Emerging drugs for the treatment of chronic obstructive pulmonary disease

Expert Opinion on Emerging Drugs

Volumn 11, Issue 2, 2006, Pages 275-291

  Malhotra, Samir ^a   Man, S F Paul ^a   Sin, Don D ^a  

^a UNIVERSITY OF BRITISH COLUMBIA   (Canada)

Author keywords

COPD; Inflammation; Pharmacotherapy

Indexed keywords

1 (2 BROMOPHENYL) 3 (2 HYDROXY 4 NITROPHENYL)UREA; ANTIOXIDANT; ARFOMOTEROL; AROFYLLINE; BRONCHODILATING AGENT; CARMOTEROL; CHEMOKINE RECEPTOR ANTAGONIST; CILOMILAST; CORTICOSTEROID; CS 003; GSK 159797; GW 3333; I KAPPA B; INDACATEROL; INFLIXIMAB; LAS 34273; LEUKOCYTE ELASTASE INHIBITOR; LEUKOTRIENE RECEPTOR BLOCKING AGENT; MCP 1 (9-76); MUCOLYTIC AGENT; ONO 6126; PHOSPHODIESTERASE IV INHIBITOR; REVATROPATE; ROFLUMILAST; SB 256610; SB 265610; SB 332235; SB 656933; SIBENADET; TUMOR NECROSIS FACTOR ALPHA CONVERTING ENZYME INHIBITOR; UNCLASSIFIED DRUG; UNINDEXED DRUG; VACCINE;

ABSENCE OF SIDE EFFECTS; ANTIINFLAMMATORY ACTIVITY; BACTERIAL COLONIZATION; CHRONIC OBSTRUCTIVE LUNG DISEASE; CLINICAL TRIAL; DIARRHEA; DISEASE COURSE; DRUG EFFICACY; DRUG MECHANISM; DRUG SAFETY; DRUG TARGETING; ENVIRONMENTAL FACTOR; FORCED EXPIRATORY VOLUME; GENETIC SUSCEPTIBILITY; GENOMICS; HAND; HUMAN; IMMUNE RESPONSE; ISCHEMIC COLITIS; META ANALYSIS; MORBIDITY; MORTALITY; MUSCLE CONTRACTION; MUSCULOSKELETAL PAIN; NAUSEA; NONHUMAN; PATHOGENESIS; POLYARTHRITIS; RESPIRATORY TRACT MUCOSA; REVIEW; SIDE EFFECT; SMOKING CESSATION; SYSTEMATIC REVIEW; TISSUE REGENERATION; UNSPECIFIED SIDE EFFECT; VACCINATION; VOMITING;

DRUGS, INVESTIGATIONAL; HUMANS; PULMONARY DISEASE, CHRONIC OBSTRUCTIVE;

EID: 33646575644     PISSN: 14728214     EISSN: None     Source Type: Journal    
DOI: 10.1517/14728214.11.2.275     Document Type: Review

References (145)

1. MICHAUD CM, MURRAY CJ, BLOOM JR: Burden of disease - implications for future research. JAMA (2001) 285:535-539.
2. PAUWELS RA, BULST AS, CALVERLY PM, JENKINS CR, HURD SS: Gold Scientific Committee Global Strategy for diagnosis, management and prevention of Chronic Obstructive Pulmonary Disease: NHLBI/WHO Global Intitative for Chronic Obstructive Lund Disease (GOLD) workshop summary. Am. J. Respir. Crit. Care Med. (2001) 163:1256-1276.
3. SANDFORD AJ, JOOS L, PARE PD: Genetic risk factors for chronic pulmonary obstructive pulmonary disease. Curr. Opin. Pulm. Med. (2002) 8:87-94.
4. HOGG JC: Chronic bronchitis: the role of viruses. Semin. Respir. Infect. (2000) 15:32-40.
5. BECKLAKE MR: Chronic airflow limitation: its relationship to work in a dusty occupations. Chest (1985) 88:608-617.
6. PEREZ-PADILLA R, REGALADO J, VEDAL S et al.: Exposure to biomass smoke and chronic airway disease in Mexican women. A case-control study. Am. J. Respir. Crit. Care Med. (1996) 154:701-706.
7. SIN DD, MCALISTER FA, MAN SF, ANTHONISEN NR: Contemporary management of chronic obstructive pulmonary disease: scientific review. JAMA (2003) 290:2301-2312.
8. HOGG J: Pathophysiology of airflow limitation in chronic obstructive pulmonary disease. Lancet (2004) 364:709-721.
9. KNOWLES M, BOUCHER R: Mucus clearance as a primary innate defense mechanism for mammalian airways. J. Clin. Invest. (2002) 109:571-577.
10. GREEN G, JAKAB G, LOW R, DAVIS G: Defense mechanisms of the respiratory membrane. Am. Rev. Respir. Dis. (1977) 115:479-514.
11. DAVIES DE: The bronchial epithelium: translating gene and environment interactions in asthma. Curr. Opin. Allergy Clin. Immunol. (2001) 1:67-71.
12. BECKER S, SOUKUP J, GALLAGHER J: Differential particulate air pollution induced oxidant stress in human granulocytes, monocytes and alveolar macrophages. Toxicol. In Vitro (2002) 16:209-218.
13. SOUKUP J, BECKER S: Human alveolar macrophages responses to air pollution particles are associated with insoluble components of coarse material including endotoxin. Toxicol. Appl. Pharmacol. (2001) 15:20-26.
14. CHUNG KF: Cytokines in chronic obstructive pulmonary disease. Eur. Respir. J. Suppl. (2001) 34:50s-59s.
15. DEBETS JM, KAMPMEIJER R, VAN DER LINDEN MP, BUURMAN WA, VAN DER LINDEN CJ: Plasma tumor necrosis factor and mortality in critically ill septic patients. Crit. Care Med. (1989) 17:489-494.
16. MEDZHITOV R, JANEWAY C JR: Innate immunity. N. Engl. J. Med. (2000) 343:338-344.
17. PUDDU P, FANTUZZI L, BORGHI P et al.: IL-12 induces IFN-γ expression and secretion in mouse peritoneal macrophages. J. Immunol. (1997) 159:3490-3497.
18. COSIO MG, MAJO J, COSIO MG: Inflammation of the airways and lung parenchyma in COPD: role of T cells. Chest (2002) 121:1605-1655.
19. DI STEFANO A, CARAMORI G, RICCIARDOLO M, CAPELLI A, ADOCKS I, DONNER C: Cellular and molecular mechanisms in chronic obstructive pulmonary disease: an overview. Clin. Exp. Allergy (2004) 34:1156-1167.
20. SIMANI AS, INOUE S, HOGG J: Penetration of respiratory epithelium of guinea pigs following exposure to cigarette smoke. Lab. Invest. (1974) 31:75-87.
21. HULBERT W, WALKER D, JACKSON A, HOGG J: Airway permeability to horseradish peroxidase in guinea pigs. The repair phase after injury by cigarette smoke. Am. Rev. Respir. Dis. (1981) 123:320-326.
22. JONES J, MINTY B, LAWLER P, HULANDS G, CRAWLEY J, VEAL N: Increased alveolar epithelial permeability in cigarette smokers. Lancet (1980) 1:66-68.
23. HILL AT, BAYLEY D, STOCKLEY RA: The interrelationship of sputum inflammatory markers in patients with chronic bronchitis. Am. J. Respir. Crit. Care Med. (1999) 160:893-898.
24. PESCI A, BALBI B, MAJORI M et al.: Inflammatory cells and mediators in bronchial lavage of patients with chronic obstructive pulmonary disease. Eur. Resp. J. (1998) 12:380-386.
25. DE GODOY I, DONAHOE M, CALHOUN WJ, MANCINO J, ROGERS R: Elevated TNF-α production by peripheral blood monocytes of weight losing COPD patients. Am. J. Resp. Crit. Care Med. 153:633-637.
26. BARNES P: New concepts in chronic obstructive pulmonary disease. Ann. Rev. Med. (2003) 54:113-129.
27. KILFEATHER S: 5-Lipooxygenase inhibitors for the treatment of COPD. Chest (2002) 121:S197-S200.
28. TETLEY TD: Macrophages and the pathogenesis of COPD. Chest (2002) 121:156S-159S.
29. NAGASE H: Activation mechanisms of matrix metalloproteinases. Biol. Chem. (1997) 378:151-160.
30. CAMPBELL EJ, WHITE RR, SENIOR RM, RODRIGUEZ RJ, KUHN C: Receptor-mediated binding and internalization of leukocyte elastase by alveolar macrophages in vitro. J. Clin. Invest. (1979) 64:824-833.
31. WHITE R, JANOFF A, GORDON R, CAMPBELL E: Evidence for in vivo internalization of human leukocyte elastase by alveolar macrophages. Am. Rev. Respir. Dis. (1982) 125:779-781.
32. CULPITT SV, ROGERS DF, SHAH P et al.: Impaired inhibition by dexamethasone of cytokine release by alveolar macrophages from patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. (2003) 167:24-31.
33. COSIO BG, TSAPROUNI L, ITO K, JAZRAWI E, ADCOCK IM, BARNES PJ: Theophylline restores histone deacetylase activity and steroid responses in COPD macrophages. J. Exp. Med. (2004) 200:689-695.
34. HOGG JC, CHU F, UTOKAPARCH S et al.: The nature of small-airway obstruction in chronic obstructive pulmonary disease. N. Engl. J. Med. (2004) 350:2645-2653.
35. SAETTA M, BARALDO S, CORBINO L et al.: CD8+ve cells in the lungs of smokers with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. (1999) 160:711-717.
36. BARNES P: Mediators of chronic obstructive pulmonary disease. Pharmacol. Rev. (2004) 56:515-548.
37. FUJIMOTO K, YASUO M, URUSHIBATA K, HANAOKA M, KOIZUMI T, KUBO K: Airway inflammation during stable and acutely exacerbated chronic obstructive pulmonary disease. Eur. Respir. J. (2005) 25:640-646.
38. GIBSON RL, BURNS JL, RAMSEY BW: Pathophysiology and management of pulmonary infections in cystic fibrosis. Am. J. Respir. Crit. Care Med. (2003) 168:918-951.
39. CHIN CL, MANZEL LJ, LEHMAN EE et al.: Haemophilus influenzae from patients with chronic obstructive pulmonary disease exacerbation induce more inflammation than colonizers. Am. J. Respir. Crit. Care Med. (2005) 172:85-91.
40. CASSATELLA M, GASPERINI S, CALZETTI F, BERTAGNIN A, LUSTERAD, MCDONALD PP: Regulated production of interferon-γ-inducible protein 10 (IP-10) chemokine by human neutrophils. Eur. J. Immunol. (1997) 27:111-115.
41. GASPERINI S, MACHI M, CALZETTI F et al.: Gene expression and production of monokine induced by IFN-γ (MIG), IFN-inducible T-cell-α chemoattractant (I-TAC), and IFN-γ-inducible protein-10 (IP-10) chemokines by human neutrophils. J. Immunol. (1999) 162:4928-4937.
42. MAJO J, GHEZZO H, COSIO MG: Lymphocyte population and apoptosis in the lungs of smokers and their relation to emphysema. Eur. Resp. J. (2001) 17:946-953.
43. ICHINOSE M, SUGIURA H, YAMAGATA S, KOARAI A, SHIRATO K: Increase in reactive nitrogen species production in chronic obstructive pulmonary disease airways. Am. J. Respir. Crit. Care Med. (2000) 162:701-706.
44. RAHMAN I, MACNEE W: Regulation of redox glutiathione levels and gene transcription in lung inflammation: therapeutic approaches. Free Radic. Biol. Med. (2000) 28:1405-1420.
45. DROST E, SKWARSKI M, SAULEDA J et al.: Oxidative stress and airway inflammation in severe exacerbations of COPD. Thorax (2005) 60:293-300.
46. WRIGHT DT, FISCHER BM, LI CM, ROCHELLE LG, AKLEY NJ, ADLER KB: Oxidant stress stimulates mucin secretion and PLC in airway epithelium via a nitric oxide-dependent mechanism. Am. J. Physiol. (1996) 271:854-861.
47. JASPERS I, FLESCHER E, CHEN LC: Ozone-induced IL-8 expression and transcription factor binding in respiratory epithelial cells. Am. J. Physiol. (1997) 272:504-511.
48. HODGE S, HODGE G, HOLMES M, REYNOLDS PN: Increased airway epithelial and T-cell apoptosis in COPD remains despite smoking cessation. Eur. Respir. J. (2005) 25:447-454.
49. VOLK T, SCHMUTZLER M, ENGELHARDT L et al.: Effects of different steroid treatment on reperfusion-associated production of reactive oxygen species and arrhythmias during coronary surgery. Acta Anaesthesiol. Scand. (2003) 47:667-674.
50. REPINE J, BAST A, LANHORST I: Oxidative stress in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. (1997) 156:341-357.
51. KIM S, NADEL JA: Role of neutrophils in mucus hypersecretion in COPD and implications for therapy. Treat. Respir. Med. (2004) 3:147-159.
52. KOHRI K, UEKI IF, NADEL JA: Neutrophil elastase induces mucin production by ligand-dependent epidermal growth factor receptor activation. Am. J. Physiol. Lung Cell Mol. Physiol. (2002) 283:531-540.
53. NADEL J, BURGEL P: The role of epidermal growth factor in mucus production. Curr. Opin. Pharmacol. (2001) 1:254-258.
54. MATA M, SARRIA B, BUENESTADO A, CORTIJO J, CERDA M, MORCILLO EJ: Phosphodiesterase 4 inhibition decreases MUC5AC expression induced by epidermal growth factor in human airway epithelial cells. Thorax (2005) 60:144-152.
55. PISTELLI R, LANGE P, MILLER DL: Determinants of prognosis of COPD in the elderly: mucus hypersecretion, infections, cardiovascular comorbidity. Eur. Respir. J. Suppl. (2003) 40:10S-14S.
56. BRUMFITT W, WILLOUGHBY M, BROMLEY L: An evaluation of sputum examination in chronic bronchitis. Lancet (1957) 270:1306-1309.
57. DONALDSON GC, SEEMUNGAL TA, BHOWMIK A, WEDZICHA JA: Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax (2002) 57:847-852.
58. MONTUSCHI P, COLLINS JV, CIABATTONI G et al.: Exhaled 8-isoprostane as an in vivo biomarker of lung oxidative stress in patients with COPD and healthy smokers. Am. J. Respir. Crit. Care Med. (2000) 162:1175-1177.
59. TSOUMAKIDOU M, TZANAKIS N, CHRYSOFAKIS G, SIAFAKAS NM: Nitrosative stress, heme oxygenase-1 expression and airway inflammation during severe exacerbations of COPD. Chest (2005) 127:1911-1918.
60. FUKE S, BETSUYAKU T, NASUHARA Y, MORIKAWA T, KATOH H, NISHIMURA M: Chemokines in bronchiolar epithelium in the development of chronic obstructive pulmonary disease. Am. J. Respir. Cell Mol. Biol. (2004) 31:405-412.
61. 4 in exhaled breath condensate and sputum supernatant in patients with COPD and asthma. Chest (2005) 127:1553-1559.
62. WILSON R: Bacteria, antibiotics and COPD. Eur. Respir. J. (2001) 17:995-1007.
63. ROSELL A, MONSO E, SOLER N et al.: Microbiologic determinants of exacerbation in chronic obstructive pulmonary disease. Arch. Intern. Med. (2005) 165:891-897.
64. PATEL IS, SEEMUNGAL TA, WILKS M, LLOYD-OWEN SJ, DONALDSON GC, WEDZICHA JA: Relationship between bacterial colonisation and the frequency, character, and severity of COPD exacerbations. Thorax (2002) 57:759-764.
65. KANNER RE, ANTHONISEN NR, CONNETT JE; LUNG HEALTH STUDY RESEARCH GROUP: Lower respiratory illnesses promote FEV(1) decline in current smokers, but not ex-smokers with mild chronic obstructive pulmonary disease: results from the lung health study. Am. J. Respir. Crit. Care Med. (2001) 164:358-364.
66. SCANLON P, CONNETT J, WALLER L, ALTOSE MD, BAILEY WC, BUIST AS: Smoking cessation and lung function in mild to moderate COPD: the Lung Health Study. Am. J. Respir. Crit. Care Med. (2000) 161:381-390.
67. CONNETT J, MURRAY R, BUIST A et al.: Changes in smoking status affect women more than men: results of the Lung Health Study. Am. J. Epidemiol. (2003) 157:973-979.
68. MULTIPLE RISK FACTOR INTERVENTION TRIAL RESEARCH GROUP: Risk factor changes and mortality results. JAMA (1982) 248:1465-1477.
69. MURRAY R, CONNETT J, RAND C, PAN W, ANTHONISEN NR: Persistence of the effect of Lung Health Study (LHS) smoking intervention over eleven years. Prev. Med. (2002) 35:314-319.
70. JAMERSON B, NIDES D, JORENBY D, DONAHUE R, GARRETT P, JOHNSTON JA: Late term smoking cessation despite initial failure: an evaluation of bupropion sustained release, nicotine patch, combination therapy; and placebo. Clin. Ther. (2001) 23:744-752.
71. HENNINGFIELD J, FANT RV, GITCHELL J, SHIFFMAN S: Tobacco dependence: global health potential for new medications for development and indications. Ann. NY Acad. Sci. (2000) 909:247-256.
72. KANTAK KM: Vaccines against drugs of abuse: a viable treatment option? Drugs (2003) 63:341-352.
73. HIEDA Y, KEYLER DE, ENNIFAR S, FATTOM A, PENTEL PR: Vaccination against nicotine during continued nicotine administration in rats: immunogenicity of the vaccine and effects on nicotine distribution to brain. Int. J. Immunopharmacol. (2000) 22:809-819.
74. NICHOL KL, NORDIN J, MULLOOLY J, LASK R, FILLBRANDT K, IWANE M: Influenzae vaccination and reduction in hospitalization from cardiac disease and stroke among the elderly. N. Engl. J. Med. (2003) 348:1322-1332.
75. LOEB M, STEVENSON KB; SHEA LONG-TERM-CARE COMMITTEE: Pneumococcal immunization in older adults: implications for the long-term-care setting. Infect. Control Hosp. Epidemiol. (2004) 25:985-994.
76. WHITNEY CG: Impact of conjugate pneumococcal vaccines. Pediatr. Infect. Dis. J. (2005) 24:729-730.
77. CALVERLY P, BURGE P, SPENCER S, ANDERSON J, JONES P: Bronchodilator reversibility testing in chronic obstructive pulmonary disease. Thorax (2003) 58:659-664.
78. HAY J, STONE P, CARTER J: Bronchodilator reversibility, exercise performance and breathlessness in stable chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. (1998) 158:1557-1565.
79. 2- agonists in development for asthma and chronic obstructive pulmonary disease. Expert Opin. Investig. Drugs (2005) 14:775-783.
80. 2- agonist, on the isolated human bronchus. Proc. Am. Thorac. Soc. (2005) 2:A356.
81. 2-agonist, is effective and well tolerated on multiple dosing in patients with mild to moderate COPD. Eur. Respir. J. (2005) 26:287s.
82. 2-agonist, in moderate to severe COPD. Eur. Respir. J. (2005) 26:295s.
83. MOLFINO N: Drugs in clinical development for chronic obstructive pulmonary disease. Respiration (2005) 72:105-112.
84. WALDECK B: Some pharmacodynamic aspects on long-lasting β-adrenoreceptor agonists. Gen. Pharmacol. (1996) 27:573-580.
85. ALABASTER V: Discovery and development of selevtive M3 antagonists for clinical use. Life Sci. (1997) 60:1053-1060.
86. SCHELFHOUT V, JOOS G, FERRER P, LURIA X, PAUWELS R: Activity of LAS 34273: a new long acting anticholinergic antagonist. Am. J. Respir. Crit. Care Med. (2003) 167:A319.
87. VAN NOORD JA, AUMANN JL, JANSSENS E et al.: Comparison of tiotropium once daily, formoterol twice daily and both combined once daily in patients with COPD. Eur. Respir. J. (2005) 26:214-222.
88. SIN DD, WU L, ANDERSON J et al.: Inhaled corticosteroids and mortality in chronic obstructive pulmonary disease. Thorax (2005) 60:992-997.
89. VESTBO J: TORCH Study Group: the TORCH (towards a revolution in COPD health) survival study protocol. Eur. Respir. J. (2004) 24:206-210.
90. CHRYSTYN H, MULLEY B, PEAKE M: Dose response relation to oral theophilline in severe chronic obstructive airway disease. Br. Med. J. (1988) 297:1506-1510.
91. ITO K, ITO M, ELLIOTT WM et al.: Decreased histone deacetylase activity in chronic obstructive pulmonary disease. N. Engl. J. Med. (2005) 352:1967-1976.
92. MARWICK JA, KIRKHAM PA, STEVENSON CS et al.: Cigarette smoke alters chromatin remodeling and induces proinflammatory genes in rat lungs. Am. J. Respir. Cell Mol. Biol. (2004) 31:633-642.
93. LARJ M, BLEECKER E: Therapeutic responses in asthma and chronic obstructive pulmonary disease. Corticosteroids. Chest (2004) 126:138S-149S.
94. ITO K, ADCOCK I, BARNES P: A mechanism of corticosteroid resistance in COPD: inactivation of histone deacetylase. Lancet (2004) 363:731-733.
95. MANNING C, BURMAN M, CHRISTENSEN S et al.: Suppression of human inflammatory cell function by subtype selective PDE4 inhibitors correlate with inhibition of PDE4A and PDE4B. Br. J. Clin. Pharmacol. 128:1393-1398.
96. LIPWORTH B: Phosphodiesterase-4-inhibitors for asthma and chronic obstructive pulmonary disease. Lancet (2005) 365:167-175.
97. HATEZELMANN A, SCHUDT C: Anti-inflammatory and immunomodulatory potential of novel PDE4 inhibitor rofulimast in vitro. J. Pharmacol. Exp. Ther. (2001) 297:280-290.
98. EDDELSTON J, COMPTON C, NEIMAN R: Cilomilast (Ariflo) a potent selective phosphodiesterase inhibitor reduces exacerbations in COPD patients: results of a 6 month trial. Am. J. Respir. Crit. Care Med. (2001) 163:A771.
99. EDDELSTON J, COMPTON C, NEIMAN R: Cilomilast (Ariflo) a potent selective phosphodiesterase improves lung function in COPD patients: results of a 6 month trial. Am. J. Respir. Crit. Care Med. (2001) 163:A277.
100. RABE KF, BATEMAN ED, O'DONNELL D, WITTE S, BREDENBROKER D, BETHKE TD: Roflumilast - an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomised controlled trial. Lancet (2005) 366:563-571.
101. SOARES A, SOUZA D, PINHO V: Impaired host defense to Klebsiellae pneumoniae infection in mice treated with the PDE4 inhibitor rolipram. Br. J. Pharamacol. (2003) 140:855-862.
102. DE BOER W: Perspectives for cytokine antagonist therapy in COPD. Drug Discov. Today. (2005) 10:93-106.
103. MOLFINO N: Drugs in clinical development for chronic obstructive pulmonary disease. Respiration (2005) 72:105-112.
104. DI FRANCIA, BARBIER D, MEGE J, OREHEK J: Tumor necrosis factor-α levels and weight loss in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. (1994) 150:1453-1455.
105. HARDAKER EL, BACON AM, CARLSON K et al.: Regulation of TNF-α-and IFN-γ-induced CXCL10 expression: participation of the airway smooth muscle in the pulmonary inflammatory response in chronic obstructive pulmonary disease. FASEB J. (2004) 18:191-193.
106. HOLTMANN M: RDP-58. Drugs (2003) 6:188-1194.
107. VAN DER VAART H, KOETER GH, POSTMA DS, KAUFFMAN HF, TEN HACKEN NH: First study of infliximab treatment in patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. (2005) 172:465-469.
108. REIMOLD A: TNF-α as therapeutic target: new drugs, more applications. Curr. Drug Targets Inflamm. Allergy (2002) 1:377-392.
109. ASADULLAH K, STERRY W, VOLK HD: Interleukin-10 therapy - review of a new approach. Pharmacol. Rev. (2003) 55:241-269.
110. OLSEN NJ, STEIN CM: New drugs for rheumatoid arthritis. N. Engl. J. Med. (2004) 350:2167-2179.
111. SAETTA M, MARIANI M, PANINA-BORDIGNON P: Increased expression of the chemokine receptor CXCR3 and its ligand CXCL10 in peripheral airways of smokers with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. (2002) 165:1404-1409.
112. WIDDOWSON K, ELLIOT J, VEBER D: Evaluation of potent and selective small-molecule antagonists for the CXCR2 chemokine receptor. J. Med. Chem. (2004) 37:1319-1321.
113. SUETOMI K, LUZ, HECK T et al.: Differential mechanisms of recognition and activation of interleukin-8 receptor subtypes. Biol. Chem. (1999) 274:11768-11772.
114. CARPENTER DC, RUMSEY WL, BUSCH-PETERSEN J, SARAU HM, SALMON M: The selective CXCR2 receptor antagonist SB-656933 inhibits CXCL1-induced neutrophil CD11b expression in human whole blood. Eur. J. Respir. Dis. Suppl. (2004) 24:218s.
115. GUGLIELMOTTI A, D'ONOFRIO E, COLETTA I, AQUILINI L, MILANESE C, PINZA M: Amelioration of rat adjuvant arthritis by therapeutic treatment with bindarit, an inhibitor of MCP-1 and TNF-α production. Inflamm. Res. (2002) 51:252-258.
116. GROSS P, PFITZER E, TOLKER E, BABYAK M, KASCHAK M: Experimental emphysema: its production with papain in normal and silicotic rats. Arch. Environ. Health. (1965) 11:50-58.
117. SHAPIRO SD: Proteolysis in the lung. Eur. Respir. J. (2003) 22:30S-32S.
118. SHAPIRO SD: Proteinases in chronic obstructive pulmonary disease. Biochem. Soc. Trans. (2002) 30:98-102.
119. LUISETTI M, STURANI C, SELLA D: MR889, a neutrophil elastase inhibitor, in patients with chronic obstructie pulmonary disease: a double blind, randomized, placebo-controlled clinical trial. Eur. Respir. J. (1996) 9:1482-1486.
120. KILFEATHER S: 5-Lipooxygenase inhibitors for the treatment of COPD. Chest (2002) 121:S197-S200.
121. MONTUSCHI P, KHARITONOV S, CIABATONI G, BARNES P: Exhaled leukotrienes and prostaglandins in COPD. Thorax (2003) 58:585-588.
122. 4 receptor antagonist ly29311: in vivo pulmonary studies. Naunyn Schiedebergs Arch Pharmacol. (2000) 361:397-404.
123. MCINTYRE KW, SHUSTER DJ, GILLOOLY KM et al.: A highly selective inhibitor of IκB kinase, BMS-345541, blocks both joint inflammation and destruction in collagen-induced arthritis in mice. Arthritis Rheum. (2003) 48:2652-2659.
124. YANG F, OZ H, BARVE S: The green tea polyphenol (-) epigallocatechin-3- gallate blocks nuclear factor-κB activation by inhibiting IκB kinase activity in the intestinal epithelial cell line IEC-6. Mol. Pharmacol. (2001) 60:528-533.
125. JOHNSON G, LAPADAT R: Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science (2002) 298:1911-1912.
126. LEE J, KUMAR S, GRISWOLD D, UNDERWOOD DC, VOTTA BJ, ADAMS JL: Inhibition of p38 MAP kinase as a therapeutic strategy. Immunopharamcology (2000) 47:185-201.
127. UNDERWOOD D, OSBORN R, BOCHNOWICZ S: SB239063, a p39 MAPK inhibitor, reduces neutrophilia, inflammatory cytokines, MMP-9, and fibrosis in lung. Am. J. Physiol. Lung Cell Mol. Physiol. (2000) 287:1040-1046.
128. DECRAMER M, RUTTEN-VAN MOLKEN M, DEKHUIJZEN PN et al.: Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial. Lancet (2005) 365:1552-1560.
129. BOMAN G, BACKER U, LARSSON S: Oral acetylcysteine reduces exacerbation rate in chronic bronchitis. Eur. J. Respir. Dis. (1983) 64:405-415.
130. CULPITT S, ROGERS D, FENWICK P: Inhibition by red wine extract, resveratrol, of cytokine release by alveolar macrophages in COPD. Thorax (2003) 58:942-946.
131. ANTONICELLI F, BROWN D, PARMENTIER M et al.: Regulation of LPS-mediated inflammation in vivo and in vitro by the thiol antioxidant nacystelyn. Am. J. Physiol. Lung Cell Mol. Physiol. (2004) 286:1319-1327.
132. BENNETT W, ZEMANK, FOY C: Effect of aerosolized uridine 5′ triphosphate on mucociliary clearance in mild chronic bronchitis. Am. J. Respir. Crit. Care Med. (2001) 164:302-306.
133. 2-agonist, viozan (sibenadet HCl), in the treatment of symptoms of chronic obstructive pulmonary disease: results of a large-scale clinical investigation. Respir. Med. (2003) 97:S23-S33.
134. JOOS G, DE SWERT K, PAUWELS R: Airway inflammation and tachykinins prospects for the development of tachykinin receptor antagonists. Eur. J. Pharmacol. (2001) 429:239-250.
135. BAI TR, ZHOU D, WEIR T et al.: (NK1)- and neurokinin A (NK2)-receptor gene expression in inflammatory airway diseases. Am. J. Physiol. (1995) 269:309-317.
136. JOOS GF, VINCKEN W, LOUIS R et al.: Dual tachykinin NK1/NK2 antagonist DNK-333 inhibits neurokinin A-induced bronchoconstriction in asthma patients. Eur. Respir. J. (2004) 23:76-81.
137. ZHOU Y, SHAPIRO M, DONG Q et al.: A calcium-activated chloride channel blocker inhibits goblet cell metaplasia and mucus overproduction. Novartis Found. Symp. (2002) 248:150-165.
138. KITAZAKI T, FUKUDA M, SODA H, KOHNO S: Novel effects of gefitinib on mucin production in bronchioloalveolar carcinoma; two case reports. Lung Cancer (2005) 49:125-128.
139. IEKI R, SAITOH E, SHIBUYA M: Acute lung injury as a possible adverse drug reaction related to gefitinib. Eur. Respir. J. (2003) 22:179-181.
140. BARNES P, STOCKLEY R: COPD: current therapeutic interventions and future approaches. Eur. Respir. J. (2005) 25:1084-1106.
141. WEISBERG J, WANGER J, OLSON J et al.: Megestrol acetate stimulates weight gain and ventilation in underweight COPD patients. Chest (2002) 121:1070-1078.
142. MASSARO D, MASSARO GD: Estrogen regulates pulmonary alveolar formation, loss, and regeneration in mice. Am. J. Physiol. Lung Cell Mol. Physiol. (2004) 287:1154-1159.
143. MASSARO G, MASSARO D: Retinoic acid treatment abrogates elastase-induced pulmonary emphysema in rats. Nat. Med. (1997) 3:675-677.
144. MAO JT, GOLDIN JG, DERMAND J et al.: A pilot study of all-trans-retinoic acid for the treatment of human emphysema. Am. J. Respir. Crit. Care Med. (2002) 165:718-723.
145. OTTO W: Lung epithelial stem cells. J. Pathol. (2002) 197:527-535.