PDE4-inhibitors: A novel, targeted therapy for obstructive airways disease

Pulmonary Pharmacology and Therapeutics

Volumn 24, Issue 4, 2011, Pages 353-360

  Diamant, Zuzana ^a   Spina, Domenico ^b  

^a ERASMUS MEDICAL CENTER   (Netherlands)

^b KING'S COLLEGE LONDON   (United Kingdom)

Author keywords

Chronic obstructive airways disease; Clinical trials; PDE4 inhibitor; Roflumilast

Indexed keywords

4 [2 [3 (CYCLOPENTYLOXY) 4 METHOXYPHENYL] 2 PHENYLETHYL]PYRIDINE; BUDESONIDE; CILOMILAST; FLUTICASONE PROPIONATE; FORMOTEROL; GSK 256066; PLACEBO; ROFLUMILAST; SALMETEROL; THEOPHYLLINE; TIOTROPIUM BROMIDE;

CARDIOTOXICITY; CHRONIC OBSTRUCTIVE LUNG DISEASE; CLINICAL TRIAL; DIARRHEA; DRUG EFFECT; DRUG EFFICACY; GASTROINTESTINAL DISEASE; HEADACHE; HUMAN; INSOMNIA; LOW DRUG DOSE; MONOTHERAPY; MULTICENTER STUDY; NAUSEA; PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; REVIEW; SIDE EFFECT; SUICIDE; WEIGHT REDUCTION;

AMINOPYRIDINES; BENZAMIDES; CLINICAL TRIALS, PHASE III AS TOPIC; CYCLIC NUCLEOTIDE PHOSPHODIESTERASES, TYPE 7; CYCLOHEXANECARBOXYLIC ACIDS; CYCLOPROPANES; HUMANS; LUNG DISEASES, OBSTRUCTIVE; NITRILES; PHOSPHODIESTERASE 4 INHIBITORS;

EID: 79956098321     PISSN: 10945539     EISSN: 15229629     Source Type: Journal    
DOI: 10.1016/j.pupt.2010.12.011     Document Type: Review

References (95)

1. Han M.K., Wise R., Mumford J., Sciurba F., Criner G.J., Curtis J.L., et al. Prevalence and clinical correlates of bronchoreversibility in severe emphysema. Eur Respir J 2010, 35:1048-1056.
2. Rodriguez-Roisin R., Anzeuto A., Bourbeau J., Calverley P.S., deGuia T., Fukuchi Y., et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease 2009, pp. 1-93.
3. Hogg J.C., Chu F., Utokaparch S., Woods R., Elliott W.M., Buzatu L., et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004, 350:2645-2653.
4. Barnes P.J. Mediators of chronic obstructive pulmonary disease. Pharmacol Rev 2004, 56:515-548.
5. Barnes P.J. The cytokine network in asthma and chronic obstructive pulmonary disease. J Clin Invest 2008, 118:3546-3556.
6. Tetley T.D. Inflammatory cells and chronic obstructive pulmonary disease. Curr Drug Targets Inflamm Allergy 2005, 4:607-618.
7. Sinden N.J., Stockley R.A. Systemic inflammation and comorbidity in COPD: a result of 'overspill' of inflammatory mediators from the lungs? Review of the evidence. Thorax 2010.
8. Singh S., Loke Y.K. An overview of the benefits and drawbacks of inhaled corticosteroids in chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 2010, 5:189-195.
9. Celli B., Vestbo J., Jenkins C.R., Jones P.W., Ferguson G.T., Calverley P.M., et al. Gender differences in mortality and clinical expressions of patients with COPD: the TORCH experience. Am J Respir Crit Care Med 2010.
10. Cazzola M., Molimard M. The scientific rationale for combining long-acting beta2-agonists and muscarinic antagonists in COPD. Pulm Pharmacol Ther 2010, 23:257-267.
11. Hawkins N.M., Wang D., Petrie M.C., Pfeffer M.A., Swedberg K., Granger C.B., et al. Baseline characteristics and outcomes of patients with heart failure receiving bronchodilators in the CHARM programme. Eur J Heart Fail 2010, 12:557-565.
12. Hawkins N.M., Jhund P.S., Simpson C.R., Petrie M.C., Macdonald M.R., Dunn F.G., et al. Primary care burden and treatment of patients with heart failure and chronic obstructive pulmonary disease in Scotland. Eur J Heart Fail 2010, 12:17-24.
13. Diamant Z., Boot J.D., Virchow J.C. Summing up 100 years of asthma. Respir Med 2007, 101:378-388.
14. To Y., Ito K., Kizawa Y., Failla M., Ito M., Kusama T., et al. Targeting phosphoinositide-3-kinase-delta with theophylline reverses corticosteroid insensitivity in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2010, 182:897-904.
15. Page CP, Spina D. PDE inhibitors in the treatment of inflammatory diseases. In: Francis, Sharron H., Conti, Marco, Houslay, Miles D. (Eds.). Handbook of Experimental Pharmacology, Vol. 204. 1st Edition. 450 p., Hardcover ISBN: 978-3-642-17968-6, in press.
16. Vestbo J., Prescott E., Lange P. Association of chronic mucus hypersecretion with FEV1 decline and chronic obstructive pulmonary disease morbidity. Copenhagen City Heart Study Group. Am J Respir Crit Care Med 1996, 153:1530-1535.
17. Compton C.H., Gubb J., Nieman R., Edelson J., Amit O., Bakst A., et al. Cilomilast, a selective phosphodiesterase-4 inhibitor for treatment of patients with chronic obstructive pulmonary disease: a randomised, dose-ranging study. Lancet 2001, 358:265-270.
18. Martorana P.A., Beume R., Lucattelli M., Wollin L., Lungarella G. Roflumilast fully prevents emphysema in mice chronically exposed to cigarette smoke. Am J Respir Crit Care Med 2005, 172:848-853.
19. Leclerc O., Lagente V., Planquois J.M., Berthelier C., Artola M., Eichholtz T., et al. Involvement of MMP-12 and phosphodiesterase type 4 in cigarette smoke-induced inflammation in mice. Eur Respir J 2006, 27:1102-1109.
20. Fortin M., D'Anjou H., Higgins M.E., Gougeon J., Aube P., Moktefi K., et al. A multi-target antisense approach against PDE4 and PDE7 reduces smoke-induced lung inflammation in mice. Respir Res 2009, 10:39.
21. Harbinson P.L., MacLeod D., Hawksworth R., O'Toole S., Sullivan P.J., Heath P., et al. The effect of a novel orally active selective PDE4 isoenzyme inhibitor (CDP840) on allergen-induced responses in asthmatic subjects. Eur Respir J 1997, 10:1008-1014.
22. Sullivan P., Bekir S., Jaffar Z., Page C., Jeffery P., Costello J. Anti-inflammatory effects of low-dose oral theophylline in atopic asthma. Lancet 1994, 343:1006-1008. [published erratum appears in Lancet 1994 Jun 11; 343(8911):1512].
23. Grootendorst D.C., Gauw S.A., Baan R., Kelly J., Murdoch R.D., Sterk P.J., et al. Does a single dose of the phosphodiesterase 4 inhibitor, cilomilast (15 mg), induce bronchodilation in patients with chronic obstructive pulmonary disease?. Pulm Pharmacol Ther 2003, 16:115-120.
24. Schmidt D.T., Watson N., Dent G., Ruhlmann E., Branscheid D., Magnussen H., et al. The effect of selective and non-selective phosphodiesterase inhibitors on allergen- and leukotriene C(4)-induced contractions in passively sensitized human airways. Br J Pharmacol 2000, 131:1607-1618.
25. Billington C.K., Le Jeune I.R., Young K.W., Hall I.P. A major functional role for phosphodiesterase 4D5 in human airway smooth muscle cells. Am J Respir Cell Mol Biol 2008, 38:1-7.
26. Rabe K.F., Tenor H., Dent G., Schudt C., Liebig S., Magnussen H. Phosphodiesterase isozymes modulating inherent tone in human airways: identification and characterization. Am J Phy 1993, 264:L458-L464.
27. Torphy T.J., Undem B.J., Cieslinski L.B., Luttmann M.A., Reeves M.L., Hay D.W. Identification, characterization and functional role of phosphodiesterase isozymes in human airway smooth muscle. J Pharmacol Exp Ther 1993, 265:1213-1223.
28. Rennard S.I., Schachter N., Strek M., Rickard K., Amit O. Cilomilast for COPD: results of a 6-month, placebo-controlled study of a potent, selective inhibitor of phosphodiesterase 4. Chest 2006, 129:56-66.
29. Gamble E., Grootendorst D.C., Brightling C.E., Troy S., Qiu Y., Zhu J., et al. Antiinflammatory effects of the phosphodiesterase-4 inhibitor cilomilast (Ariflo) in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003, 168:976-982.
30. Undem B.J., Meeker S.N., Chen J. Inhibition of neurally mediated nonadrenergic, noncholinergic contractions of guinea pig bronchus by isozyme-selective phosphodiesterase inhibitors. J Pharmacol Exp Ther 1994, 271:811-817.
31. Spina D., Harrison S., Page C.P. Regulation by phosphodiesterase isoenzymes of non-adrenergic non- cholinergic contraction in guinea-pig isolated main bronchus. Br J Pharmacol 1995, 116:2334-2340.
32. Liu S., Veilleux A., Zhang L., Young A., Kwok E., Laliberte F., et al. Dynamic activation of cystic fibrosis transmembrane conductance regulator by type 3 and type 4D phosphodiesterase inhibitors. J Pharmacol Exp Ther 2005, 314:846-854.
33. Cervin A., Lindgren S. The effect of selective phosphodiesterase inhibitors on mucociliary activity in the upper and lower airways in vitro. Auris Nasus Larynx 1998, 25:269-276.
34. Mata M., Sarria B., Buenestado A., Cortijo J., Cerda M., Morcillo E.J. Phosphodiesterase 4 inhibition decreases MUC5AC expression induced by epidermal growth factor in human airway epithelial cells. Thorax 2005, 60:144-152.
35. Rennard S., Knobil K., Rabe K.F., Morris A., Schachter N., Locantore N., et al. The efficacy and safety of cilomilast in COPD. Drugs 2008, 68(Suppl. 2):3-57.
36. Hatzelmann A., Morcillo E.J., Lungarella G., Adnot S., Sanjar S., Beume R., et al. The preclinical pharmacology of roflumilast-a selective, oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease. Pulm Pharmacol Ther 2010, 23:235-256.
37. Gross N.J., Giembycz M.A., Rennard S.I. Treatment of chronic obstructive pulmonary disease with roflumilast, a new phosphodiesterase 4 inhibitor. COPD 2010, 7:141-153.
38. Rabe K.F., Bateman E.D., O'Donnell D., Witte S., Bredenbroker D., Bethke T.D. Roflumilast-an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2005, 366:563-571.
39. Calverley P.M., Sanchez-Toril F., McIvor A., Teichmann P., Bredenbroeker D., Fabbri L.M. Effect of 1-year treatment with roflumilast in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007, 176:154-161.
40. Calverley P.M., Rabe K.F., Goehring U.M., Kristiansen S., Fabbri L.M., Martinez F.J. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet 2009, 374:685-694.
41. Fabbri L.M., Calverley P.M., Izquierdo-Alonso J.L., Bundschuh D.S., Brose M., Martinez F.J., et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials. Lancet 2009, 374:695-703.
42. Grootendorst D.C., Gauw S.A., Verhoosel R.M., Sterk P.J., Hospers J.J., Bredenbroker D., et al. Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD. Thorax 2007, 62:1081-1087.
43. Hohlfeld J.M., Schoenfeld K., Lavae-Mokhtari M., Schaumann F., Mueller M., Bredenbroeker D., et al. Roflumilast attenuates pulmonary inflammation upon segmental endotoxin challenge in healthy subjects: a randomized placebo-controlled trial. Pulm Pharmacol Ther 2008, 21:616-623.
44. Profita M., Chiappara G., Mirabella F., Di Giorgi R., Chimenti L., Costanzo G., et al. Effect of cilomilast (Ariflo) on TNF-alpha, IL-8, and GM-CSF release by airway cells of patients with COPD. Thorax 2003, 58:573-579.
45. Powrie D.J., Wilkinson T.M.A., Donaldson G.C., Jones P., Scrine K., Viel K., et al. Effect of tiotropium on sputum and serum inflammatory markers and exacerbations in COPD. Eur Respir J 2007, 30:472-478.
46. Perng D.W., Tao C.W., Su K.C., Tsai C.C., Liu L.Y., Lee Y.C. Anti-inflammatory effects of salmeterol/fluticasone, tiotropium/fluticasone or tiotropium in COPD. Eur Respir J 2009, 33:778-784.
47. Lapperre T.S., Snoeck-Stroband J.B., Gosman M.M.E., Jansen D.F., Van Schadewijk A., Thiadens H.A., et al. Effect of fluticasone with and without salmeterol on pulmonary outcomes in chronic obstructive pulmonary disease. Ann Intern Med 2009, 151:517-527.
48. Calverley P.M.A., Anderson J.A., Celli B.R., Ferguson G.T., Jenkins C.R., Jones P.W., et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007, 356:775-789.
49. Barnes N.C. Antiinflammatory effects of Salmeterol/Fluticasone propionate in chronic obstructive lung disease. Am J Respir Crit Care Med 2006, 173:736-743.
50. Bourbeau J., Christodoulopoulos P., Maltais F., Yamauchi Y., Olivenstein R., Hamid Q. Effect of salmeterol/fluticasone propionate on airway inflammation in COPD: a randomised controlled trial. Thorax 2007, 62:938-943.
51. Gizycki M.J. Effects of fluticasone propionate on inflammatory cells in COPD: an ultrastructural examination of endobronchial biopsy tissue. Thorax 2002, 57:799-803.
52. Barnes P.J. Mechanisms and resistance in glucocorticoid control of inflammation. J Steroid Biochem Mol Biol 2010, 120:76-85.
53. Burgin A.B., Magnusson O.T., Singh J., Witte P., Staker B.L., Bjornsson J.M., et al. Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety. Nat Biotechnol 2010, 28:63-70.
54. Vestbo J., Tan L., Atkinson G., Ward J. A controlled trial of 6-weeks' treatment with a novel inhaled phosphodiesterase type-4 inhibitor in COPD. Eur Respir J 2009, 33:1039-1044.
55. Singh D., Petavy F., Macdonald A.J., Lazaar A.L., O'Connor B.J. The inhaled phosphodiesterase 4 inhibitor GSK256066 reduces allergen challenge responses in asthma. Respir Res 2010, 11:26-35.
56. Selige J., Tenor H., Hatzelmann A., Dunkern T. Cytokine-dependent balance of mitogenic effects in primary human lung fibroblasts related to cyclic AMP signaling and phosphodiesterase 4 inhibition. J Cell Physiol 2010, 223:317-326.
57. Brunnee T., Engelstatter R., Steinijans V.W., Kunkel G. Bronchodilatory effect of inhaled zardaverine, a phosphodiesterase III and IV inhibitor, in patients with asthma. Eur Respir J 1992, 5:982-985.
58. Ukena D., Rentz K., Reiber C., Sybrecht G.W. Effects of the mixed phosphodiesterase III/IV inhibitor, zardaverine, on airway function in patients with chronic airflow obstruction. Respir Med 1995, 89:441-444.
59. Boswell-Smith V., Spina D., Oxford A.W., Comer M.B., Seeds E.A., Page C.P. The pharmacology of two novel long-acting phosphodiesterase 3/4 inhibitors, RPL554 [9,10-dimethoxy-2(2,4,6-trimethylphenylimino)-3-(n-carbamoyl-2-aminoethyl) -3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one] and RPL565 [6,7-dihydro-2-(2,6-diisopropylphenoxy)-9,10-dimethoxy-4H-pyrimido[6,1-a]i soquinolin-4-one]. J Pharmacol Exp Ther 2006, 318:840-848.
60. Wright L.C., Seybold J., Robichaud A., Adcock I.M., Barnes P.J. Phosphodiesterase expression in human epithelial cells. Am J Physiol Lung Cell Mol Physiol 1998, 275:L694-L700.
61. Smith S.J., Brookes-Fazakerley S., Donnelly L.E., Barnes P.J., Barnette M.S., Giembycz M.A. Ubiquitous expression of phosphodiesterase 7A in human proinflammatory and immune cells. Am J Physiol Lung Cell Mol Physiol 2003, 284:L279-L289.
62. Wouters E.F.M., Teichmann P., Brose M., Rabe K.F., Fabbri L.M. Effects of roflumilast, a phosphodiesterase 4 inhibitor, on body composition in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 2010, 181:A4473.
63. McCluskie K., Klein U., Linnevers C., Ji Y.H., Yang A., Husfeld C., et al. Phosphodiesterase type 4 inhibitors cause proinflammatory effects in vivo. J Pharmacol Exp Ther 2006, 319:468-476.
64. Hertz A.L., Bender A.T., Smith K.C., Gilchrist M., Amieux P.S., Aderem A., et al. Elevated cyclic AMP and PDE4 inhibition induce chemokine expression in human monocyte-derived macrophages. Proc Natl Acad Sci 2009, 106:21978-21983.
65. Martorana P.A., Lunghi B., Lucattelli M., De C.G., Beume R., Lungarella G. Effect of roflumilast on inflammatory cells in the lungs of cigarette smoke-exposed mice. BMC Pulm Med 2008, 8:17.
66. Gamble E., Pavord I.D., Vignola A.M., Kroegel C., Morell F., Hansel T.T., et al. Cilomilast reduces CD8+ T-lymphocytes and macrophages in patients with chronic obstructive pulmonary disease (COPD): a double-blind placebo-controlled, parallel-group quantitiative study of bronchial biopsies. Eur Respir J 2001, 17:P2238.
67. Gantner F., Tenor H., Gekeler V., Schudt C., Wendel A., Hatzelmann A. Phosphodiesterase profiles of highly purified human peripheral blood leukocyte populations from normal and atopic individuals: a comparative study. J Allergy Clin Immunol 1997, 100:527-535.
68. Hatzelmann A., Schudt C. Anti-inflammatory and immunomodulatory potential of the novel PDE4 inhibitor roflumilast in vitro. J Pharmacol Exp Ther 2001, 297:267-279.
69. Peter D., Jin S.L., Conti M., Hatzelmann A., Zitt C. Differential expression and function of phosphodiesterase 4 (PDE4) subtypes in human primary CD4+ T cells: predominant role of PDE4D. J Immunol 2007, 178:4820-4831.
70. Essayan D.M., Kagey-Sobotka A., Lichtenstein L.M., Huang S.K. Differential regulation of human antigen-specific Th1 and Th2 lymphocyte responses by isozyme selective cyclic nucleotide phosphodiesterase inhibitors. J Pharmacol Exp Ther 1997, 282:505-512.
71. Ma R., Yang B.Y., Wu C.Y. A selective phosphodiesterase 4 (PDE4) inhibitor Zl-n-91 suppresses IL-17 production by human memory Th17 cells. Int Immunopharmacol 2008, 8:1408-1417.
72. Gantner F., Gotz C., Gekeler V., Schudt C., Wendel A., Hatzelmann A. Phosphodiesterase profile of human B lymphocytes from normal and atopic donors and the effects of PDE inhibition on B cell proliferation. Br J Pharmacol 1998, 123:1031-1038.
73. Parkkonen J., Hasala H., Moilanen E., Giembycz M.A., Kankaanranta H. Phosphodiesterase 4 inhibitors delay human eosinophil and neutrophil apoptosis in the absence and presence of salbutamol. Pulm Pharmacol Ther 2007.
74. Jones N.A., Boswell-Smith V., Lever R., Page C.P. The effect of selective phosphodiesterase isoenzyme inhibition on neutrophil function in vitro. Pulm Pharmacol Ther 2005, 18:93-101.
75. Heystek H.C., Thierry A.C., Soulard P., Moulon C. Phosphodiesterase 4 inhibitors reduce human dendritic cell inflammatory cytokine production and Th1-polarizing capacity. Int Immunol 2003, 15:827-835.
76. Barber R., Baillie G.S., Bergmann R., Shepherd M.C., Sepper R., Houslay M.D., et al. Differential expression of PDE4 cAMP phosphodiesterase isoforms in inflammatory cells of smokers with COPD, smokers without COPD, and nonsmokers. Am J Physiol Lung Cell Mol Physiol 2004, 287:L332-L343.
77. Gantner F., Kupferschmidt R., Schudt C., Wendel A., Hatzelmann A. In vitro differentiation of human monocytes to macrophages: Change of PDE profile and its relationship to suppression of tumour necrosis factor-alpha release by PDE inhibitors. Br J Pharmacol 1997, 121:221-231.
78. Weston M.C., Anderson N., Peachell P.T. Effects of phosphodiesterase inhibitors on human lung mast cell and basophil function. Br J Pharmacol 1997, 121:287-295.
79. Shichijo M., Inagaki N., Nakai N., Kimata M., Nakahata T., Serizawa I., et al. The effects of anti-asthma drugs on mediator release from cultured human mast cells. Clin Exp Allergy 1998, 28:1228-1236.
80. Fuhrmann M., Jahn H.U., Seybold J., Neurohr C., Barnes P.J., Hippenstiel S., et al. Identification and function of cyclic nucleotide phosphodiesterase isoenzymes in airway epithelial cells. Am J Respir Cell Mol Biol 1999, 20:292-302.
81. Haddad J.J., Land S.C., Tarnow-Mordi W.O., Zembala M., Kowalczyk D., Lauterbach R. Immunopharmacological potential of selective phosphodiesterase inhibition. I. Differential regulation of lipopolysaccharide-mediated proinflammatory cytokine (interleukin-6 and tumor necrosis factor-alpha) biosynthesis in alveolar epithelial cells. J Pharmacol Exp Ther 2002, 300:559-566.
82. Sanz M.J., Cortijo J., Taha M.A., Cerda-Nicolas M., Schatton E., Burgbacher B., et al. Roflumilast inhibits leukocyte-endothelial cell interactions, expression of adhesion molecules and microvascular permeability. Br J Pharmacol 2007, 152:481-492.
83. Suttorp N., Ehreiser P., Hippenstiel S., Fuhrmann M., Krull M., Tenor H., et al. Hyperpermeability of pulmonary endothelial monolayer: protective role of phosphodiesterase isoenzymes 3 and 4. Lung 1996, 174:181-194.
84. Kohyama T., Liu X., Zhu Y.K., Wen F.Q., Wang H.J., Fang Q., et al. Phosphodiesterase 4 inhibitor cilomilast inhibits fibroblast-mediated collagen gel degradation induced by tumor necrosis factor-alpha and neutrophil elastase. Am J Respir Cell Mol Biol 2002, 27:487-494.
85. Martin-Chouly C.A., Astier A., Jacob C., Pruniaux M.P., Bertrand C., Lagente V. Modulation of matrix metalloproteinase production from human lung fibroblasts by type 4 phosphodiesterase inhibitors. Life Sci 2004, 75:823-840.
86. Dunkern T.R., Feurstein D., Rossi G.A., Sabatini F., Hatzelmann A. Inhibition of TGF-beta induced lung fibroblast to myofibroblast conversion by phosphodiesterase inhibiting drugs and activators of soluble guanylyl cyclase. Eur J Pharmacol 2007, 572:12-22.
87. Sabatini F., Petecchia L., Boero S., Silvestri M., Klar J., Tenor H., et al. A phosphodiesterase 4 inhibitor, roflumilast N-oxide, inhibits human lung fibroblast functions in vitro. Pulm Pharmacol Ther 2010, 23:283-291.
88. Noh A.L., Yang M., Lee J.M., Park H., Lee D.S., Yim M. Phosphodiesterase 3 and 4 negatively regulate receptor activator of nuclear factor-kappaB ligand-mediated osteoclast formation by prostaglandin E2. Biol Pharm Bull 2009, 32:1844-1848.
89. Tenor H., Hedbom E., Hauselmann H.J., Schudt C., Hatzelmann A. Phosphodiesterase isoenzyme families in human osteoarthritis chondrocytes-functional importance of phosphodiesterase 4. Br J Pharmacol 2002, 135:609-618.
90. Waddleton D., Wu W., Feng Y., Thompson C., Wu M., Zhou Y.P., et al. Phosphodiesterase 3 and 4 comprise the major cAMP metabolizing enzymes responsible for insulin secretion in INS-1 (832/13) cells and rat islets. Biochem Pharmacol 2008, 76:884-893.
91. Wang H., Edens N.K. mRNA expression and antilipolytic role of phosphodiesterase 4 in rat adipocytes in vitro. J Lipid Res 2007, 48:1099-1107.
92. Snyder P.B., Esselstyn J.M., Loughney K., Wolda S.L., Florio V.A. The role of cyclic nucleotide phosphodiesterases in the regulation of adipocyte lipolysis. J Lipid Res 2005, 46:494-503.
93. Tashkin D.P., Celli B.R., Senn S., Burkhart D., Kesten S., Menjoge S., et al. A 4 year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med 2007, 359:1543-1554.
94. Aaron S.D., Vandemheen K.L., Ferguson E.W., Maltals F., Bourbeau J., Goldstein R., et al. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease. Ann Intern Med 2007, 146:545-555.
95. Szafranski W., Cukier A., Ramirez A., Menga G., Sansores R., Nahabedian S., et al. Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease. Eur Respir J 2003, 21:74-81.