Drugs for the Treatment of Respiratory Diseases

Cover......Page 1 Half-title......Page 3 Title......Page 5 Copyright......Page 6 Contents......Page 7 Contributors......Page 9 Preface......Page 13 Part I Asthma and COPD......Page 15 Introduction......Page 17 Inflammation and remodelling......Page 18 Sputum and bronchoalveolar lavage......Page 19 Asthma......Page 20 COPD......Page 22 Similarity between COPD and asthma......Page 23 The neutrophil......Page 24 The macrophage......Page 25 Vascular inflammation......Page 26 Surface epithelium......Page 27 Reticular basement membrane......Page 28 Bronchial smooth muscle......Page 31 Airway vessels......Page 33 Emphysema......Page 34 Conclusions......Page 36 REFERENCES......Page 37 Effects on gene transcription......Page 46 Effects on chromatin structure......Page 47 Beta2-adrenoceptors......Page 48 Inflammatory receptors......Page 49 Eosinophils......Page 50 Epithelial cells......Page 51 Effects on airway hyper-responsiveness......Page 52 Studies in children......Page 53 Prevention of irreversible airway changes......Page 54 Clinical use of inhaled corticosteroids in asthma......Page 55 Corticosteroid-sparing therapy......Page 56 Pharmacokinetics......Page 57 Systemic side effects......Page 58 Hypothalamic–pituitary–adrenal axis......Page 59 Effects on connective tissue......Page 60 Central nervous system effects......Page 61 Acute severe asthma......Page 62 Mechanisms of corticosteroid resistance......Page 63 Clinical studies with inhaled corticosteroids in COPD......Page 64 REFERENCES......Page 65 Adrenaline......Page 70 Isoprenaline......Page 71 Terbutaline......Page 72 Mechanism of action......Page 73 Route of administration......Page 76 Bronchospasm......Page 77 Selectivity......Page 78 Efficacy......Page 79 Mast cells......Page 80 Endothelial cells......Page 82 Eosinophils......Page 83 Lymphocytes......Page 85 Acute bronchospasm......Page 86 Late asthmatic response......Page 87 Nocturnal asthma......Page 88 COPD......Page 89 Bronchodilator tolerance......Page 90 Loss in bronchoprotection......Page 91 Bronchial hyperresponsiveness......Page 93 Short-acting Beta-adrenoceptor agonists......Page 94 Long-acting Beta-adrenoceptor agonists......Page 96 Case control studies......Page 98 Mechanisms......Page 99 Conclusions......Page 100 REFERENCES......Page 101 Autonomic control of airway calibre......Page 119 Muscarinic receptor subtypes in airways......Page 120 Pharmacology......Page 121 Pharmacokinetics......Page 122 Stable asthma......Page 123 Pediatric airways disease......Page 124 Stable COPD......Page 125 Effects on sleep quality......Page 126 Side effects......Page 128 REFERENCES......Page 129 Mechanisms of action......Page 133 Mechanisms of action......Page 134 Clinical utility in asthma therapy......Page 135 REFERENCES......Page 136 Synthetic pathways of the leukotrienes......Page 138 Asthmatic airway obstruction......Page 139 Exercise and cold air hyperventilation......Page 140 Allergen-induced asthma......Page 142 Efficacy of antileukotriene drugs in asthma......Page 143 Role of antileukotriene drugs in asthma treatment......Page 144 REFERENCES......Page 146 Classification of phosphodiesterase enzymes......Page 150 Theophylline in the treatment of respiratory disease......Page 151 Characteristic features of asthma and COPD......Page 154 Allergy......Page 155 Properties and classification of PDE4......Page 156 Mast cells and basophils......Page 160 Eosinophil......Page 161 Methylxanthines......Page 162 Selective inhibitors......Page 163 B-lymphocyte......Page 164 Monocyte......Page 165 Bronchial epithelium......Page 166 Vascular endothelium......Page 167 Airway smooth muscle......Page 168 Clinical studies of PDE inhibitors in asthma and COPD......Page 169 REFERENCES......Page 170 Potassium channels......Page 186 Small Ca2+-activated K+ channel (SKCa)......Page 187 Potassium channel openers......Page 188 Openers of the large conductance calcium-activated K-channel (BKCa)......Page 189 K+ channels on airway nerves......Page 190 KCO and airway hyperresponsiveness......Page 191 Conclusions......Page 193 REFERENCES......Page 194 Tachykinin, CGRP and their receptors......Page 198 Neurogenic inflammation and biological responses to tachykinin......Page 199 Modulation of neurogenic inflammation......Page 200 Inflammatory models in the airways: role of kinin and tachykinin......Page 201 Tachykinin and kinin receptor antagonists......Page 202 Tachykinin and kinin receptor antagonists in the airways......Page 203 Tachykinin and kinin receptor antagonists in the human airways......Page 204 REFERENCES......Page 205 Regulation of IgE synthesis......Page 209 Signals required for IgE production......Page 210 Cytokine/cytokine receptor modulation......Page 214 Drugs in clinical use......Page 215 M50367......Page 217 Protease inhibitors......Page 218 MAb MAE11/huMAb-E25......Page 219 migis Antibodies......Page 220 Clinical......Page 221 REFERENCES......Page 225 p38 kinase pathway......Page 232 Extracellular regulated kinase (ERK) pathway......Page 238 Jun-N-terminal kinase (JNK) pathway......Page 240 IkB kinase (IKK) pathway......Page 243 Protein kinase C (PKC)......Page 246 Conclusions......Page 249 REFERENCES......Page 251 REFERENCES ADDED IN PROOF......Page 257 Part II Diffuse parenchymal lung disease......Page 259 12 Current approaches to the treatment of parenchymal lung diseases......Page 261 Cryptogenic fibrosing alveolitis/(idiopathic pulmonary fibrosis)......Page 263 Desquamative interstitial pneumonia (DIP) and respiratory bronchiolitis interstitial lung disease (RBILD)......Page 270 Acute interstitial pneumonia (Hamman–Rich syndrome)......Page 272 Non-specific interstitial pneumonitis/fibrosis (NSIP)......Page 273 Collagen vascular diseases......Page 275 Progressive systemic sclerosis (PSSc)......Page 276 Polymyositis and dermatomyositis......Page 278 Systemic lupus erythematosus......Page 279 Sjogren’s syndrome (SS)......Page 280 Occupational lung disease......Page 281 Drug-induced interstitial lung disease......Page 282 Neurofibromatosis......Page 284 Pulmonary lymphoproliferative disorders......Page 285 Lymphoid interstitial pneumonia (LIP)......Page 286 Primary pulmonary lymphoma......Page 287 Lymphomatoid granulomatosis......Page 288 Sarcoidosis......Page 289 Hypersensitivity pneumonia (extrinsic allergic alveolitis)......Page 300 Chronic eosinophilic pneumonia......Page 303 Acute eosinophilic pneumonia......Page 304 Cryptogenic organizing pneumonia (COP)......Page 305 Obliterative bronchiolitis (OB)......Page 307 ANCA-associated vasculitides......Page 312 Wegener’s granulomatosis (WG)......Page 313 Microscopic polyangiitis (MPA)......Page 317 Pulmonary eosinophilic granuloma (EG)......Page 318 Lymphangioleiomyomatosis (LAM)......Page 322 Pulmonary alveolar proteinosis......Page 325 Relapsing polychondritis......Page 327 Amyloidosis......Page 330 REFERENCES......Page 331 The problem of demonstrating benefit in a rare irreversible disease......Page 350 The problem of selection bias......Page 351 The problem of diagnostic contamination......Page 352 The problem of selection of end-points......Page 353 Pathogenesis......Page 354 Pirfenidone......Page 357 Interferon-gamma......Page 359 Relaxin......Page 361 Other fibroblast apoptotic agents......Page 362 Keratinocyte growth factor......Page 363 Antioxidants (N-acetylcysteine)......Page 364 Endothelin receptor antagonists......Page 365 REFERENCES......Page 366 Part III Infection......Page 375 Causal pathogens......Page 377 Severity as a predictor of causal pathogen......Page 379 Causal pathogens......Page 380 Ventilator-associated pneumonia......Page 381 S. pneumoniae......Page 382 S. aureus......Page 383 M. catarrhalis......Page 384 Non-fermentative gram-negative bacilli......Page 385 Pharmacokinetics and pharmacodynamics of antibiotics......Page 386 Interaction between antibiotics and the host natural defences......Page 388 Treatment......Page 390 Community-acquired pneumonia guidelines......Page 391 Nosocomial pneumonia guidelines......Page 396 Future therapeutic options......Page 398 Development of novel ‘classic’ antimicrobial agents......Page 399 Chemical modification of currently known agents......Page 401 Inhibitors of new targets......Page 403 Antisense nucleotides......Page 404 Cytokines as immunoadjuvants in the treatment of pneumonia......Page 405 REFERENCES......Page 406 Introduction......Page 417 Pathophysiology......Page 418 Bacteriology......Page 421 Clinical features......Page 422 Investigations......Page 423 Treatment of airway inflammation......Page 426 Surgical treatment......Page 427 Beta lactams......Page 428 Macrolides......Page 429 Tetracyclines......Page 430 Aminoglycosides......Page 431 General principles......Page 432 Intravenous antibiotic treatment......Page 434 Prophylactic antibiotics......Page 436 Benefits of an antibiotic policy designed to minimize chronic bronchial suppuration......Page 437 REFERENCES......Page 438 Introduction......Page 442 Antiproteases......Page 444 Interleukin-10......Page 445 Fatty acid supplementation......Page 446 Leukotriene receptor antagonists......Page 447 General principles......Page 448 Antistaphylococcal prophylaxis......Page 449 Oral treatment for P. aeruginosa infection......Page 450 Chronic suppressive therapy......Page 451 Prevention or delay of chronic infection with P. aeruginosa......Page 452 Optimal aminoglycoside dosing......Page 453 Burkholderia cepacia complex......Page 454 Non-tuberculous mycobacteria......Page 455 New antimicrobials......Page 456 REFERENCES......Page 457 Part IV Pulmonary vascular diseases......Page 465 General mechanisms of pulmonary arterial hypertension......Page 467 Pulmonary vasoconstriction......Page 468 Pathological evidence......Page 470 Abnormalities of blood coagulation and fibrinolysis......Page 471 Inherited thrombophilic states......Page 473 Abnormalities of platelet function......Page 474 Antibodies to fibrin-bound t-PA......Page 475 Introduction......Page 476 Vessel wall structural changes......Page 477 Smooth muscle changes......Page 479 Endothelial cell alterations......Page 480 Introduction......Page 481 Familial tendency of PPH......Page 482 Genetic studies......Page 483 REFERENCES......Page 484 Epidemiology......Page 489 History......Page 491 Investigation......Page 492 Right heart catheterization......Page 493 Prostacyclin......Page 494 Adenosine......Page 495 Calcium channel blockers......Page 496 Vasodilators......Page 497 Primary pulmonary hypertension......Page 499 Secondary pulmonary hypertension......Page 500 Background......Page 501 Primary pulmonary hypertension......Page 502 Secondary pulmonary hypertension......Page 503 Alternative delivery methods and prostacyclin analogues......Page 504 Other vasodilators......Page 505 Cardiac glycosides......Page 506 Secondary pulmonary hypertension: specific points and treatment summary......Page 507 Pulmonary venous hypertension......Page 508 Atrial septostomy......Page 509 Introduction......Page 511 Primary pulmonary hypertension......Page 512 REFERENCES......Page 513 Introduction......Page 518 Angiogenesis factors......Page 521 Inhibitors of inflammation......Page 522 Suppression of vascular smooth muscle cell growth and hypertrophy......Page 523 Gene therapy for the remodelled lung circulation......Page 524 Therapeutic approach to neonatal pulmonary hypertension......Page 525 REFERENCES......Page 527 Part V Lung cancer......Page 531 Preneoplasia and the development of lung cancer......Page 533 Dominant oncogenes......Page 534 Tumour type specific genetic changes in lung cancer......Page 535 Genetic abnormalities in the multistage development of lung cancer......Page 536 Sequential genetic changes in the pathogenesis of lung cancers......Page 537 Accumulation of genetic changes in the development of lung cancer......Page 539 Similar genetic changes are detected in invasive lung cancers and their precursor lesions......Page 540 Telomerase dysregulation in the pathogenesis of lung cancer......Page 541 Smoking damaged bronchial epithelium......Page 542 Size of the patches with genetic changes in the pathogenesis of lung cancer......Page 543 REFERENCES......Page 544 Introduction......Page 549 Staging of SCLC......Page 550 Prognostic factors in patients with SCLC (Tables 21.2 and 21.3)......Page 551 Chemotherapy in small cell lung cancer......Page 552 Dose intensification......Page 554 Weekly chemotherapy (Table 21.8)......Page 555 Treatment of elderly patients or patients with poor performance status......Page 556 Thoracic ionizing radiation in limited stage small cell lung cancer......Page 557 Prophylactic cranial irradiation and small cell lung cancer......Page 558 New drugs in small cell lung cancer (Table 21.4)......Page 559 Second primary cancers after surviving small cell lung cancer......Page 560 REFERENCES......Page 561 Part VI Cough......Page 565 Introduction......Page 567 Rapidly adapting stretch receptors (irritant, RARs)......Page 568 Relative roles of airway sensory receptors in the cough reflex......Page 569 Central nervous mechanisms in cough......Page 571 Cough mechanisms in humans......Page 573 Site and mechanisms of action of antitussive agents......Page 574 Conclusions......Page 576 REFERENCES......Page 577 Specific antitussive therapy......Page 579 Postnasal drip syndrome (Table 23.1)......Page 581 Asthma......Page 582 Gastroesophageal reflux disease......Page 583 Cough due to angiotensin-converting enzyme (ACE) inhibitors......Page 585 Chronic bronchitis and bronchiectasis......Page 586 Caramiphen......Page 587 Protussive therapy......Page 588 REFERENCES......Page 589 Index......Page 593 Pathology Of Asthma And Copd: Inflammation And Structure / Peter K. Jeffery -- Glucocorticosteroids / Peter J. Barnes -- [beta]2- Adrenoceptor Agonists / Domenico Spina ... [et Al.] -- Anticholinergic Bronchodilators / Jeremy M. Segal And Nicholas J. Gross -- Antiallergic Drugs / Mazakazu Ichinose -- Drugs Affecting The Synthesis And Action Of Leukotrienes / Paul M. O'byrne -- Theophylline And Selective Phosphodiesterase Inhibitors In The Treatment Of Respiratory Disease / Neil A. Jones, Domenico Spina And Clive P. Page -- Potential Therapeutic Effects Of Potassium Channel Openers In Respiratory Diseases / Ahmed Z. El-hashim -- Tachykinin And Kinin Antagonists / Pierangelo Geppetti -- Drugs Affecting Ige (synthesis Inhibitors And Monoclonal Antibodies) / Lawrence G. Garland And Alan G. Lamont -- Drugs Targeting Cell Signalling / Brydon L. Bennett, Yoshitaka Satoh And Alan J. Lewis -- Current Approaches To The Treatment Of Parenchymal Lung Diseases / Joseph P. Lynch Iii And Michael Keane -- Drug Treatments Of The Future In Fibrotic Lung Disease / Athol U. Wells -- Current And Future Management Of Pneumonia / Mario Cazzola And Maria G. Matera -- Current Treatment Of Chronic Bronchial Suppuration / Robert Wilson -- Current And Future Treatment Of Cystic Fibrosis / R. G. Gary Ruiz, Hilary H. Wyatt And John F. Price -- Pathophysiology Of Pulmonary Vascular Disease / Sanjay Mehta And David G. Mccormack -- Current Treatment Of Pulmonary Vascular Diseases / Tarek Saba And Andrew Peacock -- Future Treatment Of Pulmonary Vascular Diseases / Norbert F. Voelkel, Mark W. Geraci And Steven Abman -- Molecular Pathology Of Lung Cancer / Ignacio I. Wistuba And Adi F. Gazdar -- Small Cell Lung Cancer / Desmond N. Carney -- Mechanisms Of Cough / John J. Adcock -- Current Treatment Of Cough / Peter V. Dicpinigaitis. Edited By Domenico Spina ... [et. Al.]. Includes Bibliographical References And Index. Respiratory diseases affect millions of people each year and represent a major health burden around the world. This timely reference surveys and evaluates the drug treatments available for the main categories of lung diseases including asthma, tuberculosis, chronic obstructive pulmonary disease, lung cancer, and respiratory infections. The recent re-emergence of tuberculosis and the increase in asthma in certain populations underlines the importance of finding effective new treatments for these diseases. This publication, a comprehensive reference, is one of the first to survey current and novel drug treatments for this group of diseases. It is certain to establish itself as an essential source of reference for respiratory physicians, clinicians and clinical pharmacologists.