Phosphodiesterase inhibitors in the treatment of inflammatory diseases

Handbook of Experimental Pharmacology

Volumn 204, Issue , 2011, Pages 391-414

  Page, C P ^a   Spina, D ^a  

^a KING'S COLLEGE LONDON   (United Kingdom)

Author keywords

Asthma; Cilomilast; COPD; Emesis; Inflammation; PDE4; Roflumilast

Indexed keywords

3 (2 METHOXYBENZYLAMINO) 2 PHENYLPIPERIDINE; 4 [2 [3 (CYCLOPENTYLOXY) 4 METHOXYPHENYL] 2 PHENYLETHYL]PYRIDINE; AN 2728; AWD 12281; CILOMILAST; CYCLIC AMP DEPENDENT PROTEIN KINASE; CYCLIC AMP RESPONSIVE ELEMENT BINDING PROTEIN; GSK 256066; N (3,5 DICHLORO 4 PYRIDYL) [1 (4 FLUOROBENZYL) 5 HYDROXY 3 INDOLYL]GLYOXYLIC ACID AMIDE; ONDANSETRON; PHOSPHODIESTERASE IV; PHOSPHODIESTERASE IV INHIBITOR; PLACEBO; ROFLUMILAST; ROLIPRAM; TETOMILAST; THEOPHYLLINE; TUMOR NECROSIS FACTOR ALPHA ANTIBODY; UNCLASSIFIED DRUG;

ABDOMINAL PAIN; ANTIINFLAMMATORY ACTIVITY; ARTICLE; ASTHMA; ATOPIC DERMATITIS; CELLULAR IMMUNITY; CHRONIC OBSTRUCTIVE LUNG DISEASE; CYTOKINE PRODUCTION; DENDRITIC CELL; DIARRHEA; DIGESTIVE SYSTEM INFLAMMATION; DISEASE SEVERITY; DRUG BIOAVAILABILITY; DRUG EFFICACY; DRUG HALF LIFE; DRUG INDUCED HEADACHE; DRUG MEGADOSE; DRUG METABOLISM; DRUG POTENCY; DRUG SAFETY; DRUG TOLERABILITY; ENTERITIS; ENZYME INHIBITION; ENZYME METABOLISM; FORCED EXPIRATORY VOLUME; GASTROINTESTINAL SYMPTOM; GENE EXPRESSION REGULATION; HUMAN; HYDROLYSIS; HYDROPHOBICITY; IMMUNOREACTIVITY; INFLAMMATORY DISEASE; LIPOLYSIS; NAUSEA; NONHUMAN; PRIORITY JOURNAL; PROTEIN DOMAIN; PSORIASIS; RHEUMATOID ARTHRITIS; SIDE EFFECT; SIGNAL TRANSDUCTION; SINGLE NUCLEOTIDE POLYMORPHISM; STRUCTURAL HOMOLOGY; T LYMPHOCYTE; TH1 CELL; TH17 CELL; ULCERATIVE COLITIS; VOMITING; WEIGHT REDUCTION; X RAY CRYSTALLOGRAPHY; ANIMAL; INFLAMMATION; PHYSIOLOGY; REVIEW;

ANIMALS; ASTHMA; CYCLIC NUCLEOTIDE PHOSPHODIESTERASES, TYPE 4; HUMANS; INFLAMMATION; PHOSPHODIESTERASE 4 INHIBITORS; PULMONARY DISEASE, CHRONIC OBSTRUCTIVE;

EID: 79960928267     PISSN: 01712004     EISSN: 18650325     Source Type: Book Series    
DOI: 10.1007/978-3-642-17969-3_17     Document Type: Article

References (125)

1. Abraham C, Cho JH (2009) Inflammatory bowel disease. N Engl J Med 361:2066-2078
2. Akama T, Baker SJ, Zhang YK, Hernandez V, Zhou H, Sanders V, Freund Y, Kimura R, Maples KR, Plattner JJ (2009) Discovery and structure-activity study of a novel benzoxaborole anti-inflammatory agent (AN2728) for the potential topical treatment of psoriasis and atopic dermatitis. Bioorg Med Chem Lett 19:2129-2132
3. Aoki M, Kobayashi M, Ishikawa J, Saita Y, Terai Y, Takayama K, Miyata K, Yamada T (2000) 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: 255-260
4. Aoki M, Fukunaga M, Sugimoto T, Hirano Y, Kobayashi M, Honda K, Yamada T (2001) Studies on mechanisms of low emetogenicity of YM976, a novel phosphodiesterase type 4 inhibitor. J Pharmacol Exp Ther 298:1142-1149 (Pubitemid 32761931)
5. Ariga M, Neitzert B, Nakae S, Mottin G, Bertrand C, Pruniaux MP, Jin SL, Conti M (2004) Nonredundant function of phosphodiesterases 4D and 4B in neutrophil recruitment to the site of inflammation. J Immunol 173:7531-7538 (Pubitemid 39628194)
6. Banner KH, Press NJ (2009) Dual PDE3/4 inhibitors as therapeutic agents for chronic obstructive pulmonary disease. Br J Pharmacol 157:892-906
7. Barber R, Baillie GS, Bergmann R, Shepherd MC, Sepper R, Houslay MD, Heeke GV (2004) 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:L332-L343 (Pubitemid 38943915)
8. Barnes PJ (2008) The cytokine network in asthma and chronic obstructive pulmonary disease. J Clin Invest 118:3546-3556
9. Barnes PJ, Adcock IM, Ito K (2005) Histone acetylation and deacetylation: importance in inflammatory lung diseases. Eur Respir J 25:552-563 (Pubitemid 40331188)
10. Baumer W, Hoppmann J, Rundfeldt C, Kietzmann M (2007) Highly selective phosphodiesterase 4 inhibitors for the treatment of allergic skin diseases and psoriasis. Inflamm Allergy Drug Targets 6:17-26 (Pubitemid 46488295)
11. Boolell M, Gepi-Attee S, Gingell JC, Allen MJ (1996) Sildenafil, a novel effective oral therapy for male erectile dysfunction. Br J Urol 78:257-261 (Pubitemid 27407907)
12. Boswell-Smith V, Spina D, OxfordAW, ComerMB, Seeds EA, Page CP (2006a) 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 318:840-848
13. Boswell-Smith V, Spina D, Page CP (2006b) Phosphodiesterase inhibitors. Br J Pharmacol 147 (Suppl 1):S252-S257 (Pubitemid 43077283)
14. Bousquet J, Aubier M, Sastre J, Izquierdo JL, Adler LM, Hofbauer P, Rost KD, Harnest U, Kroemer B, Albrecht A, Bredenbroker D (2006) Comparison of roflumilast, an oral antiinflammatory, with beclomethasone dipropionate in the treatment of persistent asthma. Allergy 61:72-78 (Pubitemid 43381194)
15. Brunnee T, Engelstatter R, Steinijans VW, Kunkel G (1992) Bronchodilatory effect of inhaled zardaverine, a phosphodiesterase III and IV inhibitor, in patients with asthma. Eur Respir J 5:982-985
16. Bundschuh DS, Eltze M, Barsig J, Wollin L, Hatzelmann A, Beume R (2001) In vivo efficacy in airway disease models of roflumilast, a novel orally active PDE4 inhibitor. J Pharmacol Exp Ther 297:280-290 (Pubitemid 32242588)
17. Bureau Y, Handa M, Zhu Y, Laliberte F, Moore CS, Liu S, Huang Z, Macdonald D, Xu DG, Robertson GS (2006) 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 51:974-985 (Pubitemid 44540305)
18. Burgin AB, Magnusson OT, Singh J, Witte P, Staker BL, Bjornsson JM, Thorsteinsdottir M, Hrafnsdottir S, Hagen T, Kiselyov AS, Stewart LJ, Gurney ME (2010) Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety. Nat Biotechnol 28:63-70
19. Butcher RW, Sutherland EW (1962) Adenosine 30, 50-phosphate in biological materials. I. Purification and properties of cyclic 30, 50-nucleotide phosphodiesterase and use of this enzyme to characterize adenosine 30, 50-phosphate in human urine. J Biol Chem 237:1244-1250
20. Calverley PM, Sanchez-Toril F, McIvor A, Teichmann P, Bredenbroeker D, Fabbri LM (2007) Effect of 1-year treatment with roflumilast in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 176:154-161 (Pubitemid 47057851)
21. Calverley PM, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM, Martinez FJ (2009) Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet 374:685-694
22. Card GL, England BP, Suzuki Y, Fong D, Powell B, Lee B, Luu C, TabrizizadM, Gillette S, Ibrahim PN, Artis DR, Bollag G, Milburn MV, Kim SH, Schlessinger J, Zhang KY (2004) Structural basis for the activity of drugs that inhibit phosphodiesterases. Structure 12:2233-2247 (Pubitemid 39593200)
23. Carpenter DO, Briggs DB, Knox AP, Strominger N (1988) Excitation of area postrema neurones by transmitters, peptides and cyclic nucleotides. J Neurophysiol 59:358-369 (Pubitemid 18072250)
24. Chan SC, Reifsnyder D, Beavo JA, Hanifin JM (1993) Immunochemical characterization of the distinct monocyte cyclic AMP-phosphodiesterase from patients with atopic dermatitis. J Allergy Clin Immunol 91:1179-1188 (Pubitemid 23173186)
25. Cherry JA, Davis RL (1999) Cyclic AMP phosphodiesterases are localized in regions of the mouse brain associated with reinforcement, movement and affect. J Comp Neurol 407:287-301 (Pubitemid 29162777)
26. Conti M, Beavo J (2007) Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling. Annu Rev Biochem 76:481-511
27. David M, Zech K, Seiberling M, Weimar C, Roflumilast BTD (2004) A novel, oral, selective PDE4 inhibitor, shows high absolute bioavailability. J Allergy Clin Immunol 113:S220-S221, Ref Type: Abstract
28. Dunkern TR, Feurstein D, Rossi GA, Sabatini F, Hatzelmann A (2007) Inhibition of TGF-beta induced lung fibroblast to myofibroblast conversion by phosphodiesterase inhibiting drugs and activators of soluble guanylyl cyclase. Eur J Pharmacol 572:12-22 (Pubitemid 47374681)
29. Essayan DM, Kagey-Sobotka A, Lichtenstein LM, Huang S-K (1997) Differential regulation of human antigen-specific Th1 and Th2 lymphocyte responses by isozyme selective cyclic nucleotide phosphodiesterase inhibitors. J Pharmacol Exp Ther 282:505-512 (Pubitemid 27425580)
30. Fabbri LM, Calverley PM, Izquierdo-Alonso JL, Bundschuh DS, Brose M, Martinez FJ, Rabe KF (2009) Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials. Lancet 374:695-703
31. Fortin M, DAnjou H, Higgins ME, Gougeon J, Aube P, Moktefi K, Mouissi S, Seguin S, Seguin R, Renzi PM, Paquet L, Ferrari N (2009) A multi-target antisense approach against PDE4 and PDE7 reduces smoke-induced lung inflammation in mice. Respir Res 10:39
32. Fuhrmann M, Jahn H-U, Seybold J, Neurohr C, Barnes PJ, Hippenstiel S, Kraemer HJ, Suttorp N (1999) Identification and function of cyclic nucleotide phosphodiesterase isoenzymes in airway epithelial cells. Am J Respir Cell Mol Biol 20:292-302 (Pubitemid 129504890)
33. Gale DD, Landells LJ, Spina D, Miller AJ, Smith K, Nichols T, Rotshteyn Y, Tonelli A, Lacouture P, Burch RM, Page CP, OConnor BJ (2002) Pharmacokinetic and pharmacodynamic profile following oral administration of the phosphodiesterase (PDE)4 inhibitor V11294A in healthy volunteers. Br J Clin Pharmacol 54:478-484 (Pubitemid 35356873)
34. Gamble E, Grootendorst DC, Brightling CE, Troy S, Qiu Y, Zhu J, Parker D, Matin D, Majumdar S, Vignola AM, Kroegel C, Morell F, Hansel TT, Rennard SI, Compton C, Amit O, Tat T, Edelson J, Pavord ID, Rabe KF, Barnes NC, Jeffery PK (2003) Antiinflammatory effects of the phosphodiesterase-4 inhibitor cilomilast (Ariflo) in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 168:976-982 (Pubitemid 37267176)
35. Gantner F, Kupferschmidt R, Schudt C, Wendel A, Hatzelmann A (1997a) 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 121:221-231 (Pubitemid 27192708)
36. Gantner F, Tenor H, Gekeler V, Schudt C, Wendel A, Hatzelmann A (1997b) Phosphodiesterase profiles of highly purified human peripheral blood leukocyte populations from normal and atopic individuals: a comparative study. J Allergy Clin Immunol 100:527-535 (Pubitemid 27441312)
37. Gantner F, Gotz C, Gekeler V, Schudt C, Wendel A, Hatzelmann A (1998) Phosphodiesterase profile of human B lymphocytes from normal and atopic donors and the effects of PDE inhibition on B cell proliferation. Br J Pharmacol 123:1031-1038 (Pubitemid 28120497)
38. Gottlieb AB, Strober B, Krueger JG, Rohane P, Zeldis JB, Hu CC, Kipnis C (2008) An open-label, single-arm pilot study in patients with severe plaque-type psoriasis treated with an oral anti-inflammatory agent, apremilast. Curr Med Res Opin 24:1529-1538 (Pubitemid 351741586)
39. Grootendorst DC, Gauw SA, Verhoosel RM, Sterk PJ, Hospers JJ, Bredenbroker D, Bethke TD, Hiemstra PS, Rabe KF (2007) Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD. Thorax 62:1081-1087 (Pubitemid 350206202)
40. Gross PM, Wall KM, Pang JJ, Shaver SW, Wainman DS (1990) Microvascular specializations promoting rapid interstitial solute dispersion in nucleus tractus solitarius. Am J Physiol 259: R1131-R1138
41. Haddad JJ, Land SC, Tarnow-Mordi WO, Zembala M, Kowalczyk D, Lauterbach R (2002) 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: 559-566
42. Hansen G, Jin S, Umetsu DT, ContiM(2000) Absence of muscarinic cholinergic airway responses in mice deficient in the cyclic nucleotide phosphodiesterase PDE4D. Proc Natl Acad Sci USA 97:6751-6756 (Pubitemid 30412786)
43. Harbinson PL, MacLeod D, Hawksworth R, OToole S, Sullivan PJ, Heath P, Kilfeather S, Page CP, Costello J, Holgate ST, Lee TH (1997) The effect of a novel orally active selective PDE4 isoenzyme inhibitor (CDP840) on allergen-induced responses in asthmatic subjects. Eur Respir J 10:1008-1014 (Pubitemid 27201802)
44. Hatzelmann A, Schudt C (2001) Anti-inflammatory and immunomodulatory potential of the novel PDE4 inhibitor roflumilast in vitro. J Pharmacol Exp Ther 297:267-279 (Pubitemid 32242587)
45. Heystek HC, Thierry AC, Soulard P, Moulon C (2003) Phosphodiesterase 4 inhibitors reduce human dendritic cell inflammatory cytokine production and Th1-polarizing capacity. Int Immunol 15:827-835 (Pubitemid 36827071)
46. Himes BE, Hunninghake GM, Baurley JW, Rafaels NM, Sleiman P, Strachan DP, Wilk JB, Willis-Owen SA, Klanderman B, Lasky-Su J, Lazarus R, Murphy AJ, Soto-Quiros ME, Avila L, Beaty T, Mathias RA, Ruczinski I, Barnes KC, Celedon JC, Cookson WO, Gauderman WJ, Gilliland FD, Hakonarson H, Lange C, Moffatt MF, OConnor GT, Raby BA, Silverman EK, Weiss ST (2009) Genome-wide association analysis identifies PDE4D as an asthma-susceptibility gene. Am J Hum Genet 84:581-593
47. Homma S, Sakamoto T, Hegab AE, Saitoh W, Nomura A, Ishii Y, Morishima Y, Iizuka T, Kiwamoto T, Matsuno Y, Massoud HH, Massoud HM, Hassanein KM, Sekizawa K (2006) Association of phosphodiesterase 4D gene polymorphisms with chronic obstructive pulmonary disease: relationship to interleukin 13 gene polymorphism. Int J Mol Med 18:933-939
48. Houslay MD (2010) Underpinning compartmentalised cAMP signalling through targeted cAMP breakdown. Trends Biochem Sci 35:91-100
49. Houslay MD, Schafer P, Zhang KY (2005) Keynote review: phosphodiesterase-4 as a therapeutic target. Drug Discov Today 10:1503-1519 (Pubitemid 41527193)
50. Houslay MD, Baillie GS, Maurice DH (2007) cAMP-Specific phosphodiesterase-4 enzymes in the cardiovascular system: a molecular toolbox for generating compartmentalized cAMP signaling. Circ Res 100:950-966 (Pubitemid 46598920)
51. Huston E, Lynch MJ, Mohamed A, Collins DM, Hill EV, MacLeod R, Krause E, Baillie GS, Houslay MD (2008) EPAC and PKA allow cAMP dual control over DNA-PK nuclear translocation. Proc Natl Acad Sci USA 105:12791-12796
52. Ichikawa H, Okamoto S, Kamada N, Nagamoto H, Kitazume MT, Kobayashi T, Chinen H, Hisamatsu T, Hibi T (2008) Tetomilast suppressed production of proinflammatory cytokines from human monocytes and ameliorated chronic colitis in IL-10-deficient mice. Inflamm Bowel Dis 14:1483-1490
53. Jin SL, Conti M (2002) Induction of the cyclic nucleotide phosphodiesterase PDE4B is essential for LPS-activated TNF-alpha responses. Proc Natl Acad Sci USA 99:7628-7633 (Pubitemid 34568742)
54. Jin SL, Richard FJ, Kuo WP, DErcole AJ, Conti M (1999) Impaired growth and fertility of cAMP-specific phosphodiesterase PDE4D-deficient mice. Proc Natl Acad Sci USA 96: 11998-12003 (Pubitemid 29502847)
55. Jones NA, Boswell-Smith V, Lever R, Page CP (2005) The effect of selective phosphodiesterase isoenzyme inhibition on neutrophil function in vitro. Pulm Pharmacol Ther 18:93-101 (Pubitemid 40092659)
56. Jones NA, Leport M, Holand T, Vos T, Morgan M, Fink M, Pruniaux MP, Berthelier C, OConnor BJ, Bertrand C, Page CP (2007) Phosphodiesterase (PDE) 7 in inflammatory cells from patients with asthma and COPD. Pulm Pharmacol Ther 20:60-68 (Pubitemid 44755041)
57. Kanehiro A, Ikemura T, Makela MJ, Lahn M, Joetham A, Dakhama A, Gelfand EW (2001) Inhibition of phosphodiesterase 4 attenuates airway hyperresponsiveness and airway inflammation in a model of secondary allergen challenge. Am J Respir Crit Care Med 163:173-184 (Pubitemid 32095268)
58. Keshavarzian A, Mutlu E, Guzman JP, Forsyth C, Banan A (2007) Phosphodiesterase 4 inhibitors and inflammatory bowel disease: emerging therapies in inflammatory bowel disease. Expert Opin Investig Drugs 16:1489-1506 (Pubitemid 47491417)
59. Kobayashi K, Suda T, Manabe H, Miki I (2007) Administration of PDE4 inhibitors suppressed the pannus-like inflammation by inhibition of cytokine production by macrophages and synovial fibroblast proliferation. Mediat Inflamm 2007:58901
60. Kohyama T, Liu X, Zhu YK, Wen FQ, Wang HJ, Fang Q, Kobayashi T, Rennard SI (2002) 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 27:487-494
61. Kranz M, Wall M, Evans B, Miah A, Ballantine S, Delves C, Dombroski B, Gross J, Schneck J, Villa JP, Neu M, Somers DO (2009) Identification of PDE4B Over 4D subtype-selective inhibitors revealing an unprecedented binding mode. Bioorg Med Chem 17:5336-5341
62. Kumar RK, Herbert C, Thomas PS, Wollin L, Beume R, Yang M, Webb DC, Foster PS (2003) Inhibition of inflammation and remodeling by roflumilast and dexamethasone in murine chronic asthma. J Pharmacol Exp Ther 307:349-355 (Pubitemid 37151927)
63. Kung TT, Crawley Y, Luo B, Young S, Kreutner W, Chapman RW (2000) Inhibition of pulmonary eosinophilia and airway hyperresponsiveness in allergic mice by rolipram: involvement of endogenously released corticosterone and catecholamines. Br J Pharmacol 130:457-463 (Pubitemid 30261059)
64. Kuss H, Hoefgen N, Johanssen S, Kronbach T, Rundfeldt C (2003) 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 307:373-385 (Pubitemid 37151930)
65. Lamontagne S, Meadows E, Luk P, Normandin D, Muise E, Boulet L, Pon DJ, Robichaud A, Robertson GS, Metters KM, Nantel F (2001) Localization of phosphodiesterase-4 isoforms in the medulla and nodose ganglion of the squirrel monkey. Brain Res 920:84-96 (Pubitemid 33086782)
66. Landells LJ, Szilagy CM, Jones NA, Banner KH, Allen JM, Doherty A, OConnor BJ, Spina D, Page CP (2001) Identification and quantification of phosphodiesterase 4 subtypes in CD4 and CD8 lymphocytes from healthy and asthmatic subjects. Br J Pharmacol 133:722-729 (Pubitemid 32642878)
67. Leclerc O, Lagente V, Planquois JM, Berthelier C, Artola M, Eichholtz T, Bertrand CP, Schmidlin F (2006) Involvement of MMP-12 and phosphodiesterase type 4 in cigarette smoke-induced inflammation in mice. Eur Respir J 27:1102-1109 (Pubitemid 44914292)
68. Lehnart SE, Wehrens XH, Reiken S, Warrier S, Belevych AE, Harvey RD, Richter W, Jin SL, Conti M, Marks AR (2005) Phosphodiesterase 4D deficiency in the ryanodine-receptor complex promotes heart failure and arrhythmias. Cell 123:25-35 (Pubitemid 41414526)
69. Louw C, Williams Z, Venter L, Leichtl S, Schmid-Wirlitsch C, Bredenbroker D, Bardin PG (2007) Roflumilast, a phosphodiesterase 4 inhibitor, reduces airway hyperresponsiveness after allergen challenge. Respiration 74:411-417 (Pubitemid 47093154)
70. Lu S, Liu N, Dass SB, Reiss TF, Knorr BA (2009) Randomized, placebo-controlled study of a selective PDE4 inhibitor in the treatment of asthma. Respir Med 103:342-347
71. Ma R, Yang BY, Wu CY (2008) A selective phosphodiesterase 4 (PDE4) inhibitor Zl-n-91 suppresses IL-17 production by human memory Th17 cells. Int Immunopharmacol 8:1408-1417
72. Manning CD, Burman M, Christensen SB, Cieslinski LB, Essayan DM, Grous M, Torphy TJ, Barnette MS (1999) Suppression of human inflammatory cell function by subtype-selective PDE4 inhibitors correlates with inhibition of PDE4A and PDE4B. Br J Pharmacol 128: 1393-1398
73. Martin-Chouly CA, Astier A, Jacob C, Pruniaux MP, Bertrand C, Lagente V (2004) Modulation of matrix metalloproteinase production from human lung fibroblasts by type 4 phosphodiesterase inhibitors. Life Sci 75:823-840 (Pubitemid 38737420)
74. Martorana PA, Beume R, Lucattelli M, Wollin L, Lungarella G (2005) Roflumilast fully prevents emphysema in mice chronically exposed to cigarette smoke. Am J Respir Crit Care Med 172:848-853 (Pubitemid 41369068)
75. McCahill AC, Huston E, Li X, Houslay MD (2008) PDE4 associates with different scaffolding proteins: modulating interactions as treatment for certain diseases. Handb Exp Pharmacol (186); 125-166
76. McCluskie K, Klein U, Linnevers C, Ji YH, Yang A, Husfeld C, Thomas GR (2006) Phosphodiesterase type 4 inhibitors cause proinflammatory effects in vivo. J Pharmacol Exp Ther 319:468-476 (Pubitemid 44455154)
77. Mehats C, Jin SL, Wahlstrom J, Law E, Umetsu DT, ContiM(2003) PDE4D plays a critical role in the control of airway smooth muscle contraction. FASEB J 17:1831-1841 (Pubitemid 37214777)
78. Millar JK, Mackie S, Clapcote SJ, Murdoch H, Pickard BS, Christie S, Muir WJ, Blackwood DH, Roder JC, Houslay MD, Porteous DJ (2007) Disrupted in schizophrenia 1 and phosphodiesterase 4B: towards an understanding of psychiatric illness. J Physiol 584:401-405 (Pubitemid 47578327)
79. Nazarian R, Weinberg JM (2009) AN-2728, a PDE4 inhibitor for the potential topical treatment of psoriasis and atopic dermatitis. Curr Opin Investig Drugs 10:1236-1242
80. Nestle FO, Kaplan DH, Barker J (2009) Psoriasis. N Engl J Med 361:496-509
81. Noh AL, Yang M, Lee JM, Park H, Lee DS, Yim M (2009) Phosphodiesterase 3 and 4 negatively regulate receptor activator of nuclear factor-kappaB ligand-mediated osteoclast formation by prostaglandin E2. Biol Pharm Bull 32:1844-1848
82. Nyce JW, Metzger WJ (1997) DNA antisense therapy for asthma in an animal model. Nature 385:721-725 (Pubitemid 27098092)
83. Nyska A, Herbert RA, Chan PC, Haseman JK, Hailey JR (1998) Theophylline-induced mesenteric periarteritis in F344/N rats. Arch Toxicol 72:731-737 (Pubitemid 29001923)
84. OShaughnessy MJ, Chen ZM, Gramaglia I, Taylor PA, Panoskaltsis-Mortari A, Vogtenhuber C, Palmer E, Grader-Beck T, Boussiotis VA, Blazar BR (2007) Elevation of intracellular cyclic AMP in alloreactive CD4(+) T Cells induces alloantigen-specific tolerance that can prevent GVHD lethality in vivo. Biol Blood Marrow Transplant 13:530-542 (Pubitemid 46585930)
85. Ohta K, Fukuchi Y, Grouse L, Mizutani R, Rabe KF, Rennard SI, Zhong NS (2004) A prospective clinical study of theophylline safety in 3810 elderly with asthma or COPD. Respir Med 98:1016-1024 (Pubitemid 40029133)
86. Papakostantinou E, Xenos K, Markantonis SL, Druska S, Stratigos A, Katsambas A (2005) Efficacy of 2 weeks application of theophylline ointment in psoriasis vulgaris. J Dermatol Treat 16:169-170 (Pubitemid 41364777)
87. Parkkonen J, Hasala H, Moilanen E, Giembycz MA, Kankaanranta H (2007) Phosphodiesterase inhibitors delay human eosinophil and neutrophil apoptosis in the absence and presence of salbutamol. Pulm Pharmacol Ther 21:499-506 (Pubitemid 351635778)
88. Perez-Torres S, Miro X, Palacios JM, Cortes R, Puigdomenech P, Mengod G (2000) 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 20:349-374 (Pubitemid 32162892)
89. Peter D, Jin SL, Conti M, Hatzelmann A, Zitt C (2007) Differential expression and function of phosphodiesterase 4 (PDE4) subtypes in human primary CD4+ T cells: predominant role of PDE4D. J Immunol 178:4820-4831 (Pubitemid 46595264)
90. Phillips P, Bennetts M, Banner K, Ward J, Wessels D, Fuhr R (2007) The PDE4 inhibitor UK-500,001 does not significantly inhibit airway responses to allergen and histamine. Eur Resp J: 490s. Ref Type: Abstract
91. Rabe KF, Bateman ED, ODonnell D, Witte S, Bredenbroker D, Bethke TD (2005) Roflumilast -an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 366:563-571 (Pubitemid 41140331)
92. Rennard SI (2004) Treatment of stable chronic obstructive pulmonary disease. Lancet 364:791-802 (Pubitemid 39165101)
93. Rennard SI, Schachter N, Strek M, Rickard K, Amit O (2006) Cilomilast for COPD: results of a 6-month, placebo-controlled study of a potent, selective inhibitor of phosphodiesterase 4. Chest 129:56-66 (Pubitemid 43265243)
94. Robichaud A, Tattersall FD, Choudhury I, Rodger IW (1999) Emesis induced by inhibitors of type IV cyclic nucleotide phosphodiesterase (PDE IV) in the ferret. Neuropharmacology 38:289-297 (Pubitemid 29073550)
95. Robichaud A, Savoie C, Stamatiou PB, Tattersall FD, Chan CC (2001) PDE4 inhibitors induce emesis in ferrets via a noradrenergic pathway. Neuropharmacology 40:262-269
96. Robichaud A, Savoie C, Stamatiou PB, Lachance N, Jolicoeur P, Rasori R, Chan CC (2002a) Assessing the emetic potential of PDE4 inhibitors in rats. Br J Pharmacol 135:113-118 (Pubitemid 34102104)
97. Robichaud A, Stamatiou PB, Jin SL, Lachance N, Macdonald D, Laliberte F, Liu S, Huang Z, Conti M, Chan CC (2002b) Deletion of phosphodiesterase 4D in mice shortens alpha(2)-adrenoceptor-mediated anesthesia, a behavioral correlate of emesis. J Clin Invest 110: 1045-1052
98. Roth BL, Sheffler DJ, Kroeze WK (2004) Magic shotguns versus magic bullets: selectively nonselective drugs for mood disorders and schizophrenia. Nat Rev Drug Discov 3:353-359 (Pubitemid 38499762)
99. Salvi SS, Barnes PJ (2009) Chronic obstructive pulmonary disease in non-smokers. Lancet 374:733-743
100. Sanz MJ, Cortijo J, Taha MA, Cerda-Nicolas M, Schatton E, Burgbacher B, Klar J, Tenor H, Schudt C, Issekutz AC, Hatzelmann A, Morcillo EJ (2007) Roflumilast inhibits leukocyteendothelial cell interactions, expression of adhesion molecules and microvascular permeability. Br J Pharmacol 152:481-492 (Pubitemid 47585048)
101. Schafer P, Parton A, Gandhi A, Capone L, Adams M, Wu L, Bartlett J, Loveland M, Gilhar A, Cheung YF, Baillie G, Houslay M, Man HW, Muller G, Stirling D (2010) Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis. Br J Pharmacol 159:842-855
102. Schreiber S, Keshavarzian A, Isaacs KL, Schollenberger J, Guzman JP, Orlandi C, Hanauer SB (2007) A randomized, placebo-controlled, phase II study of tetomilast in active ulcerative colitis. Gastroenterology 132:76-86 (Pubitemid 46108758)
103. Shichijo M, Inagaki N, Nakai N, Kimata M, Nakahata T, Serizawa I, Iikura Y, Saito H, Nagai H (1998) The effects of anti-asthma drugs on mediator release from cultured human mast cells. Clin Exp Allergy 28:1228-1236 (Pubitemid 29087013)
104. Shore A, Dosch H, Gelfand EW (1978) Induction and separation of antigen-dependent T helper and T suppressor cells in man. Nature 274:586-587 (Pubitemid 8394642)
105. Singh D, Petavy F, Macdonald AJ, Lazaar AL, OConnor BJ (2010) The inhaled phosphodiesterase 4 inhibitor GSK256066 reduces allergen challenge responses in asthma. Respir Res 11:26-35
106. Smith SJ, Brookes-Fazakerley S, Donnelly LE, Barnes PJ, Barnette MS, Giembycz MA (2003) Ubiquitous expression of phosphodiesterase 7A in human proinflammatory and immune cells. Am J Physiol Lung Cell Mol Physiol 284:L279-L289 (Pubitemid 36164362)
107. Smith SJ, Cieslinski LB, Newton R, Donnelly LE, Fenwick PS, Nicholson AG, Barnes PJ, Barnette MS, Giembycz MA (2004) Discovery of BRL 50481 [3-(N, N-dimethylsulfonamido)-4-methyl-nitrobenzene], a selective inhibitor of phosphodiesterase 7: in vitro studies in human monocytes, lung macrophages, and CD8+ T-lymphocytes. Mol Pharmacol 66:1679-1689 (Pubitemid 39564796)
108. Spina D (2003) Phosphodiesterase-4 inhibitors in the treatment of inflammatory lung disease. Drugs 63:2575-2594 (Pubitemid 37491561)
109. Spina D (2004) The potential of PDE4 inhibitors in respiratory disease. Curr Drug Targets Inflamm Allergy 3:231-236 (Pubitemid 39206651)
110. Spina D (2008) PDE4 inhibitors: current status. Br J Pharmacol 155:308-315
111. Spina D, Harrison S, Page CP (1995) Regulation by phosphodiesterase isoenzymes of nonadrenergic non-cholinergic contraction in guinea-pig isolated main bronchus. Br J Pharmacol 116:2334-2340
112. Sullivan P, Bekir S, Jaffar Z, Page C, Jeffery P, Costello J (1994) Anti-inflammatory effects of low-dose oral theophylline in atopic asthma [published erratum appears in Lancet 1994 Jun 11; 343(8911):1512]. Lancet 343:1006-1008 (Pubitemid 24122609)
113. Takahashi M, Terwilliger R, Lane C, Mezes PS, Conti M, Duman RS (1999) Chronic antidepressant administration increases the expression of cAMP-specific phosphodiesterase 4A and 4B isoforms. J Neurosci 19:610-618 (Pubitemid 29036012)
114. Taylor PC, Feldmann M (2009) Anti-TNF biologic agents: still the therapy of choice for rheumatoid arthritis. Nat Rev Rheumatol 5:578-582
115. Tenor H, Hedbom E, Hauselmann HJ, Schudt C, Hatzelmann A (2002) Phosphodiesterase isoenzyme families in human osteoarthritis chondrocytes-functional importance of phosphodiesterase 4. Br J Pharmacol 135:609-618 (Pubitemid 34177638)
116. Timmer W, Leclerc V, Birraux G, Neuhauser M, Hatzelmann A, Bethke T, Wurst W (2002) 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 42:297-303 (Pubitemid 34163476)
117. van Schalkwyk E, Strydom K, Williams Z, Venter L, Leichtl S, Schmid-Wirlitsch C, Bredenbroker D, Bardin PG (2005) Roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, attenuates allergen-induced asthmatic reactions. J Allergy Clin Immunol 116:292-298 (Pubitemid 41096533)
118. Vestbo J, Tan L, Atkinson G, Ward J (2009) A controlled trial of 6-weeks treatment with a novel inhaled phosphodiesterase type-4 inhibitor in COPD. Eur Respir J 33:1039-1044
119. Wang H, Edens NK (2007) mRNA expression and antilipolytic role of phosphodiesterase 4 in rat adipocytes in vitro. J Lipid Res 48:1099-1107 (Pubitemid 46708677)
120. Wang H, Peng MS, Chen Y, Geng J, Robinson H, Houslay MD, Cai J, Ke H (2007) Structures of the four subfamilies of phosphodiesterase-4 provide insight into the selectivity of their inhibitors. Biochem J 408:193-201 (Pubitemid 350206342)
121. Weston MC, Anderson N, Peachell PT (1997) Effects of phosphodiesterase inhibitors on human lung mast cell and basophil function. Br J Pharmacol 121:287-295 (Pubitemid 27192716)
122. Wright RK, Mandy SH, Halprin KM, Hsia SL (1973) Defects and deficiency of adenyl cyclase in psoriatic skin. Arch Dermatol 107:47-53
123. Xu RX, Hassell AM, Vanderwall D, Lambert MH, Holmes WD, Luther MA, Rocque WJ, Milburn MV, Zhao Y, Ke H, Nolte RT (2000) Atomic structure of PDE4: insights into phosphodiesterase mechanism a specificity. Science 288:1822-1825 (Pubitemid 30399019)
124. Yao W, Tian XY, Chen J, Setterberg RB, Lundy MW, Chmielzwski P, Froman CA, Jee WS (2007) Rolipram, a phosphodiesterase 4 inhibitor, prevented cancellous and cortical bone loss by inhibiting endosteal bone resorption and maintaining the elevated periosteal bone formation in adult ovariectomized rats. J Musculoskelet Neuronal Interact 7:119-130 (Pubitemid 47249001)
125. Zocchi MR, Pardi R, Gromo G, Ferrero E, Ferrero ME, Besana C, Rugarli C (1985) Theophylline induced non specific suppressor activity in human peripheral blood lymphocytes. J Immunopharmacol 7:217-234 (Pubitemid 15246550)