Pharmacotherapy of Cachexia

Pharmacotherapy of Cachexia......Page 2
Preface......Page 4
Editors......Page 5
Contributors......Page 7
Contents......Page 11
Part I: Pathophysiology of Cachexia......Page 14
1.1 INTRODUCTION......Page 15
1.2 ANOREXIA......Page 16
1.3.1 Tumor-Induced Metabolic Alterations......Page 17
1.3.1.1 Protein metabolism......Page 18
1.3.1.3 Lipid metabolism......Page 19
1.4 MEDIATORS......Page 20
1.6 CONCLUSION......Page 22
REFERENCES......Page 23
SUMMARY......Page 28
2.1 INTRODUCTION......Page 29
2.2 SATIETY AND CANCER......Page 30
2.3.1 Cytokines......Page 31
2.3.2 Leptin Regulation......Page 33
2.3.3 Ghrelin......Page 34
2.3.4 Melanocortin System......Page 35
2.3.6 Neuropeptide Y System......Page 36
REFERENCES......Page 38
SUMMARY......Page 42
3.1 CLINICAL SYNDROMES......Page 43
3.2 PROTEIN SYNTHESIS PATHWAYS DOWNSTREAM OF INSULIN-LIKE GROWTH FACTOR 1 IGF1......Page 44
3.3 HYPERTROPHY MEDIATORS DOWNSTREAM OF PI3K AND AKT: THE MTOR AND GSK3 PATHWAYS......Page 45
3.4 A DISTINCT HYPERTROPHY MEDIATOR DOWNSTREAM OF PI3K AND AKT: GSK3beta......Page 46
3.7 ATROPHY VIA INDUCTION OF UBIQUITIN LIGASE PATHWAYS......Page 47
3.9 CACHECTIC TRIGGERS OF ATROPHY......Page 50
3.10 OTHER POTENTIAL MEDIATORS OF ATROPHY: MYOSTATIN......Page 52
REFERENCES......Page 53
Abbreviations......Page 60
4.1 INTRODUCTION......Page 61
4.2 APOPTOTIC SIGNALING......Page 62
4.2.1 Mitochondrion-Mediated Signaling......Page 63
4.2.2 Receptor-Mediated Signaling......Page 65
4.3 APOPTOSIS IN SKELETAL MUSCLE......Page 66
4.3.1 Skeletal Muscle Apoptosis in Cachexia......Page 67
4.3.1.1 Causes of apoptosis in cachexia......Page 68
4.3.1.2 Experimental treatments for prevention of skeletal muscle apoptosis in cachexia......Page 70
4.3.2 Skeletal Muscle Apoptosis in Normal Aging......Page 71
4.3.3 Exercise and Skeletal Muscle Apoptosis......Page 73
4.5 CONCLUSION......Page 74
REFERENCES......Page 75
SUMMARY......Page 81
5.2.1 Thyrotoxicosis......Page 82
5.2.2 Growth Hormone Deficiency......Page 84
5.2.3 Addison’s Disease and Steroid Hormones......Page 85
5.2.4 Diabetes Mellitus......Page 86
5.3.1 Sympathetic Nervous System......Page 87
5.3.2 Renin–Angiotensin System......Page 89
5.5 CACHEXIA IN SYSTEMIC DISEASE......Page 90
5.5.1 Heart Failure......Page 91
5.6 NEUROHORMONAL BALANCE AND CACHEXIA: CONCLUDING REMARKS......Page 96
REFERENCES......Page 97
SUMMARY......Page 110
6.1.1.1 The cytokine axis of skeletal muscle......Page 111
6.2 METHODS AND APPROACHES IN MUSCLE CYTOKINE RESEARCH......Page 113
6.3.2 Inhibition of GH and/or IGF-1 Signaling......Page 115
6.3.3 Cytokine-Induced Insulin Resistance......Page 116
6.4 ANABOLIC MYOTROPHIC CYTOKINES......Page 117
REFERENCES......Page 118
Part II: Diseases Associated with Cachexia......Page 124
CONTENTS......Page 125
7.1 THE DEFINITION OF CANCER CACHEXIA......Page 126
7.2 THE INCIDENCE OF CACHEXIA IN CANCER PATIENTS......Page 127
7.3 THE PATHOPHYSIOLOGY OF CANCER CACHEXIA: TUMOR VS. HOST......Page 129
7.4.1 Proteolysis-Inducing Factor......Page 130
7.4.2 Lipid Mobilizing Factor......Page 131
7.4.3 Cytokines......Page 132
7.5.1 The Acute Phase Response/Systemic Inflammation......Page 133
7.6.1 Inadequate Nutritional Intake......Page 135
7.7.1 Weight Loss and Body Composition......Page 137
7.7.3 Functional Status......Page 138
7.7.4 Quality of Life......Page 139
7.8.2 The Effect of Cachexia on Patient Response to Palliative Therapy......Page 141
7.8.3 The Effect of Cachexia on Survival......Page 142
REFERENCES......Page 143
CONTENTS......Page 151
SUMMARY......Page 152
8.2.1 Pathophysiology......Page 153
8.2.2 Clinical Aspects and Symptoms of HIV Infection......Page 154
8.3.1 Definition and Pathophysiology......Page 155
8.3.1.3 Wasting syndrome, cytokines, and hypertriglyceridemia......Page 158
8.3.1.5 Wasting syndrome of AIDS and the role of modern antiretroviral therapy......Page 159
8.4 GENERAL TARGETS AND OBJECTIVES OF ANTICACHEXIA THERAPY IN AIDS......Page 160
8.4.2.1.1 Cannabinoids......Page 161
8.4.2.2 Protein anabolic agents......Page 164
8.5 CONCLUSIONS......Page 165
REFERENCES......Page 166
SUMMARY......Page 173
9.2.1 Epidemiology......Page 175
9.2.4.2 Corticosteroids......Page 176
9.3.2 Loss of Lean Mass in Aging vs. Inflammation......Page 177
9.3.3.1 Role of sarcoactive cytokines......Page 178
9.3.3.2 Energy expenditure profile......Page 179
9.3.3.5.1 Growth hormone GH and insulin-like growth factor-I IGF-I......Page 180
9.3.4.1 Exercise......Page 181
9.3.4.2.1 Energy and protein......Page 182
9.3.4.3 Cytokine antagonists......Page 183
REFERENCES......Page 184
CONTENTS......Page 188
SUMMARY......Page 189
10.1 INTRODUCTION......Page 190
10.2.1 Signs of Protein-Energy Malnutritions......Page 192
10.2.1.1 Subjective global assessment of nutritional status......Page 193
10.2.2 Prevalence of PEM/Wasting in ESRD......Page 194
10.3 CAUSES OF PEM/WASTING IN ESRD PATIENTS......Page 195
10.3.1 Inflammation as Cause of PEM/Wasting in ESRD......Page 196
10.4.1 General Aspects......Page 198
10.4.1.1 Treatment of metabolic acidosis......Page 200
10.4.2.1 Protein requirements in ESRD patients......Page 201
10.4.2.3 Monitoring and maintenance of adequate protein and energy intakes......Page 202
10.4.2.4 Vitamin and trace mineral requirements of ESRD patients......Page 203
10.4.2.6 Carnitine depletion......Page 204
10.4.3.1 Clinical cause of amino acid-based peritoneal dialysis fluids......Page 205
10.4.4 Is There a Role for Appetite Stimulants in ESRD?......Page 206
10.4.5.1 Correction of anemia and erythropoietin treatment......Page 207
10.4.5.3 Growth hormone and insulin-like growth factor-1......Page 208
10.5.1 Anti-Inflammatory Nutritional Treatment Strategies......Page 209
10.5.2.1 Anti-inflammatory effects of regularly used drugs......Page 210
10.5.2.3 Targeted anticytokine treatment strategies......Page 212
10.6 SUMMARY AND CONCLUSIONS......Page 213
REFERENCES......Page 214
11.1 INTRODUCTION......Page 228
11.2 DIAGNOSIS OF CARDIAC CACHEXIA......Page 230
11.3 COMPOSITION OF BODY TISSUES......Page 232
11.5 UNDERLYING CAUSES OF CARDIAC CACHEXIA......Page 233
11.6 CLINICAL RELEVANCE......Page 234
REFERENCES......Page 236
12.1 INTRODUCTION......Page 239
12.2 CONSEQUENCES OF WEIGHT LOSS AND MUSCLE WASTING IN COPD......Page 240
12.3.1 Energy Expenditure......Page 241
12.3.2 Dietary Intake......Page 242
12.4 STRATEGY AND EFFICACY OF NUTRITIONAL INTERVENTION......Page 243
12.6 PROTEIN METABOLISM......Page 244
12.7 AMINO ACID METABOLISM......Page 245
12.8 INFLAMMATORY MODULATION......Page 246
12.9 INTRINSIC ABNORMALITIES IN SKELETAL MUSCLE......Page 247
REFERENCES......Page 248
SUMMARY......Page 254
13.2 ANOREXIA......Page 255
13.2.1 Pharmacotherapy......Page 256
13.4 CACHEXIA......Page 259
REFERENCES......Page 260
Part III: General Therapeutic Aspects......Page 264
14.1 INTRODUCTION......Page 265
14.3 CHOICE OF A TREATMENT EFFECT......Page 266
14.4 TYPES OF INDICATIONS......Page 268
14.6 EXTRAPOLATION TO ALL CACHECTIC PATIENTS......Page 269
REFERENCES......Page 270
SUMMARY......Page 271
15.1 ROLE OF UNDERNUTRITION VS. UNDERLYING DISEASE IN THE PATHOGENESIS AND TREATMENT OF CACHEXIA......Page 272
15.2.1 Assessment of the Nutritional State Using a Nutrition Risk Score......Page 274
15.3.2 Energy Requirements and Energy Substrates......Page 277
15.3.4 Mineral and Vitamin Requirements......Page 278
15.3.7 Enteral Nutrition \0吀甀戀攀 䘀攀攀搀椀渀最......Page 279
15.3.8 Parenteral Nutrition......Page 280
15.3.9 Refeeding Syndrome......Page 282
15.3.10 Costs and Economical Aspects......Page 285
15.4.1 Long-Chain Omega-3 Polyunsaturated Fatty Acids Fish Oil......Page 286
15.5 PERSPECTIVES......Page 287
REFERENCES......Page 288
Part IV: Drugs in Clinical Use......Page 292
SUMMARY......Page 293
16.2 MEGESTROL ACETATE AND MEDROXYPROGESTERONE ACETATE......Page 294
16.3 CANNABINOIDS......Page 297
16.4 OTHER APPETITE STIMULANTS ? CYPROHEPTADINE, CORTICOSTEROIDS, AND HYDRAZINE SULFATE......Page 299
REFERENCES......Page 301
17.1 INTRODUCTION......Page 305
17.2 PATHOPHYSIOLOGIC MECHANISMS......Page 306
17.3 HUMAN STUDIES — ACE INHIBITORS......Page 307
17.4 HUMAN STUDIES — BETA-BLOCKERS......Page 308
17.5 OTHER CACHECTIC DISEASES......Page 309
REFERENCES......Page 310
SUMMARY......Page 313
18.2.1 Inhibition of Skeletal Muscle Proteolysis......Page 314
18.2.2 Stimulation of Skeletal Muscle Protein Synthesis......Page 315
18.4 EFFECTS OF beta2-AGONISTS ON MUSCLE STRENGTH AND MUSCLE MASS: HUMAN CLINICAL TRIALS......Page 316
18.5 EFFECTS OF beta2-AGONISTS ON MUSCLE STRENGTH AND MUSCLE MASS, AND MYOSIN HEAVY-CHAIN CHANGES: ANIMAL STUDIES......Page 320
18.6 SIDE EFFECTS OF beta2-AGONISTS......Page 322
REFERENCES......Page 323
CONTENTS......Page 327
19.1 INTRODUCTION......Page 328
19.2.2 Glucocorticoids......Page 329
19.3.1 Testosterone and Other Anabolic Steroids......Page 330
19.4.1.1 Increased protein synthesis......Page 331
19.4.1.5 Decreased inflammatory cytokine production......Page 332
19.4.2 Glucocorticoids......Page 333
19.4.2.3.1 HIV......Page 334
19.4.4 Studies with Anabolic Steroids......Page 335
19.5.1 Studies with Anabolic Steroids......Page 337
19.6.1 Studies with Testosterone......Page 339
19.7.2 Studies with Anabolic Steroids......Page 340
19.9.1 Studies with Testosterone......Page 341
REFERENCES......Page 342
SUMMARY......Page 348
20.2 GROWTH HORMONE: PHYSIOLOGY AND REGULATION IN HEALTH......Page 349
20.3.2 Hormonal Effects......Page 350
20.3.2.3 IGF-I......Page 351
20.5 THE GH/IGF-I AXIS IN CACHEXIA......Page 352
20.6.1 GH in Surgery......Page 353
20.6.2 GH in Burns......Page 355
20.6.3 GH in Sepsis and Trauma......Page 356
20.6.4 GH Treatment in Chronic Heart Failure......Page 357
20.6.5 GH in AIDS Wasting......Page 358
20.7 COMBINED ADMINISTRATION OF GH AND IGF-I IN CACHEXIA......Page 359
20.8 SAFETY OF GH TREATMENT IN CACHEXIA......Page 360
20.9 CONCLUSIONS......Page 361
REFERENCES......Page 362
SUMMARY......Page 370
21.1 INTRODUCTION......Page 371
21.2 PROSTAGLANDINS......Page 372
21.4 CYCLOOXYGENASE......Page 374
21.5 NF KAPPA B......Page 375
21.7 ANTI-INFLAMMATORY AGENTS IN CACHEXIA......Page 376
21.7.1 Corticosteroids......Page 377
21.7.2 Nonsteroidal Anti-Inflammatory Drugs......Page 378
21.7.2.3 Animal studies with NSAIDs......Page 380
21.7.2.4 Clinical studies......Page 381
21.7.3.2 Clinical studies......Page 382
REFERENCES......Page 383
Part V: Drugs in Research and Development......Page 393
SUMMARY......Page 394
22.1 INTRODUCTION......Page 395
22.2 REPLACEMENT THERAPY FOR GH DEFICIENCY, IGF-1 DEFICIENCY, OR GHRELIN DEFICIENCY......Page 396
22.3.1 Short Stature......Page 397
22.3.3 Immune System......Page 398
22.3.5 Beneficial Effects of GH/IGF-1 on the Brain......Page 399
22.5 THE USE OF IGF-1 RECEPTOR ANTAGONISTS IN CANCER......Page 400
REFERENCES......Page 401
SUMMARY......Page 405
23.2 ANEMIA ? AN ESTABLISHED INDICATION FOR EPO IN CACHEXIA......Page 406
23.3 PLEIOTROPIC EFFECTS OF ERYTHROPOIETIN......Page 409
23.4 ERYTHROPOIETIN FOR THE IMPROVEMENT OF EXERCISE INTOLERANCE IN CACHECTIC PATIENTS......Page 410
23.5 EFFECTS OF EPO ON BODY COMPOSITION AND NUTRITIONAL STATUS......Page 412
23.6 ANTI-APOPTOTIC AND ISCHEMIA-PROTECTIVE EFFECTS OF EPO WITHIN MYOCARDIUM......Page 413
23.7 THERAPY WITH EPO ? REMAINING CONCERNS......Page 414
REFERENCES......Page 415
SUMMARY......Page 423
24.2.1 Statin Development......Page 424
24.2.2 Basic Mechanisms of Action......Page 425
24.2.3 Statin Classification......Page 428
24.2.4 Side Effects......Page 429
24.3 POTENTIAL PLEIOTROPIC EFFECTS ON THE CARDIOVASCULAR SYSTEM......Page 430
24.3.1 Endothelial Dysfunction, Nitric Oxide, and Oxidative Stress......Page 431
24.3.2 Endothelial Progenitor Cells......Page 432
24.4 POTENTIAL PLEIOTROPIC EFFECTS ON THE IMMUNE SYSTEM......Page 433
24.5.1 Statin-Mediated Effects on Skeletal Muscle......Page 435
24.5.2 Statin-Mediated Effects on the Proteasome......Page 436
24.6.1 Growth Arrest and Apoptosis......Page 437
24.6.2 Anti-Metastatic Properties......Page 438
24.6.3 Angiogenesis......Page 439
24.7 CONCLUSION......Page 440
REFERENCES......Page 441
25.1 INTRODUCTION......Page 449
25.1.1 Historic Milestones in Metabolic Studies......Page 450
25.2.2 Insulin Resistance is Associated with Myocardial and Skeletal Muscle Functional Impairment......Page 451
25.2.5 Insulin Sensitivity and Prognosis......Page 453
25.2.6 Mechanisms of Insulin Resistance in Chronic Disease......Page 454
25.2.7 Insulin Resistance as a Potential Novel Therapeutic Target......Page 455
25.3.1 Introduction......Page 457
25.3.2 The XO Metabolic Pathway as One Part of a Complex Metabolic Web......Page 459
25.3.3 Cardiovascular Effect of XO-Derived Free Oxygen Radicals......Page 460
25.3.4 Hyperuricemia as a Novel Prognostic Marker......Page 462
REFERENCES......Page 463
SUMMARY......Page 471
26.2 OVERVIEW OF THE CANCER ANOREXIA/WEIGHT LOSS SYNDROME......Page 472
26.3 MECHANISMS AND MEDIATORS: RECENT DATA ON TUMOR NECROSIS FACTOR......Page 474
26.4 THERAPEUTICS: WHAT DOES NOT WORK ? AND WHAT MIGHT WORK......Page 475
26.5 TUMOR NECROSIS FACTOR BLOCKADE WITH INFLIXIMAB AND ETANERCEPT: A POTENTIAL TREATMENT STRATEGY......Page 480
26.6 A BRIEF OVERVIEW OF ONGOING CLINICAL TRIALS FROM THE NORTH CENTRAL CANCER TREATMENT GROUP......Page 482
REFERENCES......Page 483
Part VI: Future Drug Targets......Page 486
27.1 INTRODUCTION: THE CENTRAL CONTROL BODY WEIGHT......Page 487
27.2 THE ROLE OF THE HYPOTHALAMUS IN THE REGULATION OF ENERGY BALANCE......Page 488
27.3.1 Hypothalamic Systems Involved in Energy Balance and their Potential Role in Cachexia......Page 490
27.4 NEUROPEPTIDE SYSTEMS IN THE ARCUATE NUCLEUS......Page 491
27.5 NEUROPEPTIDE SYSTEMS IN THE LHA......Page 493
27.7 OTHER NEUROPEPTIDES AND NONPEPTIDE NEUROTRANSMITTERS......Page 495
REFERENCES......Page 497
CONTENTS......Page 506
SUMMARY......Page 507
28.2.1 The Ubiquitin-Proteasome System as Central Regulator of Cellular Functions......Page 508
28.2.3 Ubiquitinating Enzymes Ensure Selectivity and Specificity......Page 509
28.3.1 Multiple Methods Provide Evidence in Rodent Models......Page 510
28.3.2 Involvement of the E3alpha/E214k Enzymes in Muscle Wasting......Page 513
28.3.4 Nedd4 and KIAA10......Page 514
28.4 MAKING MYOFIBRILLAR PROTEINS AVAILABLE FOR DEGRADATION BY THE UBIQUITIN-PROTEASOME PATHWAY: PREPROTEASOMAL PROTEOLYTIC MECHANISMS......Page 515
28.4.1 Calcium-Dependent Release of Contractile Proteins by Calpains......Page 516
28.4.3 Cathepsins......Page 517
28.5 SIGNALING MOLECULES INVOLVED IN ACTIVATION OF THE UBIQUITIN-PROTEASOME SYSTEM......Page 518
28.5.1 The Role of Glucocorticoids......Page 519
28.5.2 IGF-I Prevents Induction of Components of the Ubiquitin-Proteasome System......Page 520
28.5.3 IGF-I-Mediated Regulation of Atrogin-1 Involves PI3K/Akt/Foxo Signaling......Page 521
28.5.4 IGF-I Regulation of Caspase and Calpain Activity......Page 522
28.5.5 The Role of TNF-alpha and NF-kappaB......Page 523
28.6.1 Evidence for a Role of the Ubiquitin-Proteasome System in Patients......Page 525
28.6.2 Cancer and Inflammatory Disease......Page 526
REFERENCES......Page 527
CONTENTS......Page 538
29.1 INTRODUCTION......Page 539
29.2 THE CALCINEURIN/NF-AT SIGNALING PATHWAY......Page 540
29.3 THE IGF-1/PI3K/AktPKB/mTOR SIGNALING PATHWAYS......Page 542
29.3.1 The Central Elements AktPKB and mTOR are Positive Regulators of Muscle Size......Page 543
29.3.2 mTOR Assembles into Two Distinct Complexes......Page 545
29.4 THE NF-kappaB SIGNALING PATHWAY......Page 546
29.4.2 The Role of NF-kappaB in Muscle Growth......Page 547
29.4.2.2 NF-kappaB enhances muscle degradation through activation of the ubiquitin-proteasome system......Page 549
29.4.3 NF-kappaB as a Potential Drug Target for the Treatment of Cancer Cachexia......Page 550
29.5.1 Myostatin-Mediated Regulation of Muscle Growth......Page 551
29.5.2 Processing of Myostatin Protein......Page 552
29.5.3 Therapeutic Relevance of Myostatin Signaling......Page 553
29.5.4 Myostatin as a Potential Drug Target to Prevent Muscle Loss......Page 555
REFERENCES......Page 556
30.1 DEFINITION......Page 560
30.2 CLINICAL ASPECTS......Page 561
30.4 THERAPEUTIC ASPECTS......Page 562
30.5 POSSIBLE FUTURE DEVELOPMENTS......Page 563
REFERENCES......Page 564