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Physiology and Pharmacologyof Biological Rhythms

Contributors

F. Andreotti, J. Arendt, P.M. Belanger, G.D. Block, B. BruguerolleJ. Camber, G.E. D'Alonzo, L.N. Edmunds, Jr., M.H. HastingsE. Haus, M. Karzazi, G. Labrecque, B. Lemmer, F. Levi, A. LluchK.F. Martin, L. Mejean, H. Merki, S. Michel, J.G. MooreR.Y. Moore, N. Mrosovsky, G. Patti, M. Pons, F. PortaluppiP.H. Redfern, A.E. Reinberg, L. Rensing, A.M. RosenwasserR. Smaaland, M.H. Smolensky, A. Stricker-Krongrad, Y. TouitouM.-C. Vanier, A. Wirz-Justice, K. Witte

Editors

P.H. Redfern and B. Lemmer

Springer

Contents

CHAPTER 1

The Vertebrate Clock: Localisation, Connection and EntrainmentM.H. HASTINGS. With 4 Figures 1

A. Introduction 1I. Rhythms and Our Lives 1

II. Circadian Rhythms and Internal Temporal Order 1III. Entrainment and the Phase Response Curve 3

B. Localisation of the Circadian Clock in Vertebrates 4I. Criteria for Identifying the Clock 4

II. The Retina as a Circadian Oscillator 5III. The Pineal Gland as a Circadian Oscillator 6IV. The Suprachiasmatic Nuclei of the Hypothalamus

as a Circadian Oscillator 8C. Neuroanatomy of the SCN 9

I. Internal Structure and Organisation of the SCN 9II. Afferent Connections of the SCN 11

III. Outputs of the SCN 12D. Entrainment of the SCN 13

I. Light and Glutamate 13II. Glutamatergic Signals and Gene Expression in the SCN . . . 14

III. Non-photic Entrainment of the Circadian System 17IV. Melatonin and Entrainment of the Circadian System 18V. Conclusion 20

References 21

CHAPTER 2

Regulation of Cell Division Cycles by Circadian Oscillators:Signal Transduction Between ClocksL.N. EDMUNDS, JR. With 10 Figures 29

A. Introduction 29I. Regulation of the Cell Division Cycle 31

II. Cell Division Rhythmicity in Wild-Typeand Mutant Euglena 32

XII Contents

B. Coupling Between Oscillator and Cell Cycle: Role of Cyclic AMP 33I. Perturbation of the Cell Division Rhythm by Cyclic AMP 34

II. Upstream Analysis: Genesis of the Oscillationin Cyclic AMP 41

III. Downstream Pathway: Cyclic AMP-Dependent Kinases . . . 43IV. Model for Circadian Control of the Cell Division Cycle . . . 47

C. Problems and Prospects: Interface with the Cyclin Clock 48References 50

CHAPTER 3

Genetics and Molecular Biology of Circadian ClocksL. RENSING. With 6 Figures 55

A. Introduction 55I. Oscillations and Genes 55

II. Analytical Approaches to the Basic Circadian Oscillator . . . 56B. Genetics and Molecular Biology of the Clock 58

I. Overview and Generalizations 58II. Neurospora 60

1. Circadian Rhythm 602. Clock Mutants 603. Molecular Biology of frq 62

III. Drosophila 641. Circadian Rhythms 642. Clock Mutants 653. Molecular Biology of per 66

IV. Mammals 69V. Conclusions 70

C. Zeitgeber Signal Pathways to the Clock 71I. Neurospora 72

II. Molluscs 73III. Mammals 73

D. Output Signals from the Clock 73References 75

CHAPTER 4

Chemical Neuroanatomy of the Mammalian Circadian SystemR.Y. MOORE. With 7 Figures 79

A. Introduction 79B. Entrainment Pathways 80

I. Retinohypothalamic Tract 80II. Geniculohypothalamic Tract 83

Contents XIII

III. Other Inputs to the Suprachiasmatic Nucleus 85C. Pacemaker-Suprachiasmatic Nucleus 85

I. Suprachiasmatic Nucleus Organization 85-> II. Suprachiasmatic Nucleus Efferents 87

D. Conclusions 89References 90

CHAPTER 5

Chronobiology of Development and AgingE. HALTS and Y. TOUITOU 95

A. Introduction 95B. Developmental Chronobiology 97

I. Biologic Rhythms in the Human Fetus 97II. Fetal Rhythms of Susceptibility

to Toxic and Teratogenic Agents 97III. Rhythms in the Newborn and During Infancy 100

C. Chronobiology of Aging 100I. Changes in Sleep Patterns During Aging 100

II. Body Temperature 101III. Blood Pressure and Heart Rate 104IV. Hypothalamic-Pituitary-Adrenal Axis 106

1. Dehydroepiandrosterone and Aging 107V. Pineal Gland 109

VI. Growth Hormone and Prolactin 110VII. Pituitary-Gonadal Axis I l l

VIII. Catecholamines 112IX. Age-Related Changes in the Pituitary-Thyroid Axis

During Aging 113X. Clinical Chemical Variables and Aging 113

1. Plasma Proteins and Volemia 114X. Hematology 115

D. Conclusions 116References 122

CHAPTER 6

Rhythms in Second Messenger MechanismsK. WiTTE and B. LEMMER. With 4 Figures 135

A. Introduction 135B. Principles of Transmembraneous Signal Transduction 135

I. Adenylyl Cyclase Pathway 135II. Guanylyl Cyclase Pathway 137

XIV , Contents

III. Phospholipase C Pathway 138C. Rhythms in Signal Transduction

in the Cardiovascular System 138-i I. Adenylyl Cyclase Pathway 138

II. Guanylyl Cyclase Pathway 145III. Phospholipase C Pathway 145

D. Rhythms in Signal Transductionin the Central Nervous System 146

I. Adenylyl Cyclase Pathway 146II. Guanylyl Cyclase Pathway 147

III. Phospholipase C Pathway 151E. Rhythms in Signal Transduction in Other Tissues 151

I. Adenylyl Cyclase Pathway 151II. Guanylyl Cyclase Pathway 152

III. Phospholipase C Pathway 152F. Conclusions and Perspectives 153References 153

CHAPTER 7

5-Hydroxytryptamine and Noradrenaline Synthesis,Release and Metabolism in the Central Nervous System:Circadian Rhythms and Control MechanismsK.F. MARTIN and P.H. REDFERN. With 2 Figures 157

A. Introduction 157B. Circadian Rhythms in Turnover of Serotonin 158

I. Tissue Levels of Serotonin 158II. Tryptophan Hydroxylase 160

III. Tryptophan Availability 160IV. Tryptophan Uptake 161V. 5-Hydroxytryptophan Decarboxylase Activity 161

VI. 5-Hydroxytryptamine Release and Metabolism 162VII. Firing Rate of Serotonergic Neurones 165

VIII. 5-Hydroxytryptamine Autoreceptor Activity 165IX. What Is the Function of the Circadian Rhythm

in 5-Hydroxytryptamine Turnover? 168C. Circadian Rhythms in Noradrenaline Turnover 169D. Conclusions 171E. References 171

Contents XV

CHAPTER 8

Rhythms in Pharmacokinetics; Absorption, Distribution, Metabolismand ExcretionP.M. BELANGER, B. BRUGUEROLLE, and G. LABRECQUE.

With 13 Figures 177

A. Introduction 177B. Absorption 178

I. Parameters and Modifying Factors 178II. Inorganic Compounds and Macromolecules 179

III. Organic Compounds 179IV. Factors Modifying the Temporal Variation

in Gastrointestinal Absorption 1811. Solubility 1812. Pharmaceutical Formulation 1823. Secretion and Motility 1824. Blood Flow 183

C. Distribution 185I. Plasma Protein Binding 185

II. Binding to Erythrocytes 187D. Biotransformation 188

I. Oxidation: The Cytochrome P-450 Monooxygenase 188II. Conjugations 192

1. Conjugations to Acetate, Glucuronic Acid and Sulfate . 1922. Conjugation to Glutathione 193

III. Factors Related to Biotransformation 1951. Hepatic Blood Flow 1952. First-Pass Effect 196

E. Excretion 196F. Conclusions and Perspectives 197References 199

CHAPTER 9

Progress in the Chronotherapy of Nocturnal AsthmaM.H. SMOLENSKY and G.E. D'ALONZO. With 19 Figures 205

A. Introduction 205B. Day-Night Pattern of Acute Asthma 205C. Early, Late, and Recurrent Asthma Reactions 207D. The Chronobiology of Asthma 208E. Pharmacotherapy of Asthma 211F. The Chronopharmacology and Chronotherapy

of Asthma Medications 212

XVI Contents

G. p2-Adrenergic Agonist Medications 213H. Anticholinergic Agents 219I. Theophylline 221J. Chronotherapy of Glucocorticoids 227

K. Mast Cell Stabilizers 239L. Conclusion 240References 241

CHAPTER 10

Chronopharmacology of Cardiovascular DiseasesB. LEMMER and F. PORTALUPPI. With 2 Figures 251

A. Historical Background 251B. Chronobiological Mechanisms of the Cardiovascular System . . . . 252

I. Physiology and Pathophysiologyof Blood Pressure Regulation 252

II. Cardiovascular Haemodynamics 258III. Electrical Properties of the Heart 260IV. Pathophysiology in Coronary Heart Disease 261

C. Chronopharmacology of Hypertension 262I. (3-Adrenoceptor Antagonists 262

1. Pharmacological Characterization 2622. Clinical Data 262

II. Calcium Channel Blockers 2671. Pharmacological Characterization 2672. Clinical Data 2673. Chronopharmacokinetics 269

III. Converting Enzyme Inhibitors 2701. Pharmacological Characterization 2702. Clinical Data 270

IV. Other Antihypertensives 271V. Chronopharmacology of Blood Pressure

in Congestive Heart Failure 271VI. Conclusion 271

D. Chronopharmacology of Coronary Heart Disease 272I. (3-Adrenoceptor Antagonists 272

II. Calcium Channel Blockers 278III. Organic Nitrates 280

1. Pharmacological Characterization 2802. Clinical Data 280

IV. Drugs Affecting Coagulation 281V. Conclusion 282

E. Concluding Remarks 282References 283

Contents XVII

CHAPTER 11

Chronopharmacology of Anticancer AgentsF. LEVI. With 10 Figures 299

A. Introduction 299B. Experimental Chronopharmacology 299

I. Toxicity Rhythms 299II. Chronopharmacokinetics 301

III. Rhythms in Susceptibility of Target Tissues 303IV. Circadian Rhythms in Antitumor Efficacy 305

C. Clinical Chronopharmacology 307I. Rhythms in Target Tissues 307

II. Chronopharmacokinetics 309D. Clinical Validation of Chronotherapy in Oncology 314

I. Phase I Trials of Chronomodulated Chemotherapy 315II. Phase II Trials 321

III. Chronotherapy of Metastatic Colorectal Cancerwith 5-Fluorouracil, Folinic Acid and Oxaliplatin(Chrono-FFL) 322

E. Conclusions and Perspectives 324References 325

CHAPTER 12

The Endocrine System and DiabetesL. MEJEAN, A. STRICKER-KRONGRAD, and A. LLUCH.With 4 Figures 333

A. Introduction 333B. Chronobiology of Blood Glucose Levels 334C. Chronobiology of Glucose Tolerance 335D. Chronobiology of Plasma Insulin 335E. Chronobiology of the Corticotropic Axis 337F. Chronobiology of Feeding Behaviour 338G. Chronopharmacological Approach to Diabetes 339References 345

CHAPTER 13

Gastrointestinal TractJ.G. MOORE and H. MERKI. With 21 Figures 351

A. Introduction 351B. Gastrointestinal Motility Rhythms 351

I. Pharmacological and Therapeutic Implications 354

XVIII Contents

II. Other Circadian RhythmsInfluencing Drug Bioavailability 355

C. Rhythms in Gastric Acid Secretion 357I. Pharmacological Implications 361

II. Therapeutic Implications 367D. Rhythms in Gastric Mucosal Defense 367E. Circadian Influence

in Cancer Chemotherapeutic Treatment Regimens 369References 371

CHAPTER 14

The Pineal Gland, Circadian Rhythms and PhotoperiodismJ. ARENDT. With 10 Figures 375

A. Introduction 375B. Melatonin Production 376C. Light Control of Melatonin Secretion 380D. Control of Seasonal Cycles 383E. Mechanism of Action of Melatonin

in Control of Seasonal Rhythms 385F. Human Seasonally 387G. Melatonin as a Circadian Marker Rhythm 387H. Effects of Melatonin on Circadian Rhythms 391I. Melatonin and Core Body Temperature 395J. Therapeutic Uses of Melatonin 395

K. Mechanism of Action of Melatoninin the Control of Circadian Rhythms 398

L. Melatonin Receptors 401M. Melatonin Antagonists and Agonists 401References 404

CHAPTER 15

Problems in Interpreting the Effects of Drugson Circadian RhythmsN. MROSOVSKY. With 8 Figures 415

A. Multiplicity of Sites for Chronotypic Action 415B. Alternative Interpretations for Mode of Drug Action 416

I. Gonadal Steroids and Changes in Period 416II. Benzodiazepines and Phase Shifts 418

III. Periodicity After a Single Treatment 420IV. Melatonin Injections and Infusions 420

Contents XIX

C. Tactics for Research on Behavioural Mediation 422I. Measuring Activity 422

II. Altering Opportunities for Activity 422, III. Confinement and Restraint 423

IV. Testing Drugs In Vitro 424D. Problems in Assessing Behavioural Mediation 424E. Mimicking and Modulation of Photic Effects 425

I. The Retinohypothalamic Tract Transmitter 425II. Period and AschofFs Rule 427

III. Sensitivity to Light and Phase Shifts 427IV. Behavioural Inhibition of Photic Shifts 427

F. Saline Injections 428I. Peripheral Injections 428

II. Central Injections 429G. Concluding Remarks 431References 431

CHAPTER 16

Rhythms in Retinal MechanismsG.D. BLOCK and S. MICHEL. With 7 Figures 435

A. Introduction 435B. Retinal Rhythmicity in Xenopus 435

I. Pacemaker Localization 436II. Rhythm Generation 436

III. Pacemaker Entrainment 436IV. Rhythm Expression 439

C. Retinal Rhythmicity in Aplysia californica 440I. Pacemaker Localization 441

II. Rhythm Generation 441III. Pacemaker Entrainment 442

1. Light-Induced Phase Shifts 4422. Serotonin-Induced Phase Shifts 444

IV. Rhythm Expression 446D. Retinal Rhythmicity in Bulla gouldiana 446

I. Pacemaker Localization 447II. Rhythm Generation 447

III. Pacemaker Entrainment 449IV. Rhythm Expression 450

E. Conclusions 451References 451

XX Contents

CHAPTER 17

Circadian Rhythms and Depression: Clinical and Experimental ModelsA.M. ROSENWASSER and A. WIRZ-JUSTICE. With 5 Figures 457

A. Introduction and Scope 457B. Measurement of Circadian Rhythms 458C. Circadian Rhythms and Depression: Clinical Research 459

I. Phase-Advanced Circadian Rhythms 459II. Depression, Sleep, and Rhythmicity 460

III. Seasonal Depression: A Circadian Rhythm Disorder? 461IV. Circadian Amplitude and Waveform 464V. Instability and Zeitgeber Coupling 465

VI. Free-Running Rhythms 466VII. Activity Feedback 466

VIII. Summary 467D. Circadian Rhythms and Depression: Animal Models 468

I. Psychopharmacology of Circadian Rhythms 4681. Phase-Shifting and Free-Running Period 4682. Antidepressants 4713. A Pharmacogenic-Developmental Model 472

II. Stress-Induced Depression Models 472III. Behaviorally Characterized Inbred Strains 473

1. Selection for Hypertension 4732. Selection for Drug Sensitivity 4743. Inbred Mice Differing in Affective Behavior 474

IV. Ablation-Based Depression Models 4751. Olfactory Bulbectomy 4752. Thyroidectomy 475

V. Animal Models of SAD? 476VI. Behavioral Feedback Effects 476

VII. Summary 477E. Conclusions 479References 479

CHAPTER 18

Chronobiology and Chronopharmacology of the Haemopoietic SystemR. SMAALAND. With 8 Figures 487

A. Outline of Haemopoiesis 487B. The Haemopoietic System and the Clinician 491C. Circadian Aspects of the Haemopoietic System 494

I. Circadian Aspects of Proliferative Activityin Murine Bone Marrow 494

II. Circadian Stage-Dependent Cytotoxicityof Murine Bone Marrow 498

Contents XXI

III. Circadian and Circannual Proliferative Activityin Healthy Human Bone Marrow 499

IV. Circadian Variation in Bone Marrow DNA Synthesisin Cancer Patients 504

D. Regulation of Haemopoietic Circadian Rhythms 507E. Chronopharmacological Aspects of the Haemopoietic System . . . 508F. Disease-Dependent Chronotherapeutic Effects

and Consequences 511G. Marker Rhythms for Proliferative Activity and Cytotoxicity

of the Bone Marrow 513H. Chronobiology of Peripheral Blood in Health and Disease 513

I. Total White Blood Cells 514II. Neutrophil Leucocytes 515

III. Lymphocytes 515IV. Eosinophil Leucocytes 516V. Natural Killer Cells 516

VI. Platelets 517I. Cyclic Haemopoiesis 517J. Scientific and Clinical Implications 519

References 522

CHAPTER 19

Chronobiology of the Haemostatic SystemF. ANDREOTTI and G. PATTI. With 2 Figures 533

A. The Haemostatic System and Its Laboratory Evaluation 533I. The Endothelium 533

II. Vasomotion 533III. Platelets 534IV. Coagulation and Viscosity 535V. Fibrinolysis 536

B. Chronobiology of the Haemostatic System 537I. Circadian Variation of Endothelial Cell Function 537

1. Endothelium-Related Factors in Plasma 5372. Effect of Endothelial Removal 5393. Endothelial Reaction to Stimuli 539

II. Circadian Variation of Vasomotor Function 5391. Coronary Artery Tone 5392. Forearm Arterial Tone 5393. Response to Constrictor or Dilator Stimuli 540

III. Circadian Variation of Platelet Function 5411. Platelet Adhesiveness and Serotonin Content 5412. In Vivo Platelet Activation and Aggregation 5413. Platelet Aggregation In Vitro 5424. Platelet <X2-Adrenoceptor Activity 543

XXII Contents

IV. Circadian Variation of Coagulation 5441. Global Measures of Coagulation 5442. Specific Coagulation-Related Factors 5453. Blood Viscosity 546

V. Circadian Variation of Fibrinolytic Activity 5461. Global Assays of Fibrinolysis 5462. Individual Fibrinolytic Factors 5473. Possible Determinants of the Circadian Variation

ofPAI-1 548C. Conclusions 549References 550

CHAPTER 20

New Trends in ChronotoxicologyJ. CAMBAR and M. PONS. With 9 Figures 557

A. Introduction 557B. General Chronotoxicity 558

I. Chemical Toxic Agents 558II. Nonchemical Toxic Agents 562

C. Chronotoxicological Examples in Nonrodents 563D. Organ Specific Circadian Chronotoxicity 563

I. Liver Chronotoxicity (Chronohepatotoxicity) 564II. Ear Chronotoxicity 565

III. Gastric Chronotoxicity 567IV. Renal Chronotoxicity 568

1. Heavy Metal Chrononephrotoxicity 5682. Antibiotic Chrononephrotoxicity 5703. Cyclosporine Chronotoxicity 573

E. Chronesthesy as a Mechanistic Approach to Chronotoxicology . . 578F. Circannual Chronotoxicology 580G. General Conclusions 582References 583

CHAPTER 21

Chronopharmacology of Hi-Receptor Antagonists:Experimental and Clinical Aspects (Allergic Diseases)A.E. REINBERG. With 7 Figures .589

A. Histamine and HrReceptor Antagonists:The Conventional Pharmacological Approach 589

B. Skin Reactivity to Histamine and Allergens 590C. Lung Reactivity to Histamine and Allergens 592

Contents XXIII

D. Dosing-Time-Dependent Changesin the Acute HrReceptor Antagonist Effectsof Four Agents 592

I. Cyproheptadine 592II. Clemastine and Terfenadine 595

r- III. Mequitazine 5961. Skin Tests 5962. Psychopharmacologic Tests and Performance 596

IV. Remarks 596E. Chronopharmacokinetics of Mequitazine 597F. Chronesthesy of Mequitazine with Reference

to Chronic Administration 599I. Skin Tests • 599

II. Bronchial Tests and Temperature 599HI. Psychopharmacological and Performance Tests 599IV. Remarks 601

G. Chronoepidemiology of a Populationof 765 Allergic Patients 601

I. Circadian and Circannual Rhythmsin Allergic Symptoms 601

H. Chronotherapy of Allergic Rhinitis with Mequitazine 603I. Chronotolerance 603

II. Chronoeffectiveness 603III. Remarks 603

I. General Comments 604References 605

CHAPTER 22

Local AnaestheticsB. BRUGUEROLLE. With 3 Figures 607

A. Introduction 607B. Experimental Chronopharmacology of Local Anaesthetics 607

I. Time Dependency in Toxicity 607II. Time Dependency in Kinetics 610

C. Clinical Pharmacology of Local Anaesthetics 611I. Basis for Clinical Chronopharmacology 611

II. Time Dependency in Efficiency 611III. Time Dependency of Pharmacokinetics in Man 612

D. Possible Mechanisms Involved 614E. Conclusions 616References 616

XXIV Contents

CHAPTER 23

Biological Rhythms in Pain and AnalgesiaG. LABRECQUE, M. KARZAZI, and M.-C. VANIER. With 2 Figures . . . 619

A. Introduction 619B. Physiological Mechanisms of Pain 620

I. Pain Conduction Pathways 620II. Neurotransmitters and Pain Perception 621

III. Measurements of Pain 6221. The Pain Questionnaires 6222. The Rating Scales 623

C. Chronobiology of Pain 624I. Biological Rhythms in Pain Control Mechanisms 624

II. Biological Rhythms of Pain 6281. Pain Studies in Experimental Models 6282. Pain Studies in Patients 632

D. Chronopharmacology of Analgesics 636I. Animal Studies 636

II. Human Studies 6371. Patients with Arthritic Pain 638

. 2. Patients with Postoperative and Cancer Pain 640E. Conclusions 642References 644

Subject Index 651