Table Of ContentHandbook of
Experimental Pharmacology
Continuation of Handbuch der experimentellen Pharmakologie
Vol. 60
Editorial Board
G. V. R. Born, London· A. Farah, Rensselaer, New York
H. Herken, Berlin' A. D. Welch, Memphis, Tennessee
Advisory Board
S. Ebashi· E. G. Erdos' V Erspamer' U. S. von Euler· W S. Feldberg
G. B. Koelle' M. Rocha e Silva' J. R. Vane' P. G. Waser
Pyretics and Antipyretics
Contributors
C. G. Van Arman· D.A. 1. Armstrong· 1. Bligh· B. A. Britt
M. E. Casterlin . K. E. Cooper' B. Cox' M.1. Dascombe
C. A. Dinarello . 1. S. Eisenman· G. W Gander· N. W Kasting
D.H. Kim· T.F. Lee' A.S. Milton' R.D. Myers' C. Ounsted
R. G. Pertwee . W W Reynolds' V. K. Sawhney
J. B. P. Stephenson' M. Szekely· Z. Szelenyi . J. Szolcsanyi
W. L. Veale' S. M. Wolff
Editor
A. S. Milton
Springer-Verlag Berlin Heidelberg New York 1982
Professor ANTHONY S. MILTON
University of Aberdeen, Marischal College
Department of Pharmacology
Aberdeen AB91AS, Scotland, Great Britain
With 82 Figures
ISBN-13: 978 -3-642-68571-2 e-ISBN-13 : 978 -3-642-68569-9
DOl: 10.1007/978 -3-642-68569-9
Library of Congress Cataloging in Publication Data. Main entry under title:
Pyretics and antipyretics. (Handbook of experimental pharmacology; v. 60) Includes bibliographies and index.
I. Fever - Chemotherapy. 2. Antipyretics. 3. Pyrogens - Physiological effect. 4. Body temperature - Regulation.
I. Van Arman, C. G. II. Milton A. S. (Anthony Stuart), 1934-. III. Series.
[DNLM: I. Body temperature regulation - Drug effects. 2. Pyrogens. 3. Fever - Drug therapy. 4. Analgesics,
Anti-inflammatory. WI HA5IL v. 60/WB 152 P998] QP905.H3 vol. 60 [RB129] 615';.ls 82-5553
ISBN-13:978-3-642-68571-2 (U.S.) [616'.04] AACR2
This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned,
specifically those of translation, reprinting, re-use of illustrations, broadcasting, reproduction by photocopying
machine or similar means, and storage in data banks. Under § 54 of the German Copyright Law where copies are
made for other than private use a fee is payable to "Verwertungsgesellschaft Wort", Munich.
© by Springer-Verlag Berlin Heidelberg 1982
Softcover reprint of the hardcover 1st edition 1982
The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific
statement, that such names are exempt from the relevant protective laws and regulations and therefore free for
general use.
2122/3130-543210
List of Contributors
Dr. C. G. VAN ARMAN, Department of Biological Research, Wyeth Laboratories
Inc., P.O. Box 8299, Philadelphia, PA 19101jUSA
Dr. D. A. J. ARMSTRONG, Department of Pharmacology, University of
Pennsylvania, School of Medicine, Philadelphia, PA 19104jUSA
Dr. J. BLIGH, Ph.D., D.Sc., Director, Division of Life Sciences and Institute of
Arctic Biology, University of Alaska, Fairbanks, AK 99701jUSA
Dr. B. A. BRITT, M.D., Associate Professor, Departments of Anaesthesia and
Pharmacology, University of Toronto, Medical Sciences Building, Toronto,
Ontario M5S lA8, Canada
Dr. M. E. CASTERLIN, Biothermal Research Institute, Northeast Limnological
Laboratory, R. D. 3, Box 10, Wyoming, PA 18644jUSA
Dr. K. E. COOPER, Department of Medical Physiology, Faculty of Medicine,
The University of Calgary, Calgary, Alberta T2N IN4, Canada
Dr. B. Cox, D.Sc., Bioscience II Department, ICI Ltd. Pharmaceuticals Division,
Alderly Park, Macclesfield, Cheshire SK104TG, Great Britain
Dr. M. J. DASCOMBE, Department of Pharmacology, Materia Medica and
Therapeutics, Stopford Building, The Medical School, University of
Manchester, Oxford Road, Manchester M13 9PT, Great Britain
Dr. C. A. DINARELLO, M.D., Assistant Professor of Medicine and Pediatrics,
Division of Experimental Medicine, Tufts University School of Medicine,
New England Medical Center, 136 Harrison Avenue, Boston, MA 021 lljUSA
Dr. J. S. EISENMAN, Department of Physiology and Biophysics, Mount Sinai
School of Medicine, One Gustave Levy Place, New York, NY 10029/USA
Dr. G. W. GANDER, Ph.D., Professor of Pathology, Medical College of Virginia,
Virginia Commonwealth University, Box 622, Richmond, VA 23298/USA
Dr. N. W. KASTING, Neuroendocrine Research Lab, 4th Floor Research Building,
Massachusetts General Hospital, Boston, MA 02114jUSA
VI List of Contributors
Dr. D. H. KIM, Medicinal Chemistry Section, Wyeth Laboratories Inc.,
P.O. Box 8299, Philadelphia, PA 191Ol/USA
Dr. T. F. LEE, Department of Pharmacology, Materia Medica and Therapeutics,
Stopf ord Building, The Medical School, Manchester University,
Manchester M13 9PT, Great Britain
Professor A. S. MILTON, Department of Pharmacology, Marischal College,
University of Aberdeen, Aberdeen AB9lAS, Scotland, Great Britain
Dr. R. D. MYERS, Professor of Psychiatry and Pharmacology, University of North
Carolina, School of Medicine, Chapel Hill, NC 275l4/USA
Dr. C. OUNSTED, Consultant Physician, The Park Hospital for Children,
Old Road, Headington, Oxford OX37LQ, Great Britain
Dr. R. G. PERTWEE, Department of Pharmacology, Marischal College,
Aberdeen AB91AS, Scotland, Great Britain
Dr. W. W. REYNOLDS, Director, Biothermal Research Institute, Northeast
Limnological Laboratory, R.D. 3, Box 10, Wyoming, PA l8644/USA
Miss V. K. SAWHNEY, Department of Pharmacology, University of Aberdeen,
Marischal College, Aberdeen AB9 lAS, Scotland, Great Britain
Dr. J. B. P. STEPHENSON, Consultant in Paediatric Neurology, The Royal Hospital
for Sick Children, Y orkhill, Glasgow G 3 8SJ, Scotland, Great Britain
Dr. M. SZEKELY, Department of Pathophysiology, University Medical School,
Pees, Szigeti itt l2.Pf.99, 7643 Pees, Hungary
Dr. Z. SZELENYI, Department of Pathophysiology, University Medical School,
Pees, Szigeti itt l2.Pf.99, 7643 Pees, Hungary
Dr. J. SZOLCSANYI, Department of Pharmacology, University Medical School,
Pees, Szigeti itt 12., 7643 Pees, Hungary
Professor W. L. VEALE, Department of Medical Physiology, Faculty of Medicine,
The University of Calgary, 2929 24 Avenue N.W., Calgary Alberta T2N lN4,
Canada
Dr. S. M. WOLFF, M.D., Endicott Professor and Chairman, Department of
Medicine, Physician-in-Chief, Tufts University School of Medicine, New
England Medical Center Hospital, 171 Harrison Avenue, Boston,
MA 02lll/USA
To Wilhelm Feldberg
Preface
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.
I would like to express my sincere thanks to every one of the authors who have
written chapters and thus have made this volume possible. I very much appreciate
the help which I have received from the staff of Springer-Verlag, in particular from
DORIS WALKER. Last but not least, I wish to thank my secretary Mrs. VA LERIE LYON
(and her word processor) for not only typing my own chapters but also re-typing
chapters from other authors, for keeping a complete tally of the references and
for dealing with all the other secretarial work and problems associated with editing
this volume.
A. S. MILTON
Contents
CHAPTER 1
Body Heat. A. S. MIL TON
CHAPTER 2
Fever and Its Role in Disease: Rationale for Antipyretics
N. W. KASTING, W. L. VEALE, and K. E. COOPER. With 1 Figure
A. Fever. . . . . . . . . . . 5
B. The Role of Fever in Disease . . 8
C. Antipyretic Drugs . . . . . . . 12
D. Effects of Antipyresis on Survival 16
E. Clinical Indications and Contraindications for Antipyretic Therapy 17
References . . . . . . . . . . . . . . . . . . . . . . . . . . 19
CHAPTER 3
Thermoregulation: Its Change During Infection with Endotoxin-Producing
Micro-organisms. J. BLIGH. With 11 Figures
A. Introduction. . . . . . . . . . . . . 25
B. The Elevated Set-Point Concept of Fever 26
C. The Pyrogens . . . . . . . . . . . 27
I. Bacterial Endotoxins . . . . . . 27
II. Endogenous (Leucocyte) Pyrogens 27
III. The Prostaglandins. . . . . . . 28
D. Pyrogen Action . . . . . . . . . . 29
I. Points of Action in the Central Nervous System 29
II. Effects on the Electrical Activities of Hypothalamic Neurones 31
E. Areas of Current Concern and Doubt. . . . . . . . . . 32
I. More than One Central Point of Action of Pyrogens? . 32
II. The Biphasic Pattern of Experimentally Induced Fever:
Two Causative Factors? . . . . . . . . . . 34
III. The Pyrogenic Metabolites of Arachidonic Acid 36
IV. Are Pyrogens Only Pyrogens? . . 38
V. Is Fever of Physiological Benefit? . 40
F. Mechanisms of Thermoregulation 42
I. The Set-Point Machinery: Theory 42
II. The Antiquity of Homeostasis and of Pyrogen Responsiveness 45
III. The Pattern of Neural Connections. . . . . . . . . . . . 46
XII Contents
G. Models for Thermoregulation . . . . . . . . . . . . . . . . . . 48
I. Point (or Points) of Action of Pyrogens. . . . . . . . . . . . 48
II. Neuronal Model of Central Thermoregulatory Connections in Sheep 49
III. Point of Action of Bacterial Endotoxin in Sheep 50
IV. Neuronal Theory of Fever Induction 53
H. Thermoregulatory Agents . . . . . . 54
I. Central Nervous 5HT . . . . . . 54
II. Central Nervous Norepinephrine. . 56
III. The Central Thermoregulatory Effects of ACh 57
J. Other Set-Point Theories . . . . . . . . . . 58
I. The Monoamine Balance Set-Point Theory 58
II. The Ionic Balance Set-Point Theory . . . 59
K. Concluding Comments . . . . . . . . . . . 60
I. The Independence of Fever from the Influence of Ambient
Temperature. . . . . . . . . . . . . . . . . 61
II. The Upper Limit to the Febrile Response . . . . 61
III. More than One Pathway from Infection to Fever? 62
References . . . . . . . . . . . . . . . . . . . . . 63
CHAPTER 4
Exogenous Pyrogens. C. A. DINARELLO and S. M. WOLFF
A. Introduction. . . . . . . 73
I. General Considerations . . . . . 74
B. Viruses ............. . 74
I. Experimental Fevers with Viruses. 75
II. Interferon. . . . . 76
C. Gram-Positive Organisms . 76
I. Intact Organisms. . . 77
II. Extracellular Products 77
III. Cell Wall Components 79
D. Gram-Negative Bacteria. 82
I. Cell Wall Structure. . 82
II. Pyrogenicity of LPS . 83
III. LPS Fever and EP Production . 84
IV. LPS Structure and Ability to Produce Fever 85
V. Lipid A and Pyrogenicity . 86
VI. Pyrogenic Tolerance to LPS ...... . 87
E. Mycobacteria . . ............ . 91
I. Febrile Reactions of BCG-Sensitized Animals 92
II. Release of EP from Cells Incubated with Tuberculin 93
F. Fungi ............ . 93
I. Pyrogenicity of Fungal Cells . 93
II. Fever from Fungal Products. 94
G. Non-Microbial Antigens . . . . 95
I. Antibody-Mediated Fever. . 95
II. Cell-Mediated Immune Fever 97
Contents XIII
H. Pyrogenic Steroids . . . . . . . 98
I. Fever in Humans. . . . . . 98
II. Pyrogenic Steroid-Induced EP 99
J. Miscellaneous Exogenous Pyrogens . 99
I. Polynucleotides . . . . . 99
II. Colchicine and Vinblastine 100
III. Bleomycin. . . . . 100
IV. Synthetic Adjuvants 101
References . . . . . . . . 102
CHAPTER 5
Endogenous Pyrogens. G. W. GANDER
A. Introduction. . . . . . . . . 113
B. Nomenclature . . . . . ... 113
C. Assay of Endogenous Pyrogen . 113
D. Sources of LP . . . . . . . . 115
I. Cells Capable of Pyrogen Release . 115
II. Animal Species Releasing EP. . 116
E. Cellular Events . . . . . . . . . 117
F. Isolation and Characterization of EP 119
I. Methods for Purification. 119
II. Heterogeneity of EP . 120
References . . . . . . . . . . 120
CHAPTER 6
Role of Central Neurotransmitters in Fever. B. Cox and T. F. LEE
A. Introduction. . . . . 125
B. Noradrenaline . . . . . . . . . . . . . . . . . . . . . 126
I. Depleting Agents. . . . . . . . . . . . . . . . . . 126
II. Sympathomimetic Agents and Monoamine Oxidase Inhibitors 128
III. Adrenoceptor Antagonists . 129
IV. Brain Catecholamine Levels 129
V. Conclusion . . . 133
C. 5-Hydroxytryptamine. . . . . 134
I. Depleting Agents. . . . . 134
II. 5-Hydroxytryptamine Agonists and Uptake Inhibitors. 136
III. Indoleamine Antagonists . . . . . . . . . . . 136
IV. Brain 5-Hydroxytryptamine Levels and Turnover. 138
V. Conclusion . . . . . . 141
D. Acetylcholine . . . . . . . . . . . . . . 141
I. Cholinergic Antagonists. . . . . . . . 141
II. Cholinomimetics and Anticholinesterases 143
III. Conclusion 143
E. Other Amines . 143
I. Dopamine. 143
