The Emergence of Drugs which Block Calcium Entry

Overview

Calcium Entry Blockers (CEBs) are a new class of drugs which have been pushing back the frontiers of science and medicine for almost two decades. This report reviews some of the wealth of chemical, biological and clinical data describing the discovery and development of these compounds. The scientific importance, therapeutic benefit and marketing potential of these compounds have caused an explosion of scientific literature describing their effects in many preclinical and clinical settings. The definitional ...
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Overview

Calcium Entry Blockers (CEBs) are a new class of drugs which have been pushing back the frontiers of science and medicine for almost two decades. This report reviews some of the wealth of chemical, biological and clinical data describing the discovery and development of these compounds. The scientific importance, therapeutic benefit and marketing potential of these compounds have caused an explosion of scientific literature describing their effects in many preclinical and clinical settings. The definitional characteristics of these compounds suggest a certain predictability of their biological profile but their therapeutic usefulness varies widely dependent upon their physical properties, net hemodynamic effects, duration of action and incidence of side effects. CEBs appear uniquely suited to the treatment of the underlying complexity of cardiovascular disease. The CEBs of the future may live up to the expectations of pathophysiologically based therapeutics and allow the heart and blood vessels to outlive the cells which they support. The development of CEBs is an evolving story of epic proportions and represents the cooperative efforts of individuals in all areas of science.
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Table of Contents

Abstracts.- 1 Introduction: Calcium Entry Blockers (CEBs).- 1.1 History of Calcium Entry Blocker New Drug Discovery.- 1.1.1 Calcium Entry Channels.- 1.1.2 Calcium Channel Determinates of Drug Action.- 1.1.3 Alpha-2 Receptor Activated Channels.- 1.1.4 Labeling Calcium Entry Channels.- 1.2 Nomenclature and Classification.- 1.3 Definitional Characteristics.- 1.4 Screening Philosophy.- 1.5 Methodological Notes for Screening Vascular Effects.- 2 Current Calcium Entry Blocker.- 2.1 Status of CEB New Drug Discovery.- 2.1.1 First Generation “Standard Triad” Compounds.- 2.1.2 Other Vintage Compounds.- 2.1.3 Second Generation CEBs.- 2.1.4 New or Little Studied CEBs.- 2.1.5 Compounds with Secondary Calcium Entry Blocking Actions.- 2.1.6 Intracellular Calcium Antagonists.- 2.1.7 Status: “Conclusion”.- 2.2 Additional Sites of Action.- 2.2.1 Inhibition of Phosphodiesterase.- 2.2.2 Interaction with Calmodulin.- 2.2.3 Inhibition of Intracellularly Released Calcium.- 2.2.4 Stimulation of Calcium Extrusion.- 2.2.5 Interaction with Alpha Adrenoceptors.- 3 Preclinical Pharmacology.- 3.1 Vasodilator Effects of CEBs.- 3.2 Antihypertensive Effects of CEBs.- 3.3 CEB Effects on Myocardial Rate and Rhythm.- 3.4 Anti-Ischemic/Myocardial Protective Effects of CEBs.- 3.5 Cytoprotective Effects of CEBs in Hepatic Injury.- 3.6 Cytoprotective Actions of CEBs in Models of Cerebral Ischemic Injury.- 3.7 Effects of CEBs on Airway Smooth Muscle and Mast Cell Mediator Release.- 3.8 CEBs in Atherosclerosis.- 3.9 Effects of CEBs on Platelet Aggregation.- 3.10 Effects of CEBs on Red Blood CElls.- 3.11 CEBs and Neutrophil Function.- 3.12 Endocrine Effects of CEBs.- 4 Therapeutic Indications.- 4.1 Angina Pectoris.- 4.1.1 Chronic Stable Angina.- 4.1.2 Vasospastic Angina.- 4.1.3 Unstable Angina.- 4.1.4 Acute Myocardial Infarction.- 4.2 Arterial Hypertension.- 4.2.1 Essential Hypertension.- 4.2.2 Pulmonary Hypertension.- 4.3 Vascular Disease.- 4.3.1 Peripheral Vascular Disease.- 4.3.2 Cerebral Vascular Disease.- 4.4 Congestive Heart Failure.- 4.5 Myocardial Arrhythmias.- 4.5.1 Artial Arryhthmias.- 4.5.2 Ventricular Arrhythmias.- 4.6 Asthma.- 4.7 Other Therapeutic Indications.- 4.7.1 Cardiovascular Indications.- 4.7.2 Non-Cardiovascular Indications.- 4.7.3 Miscellaneous “NEW” Possibilities.- 5 Adverse Effects.- 6 Perspectives: CEB New Drug Discovery.- 7 Acknowledgement.- 8 References.- Author Index Volumes 1–6.
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