Handbuch der experimentellen Pharmakologie Vol. 49 Heffter-Heubner New Series

Handbook of Experimental Pharmacology

Herausgeber Editorial Board G. V. R. Born, Cambridge' O. Eichler, Heidelberg A. Farah, Rensselaer, NY . H. Herken, Berlin A. D. Welch, Memphis, TN

Beirat Advisory Board E. J. Ariens . Z. M. Bacq . P. Calabresi . S. Ebashi . E. G. Erdos V Erspamer . U. S. von Euler' W. S. Feldberg· G. B. Koelle' O. Krayer T. A. Loomis' H. Raskova . M. Rocha e Silva' F. Sakai' J. R. Vane P. G. Waser . W. Wilbrandt

Ergot Alkaloids and Related Compounds Contributors

W. H. Aellig . B. Berde . Th. Bucher· D. Chu . B.J. Clark E. B. van Deusen . H. Eckert· A. Fanchamps . E. Fllickiger J. Grauwiler . R. W Griffith· D. Hauser· Ch. Hodel J. R. Kiechel . K. H. Leist· D. M. Loew . B. Matter W Meier-Ruge . E. Mtiller-Schweinitzer . T. J. Petcher E. del Pozo . B. P. Richardson· J. Rosenthaler . J. Rutschmann K. Saameli . R. Salzmann· H. O. Schild· R. Schmidt E. Schreier· P. A. Stadler· E. StUrmer· R. D. Venn· H. Wagner H. P. Weber· H. Weidmann

Editors

B. Berde and H.O. Schild

Springer-Verlag Berlin Heidelberg New York 1978

B. BERDE, Forschung und Entwicklung, Pharmazeutisches Departement, Sandoz AG, 4002 Basel, Schweiz

H. O. SCHILD, Emeritus Professor of Pharmacology in the University of London, University College London, London WCI, Great Britain

With 159 Figures

ISBN-13: 978-3-642-66777-0 e-ISBN-13: 978-3-642-66775-6 001: 10.1007/978-3-642-66775-6

Library of Congress Cataloging in Publication Data. Main entry under title: Ergot alkaloids and related compounds. (Handbook of experimental pharmacology: New series; v. 49) Bibliography: p. . Includes index. I. Ergot. 2. Alkaloids. I. Aellig. W.H. II. Berde. Botond. 1919- . III. Schild. Heinz Otto. IV. Series: Handbuch der experimentellen Pharmakologie: New series; v. 49. QP905.H3 vol. 49 [RM666.E8]615'.1'08s [615'.7]77-14126

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Preface

Une decouverte scientifique ... n'est ja­mais l'reuvre d'un seul homme et chacun de ceux qui y ont concouru lui ont donne bien des veilles.

Louis Pasteur

Traditionally every volume of the Handbook of Experimental Pharmacology is expected to give a comprehensive account of the topic it is devoted to. This is a relatively easy task if the subject has a short history, but if the problems in question have been worked on for half a century or longer the feasibility of integral coverage becomes questionable. In such cases more attention is usually given to the literature of the last decades, whereas older findings are dealt with in a summary fashion - with due exception to findings which can be considered classic. The situation is particularly complex if the origin of the subject is a natural drug whose actions - proven or alleged - were first recorded several centuries ago and where medical use can be traced back at least one and a half centuries (STEARNS, 1808) - as is the case of ergot of rye.

As editors of the present volume of this Handbook, we did not have to face the full impact of these difficulties as two previous volumes have already been devoted to the pharmacologic actions of substances extracted from ergot of rye. The first of these, written by Arthur Cushny in 1914, was published in 1924 [A.R. CUSHNY: Mutterkorn. Handb. exper. Pharmakol. II, 2, 1297-1354 (1924)]. The second, by George Barger, appeared in 1938 [G. BARGER: The Alkaloids of Ergot. Handb. exper. Pharmakol. (Erg.-Werk) VI, 84-226 (1938)]. Nevertheless, the present volume had to bridge a gap of nearly four decades during which time tremendous developments have taken place in this field. Besides reviewing this progress, we have attempted a synopsis of the whole field in which recent work is of course treated preferentially, but without neglecting the older literature whenever this was necessary for the understanding of the present state of knowledge. Only data obtained with chemically defined compounds, namely chemical entities containing the tetracyclic ergolene- or ergoline-ring system, were considered.

A history of ergot with its colorful medieval aspects - mainly the history of ergot intoxication due to the agricultural standards of the time - has been excluded from this volume. This subject is dealt with in considerable detail in a number of treatises such as DE JUSSIEU et aI., 1779 ; FALCK, 1855; KOBERT, 1889; HUSEMANN, 1903; BARGER, 1931; STOLL, 1943; GUGGISBERG, 1954; HOFMANN, 1964; LEDERER, 1961; BOVE, 1970; BAUER, 1973, and there is not much to be added to the story.

An important question was, of course, where the limits of "pharmacology" were to be drawn in this volume. That human pharmacology or clinical pharmacol­ogy had to be included seemed self-evident, the aim of the development of agents with therapeutic usefulness being ultimately directed for usage in man. Admittedly, it is not always easy to draw the line between clinical pharmacology and therapeu­tics, the latter being outside the scope of this volume. We aimed at a rather

VI Preface

restrictive definition of clinical pharmacology, and pharmacologic findings in man were in principle incorporated in individual chapters in relation to specific groups of problems such as circulation and nervous system. Only in two instances (Chapters VII and VIII) have chapters exclusively devoted to human pharmacologic aspects been included, due to the complexity of the topics in question.

According to tradition, but also of necessity, a chapter dealing with chemical aspects (Chapter II) is included. Its aim is to give an overview of the complex chemistry of ergot alkaloids. It is deliberately entitled "chemical background," but is addressed particularly to pharmacologists, biologists, and doctors, rather than to chemists.

Pharmacokinetics and data concerning drug metabolism are dealt with in a separate chapter (Chapter XI). This aspect is of evident importance although as in most other well-studied fields of pharmacology, much more is known of what the compounds do to the living body than what the living body does to the active compounds.

We believe that the description of a group of biologically active substances is incomplete without their toxicologic characterization. The chapter in question (Chapter XII), however, makes no attempt at completeness. It should rather serve to give the reader some degree of general orientation.

The bulk of the book is devoted to traditional pharmacology. It includes an introductory section placing the therapeutically important ergot alkaloids in per­spective (Chapter 1) and a series of main sections dealing with fundamental receptor considerations (Chapter III) and various body systems on which ergot alkaloids exert their effects.

The Subject Index was prepared by Dr. U. BRUCKNER. We wish to thank him for making this important contribution. Our gratitude is also expressed to Mr. E. ERFLING for compiling the Author Index.

Basel and London, May 1977 B. BERDE and H.O. SCHILD

References

Barger, G.: Ergot and Ergotism. Edinburgh: Gurney & Jackson 1931 Barger, G.: The alkaloids of ergot. Handb. exper. Pharmakol. (Erg.-Werk) 6,84-226 (1938) Bauer, V.H.: Das Antonius-Feuer in Kunst und Medizin. In: Sitzungsberichte der Heidelberger

Akademie der Wissenschaften. Mathematisch-Naturwissenschaftliche Klasse. Suppl. Jahr­gang 1973. Berlin-Heidelberg-New York: Springer 1973

Bove, F.J.: The Story of Ergot. Basel-New York: Karger 1970 Cushny, A.R.: Mutterkorn. Handb. exper. Pharmakol. 11/2, 1297-1354 (1924) De Jussieu, A.-L., Paulet, Saillant, Tessier, H.A.: Recherches sur Ie feu Saint-Antoine. Histoire

de la Societe Royale de Medicine. Annee 1776, pp. 260-302. Paris: Pierres 1779 Hofmann, A.: Die Mutterkorn-Alkaloide. Stuttgart: Enke 1964 Falck, C.Ph.: Vergiftungen durch Mutterkorn. In: Handb. der speziellen Pathologie und Thera­

pie, Vol. II, Part I, pp. 311-327. Erlangen: Enke 1855 Guggisberg, H.: Mutterkorn. Vom Gift zum Heilstoff. Basel-New York: Karger 1954 Husemann, T.: Ergotismus. In: Handb. der Geschichte der Medizin. Neuburger, M., Pagel,

J. (eds.), Vol. II, pp. 916-926. Jena: G. Fischer 1903

Preface VII

Kobert, R.: Zur Geschichte des M utterkorns. In: Historische Studien aus dem Pharmakologi­schen Institute der Kaiserlichen Universitiit Dorpat, Vo!. I, pp. 1-47. Halle a.S.: von Tausch & Grosse 1889

Lederer, J.: Les mendiants de Bruegel, un document pour I'histoire des Flandres sous I'occupa­tion espagnole. Scrinium Lovaniense Melanges historiques Etienne van Cauwenbergh. Lou­vain 1961, pp. 452-465 (Univ. de Louvain, Recueil de travaux d'histoire et de philo!. 4e serie, fasc. 24)

Stearns, J.: Account of the pulvis parturiens, a remedy for quickening child-birth. Med. Repository N.Y. 5, 308 (1808)

Stoll, A.: Altes und Neues tiber Mutterkorn. Mitteilungen der Naturforschenden Gesellschaft Bern aus dem Jahre 1942, pp. 45-80. Bern: P. Haupt 1943

Contents

CHAPTER I

Introduction to the Pharmacology of Ergot Alkaloids and Related a Basis of Their Therapeutic Application.

B. BERDE and E. STURMER. With 16 Figures. . . . . . . . ..

CHAPTER II

Compounds as

Chemical Background. J. RUTSCHMANN and P.A. STADLER. With 32 Figures

A. Occurrence, Biosynthesis, and Production . . . . . 29 I. Presence of Ergot Alkaloids in the Plant Kingdom 29 2. Biogenesis. . . . . . . . . . . . . . . . 29 3. Production . . . . . . . . . . . . . . . 31

B. Structure and Synthesis of the Natural Alkaloids 32 I. General Structural Aspects 32 2. Structure of Ergot Alkaloids. . . . . . . . 34 3. Synthesis of Ergot Alkaloids. . . . . . . . 37

C. Chemical Modifications in the Lysergic Acid Half of Ergot Alkaloids 38 I. Substitutions in Position I. . . . . . . . . . 38 2. Substitutions in Position 2. . . . . . . . . . . . . . . . 40 3. Chemical Transformations in Positions 4 and 5. . . . . . . 43 4. Replacement of the N-Methyl Group in Position 6 by Other

Substituents . . . . . . . . . . . . . . . . . . . . . . 45 5. Reactions Involving Position 7. . . . . . . . . . . . . . 46 6. Modifications of the Carboxylic Acid Function of d-Lysergic Acid 46 7. Reactions at Position 8 . . . . . . . . . . . . . . . . . 53 8. Derivatives of 6-Methyl-8-ergolene-8-carboxylic Acid . . . . 55 9. Chemical Transformations on the Double Bond in Position 9, 10. 57

10. Substitution Reactions in the Benzene Ring . . . . . . 60 D. Chemical Modification in the Peptide Part of Ergot Alkaloids 61

I. The Aci-Rearrangement. . . . . . . . . . . . . . . 61 2. Synthesis of Analoga of Natural Ergot Peptide Alkaloids 62 3. Substitution of L-Proline by Other Amino Acids in Ergot Peptide

Alkaloids . . . . . . . . . . . . . . . . . . . . . . . 64 4. Synthetic Ergot Peptide Alkaloids Modified in Position 5' . . 64

E. Some Analytical Tools for the Determination of Ergot Alkaloids 67 1. Separation of Ergot Alkaloids . . . . . . . . . . . . . . 67

x Contents

2. Assay of Ergot Alkaloids F. Subject Index.

68 69 78 G. References. . . . . . . .

CHAPTER III

Basic Pharmacological Properties. E. MOLLER-SCHWEINITZER and H. WEIDMANN. With Contributions by R. SALZMANN, D. HAUSER, H.P. WEBER, T.J. PETCHER, and TH. BUCHER. With 42 Figures

A. Introduction . . . . . . . . . . . . 87 Competitive Drug Antagonism . . . . 88 Corollaries of Competitive Antagonism 90 Affinity and Intrinsic Activity (Efficacy) 90 Receptor Classification . . . . . . . 91 Noncompetitive Antagonism . . . . . 93

B. Actions of Ergot Alkaloids at 5-HT Receptors 94 I. Actions of Ergot Alkaloids at Extraneuronal 5-HT Receptors 94 2. Effects of Ergot Alkaloids on 5-HT Metabolism . . . . . . 112 3. Effects of Ergot Alkaloids on Neuronal 5-HT Receptors. . . 120 4. Effects of Ergot Alkaloids on 5-HT -Sensitive Enzyme Systems 131

C. Actions of Ergot Alkaloids at Dopamine Receptors . . . . . . 133 I. Actions of Ergot Alkaloids at Extraneuronal Dopamine Receptors 133 2. Interaction of Ergot Alkaloids With Indirect Dopamine Effects.. 134 3. Actions of Ergot Alkaloids at Neuronal Dopamine Receptors .. 134 4. Effects of Ergot Alkaloids on Dopamine-Sensitive Enzyme Systems. 138 5. Effects of Ergot Alkaloids on Dopamine Receptors Mediating Hormone

Secretion . . . . . . . . . . . . . . . . . . . . . . . 139 D. Actions of Ergot Alkaloids at Adrenoceptors. R. SALZMANN and

TH. BUCHER . . . . . . . . . . . . . . . . . . . . . . . 140 I. Effects of Ergot Alkaloids Mediated by Peripheral tx-Adrenoceptors . 140 2. Depletion of Noradrenaline From Tissues by Ergot Alkaloids .. 159 3. Effects of Ergot Alkaloids on Noradrenaline Release and Theories

on the Mechanism of Noradrenaline" Overflow". . . . . . .. 161 4. Effects of Ergot Alkaloids on the Responses of Organs to Stimulation

of Their Sympathetic Innervation. . . . . . . . . . . . . . .. 170 5. Actions of Ergot Alkaloids at fJ-Adrenoceptors. . . . . . . . .. 177

E. The Shape of Ergotamine and Dihydroergotamine in Relation to Their Interaction With tx-Adrenoceptors. H.P. WEBER and T.J. PETCHER 177

F. Actions of Ergot Alkaloids at Acetylcholine Receptors. 182 G. Actions of Ergot Alkaloids at Histamine Receptors . . . . . . 182 H. Interaction of Ergot Alkaloids With Prostaglandins ..... 182

1. Interference of Ergot Alkaloids With Endogenous Prostaglandin Synthesis . . . . . . . . . . . . . . . . . . . . . . . 182

2. Interference of Ergot Alkaloids With Prostaglandin Effects 184 J. Stimulation of Smooth Muscle by Ergot Alkaloids Mediated by

Miscellaneous Mechanisms. . . . . . . . . . . . . . . . . 185

Contents XI

1. Enhancement of Responses to Biogenic Amines by Ergot Alkaloids in Vascular Smooth Muscles. . . . . . . . . . . . . . . .. 186

2. Enhancement of Responses to Biogenic Agents by Ergot Alkaloids in Nonvascular Smooth Muscles . . . . . . . . . . . . 188

K. Biochemical Identification of Specific Binding Sites for Ergot Alkaloids. D. HAUSER. . . . . . . . . . . . . . . . . . 191 1. Interaction of Ergot Compounds With Specific Sites in the

Central Nervous System. . . . . . . . . . . 192 2. Peripheral Binding Sites for Ergot Compounds. 196

L. References. . . . . . . . . . . . . . . . . . 196

CHAPTER IV

Effects on the Uterus. K. SAAMELI. With 16 Figures

A. Introduction . . . . . . . . . . B. Actions on Uterine Motor Activity .

1. Peptide Alkaloids. . . . . . . . 2. Dihydrogenated Peptide Alkaloids 3. Lysergic Acid-Amides .

C. References. . . . . . . . . . . .

CHAPTER V

233 234 235 252 273 314

Actions on the Heart and Circulation. B.1. CLARK, D. CHU, and W.H. AELLIG. With 15 Figures

A. Actions on Systemic Blood Pressure. . . . . . . 321 1. Nature of the Effect . . . . . . . . . . . . 321 2. Effects on Blood Pressure Control Mechanisms. 325 3. Effects on the Carotid Sinus and Impulse Transmission in

Sino-Aortic Nerves. . . . . . . . . . . . . . . . . 334 4. Effects on Responses to Catecholamines and 5-Hydroxytryptamine 335 5. Mechanisms Involved in the Hypotensive Action 339 6. Mechanisms Involved in the Pressor Action 345

B. Hemodynamic Effects . . . . . . 348 C. Effects on Regional Hemodynamics 352

1. Effects on Limb Blood Vessels . 352 2. Effects on Cranial Blood Vessels 363 3. Effects on Renal Blood Vessels. 366 4. Effects on Mesenteric Blood Vessels 368 5. Effects on Coronary Blood Vessels 369 6. Effects on Uterine Blood Vessels 370

D. Actions on the Heart . 371 1. Effects in Mammals 371 2. Effects in Amphibia 382 3. Effects in Molluscs . 385

E. Pharmacologic Basis for the Clinical Use of Ergot Alkaloids 387 1. Orthostatic Hypotension . . . . . . . . . . . . . . 387

XII Contents

2. Venous Thrombosis. 389 3. Shock. 390 4. Migraine 390

F. References . 399

CHAPTER VI

Effects on the Central Nervous System. D.M. LOEW, E.B. VAN DEUSEN, and W. MEIER-RuGE. With 8 Figures

A. Introduction . . . . . . . . . B. Early Evidence of Central Effects

I. Convulsive Ergotism in Man. 2. Early Description of Central Effects in Animals 3. The Question of" Toxic" versus" Therapeutic" Dose.

C. Whole-Animal Studies. . I. Behavioral Excitation. . . . . . . . . . . 2. Behavioral Depression . . . . . . . . . . 3. Interaction With Centrally Depressant Drugs 4. Anticonvulsant Effects 5. Electroencephalogram. 6. Cerebral Blood Flow 7. Body Temperature . . 8. Emesis ...... .

D. Synaptic Transmission: Catecholaminergic Mechanisms I. Criteria of Catecholaminergic Stimulation and Antagonism

at the Synaptic Level . . . . . . . 2. Agroclavine-Type Ergot Derivatives. . 3. Ergometrine . . . . . . . . . . . . 4. D-LSD, 2-Br-LSD, and Methysergide . 5. PRT 17-402 . 6. Ergocornine . . . . . . . . 7. Bromocriptine . . . . . . . 8. Other Ergopeptine Derivatives 9. Efficacy of Ergot Derivatives as Antiparkinsonian Agents

E. Synaptic Transmission: Serotoninergic Mechanisms . . . . I. Criteria of Serotoninergic Stimulation and Antagonism at the

Synaptic Level 2. D-LSD ... 3. 2-Br-LSD .. 4. Methysergide 5. Other Lysergic Acid Derivatives 6. Ergopeptine Derivatives. . . .

F. Brain Metabolism. . . . . . . . I. Brain Cyclic Adenosine Monophosphate. 2. Adenosine Triphosphate Metabolism in the Brain.

421 422 422 423 426 426 427 428 430 435 439 448 453 457 461

461 469 472 475 478 479 479 484 484 489

489 491 495 495 497 498 500 500 503

Contents XIII

3. Transformation of Biosubstrates by Demethylation, Acetylation and Glucuronoconjugation 507

G. References. . . . . . . . . . . . . . . . . . . . . . . . . 508

CHAPTER VII

Clinical Pharmacology of Ergot Alkaloids in Senile Cerebral Insufficiency. R.D. VENN. With 7 Figures

A. Introduction . . . . . . . . . . . . . . . . . . . . 533 B. Terminology, Etiology, and Pathology of the Aging Process

of the Brain . . 533 I. Terminology. . . . . 533 2. Definition. . . . . . 534 3. Etiology and Pathology 534

C. Research Techniques Used in Clinical Pharmacologic Studies of Ergot Alkaloids in Senile Cerebral Insufficiency . . . . . 536 I. Methods for Measuring Cerebral Bloodflow and Metabolism. 537 2. Methods for the Clinical Assessment of Brain Function . . . 539 3. Electroencephalography. . . . . . . . . . . . . . . . . 544

D. Results of Clinical Pharmacology Studies With Ergot Alkaloids. 550 I. Cerebral Bloodflow and Metabolic Studies. . . . . . . . . 550 2. Clinical Pharmacologic Studies With Ergot Alkaloids in Senile

Cerebral Insufficiency. 551 E. Summary 559 F. References. . . . . . . 560

CHAPTER VIII

Some Compounds With Hallucinogenic Activity. A. F ANCHAMPS. With 3 Figures

A. Introduction 567 B. Discovery of LSD. 567 C. Effects of LSD in Man 569

1. Somatic Actions 569 2. Psychic Actions 570 3. Effects of LSD on the Human EEG 578 4. Clinical Laboratory Investigations 578 5. Tolerance to LSD Effect 581 6. Inhibitors of LSD Reaction 581 7. Side-Effects and Complications. 583 8. Illicit Use and Addiction 584

D. Clinical Applications of LSD. 586 I. Adjuvant to Psychotherapy 586 2. Psychedelic Therapy 587 3. Use in Psychoses. 588

XIV

4. Therapeutic Use in Children. . 5. Use in Terminal Cancer Patients

E. LSD Analogues Tested in Man I. LSD Isomers . . . . . . 2. Hydrogenated Derivatives . 3. Unsubstituted and Monosubstituted Amide Derivatives 4. Disubstituted Amide Derivatives 5. Cyclic Amide Derivatives . . 6. Ring-Substituted Derivatives. 7. Ololiuqui . . 8. Discussion. .

F. Cross-Tolerance G. References. . .

CHAPTER IX

Contents

588 589 590 590 590 591 591 592 592 594 595 598 600

Influence on the Endocrine System. E. FLUCKIGER and E. DEL Pozo. With a Contri­bution by B.P. RICHARDSON. With II Figures

A. Animal Data. . . . . . . . . . . . . . I. Actions on Pituitary Hormones . . . . 2. Actions on Peripheral Endocrine Systems

B. Human Data ......... . I. Actions on Pituitary Hormones

C. References. . . . . . . . . . .

CHAPTER X

Metabolic Effects. H. WAGNER. With 2 Figures

615 615 653 659 659 674

A. Introduction . . 691 B. In Vitro Systems . 692

I. Liver . . . . . 692 2. Adipose Tissue. 694 3. Various Tissues 698

C. Intact Animals and Men. 699 I. Influence on Catecholamine-Stimulated Carbohydrate Mobilization. 699 2. Influence on Catecholamine-Stimulated Lipolysis. . . . . . .. 706 3. Influence on Other Catecholamine-Stimulated Metabolic Processes 706 4. Influence on Stress-Stimulated Metabolic Parameters . . . . 707 5. Influence on the Effects of Adrenalectomy or Sympathectomy 707 6. Influence on Glucose or Galactose Tolerance . . . . 707 7. Influence on Serotonin Effects . . . . . . . . . . . . . 708 8. Interaction With Pancreas, Hypophysis, and Thyroidea . . 708 9. Actions of Ergot Alkaloids Alone on Metabolic Parameters 709

Contents

D. Various Actions of Ergot Alkaloids E. References . . . . . . . . . . .

CHAPTER XI

xv

710 710

Biopharmaceutical Aspects. Analytical Methods, Pharmacokinetics, Metabolism and Bioavailability. H. ECKERT, 1.R. KIECHEL, 1. ROSEN THALER, R. SCHMIDT, and E. SCHREIER. With 7 Figures

A. Introduction . . . . . . B. Assay of Ergot Alkaloids

I. Introduction. . . . . 2. Radiotracer Methods . 3. Nonradioisotopic Physicochemical Methods 4. Radioimmunoassay.

C. Pharmacokinetics . . . . . \. Introduction. . . . . . 2. Experiments in Animals. 3. Experiments in Man . . 4. Interactions in Man. . . 5. Physicochemical Properties of Ergot Alkaloids Which May

Affect Enteral Absorption . 6. Synopsis

D. Metabolism . . I. Introduction. 2. Experiments . 3. Biotransformation Sites in the Molecule. 4. Interaction of Ergot Derivatives With Cytochrome P 450 5. Conclusions and Prospects.

E. References. . . . . . . . . . . . . . . . . . . . . .

CHAPTER XII

719 721 721 723 732 738 741 741 742 755 760

761 764 766 766 768 776 782 783 796

Toxicologic Considerations. R. W. GRIFFITH, 1. GRAUWILER, CH. HODEL, K.H. LEIST, and B. MATTER

A. Introduction . . B. Systemic Toxicity

I. Animals .. . 2. Man ... .

C. Effects on Reproductive Processes. \. Implantation and Early Pregnancy 2. Embryonic and Fetal Development 3. Lactation and the Offspring

D. Potential Genetic Effects. I. LSD ......... .

805 805 805 815 823 823 826 831 833 833

XVI

2. Other Ergot Alkaloids . . . . . . . . 3. Conclusions . . . . . . . . . . . . .

E. Interactions Leading to Enhanced Toxicity. I. Disease Processes. . . . 2. Concomitant Medication

F. Summary G. References

Authors Index

Subject Index

Contents

835 835 836 837 837 838 838

853

941

List of Contributors

W.H. AELLlG, Experimentelle Therapie, Medizinisch-Biologische Forschung, San­doz A.G., 4002 Basel, Schweiz.

B. BERDE, Forschung und Entwicklung Pharma, Sandoz A.G., 4002 Basel, Schweiz.

TH. BUCHER. Pharmakologie, Medizinisch-Biologische Forschung, Sandoz A.G., 4002 Basel, Schweiz.

D. CHU, Pharmakologie, Medizinisch-Biologische Forschung, Sandoz A.G., 4002 Basel, Schweiz.

B.l. CLARK, Pharmakologie. Medizinisch-Biologische Forschung, Sandoz A.G., 4002 Basel, Schweiz.

E. B. VAN DEUSEN, Pharmakologie, Medizinisch-Biologische Forschung, Sandoz A.G., 4002 Basel, Schweiz.

H. ECKERT, Biopharmazeutik, Pharmazeutische Entwicklung, Sandoz A.G., 4002 Basel, Schweiz.

A. FANCHAMPS, Medizinische Beratung Pharma-Forschung, Sandoz A.G., 4002 Basel, Schweiz.

E. FLOCKIGER, Pharmakologie, Medizinisch-Biologische Forschung, Sandoz A.G., 4002 Basel, Schweiz.

1. GRAUWILER, Toxikologie, Medizinisch-Biologische Forschung, Sandoz A.G., 4002 Basel, Schweiz.

R. W. GRIFFITH, Klinische Forschung, Medizinisch-Biologische Forschung, San­doz A.G., 4002 Basel, Schweiz.

D. HAUSER, Biochemie, Pharmazeutisch-Chemische Forschung, Sandoz A.G., 4002 Basel, Schweiz.

CH. HODEL, Toxikologie, Medizinisch-Biologische Forschung, Sandoz A.G., 4002 Basel, Schweiz.

1.R. KIECHEL, Biopharmazeutik, Pharmazeutische Entwicklung, Sandoz A.G., 4002 Basel, Schweiz.

K.H. LEIST, Toxikologie, Medizinisch-Biologische Forschung, Sandoz A.G., 4002 Basel, Schweiz.

D.M. LOEw, Pharmakologie, Medizinisch-Biologische Forschung, Sandoz A.G., 4002 Basel, Schweiz.

XVIII List of Contributors

B. MATTER, Toxikologie, Medizinisch-Biologische Forschung, Sandoz A.G., 4002 Basel, Schweiz.

W. MEIER-RuGE, Medizinische Grundlagenforschung, Sandoz A.G., 4002 Basel, Schweiz.

E. MULLER-SCHWEINITZER, Pharmakologie, Medizinisch-Biologische Forschung, Sandoz A.G., 4002 Basel, Schweiz.

T.J. PETCHER, Physikalische Chemie, Pharmazeutisch-Chemische Forschung, San­doz A.G., 4002 Basel, Schweiz.

E. DEL POZO, Experimentelle Therapie, Medizinisch-Biologische Forschung, San­doz A.G., 4002 Basel, Schweiz.

B.P. RICHARDSON, Toxikologie, Medizinisch-Biologische Forschung, Sandoz A.G., 4002 Basel, Schweiz.

J. ROSEN THALER, Biopharmazeutik, Pharmazeutische Entwicklung, Sandoz A.G., 4002 Basel, Schweiz.

J. RUTSCHMANN, Pharmazeutisch-Chemische Forschung, Sandoz A.G., 4002 Basel, Schweiz.

K. SAAMELI, Medizinisch-Biologische Forschung, Sandoz A.G., 4002 Basel, Schweiz.

R. SALZMANN, Pharmakologie, Medizinisch-Biologische Forschung, Sandoz A.G., 4002 Basel, Schweiz.

H.O. SCHILD, Department of Pharmacology, University College London, London WCI, Great Britain.

R. SCHMIDT, Experimentelle Therapie, Medizinisch-Biologische Forschung, San­doz A.G., 4002 Basel, Schweiz.

E. SCHREIER, Biopharmazeutik, Pharmazeutische Entwicklung, Sandoz A.G., 4002 Basel, Schweiz.

P.A. STADLER, Pharmazeutisch-Chemische Forschung, Sandoz A.G., 4002 Basel, Schweiz.

E. STURMER, Pharmakologie, Medizinisch-Biologische Forschung, Sandoz A.G., 4002 Basel, Schweiz.

R.D. VENN, Medical Research, Pharmaceutical Research & Development, Sandoz Inc., East Hanover, N.J. 07936, USA.

H. WAGNER, Pharmakologie, Medizinisch-Biologische Forschung, Sandoz A.G., 4002 Basel, Schweiz.

H.P. WEBER, Physikalische Chemie, Pharmazeutisch-Chemische Forschung, San­doz A.G., 4002 Basel, Schweiz.

H. WEIDMANN, Praklinische Forschung, Medizinisch-Biologische Forschung, San­doz A.G., 4002 Basel, Schweiz.