I: Recent Developments of the Histamine Problem.- Section A: Pharmacological Actions.- 1. Cardiovascular Actions of Histamine.- I. Introduction.- II. Systemic Vascular Effects of Histamine.- A. Rat.- B. Guinea-Pig.- C. Rabbit.- D. Dog.- E. Cat.- F. Calf, Horse, and Sheep.- G. Man.- III. Cardiac Actions of Histamine.- A. Intact Animals.- 1. Inotropic Action.- 2. Chronotropic Action.- 3. Dromotropic Action.- 4. Cardiac Output.- B. Isolated Heart Preparations.- 1. Inotropic Action.- 2. Chronotropic Action.- 3. Dromotropic Action.- 4. Coronary Flow.- IV. Effects of Histamine on Regional Vasculatures.- A. Coronary.- B. Pulmonary Lung.- C. Splanchnic.- D. Liver-Portal.- E. Renal.- F. Musculo-Cutaneous.- G. Cerebral.- H. Miscellaneous.- V. Microcirculatory Actions of Histamine.- A. Direct In-Vivo Microcirculatory Actions of Histamine.- B. H1 Versus H2-Receptors in Microcirculation.- C. Effects of Histamine on Vascular Permeability and Endothelial Cells.- VI. Isolated Vascular Smooth Muscle and Histamine.- VII. Conclusions.- References.- 2. Histamine and Gastric Secretion.- I. Introduction.- II. Historical Review.- III. Physiologic Evidence.- A. Histidine Decarboxylase Activation.- B. Histamine Release and Gastric Secretion.- IV. H2-Receptor Antagonists: Gastric Secretion and the Role of Histamine.- V. Conclusions.- References.- Section B: Histamine Release.- 1. On the General Problem of the Release of Histamine.- I. Introduction.- II. The Noncytotoxic Nature of Histamine Secretion.- III. Histamine Release and Complement.- IV. The IgE Receptor.- V. Control Mechanisms of Histamine Release.- Cyclic Nucleotides and Histamine Release.- VI. Enhancers and Inhibitors of Histamine Release.- A. Enhancers of Histamine Release.- 1. Phosphatidyl Serine.- 2. Deuterium Oxide (D2O).- 3. Cholinergic Stimulation.- B. Inhibitors of Histamine Release.- 1. The Role of Calcium in Histamine Release.- 2. Desensitization.- VII. Histamine Release from Tissues and Platelets.- A. Histamine Release from Isolated Tissues and Organs.- B. Histamine Release from Platelets.- VIII. Concluding Remarks.- References.- 2. The Mechanism of Histamine Release from Mast Cells.- I. Introduction.- II. The Normal Mast Cells.- A. Morphology.- B. Contents.- III. The Degranulating Mast Cell.- A. Degranulating Agents.- B. Noncytotoxic Character of the Degranulation Process.- C. Electron-Microscopic Changes.- IV. Storage Properties of Basophil Granules.- A. Role of Heparin.- B. Role of Zinc.- C. Role of the Granule Protein-Heparin Complex.- V. Relationship Between Degranulation and Histamine Release.- References.- 3. Metabolic Changes in Mast Cells Associated with Histamine Release.- I. Energy Dependence of Anaphylactic Histamine Release.- II. Energy Metabolism of Mast Cells.- III. Changes in Mast Cell Respiration in Relation to Histamine Release.- IV. Changes in Glucose Metabolism in Mast Cells Associated with Histamine Release.- V. Changes in Adenosine Triphosphate Content of Mast Cells Associated with Histamine Release.- VI. Conclusion.- References.- Section C: Metabolism and Excretion of Histamine.- 1. Biogenesis of Histamine.- I. Introduction.- II. Methods for Determination of Histidine Decarboxylase Activity of Mammalian Tissues.- III. Histamine Formation in vitro.- IV. Histamine Formation in vivo.- V. Inhibition of Histamine Formation in vitro.- VI. Inhibition of Histamine Formation in vivo.- VII. Histidine Decarboxylase Activation and Deactivation; Role of Protein and RNA Synthesis.- VIII. Effect of Hormones on Histamine Formation.- IX. Histamine Formation in Brain.- X. Histamine Formation and Antihistamines.- XL Conclusion.- References.- 2. Histamine Metabolism and Excretion.- I. Histamine Metabolism in Tissues.- II. Changes in Histamine Metabolism in Tissues.- III. Histamine Metabolism and Excretion in Animals.- A. Rat.- B. Mouse.- C. Guinea Pig.- D. Hamster.- E. Rabbit.- F. Sheep.- G. Goat.- H. Pig.- I. Cow.- J. Horse.- K. Cat.- L. Toad, Tortoise, Terrapin.- IV. Changes in Histamine Metabolism and Excretion in Animals.- V. Histamine Metabolism in Human Tissues.- VI. Histamine Metabolism and Excretion in Man.- VII. Changes in Histamine Metabolism and Excretion in Man.- VIII. Blood Diseases.- IX. Allergy.- X. Burns.- XL Miscellaneous.- XII. Comments.- References.- 3. The Enzymatic Isotonic Assay of Histamine.- I. Introduction.- A. Principle of Isotope Derivative Dilution Assays.- B. Applications of Isotope Derivative Dilution Analysis in Biological Work.- C. Enzymatic Isotope Derivative Dilution Assays.- II. Double Isotope Assay (with ?-3H-Histamine as Internal Standard).- A. Principle.- B. Chemicals.- C. Preparation of ?-3H-(side-chain label)-Histamine.- D. Preparation of Histamine-N-Methyltransferase.- E. Storage and Preparation of Samples for Analysis.- F. Reagents and Stock Solutions (in Order of Use).- G. Incubation Procedure.- H. Extraction and Measurement of Labeled Methylhistamine.- I. Calculation.- J. Comments.- III. Single Isotope Microenzymatic Assay of Histamine.- A. Introduction.- B. Chemicals.- C. Reagents.- D. Procedure.- E. Calculation.- F. Comments.- IV. General Precautions to Be Observed with Enzymatic Assays of Histamine.- A. Specificity of Assay.- B. Assay Blanks and Precision of Assay.- C. Extraction Procedure and Use of Unlabeled Methylhistamine as Carrier.- D. Interference from Drugs and Tissue Constituents.- E. Importance of Purity of Labeled SAMe.- V. Use of Enzymatic Assay in Measurement of Histamine, L-Histidine, and Histamine-Metabolizing Enzymes in Tissues.- A. Histamine.- B. Assay of Histidine.- C. Histidine Decarboxylase.- D. Assay of Histamine-N-Methyltransferase.- References.- II: Chemistry and Structure-Activity Relationships of Synthetic Anti-Histaminics.- Section A: Chemistry of Anti-H1 Histamine Antagonists.- I. Introduction.- II. Chemical Types of H1Antihistaminic Drugs.- A. Early Work.- B. Ethylenediamines.- C. Tertiary-aminoalkyl Ethers.- D. 1,2-Diaryl-4-Aminobutenes.- E. 1,1-Diaryl-3-Aminopropenes.- F. 3-Amino-1-Aryl-1-(2-Pyridyl)Propanes(Pheniramines).- G. Phenothiazine Derivatives.- H. Further Tricyclic Derivatives.- I. Miscellaneous Types.- References.- Section B: Structure-Activity Relationships of H1 -Receptor Antagonists.- I. Introduction.- II. Compilation of the Most Important Structures with Anti-H1 Activity. Classification of the Structures Considered and Review of Measured Anti-H1 Activities.- III. Physical Properties and Anti-H1 Activity.- A. Qualitative Drug Design Based on the Physical Properties of Structures.- 1. Ionization Constants.- 2. Solubilities.- 3. Surface Properties.- 4. Spectral Data.- 5. Bond Stabilities.- 6. Charge Localizations.- 7. Dipole Moments.- B. Quantitative Design. The Hansch Approach.- 1. Introduction.- 2. The Hansch Approach Applied to a Series of Ring-Substituted Diphenhydramine Derivatives.- 3. The Hansch Approach Applied to a Series of Diphenhydramines with the Nitrogen Atom Included in a Ring System.- 4. The Activities of 1,1-Diaryl-3-Aminopropenes, and Some Related Compounds.- C. Some Features of Anti-H1 Activity Connected with Stereospecificity. Conformational Preferences.- 1. Anti-H1 Activities of Structures with an Optically Active Center.- 2. Anti-H1 Activities of Cis-Trans Isometric Structures.- 3. The Inclusion of Optically Active Structures into the Hansch Approach.- D. Integrated QSAR of H1-Receptor Antagonists.- IV. Conclusion.- References.- Section C: Chemistry and Structure-Activity Relationships of H2-Receptor Antagonists.- I. Introduction.- II. Development of H2-Receptor Antagonists.- A. The Search for an Antagonist.- B. Development of Burimamide.- C. Development of Metiamide.- D. Development of Cimetidine.- III. Chemical Constitution.- A. Introduction.- B. Burimamide and Metiamide.- C. Cimetidine.- IV. Chemical Mode of Action.- V. Pharmacokinetics.- A. Absorption and Distribution.- B. Metabolism and Elimination.- VI. Chemical Differentiation Between H1- and H2-Receptor Antagonists.- VII. Synthesis of Burimamide, Metiamide, and Cimetidine.- References.- III: Mechanism of Action of Antihistaminics.- Section A: Kinetics of Antagonist Action.- I. The Charniere Theory.- II. Applications of the Theory.- III. Appendix.- References.- Section B: Competitive and Noncompetitive Antagonism.- I. Introduction.- II. Material and Methods.- A. Test Organs.- B. Affinity and Intrinsic Activity Values.- C. Test Substances.- III. Results and Discussion.- A. Closer Inspection of the Intrinsic Activity and Affinity Values in Table 1.- 1. Intrinsic Activity and Affinity Values of Partial Agonists.- 2. pA2-Values Based on a Smaller Number of Animals than the Accompanying pD'2-Values, and Vice Versa.- B. The Interaction of Agonists and Competitive Antagonists with the Histamine Receptors; the Role of Additional Receptor Areas.- C. Competitive Antagonists and Their Affinity to the Metactoid Receptor.- 1. The pA2/pD'2-Ratios in the Histaminergic System.- 2. The pA2/pD'2-Ratios in the Cholinergic System.- 3. Comparison of the pD'2-Values in the Histaminergic and the Cholinergic System.- D. Influence of Some Molecular Modifications on the Affinity Values.- 1. The Influence of the Substitution of a Methyl Group to the Secondary N-Atom. The Rule of Pfeiffer.- 2. The Influence of the Presence or Absence of an N-Atom in the Ring in the Mimetic Moiety (Pyridyl or Phenyl Ring).- 3. The Influence of Para-Substitution of a Cl-Atom at the Phenyl Ring in the N-phenyl-N-benzyl-ethylamine Group.- 4. The Influence of Para-Substitution at the Phenyl Ring of N-(N'-phenyl-N'-benzyl-?-aminoethyl)-N-methyl-{2-(?-aminoethyl)-pyridine-}.- E. Quantitative Structure-Activity Correlations of 2-(?-aminoethyl)-pyridines.- F. Pitfalls in Structure-Activity Relationship Studies.- References.- Section C: Naturally Occuring Antihistaminics in Body Tissues.- I. Introduction.- II. Methods of Extraction of Antihistamine Activity.- General Considerations.- III. Methods of Assay of Natural Antihistamine Substance(s) (NAS).- Units of Activity.- IV. Estimation of Antihistamine Activity in Mammals.- V. Modifications of Amount of NAS Present in Tissues and Fluids.- A. Elevation of NAS.- B. Diminution of NAS.- VI. Mechanism of Action of NAS.- VII. Physical and Chemical Aspects of NAS.- A. Molecular Weight.- B. Solubility.- C. Stability.- D. Chemical Structure.- VIII. Role of NAS.- References.- IV: Pharmacological Actions of Antihistaminics.- Section A: Bioassay of Antihistaminic Action.- I. Introduction.- II. In Vitro Assays for Antihistaminics.- A. Assays on the Guinea Pig Ileum and Other Smooth Muscle Structures.- B. On the Schultz-Dale Reaction of the Sensitized Strips of the Guinea Pig Ileum and Uterus.- C. Bioassay of Antihistaminics on the Isolated Mammalian Heart.- D. Interrelations Between Antihistaminics and the Histamine(H1) Receptors.- III. In Vivo Assays of Antihistaminics.- A. Protection Against the Lethal Effects of Histamine.- B. Protection Against Asthma (Bronchospasm) Produced by Inhalation of a Histamine Aerosol.- C. Protection of Sensitized Guinea Pigs Submitted to the Challenging Dose of the Antigen.- D. Atropine-like Effects of Antihistaminics.- E. Local Anesthetic Action of Antihistaminics.- F. Action on the Skin Vessels and on Vascular Permeability.- IV. Conclusions.- References.- Section B: Antianaphylactic and Antiallergic Effects.- I. Introduction.- II. General Aspects of Antianaphylactic and Antiallergic Effects of Antihistaminics.- A. Receptor Specificity.- B. Potency of Antihistaminics.- C. Effect of Antihistaminics on Endogenously Released Histamine.- D. Nonspecific Effects of Antihistaminics.- III. Effects of Antihistaminics on Guinea Pig Anaphylaxis.- A. Systemic Shock.- 1. Antilethal Effects.- 2. Effect of Antihistaminics on Bronchospasm in vivo.- B. Action of Antihistaminics in Isolated Organs.- 1. Lung and Trachea.- 2. Isolated Gut.- 3. Uterus.- 4. Striated Muscle.- C. Heart Anaphylaxis.- D. Heart-Lung Preparation (HLP).- E. Adrenals and Adrenergic System.- 1. Role of Catecholamine Release in the Antianaphylactic Action of Antihistaminics on Acute Shock.- 2. Protracted Shock and Adrenal Glands.- F. Action of Antihistaminics on Antigen Aerosols.- G. Action of Antihistaminics on Cutaneous Anaphylaxis.- H. Forssman Shock.- I. Miscellaneous.- IV. Anaphylaxis in Dogs.- V. Anaphylaxis in Rabbits.- VI. Anaphylaxis in Rats.- VII. Anaphylaxis in Mice.- VIII. Other Species.- Summary and Conclusions.- References.- Section C: Antiinflammatory Effects.- I. Recent Work Involving H2-Receptors.- II. Effect of Antiinflammatory Drugs on the Interactions of Histamine with Other Possible Mediators of Inflammation.- III. Implications of Antiinflammatory Drugs for Elucidating Possible Roles of Histamine.- A. In Anaphylactic Shock.- B. In Allergy.- C. Responses of Tracheal Muscle.- IV. Inflammations in Which Antihistaminics Have Little or No Effect 510 V. Evidence from Depletion Experiments.- References.- V: Absorption, Distribution, Metabolism, and Elimination of Antihistamines.- I. Early Studies of Antihistamine Distribution, Excretion, and Metabolism.- II. Diphenhydramine and Orphenadrine.- III. Tripelennamine Metabolism.- IV. Cyclizine, Chlorcyclizine, and Related Compounds.- V. Chlorpheniramine and Brompheniramine.- VI. Chlorphenesin, Chlorphenesin Carbamate, and Related Phenoxy Propanediols.- VII. Perazine, Prochlorperazine, Trifluperazine, and Fluphenazine.- VIII. Promethazine, Chlorpromazine, and Related Compounds.- IX. Cyproheptadine, Amitriptyline, Nortriptyline, and Protriptyline.- X. Doxepin.- XL Hepzidine.- XII. Drug Metabolism and Enzyme Induction.- XIII. H2 Histamine Antagonists.- References.- VI: Therapeutic Action of Anti-Histaminics.- Section A: Antihistaminics as Central Nervous System Depressants.- I. Introduction.- II. Laboratory Studies.- A. Behavioral Studies.- B. Drug Interaction Studies.- C. EEG Studies.- III. Clinical Studies.- A. Ethylenediamine Agents.- B. Alkylamine Agents.- C. Piperazine Agents.- D. Phenothiazine Agents.- E. Aminoalkyl Ether Agents.- IV. Mechanism of Action.- References.- Section B. Circulatory Shock, Histamine and Antihistamines: Therapeutic Aspects.- I. Introduction.- II. Vasoactive Agents: Use and Misuse in Low-Flow States.- III. Failure of Peripheral Vascular-Homeostatic Mechanisms.- IV. Vasoactive Mediators in Circulatory Shock.- V. Is Histamine the Mediator of the Shock Syndrome?.- VI. Plasma Histamine Levels in Man and Animals in Shock.- A. Hemorrhage.- B. Trauma.- C. Endotoxemia-Sepsis.- D. Burns-Scalding.- E. Anaphylactic Shock.- VII. Influence of Antihistamines on Survival after Circulatory Shock.- A. Histamine Shock.- B. Hemorrhage.- C. Trauma.- D. Endotoxemia-Sepsis.- E. Burns-Scalding.- F. Anaphylactic Shock.- VIII. Conclusions and Future Outlook for Antihistamine Therapy in Circulatory Shock and Low-Flow States.- References.- Author Index.