Snake Venoms by C.-Y. LeeSnake Venoms by C.-Y. Lee

Snake Venoms

EditorC.-Y. Lee

Paperback | November 15, 2011

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The past decade has been a period of explosion of knowledge on the chemistry and pharmacology of snake toxins. Thanks to the development of protein chemistry, nearly a hundred snake toxins have been purified and sequenced, representing one of the largest families of sequenced proteins. Moreover, the mode of action of these toxins has been largely elucidated by the concerted efforts of pharmacologists, electro physiologists, and biochemists. As a result of these studies, some of the snake toxins, e.g., a-bungarotoxin and cobra neurotoxins, have been extensively used as specific markers in the study of the acetylcholine receptors. Indeed, without the discovery of these snake toxins, our knowledge of the structure and function of nicotinic acetylcholine receptors would not have advanced so rapidly. The contribution of snake venom research to the biomedical sciences is not limited to the study of cholinergic receptors. Being one of the most concentrated enzyme sources in nature, snake venoms are also valuable tools in biochemical research. Venom phosphodiesterase, for example, has been widely used for structural studies of nucleic acids; proteinase, for the sequence studies of proteins and pep tides ; phospholipase A , for lipid research; and L-amino acid oxidase for identifying optical z isomers of amino acids. Furthermore, snake venoms have proven to be useful agents for clarifying some basic concepts on blood coagulation and some venom enzymes, e.g., thrombin-like enzymes and pro coagulants have been used as therapeutic agents.
Title:Snake VenomsFormat:PaperbackPublished:November 15, 2011Publisher:Springer Berlin HeidelbergLanguage:English

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ISBN - 10:3642669158

ISBN - 13:9783642669156

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Table of Contents

I: History, Ecological and Zoological Aspects.- 1 History of Snake Venom Research.- References.- 2 Classification and Distribution of Venomous Snakes in the World.- References.- 3 The Venom Glands of Snakes and Venom Secretion.- A. Introduction.- B. General Morphology and Histology.- I. Venom Glands of Elapidae.- II. Venom Glands of Viperidae.- C. The Fine Structure of the Secretory Cell During the Venom Regeneration Cycle.- D. Intracellular Transport of Venom Proteins.- E. Venom Synthesis and Secretion.- I. The Venom Regeneration Cycle.- II. Synthesis and Secretion of Different Venom Components.- III. Total Venom Yield and the Amount of Venom Expelled During the Bite.- F. Concluding Remarks.- References.- II: Chemistry and Biochemistry of Snake Venoms.- 4 Enzymes in Snake Venom.- A. Introduction.- B. Distribution of Enzymes in Snake Venoms.- C. Methods for Purification, Isolation, and Crystallization of Snake Venom Enzymes.- I. Polyacrylamide Gel Electrophoresis.- II. Isoelectric Focusing.- III. Molecular-Sieve Chromatography.- IV. Ion-Exchange Chromatography.- D. Biochemical Properties of Snake Venom Enzymes.- I. Oxidoreductases.- 1. L-Amino Acid Oxidase.- 2. Lactate Dehydrogenase.- II. Enzymes Acting on Phosphate Esters.- 1. Endonuclease.- 2. Phosphodiesterase.- 3. 5?-Nucleotidase.- 4. Nonspecific Phosphomonoesterase.- 5. "Paraoxonase" (O,O-Diethyl O-p-Nitrophenyl Phosphate, O-p-Nitrophenyl Hydrolase).- III. Enzymes Acting on Glycosyl Compounds.- 1. Hyaluronidase.- 2. Heparinase-like Enzyme.- 3. NAD Nucleosidase.- IV. Enzymes Acting on Peptide Bonds.- 1. Endopeptidases.- 2. Peptidases.- 3. Arginine Ester Hydrolases.- 4. Kininogenase.- V. Enzymes Acting on Carboxylic Ester Bonds.- 1. Phospholipase A2.- 2. Phospholipase B and Phospholipase C.- 3. Acetylcholinesterase.- VI. Enzyme Acting on Arylamides.- E. Summary.- References.- 5 Chemistry of Protein Toxins in Snake Venoms.- A. Introduction.- B. Toxins with Postsynaptic Neurotoxin-Membrane Toxin Structure.- I. Curaremimetic Toxins.- 1. Introduction.- 2. Isolation of Curaremimetic Toxins.- 3. Characteristics of Curaremimetic Toxins.- 4. Interaction with the Acetylcholine Receptor.- 5. Structural Information.- 6. Chemical Modifications.- a) Amino Groups.- b) Arginine Residues.- c) Carboxyl Groups.- d) Tryptophan.- e) Tyrosine.- f) Disulfide Bridges.- g) Histidine.- h) Modifications Involving a Large Increase in Size.- 7. Discussion.- II. Membrane Toxins.- 1. Introduction.- 2. Mode of Action.- 3. Structural Information.- 4. Chemical Modifications.- C. Toxins with Phospholipase Structure.- I. Notexin and its Homologues.- II. Taipoxin.- III. Crotoxin.- IV. ?-Bungarotoxin.- V. Enhydrina schistosa Myonecrotic Toxins.- VI. Some Other Toxic Phospholipases A.- VII. Pharmacologic and Biochemical Effects.- 1. Presynaptic Neurotoxicity.- 2. Inhibition of High Affinity Choline Uptake.- 3. Postsynaptic Effects and Myotoxicity.- 4. Antagonism by High Mg2+, Ca2+, and Low Ca2+.- VIII. Phospholipase A Activity and Presynaptic Neurotoxicity.- IX. Concluding Remarks.- D. Other Toxins.- I. Crotamine.- II. Convulxin and Gyroxin.- III. Mojave Toxin.- IV. Other Crotalid Toxins.- V. Viperotoxin.- VI. Toxins from Bungarus caeruleus Venom.- 1. Ceruleotoxin.- 2. Post- and Presynaptic Neurotoxins.- E. Conclusion.- References.- 6 The Three-Dimensional Structure of Postsynaptic Snake Neurotoxins: Consideration of Structure and Function.- A. Introduction.- B. The Postsynaptic Neurotoxins: Survey of Three-Dimensional Prototype Structure; Deviant Toxins, Chemical Modification Studies. Preliminary Review.- I. Primary Sequence of Erabutoxin b.- II. Three-Dimensional Structure of Erabutoxin b.- 1. Molecular Size and Shape.- 2. Backbone Chain Conformation in the Erabutoxin Molecule.- III. Residue Sequences: Invariant and Conservative Substitutions in the Long and Short Chain Series of Neurotoxins.- IV. Chemistry and Chemical Modification Studies.- 1. Residues not Subject to Study by Group-Specific Reagents.- a) Serine-Threonine.- b) Glycine.- c) Proline.- d) Asparagine.- e) Alanine, Leucine, Isoleucine, and Valine.- 2. Invariant and Conservatively Substituted Residues as Studied by Chemical Modification.- a) Disulfide Linkages.- b) Tyrosine.- c) Tryptophan.- d) Aspartic Acid, Glutamic Acid.- e) Arginine.- f) Amino Groups.- 3. Toxin Modification by Deletion or by Size Increase.- a) Carboxyl-Terminal Deletion of a Long Chain Toxin.- b) Polymerization.- 4. Summary.- V. Physicochemical Studies of Neurotoxins and Their Derivatives.- 1. Spectroscopic Studies of Native Toxin Conformation in Aqueous and Aqueous-Organic olvent.- a) Optical Rotatory Dispersion (ORD) and Circular Dichroism (CD) Spectra.- b) Laser-Raman Spectra.- 2. Spectroscopic Studies of Chemically Modified and/or Denatured Neurotoxins.- a) Disulfide Linkages.- b) Tyrosine.- c) Tryptophan.- VI. Theoretical and Model Studies of Neurotoxin Conformation and Three-Dimensional Structure.- 1. Prediction of Conformation in the Neurotoxins.- a) ? Helix.- b) ? Pleated Sheet.- c) ? Turns.- 2. Predictions of Three-Dimensional Structure in the Neurotoxin Series.- a) Model Structure Studies.- b) Energy Minimization Studies.- c) Theoretical Chemical Models.- VII. X-ray Crystal Structure Studies of Other Neurotoxins.- 1. Erabutoxin a (Asn 26 Erabutoxin b).- 2. Neurotoxin b from Laticauda semifasciata (Philippines).- 3. Erabutoxin c.- 4. Laticotoxin a and Cobrotoxin.- C. Structure-Function Relationship in the Postsynaptic Neurotoxins. The Three-Dimensional Structure of Erabutoxin b as Prototype in both Long and Short Toxins.- I. Erabutoxin b and the Short Toxins: The Reactive Site.- II. Erabutoxin b and the Short Toxins: Nonreactive Site Regions.- III. Erabutoxin and the Long Toxins: Reactive Site.- IV. Erabutoxin and the Long Toxins: Nonreactive Site Regions.- V. Long and Short Toxins: Biochemical and Biological Differences.- VI. Erabutoxin b and the Short Toxin Series: Detailed Intramolecular Packing.- 1. ? Pleated Sheet and ? Turns.- 2. Intramolecular Interactions: Particularly Those Involving Invariant and Type-Conserved Residues.- a) Main Chain-Main Chain and Main Chain-Side Chain Hydrogen Bonds.- b) Side Chain-Side Chain Interactions.- D. Conclusions.- I. The Present View.- 1. Structure: General.- 2. Comparison of Short and Long Toxins.- 3. Structural and Functional Residues.- a) Structural Residues.- b) Functional Groupings.- c) Residues of Uncertain Role.- II. Future Studies-New Questions and Their Resolution.- References.- 7 The Evolution of Toxins Found in Snake Venoms.- A. Introduction.- I. The Toxin-Types of Snake Venoms.- II. Methods Used in Studying Protein Phylogenetics.- 1. Matrix Methods.- 2. Ancestor Sequence Method.- 3. Maximum Parsimony Method.- 4. Subjective Methods.- B. Historic Development of Snake Toxin Phylogenetics.- C. Current Views on the Evolution of Snake Toxins.- D. Future Possibilities.- References.- 8 Nerve Growth Factors in Snake Venoms.- A. Introduction.- B. Distribution.- C. Properties.- I. Elapidae.- 1. Naja naja.- 2. Other Elapids.- II. Crotalidae.- 1. Agkistrodon piscivorus.- 2. Crotalus adamanteus.- 3. Bothrops jararaca.- 4. Other Crotalids.- III. Viperidae.- 1. Vípera russellii.- 2. Other Viperids.- D. Comparison of Nerve Growth Factors.- I. Relationship of Venom NGFs.- 1. Intrafamily.- a) Elapidae.- b) Crotalidae.- c) Viperidae.- 2. Interfamily.- II. Relationship of Venom and Mouse NGFs.- E. Role of NGF in Snake Venom.- F. Concluding Remarks.- References.- 9 Metal and Nonprotein Constituents in Snake Venoms.- A. Introduction.- B. Inorganic Constituents.- I. Metal Content.- II. Nonmetal Inorganic Content.- C. Organic Constituents.- I. Lipids.- II. Carbohydrates.- III. Riboflavin.- IV. Nucleosides and Nucleotides.- V. Amino Acids and Peptides.- 1. Amino Acids.- 2. Peptides.- a) Structural Studies.- b) Physiologic Studies.- VI. Amines.- D. Summary.- References.- III: Pharmacology of Snake Venoms.- 10 The Action of Snake Venoms on Nerve and Muscle.- A. Introduction.- B. Pharmacokinetics of Snake Venoms.- I. Absorption.- II. Distribution.- 1. Elapid Venoms and Postsynaptic Toxins.- 2. Viperid and Crotalid Venoms.- 3. Distribution in the Central Nervous System.- III. Fate and Excretion.- C. Toxicity and Cause of Death.- I. Cobra Venoms.- 1. Toxicity.- 2. Symptoms.- 3. Cause of Respiratory Paralysis.- II. Krait Venoms.- III. Australian Snake Venoms.- IV. Other Elapid Venoms.- 1. Desert Cobra (Walterinnesia aegyptia) Venoms.- 2. Coral Snake (Micrurus) Venoms.- 3. Mamba (Dendroaspis) Venoms.- V. Sea Snake (Hydrophiidae) Venoms.- VI. Viperid and Crotalid Venoms.- D. Effects on Neuromuscular Transmission.- I. Introduction to Pharmacology of Neuromuscular Transmission.- II. Cobra Venoms and Cobra Neurotoxins.- 1. Whole Venom.- 2. Postsynaptic Toxins.- III. Krait (Bungarus) Venoms and Their Toxins.- 1. Formosan Krait (Bungarus multicinctus) Venom.- 2. Indian Krait (Bungarus caeruleus) Venom.- 3. Banded Krait (Bungarus fasciatus) Venom.- 4. ?-Bungarotoxin.- 5. ?-Bungarotoxin.- a) Electrophysiologic Study.- b) Ultrastructural Effects.- c) Kinetic Study and Mode of Action.- d) Specificity of Action.- e) Biochemical Study.- IV. Australian Snake Venoms and Their Toxins.- 1. Tiger Snake (Notechis scutatus) Venom ans Notexin.- 2. Taipan (Oxyuranus scutellatus) Venom and Taipoxin.- 3. Death Adder (Acanthophis antarcticus) and Copperhead (Denisonia superba) Venoms.- V. Other Elapid Venoms.- 1. Mamba (Dendroaspis) Venoms.- 2. Desert Cobra (Walterinnesia aegyptia) Venom.- 3. Coral Snake (Micrurus) Venoms.- VI. Sea Snake Venoms.- VII. Viperid and Crotalid Venoms.- 1. Rattlesnake Venoms.- 2. Crotoxin.- 3. Mojave Toxin.- VIII. Postsynaptic Toxins, Specificity and Reversibility of Action.- 1. Specificity and Reversibility.- 2. Comparison with D-Tubocurarine.- IX. Comparison of Presynaptic Toxins.- 1. Pharmacologic Considerations.- 2. The Relation with Phospholipase A.- 3. Presynaptic Toxins of Other Origins.- 4. Mutual Antagonism Between Presynaptic Toxins.- E. Effects on Skeletal Muscle.- I. Cobra, Mamba, and Coral Snake Venoms.- 1. Cardiotoxins - Membrane-Active Polypeptides.- a) Pharmacologic Effects.- b) Antagonism by Ca2+ and Other Cations.- c) Histologic Effects.- d) Concluding Remarks.- 2. Phospholipase A and Its Interaction with Cardiotoxin.- II. Krait Venoms.- III. Australian Elapid Venoms.- IV. Sea Snake Venoms.- V. Viperid and Crotalid Venoms.- 1. Whole Venoms and Phospholipase A.- 2. Crotamine and Related Basic Polypeptides.- F. Effects on Peripheral Nerve.- I. Effects on Ganglionic Transmission.- II. Effects on Axonal Conduction.- G. Effects on the Central Nervous System.- I. Central Effects After Systemic Application.- 1. Neuropathologic Effects.- 2. Pharmacologic Effects.- II. Effects when Applied Directly to the Central Nervous System.- References.- 11 The Use of Snake Toxins for the Study of the Acetylcholine Receptor and its Ion-Conductance Modulator.- A. Introduction.- B. Isolation and Radiolabeling of Neurotoxins.- C. Neurotoxins as Specific Labels for Nicotinic ACh Receptors.- I. Techniques Used for Detection of Binding.- II. Use in Identification and Localization of ACh Receptors.- III. Use in Purification and Characterization of Nicotinic ACh Receptors.- D. Utilization of Neurotoxins to Compare Junctional and Extrajunctional ACh Receptors.- E. Neurotoxins as a Tool for Studies of Drug-Receptor Interactions.- F. Use in Studies of the Ion Conductance Modulator of the ACh-Receptor.- G. Use of Neurotoxins in Myasthenia Gravis Research.- H. Conclusion.- References.- 12 Pharmacology of Phospholipase A2 from Snake Venoms.- A. Introduction.- I. Scope of Chapter and Prior Reviews.- II. Purification, Properties, Assays, and Inhibitors of PhA2.- III. Sources of Error in Interpreting PhA2 Data.- 1. Use of Impure Preparations of PhA2.- 2. Neglecting Effects of Hydrolytic Products.- 3. Failure to Quantitate Extent of Phospholipid Hydrolysis.- 4. Assumption that all Snake Venom Preparations of PhA2 are Similar.- 5. Conclusions.- B. Lethality of PhA2.- C. Actions of PhA2 on Bioelectrically Excitable Tissues.- I. Axons.- II. Synapses.- III. Muscles.- IV. Central Nervous System.- D. Release of Physiologically Active Compounds by PhA2.- E. Antimicrobial Properties of PhA2.- F. Effects of PhA2 on Metabolism.- G. Summary and Conclusions.- References.- 13 Hemolytic Effects of Snake Venoms.- A. Introduction.- B. Hemolysis in Envenomation.- I. Elapid Venoms.- II. Viperid and Crotalid Venoms.- C. Venom Factors Involved in the Hemolytic Process.- I. Phospholipase A.- II. The Direct Lytic Factor.- D. Nonmediated Effects of Phospholipase A and Direct Lytic Factor on the Red Cell Membrane.- I. Red Cell Membrane Structure and Function.- II. Action of Phospholipases on Red Cell Membrane Phospholipids.- 1. Nonlytic Phospholipid Degradation.- 2. Lytic Phospholipid Degradation.- III. Action of the Direct Lytic Factor on the Red Cell Membrane.- 1. Direct Hemolysis.- 2. Attachment to Membranes.- 3. Effects on Membrane Permeability and Transport.- IV. Synergistic Action of Phospholipase A and the Direct Lytic Factor.- V. Mode of Action of the Direct Lytic Factor.- VI. Sensitivity of Erythrocytes from Various Animal Species to Venom-Induced Hemolysis.- E. Mediated Effects of Venom Phospholipase A.- I. The Disk-Sphere Transformation.- 1. In Vitro Red Cell Shape Changes.- 2. In Vivo Red Cell Shape Changes.- II. The Indirect Hemolysis; Lytic Effects of Lysolecithin and Fatty Acids.- III. Effects of Serum Proteins on Phospholipase-Induced Hemolysis.- F. Hemolysis by a Cobra Venom Factor Acting Through the Complement System.- G. Concluding Remarks.- References.- 14 Hemorrhagic, Necrotizing and Edema-Forming Effects of Snake Venoms.- A. Introduction.- B. The Use of Weil-Defined Lesions in Experimental Animals to Specify and Determine Local Effects of Snake Venom.- C. Necrotizing Effect.- D. Edema-Forming Effect.- E. Hemorrhagic Effect.- I. Methods for Determining Hemorrhagic Activity.- 1. Skin Reaction.- 2. Lung Surface Reaction.- II. Distribution of Hemorrhagic Activity in Venoms of Crotalidae, Viperidae, and Elapidae.- III. Purification and Characterization of Hemorrhagic Principles.- 1. Purification and Characterization of HR 1.- a) Purification.- b) Properties.- 2. Purification and Characterization of HR 2.- a) Purification.- b) Properties.- IV. Dynamic Aspects of the Action of Hemorrhagic Principles on Microcirculation as Revealed by Cinematography.- V. Action of Hemorrhagic Principles on Smooth Muscles.- 1. Actions of Hemorrhagic Principles (HR 1 and HR 2) on Isolated Smooth Muscle Preparations.- 2. Mediators Released from Guinea-Pig Lungs and from Rat Peritoneal Cells by the Action of Hemorrhagic Principles (HRlandHR2).- VI. Mechanisms of Action of Hemorrhagic Principles.- 1. Effect on Vascular Permeability.- 2. Effect on Vessel Wall.- a) Effect on Vascular Endothelium.- b) Effect on Basement Membrane.- 3. Effect on the Hemostatic Mechanism.- VII. Involvement of an Endogenous or Exogenous Hemorrhagic Principle in General Physiological Mechanism of Hemorrhage A Suggestion from Venom Studies.- VIII. Antihemorrhagic Factor Present in the Sera of Snakes.- 1. Purification and Characterization of an Antihemorrhagic Factor from the Serum of Trimeresurus flavoviridis.- a) Purification.- b) Characterization.- c) Effects on the Hemorrhagic Activity of HR 1 and HR 2 and on the Lethal Toxicity of HR 1.- d) Inhibition of Hemorrhagic Activity of Venoms from Different Species of Snakes.- 2. Mechanism Involved in the Neutralization by the Serum of Vípera palestinae of a Toxic Fraction of Its Venom.- IX. Treatment with Specific Antivenin (Antiserum) and Prophylaxis with Toxoid (Vaccine) of Hemorrhagic Snake Venom Poisoning.- 1. Neutralization of Hemorrhagic Principles by Specific Antivenin (Antiserum).- 2. Prophylaxis of Envenomation with Toxoids (Vaccines) Prepared from Purified Hemorrhagic Principles.- F. Concluding Remarks.- References.- 15 Cardiovascular Effects of Snake Venoms.- Cardiovascular Effects of Crotalid and Viperid Venoms.- A. Hemodynamic Effects of Crotalid Venoms.- I. Rattlesnake (Crotalus) Venoms.- 1. C. horridus (Timber Rattlesnake) and C. atrox (Western Diamond-back Rattlesnake) Venoms.- 2. C. adamanteus (Eastern Diamond Rattlesnake) Venom.- 3. C. viridis helleri (Southern Pacific Rattlesnake) Venom.- 4. C. durissus terrificus (Tropical Rattlesnake) Venom.- 5. C. scutulatus (Mojave Rattlesnake) Venom and Mojave Toxin.- 6. Basic Protein Toxins from Rattlesnake Venoms.- II. Other Crotalid Venoms.- 1. Agkistrodon Venoms.- 2. Trimeresurus Venoms.- 3. Bothrops Venoms.- III. Thrombinlike Enzymes from Crotalid Venoms.- B. Mechanism of the Depressor Action of Crotalid Venoms.- I. Site of Action.- II. Venom Components Responsible for the Depressor Action.- C. Hemodynamic Effects of Viperid Venoms.- I. Russell's Viper (Vipera russellii) Venom.- II. Other Viper Venoms.- 1. Vipera ammodytes Venom.- 2. Vipera palestinae Venom.- 3. Echis carinatus and Echis coloratus Venoms.- 4. Bitis arietans Venom.- D. Mechanism of the Depressor Action of Viperid Venoms.- I. Mode of Hypotensive Action.- II. Venom Components Responsible for the Hypotensive Action.- Cardiovascular Effects of Elapid and Sea Snake Venoms.- A. Cobra (Naja) Venoms.- I. Action on the Heart.- II. Cardiotoxin and its Action on the Heart.- III. Hemodynamic Effects.- 1. Pressor Effect.- 2. Depressor Effect.- a) Analysis of the Initial Depressor Effect.- b) Venom Components Responsible for the Initial Depressor Effect.- B. Other Elapid Venoms.- I. Krait (Bungarus) Venoms.- II. Mamba (Dendroaspis) Venoms.- III. Coral Snake (Micrurus) Venoms.- IV. Australian Elapid Venoms.- C. Sea Snake Venoms.- Summary and Conclusions.- A. Crotalid and Viperid Venoms.- B. Elapid and Sea Snake Venoms.- References.- 16 Liberation of Pharmacologically Active Substances by Snake Venoms.- General Introduction.- A. Histamine.- I. Introduction.- II. Survey of the Histamine-Releasing Activity of Snake Venoms.- III. Mechanistic Aspects.- 1. Phospholipase A Activity and Histamine Release.- 2. Histamine Release by Snake Venom Components Other Than Phospholipase A.- IV. Contribution of Histamine Toward Toxic Effects of Snake Venoms.- B. 5-Hydroxytryptamine.- I. Survey of 5-Hydroxytryptamine-Releasing Activity of Snake Venoms.- II. Systemic Effects.- III. Local Effects.- C. Bradykinin.- I. Introduction.- II. Survey of the Kinin-Forming Capacity of Snake Venoms.- III. Mechanistic Aspects.- 1. Arginine Ester Hydrolase Activity and Kinin Release.- 2. Substrate Requirements.- 3. Kinin Peptides Released by Snake Venoms.- 4. Inhibition of Kinin-Releasing Activity.- IV. Contribution of Bradykinin Toward Systemic and Local Effects of Snake Venoms.- 1. Hypotension.- 2. Lethality.- 3. Increased Vascular Permeability and Pain.- 4. Potentiation of Bradykinin Effects.- D. Slow-Reacting Substances, Prostaglandins, and Lysophosphatides.- I. Background.- II. Mechanistic Aspect.- III. Sites of Formation.- 1. Tissues.- 2. Cells.- IV. Contribution Toward Toxic Effects of Venoms.- 1. Lysophosphatides.- 2. Prostaglandins.- E. Catecholamines.- Adrenaline.- F. Anaphylatoxin.- I. Background.- II. Contribution Toward Toxic Effects of Elapid Snake Venoms.- References.- 17 Snake Venoms as an Experimental Tool to Induce and Study Models of Microvessel Damage.- A. Introduction.- I. By Way of Speculating About Disease Models.- II. Venoms as Stores of Vasculotoxic Materials.- B. Morphology, Methodology, and Phenomenology of Venom-Induced Vessel Lesion.- I. Comparative Morphology of Lung and Cremaster Vessels.- 1. Capillaries.- 2. Arterioles and Venules.- II. Methology and Phenomenology of Vessel Lesions in Different Tissues.- 1. Pulmonary Vessels.- a) Canine Lung Surface Test.- b) Rodent Intrathoracic Test.- 2. Cremaster Vessels.- 3. Rat Paw Edema.- 4. Skin Vascular Lesions.- 5. Miscellaneous Vascular Beds.- C. Elapid Snake and Bee Venoms.- I. Morphologic Aspects of Elapid Venom Effects on Lung and Cremaster.- 1. Lung Effects.- 2. Cremaster Effects.- II. Pharmacologic Aspects.- 1. Individual Venom Components: Role of Various Polypeptides and Phospholipase A2.- 2. Pharmacologic Influences on Venom-Induced Vessel Injury.- a) Antihistamines.- b) Nonsteroid (Acidic) Anti-Inflammatory Drugs (NSAID).- c) Corticosteroids.- d) Protease Inhibitors.- e) Estrogens.- f) Flavonoids.- g) Polyphloretin Phosphate.- h) Heparin.- i) Cyclic Adenosine Monophosphate (cAMP).- 3. Rat Paw Edema and Permeability Increase Due to Elapid and Bee Venoms.- a) Rat Paw Edema.- b) Skin Vascular Permeability.- D. Crotalid Venoms and Enzymes Simulating Their Effects.- I. Morphologic Aspects of Crotalid Venom: Effects on Lung and Cremaster.- 1. Lung Effects.- 2. Cremaster Effects.- II. Pharmacologic Aspects.- 1. Similarities and Differences Between Effects of Some Crotalid Snake Venoms.- 2. Lung Effects of Collagenase and Other Proteolytic Enzymes.- III. Pharmacologic Influences on Crotalid Snake Venoms and Collagenase-Induced Hemorrhagic Effects.- 1. In Vitro Inactivation of Vasculotoxic Materials.- 2. Local Application of Putative Inhibitors to the Tissue.- 3. Intravenous Administration of Putative Inhibitors.- 4. Effects of Collagenase in the Rodent Intrathoracic Test.- IV. Effects of Different Enzymes on the Lung Surface Vessels.- V. Rat Paw Edema Due to Crotalid Snake Venoms.- VI. Rat Paw Edema and Skin Vascular Permeability Effects of Bacterial Collagenase.- VIL Increase in Skin Vascular Permeability Due to Crotalid Snake Venoms.- E. General Conclusions: Interrelationships Between Morphology and Function.- F. Speculations on the Significance of Venom-Induced Inflammation of Microvessels.- References.- 18 Snake Venoms and Blood Coagulation.- A. Blood Coagulation Mechanisms.- I. Blood Coagulation Nomenclature.- II. Three Basic Reactions of Blood Coagulation.- III. Formation of Fibrin.- IV. Cross Linking of Fibrin.- V. Formation of Thrombin.- VI. Formation of Autoprothrombin C (Factor Xa).- VII. General Procoagulant Effects.- VIII. Inhibition of Procoagulants.- 1. Nature of Anticoagulant Systems.- 2. Fibrinogen and Fibrin Degradation Products (FDP).- 3. Prothrombin Derivatives.- 4. Antithrombin III.- 5. Other Plasma Inhibitors.- 6. Thrombin.- IX. Clot Retraction.- X. Fibrinolytic System.- B. Physiology of Hemostasis.- C. Snake Venoms and Blood Coagulation.- I. Introductory Remarks.- II. Snake Venoms and Fibrinogen.- III. Formation of Fibrin.- IV. Thrombin-Like Enzymes and Cross-Linking of Fibrin.- V. Platelets and Thrombin-Like Enzymes.- VI. Animal and Clinical Work.- VII. Autoprothrombin II-A and Fibrinolysis.- VIII. Defibrination and Fibrinolysis with Acetylated Thrombin.- IX. Miscellaneous Aspects.- 1. Units of Activity.- 2. Elimination of Thrombin-Like Enzyme.- 3. Inhibitors.- 4. Hemostasis.- 5. Rheology.- 6. Metastasis Formation.- 7. Phospholipase A2.- X. Venoms and Direct Fibrinolysis.- XI. Snake Venoms and Thrombin Formation.- XII. Snake Venoms and Autoprothrombin C (Factor Xa) Formation.- XIII. Snake Venoms and Platelets.- 1. Platelet Membrane Structural Changes Induced by Phospholipase A and Direct Lytic Factor (DLF) of Snake Venoms.- 2. Platelet Aggregation Induced by Coagulant and Noncoagulant Venoms.- 3. Venom Inhibitors of Platelet Aggregation.- D. Overview.- References.- IV: Immunological and Clinical Aspects.- 19 Immunological Properties of Snake Venoms.- A. Introduction.- I. Definitions.- II. Historical Data.- B. Snake Venoms are a Mosaic of Antigens.- C. Stimulation of the Immune System by Venom Antigens.- I. General Remarks on Antivenom Sera.- II. Immunogenic Properties of Some Proteins Extracted from Snake Venoms.- III. Role of Adjuvant Substances.- IV. Other Examples of Immunogenicity of Proteins Extracted in a Pure Form from Snake Venoms.- V. Relationships Between Chemical Composition, Structure and Immunological Properties of Some Antigens of Snake Venoms.- 1. Chemical Modifications.- a) Influence of S-S Bridges.- b) Modification of Amino-Groups.- c) Modification of Histidyl Residues.- d) Modification of Tryptophanyl Residues.- e) Modification of Tyrosyl Residues.- f) The Problem of Aminoacid Residue Modifications.- 2. Immunological Analysis.- D. Nature of Antivenom Antibodies and Measurement of the Activity of Immune Sera.- E. Hypersensitivity to Snake Venoms.- F. Action of Snake Venoms on Cellular and Humoral Factors of Immunity.- References.- 20 Production and Standardization of Antivenin.- A. Introduction.- B. Antivenin Production.- I. The Animal.- II. The Antigens.- III. Immunization.- 1. New Horses.- 2. Immune Horses.- IV. Collection and Processing of Plasma.- C. Antivenin Standardization.- D. Conclusions.- E. List of Antivenin Producers.- References.- 21 Common Antigens in Snake Venoms.- A. Introduction.- B. Paraspecific Neutralization in Animals.- C. Demonstration of Common Antigens by Immunodiffusion.- D. Common Antigens in Venom and Snake Serum.- E. Discussion and Summary.- References.- 22 Snakes and the Complement System.- A. Introduction.- B. Early Complement Research.- C. Early Work on Snake Body Fluids and Complement.- D. Present State of Knowledge of the Complement System.- E. Modern Studies of the Interaction Between Snake Venom and Complement.- F. Epilog.- References.- 23 Vaccination Against Snake Bite Poisoning.- A. Historic Outlook.- B. Snake Venom Toxoids.- I. Habu Toxoids.- 1. DHTA Toxoid.- a) Preparation of the Toxoid.- b) Detoxification Tests.- c) Toxicity of the Toxoid.- d) Sterility Test.- e) Safety Test.- f) Immunogenicity Test.- 2. Crude Formalin Toxoid (CRF).- 3. Heat and Alcohol-Treated Formalin Toxoid (HAF).- a) Preparation of the Toxoid.- b) Immunogenicity of the Toxoid.- 4. Alcohol-Precipitated Formalin Toxoid (APF).- a) Purification and Detoxification of the Venom.- b) Immunogenicity of the Toxoid.- 5. Mixed Toxoid (MiF).- a) Preparation of MiF Toxoid.- b) Safety Test of MiF Toxoid.- c) Immunogenicity of the MiF and CRF Toxoids.- 6. Comparison of Antihemorrhagic, Antinectrotic and Antilethal Effect of APF, CRF, MiF, and DHTA Toxoids.- II. Toxoids from Venoms of Other Trimeresurus Species.- III. Toxoids from Venoms of Agkistrodon Species.- IV. Toxoids from Venoms of Other Viperidae Snakes.- V. Toxoid from Venoms of Elapidae Snakes.- 1. Toxoid from the Venom of Naja naja atra (Taiwan Cobra).- a) Preparation of the Toxoid.- b) Immunogenicity of the Toxoid.- c) Relationship Between Antilethal Antibody in the Blood of Immunized Rabbits and Resistance to Challenge with the Venom.- d) Reversion of Toxicity of the Toxoid.- 2. Toxoid from the Venom of Bungarus multicinctus.- 3. Toxoid from the Venom of Notechis scutatus.- C. Active Immunization.- I. Habu Toxoids.- 1. DHTA Toxoid.- a) Dosage and Interval of Injection of the Toxoid.- b) Reactions.- c) The Antivenin Level of Circulating Blood.- d) Clinical Analysis of the Habu Bites After the Immunization.- e) Hypersensitivity Acquired After Injection of the Toxoid.- 2. APF and MiF Toxoids.- a) Dosage and Intervals.- b) Reactions.- II. Tiger Snake Venom and Toxoid.- 1. Dosage and Intervals.- 2. Level of Circulating Antivenin.- 3. Reactions.- III. Indian Cobra (Naja naja) Venom.- 1. Dosage and Intervals.- 2. Antivenin Titer of Serum.- 3. Reactions.- 4. Effectiveness of the Vaccination.- D. Antigenic Quality of the Prophylactic Toxoid.- 1. Immunogenicity of the Toxoid.- 2. Detoxification and Immunogenicity of Toxoid.- 3. Differences in Antigenicity of Toxoid for Various Animal Species.- 4. Chemical Modification of Antigen.- E. Concluding Remarks.- References.- 24 Symptomatology, Pathology, and Treatment of the Bites of Elapid Snakes.- A. The Incidence of Envenomation.- B. Snakebite Wound.- I. The Wound.- II. Local Evidence of Envenomation.- 1. Most Elapids.- 2. Cobra.- C. Preparalytic Symptoms and Signs of Envenomation.- I. Those Common to Most Elapid Bites.- 1. Vomiting.- 2. Headache.- 3. Loss of Consciousness.- 4. Vasomotor Signs (Pallor, Sweating, Weak to Absent Pulse, Hypotension).- 5. Abdominal Pain.- II. Other Preparalytic Symptoms and Signs.- 1. Pain in Regional Lymph Nodes - Tenderness and Enlargement.- 2. Spitting, Vomiting, Coughing of Blood.- 3. The Passing of Blood-stained Urine.- 4. Other Nervous System Symptoms.- 5. Drowsiness.- 6. Allergic Reaction Following Snakebite.- 7. Cobra Venom Conjunctivitis.- D. Clinical Signs of Elapid Envenomation.- I. Muscle Paralysis.- 1. Clinical Picture.- 2. Duration of Muscle Paralysis.- II. Other Effects of Elapid Envenomation.- 1. Blood.- 2. Kidney.- 3. Heart and Blood Pressure.- III. Features of Envenomation from Different Elapid Snakes.- 1. Cobra.- 2. Krait.- 3. Mamba.- 4. Coral Snake.- E. Pathology.- I. Local Reaction.- II. Viscera.- III. Lymph Nodes.- IV. Muscles.- V. Post-Mortem Diagnosis.- F. The Treatment of Snakebite.- I. First-Aid Treatment.- II. Management of a Suspected Venomous Snakebite.- III. Definite Elapid Bite-No Evidence of Envenomation.- IV. Antivenene (AV).- 1. Dosage and Route of Administration.- 2. Method of Administration.- 3. Complications of Antivenene Therapy.- V. Other Modes of Treatment.- 1. Neostigmine.- 2. Corticosteroids.- 3. Intubation, Tracheostomy, IPPR, Intensive Care Nursing.- VI. Treatment of Local Wound (Cobra Bites).- References.- 25 Symptomatology, Pathology, and Treatment of the Bites of Sea Snakes.- A. Epidemiology.- I. Incidence of Sea Snakebite.- II. Incidence of Poisoning in Sea Snakebites.- III. Sex, Age, and Race of Victims.- IV. Occupation of Victims and Circumstances of Bites.- V. Site of the Bite, Repeated Bites, Other Factors.- VI. Village Treatment; Bite-Hospital Admission Interval.- VII. Conclusions on Epidemiology.- B. Medically Important Sea Snakes.- I. World Distribution.- II. Venom Yields and Lethal Toxicity.- C. Symptomatology of Sea Snakebite Poisoning.- I. Medical Literature.- II. Bite Marks: Early Symptoms.- III. Trivial Poisoning.- IV. Serious Poisoning.- V. Fatal Poisoning.- D. Diagnosis.- E. Prognosis.- F. Pathology.- I. Clinical Pathology.- II. Pathophysiology in Experimental Animals.- III. Pathophysiology in Man.- G. Treatment.- I. First-Aid Measures.- II. Medical Treatment.- 1. Supportive Treatment.- 2. Antivenom.- H. Summary.- References.- 26 Symptomatology, Pathology, and Treatment of the Bites of Viperid Snakes.- A. Introduction.- B. Incidence.- C. Symptomatology.- I. Natural History.- Case Report 1.- Case Report 2.- II. Review of Recent Literature.- III. Envenomation Caused by Other Genera of Viperid Snakes.- 1. Echis colorata.- 2. Atractaspis.- D. Prognosis and Sequela.- E. Pathology.- I. Gross Anatomy.- II. Histology.- III. Laboratory Examinations.- F. Pathogenesis of the Envenomation.- G. Treatment of Viper Bite.- H. Summary of Management of Snakebites.- References.- 27 The Clinical Problem of Crotalid Snake Venom Poisoning.- A. Introduction.- B. Identification.- C. Epidemiology.- D. Clinical Manifestations.- E. Laboratory Tests.- F. Treatment.- I. First Aid.- II. Medical Treatment.- References.- 28 Snake Venoms and Nephrotoxicity.- A. Introduction.- B. Renal Pathologic Changes.- I. Glomerular Lesions.- II. Vascular Lesions.- III. Tubulointerstitial Lesions.- IV. Cortical Necrosis.- C. Pathogenesis.- I. Glomerular Lesions.- 1. Direct Irritation by Snake Venom.- 2. Fibrin Deposition.- 3. Immunologic Reaction.- II. Vascular Lesions.- III. Renal Failure.- 1. Role of Hypotension.- 2. Role of Intravascular Coagulation.- 3. Role of Intravascular Hemolysis.- 4. Role of Myoglobinuria.- 5. Role of Arteritis.- 6. Role of Glomerular Lesions.- 7. Nephrotoxic Effect of the Venom.- D. Clinical Manifestations.- I. General Manifestations.- II. Renal Manifestations.- E. Treatment.- References.- Author Index.