antagonist, in isolated, blood-perfused dog hearts. Cardiovasc Drugs Ther 1990; 4:1469-76. [PMID: 2081139 DOI: 10.1007/bf02026494] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Coronary and cardiac effects of SD-3211 were compared in isolated, blood-perfused sinoatrial (SA) node, atrioventricular (AV) node, and papillary muscle preparations of dogs. SD-3211 was administered intraarterially. In all preparations SD-3211 produced an increase in coronary blood flow. In SA node preparations, the drug produced a decrease in sinus rate, and in high doses atrial standstill occurred. The dose that produced a 15% decrease in sinus rate was about 5.6 times the dose that doubled coronary blood flow. In AV node preparations, when injected into the artery supplying the AV node, the drug produced an increase in AV conduction time, and in high doses second- or third-degree AV block occurred. The dose that produced a 15% increase in AV conduction time was about 1.6 times the dose that doubled coronary blood flow. In the same preparations the drug slightly increased AV conduction time only at high doses when injected into the artery supplying the His-Purkinje-ventricular system. In paced papillary muscle preparations, the drug produced a decrease in the force of contraction. The dose that produced a 50% decrease in the force of contraction of the paced papillary muscle was about 50 times the dose that doubled coronary blood flow. The drug was virtually ineffective on ventricular automaticity. In short, in doses that doubled coronary blood flow, SD-3211 depressed only AV nodal conduction. This cardiovascular profile differs from those of diltiazem and verapamil, which do not discriminate between coronary vasculature and the SA and the AV node.
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Affiliation(s)
- F Yoneyama
- Department of Pharmacology, Tohoku University School of Medicine, Sendai, Japan
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36
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Gotanda K, Yokoyama H, Satoh K, Taira N. Cardiohemodynamic effects of cromakalim and pinacidil, potassium-channel openers, in the dog, special reference to venous return. Cardiovasc Drugs Ther 1989; 3:507-15. [PMID: 2488102 DOI: 10.1007/bf01865509] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
The cardiohemodynamic effects of the potassium-channel openers, cromakalim and pinacidil, were studied by the use of the closed-loop method (for both drugs) and the cardiopulmonary bypass technique (for cromakalim only) in anesthetized, open-chest dogs. In closed-loop preparations, both drugs (cromakalim, 3 to 100 micrograms/kg; pinacidil, 10 to 300 micrograms/kg) administered intravenously decreased systemic blood pressure and increased venous return (sum of the flow through the inferior and the superior vena cava) and cardiac output (CO). With the highest doses of both drugs, venous return and CO decreased in some preparations in which right atrial pressure rose, and the maximum rate of rise of left ventricular pressure (LV dP/dt max) diminished. Except such preparations, right atrial pressure, heart rate, and atrioventricular conduction time remained virtually unchanged. The fall in systemic blood pressure produced by intermediate doses of pinacidil was greater in the preparations in which baroceptor reflexes were eliminated (denervated preparations) than in those with the reflexes left intact (nerve-intact preparations). The increases in venous return and CO, however, were not different when comparing the nerve-intact and the denervated preparations. In cardiopulmonary-bypass preparations, higher doses of cromakalim increased venous return while producing a fall in systemic blood pressure, suggesting that the decreased venous return and CO seen with higher doses of the potassium-channel openers in the closed-loop preparations were secondary to the decreased cardiac contractility. The potassium-channel openers should be characterized as vasodilators, which preferentially reduce afterload and increase venous return.
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Affiliation(s)
- K Gotanda
- Department of Pharmacology, Tohoku University School of Medicine, Sendai, Japan
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