Alkylxanthines and Phosphodiesterase 4 Inhibitors for Allergic Diseases

  • Mark A. Giembycz
Part of the Allergy Frontiers book series (ALLERGY, volume 5)

Despite significant advances in our understanding of the pathogenesis of many allergic disorders, the etiology of allergy is still incompletely understood. However, both the World Allergy and World Health Organization [1] have identified and recognized the participation of immunoglobulin (Ig) E-driven mechanisms in many allergic diseases (Table 1). Since the incidence of allergy has reached epidemic proportions, it is very clear that drugs, which can prevent the overt and covert manifestations of allergic reactions and, ideally, suppress or even prevent the process of host sensitiza-tion can have a profound clinical and economic impact. While corticosteroids are considered the most effective antiallergic/anti-inflammatory drugs currently available, they are nonselective in action and not without adverse effects. Moreover, in diseases such as asthma, a significant proportion of patients who are treated with corticosteroids remain symptomatic [2]. Thus, new drugs with enhanced selectivity and improved side-effect profiles are clearly required. One group of drugs, which from a theoretical perspective, may exhibit powerful anti-inflammatory and immunomodulatory activity are inhibitors of certain of the cyclic nucleotide phospho-diesterase (PDE) isoenzymes that selectively degrade cyclic adenosine-3 ′,5′-monophosphate (cAMP) and/or cyclic guanosine-3 ′,5′-monophosphate (cGMP) [3– 9]. The prototype PDE inhibitors that have been used in the treatment of asthma for many years are the alkylxanthines of which theophylline is the most widely prescribed. The main beneficial activity of theophylline was originally attributed to its weak bronchodilator action. However, evidence accumulated in the 1990s suggested that this molecule might have anti-inflammatory activity at subbronchodilator doses [10– 12]. These, somewhat surprising data fuelled the idea that theophylline and, so-called, “second generation” PDE inhibitors could act as bronchodilators and potential antiallergic and/or anti-inflammatory agents [7, 13–18].


Atopic Dermatitis Respir Crit Peak Expiratory Flow Rate Cyclic Nucleotide Phosphodiesterase Microvascular Leakage 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Asher I, Baena-Cagnani C, Boner A, Canonica GW, Chuchalin A, Custovic A, et al. World Allergy Organization guidelines for prevention of allergy and allergic asthma. Int Arch Allergy Immunol. 2004;135:83–92.PubMedCrossRefGoogle Scholar
  2. 2.
    Lemiere C, Bai T, Balter M, Bayliff C, Becker A, Boulet LP, et al. Adult Asthma Consensus Guidelines Update 2003. Can Respir J. 2004;11:9A–18A.PubMedGoogle Scholar
  3. 3.
    Bender AT, Beavo JA. Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev. 2006;58:488–520.PubMedCrossRefGoogle Scholar
  4. 4.
    Lugnier C. Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new target for the development of specific therapeutic agents. Pharmacol Ther. 2006;109:366–398.PubMedCrossRefGoogle Scholar
  5. 5.
    Houslay MD. The long and short of vascular smooth muscle phosphodiesterase-4 as a putative therapeutic target. Mol Pharmacol. 2005;68:563–567.PubMedGoogle Scholar
  6. 6.
    Houslay MD, Schafer P, Zhang K Y. Phosphodiesterase-4 as a therapeutic target. Drug Discov Today. 2005;10:1503–1519.PubMedCrossRefGoogle Scholar
  7. 7.
    Torphy TJ. Phosphodiesterase isozymes: molecular targets for novel antiasthma agents. Am J Respir Crit Care Med. 1998;157:351–370.PubMedGoogle Scholar
  8. 8.
    Giembycz MA. Phosphodiesterase 4: selective and dual-specificity inhibitors for the therapy of chronic obstructive pulmonary disease. Proc Am Thor Soc. 2005;2:326–333.CrossRefGoogle Scholar
  9. 9.
    Giembycz MA. Life after PDE4: overcoming adverse events with dual-specificity phosphodi-esterase inhibitors. Curr Opin Pharmacol. 2005;5:238–244.PubMedCrossRefGoogle Scholar
  10. 10.
    Ward AJ, McKenniff M, Evans JM, Page CP, Costello JF. Theophylline — an immunomodula-tory role in asthma? Am Rev Respir Dis. 1993;147:518–523.PubMedGoogle Scholar
  11. 11.
    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.PubMedCrossRefGoogle Scholar
  12. 12.
    Djukanovic R, Finnerty JP, Lee C, Wilson S, Madden J, Holgate ST. The effects of theophylline on mucosal inflammation in asthmatic airways: biopsy results. Eur Respir J. 1995;8:831–833.PubMedGoogle Scholar
  13. 13.
    Banner KH, Page CP. Theophylline and selective phosphodiesterase inhibitors as anti-inflammatory drugs in the treatment of bronchial asthma. Eur Respir J. 1995;8:996–1000.PubMedGoogle Scholar
  14. 14.
    Giembycz MA. Phosphodiesterase 4 inhibitors and the treatment of asthma: where are we now and where do we go from here? Drugs. 2000;59:193–212.PubMedCrossRefGoogle Scholar
  15. 15.
    Palfreyman MN, Souness JE. Phosphodiesterase type IV inhibitors. Prog Med Chem. 1996;33:1–52.PubMedCrossRefGoogle Scholar
  16. 16.
    Dent G, Giembycz MA. Phosphodiesterase inhibitors: lily the Pink's medicinal compound for asthma? Thorax. 1996;51:647–649.PubMedCrossRefGoogle Scholar
  17. 17.
    Essayan DM. Cyclic nucleotide phosphodiesterase (PDE) inhibitors and immunomodulation. Biochem Pharmacol. 1999;57:965–973.PubMedCrossRefGoogle Scholar
  18. 18.
    Doherty AM. Phosphodiesterase 4 inhibitors as novel anti-inflammatory agents. Curr Opin Chem Biol. 1999;3:466–473.PubMedCrossRefGoogle Scholar
  19. 19.
    Cyclic nucleotide phosphodiesterases in health and disease. Beavo JA, Francis SH, Houslay MD (eds). Boca Raton: CRC Press; 2007.Google Scholar
  20. 20.
    Newton RP, Salih SG. Cyclic CMP phosphodiesterase: isolation, specificity and kinetic properties. Int J Biochem. 1986;18:743–752.PubMedCrossRefGoogle Scholar
  21. 21.
    Butcher RW, Sutherland EW. 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. 1962;237:1244–1250.PubMedGoogle Scholar
  22. 22.
    Conti M, Jin SL. The molecular biology of cyclic nucleotide phosphodiesterases. Prog Nucleic Acid Res Mol Biol. 1999;63:1–38.PubMedCrossRefGoogle Scholar
  23. 23.
    Houslay MD, Adams DR. PDE4 cAMP phosphodiesterases: modular enzymes that orchestrate signalling cross-talk, desensitization and compartmentalization. Biochem J. 2003;370:1–18.PubMedCrossRefGoogle Scholar
  24. 24.
    Houslay MD. PDE4 cAMP-specific phosphodiesterases. Prog Nucleic Acid Res Mol Biol. 2001;69:249–315.PubMedCrossRefGoogle Scholar
  25. 25.
    Soderling SH, Beavo JA. Regulation of cAMP and cGMP signaling: new phosphodiesterases and new functions. Curr Opin Cell Biol. 2000;12:174–179.PubMedCrossRefGoogle Scholar
  26. 26.
    Conti M. Phosphodiesterases and cyclic nucleotide signaling in endocrine cells. Mol Endocrinol. 2000;14:1317–1327.PubMedCrossRefGoogle Scholar
  27. 27.
    Charbonneau H, Beier N, Walsh KA, Beavo JA. Identification of a conserved domain among cyclic nucleotide phosphodiesterases from diverse species. Proc Natl Acad Sci USA. 1986;83:9308–9312.PubMedCrossRefGoogle Scholar
  28. 28.
    Martinez SE, Beavo JA, Hol WG. GAF domains: two-billion-year-old molecular awitches that bind cyclic nucleotides. Mol Interv. 2002;2:317–323.PubMedCrossRefGoogle Scholar
  29. 29.
    Martinez SE, Wu AY, Glavas NA, Tang XB, Turley S, Hol WG, et al. The two GAF domains in phosphodiesterase 2A have distinct roles in dimerization and in cGMP binding. Proc Natl Acad Sci USA. 2002;99:13260–13265.PubMedCrossRefGoogle Scholar
  30. 30.
    Charbonneau H, Kumar S, Novack JP, Blumenthal DK, Griffin PR, Shabanowitz J, et al. Evidence for domain organization within the 61-kDa calmodulin-dependent cyclic nucleotide phosphodiesterase from bovine brain. Biochemistry. 1991;30:7931–7940.PubMedCrossRefGoogle Scholar
  31. 31.
    Kovala T, Sanwal BD, Ball EH. Recombinant expression of a type IV, cAMP-specific phos-phodiesterase: characterization and structure-function studies of deletion mutants. Biochemistry. 1997;36:2968–2976.PubMedCrossRefGoogle Scholar
  32. 32.
    Richter W, Conti M. Dimerization of the type 4 cAMP-specific phosphodiesterases is mediated by the upstream conserved regions (UCRs). J Biol Chem. 2002;277:40212–40221.PubMedCrossRefGoogle Scholar
  33. 33.
    Zoraghi R, Bessay EP, Corbin JD, Francis SH. Structural and functional features in human PDE5A1 regulatory domain that provide for allosteric cGMP binding, dimerization, and regulation. J Biol Chem. 2005;280:12051–12063.PubMedCrossRefGoogle Scholar
  34. 34.
    Hoffmann R, Wilkinson IR, McCallum JF, Engels P, Houslay MD. cAMP-specific phospho-diesterase HSPDE4D3 mutants which mimic activation and changes in rolipram inhibition triggered by protein kinase A phosphorylation of Ser-54: generation of a molecular model. Biochem J. 1998;333:139–149.PubMedGoogle Scholar
  35. 35.
    MacKenzie SJ, Baillie GS, McPhee I, Bolger GB, Houslay MD. ERK2 mitogen-activated protein kinase binding, phosphorylation, and regulation of the PDE4D cAMP-specific phos-phodiesterases. The involvement of COOH-terminal docking sites and NH 2-terminal UCR regions. J Biol Chem. 2000;275:16609–16617.PubMedCrossRefGoogle Scholar
  36. 36.
    Thompson WJ, Epstein PM, Strada SJ. Purification and characterization of high-affinity cyclic adenosine monophosphate phosphodiesterase from dog kidney. Biochemistry. 1979;18:5228–5237.PubMedCrossRefGoogle Scholar
  37. 37.
    Epstein PM, Strada SJ, Sarada K, Thompson WJ. Catalytic and kinetic properties of purified high-affinity cyclic AMP phosphodiesterase from dog kidney. Arch Biochem Biophys. 1982;218:119–133.PubMedCrossRefGoogle Scholar
  38. 38.
    Torphy TJ, DeWolf WE Jr, Green DW, Livi GP. Biochemical characteristics and cellular regulation of phosphodiesterase IV. Agents Actions Suppl. 1993;43:51–71.PubMedGoogle Scholar
  39. 39.
    Truong VH, Muller T. Isolation, biochemical characterization and N-terminal sequence of rolipram-sensitive cAMP phosphodiesterase from human mononuclear leukocytes. FEBS Lett. 1994;353:113–118.PubMedCrossRefGoogle Scholar
  40. 40.
    Salanova M, Jin SC, Conti M. Heterologous expression and purification of recomb-inant rolipram-sensitive cyclic AMP-specific phosphodiesterases. Methods. 1998;14:55–64.PubMedCrossRefGoogle Scholar
  41. 41.
    Colicelli J, Birchmeier C, Michaeli T, O'Neill K, Riggs M, Wigler M. Isolation and characterization of a mammalian gene encoding a high-affinity cAMP phosphodiesterase. Proc Natl Acad Sci USA. 1989;86:3599–3603.PubMedCrossRefGoogle Scholar
  42. 42.
    Swinnen JV, Joseph DR, Conti M. Molecular cloning of rat homologues of the Drosophila melanogaster dunce cAMP phosphodiesterase: evidence for a family of genes. Proc Natl Acad Sci USA. 1989;86:5325–5329.PubMedCrossRefGoogle Scholar
  43. 43.
    Swinnen JV, Joseph DR, Conti M. The mRNA encoding a high-affinity cAMP phosphodi-esterase is regulated by hormones and cAMP. Proc Natl Acad Sci USA. 1989;86:8197–8201.PubMedCrossRefGoogle Scholar
  44. 44.
    Houslay MD, Sullivan M, Bolger GB. The multienzyme PDE4 cyclic adenosine monophos-phate-specific phosphodiesterase family: intracellular targeting, regulation, and selective inhibition by compounds exerting anti-inflammatory and antidepressant actions. Adv Pharmacol. 1998;44:225–342.PubMedCrossRefGoogle Scholar
  45. 45.
    Dyke HJ, Montana JG. Update on the therapeutic potential of PDE4 inhibitors. Expert Opin Investig Drugs. 2002;11:1–13.PubMedCrossRefGoogle Scholar
  46. 46.
    Sommer N, Martin R, McFarland HF, Quigley L, Cannella B, Raine CS, et al. Therapeutic potential of phosphodiesterase type 4 inhibition in chronic autoimmune demyelinating disease. J Neuroimmunol. 1997;79:54–61.PubMedCrossRefGoogle Scholar
  47. 47.
    Moore CS, Earl N, Frenette R, Styhler A, Mancini JA, Nicholson DW, et al. Peripheral phos-phodiesterase 4 inhibition produced by 4-[2-(3, 4-Bis-difluoromethoxyphenyl)-2-[4-(1, 1, 1, 3, 3, 3-hexafluoro-2-hydroxypropan-2-yl)-phenyl]-ethyl]-3-methylpyridine-1-oxide (L-826, 141) prevents experimental autoimmune encephalomyelitis. J Pharmacol Exp Ther. 2006;319:63–72.PubMedCrossRefGoogle Scholar
  48. 48.
    Banner KH, Trevethick MA. PDE4 inhibition: a novel approach for the treatment of inflammatory bowel disease. Trends Pharmacol Sci. 2004;25:430–436.PubMedCrossRefGoogle Scholar
  49. 49.
    Aricha R, Feferman T, Souroujon MC, Fuchs S. Overexpression of phosphodiesterases in experimental autoimmune myasthenia gravis: suppression of disease by a phosphodiesterase inhibitor. FASEB J. 2006;20:374–376.PubMedGoogle Scholar
  50. 50.
    Souness JE, Villamil ME, Scott LC, Tomkinson A, Giembycz MA, Raeburn D. Possible role of cyclic AMP phosphodiesterases in the actions of ibudilast on eosinophil thromboxane generation and airways smooth muscle tone. Br J Pharmacol. 1994;111:1081–1088.PubMedGoogle Scholar
  51. 51.
    Kawasaki A, Hoshino K, Osaki R, Mizushima Y, Yano S. Effect of ibudilast: a novel antiasth-matic agent, on airway hypersensitivity in bronchial asthma. J Asthma. 1992;29:245–252.PubMedCrossRefGoogle Scholar
  52. 52.
    Harada D, Tsukumo Y, Takashima Y, Manabe H. Effect of orally administered rolipram, a phosphodiesterase 4 inhibitor, on a mouse model of the dermatitis caused by 2, 4, 6-trinitro-1-chlorobenzene (TNCB)-repeated application. Eur J Pharmacol. 2006;532:128–137.PubMedCrossRefGoogle Scholar
  53. 53.
    Davies GE, Evans DP. Studies with two new phosphodiesterase inhibitors (ICI 58, 301 and ICI 63, 197) on anaphylaxis in guinea pigs, mice and rats. Int Arch Allergy Appl Immunol. 1973;45:467–478.PubMedCrossRefGoogle Scholar
  54. 54.
    Broughton BJ, Chaplen P, Knowles P, Lunt E, Marshall SM, Pain DL, et al. Antiallergic activity of 2-phenyl-8-azapurin-6-ones. J Med Chem. 1975;18:1117–1122.PubMedCrossRefGoogle Scholar
  55. 55.
    Teixeira MM, Rossi AG, Williams TJ, Hellewell PG. Effects of phosphodiesterase isoenzyme inhibitors on cutaneous inflammation in the guinea-pig. Br J Pharmacol. 1994;112:332–340.PubMedGoogle Scholar
  56. 56.
    Howell RE, Sickels BD, Woeppel SL. Pulmonary antiallergic and bronchodilator effects of isozyme-selective phosphodiesterase inhibitors in guinea pigs. J Pharmacol Exp Ther. 1993;264:609–615.PubMedGoogle Scholar
  57. 57.
    Andersson P, Brange C, Sonmark B, Stahre G, Erjefalt I, Wieslander E, et al. Anti-anaphylactic and ant-inflammatory effects of xanthines in the lung. In: Andersson KE, Persson CG, editors. Antiasthma xanthines and adenosine. Amsterdam: Excerpta Medica; 1985. p. 187–192.Google Scholar
  58. 58.
    Ali S, Mustafa SJ, Metzger WJ. Modification of allergen-induced airway obstruction and bronchial hyperresponsiveness in the allergic rabbit by theophylline aerosol. Agents Actions. 1992;37:168–170.PubMedCrossRefGoogle Scholar
  59. 59.
    Gristwood RW, Llupia J, Fernandez AG, Berga P. Effects of theophylline compared with prednisolone on late phase airway leukocyte infiltration in guinea pigs. Int Arch Allergy Appl Immunol. 1991;94:293–294.PubMedCrossRefGoogle Scholar
  60. 60.
    Sanjar S, Aoki S, Kristersson A, Smith D, Morley J. Antigen challenge induces pulmonary airway eosinophil accumulation and airway hyperreactivity in sensitized guinea-pigs: the effect of anti-asthma drugs. Br J Pharmacol. 1990;99:679–686.PubMedGoogle Scholar
  61. 61.
    Tarayre JP, Aliaga M, Barbara M, Malfetes N, Vieu S, Tisne-Versailles J. Theophylline reduces pulmonary eosinophilia after various types of active anaphylactic shock in guinea-pigs. J Pharm Pharmacol. 1991;43:877–879.PubMedGoogle Scholar
  62. 62.
    Tarayre JP, Aliaga M, Barbara M, Tisseyre N, Vieu S, Tisne-Versailles J. Pharmacological modulation of a model of bronchial inflammation after aerosol-induced active anaphylactic shock in conscious guinea pigs. Int J Immunopharmacol. 1991;13:349–356.PubMedCrossRefGoogle Scholar
  63. 63.
    Tarayre JP, Aliaga M, Barbara M, Tisseyre N, Vieu S, Tisne-Versailles J. Model of bronchial allergic inflammation in the brown Norway rat. Pharmacological modulation. Int J Immunopharmacol. 1992;14:847–855.PubMedCrossRefGoogle Scholar
  64. 64.
    Manzini S, Perretti F, Abelli L, Evangelista S, Seeds EA, Page CP. Isbufylline, a new xanthine derivative, inhibits airway hyperresponsiveness and airway inflammation in guinea pigs. Eur J Pharmacol. 1993;249:251–257.PubMedCrossRefGoogle Scholar
  65. 65.
    Lagente V, Moodley I, Perrin S, Mottin G, Junien JL. Effects of isozyme-selective phospho-diesterase inhibitors on eosinophil infiltration in the guinea-pig lung. Eur J Pharmacol. 1994;255:253–256.PubMedCrossRefGoogle Scholar
  66. 66.
    Sanjar S, Aoki S, Boubekeur K, Chapman ID, Smith D, Kings MA, et al. Eosinophil accumulation in pulmonary airways of guinea-pigs induced by exposure to an aerosol of platelet-activating factor: effect of anti-asthma drugs. Br J Pharmacol. 1990;99:267–272.PubMedGoogle Scholar
  67. 67.
    Schudt C, Winder S, Eltze M, Kilian U, Beume R. Zardaverine: a cyclic AMP specific PDE III/IV inhibitor. Agents Actions Suppl. 1991;34:379–402.PubMedGoogle Scholar
  68. 68.
    Griswold DE, Webb EF, Badger AM, Gorycki PD, Levandoski PA, Barnette MA, et al. SB 207499 (Ariflo), a second generation phosphodiesterase 4 inhibitor, reduces tumor necrosis factor alpha and interleukin-4 production in vivo. J Pharmacol Exp Ther. 1998;287:705–711.PubMedGoogle Scholar
  69. 69.
    Underwood DC, Osborn RR, Novak LB, Matthews JK, Newsholme SJ, Undem BJ, et al. Inhibition of antigen-induced bronchoconstriction and eosinophil infiltration in the guinea pig by the cyclic AMP-specific phosphodiesterase inhibitor, rolipram. J Pharmacol Exp Ther. 1993;266:306–313.PubMedGoogle Scholar
  70. 70.
    Underwood DC, Kotzer CJ, Bochnowicz S, Osborn RR, Luttmann MA, Hay DW, et al. Comparison of phosphodiesterase III, IV and dual III/IV inhibitors on bronchospasm and pulmonary eosinophil influx in guinea pigs. J Pharmacol Exp Ther. 1994;270:250–259.PubMedGoogle Scholar
  71. 71.
    Underwood DC, Bochnowicz S, Osborn RR, Kotzer CJ, Luttmann MA, Hay DW, et al. Antiasthmatic activity of the second-generation phosphodiesterase 4 (PDE4) inhibitor SB 207499 (Ariflo) in the guinea pig. J Pharmacol Exp Ther. 1998;287:988–995.PubMedGoogle Scholar
  72. 72.
    Bundschuh DS, Eltze M, Barsig J, Wollin L, Hatzelmann A, Beume R. In vivo efficacy in airway disease models of roflumilast, a novel orally active PDE4 inhibitor. J Pharmacol Exp Ther. 2001;297:280–290.PubMedGoogle Scholar
  73. 73.
    Baumer W, Gorr G, Hoppmann J, Ehinger AM, Ehinger B, Kietzmann M. Effects of the phosphodiesterase 4 inhibitors SB 207499 and AWD 12–281 on the inflammatory reaction in a model of allergic dermatitis. Eur J Pharmacol. 2002;446:195–200.PubMedCrossRefGoogle Scholar
  74. 74.
    Baumer W, Gorr G, Hoppmann J, Ehinger AM, Rundfeldt C, Kietzmann M. AWD 12–281, a highly selective phosphodiesterase 4 inhibitor, is effective in the prevention and treatment of inflammatory reactions in a model of allergic dermatitis. J Pharm Pharmacol. 2003;55:1107–1114.PubMedCrossRefGoogle Scholar
  75. 75.
    Hoppmann J, Baumer W, Galetzka C, Hofgen N, Kietzmann M, Rundfeldt C. The phospho-diesterase 4 inhibitor AWD 12–281 is active in a new guinea-pig model of allergic skin inflammation predictive of human skin penetration and suppresses both Th1 and Th2 cytok-ines in mice. J Pharm Pharmacol. 2005;57:1609–1617.PubMedCrossRefGoogle Scholar
  76. 76.
    Kuss H, Hoefgen N, Johanssen S, Kronbach T, Rundfeldt C. 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. 2003;307:373–385.PubMedCrossRefGoogle Scholar
  77. 77.
    Draheim R, Egerland U, Rundfeldt C. Anti-inflammatory potential of the selective phospho-diesterase 4 inhibitor N-(3, 5-dichloro-pyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indole-3-yl]-gly oxylic acid amide (AWD 12–281), in human cell preparations. J Pharmacol Exp Ther. 2004;308:555–563.PubMedCrossRefGoogle Scholar
  78. 78.
    Turner CR, Andresen CJ, Smith WB, Watson JW. Effects of rolipram on responses to acute and chronic antigen exposure in monkeys. Am J Respir Crit Care Med. 1994;149:1153–1159.PubMedGoogle Scholar
  79. 79.
    Erjefalt I, Persson CG. Pharmacologic control of plasma exudation into tracheobronchial airways. Am Rev Respir Dis. 1991;143:1008–1014.PubMedGoogle Scholar
  80. 80.
    Boschetto P, Roberts NM, Rogers DF, Barnes PJ. Effect of antiasthma drugs on microvascular leakage in guinea pig airways. Am Rev Respir Dis. 1989;139:416–421.PubMedGoogle Scholar
  81. 81.
    Raeburn D, Karlsson JA. Effects of isoenzyme-selective inhibitors of cyclic nucleotide phos-phodiesterase on microvascular leak in guinea pig airways in vivo. J Pharmacol Exp Ther. 1993;267:1147–1152.PubMedGoogle Scholar
  82. 82.
    Raeburn D, Woodman VR. Effect of theophylline administered intratracheally as a dry powder formulation on bronchospasm and airway microvascular leakage in the anesthetized guinea-pig. Pulm Pharmacol. 1994;7:243–249.PubMedCrossRefGoogle Scholar
  83. 83.
    Ortiz JL, Cortijo J, Valles JM, Morcillo EJ. Rolipram inhibits PAF-induced airway microvas-cular leakage in guinea-pig: a comparison with milrinone and theophylline. Fundam Clin Pharmacol. 1992;6:247–249.PubMedCrossRefGoogle Scholar
  84. 84.
    Raeburn D, Underwood SL, Lewis SA, Woodman VR, Battram CH, Tomkinson A, et al. Anti-inflammatory and bronchodilator properties of RP 73401, a novel and selective phosphodi-esterase type IV inhibitor. Br J Pharmacol. 1994;113:1423–1431.PubMedGoogle Scholar
  85. 85.
    Svensjo E, Andersson KE, Bouskela E, Cyrino FZ, Lindgren S. Effects of two vasodilatory phosphodiesterase inhibitors on bradykinin-induced permeability increase in the hamster cheek pouch. Agents Actions. 1993;39:35–41.PubMedCrossRefGoogle Scholar
  86. 86.
    Crummey A, Harper GP, Boyle EA, Mangan FR. Inhibition of arachidonic acid-induced ear oedema as a model for assessing topical anti-inflammatory compounds. Agents Actions. 1987;20:69–76.PubMedCrossRefGoogle Scholar
  87. 87.
    Krause W, Kuhne G. Anti-inflammatory activity of rolipram in a rat ear edema model. Arzneimittelforschung. 1994;44:163–165.PubMedGoogle Scholar
  88. 88.
    Ehinger AM, Gorr G, Hoppmann J, Telser E, Ehinger B, Kietzmann M. Effects of the phos-phodiesterase 4 inhibitor RPR 73401 in a model of immunological inflammation. Eur J Pharmacol. 2000;392:93–99.PubMedCrossRefGoogle Scholar
  89. 89.
    Baumer W, Seegers U, Braun M, Tschernig T, Kietzmann M. TARC and RANTES, but not CTACK, are induced in two models of allergic contact dermatitis. Effects of cilomilast and diflorasone diacetate on T-cell-attracting chemokines. Br J Dermatol. 2004;151:823–830.PubMedCrossRefGoogle Scholar
  90. 90.
    Spina D. Theophylline and PDE4 inhibitors in asthma. Curr Opin Pulm Med. 2003;9:57–64.PubMedCrossRefGoogle Scholar
  91. 91.
    Nieman RB, Fisher BD, Amit O, Dockhorn RJ. SB207499 (Ariflo), a second generation, selective oral phosphodiesterase type 4 (PDE4) inhibitor, attenuates exercise-induced bron-choconstriction in patients with asthma. Am J Respir Crit Care Med. 2007;157:A413.Google Scholar
  92. 92.
    Timmer W, Leclerc V, Birraux G, Neuhauser M, Hatzelmann A, Bethke T, et al. The new phosphodiesterase 4 inhibitor roflumilast is efficacious in exercise-induced asthma and leads to suppression of LPS-stimulated TNF a ex vivo. J Clin Pharmacol. 2002;42:297–303.PubMedCrossRefGoogle Scholar
  93. 93.
    Compton C, Cedar E, Nieman RB, Amit O, Langley SJ, Sapene M. Ariflo improves pulmonary function in patients with asthma: results of a study in patients taking inhaled corticoster-oids. Am J Respir Crit Care Med. 1999;159:A522.Google Scholar
  94. 94.
    Compton CH, Duggan M, Cedar E, Nieman RB, Amit O, Tabona MV, et al. Ariflo efficacy in a 12-month study of patients with asthma. Am J Respir Crit Care Med. 2000;161:A505.Google Scholar
  95. 95.
    Compton CH, Duggan M, Cedar E, Tabona MV, Nieman RB, Amit O, et al. Safety of Ariflo in a 12-month study of patients with asthma. Am J Respir Crit Care Med. 2000;161:A200.Google Scholar
  96. 96.
    van Schalkwyk E, Strydom K, Williams Z, Venter L, Leichtl S, Schmid-Wirlitsch C, et al. Roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, attenuates allergen-induced asthmatic reactions. J Allergy Clin Immunol. 2005;116:292–298.PubMedCrossRefGoogle Scholar
  97. 97.
    Bateman ED, Izquierdo JL, Harnest U, Hofbauer P, Magyar P, Schmid-Wirlitsch C, et al. Efficacy and safety of roflumilast in the treatment of asthma. Ann Allergy Asthma Immunol. 2006;96:679–686.PubMedCrossRefGoogle Scholar
  98. 98.
    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 (Epub)Google Scholar
  99. 99.
    Bousquet J, Aubier M, Sastre J, Izquierdo JL, Adler LM, Hofbauer P, et al. Comparison of roflumilast, an oral anti-inflammatory, with beclomethasone dipropionate in the treatment of persistent asthma. Allergy. 2006;61:72–78.PubMedGoogle Scholar
  100. 100.
    Schmidt BM, Kusma M, Feuring M, Timmer WE, Neuhauser M, Bethke T, et al. The phos-phodiesterase 4 inhibitor roflumilast is effective in the treatment of allergic rhinitis. J Allergy Clin Immunol. 2001;108:530–536.PubMedCrossRefGoogle Scholar
  101. 101.
    Baumer W, Hoppmann J, Rundfeldt C, Kietzmann M. Highly selective phosphodiesterase 4 inhibitors for the treatment of allergic skin diseases and psoriasis. Inflamm Allergy Drug Targets. 2007;6:17–26.PubMedCrossRefGoogle Scholar
  102. 102.
    Stawiski MA, Rusin LJ, Burns TL, Weinstein GD, Voorhees JJ. Ro 20–1724: an agent that significantly improves psoriatic lesions in double-blind clinical trials. J Invest Dermatol. 1979;73:261–263.PubMedCrossRefGoogle Scholar
  103. 103.
    Goyarts E, Mammone T, Muizzuddin N, Marenus K, Maes D. Correlation between in vitro cyclic adenosine monophosphate phosphodiesterase inhibition and in vivo anti-inflammatory effect. Skin Pharmacol Appl Skin Physiol. 2000;13:86–92.PubMedGoogle Scholar
  104. 104.
    Hanifin JM, Chan SC, Cheng JB, Tofte SJ, Henderson WR Jr, Kirby DS, et al. Type 4 phos-phodiesterase inhibitors have clinical and in vitro anti-inflammatory effects in atopic dermatitis. J Invest Dermatol. 1996;107:51–56.PubMedCrossRefGoogle Scholar
  105. 105.
    Griffiths CE, Van Leent EJ, Gilbert M, Traulsen J. Randomized comparison of the type 4 phosphodiesterase inhibitor cipamfylline cream, cream vehicle and hydrocortisone 17-butyrate cream for the treatment of atopic dermatitis. Br J Dermatol. 2002;147:299–307.PubMedCrossRefGoogle Scholar
  106. 106.
    Kucharekova M, Hornix M, Ashikaga T, T'kint S, de Jongh GJ, Schalkwijk J, et al. The effect of the PDE-4 inhibitor (cipamfylline) in two human models of irritant contact dermatitis. Arch Dermatol Res. 2003;295:29–32.PubMedGoogle Scholar
  107. 107.
    Khobzaoui M, Gutke HJ, Burnet M. CC-10004. Curr Opin Investig Drugs. 2005;6:518–525.PubMedGoogle Scholar
  108. 108.
    Vignola AM. PDE4 inhibitors in COPD — a more selective approach to treatment. Respir Med. 2004;98:495–503.PubMedCrossRefGoogle Scholar
  109. 109.
    Shimada T, Iwasaki M, Martin MV, Guengerich FP. Human liver microsomal cytochrome P-450 enzymes involved in the bioactivation of procarcinogens detected by umu gene response in Salmonella typhimurium TA 1535/pSK1002. Cancer Res. 1989;49:3218–3228.PubMedGoogle Scholar
  110. 110.
    Campbell ME, Spielberg SP, Kalow W. A urinary metabolite ratio that reflects systemic caffeine clearance. Clin Pharmacol Ther. 1987;42:157–165.PubMedGoogle Scholar
  111. 111.
    Vistisen K, Poulsen HE, Loft S. Foreign compound metabolism capacity in man measured from metabolites of dietary caffeine. Carcinogenesis. 1992;13:1561–1568.PubMedCrossRefGoogle Scholar
  112. 112.
    Fuhr U, Doehmer J, Battula N, Wolfel C, Kudla C, Keita Y, et al. Biotransformation of caffeine and theophylline in mammalian cell lines genetically engineered for expression of single cytochrome P450 isoforms. Biochem Pharmacol. 1992;43:225–235.PubMedCrossRefGoogle Scholar
  113. 113.
    Sarkar MA, Hunt C, Guzelian PS, Karnes HT. Characterization of human liver cytochromes P-450 involved in theophylline metabolism. Drug Metab Dispos. 1992;20:31–37.PubMedGoogle Scholar
  114. 114.
    Jusko WJ. Influence of cigarette smoking on drug metabolism in man. Drug Metab Rev. 1979;9:221–236.PubMedCrossRefGoogle Scholar
  115. 115.
    Jusko WJ, Schentag JJ, Clark JH, Gardner M, Yurchak AM. Enhanced biotransformation of theophylline in marihuana and tobacco smokers. Clin Pharmacol Ther. 1978;24:405–410.PubMedGoogle Scholar
  116. 116.
    Hunt SN, Jusko WJ, Yurchak AM. Effect of smoking on theophylline disposition. Clin Pharmacol Ther. 1976;19:546–551.PubMedGoogle Scholar
  117. 117.
    Antal EJ, Kramer PA, Mercik SA, Chapron DJ, Lawson IR. Theophylline pharmacokinetics in advanced age. Br J Clin Pharmacol. 1981;12:637–645.PubMedGoogle Scholar
  118. 118.
    Ohnishi A, Kato M, Kojima J, Ushiama H, Yoneko M, Kawai H. Differential pharmacokinet-ics of theophylline in elderly patients. Drugs Aging. 2003;20:71–84.PubMedCrossRefGoogle Scholar
  119. 119.
    Shin SG, Juan D, Rammohan M. Theophylline pharmacokinetics in normal elderly subjects. Clin Pharmacol Ther. 1988;44:522–530.PubMedGoogle Scholar
  120. 120.
    Giembycz MA. Development status of second generation PDE4 inhibitors for asthma and COPD: the story so far. Monaldi Arch Chest Dis. 2002;57:48–64.PubMedGoogle Scholar
  121. 121.
    Giembycz MA. Cilomilast: a second generation phosphodiesterase 4 inhibitor for asthma and chronic obstructive pulmonary disease. Expert Opin Investig Drugs. 2001;10:1361–1379.PubMedCrossRefGoogle Scholar
  122. 122.
    Barnes PJ. Theophylline: new perspectives for an old drug. Am J Respir Crit Care Med. 2003;167:813–818.PubMedCrossRefGoogle Scholar
  123. 123.
    Compton CH, 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.PubMedCrossRefGoogle Scholar
  124. 124.
    Fredholm BB. Are methylxanthine effects due to antagonism of endogenous adenosine? Trends Pharmacol Sci. 1980;1:129–132.CrossRefGoogle Scholar
  125. 125.
    GlaxoSmithKline (2003) SB 207499 (Ariflo, Cilomilast) — New Drugs Application (21-573). Pulmonary and Allergy Drug Products Advisory Committee Briefing Document.
  126. 126.
    Larson JL, Pino M V, Geiger LE, Simeone CR. The toxicity of repeated exposures to rolip-ram, a type IV phosphodiesterase inhibitor, in rats. Pharmacol Toxicol. 1996;78:44–49.PubMedCrossRefGoogle Scholar
  127. 127.
    Robertson DG, Reily MD, Albassam M, Dethloff LA. Metabonomic assessment of vasculitis in rats. Cardiovasc Toxicol. 2001;1:7–19.PubMedCrossRefGoogle Scholar
  128. 128.
    Ruben Z, Deslex P, Nash G, Redmond NI, Poncet M, Dodd DC. Spontaneous disseminated panarteritis in laboratory beagle dogs in a toxicity study: a possible genetic predilection. Toxicol Pathol. 1989;17:145–152.PubMedGoogle Scholar
  129. 129.
    Bishop SP. Animal models of vasculitis. Toxicol Pathol. 1989;17:109–117.PubMedGoogle Scholar
  130. 130.
    GlaxoSmithKline (2003) SB 207499 (Ariflo, Cilomilast) — New Drugs Application (21-573). Pulmonary and Allergy Drug Products Advisory Committee. Nonclinical Findings.
  131. 131.
    Losco PE, Evans EW, Barat SA, Blackshear PE, Reyderman L, Fine JS, et al. The toxicity of SCH 351591, a novel phosphodiesterase-4 inhibitor, in Cynomolgus monkeys. Toxicol Pathol. 2004;32:295–308.PubMedCrossRefGoogle Scholar
  132. 132.
  133. 133.
    Nyska A, Herbert RA, Chan PC, Haseman JK, Hailey JR. Theophylline-induced mesenteric periarteritis in F344/N rats. Arch Toxicol. 1998;72:731–737.PubMedCrossRefGoogle Scholar
  134. 134.
    Collins JJ, Elwell MR, Lamb JC, Manus AG, Heath JE, Makovec GT. Subchronic toxicity of orally administered (gavage and dosed-feed) theophylline in Fischer 344 rats and B6C3F1 mice. Fundam Appl Toxicol. 1988;11:472–484.PubMedCrossRefGoogle Scholar
  135. 135.
    GlaxoSmithKline (2003) SB 207499 (Ariflo, Cilomilast) — New Drugs Application (21-573). Pulmonary and Allergy Drug Products Advisory Committee. Clinical Pharmacology.
  136. 136.
    GlaxoSmithKline (2003) SB 207499 (Ariflo, Cilomilast) — New Drugs Application (21-573). Pulmonary and Allergy Drug Products Advisory Committee. Preclinical Considerations.
  137. 137.
    Torphy TJ, Barnette MS, Underwood DC, Griswold DE, Christensen SB, Murdoch RD, et al. Ariflo (SB 207499), a second generation phosphodiesterase 4 inhibitor for the treatment of asthma and COPD: from concept to clinic. Pulm Pharmacol Ther. 1999;12:131–135.PubMedCrossRefGoogle Scholar
  138. 138.
    Souness JE, Rao S. Proposal for pharmacologically distinct conformers of PDE4 cyclic AMP phosphodiesterases. Cell Signal. 1997;9:227–236.PubMedCrossRefGoogle Scholar
  139. 139.
    Robichaud A, Stamatiou PB, Jin SL, Lachance N, MacDonald D, Laliberte F, et al. Deletion of phosphodiesterase 4D in mice shortens a2 -adrenoceptor-mediated anesthesia, a behavioral correlate of emesis. J Clin Invest. 2002;110:1045–1052.PubMedGoogle Scholar
  140. 140.
    Giembycz MA. 4D or not 4D — the emetogenic basis of PDE4 inhibitors uncovered? Trends Pharmacol Sci. 2002;23:548.PubMedCrossRefGoogle Scholar
  141. 141.
    Hansen G, Jin S, Umetsu DT, Conti M. Absence of muscarinic cholinergic airway responses in mice deficient in the cyclic nucleotide phosphodiesterase PDE4D. Proc Natl Acad Sci USA. 2000;97:6751–6756.PubMedCrossRefGoogle Scholar
  142. 142.
    Ahn HS, Bercovici A, Boykow G, Bronnenkant A, Chackalamannil S, Chow J, et al. Potent tetracyclic guanine inhibitors of PDE1 and PDE5 cyclic guanosine monophosphate phospho-diesterases with oral antihypertensive activity. J Med Chem. 1997;40:2196–2210.PubMedCrossRefGoogle Scholar
  143. 143.
    Ichimura M, Eiki R, Osawa K, Nakanishi S, Kase H. KS-505a, an isoform-selective inhibitor of calmodulin-dependent cyclic nucleotide phosphodiesterase. Biochem J. 1996;316:311–316.PubMedGoogle Scholar
  144. 144.
    Snyder PB, Esselstyn JM, Loughney K, Wolda SL, Florio VA. The role of cyclic nucleotide phosphodiesterases in the regulation of adipocyte lipolysis. J Lipid Res. 2005;46:494–503.PubMedCrossRefGoogle Scholar
  145. 145.
    Podzuweit T, Nennstiel P, Muller A. Isozyme selective inhibition of cGMP-stimulated cyclic nucleotide phosphodiesterases by erythro-9-(2-hydroxy-3-nonyl) adenine. Cell Signal. 1995;7:733–738.PubMedCrossRefGoogle Scholar
  146. 146.
    Chambers RJ, Abrams K, Garceau NY, Kamath AV, Manley CM, Lilley SC, et al. A new chemical tool for exploring the physiological function of the PDE2 isozyme. Bioorg Med Chem Lett. 2006;16:307–310.PubMedCrossRefGoogle Scholar
  147. 147.
    Boess FG, Hendrix M, van der Staay FJ, Erb C, Schreiber R, van Staveren W, et al. Inhibition of phosphodiesterase 2 increases neuronal cGMP, synaptic plasticity and memory performance. Neuropharmacology. 2004;47:1081–1092.PubMedCrossRefGoogle Scholar
  148. 148.
    Seybold J, Thomas D, Witzenrath M, Boral S, Hocke AC, Burger A, et al. Tumor necrosis factor- a -dependent expression of phosphodiesterase 2: role in endothelial hyperpermeabil-ity. Blood. 2005;105:3569–3576.PubMedCrossRefGoogle Scholar
  149. 149.
    Murray KJ, England PJ, Hallam TJ, Maguire J, Moores K, Reeves ML, et al. The effects of siguazodan, a selective phosphodiesterase inhibitor, on human platelet function. Br J Pharmacol. 1990;99:612–616.PubMedGoogle Scholar
  150. 150.
    Murray KJ, Eden RJ, Dolan JS, Grimsditch DC, Stutchbury CA, Patel B, et al. The effect of SK&F 95654, a novel phosphodiesterase inhibitor, on cardiovascular, respiratory and platelet function. Br J Pharmacol. 1992;107:463–470.PubMedGoogle Scholar
  151. 151.
    Hidaka H, Hayashi H, Kohri H, Kimura Y, Hosokawa T, Igawa T, et al. Selective inhibitor of platelet cyclic adenosine monophosphate phosphodiesterase, cilostamide, inhibits platelet aggregation. J Pharmacol Exp Ther. 1979;211:26–30.PubMedGoogle Scholar
  152. 152.
    Tanaka T, Ishikawa T, Hagiwara M, Onoda K, Itoh H, Hidaka H. Effects of cilostazol, a selective cAMP phosphodiesterase inhibitor on the contraction of vascular smooth muscle. Pharmacology. 1988;36:313–320.PubMedCrossRefGoogle Scholar
  153. 153.
    Schwabe U, Miyake M, Ohga Y, Daly JW. 4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone (ZK 62711): a potent inhibitor of adenosine cyclic 3', 5'-monophosphate phos-phodiesterases in homogenates and tissue slices from rat brain. Mol Pharmacol. 1976;12:900–910.PubMedGoogle Scholar
  154. 154.
    Reeves ML, Leigh BK, England PJ. The identification of a new cyclic nucleotide phospho-diesterase activity in human and guinea-pig cardiac ventricle. Implications for the mechanism of action of selective phosphodiesterase inhibitors. Biochem J. 1987;241:535–541.PubMedGoogle Scholar
  155. 155.
    Sheppard H, Tsien WH. Alterations in the hydrolytic activity, inhibitor sensitivity and molecular size of the rat erythrocyte cyclic AMP phosphodiesterase by calcium and hyper-tonic sodium chloride. J Cyclic Nucleotide Res. 1975;1:237–242.PubMedGoogle Scholar
  156. 156.
    Barnette MS, Christensen SB, Essayan DM, Grous M, Prabhakar U, Rush JA, et al. SB 207499 (Ariflo), a potent and selective second-generation phosphodiesterase 4 inhibitor: in vitro anti-inflammatory actions. J Pharmacol Exp Ther. 1998;284:420–426.PubMedGoogle Scholar
  157. 157.
    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.PubMedGoogle Scholar
  158. 158.
    Souness JE, Maslen C, Webber S, Foster M, Raeburn D, Palfreyman MN, et al. Suppression of eosinophil function by RP 73401, a potent and selective inhibitor of cyclic AMP-specific phosphodiesterase: comparison with rolipram. Br J Pharmacol. 1995;115:39–46.PubMedGoogle Scholar
  159. 159.
    Lugnier C, Schoeffter P, Le Bec A, Strouthou E, Stoclet JC. Selective inhibition of cyclic nucleotide phosphodiesterases of human, bovine and rat aorta. Biochem Pharmacol. 1986;35:1743–1751.PubMedCrossRefGoogle Scholar
  160. 160.
    Boolell M, Allen MJ, Ballard SA, Gepi-Attee S, Muirhead GJ, Naylor AM, et al. Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int J Impot Res. 1996;8:47–52.PubMedGoogle Scholar
  161. 161.
    Saenz de T, I, Angulo J, Cuevas P, Fernandez A, Moncada I, Allona A, Lledo E, Korschen HG, Niewohner U, Haning H, Pages E, Bischoff E (2001) The phosphodiesterase inhibitory selectivity and the in vitro and in vivo potency of the new PDE5 inhibitor vardenafil. Int J Impot Res 13:282–290CrossRefGoogle Scholar
  162. 162.
    Padma-Nathan H, McMurray JG, Pullman WE, Whitaker JS, Saoud JB, Ferguson KM, et al. On-demand IC351 (Cialis) enhances erectile function in patients with erectile dysfunction. Int J Impot Res. 2001;13:2–9.PubMedCrossRefGoogle Scholar
  163. 163.
    Smith SJ, Cieslinski LB, Newton R, Donnelly LE, Fenwick PS, Nicholson AG, et al. Discovery of BRL 50481 [3-(N, N-dimethylsulfonamido)-4-methylnitrobenzene), a selective inhibitor of phosphodiesterase 7: in vitro studies in human monocytes, lung macrophage and CD8+ T-lymphocytes. Mol Pharmacol. 2004;66:1679–1689.PubMedCrossRefGoogle Scholar
  164. 164.
    Jones NA, Leport M, Holand T, Vos T, Morgan M, Fink M, et al. Phosphodiesterase (PDE) 7 in inflammatory cells from patients with asthma and COPD. Pulm Pharmacol Ther. 2006;20:60–68.PubMedCrossRefGoogle Scholar
  165. 165.
    Giembycz MA, Smith SJ. Phosphodiesterase 7 as a therapeutic target. Drugs Future. 2006;31:207–229.CrossRefGoogle Scholar
  166. 166.
    Lee R, Wolda S, Moon E, Esselstyn J, Hertel C, Lerner A. PDE7A is expressed in human B-lymphocytes and is up-regulated by elevation of intracellular cAMP. Cell Signal. 2002;14:277–284.PubMedCrossRefGoogle Scholar
  167. 167.
    Wunder F, Tersteegen A, Rebmann A, Erb C, Fahrig T, Hendrix M. Characterization of the first potent and selective PDE9 inhibitor using a cGMP reporter cell line. Mol Pharmacol. 2005;68:1775–1781.PubMedGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  1. 1.Department of Pharmacology and TherapeuticsInstitute of Infection, Immunity and Inflammation, Faculty of Medicine, University of CalgaryCalgaryCanada

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