Gth-FOi H

Drugs forthe Treatment ofParkinson's Disease

Contributors

R. D. G. Blair, D. B. Calne, S. G. Diamond, S. Fahn, A. Fine,V. Glover, M. Goldstein, G. Gopinathan, O. Hornykiewicz,R. Horowski, J. Irwin, J. Jankovic, K. Jellinger,H. Kaufmann, H. L. Klawans, A. E. Lang, J. W. Langston,P. A. LeWitt, A. N. Lieberman, C. H. Markham,W. R. W. Martin, E. G. McGeer, P. L. McGeer, J. A.Obeso,J.D. Parkes, J. B. Penney, R. F. Peppard, H. A. Robertson,M. Sandier, W. Schultz, I. Shoulson, S.M. Stahl, I. Suchy,C. M. Tanner, H. Teravainen, J. K. Tsui, M. D. Yahr,A.B. Young

Editor

Donald B. Calne

Springer-Verlag Berlin Heidelberg New YorkLondon Paris Tokyo Hong Kong

Contents

CHAPTER 1

Neurophysiology of Basal GangliaW. SCHULTZ , 1

A. Introduction 1B. Electrophysiology of Connections 2

I. Peripheral and Cerebral Input to Basal Ganglia 21. Striatum 2

a. Peripheral Input 2b. Cerebral Input 3

2. Nucleus Subthalamicus 43. Substantia Nigra 4

II. Internal Basal Ganglia Connections 41. Nigrostriatal Dopamine System 5

a. Substantia Nigra 5b. Striatum 5

2. Striatopallidal . 63. Striatonigral 74. Nucleus Subthalamicus 75. Nucleus Tegmenti Pedunculopontinus 8

III. Output of Basal Ganglia . . . 81. Pallidothalamic . \ . 82. Nigrothalamic '. 93. Pallidohabenular 94. Nigrocollicular 95. Nucleus Tegmenti Pedunculopontinus 10

C. Motor Control Functions 10I. Anatomic Considerations 10II. Lesions, Cooling, and Local Drug Injections 11

1. Striatum 112. Globus Pallidus 113. Substantia Nigra Pars Reticulata 124. Nucleus Subthalamicus 12

III. Neuronal Recordings 131. Striatum 132. Globus Pallidus 143-. Substantia Nigra Pars Reticulata 15

XII Contents

4. Nucleus Subthalamicus 15D. Higher Functions 16

I. Anatomy of Connections 161. Cortical Input . 162. Limbic Input 163. Output 17

II. Neuropsychologic Deficits After Lesions 17III. Neuronal Recordings 18

1. Untrained Behavior 182. Context-Dependent Responses to Directly Triggering Stimuli 183. Preparation to Act . 20

a. Nondiscriminative Instructions 21b. Discriminative Instructions 21c. Delayed Response Tasks 22d. Self-Initiated Acts 23

E. Dopaminergic Functions 24I. Animal Models of Parkinsonism . 24

1. Monkey - . . 242. Rodent 25

II. Impulse activity of Dopamine Neurons 261. Peripheral Input Under Anesthesia 262. Relations to Behavior 27

a. Execution of Movements 27b. Responses to Stimuli 27c. Preparation to Act 28

3. Comparison with Deficits 29F. Conclusions 30

I. Functional Connectivity 301. Lateralization of Function 302. Disinhibition of Target Structures 303. The "Extrapyramidal Motor System" . . . . . . . . 31

II. Dopamine System \ • • • 311. Mismatch Between Negative and Positive Image . . . . 312. Paradoxical Kinesia 313. Neuronal Activity in Target Areas of DA Neurons . . . . 32

III. Corticostriatal Activity 32References 33

CHAPTER 2

Pathology of Parkinson's SyndromeK.JELLINGER. With 9 Figures 47

A. Introduction 47B. Cytoskeletal Pathology 49

I. Lewy Bodies 49II. Hirano Bodies 51

Contents XIII

III. Intracytoplasmic Eosinophilic Granules 51IV. Marinesco Bodies 51V. Neurofibrillary Tangles 51

1. Alzheimer's Neurofibrillary Tangles 512. Tangles in Progressive Supranuclear Palsy 52

VI. Granulovacuolar Degeneration 52VII. Axonal Dystrophy and Grumelous Degeneration 53VIII. Neuritic Plaques and Amyloid . 53

C. Major Types of Parkinsonism 53I. Parkinson's Disease 54II. Parkinson's Disease and Alzheimer's Disease 59III. Diffuse Lewy Body Disease 62IV. Multisystem Degenerations 63V. Parkinson-Dementia Complex '. 63VI. Progressive Supranuclear Palsy 64VII. Postencephalitic Parkinsonism 64VIII. Vascular or Multi-infarct Parkinsonism 66IX. Toxic Parkinsonism 66X. Symptomatic Parkinsonism 67

D. Morphological Correlates of Pathobiochemistry 67I. Dopaminergic System 67

1. Substantia Nigra and Ventral Tegmental Area 682. Striatopallidum and Other CNS Areas . 71

II. Noradrenergic System 721. Locus Ceruleus 722. Dorsal Vagal Nucleus 75

III. Serotonergic System 75IV. Cholinergic Systems . 77

1. Nucleus Basalis of Meynert 772. Nucleus Tegmenti Pedunculopantinus 803. Westphal-Edinger Nucleus , . 81

V. Peptidergic Systems \ . 81E. Morphological Effects of Levodopa Treatment \ 82F. Pathology of Dementia in Parkinson's Disease 82G. Concluding Remarks 91References 94

CHAPTER 3

Biochemical Neuroanatomy of the Basal GangliaE.G. MCGEER and P.L. MCGEER. With 12 Figures 113

A. Introduction 113B. Neurotransmitters in the Extrapyramidal System 114

I. Type I: Amino Acid Neurotransmitters 114II. Type II: Amine Neurotransmitters 116III. Type III: Peptide Neurotransmitters 118

XIV Contents

IV. Receptor Subtypes . 120C. Heterogeneities in Extrapyramidal Nuclei 121

I. Mosaics or Gradients . 121II. Differences Between Caudate, Putamen, and Nucleus

Accumbens 123D. Interconnections in the Extrapyramidal System 124E. Some Hypotheses as to the Role of Various Tracts

in the Extrapyramidal System 128F. Conclusions 130G. Appendix: Afferents and Efferents of Extrapyramidal Nuclei . . . 130References 137

CHAPTER 4

Receptors in the Basal GangliaA.B. YOUNG and J.B. PENNEY. With 2 Figures 149

A. Introduction 149B. Neurotransmitter Receptor Properties 149C. Dopamine Receptors 150

I. Properties and Subtypes 150II. Distribution 152III. Dopamine Receptors in Parkinson's Disease 155IV. In Vivo Studies . 1 5 6

D. GABA Receptors 156E. Acetylcholine Receptors . . . 1 5 6F. Opiate Receptors 157G. Other Receptors 158H. Summary 158References . . . . . 159

CHAPTER 5 \

Imaging the Basal GangliaW.R.W. MARTIN. With 3 Figures 165

A. Introduction 165B. Structural Imaging Techniques 166

I. Methodology 1661. X-Ray Computed Tomography (CT) . 1662. Magnetic Resonance Imaging (MRI) 166

II. Parkinson's Disease 166III. Huntington's Disease 167IV. Dystonia 167V. Other Movement Disorders 168

C. Functional Imaging Techniques 168I. Methodology 168

1. Positron Emission Tomography (PET) 168

Contents XV

a. Cerebral Blood Flow and Metabolism 168b. Presyriaptic Dopaminergic Function 169c. Dopamine Receptors 171

2. Single-Photon Emission Computed Tomography (SPECT) . 172II. Parkinson's Disease . 172III. Huntington's Disease 174IV. Dystonia 177

D. Conclusions 178References 178

CHAPTER 6

The Neurochemical Basis of the Pharmacology ofParkinson's Disease0.HORNYKIEWICZ. With 4 Figures 185

A. Introduction 185B. The Basic Neurochemical Pathology of Parkinson's Disease . . . 1 8 5

I. The Nigrostriatal Dopamine Neuron System 186II. Extrastriatal Dopamine Neurons 187III. Nondopamine Neuron Systems 188

C. Pathophysiologic and Pharmacologic Significance of theBiochemical Brain Abnormalities in Parkinson's Disease . . . . 1 8 9I. Nigrostriatal Dopamine Loss 189II. Extrastriatal Dopamine Changes 190III. Nondopamine Changes 190

1. Changes in the Basal Ganglia 190a. Norepinephrine .• • • 191b. Acetylcholine 192c. Y-Aminobutyric Acid . 192d. Serotonin, Neuropeptides 193

2. Changes Outside the Basal Ganglia , . 193D. Striatal Dopamine Deficiency and the Pharmacotherapy of \

Parkinson's Disease: Special Aspects of Dopamine Substitution . . 194I. Compensatory Changes in the Nigrostriatal Dopamine Neurons 194II. Compensated and Decompensated Stages of Parkinson's Disease

and the Goal of Dopamine Substitution 195III. The Role of the Compensatory Changes for Dopamine

Substitution . 1961. The Role of Presynaptic Overactivity 1962. The Importance of Postsynaptic Supersensitivity for

the Pharmacology of Parkinson's Disease 196a. Special Sensitivity of the Parkinsonian Striatum to

Dopamine Substitution 197b. Regional Selectivity of Dopamine Substitution Therapy . 197c. New approaches to Dopamine Substitution 198

a. Selective Dopamine Autoreceptor Agonists as a NewClass of Specific Potential Antiparkinsonian Agents . 198

XVI Contents

p. Autografting of Dopamine-Producing Cells intothe Parkinsonian Striatum 198.

E. Prospects of Preventive Drug Treatment in Parkinson's Disease . . 199References 199

CHAPTER 7

Pyridine ToxinsJ.W. LANGSTON and I. IRWIN. With 3 Figures 205

A. Introduction 205B. What are Pyridines? 205

I. Historical Background 205II. Structure and Chemistry 205III. Biologic Role 207IV. Distribution of Pyridines 207

C. Pyridines as Toxins 208I. History 208II. Animal Models 209

1. Invertebrates 2092. Amphibia 2103. Rodents 2104. Cat 2115. Dog 2116. Primates 212

D. Factors Affecting Toxicity 212I. Mechanism of Action 213II. Toxicokinetic and Toxicodynamic Effects 213III. Species Differences 214IV. Neuromelanin . 215V. Age Differences . ,. . . 216

E. Pyridines as Protectors? , . . .\ . . 217F. Toxic Tetrahydropyridines: A Growing Family '• . . 218G. Pyridines and Parkinson's Disease 220References '. . . . 220

CHAPTER 8

The Relationship Between Parkinson's Disease andOther Movement DisordersJ.JANKOVIC. With 4 Figures. . . : 227

A. Introduction 227B. Secondary Parkinsonism . 232

I. Drug-Induced Parkinsonism 232II. Toxin-Induced Parkinsonism 233

1. Manganese 2332. Carbon Monoxide 234

Contents XVII

3. Cyanide 2364. Carbon Disulfide 2365. Other Toxins 237

III. Metabolic Causes of Parkinsonism 2381. Hypoparathyroidism 2382. Acquired Hepatocerebral Degeneration 2393. Other Metabolic Causes 239

IV. Postencephalitic Parkinsonism and Slow Virus Infections . . 239V. Vascular Parkinsonism 242VI. Brain Tumors 243VII. Trauma 244VIII. Hydrocephalus 245IX. Syringomesencephalia 246

C. Sporadic Multiple System Degenerations (Parkinsonism-Plus) . . 246I. Progressive Supranuclear Palsy 246II. Shy-Drager Syndrome 249III. Olivopontocerebellar Atrophies 250IV. Corticobasal Degeneration . 252V. Parkinsonism-Dementia-ALS Complex 252VI. Striatonigral Degeneration 254

D. Inherited Multiple System Degenerations 256I. Huntington's Disease 256II. Wilson's Disease 258III. Hallervorden-Spatz Disease 258IV. Other Familial Parkinsonian Syndromes 259V. Familial Basal Ganglia Calcifications 259VI. Neuroacanthocytosis 259

References 260

CHAPTER 9

Evaluation of Parkinson's Disease ' \H.TERAVAINEN, J.Tsui and D.B. CALNE. With 2 Figures . . . . . . 2 7 1

A. Introduction 271B. Subjective Assessment 271C. Objective Assessment 275

I. Tremor , 275II. Rigidity 276III. Hypokinesia 277

D. Summary 278References 278

CHAPTER 10

Clinical Trials for Parkinson's DiseaseJ.K.Tsui, H.TERAVAINEN and D.B. CALNE 281

XVIII Contents

A. Introduction 281B. Phases 281C. Design 282D. Recruitment 284E. Assessment 284F. Statistical Analysis 285G. Conclusions 286References 286

CHAPTER 11

Experimental Therapeutics Directed at the Pathogenesis ofParkinson's DiseaseI. SHOULSON. With 1 Figure 289

A. Introduction 289B. General Strategies for Prevention and Protection 289C. Antioxidative Pharmacotherapies 290D. Clinical Trial of Deprenyl and Tocopherol Antioxidative Therapy of

Parkinsonism (DATATOP) 293I. Pilot Studies and Candidate Drugs 293II. Factorial Design 295III. Major Response Variable 295IV. Sample Size Estimates 297V. Symptomatic or Protective Effects? 298VI. Recruitment 299VII. Potential Pitfalls 299

E. Animal Models 300F. Neural Grafting 301G. Summary 301References • • • 302

V

CHAPTER 12

Anticholinergic Drugs and Amantadine in the Treatment ofParkinson's DiseaseA. E. LANG and R.D.G. BLAIR 307

A. Introduction 307B. Anticholinergics 307

I. Introduction 307II. Mechanism of Action 308III. Pharmacokinetics 309IV. Clinical Effects 309V. Side Effects 311VI. Conclusions 312

C. Amantadine 312I. Introduction 312

Contents XIX

II. Mechanism of Action 313III. Pharmacokinetics 314IV. Clinical Effects 314V. Side Effects . . • 315VI. Conclusions 317

References 318

CHAPTER 13

The Pharmacology of Levodopa in Treatment of Parkinson's Disease:An UpdateP.A. LEWITT 325

A. Introduction , 325B. The Efficacy of Levodopa in Parkinsonism 326

I. Background 326II. Clinical Effectiveness of Levodopa in Parkinson's Disease . . 328III. Use of Levodopa in Other Forms of Parkinsonism and

Other Movement Disorders 330IV. Therapeutic Principles for Levodopa 331

C. Clinical Aspects of Levodopa Pharmacokinetics, Pharmacodynamics,and Metabolism 333I. Levodopa Pharmacokinetics 333II. Levodopa Metabolism: 3-O-Methyldopa and Other Metabolites 337III. Other Metabolic Effects of Levodopa 338

D. Other Effects of Levodopa 340E. Pharmacodynamics of Levodopa Therapy 342F. Mechanism of Action of Levodopa in Parkinsonism 344G. Levodopa Preparations 348

I. Decarboxylase Inhibitors 348II. Sustained-Release Forms 352III. Enhanced Delivery and Uptake \ . 354

H. Therapeutic Uses for Levodopa Other Than Parkinsonism . . . . 354J. Clinical Issues Regarding Initiation of Levodopa Therapy . . . . 355

I. "Early" Versus "Delayed" Use of Levodopa 355II. "Low Dose" Levodopa Regimens 359

K. Clinical Issues Regarding "Drug Holiday" 359References 361

CHAPTER 14

Adverse Effects of Levodopa in Parkinson's DiseaseS.FAHN 385

A. Historical Aspects of Adverse Effects 385B. Classification, Pathophysiology, and Treatment of Adverse Effects . 389

I. Peripheral Adverse Effects . 3 9 21. Gastrointestinal Symptoms 392

XX Contents

2. Cardiac Dysrhythmias 3933. Melanoma 393

II. Central Adverse Effects 3931. Dyskinesias 393

a. Chorea 393a. Peak-Dose Chorea . . . 3 9 3p. Diphasic Chorea 393

b. Dystonia 394a. Peak-Dose Dystonia 394p. Diphasic Dystonia 394Y. "Off" Dystonia 394

c. Myoclonus 395d. Simultaneous Dyskinesias with Parkinsonism . . . . 3 9 5

2. Tachykinesia with Hypokinesia 395a. Tachyphemia 395b. Running Gait 396

3. Fluctuations 396a. "Wearing-Off" 396b. "Sudden Off" 397c. "Random Off" 397d. Yo-yo-ing . 398e. Episodic Failure to Respond to Each Dose 398f. "Delayed On" 398g. Weak Levodopa Response at End of Day 399h. Response Varies in Relation to Meals 399

.4. "Freezing" 3995. Mental Changes 4006. Loss of Efficacy 400

a. Caused by Pyridoxine 400b. With Continuing Treatment 400

7. Miscellaneous 401a. Altered Sleep-Wake Cycle . .\ . . . 4 0 1b. Hypersexuality 401c. Akathisia . 402d. Sweating 403e. Postural Hypotension 403f. Respiratory Distress 403g. Falling . 404h. Pain 404j . Increased Parkinsonism 404k. "Neuroleptic Malignant Syndrome" 404

References 405

CHAPTER 15

Monoamine Oxidase Inhibitors in Parkinson's DiseaseM. SANDLER and V. GLOVER. With 8 Figures 411

Contents XXI

A. Introduction 411B. The Inhibition of Dopamine Oxidation by (-)-Deprenyl 414C. Cellular Localisation of MAO in the Brain 416D. Safety of (-)-Deprenyl • . 416E. Assessment of MAO Inhibition In Vivo . . . 4 1 8F. Distribution of (-)-Deprenyl in Brain and Body 419G. Metabolism of (-)-Deprenyl to Amphetamine 420H. Other Actions of (-)-Deprenyl 421J. MAOandMPTP 422K. Postscript 423References 426

CHAPTER 16

Clinical Actions of L-Deprenyl in Parkinson's DiseaseM.D. YAHRandH.KAUFMANN 433

A. Introduction 433B. Pharmacology 434C. Clinical Trials 435

I. Combined Use of Deprenyl with Levodopa 435II. L-Deprenyl as Monotherapy . 438

D. Summary 438References 439

CHAPTER 17

Update on Bromocriptine in Parkinson's DiseaseA.N. LIEBERMAN and M.GOLDSTEIN. With 9 Figures 443

A. Introduction 443B. Side Effects of Levodopa . 444C. Mechanisms for Decline in Response . . . • . 445D. Treatment of Response Fluctuations: Bromocriptine . . . . . 446E. Studies of Bromocriptine Therapy 449F. Pharmacology of Bromocriptine 454References 456

CHAPTER 18

Pergolide in the Treatment of Parkinson's DiseaseC.H. MARKHAM and S.G. DIAMOND. With 3 Figures 459

A. Chemistry and Pharmacology 459B. Clinical Studies 460

I. Open-Label Studies 460II. Double-Blind Studies 462III. A Long-term Follow-up Study 462

XXII Contents

C. How to Administer 465D. Side Effects 467References ; 468

CHAPTER 19

Lisuride Pharmacology and Treatment of Parkinson's DiseaseG. GOPINATHAN, R. HOROWSKI and I. SUCHY 471

A. Chemistry 471B. Toxicology . 471C. Pharmacokinetics 472D. Biochemistry and Pharmacology 473

I. Receptor Binding 473II. Biochemistry 475III. Pharmacology 475IV. Neurophysiology 478

E. Clinical Applications 481I. Clinical Pharmacology 481II. Applications in Clinical Endocrinology 482

F. Lisuride in Neurological Diseases 487I. Parkinson's Disease and Related Disorders 487

1. Oral Application 4882. Parenteral Application . 4973. Subcutaneous Lisuride: Continuous Dopaminergic

Stimulation 498II. Other Motor Disturbances 499III. Migraine 500

G. Conclusion 501References 501

CHAPTER 20 \

Domperidone and Parkinson's DiseaseJ . D . P A R K E S . With 1 Figure 515

A. Introduction 515B. Domperidone 516

I. Animal Pharmacology 516II. Pharmacokinetics in Humans 516III. Behavioural Effects 517IV. Effect on the Pharmacokinetic Behaviour of Levodopa . . . 5 1 8

C. Effect of Domperidone on Levodopa Response 519I. Therapeutic Response to Levodopa in Parkinsonism . . . . 5 1 9II. Dopamine Agonist-Induced Sickness 522III. Levodopa-Associated Cardiovascular Problems . . . . . . 522

1. Domperidone- and Levodopa-Induced Hypotension . . . 5222. Domperidone and Cardiac Dysrhythmias . 5 2 3

Contents XXIII

3. Domperidone and Cerebral Blood Flow . 523IV. Levodopa-Associated Respiratory Problems 523

D. Comparison of Domperidone with Metoclopramide andOther Neuroleptics in the Management of Parkinson's Disease . . 5 2 5

E. Comparison of Domperidone with Decarboxylase Inhibitors in theManagement of Parkinson's Disease 526

References 527

CHAPTER 21

New Routes of Administration for Antiparkinsonian TherapyJ.A. OBESO and S.MSTAHL. With 2 Figures 531

A. Introduction 531B. Delivery Methods 532

I. Enteral Administration 532II. Intravenous Administration 533III. Subcutaneous Administration 533IV. Transcutaneous Administration . . . . . 5 3 4

C. Clinical Studies . 5 3 4I. Enteral Routes 534II. Intravenous Administration 535

1. Levodopa 5352. Lisuride 5363. Apomorphine . 537

III. Subcutaneous Infusions 537IV. Transdermal Application 539

D. Conclusion 539References 539

CHAPTER 22 \

Treatment of Parkinsonian Features in Neurological Disorders Otherthan Parkinson's DiseaseR.F. PEPPARD and D.B. CALNE 543

A. Introduction 543B. Drug-Induced Parkinsonism . . . ' 543C. Wilson's Disease . 547D. Multiple System Degenerations 549

I. Striatonigral Degeneration 549II. Olivopontocerebellar Atrophy 549III. Shy-Drager Syndrome 550IV. Progressive Supranuclear Palsy 550V. Senile Parkinsonism 551VI. The ALS-Parkinson-Dementia Complex of Guam . . . . 551VII. Joseph Disease 551

XXIV Contents

E. Other Types of Parkinsonism 551I. Postencephalitic Parkinsonism 551II. Parkinsonism Due to Toxins 552III. Hypoparathyroidism 552IV. Huntington's Disease . 552

F. Conclusions 552References 552

CHAPTER 23

Management of Psychiatric Symptoms in Parkinson's DiseaseH.L. KLAWANS and CM. TANNER 557

A. Introduction 557B. Depression 557C. Psychosis and Related Disorders 560

I. Early Onset Psychosis 560II. Late Onset Psychosis 561

D. Drug-Induced Hallucinatory Syndromes 564I. Anticholinergic Delirium 564II. Hallucinations with a Clear Sensorium 565

E. Treatment of Psychosis . . 566F. Aberrant Sexual Behavior 568References 568

CHAPTER 24

Intracranial grafts for the treatment of Parkinson's DiseaseA.FINE and H. A. ROBERTSON 573

A. Introduction 573B. Sources of Dopamine-Secreting Cells 574C. Neural and Adrenal Grafts in Animal Models of Parkinson's Disease 575

I. Studies in the Rat 576II. Studies in Primates . 5 7 8

D. Dopaminergic Grafts in Humans 580E. Conclusions 583References 583