Main description:

Fever has always been recognised as the major sign of infectious disease as well as being associated with other illnesses. The suggestion of publishing a volume dedicated exclusively to the subject of fever in the Handbook of Experimental Pharmacology series was one that greatly appealed to me, and I felt very honoured when I was invited to edit it. The first ideas about this volume were conceived in the latter part of 1977 and by the middle of 1978 the first authors had been approached. As is usual with such publications, by the time the first manuscripts were beginning to arrive in the late spring of 1979 there were still a few chapters for which authors had not yet been found. Finally by the end of 1981 the volume was complete. Because of the span of time over which the chapters were written, some refer to more recent work than others; however, I do not feel that this detracts from the overall contribution of all the chapters.

Contents:

1 Body Heat.- 2 Fever and its Role in Disease: Rationale for Antipyretics.- A. Fever.- B. The Role of Fever in Disease.- C. Antipyretic Drugs.- D. Effects of Antipyresis on Survival.- E. Clinical Indications and Contraindications for Antipyretic Therapy.- References.- 3 Thermoregulation: Its Change During Infection with Endotoxin-Producing Micro-organisms.- A. Introduction.- B. The Elevated Set-Point Concept of Fever.- C. The Pyrogens.- I. Bacterial Endotoxins.- II. Endogenous (Leucocyte) Pyrogens.- III. The Prostaglandins.- D. Pyrogen Action.- I. Points of Action in the Central Nervous System.- II. Effects on the Electrical Activities of Hypothalamic Neurones.- E. Areas of Current Concern and Doubt.- I. More than One Central Point of Action of Pyrogens?.- II. The Biphasic Pattern of Experimentally Induced Fever: Two Causative Factors?.- III. The Pyrogenic Metabolites of Arachidonic Acid.- IV. Are Pyrogens Only Pyrogens?.- V. Is Fever of Physiological Benefit?.- F. Mechanisms of Thermoregulation.- I. The Set-Point Machinery: Theory.- II. The Antiquity of Homeostasis and of Pyrogen Responsiveness.- III. The Pattern of Neural Connections.- G. Models for Thermoregulation.- I. Point (or Points) of Action of Pyrogens.- II. Neuronal Model of Central Thermoregulatory Connections in Sheep.- III. Point of Action of Bacterial Endotoxin in Sheep.- IV. Neuronal Theory of Fever Induction.- H. Thermoregulatory Agents.- I. Central Nervous 5HT.- II. Central Nervous Norepinephrine.- III. The Central Thermoregulatory Effects of ACh.- J. Other Set-Point Theories.- I. The Monoamine Balance Set-Point Theory.- II. The Ionic Balance Set-Point Theory.- K. Concluding Comments.- I. The Independence of Fever from the Influence of Ambient Temperature.- II. The Upper Limit to the Febrile Response.- III. More than One Pathway from Infection to Fever?.- References.- 4 Exogenous Pyrogens.- A. Introduction.- I. General Considerations.- B. Viruses.- I. Experimental Fevers with Viruses.- II. Interferon.- C. Gram-Positive Organisms.- I. Intact Organisms.- II. Extracellular Products.- III. Cell Wall Components.- D. Gram-Negative Bacteria.- I. Cell Wall Structure.- II. Pyrogenicity of LPS.- III. LPS Fever and EP Production.- IV. LPS Structure and Ability to Produce Fever.- V. Lipid A and Pyrogenicity.- VI. Pyrogenic Tolerance to LPS.- E. Mycobacteria.- I. Febrile Reactions of BCG-Sensitized Animals.- II. Release of EP from Cells Incubated with Tuberculin.- F. Fungi.- I. Pyrogenicity of Fungal Cells.- II. Fever from Fungal Products.- G. Non-Microbial Antigens.- I. Antibody-Mediated Fever.- II. Cell-Mediated Immune Fever.- H. Pyrogenic Steroids.- I. Fever in Humans.- II. Pyrogenic Steroid-Induced EP.- J. Miscellaneous Exogenous Pyrogens.- I. Polynucleotides.- II. Colchicine and Vinblastine.- III. Bleomycin.- IV. Synthetic Adjuvants.- References.- 5 Endogenous Pyrogens.- A. Introduction.- B. Nomenclature.- C. Assay of Endogenous Pyrogen.- D. Sources of LP.- I. Cells Capable of Pyrogen Release.- II. Animal Species Releasing EP.- E. Cellular Events.- F. Isolation and Characterization of EP.- I. Methods for Purification.- II. Heterogeneity of EP.- References.- 6 Role of Central Neurotransmitters in Fever.- A. Introduction.- B. Noradrenaline.- I. Depleting Agents.- II. Sympathomimetic Agents and Monoamine Oxidase Inhibitors.- III. Adrenoceptor Antagonists.- IV. Brain Catecholamine Levels.- V. Conclusion.- C. 5-Hydroxytryptamine.- I. Depleting Agents.- II. 5-Hydroxytryptamine Agonists and Uptake Inhibitors.- III. Indoleamine Antagonists.- IV. Brain 5-Hydroxytryptamine Levels and Turnover.- V. Conclusion.- D. Acetylcholine.- I. Cholinergic Antagonists.- II. Cholinomimetics and Anticholinesterases.- III. Conclusion.- E. Other Amines.- I. Dopamine.- II. ?-Aminobutyric Acid.- III. Histamine and Taurine.- F. Peptides.- I. Kinins.- II. Thyroid-Releasing Hormone.- III. Opioids.- G. Conclusion.- References.- 7 The Role of Ions in Thermoregulation and Fever.- A. Introduction.- B. Systemic Effects of Altered Ion Levels.- C. Action of Cations in the Cerebral Ventricles.- D. Action of Cations on the Hypothalamus.- I. Anatomical Localization of Ion-Induced Temperature Changes.- II. Specificity of Cation Actions.- E. Exercise, Cations, and Temperature Set-Point.- I. Hypothalamic Na+:Ca2+Ratio and Exercise.- F. Fever, Na+:Ca2+ Ratio, and Set-Point Shift.- I. In Vivo Cation Activity in the Diencephalon.- II. Antipyresis and Na+:Ca2+Efflux.- G. Critique of the Ionic Set-Point Mechanism for Body Temperature.- I. Experimental Evidence for the Ionic Set-Point Theory.- II. Primate Model of Temperature Control.- References.- 8 Electrophysiology of the Anterior Hypothalamus: Thermoregulation and Fever.- A. Introduction.- B. Microelectrode Recording Techniques.- I. Single-Unit Recordings.- II. Functional Characterization of Neurones.- 1. Physiological Stimuli.- 2. Electrical Stimuli.- 3. Pharmacological Stimuli.- III. In Vitro Recording.- IV. Data Analysis.- 1. Mean Firing Frequency and Thermosensitivity.- 2. Patterns of Neuronal Discharge.- V. Critique of Microelectrophysiology.- 1. Non-Random Selection of Neuronal Population.- 2. Lack of Positive Functional Characterization.- C. Thermosensitivity of PO/AH Neurones.- I. Thermoresponsiveness.- 1. Proportions of Thermosensitive Cells.- 2. Ratio of Warm-to Cool-Sensitive Cells.- II. Detectors Versus Interneurones.- 1. Thermal Response Form.- 2. Extrahypothalamic Inputs.- 3. Firing Pattern Analysis.- III. In Vitro Recording of PO/AH Activity.- D. Pyrogenic and Antipyretic Actions.- I. Pyrogens and Antipyretics.- 1. Pyrogenic Agents.- 2. Antipyretics.- II. Electrophysiology of Pyrogen Action.- 1. Bacterial and Leucocyte Pyrogens.- 2. Prostaglandins.- 3. Pyrogen Action on Peripheral Receptors.- III. Electrophysiology of Antipyretic Action.- E. Summary.- References.- 9 Cyclic Nucleotides and Fever.- A. Introduction.- B. Temperature Responses to Cyclic AMP in Different Species.- I. Mice.- II. Rats.- III. Rabbits.- IV. Cats.- V. Dogs.- VI. Primates.- VII. Birds.- C. Enzymes Related to Cyclic AMP.- I. Adenylate Cyclase.- 1. Activators of Adenylate Cyclase.- 2. Inhibitors of Adenylate Cyclase.- II. Cyclic Nucleotide Phosphodiesterase.- 1. Activators of Cyclic Nucleotide Phosphodiesterase.- 2. Inhibitors of Cyclic Nucleotide Phosphodiesterase.- D. Endogenous Cyclic AMP in Fever.- I. Cyclic AMP in Brain Tissue.- II. Cyclic AMP in Cerebrospinal Fluid.- E. Cyclic GMP in Fever.- F. Summary.- References.- 10 Prostaglandins in Fever and the Mode of Action of Antipyretic Drugs.- A. Introduction.- B. Temperature Responses to Prostaglandins.- I. Cats.- 1. Prostaglandins E1 and E2.- 2. Prostaglandins Fl? and F2?.- 3. Prostaglandin A1.- 4. Prostaglandin D2.- 5. Environmental Temperature and PGE1 Response.- II. Rabbits.- III. Sheep.- 1. Adult Sheep.- 2. New-born Lambs.- IV. Rats.- V. Mice.- VI. Guinea-pigs.- VII. Monkeys.- VIII. Man.- IX. Monotremes.- X. Birds.- 1. Adult Chickens.- 2. Chicks.- XI. Miscellaneous Species.- C. Prostacyclin.- D. Prostaglandin Endoperoxide Analogues.- E. Brain Trauma and Prostaglandin Synthesis.- F. Endogenous Pyrogen and Prostaglandin Synthesis In Vitro.- G. Release of Prostaglandins by Pyrogens.- I. Release of Prostaglandin in the CNS by Bacterial Pyrogen.- 1. Prostaglandins in Cat Cerebrospinal Fluid.- 2. Prostaglandins in Rabbit Cerebrospinal Fluid.- 3. Prostaglandins in Human Cerebrospinal Fluid.- II. Release of Prostaglandins by Endogeneous Pyrogen.- 1. Cats.- 2. Rabbits.- III. Peripheral Actions of Antipyretics.- H. Antipyretics and Prostaglandin Synthesis.- I. Action on Prostaglandin Fever.- II. Action on Prostaglandin Release During Endotoxin and Endogenous Pyrogen Fever.- III. Antagonism of Sodium Arachidonate Hyperthermia by Antipyretics.- J. Interactions Between Prostaglandins and Endotoxins.- I. Hypothalamic Destruction.- II. Inhibition of Prostaglandin Breakdown.- K. Effects of Prostaglandins on Neuronal Activity in the PO/AH.- L. Prostaglandin Antagonists.- M. Prostaglandins and Thermoregulation.- N. Prostaglandins and Cyclic Nucleotides.- I. Cyclic GMP.- II. Cyclic AMP.- 1. Mice.- 2. Rats.- 3. Monkeys.- 4. Cats.- 5. Rabbits.- O. Non-specific Febrile Response.- P. Sodium Fever.- Q. Discussion.- References.- 11 Protein Synthesis and Fever.- A. Introduction.- B. Experimental Evidence.- C. Conclusions.- References.- 12 The Chemistry of the Non-Steroidal Antipyretic Agents: Structure-Activity Relationships.- A. Introduction.- B. Receptor Models for Antipyretic and Anti-Inflammatory Actions.- C. Antipyretic Assay Methods.- D. Structure-Activity Relationships.- I. Enolic Acids.- II. Salicylic Acid and Related Compounds.- III. N-Arylanthranilic Acids.- IV. Aryl- and Heteroarylalkanoic Acids and Related Compounds.- 1. Substituted Arylalkanoic Acids.- 2. Alkyl- or Aryloxyarylalkanoic Acids and Related Compounds.- 3. Indanecarboxylic Acids and Related Compounds.- 4. Aroylarylalkanoic Acids and Related Compounds.- 5. Indoleacetic Acids and Analogues.- 6. Polycycloaromatic Alkanoic Acids.- V. Non-Acidic Compounds.- VI. Derivatives of Aniline and Aminophenol.- VII. Compounds of Natural Origin.- E. Conclusions.- References.- 13 Therapeutic Agents Affecting Body Temperature.- A. Introduction.- B. Effects of General Anaesthetics, Barbiturates, Narcotic Analgesics and Phenothiazines on Thermoregulation in Mammalian Species Other than Humans.- I. Effects on Body Temperature.- 1. General Anaesthetics and Barbiturates.- 2. Narcotic Analgesics.- 3. Phenothiazines.- II. Sites of Action.- 1. General Anaesthetics and Barbiturates.- 2. Morphine.- 3. Chlorpromazine.- III. Effects on Heat Gain and Heat Loss Mechanisms.- 1. General Anaesthetics and Barbiturates.- 2. Morphine.- 3. Phenothiazines.- IV. Neuropharmacology.- 1. General Anaesthetics and Barbiturates.- 2. Narcotic Analgesics.- 3. Phenothiazines.- V. Effects of Repeated Administration.- 1. Barbiturates and Ethanol.- 2. Narcotic Analgesics.- 3. Phenothiazines.- VI. Drug Interactions Producing Hyperthermia.- 1. Narcotic Analgesics.- 2. Chlorpromazine.- VII. Effects of Methionine Enkephalin and ?-Endorphin on Thermoregulation.- C. Effects of General Anaesthetics, Barbiturates, Narcotic Analgesics and Phenothiazines on Human Thermoregulation.- I. General Anaesthetics and Barbiturates.- II. Narcotic Analgesics.- 1. Single and Repeated Administration.- 2. Drug Interactions.- III. Phenothiazines.- D. Concluding Summary.- References.- 14 Capsaicin Type Pungent Agents Producing Pyrexia.- A. Introduction.- B. Historical Background.- C. Chemical Structure.- I. Natural Pungent Substances.- 1. Capsaicin.- 2. Piperine and Chavicine.- 3. Zingerone and Other Natural Pungent Agents.- II. Synthetic Congeners.- D. Heat Loss Responses Produced by Pungent Agents.- I. Effects on the Mouse.- II. Effects on the Rat.- III. Effects on the Guinea-pig.- IV. Effects on Other Animal Species.- V. Effects on Human Subjects.- E. Long-Term Thermoregulatory Changes Induced by Pungent Agents.- I. Desensitization to Pungent Agents by Capsaicin.- 1. Desensitization of the Rat.- 2. Desensitization of Other Animal Species.- II. Impairment in Thermoregulation After Capsaicin Desensitization.- 1. Thermoregulation in Cool, Cold, and Thermoneutral Environments.- 2. Thermoregulation at High Ambient Temperatures.- III. Structure-Activity Relationship.- F. Interaction with Fever, Drugs, and Neurotransmitters.- I. Interaction with the Effects of Pyrogens and Antipyretics.- II. Interactions with Neurotransmitters and Drugs.- G. Action of Capsaicin on Hypothalamic Warm-Sensors.- I. Effect of Intrahypothalamic Injection of Capsaicin.- II. Action on Hypothalamic Thermosensitive Neural Responses.- III. Ultrastructural and Biochemical Changes in the PO/AH Induced by Capsaicin.- H. Action of Pungent Agents on Sensory Receptors.- I. Capsaicin Desensitization and Sensation.- II. Electrophysiological Recordings from Exteroceptive Nerves.- III. Effects on Interoceptors.- 1. Vagal Interoceptors.- 2. Non-Vagal Pressor Chemoreflexes.- IV. Local Efferent Function of Capsaicin-Sensitive Sensory Nerve Endings.- 1. Skin and Exteroceptive Mucous Membranes.- 2. Internal Organs.- V. Concept of Sensory Neurone Blocking Effect of Pungent Acylamides.- 1. Neurone-Selective Site of Action.- 2. Mode of Action at the Neural Level.- 3. Structure-Activity Relationship.- J. Concluding Remarks.- References.- 15 The Pathophysiology of Fever in the Neonate.- A. Introduction.- B. Characteristics of Temperature Regulation in the Newborn.- I. Heat Production.- II. Heat Loss.- III. "Normal" Body Temperature.- IV. Immaturity and Malnutrition.- C. Central Mechanisms of Body Temperature Control.- I. Central Thermosensitivity.- II. Thermoregulatory Effects Evoked by Centrally Applied Monoamines.- D. Fever in the Human Neonate.- I. Definition.- II. Occurrence of Fever and/or Changes in Body Temperature During Infections.- E. Experimental Fever in Newborn Animals.- I. Characteristics of Experimental Neonatal Fever.- II. Differences Between Adult and Neonatal Febrile Responses.- F. Reasons for Differences Between Neonatal and Adult Febrile Responses.- I. Surface/Weight Ratio of the Body.- II. Ability to Produce Endogenous Pyrogen.- III. Role of Central Mediatory/Modulatory Substances.- 1. Prostaglandins.- 2. Serotonin.- 3. Noradrenaline.- 4. Other Factors.- 5. Similarities of Fever Mediation in Newborn and Adult Animals.- IV. Fever as an Abnormal Drive.- V. Relation Between Responsiveness to Thermal and Pyrogenic Stimuli.- VI. Relationship of Factors Influencing Neonatal Febrile Response.- G. Concluding Remarks.- I. Human Applications.- II. Definition of Fever.- III. Set-Point Change in Fever.- References.- 16 The Treatment of Fever from a Clinical Viewpoint.- A. Introduction.- B. The Treatment of Uncomplicated Fever.- C. The Treatment of Hyperpyrexia.- D. The Treatment of Prolonged Fevers.- E. The Treatment of Fever in High-Risk Patients.- I. Children with Febrile Seizures.- II. Patients with Head Injury.- III. Patients with Severe Mental Disorder.- IV. Patients with a Compromised Cardiovascular System.- V. Pregnant Women.- F. The Treatment of Hyperthermias.- I. Overinsulation.- II. Metabolic Disorders.- III. Drug-Induced Hyperthermia.- IV. Drug Hypersensitivity.- V. Heat Stroke Syndromes.- References.- 17 Malignant Hyperthermia: A Review.- A. Introduction.- B. History.- C. Epidemiology.- I. Previous Anaesthetics.- II. Incidence.- III. Sex and Age.- IV. Geographical Distribution and Racial Incidence.- V. Species.- VI. Heredity.- VII. Triggering Factors.- 1. Drugs.- 2. Stress.- 3. Diet.- 4. Climate.- 5. Elevated Serum Calcium.- D. The Acute Reactions.- I. Clinical Appearance.- II. Laboratory Changes.- III. Late Complications.- IV. Post Mortem Examination.- V. Prognosis.- VI. Differential Diagnosis.- E. Aetiology and Pathophysiology of Rigid MH.- I. Aetiology.- 1. Defective Calcium Uptake into, Binding by and/or Release from the Sarcoplasmic Reticulum.- 2. Defective Calcium Uptake into, Binding by and/or Release from the Mitochondria.- 3. Passive Diffusion of Extracellular Fluid Calcium Across a Defective Sarcolemma into the Myoplasm or Release of Bound Calcium from the Sarcolemma to the Myoplasm.- 4. Exaggerated Catecholamine Innervation.- II. Pathophysiology.- III. Malignant Hyperthermia - Widespread Membrane Defect.- IV. Miscellaneous Observations on the Aetiology of MH.- F. Preanaesthetic Diagnosis of MH.- I. Skeletal Muscle Studies.- 1. Signs and Symptoms of Musculoskeletal System.- 2. Electromyography.- 3. Serum Creatine Kinase Elevations.- 4. Serum Pyrophosphate.- 5. Skeletal Muscle Biopsy.- 6. Caffeine and Halothane Contracture Tests.- 7. Skinned Fibre Test.- 8. Halothane-Induced Contracture of Thin Muscle Sections.- 9. ATP Depletion Test.- II. Microscopy.- III. Heart Muscle Studies.- 1. Clinical Features.- 2. Electrocardiograms.- 3. Echocardiogram s.- 4. Myocardial Scanning with Thallium-201 (Rest and Exercise).- 5. Cardiac Catheterization and Angiography.- 6. Heart Muscle Biopsy.- IV. Extramuscular Nerves.- V. Platelets.- VI. Red Blood Cells.- VII. Endocrines.- VIII. Bone and Appendages.- IX. Miscellaneous.- G. Management of Inadvertent Fulminant Malignant Hyperthermia Reactions.- I. Stop Triggering Agents.- II. Lower Body Temperature.- III. Correct Blood Gases.- 1. Oxygen and Carbon Dioxide Tensions.- 2. Base Deficit.- IV. Lower Myoplasmic Calcium.- 1. Dantrolene.- 2. Procaine HC1 and Procaine Amide.- 3. Verapamil.- 4. Diltiazem.- V. Correct Abnormal Serum Potassium Levels.- VI. Control Arrhythmias.- VII. Stabilize Membranes.- VIII. Administer Drugs Which Exert Osmotic Force.- IX. Use Drugs of Supportive Value in the Therapy of MH Reactions: Narcotics, Barbiturates and Antipyretics.- X. Treat Acute Consumption Coagulopathy.- XI. Avoid Drugs Contraindicated During MH Reactions.- 1. Lidocaine.- 2. Cardiac Glycosides.- 3. Calcium Salts.- 4. Sympathomimetics.- 5. Parasympatholytics.- XII. Prevent Endogenous Catecholamine Release.- XIII. Monitoring.- H. Summary.- References.- 18 Febrile Convulsions.- A. Introduction.- B. Definitions: Tautology and Bogus Dichotomy.- C. Difficulties in Definition.- D. Cerebral Pathology.- I. Acute.- II. Chronic.- E. Mechanisms of Febrile Convulsions.- I. Epileptic Seizure Mechanism.- II. Anoxic Seizure Mechanism.- III. Combined Anoxic and Epileptic Mechanism.- F. Ocular Compression Study of Febrile Convulsion Phenotypes and Genotypes.- I. Syncope: Relation to Previous Febrile Convulsions.- II. Febrile Convulsion Trial.- III. Pertussis Immunization Convulsions.- IV. Genetic Analysis: Febrile Convulsions and/or Reflex Anoxic Seizures.- V. Clinical Example: Genetic Anoxic Seizures, Syncope, and Febrile Convulsions.- VI. Summary of Results from Ocular Compression Studies.- G. Genetics.- H. Brain Damage from Febrile Convulsions.- J. Prophylactic Drug Therapy of Febrile Convulsions.- K. Special Cases: Familial Dysautonomia and Down's Syndrome.- L. New Pharmacological Aspects of Febrile Convulsions.- M. Hypotheses.- References.- 19 The Pyrogenic Responses of Non-mammalian Vertebrates.- A. Thermoregulation in Non-mammalian Vertebrates.- B. Febrile Responses of Birds.- C. Febrile Responses of Reptiles.- D. Febrile Responses of Amphibians.- E. Febrile Responses of Fishes.- F. Pyretic and Antipyretic Agents.- I. Bacterial Pyrogens.- II. Endogenous Leucocytic Pyrogen.- III. Prostaglandins.- IV. Antipyretics.- V. Parietalectomy.- VI. Hormones.- VII. Pesticides.- 1. Organochlorines.- 2. Organophosphates.- 3. Other Pesticides.- VIII. Heavy Metals and Their Salts.- IX. Inorganic Ions (Salinity).- X. Nutritive Substances.- XI. Other Substances Affecting Thermoregulation.- G. Survival Value of Fever in Non-mammalian Vertebrates.- H. Summary of Agents Found to Induce Fever in Non-mammalian Vertebrates.- J. Summary of Antipyretics Found to Block Fever in Non-mammalian Vertebrates.- References.- 20 The Pyrogenic Responses of Invertebrates.- A. Thermoregulatory Responses of Invertebrates.- B. Febrile Responses of Invertebrates.- C. Doses and Routes of Administration.- D. Similarities of Febrile Responses of Vertebrates and Invertebrates.