Selective PDE inhibitors as novel treatments for respiratory diseases

Current Opinion in Pharmacology

Volumn 12, Issue 3, 2012, Pages 275-286

  Page, Clive P ^a   Spina, Domenico ^a  

^a KING'S COLLEGE LONDON   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIASTHMATIC AGENT; BIOLOGICAL MARKER; CILOMILAST; CYCLIC AMP; GSK 256066; MK 0359; PHOSPHODIESTERASE IV; PHOSPHODIESTERASE IV INHIBITOR; ROFLUMILAST; ROLIPRAM; UNCLASSIFIED DRUG;

ADVERSE OUTCOME; ALLERGIC AIRWAY INFLAMMATION; ALLERGIC ASTHMA; ANTIINFLAMMATORY ACTIVITY; ARTICLE; ASTHMA; CHRONIC OBSTRUCTIVE LUNG DISEASE; DIARRHEA; DISEASE MARKER; DRUG EFFECT; DRUG EFFICACY; DRUG HALF LIFE; DRUG POTENCY; DRUG SAFETY; DRUG TREATMENT FAILURE; DRUG WITHDRAWAL; ENZYME ACTIVE SITE; ENZYME ACTIVITY; ENZYME DEGRADATION; ENZYME INHIBITION; ENZYME MECHANISM; GASTROINTESTINAL SYMPTOM; HEADACHE; HUMAN; HYDROGEN BOND; MOLECULAR PATHOLOGY; NAUSEA; NONHUMAN; OUTCOME ASSESSMENT; PRIORITY JOURNAL; PROTEIN EXPRESSION; RESPIRATORY TRACT ALLERGY; RESPIRATORY TRACT DISEASE; SIDE EFFECT; VOMITING; WEIGHT REDUCTION;

EID: 84862290893     PISSN: 14714892     EISSN: 14714973     Source Type: Journal    
DOI: 10.1016/j.coph.2012.02.016     Document Type: Review

References (124)

1. A.K. Tee, M.S. Koh, P.G. Gibson, T.J. Lasserson, A.J. Wilson, and L.B. Irving Long-acting beta2-agonists versus theophylline for maintenance treatment of asthma Cochrane Database Syst Rev 2007 CD001281
2. R.J. Dennis, and I. Solarte Asthma in adults Clin Evid 2011 1512 1572 (Online)
3. D.D. Sin, F.A. McAlister, S.F. Man, and N.R. Anthonisen Contemporary management of chronic obstructive pulmonary disease: scientific review JAMA 290 2003 2301 2312
4. R.A. McIvor, M. Tunks, and D.C. Todd Copd Clin Evid 2011 1502 1602 (Online)
5. D.K. Kirsten, R.E. Wegner, R.A. Jorres, and H. Magnussen Effects of theophylline withdrawal in severe chronic obstructive pulmonary disease Chest 104 1993 1101 1107
6. J. Kidney, M. Dominguez, P.M. Taylor, M. Rose, K.F. Chung, and P.J. Barnes Immunomodulation by theophylline in asthma. Demonstration by withdrawal of therapy Am J Respir Crit Care Med 151 1995 1907 1914
7. R.W. Butcher, and E.W. Sutherland Adenosine 3′,5′-phosphate in biological materials. I. Purification and properties of cyclic 3′,5′-nucleotide phosphodiesterase and use of this enzyme to characterize adenosine 3′,5′-phosphate in human urine J Biol Chem 237 1962 1244 1250
8. M.J. O'Shaughnessy, Z.M. Chen, I. Gramaglia, P.A. Taylor, A. Panoskaltsis-Mortari, C. Vogtenhuber, E. Palmer, T. Grader-Beck, V.A. Boussiotis, and B.R. Blazar Elevation of intracellular cyclic AMP in alloreactive CD4(+) T cells induces alloantigen-specific tolerance that can prevent GVHD lethality in vivo Biol Blood Marrow Transpl 13 2007 530 542
9. P. Sullivan, S. Bekir, Z. Jaffar, C. Page, P. Jeffery, and J. Costello Anti-inflammatory effects of low-dose oral theophylline in atopic asthma Lancet 343 1994 1006 1008 [published erratum appears in Lancet 1994;343(8911):1512]
10. S.I. Rennard Treatment of stable chronic obstructive pulmonary disease Lancet 364 2004 791 802
11. M.D. Houslay Underpinning compartmentalised cAMP signalling through targeted cAMP breakdown Trends Biochem Sci 35 2010 91 100
12. P.J. Barnes Emerging pharmacotherapies for COPD Chest 134 2008 1278 1286
13. M. Boolell, S. Gepi-Attee, J.C. Gingell, and M.J. Allen Sildenafil, a novel effective oral therapy for male erectile dysfunction Br J Urol 78 1996 257 261
14. M.R. Wilkins, G.A. Paul, J.W. Strange, N. Tunariu, W. Gin-Sing, W.A. Banya, M.A. Westwood, A. Stefanidis, L.L. Ng, and D.J. Pennell Sildenafil versus Endothelin Receptor Antagonist for Pulmonary Hypertension (SERAPH) study Am J Respir Crit Care Med 171 2005 1292 1297
15. L.J. Rubin, D.B. Badesch, T.R. Fleming, N. Galie, G. Simonneau, H.A. Ghofrani, M. Oakes, G. Layton, M. Serdarevic-Pehar, V.V. McLaughlin, and R.J. Barst Long-term treatment with sildenafil citrate in pulmonary arterial hypertension: the SUPER-2 study Chest 140 2011 1274 1283
16. Z.C. Jing, Z.X. Yu, J.Y. Shen, B.X. Wu, K.F. Xu, X.Y. Zhu, L. Pan, Z.L. Zhang, X.Q. Liu, and Y.S. Zhang Vardenafil in pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled study Am J Respir Crit Care Med 183 2011 1723 1729
17. C.T. Sousa, T.S. Brito, F.J. Lima, R.J. Siqueira, P.J. Magalhaes, A.A. Lima, A.A. Santos, and A. Havt Sildenafil decreases rat tracheal hyperresponsiveness to carbachol and changes canonical transient receptor potential gene expression after antigen challenge Braz J Med Biol Res 44 2011 562 572
18. R.X. Xu, A.M. Hassell, D. Vanderwall, M.H. Lambert, W.D. Holmes, M.A. Luther, W.J. Rocque, M.V. Milburn, Y. Zhao, H. Ke, and R.T. Nolte Atomic structure of PDE4: insights into phosphodiesterase mechanism a specificity Science 288 2000 1822 1825
19. G.L. Card, B.P. England, Y. Suzuki, D. Fong, B. Powell, B. Lee, C. Luu, M. Tabrizizad, S. Gillette, and P.N. Ibrahim Structural basis for the activity of drugs that inhibit phosphodiesterases Structure 12 2004 2233 2247
20. H. Wang, M.S. Peng, Y. Chen, J. Geng, H. Robinson, M.D. Houslay, J. Cai, and H. Ke Structures of the four subfamilies of phosphodiesterase-4 provide insight into the selectivity of their inhibitors Biochem J 408 2007 193 201
21. M. Kranz, M. Wall, B. Evans, A. Miah, S. Ballantine, C. Delves, B. Dombroski, J. Gross, J. Schneck, and J.P. Villa Identification of PDE4B over 4D subtype-selective inhibitors revealing an unprecedented binding mode Bioorg Med Chem 17 2009 5336 5341
22. K.H. Banner, and N.J. Press Dual PDE3/4 inhibitors as therapeutic agents for chronic obstructive pulmonary disease Br J Pharmacol 157 2009 892 906
23. B.L. Roth, D.J. Sheffler, and W.K. Kroeze Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia Nat Rev Drug Discov 3 2004 353 359
24. P.J. Barnes The cytokine network in asthma and chronic obstructive pulmonary disease J Clin Invest 118 2008 3546 3556
25. S.C. Chan, D. Reifsnyder, J.A. Beavo, and J.M. Hanifin Immunochemical characterization of the distinct monocyte cyclic AMP-phosphodiesterase from patients with atopic dermatitis J Allergy Clin Immunol 91 1993 1179 1188
26. F. Gantner, H. Tenor, V. Gekeler, C. Schudt, A. Wendel, and A. Hatzelmann Phosphodiesterase profiles of highly purified human peripheral blood leukocyte populations from normal and atopic individuals: a comparative study J Allergy Clin Immunol 100 1997 527 535
27. L.J. Landells, C.M. Szilagy, N.A. Jones, K.H. Banner, J.M. Allen, A. Doherty, B.J. O'Connor, D. Spina, and C.P. Page Identification and quantification of phosphodiesterase 4 subtypes in CD4 and CD8 lymphocytes from healthy and asthmatic subjects Br J Pharmacol 133 2001 722 729
28. N.A. Jones, M. Leport, T. Holand, T. Vos, M. Morgan, M. Fink, M.P. Pruniaux, C. Berthelier, B.J. O'Connor, C. Bertrand, and C.P. Page Phosphodiesterase (PDE) 7 in inflammatory cells from patients with asthma and COPD Pulm Pharmacol Ther 20 2007 60 68
29. B.E. Himes, G.M. Hunninghake, J.W. Baurley, N.M. Rafaels, P. Sleiman, D.P. Strachan, J.B. Wilk, S.A. Willis-Owen, B. Klanderman, and J. Lasky-Su Genome-wide association analysis identifies PDE4D as an asthma-susceptibility gene Am J Hum Genet 84 2009 581 593
30. C.D. Manning, M. Burman, S.B. Christensen, L.B. Cieslinski, D.M. Essayan, M. Grous, T.J. Torphy, and M.S. Barnette Suppression of human inflammatory cell function by subtype-selective PDE4 inhibitors correlates with inhibition of PDE4A and PDE4B Br J Pharmacol 128 1999 1393 1398
31. G. Hansen, S. Jin, D.T. Umetsu, and M. Conti Absence of muscarinic cholinergic airway responses in mice deficient in the cyclic nucleotide phosphodiesterase PDE4D Proc Natl Acad Sci USA 97 2000 6751 6756
32. T.T. Kung, Y. Crawley, B. Luo, S. Young, W. Kreutner, and R.W. Chapman Inhibition of pulmonary eosinophilia and airway hyperresponsiveness in allergic mice by rolipram, involvement of endogenously released corticosterone and catecholamines Br J Pharmacol 130 2000 457 463
33. A. Kanehiro, T. Ikemura, M.J. Makela, M. Lahn, A. Joetham, A. Dakhama, and E.W. Gelfand Inhibition of phosphodiesterase 4 attenuates airway hyperresponsiveness and airway inflammation in a model of secondary allergen challenge Am J Respir Crit Care Med 163 2001 173 184
34. C. Mehats, S.L. Jin, J. Wahlstrom, E. Law, D.T. Umetsu, and M. Conti PDE4D plays a critical role in the control of airway smooth muscle contraction FASEB J 17 2003 1831 1841
35. S.L. Jin, S. Goya, S. Nakae, D. Wang, M. Bruss, C. Hou, D. Umetsu, and M. Conti Phosphodiesterase 4B is essential for T(H)2-cell function and development of airway hyperresponsiveness in allergic asthma J Allergy Clin Immunol 126 2010 1252 1259
36. R.K. Kumar, C. Herbert, P.S. Thomas, L. Wollin, R. Beume, M. Yang, D.C. Webb, and P.S. Foster Inhibition of inflammation and remodeling by roflumilast and dexamethasone in murine chronic asthma J Pharmacol Exp Ther 307 2003 349 355
37. P.L. Harbinson, D. MacLeod, R. Hawksworth, S. O'Toole, P.J. Sullivan, P. Heath, S. Kilfeather, C.P. Page, J. Costello, S.T. Holgate, and T.H. Lee The effect of a novel orally active selective PDE4 isoenzyme inhibitor (CDP840) on allergen-induced responses in asthmatic subjects Eur Respir J 10 1997 1008 1014
38. E. van Schalkwyk, K. Strydom, Z. Williams, L. Venter, S. Leichtl, C. Schmid-Wirlitsch, D. Bredenbroker, and P.G. Bardin Roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, attenuates allergen-induced asthmatic reactions J Allergy Clin Immunol 116 2005 292 298
39. S. Lu, N. Liu, S.B. Dass, T.F. Reiss, and B.A. Knorr Randomized, placebo-controlled study of a selective PDE4 inhibitor in the treatment of asthma Respir Med 103 2009 342 347
40. G.M. Gauvreau, L.P. Boulet, C. Schmid-Wirlitsch, J. Cote, M. Duong, K.J. Killian, J. Milot, F. Deschesnes, T. Strinich, and R.M. Watson Roflumilast attenuates allergen-induced inflammation in mild asthmatic subjects Respir Res 12 2011 140
41. D. Singh, F. Petavy, A.J. Macdonald, A.L. Lazaar, and B.J. O'Connor The inhaled phosphodiesterase 4 inhibitor GSK256066 reduces allergen challenge responses in asthma Respir Res 11 2010 26 35
42. V. Boswell-Smith, D. Spina, A.W. Oxford, M.B. Comer, E.A. Seeds, and C.P. Page 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 318 2006 840 848
43. C. Louw, Z. Williams, L. Venter, S. Leichtl, C. Schmid-Wirlitsch, D. Bredenbroker, and P.G. Bardin Roflumilast, a phosphodiesterase 4 inhibitor, reduces airway hyperresponsiveness after allergen challenge Respiration 74 2007 411 417
44. D. Spina, L.J. Landells, and C.P. Page The role of phosphodiesterase enzymes in allergy and asthma Adv Pharmacol 44 1998 33 89
45. M. David, K. Zech, M. Seiberling, C. Weimar, and T.D. Bethke Roflumilast, a novel, oral, selective PDE4 inhibitor, shows high absolute bioavailability J Allergy Clin Immunol 113 2004 S220 S221
46. W. Timmer, V. Leclerc, G. Birraux, M. Neuhauser, A. Hatzelmann, T. Bethke, and W. Wurst The new phosphodiesterase 4 inhibitor roflumilast is efficacious in exercise-induced asthma and leads to suppression of LPS-stimulated TNF-alpha ex vivo J Clin Pharmacol 42 2002 297 303
47. H. Ichikawa, S. Okamoto, N. Kamada, H. Nagamoto, M.T. Kitazume, T. Kobayashi, H. Chinen, T. Hisamatsu, and T. Hibi Tetomilast suppressed production of proinflammatory cytokines from human monocytes and ameliorated chronic colitis in IL-10-deficient mice Inflamm Bowel Dis 14 2008 1483 1490
48. J. Bousquet, M. Aubier, J. Sastre, J.L. Izquierdo, L.M. Adler, P. Hofbauer, K.D. Rost, U. Harnest, B. Kroemer, A. Albrecht, and D. Bredenbroker Comparison of roflumilast, an oral anti-inflammatory, with beclomethasone dipropionate in the treatment of persistent asthma Allergy 61 2006 72 78
49. S.S. Salvi, and P.J. Barnes Chronic obstructive pulmonary disease in non-smokers Lancet 374 2009 733 743
50. R. Barber, G.S. Baillie, R. Bergmann, M.C. Shepherd, R. Sepper, M.D. Houslay, and G.V. Heeke 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 287 2004 L332 L343
51. F. Gantner, R. Kupferschmidt, C. Schudt, A. Wendel, and A. Hatzelmann 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 121 1997 221 231
52. S.J. Smith, S. Brookes-Fazakerley, L.E. Donnelly, P.J. Barnes, M.S. Barnette, and M.A. Giembycz Ubiquitous expression of phosphodiesterase 7A in human proinflammatory and immune cells Am J Physiol Lung Cell Mol Physiol 284 2003 L279 L289
53. S. Homma, T. Sakamoto, A.E. Hegab, W. Saitoh, A. Nomura, Y. Ishii, Y. Morishima, T. Iizuka, T. Kiwamoto, and Y. Matsuno Association of phosphodiesterase 4D gene polymorphisms with chronic obstructive pulmonary disease, relationship to interleukin 13 gene polymorphism Int J Mol Med 18 2006 933 939
54. M. Ariga, B. Neitzert, S. Nakae, G. Mottin, C. Bertrand, M.P. Pruniaux, S.L. Jin, and M. Conti Nonredundant function of phosphodiesterases 4D and 4B in neutrophil recruitment to the site of inflammation J Immunol 173 2004 7531 7538
55. P.A. Martorana, R. Beume, M. Lucattelli, L. Wollin, and G. Lungarella Roflumilast fully prevents emphysema in mice chronically exposed to cigarette smoke Am J Respir Crit Care Med 172 2005 848 853
56. O. Leclerc, V. Lagente, J.M. Planquois, C. Berthelier, M. Artola, T. Eichholtz, C.P. Bertrand, and F. Schmidlin Involvement of MMP-12 and phosphodiesterase type 4 in cigarette smoke-induced inflammation in mice Eur Respir J 27 2006 1102 1109
57. K.F. Rabe, E.D. Bateman, D. O'Donnell, S. Witte, D. Bredenbroker, and T.D. Bethke Roflumilast - an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomised controlled trial Lancet 366 2005 563 571
58. S.I. Rennard, N. Schachter, M. Strek, K. Rickard, and O. Amit Cilomilast for COPD: results of a 6-month, placebo-controlled study of a potent, selective inhibitor of phosphodiesterase 4 Chest 129 2006 56 66
59. P.M. Calverley, F. Sanchez-Toril, A. McIvor, P. Teichmann, D. Bredenbroeker, and L.M. Fabbri Effect of 1-year treatment with roflumilast in severe chronic obstructive pulmonary disease Am J Respir Crit Care Med 176 2007 154 161
60. L.M. Fabbri, P.M. Calverley, J.L. Izquierdo-Alonso, D.S. Bundschuh, M. Brose, F.J. Martinez, and K.F. Rabe Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials Lancet 374 2009 695 703
61. P.M. Calverley, K.F. Rabe, U.M. Goehring, S. Kristiansen, L.M. Fabbri, and F.J. Martinez Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials Lancet 374 2009 685 694
62. D.C. Grootendorst, S.A. Gauw, R.M. Verhoosel, P.J. Sterk, J.J. Hospers, D. Bredenbroker, T.D. Bethke, P.S. Hiemstra, and K.F. Rabe Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD Thorax 62 2007 1081 1087
63. E. Gamble, D.C. Grootendorst, C.E. Brightling, S. Troy, Y. Qiu, J. Zhu, D. Parker, D. Matin, S. Majumdar, and A.M. Vignola Antiinflammatory effects of the phosphodiesterase-4 inhibitor cilomilast (Ariflo) in chronic obstructive pulmonary disease Am J Respir Crit Care Med 168 2003 976 982
64. O. Michel, M. Dentener, D. Cataldo, B. Cantinieaux, F. Vertongen, C. Delvaux, and R.D. Murdoch Evaluation of oral corticosteroids and phosphodiesterase-4 inhibitor on the acute inflammation induced by inhaled lipopolysaccharide in human Pulm Pharmacol Ther 20 2007 676 683
65. J.A. Nightingale, D.F. Rogers, K.F. Chung, and P.J. Barnes No effect of inhaled budesonide on the response to inhaled ozone in normal subjects Am J Respir Crit Care Med 161 2000 479 486
66. N.E. Alexis, J.C. Lay, A. Haczku, H. Gong, W. Linn, M.J. Hazucha, B. Harris, R. Tal-Singer, and D.B. Peden Fluticasone propionate protects against ozone-induced airway inflammation and modified immune cell activation markers in healthy volunteers Environ Health Perspect 116 2008 799 805
67. B. Vagaggini, M. Taccola, I. Conti, S. Carnevali, S. Cianchetti, M.L. Bartoli, E. Bacci, F.L. Dente, A. Di Franco, D. Giannini, and P.L. Paggiaro Budesonide reduces neutrophilic but not functional airway response to ozone in mild asthmatics Am J Respir Crit Care Med 164 2001 2172 2176
68. O. Holz, S. Khalilieh, A. Ludwig-Sengpiel, H. Watz, P. Stryszak, P. Soni, M. Tsai, J. Sadeh, and H. Magnussen SCH527123, a novel CXCR2 antagonist, inhibits ozone-induced neutrophilia in healthy subjects Eur Respir J 35 2009 564 570
69. A.L. Lazaar, L.E. Sweeney, A.J. MacDonald, N.E. Alexis, C. Chen, and R. Tal-Singer SB-656933, a novel CXCR2 selective antagonist, inhibits ex vivo neutrophil activation and ozone-induced airway inflammation in humans Br J Clin Pharmacol 72 2011 282 293
70. J.M. Hohlfeld, K. Schoenfeld, M. Lavae-Mokhtari, F. Schaumann, M. Mueller, D. Bredenbroeker, N. Krug, and R. Hermann Roflumilast attenuates pulmonary inflammation upon segmental endotoxin challenge in healthy subjects: a randomized placebo-controlled trial Pulm Pharmacol Ther 21 2008 616 623
71. J. Vestbo, L. Tan, G. Atkinson, and J. Ward A controlled trial of 6-weeks' treatment with a novel inhaled phosphodiesterase type-4 inhibitor in COPD Eur Respir J 33 2009 1039 1044
72. D.O. Carpenter, D.B. Briggs, A.P. Knox, and N. Strominger Excitation of area postrema neurones by transmitters, peptides and cyclic nucleotides J Neurophysiol 59 1988 358 369
73. Y. Bureau, M. Handa, Y. Zhu, F. Laliberte, C.S. Moore, S. Liu, Z. Huang, D. Macdonald, D.G. Xu, and G.S. Robertson Neuroanatomical and pharmacological assessment of Fos expression induced in the rat brain by the phosphodiesterase-4 inhibitor 6-(4-pyridylmethyl)-8-(3-nitrophenyl) quinoline Neuropharmacology 51 2006 974 985
74. A. Robichaud, F.D. Tattersall, I. Choudhury, and I.W. Rodger Emesis induced by inhibitors of type IV cyclic nucleotide phosphodiesterase (PDE IV) in the ferret Neuropharmacology 38 1999 289 297
75. A. Robichaud, C. Savoie, P.B. Stamatiou, F.D. Tattersall, and C.C. Chan PDE4 inhibitors induce emesis in ferrets via a noradrenergic pathway Neuropharmacology 40 2001 262 269
76. S. Lamontagne, E. Meadows, P. Luk, D. Normandin, E. Muise, L. Boulet, D.J. Pon, A. Robichaud, G.S. Robertson, K.M. Metters, and F. Nantel Localization of phosphodiesterase-4 isoforms in the medulla and nodose ganglion of the squirrel monkey Brain Res 920 2001 84 96
77. J.A. Cherry, and R.L. Davis Cyclic AMP phosphodiesterases are localized in regions of the mouse brain associated with reinforcement, movement and affect J Comp Neurol 407 1999 287 301
78. M. Takahashi, R. Terwilliger, C. Lane, P.S. Mezes, M. Conti, and R.S. Duman Chronic antidepressant administration increases the expression of cAMP-specific phosphodiesterase 4A and 4B isoforms J Neurosci 19 1999 610 618
79. S. Perez-Torres, X. Miro, J.M. Palacios, R. Cortes, P. Puigdomenech, and G. Mengod Phosphodiesterase type 4 isozymes expression in human brain examined by in situ hybridization histochemistry and [3H]rolipram binding autoradiography. Comparison with monkey and rat brain J Chem Neuroanat 20 2000 349 374
80. F. Mori, S. Pérez-Torres, R. De Caro, A. Porzionato, V. Macchi, J. Beleta, A. Gavaldà, J.M. Palacios, and G. Mengod The human area postrema and other nuclei related to the emetic reflex express cAMP phosphodiesterases 4B and 4D J Chem Neuroanat 40 2010 36 42
81. A. Robichaud, C. Savoie, P.B. Stamatiou, N. Lachance, P. Jolicoeur, R. Rasori, and C.C. Chan Assessing the emetic potential of PDE4 inhibitors in rats Br J Pharmacol 135 2002 113 118
82. A. Robichaud, P.B. Stamatiou, S.L. Jin, N. Lachance, D. Macdonald, F. Laliberte, S. Liu, Z. Huang, M. Conti, and C.C. Chan Deletion of phosphodiesterase 4D in mice shortens alpha(2)-adrenoceptor-mediated anesthesia, a behavioral correlate of emesis J Clin Invest 110 2002 1045 1052
83. M. Aoki, M. Kobayashi, J. Ishikawa, Y. Saita, Y. Terai, K. Takayama, K. Miyata, and T. Yamada A novel phosphodiesterase type 4 inhibitor, YM976 (4-(3-chlorophenyl)-1,7-diethylpyrido[2,3-d]pyrimidin-2(1H)-one), with little emetogenic activity J Pharmacol Exp Ther 295 2000 255 260
84. M. Aoki, M. Fukunaga, T. Sugimoto, Y. Hirano, M. Kobayashi, K. Honda, and T. Yamada Studies on mechanisms of low emetogenicity of YM976, a novel phosphodiesterase type 4 inhibitor J Pharmacol Exp Ther 298 2001 1142 1149
85. D.D. Gale, L.J. Landells, D. Spina, A.J. Miller, K. Smith, T. Nichols, Y. Rotshteyn, A. Tonelli, P. Lacouture, and R.M. Burch Pharmacokinetic and pharmacodynamic profile following oral administration of the phosphodiesterase (PDE)4 inhibitor V11294A in healthy volunteers Br J Clin Pharmacol 54 2002 478 484
86. A.B. Burgin, O.T. Magnusson, J. Singh, P. Witte, B.L. Staker, J.M. Bjornsson, M. Thorsteinsdottir, S. Hrafnsdottir, T. Hagen, and A.S. Kiselyov Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety Nat Biotechnol 28 2010 63 70
87. P.M. Gross, K.M. Wall, J.J. Pang, S.W. Shaver, and D.S. Wainman Microvascular specializations promoting rapid interstitial solute dispersion in nucleus tractus solitarius Am J Physiol 259 1990 R1131 R1138
88. D. Spina The potential of PDE4 inhibitors in respiratory disease Curr Drug Targets Inflamm Allergy 3 2004 231 236
89. S.E. Lehnart, X.H. Wehrens, S. Reiken, S. Warrier, A.E. Belevych, R.D. Harvey, W. Richter, S.L. Jin, M. Conti, and A.R. Marks Phosphodiesterase 4D deficiency in the ryanodine-receptor complex promotes heart failure and arrhythmias Cell 123 2005 25 35
90. A. Nyska, R.A. Herbert, P.C. Chan, J.K. Haseman, and J.R. Hailey Theophylline-induced mesenteric periarteritis in F344/N rats Arch Toxicol 72 1998 731 737
91. K. Ohta, Y. Fukuchi, L. Grouse, R. Mizutani, K.F. Rabe, S.I. Rennard, and N.S. Zhong A prospective clinical study of theophylline safety in 3810 elderly with asthma or COPD Respir Med 98 2004 1016 1024
92. K. McCluskie, U. Klein, C. Linnevers, Y.H. Ji, A. Yang, C. Husfeld, and G.R. Thomas Phosphodiesterase type 4 inhibitors cause proinflammatory effects in vivo J Pharmacol Exp Ther 319 2006 468 476
93. D.S. Bundschuh, M. Eltze, J. Barsig, L. Wollin, A. Hatzelmann, and R. Beume In vivo efficacy in airway disease models of roflumilast, a novel orally active PDE4 inhibitor J Pharmacol Exp Ther 297 2001 280 290
94. A. Hatzelmann, and C. Schudt Anti-inflammatory and immunomodulatory potential of the novel PDE4 inhibitor roflumilast in vitro J Pharmacol Exp Ther 297 2001 267 279
95. J. Parkkonen, H. Hasala, E. Moilanen, M.A. Giembycz, and H. Kankaanranta Phosphodiesterase 4 inhibitors delay human eosinophil and neutrophil apoptosis in the absence and presence of salbutamol Pulm Pharmacol Ther 21 2007 499 506
96. A.L. Hertz, A.T. Bender, K.C. Smith, M. Gilchrist, P.S. Amieux, A. Aderem, and J.A. Beavo Elevated cyclic AMP and PDE4 inhibition induce chemokine expression in human monocyte-derived macrophages Proc Natl Acad Sci 106 2009 21978 21983
97. S.L. Jin, F.J. Richard, W.P. Kuo, A.J. D'Ercole, and M. Conti Impaired growth and fertility of cAMP-specific phosphodiesterase PDE4D-deficient mice Proc Natl Acad Sci USA 96 1999 11998 12003
98. S.L. Jin, and M. Conti Induction of the cyclic nucleotide phosphodiesterase PDE4B is essential for LPS-activated TNF-alpha responses Proc Natl Acad Sci USA 99 2002 7628 7633
99. H. Wang, and N.K. Edens mRNA expression and antilipolytic role of phosphodiesterase 4 in rat adipocytes in vitro J Lipid Res 48 2007 1099 1107
100. V. Boswell-Smith, D. Spina, and C.P. Page Phosphodiesterase inhibitors Br J Pharmacol 147 Suppl. 1 2006 S252 S257
101. H. Kuss, N. Hoefgen, S. Johanssen, T. Kronbach, and C. Rundfeldt In vivo efficacy in airway disease models of N-(3,5-dichloropyrid-4-yl)-[1-(4- fluorobenzyl)-5-hydroxy-indole-3-yl]-glyo xylic acid amide (AWD 12-281), a selective phosphodiesterase 4 inhibitor for inhaled administration J Pharmacol Exp Ther 307 2003 373 385
102. P. Phillips, M. Bennetts, K. Banner, J. Ward, D. Wessels, and R. Fuhr The PDE4 inhibitor UK-500,001 does not significantly inhibit airway responses to allergen and histamine Eur Respir J 30 2007 491s Abstr. 2964
103. T. Brunnee, R. Engelstatter, V.W. Steinijans, and G. Kunkel Bronchodilatory effect of inhaled zardaverine, a phosphodiesterase III and IV inhibitor, in patients with asthma Eur Respir J 5 1992 982 985
104. J.W. Nyce, and W.J. Metzger DNA antisense therapy for asthma in an animal model Nature 385 1997 721 725
105. M. Fortin, H. D'Anjou, M.E. Higgins, J. Gougeon, P. Aube, K. Moktefi, S. Mouissi, S. Seguin, R. Seguin, and P.M. Renzi A multi-target antisense approach against PDE4 and PDE7 reduces smoke-induced lung inflammation in mice Respir Res 10 2009 39
106. J. Milara, A. Navarro, P. Almudever, J. Lluch, E.J. Morcillo, and J. Cortijo Oxidative stress-induced glucocorticoid resistance is prevented by dual PDE3/PDE4 inhibition in human alveolar macrophages Clin Exp Allergy 41 2011 535 546
107. D.M. Essayan, A. Kagey-Sobotka, L.M. Lichtenstein, and S.K. Huang Differential regulation of human antigen-specific Th1 and Th2 lymphocyte responses by isozyme selective cyclic nucleotide phosphodiesterase inhibitors J Pharmacol Exp Ther 282 1997 505 512
108. D. Peter, S.L. Jin, M. Conti, A. Hatzelmann, and C. Zitt Differential expression and function of phosphodiesterase 4 (PDE4) subtypes in human primary CD4+ T cells, predominant role of PDE4D J Immunol 178 2007 4820 4831
109. R. Ma, B.Y. Yang, and C.Y. Wu A selective phosphodiesterase 4 (PDE4) inhibitor Zl-n-91 suppresses IL-17 production by human memory Th17 cells Int Immunopharmacol 8 2008 1408 1417
110. F. Gantner, C. Gotz, V. Gekeler, C. Schudt, A. Wendel, and A. Hatzelmann Phosphodiesterase profile of human B lymphocytes from normal and atopic donors and the effects of PDE inhibition on B cell proliferation Br J Pharmacol 123 1998 1031 1038
111. N.A. Jones, V. Boswell-Smith, R. Lever, and C.P. Page The effect of selective phosphodiesterase isoenzyme inhibition on neutrophil function in vitro Pulm Pharmacol Ther 18 2005 93 101
112. H.C. Heystek, A.C. Thierry, P. Soulard, and C. Moulon Phosphodiesterase 4 inhibitors reduce human dendritic cell inflammatory cytokine production and Th1-polarizing capacity Int Immunol 15 2003 827 835
113. A.L. Noh, M. Yang, J.M. Lee, H. Park, D.S. Lee, and M. Yim Phosphodiesterase 3 and 4 negatively regulate receptor activator of nuclear factor-kappaB ligand-mediated osteoclast formation by prostaglandin E2 Biol Pharm Bull 32 2009 1844 1848
114. H. Tenor, E. Hedbom, H.J. Hauselmann, C. Schudt, and A. Hatzelmann Phosphodiesterase isoenzyme families in human osteoarthritis chondrocytes - functional importance of phosphodiesterase 4 Br J Pharmacol 135 2002 609 618
115. M.C. Weston, N. Anderson, and P.T. Peachell Effects of phosphodiesterase inhibitors on human lung mast cell and basophil function Br J Pharmacol 121 1997 287 295
116. M. Shichijo, N. Inagaki, N. Nakai, M. Kimata, T. Nakahata, I. Serizawa, Y. Iikura, H. Saito, and H. Nagai The effects of anti-asthma drugs on mediator release from cultured human mast cells Clin Exp Allergy 28 1998 1228 1236
117. M. Fuhrmann, H.U. Jahn, J. Seybold, C. Neurohr, P.J. Barnes, S. Hippenstiel, H.J. Kraemer, and N. Suttorp Identification and function of cyclic nucleotide phosphodiesterase isoenzymes in airway epithelial cells Am J Respir Cell Mol Biol 20 1999 292 302
118. J.J. Haddad, S.C. Land, W.O. Tarnow-Mordi, M. Zembala, D. Kowalczyk, and R. Lauterbach 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 300 2002 559 566
119. M.J. Sanz, J. Cortijo, M.A. Taha, M. Cerda-Nicolas, E. Schatton, B. Burgbacher, J. Klar, H. Tenor, C. Schudt, and A.C. Issekutz Roflumilast inhibits leukocyte-endothelial cell interactions, expression of adhesion molecules and microvascular permeability Br J Pharmacol 152 2007 481 492
120. T. Kohyama, X. Liu, Y.K. Zhu, F.Q. Wen, H.J. Wang, Q. Fang, T. Kobayashi, and S.I. Rennard 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 27 2002 487 494
121. C.A. Martin-Chouly, A. Astier, C. Jacob, M.P. Pruniaux, C. Bertrand, and V. Lagente Modulation of matrix metalloproteinase production from human lung fibroblasts by type 4 phosphodiesterase inhibitors Life Sci 75 2004 823 840
122. T.R. Dunkern, D. Feurstein, G.A. Rossi, F. Sabatini, and A. Hatzelmann Inhibition of TGF-beta induced lung fibroblast to myofibroblast conversion by phosphodiesterase inhibiting drugs and activators of soluble guanylyl cyclase Eur J Pharmacol 572 2007 12 22
123. J. Selige, H. Tenor, A. Hatzelmann, and T. Dunkern Cytokine-dependent balance of mitogenic effects in primary human lung fibroblasts related to cyclic AMP signaling and phosphodiesterase 4 inhibition J Cell Physiol 223 2010 317 326
124. D. Spina, S. Harrison, and C.P. Page Regulation by phosphodiesterase isoenzymes of non-adrenergic non-cholinergic contraction in guinea-pig isolated main bronchus Br J Pharmacol 116 1995 2334 2340