Abstract
Research conducted over the last 20 years has established that inflammation of the airways is central to the airway dysfunction that characterises asthma. Typically, the airway wall is infiltrated by a variety of cells including mast cells, eosinophils and T lymphocytes, which have deviated towards a Th2 phenotype. Together, these cells release a plethora of mediators including interleukin (IL)-4, IL-5, granulocyte/macrophage colony-stimulating factor and eotaxin which ultimately cause the histopathology and symptoms of asthma. Glucocorticosteroids are the only drugs currently available that effectively impact upon this inflammation and resolve, to a greater or lesser extent, compromised lung function. However, steroids are nonselective and generally unsuitable for paediatric use. New drugs are clearly required. One group of potential therapeutic agents for asthma are inhibitors of cyclic AMP-specific phosphodiesterase (PDE), of which theophylline may be considered a prototype. It is now known that PDE is a generic term which refers to at least 11 distinct enzyme families that hydrolyse cAMP and/or cGMP. Over the last decade, inhibitors of PDE4 (a cAMP-specific family that negatively regulates the function of almost all pro-inflammatory and immune cells, and exerts widespread anti-inflammatory activity in animal models of asthma) have been developed with the view to reducing the adverse effects profile associated with non-selective inhibitors such as theophylline. Such is the optimism regarding PDE4 as a viable therapeutic target that more than 100 PDE4 inhibitor patent applications have been filed since 1996 by 13 major pharmaceutical companies. This article reviews the progress of PDE4 inhibitors as anti-inflammatory agents, and identifies problems that have been encountered by the pharmaceutical industry in the clinical development of these drugs and what strategies are being considered to overcome them.
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References
Flemming DM, Crombie DL. Prevalence of asthma and hay fever in England and Wales. BMJ 1987; 294: 279–83
Sly RM. Increases in death from asthma. Ann Allergy 1984;53: 2–25
Barnes PJ. Asthma deaths: a continuing problem. In: Sheppard M, editor. Advanced medicine. London: Bailliere Tindall, 1988: 53–61
Keating G, Mitchell EA, Jackson R, et al. Trends in the sales of drugs for asthma in New Zealand, Australia and the United Kingdom. BMJ 1983; 289: 348–51
Hay IFC, Higgenbotham TW. Has the management of asthma improved? Lancet 1987; II: 609–11
Beavo JA, Conti M, Heaslip RJ. Multiple cyclic nucleotide phosphodiesterases. Mol Pharmacol 1994; 46: 399–405
Michaeli T, Bloom TJ, Martins T, et al. Isolation and characterization of a previously undetected human cAMP phosphodiesterase by complementation of cAMP phosphodiesterase-deficient Saccharomyces cerevisiae. J Biol Chem 1993; 268: 12925–32
Han P, Zhu X, Michaeli T. Alternative splicing of the high affinity cAMP-specific phosphodiesterase (PDE7A) mRNA in human skeletal muscle and heart. J Biol Chem 1997; 272: 16152–7
Bloom TJ, Beavo JA. Identification and tissue-specific expression of PDE7 phosphodiesterase splice variants. Proc Natl Acad Sci U S A 1996; 93: 14188–92
Soderling SH, Bayuga SJ, Beavo JA. Identification and characterization of a novel family of cyclic nucleotide phosphodiesterases. J Biol Chem 1998; 273: 15553–8
Soderling SH, Bayuga SJ, Beavo JA. Cloning and characterization of a cAMP-specific cyclic nucleotide phosphodiesterase. Proc Natl Acad Sci U S A 1998; 95: 8991–6
Soderling TR, Bayuga SJ, Beavo JA. Isolation and characterization of a dual substrate phosphodiesterase gene family: PDE10A. Proc Natl Acad Sci U S A 1999; 96: 7071–6
Fisher DA, Smith JF, Pillar JS, et al. Isolation and characterization of PDE8A, a novel human cAMP-specific phosphodiesterase. Biochem Biophys Res Commun 1998; 246: 570–7
Fisher DA, Smith JF, Pillar JS, et al. Isolation and characterization of PDE9A, a novel human cGMP-specific phosphodiesterase. J Biol Chem 1998; 273: 15559–64
Fujishige K, Kotera J, Michibata H, et al. Cloning and characterization of a novel human phosphodiesterase that hydrolyses both cAMP and cGMP (PDE10A). J Biol Chem 1999; 274: 18438–45
Giembycz MA, Dent G, Souness JE. Theophylline and isoenzyme-selective phosphodiesterase inhibitors. In: Kay AB, editor. Allergy and allergic diseases. Oxford: Blackwell Scientific, 1997: 531–67
Torphy TJ. Phosphodiesterase isozymes: molecular targets for novel antiasthma agents. Am J Respir Crit Care Med 1998; 157: 351–70
Torphy TJ, Undem BJ. Phosphodiesterase inhibitors: new opportunities for the treatment of asthma. Thorax 1991;46: 512–23
Torphy TJ, Murray KJ, Arch JRS. Selective phosphodiesterase isoenzyme inhibitors. In: Page CP, Metzger WJ, editors. Drugs and the lung. New York: Raven Press, 1994: 397–477
Giembycz MA. Could isoenzyme-selective phosphodiesterase inhibitors render bronchodilator therapy redundant in the treatment of bronchial asthma? Biochem Pharmacol 1992; 43: 2041–51
Giembycz MA, Dent G. Prospects for selective cyclic nucleotide phosphodiesterase inhibitors in the treatment of bronchial asthma. Clin Exp Allergy 1992; 22: 337–44
Raeburn D, Souness JE, Tomkinson A, et al. Isoenzyme-selective cyclic nucleotide phosphodiesterase inhibitors: biochemistry, pharmacology and therapeutic potential in asthma. Prog Drug Res 1993; 40: 9–31
Dent G, Giembycz MA. Phosphodiesterase inhibitors: Lily the Pink’s medicinal compound for asthma? Thorax 1996; 51: 647–9
Nicholson CD, Shahid M. Inhibitors of cyclic nucleotide phosphodiesterase isoenzymes: their potential utility in the therapy of asthma. Pulmon Pharmacol 1994; 7: 1–17
Torphy TJ, Barnette MS, Hay DW, et al. Phosphodiesterase IV inhibitors as therapy for eosinophil-induced lung injury in asthma. Environ Health Perspect 1994; 102 Suppl. 10: 79–84
Dent G, Giembycz MA. Interaction of PDE4 inhibitors with enzymes and cell functions. In: Schudt C, Dent G, Rabe K, editors. Handbook of immunopharmacology: phosphodiesterase inhibitors. London: Academic Press, 1996: 111–26
Giembycz MA, Souness JE. Phosphodiesterase IV inhibitors as potential therapeutic agents in allergic disease. In: Townley RG, Agarwal DK, editors. Immunopharmacology of allergic disease. New York: Marcel-Dekker, 1996: 523–59
Skoyles JR, Sherry KM. Pharmacology, mechanisms of action and uses of selective phosphodiesterase inhibitors. Br J Anaesth 1992; 68: 293–302
Leeman M, Lejeune P, Melot C, et al. Reduction in pulmonary hypertension and in airway resistance by enoximone (MDL 17,043) in decompensated COPD. Chest 1987; 91: 662–6
Fujimura M, Kamio Y, Saito M, et al. Bronchodilator and bronchoprotective effects of cilostazol in humans in vivo. Am J Respir Crit Care Med 1995; 151: 222–5
Bardin PG, Dorward MA, Lampe FC, et al. Effect of selective phosphodiesterase 3 inhibition on the early and late asthmatic responses to inhaled allergen. Br J Clin Pharmacol 1998; 45: 387–91
Conti M, Swinnen JV. Structure and function of the rolipram-sensitive, low Km cyclic AMP phosphodiesterase: a family of highly related proteins. In: Houslay MD, Beavo J, editors. Molecular pharmacology of cell regulation: cyclic nucleotide phosphodiesterase structure and drug action. New York: Wiley, 1990: 243–66
Bolger G, Michaeli T, Martins T, et al. A family of human phosphodiesterases homologous to the dunce learning and memory gene product of Drosophila melanogaster are potential targets for antidepressant drugs. Mol Cell Biol 1993; 13: 6558–71
Colicelli J, Birchmeier C, Michaeli T, et al. Isolation and characterization of a mammalian gene encoding a high-affinity cAMP phosphodiesterase. Proc Natl Acad Sci U S A 1989; 86: 3599–603
Davis RL, Takayasu H, Eberwine M, et al. Cloning and characterization of mammalian homologs of the Drosophila dunce+ gene. Proc Natl Acad Sci U S A 1989; 86: 3604–8
Swinnen JV, Joseph DR, Conti M. The mRNA encoding a high-affinity cAMP phosphodiesterase is regulated by hormones and cAMP. Proc Natl Acad Sci U S A 1989; 86: 8197–201
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 U S A 1989; 86: 5325–9
Chen CN, Denome S, Davis RL. Molecular analysis of cDNA clones and the corresponding genomic coding sequences of the Drosophila dunce+ gene, the structural gene for cAMP phosphodiesterase. Proc Natl Acad Sci U S A 1986; 83: 9313–7
Livi GP, Kmetz P, McHale MM, et al. Cloning and expression of cDNA for a human low-Km, rolipram-sensitive cyclic AMP phosphodiesterase. Mol Cell Biol 1990; 10: 2678–86
McLaughlin MM, Cieslinski LB, Burman M, et al. A low-Km, rolipram-sensitive, cAMP-specific phosphodiesterase from human brain. Cloning and expression of cDNA, biochemical characterization of recombinant protein, and tissue distribution of mRNA. J Biol Chem 1993; 268: 6470–6
Obernolte R, Bhakta S, Alvarez R, et al. The cDNA of a human lymphocyte cyclic-AMP phosphodiesterase (PDEIV) reveals a multigene family. Gene 1993; 129: 239–47
Sullivan M, Egerton M, Shakur Y, et al. Molecular cloning and expression, in both COS-1 cells and S. cerevisiae, of a human cytosolic type-IVA, cyclic AMP specific phosphodiesterase (hPDE-IVA-h6.1). Cell Signal 1994; 6: 793–812
Obernolte R, Ratzliff J, Baecker PA, et al. Multiple splice variants of phosphodiesterase PDE4C cloned from human lung and testis. Biochim Biophys Acta 1997; 1353: 287–97
Baecker PA, Obernolte R, Bach C, et al. Isolation of a cDNA encoding a human rolipram-sensitive cyclic AMP phosphodiesterase (PDE IVD). Gene 1994; 138: 253–6
Engels P, Sullivan M, Muller T, et al. Molecular cloning and functional expression in yeast of a human cAMP-specific phosphodiesterase subtype (PDE IV-C). FEBS Lett 1995; 358: 305–10
Milatovich A, Bolger G, Michaeli T, et al. Chromosome localizations of genes for five cAMP-specific phosphodiesterases in man and mouse. Somat Cell Mol Genet 1994; 20: 75–86
Szpirer C, Szpirer J, Riviere M, et al. Chromosomal localization of the human and rat genes (PDE4D and PDE4B) encoding the cAMP-specific phosphodiesterases 3 and 4. Cytogenet Cell Genet 1995; 69: 11–4
Conti M, Nemoz G, Sette C, et al. Recent progress in understanding the hormonal regulation of phosphodiesterases. Endocr Rev 1995; 16: 370–89
Houslay MD, Sullivan M, Bolger GB. The multienzyme PDE4 cyclic adenosine monophosphate-specific phosphodiesterase family: intracellular targeting, regulation, and selective inhibition by compounds exerting anti-inflammatory and antidepressant actions. Adv Pharmacol 1998; 44: 225–342
Seybold J, Newton R, Wright L, et al. Induction of phosphodiesterases 3B, 4A4, 4D1, 4D2, and 4D3 in Jurkat T-cells and in human peripheral blood T-lymphocytes by 8-bromo-cAMP and Gs-coupled receptor agonists: potential role in β2-adrenoreceptor desensitization. J Biol Chem 1998; 273: 20575–88
Monaco L, Vicini E, Conti M. Structure of two rat genes coding for closely related rolipram-sensitive cAMP phosphodiesterases: multiple mRNA variants originate from alternative splicing and multiple start sites. J Biol Chem 1994; 269: 347–57
Houslay MD, Milligan G. Tailoring cAMP-signalling responses through isoform multiplicity. Trends Biochem Sci 1997; 22: 217–24
Shakur Y, Pryde JG, Houslay MD. Engineered deletion of the unique N-terminal domain of the cyclic AMP-specific phosphodiesterase RD1 prevents plasma membrane association and the attainment of enhanced thermostability without altering its sensitivity to inhibition by rolipram. Biochem J 1993; 292: 677–86
Smith KJ, Scotland G, Beattie J, et al. Determination of the structure of the N-terminal splice region of the cyclic AMP-specific phosphodiesterase RDI (RNPDE4A1) by 1H NMR and identification of the membrane association domain using chimeric constructs. J Biol Chem 1996; 271: 16703–11
Scotland G, Houslay MD. Chimeric constructs show that the unique N-terminal domain of the cyclic AMP phosphodiesterase RD1 (RNPDE4A1A; rPDE-IVA1) can confer membrane association upon the normally cytosolic protein chloramphenicol acetyltransferase. Biochem J 1995; 308: 673–81
McPhee I, Pooley L, Lobban M, et al. Identification, characterization and regional distribution in brain of RPDE-6 (RNPDE4A5), a novel splice variant of the PDE4A cyclic AMP phosphodiesterase family. Biochem J 1995; 310: 965–74
Houslay MD, Scotland G, Pooley L, et al. Alternative splicing of the type-IVA cyclic AMP phosphodiesterase gene provides isoform variants with distinct N-terminal domains fused to a common, soluble catalytic unit: ‘designer’ changes in Vmax, stability and membrane association. Biochem Soc Trans 1995; 23: 393–8
Houslay MD. The N-terminally alternately spliced regions of PDE4A cAMP-specific phosphodiesterases determine intracellular targeting andregulation of catalytic activity. Biochem Soc Trans 1996; 24: 980–6
Houslay MD, Scotland G, Erdogan S, et al. Intracellular targeting, interaction with Src homology 3 (SH3) domains and rolipram-detected conformational switches in cAMP-specific PDE4A phosphodiesterase. Biochem Soc Trans 1997; 25: 374–81
Yarwood SJ, Steele MR, Scotland G, et al. The RACK1 signalling scaffold protein selectively interacts with the cAMP-specific phosphodiesterase PDE4D5 isoform. EMBO J 1999; 274: 14909–17
Conti M. Subcellular localization of PDE4 variants: interactions with scaffold/adapter proteins [abstract]. Gordon Research Conference on Cyclic Nucleotide Phosphodiesterases, 1999
Bolger GB. Molecular biology of the cyclic AMP-specific cyclic nucleotide phosphodiesterases: a diverse family of regulatory enzymes. Cell Signal 1994; 6: 851–9
Ward AJM, McKenniff M, Evans JM, et al. Theophylline: an immunomodulatory role in asthma. Am Rev Respir Dis 1993; 147: 518–23
Sullivan PJ, Bekir S, Jaffar Z, et al. The effect of low dose theophylline on the bronchial wall infiltrate after antigen challenge. Lancet 1994; 343: 1006–8
Djukanovic R, Finnerty JP, Lee C, et al. The effect of theophylline on mucosal inflammation in asthmatic airways: biopsy results. Eur Resp J 1995; 8: 831–3
Louis R, Bury T, Corhay JL, et al. LY186655, a phosphodiesterase inhibitor, inhibits histamine release from human basophils, lung and skin fragments. Int J Immunopharmacol 1992; 14: 191–4
Peachell PT, Undem BJ, Schleimer RP, et al. Preliminary identification and role of phosphodiesterase isozymes in human basophils. J Immunol 1992; 148: 2503–10
Weston MC, Anderson N, Peachell PT. Effects of phosphodiesterase inhibitors on human lung mast cell and basophil function. Br J Pharmacol 1997; 121: 287–95
Cooper KD, Kang K, Chan SC. Phosphodiesterase inhibition by Ro 20-1724 reduces hyper-IgE synthesis by atopic dermatitis in vitro. J Invest Dermatol 1985; 84: 477–82
Dent G, Giembycz MA, Rabe KF, et al. Inhibition of eosinophil cyclic nucleotide PDE activity and opsonised zymosan-stimulated respiratory burst by ‘type IV’ -selective PDE inhibitors. Br J Pharmacol 1991; 103: 1339–46
Dent G, Giembycz MA, Evans PM, et al. Suppression of human eosinophil respiratory burst and cyclic AMP hydrolysis by inhibitors of type IV phosphodiesterase: interaction with the beta adrenoceptor agonist albuterol. J Pharmacol Exp Ther 1994; 271: 1167–74
Souness JE, Carter CM, Diocee BK, et al. Characterization of guinea-pig eosinophil phosphodiesterase activity. Assessment of its involvement in regulating Superoxide generation. Biochem Pharmacol 1991; 42: 937–45
Souness JE, Villamil ME, Scott LC, et al. 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: 1081–8
Souness JE, Maslen C, Webber S, 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
Hatzelmann A, Tenor H, Schudt C. Differential effects of non-selective and selective phosphodiesterase inhibitors on human eosinophil functions. Br J Pharmacol 1995; 114: 821–31
Berends C, Dijkhuizen B, Demonchy JGR, et al. Inhibition of PAF-induced expression of CD11b and shedding of L-selectin on human neutrophils and eosinophils by the type IV selective PDE inhibitor, rolipram. Eur Respir J 1997; 10: 1000–7
Kaneko T, Alvarez R, Ueki IF, et al. Elevated intracellular cyclic AMP inhibits chemotaxis in human eosinophils. Cell Signal 1995; 7: 527–34
Tenor H, Hatzelmann A, Church MK, et al. Effects of theophylline and rolipram on leukotriene C4 (LTC4) synthesis and chemotaxis of human eosinophils from normal and atopic subjects. BrJ Pharmacol 1996; 118: 1727–35
Schudt C, Tenor H, Hatzelmann A. PDE isoenzymes as targets for anti-asthma drugs. Eur Respir J 1995; 8: 1179–83
Seldon PM, Barnes PJ, Meja K, et al. Suppression of lipopoly-saccharide-induced tumor necrosis factor-α generation from human peripheral blood monocytes by inhibitors of phospho-diesterase 4: interaction with stimulants of adenylyl cyclase. Mol Pharmacol 1995; 48: 747–57
Semmler J, Wachtel H, Endres S. The specific type IV phosphodiesterase inhibitor rolipram suppresses tumor necrosis factor-a production by human mononuclear cells. Int J Immunopharmacol 1993; 15: 409–13
Molnar Kimber K, Yonno L, Heaslip R, et al. Modulation of TNFα and IL-1β from endotoxin-stimulated monocytes by selective PDE isozyme inhibitors. Agents Actions 1993; 39: C77–9
Prabhakar U, Lipshutz D, Bartus JO, et al. Characterization of cAMP-dependent inhibition of LPS-induced TNFα production by rolipram, a specific phosphodiesterase IV (PDE IV) inhibitor. Int J Immunopharmacol 1994; 16: 805–16
Griswold DE, Webb EF, Breton J, et al. Effect of selective phosphodiesterase type IV inhibitor, rolipram, on fluid and cellular phases of inflammatory responses. Inflammation 1993; 17: 333–44
Derian CK, Santulli RJ, Rao PE, et al. Inhibition of chemotactic peptide-induced neutrophil adhesion to vascular endothelium by cAMP modulators. J Immunol 1995; 154: 308–17
Wright CD, Kuipers PJ, Lobylarz-Singer D, et al. Differential inhibition of human neutrophil functions: role of cyclic AMP-specific and cyclic GMP-insensitive phosphodiesterase. Biochem Pharmacol 1990; 40: 699–707
Schudt C, Winder S, Forderkunz S, et al. Influence of selective phosphodiesterase inhibitors on human neutrophil functions and levels of cAMP and Cai. Naunyn Schmiedebergs Arch Pharmacol 1991; 344: 682–90
Ottonello L, Morone MP, Dapino P, et al. Cyclic AMP-elevating agents down-regulate the oxidative burst induced by granulocyte/macrophage colony-stimulating factor (GM-CSF) in adherent neutrophils. Clin Exp Immunol 1995; 101: 502–6
Ottonello L, Marone G, Dapino G, et al. Tumour necrosis factor α-induced oxidative burst in neutrophils adherent to fibronectin: effects of cyclic AMP-elevating agents. Br J Haematol 1995; 91: 566–70
Nourshargh S, Hoult JRS. Inhibition of human neutrophil degranulation by forskolin in the presence of phosphodiesterase inhibitors. Eur J Pharmacol 1986; 122: 205–12
Barnette MS, Bartus JO, Burman M, et al. Association of the anti-inflammatory activity of phosphodiesterase 4 (PDE4) inhibitors with either inhibition of PDE4 catalytic activity or competition for [3H]rolipram binding. Biochem Pharmacol 1996; 51: 949–56
Barnette MS, Christensen SB, Essayan DM, 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: 420–6
Nielson CP, Vestal RE, Sturm RJ, et al. Effects of selective phosphodiesterase inhibitors on the polymorphonuclear leukocyte respiratory burst. J Allergy Clin Immunol 1990; 86: 801–8
Fonteh AN, Winkler JD, Torphy TJ, et al. Influence of isoproterenol and phosphodiesterase inhibitors on platelet-activating factor biosynthesis in the human neutrophil. J Immunol 1993; 151: 339–50
Giembycz MA, Corrigan CJ, Seybold J, et al. Identification of cyclic AMP phosphodiesterases 3, 4 and 7 in human CD4+ and CD8+ T-lymphocytes: role in regulating proliferation and the biosynthesis of interleukin-2. Br J Pharmacol 1996; 118: 1945–58
Essayan DM, Huang S, Undem BJ, et al. Modulation of antigen-and mitogen-induced proliferative responses of peripheral blood mononuclear cells by non-selective and isozyme-selective cyclic nucleotide phosphodiesterase inhibitors. J Immunol 1994; 153: 3408–13
Essayan DM, Huang S, Kagey Sobotka A, et al. Effects of non-selective and isozyme selective cyclic nucleotide phosphodiesterase inhibitors on antigen-induced cytokine gene expression in peripheral blood mononuclear cells. Am J Respir Cell Mol Biol 1995; 13: 692–702
Banner KH, Roberts NM, Page CP. Differential effect of phosphodiesterase 4 inhibitors on the proliferation of human peripheral blood mononuclear cells from normals and subjects with atopic dermatitis. Br J Pharmacol 1995; 116: 3169–74
Van Wauwe J, Aerts F, Walter H, et al. Cytokine production by phytohemagglutinin-stimulated human blood cells: effect of corticosteroids, T-cell immunosuppressants and phosphodiesterase IV inhibitors. Inflamm Res 1995; 44: 400–5
Anastassiou ED, Paliogianni F, Balow JP, et al. Prostaglandin E2 and other cyclic AMP-elevating agents modulate IL-2 and IL-2α(gene expression at multiple levels. J Immunol 1992; 148: 2845–52
Chan SC, Li SH, Hanifin JM. Increased interleukin-4 production by atopic mononuclear leukocytes correlates with increased cyclic adenosine monophosphate-phosphodiesterase activity and is reversible by phosphodiesterase inhibition. J Invest Dermatol 1993; 100: 681–4
Crocker IC, Townley RG, Khan MM. Phosphodiesterase inhibitors suppress proliferation of peripheral blood mononuclear cells and interleukin-4 and −5 secretion by human T-helper type 2 cells. Immunopharmacol 1996; 31: 223–35
Crocker IC, Ohia SE, Church MK, et al. Phosphodiesterase type 4 inhibitors, but not glucocorticoids, are more potent in suppression of cytokine secretion by mononuclear cells from atopic than nonatopic donors. J Allergy Clin Immunol 1998; 102: 797–804
Essayan DM, Kagey Sobotka A, Lichtenstein LM, et al. Regulation of interleukin-13 by type 4 cyclic nucleotide phosphodiesterase (PDE) inhibitors in allergen-specific human T-lymphocyte clones. Biochem Pharmacol 1997; 53: 1055–60
Kaminuma O, Mori A, Wada K, et al. A selective type 4 phosphodiesterase inhibitor, T-440, modulates intracellular cyclic AMP level and interleukin-2 production of Jurkat cells. Immunopharmacol 1998; 38: 247–52
Kaminuma O, Mori A, Suko M, et al. Interleukin-5 production by peripheral blood mononuclear cells of asthmatic patients is suppressed by T-440: relation to phosphodiesterase inhibition. J Pharmacol Exp Ther 1996; 279: 240–6
Seldon PM, Barnes PJ, Giembycz MA. Interleukin-10 does not mediate the inhibitory effect of PDE4 inhibitors and other cAMP-elevating drugs on lipopolysaccharide-induced tumor necrosis factor-α generation from human peripheral blood monocytes. Cell Biochem Biophys 1998; 29: 179–201
Blease K, Burke-Gaffney A, Hellewell PG. Modulation of cell adhesion molecule expression and function on human lung microvascular endothelial cells by inhibitors of phosphodiesterases 3 and 4. Br J Pharmacol 1998; 124: 229–37
Kuehl FA, Zanetti ME, Soderman DD, et al. Cyclic AMP-dependent regulation of lipid mediators in white cells: a unifying concept for explaining the efficacy of theophylline in asthma. Am Rev Respir Dis 1987; 136: 210–3
Howell RE, Sickles BD, Woeppel SL. Pulmonary anti-allergic and bronchodilator effects of isozyme-selective phosphodiesterase inhibitors in guinea-pigs. J Pharmacol Exp Ther 1993; 264: 609–15
Underwood DC, Osborn RR, Novak LB, 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: 306–13
Raeburn D, Underwood SL, Lewis SA, et al. Anti-inflammatory and bronchodilator properties of RP 73401, a novel and selective phosphodiesterase type IV inhibitor. Br J Pharmacol 1994; 113: 1423–31
Hughes B, Howat D, Lisle H, et al. The inhibition of antigen-induced eosinophilia and bronchoconstriction by CDP 840, a novel stereo-selective inhibitor of phosphodiesterase type 4. Br J Pharmacol 1996; 118: 1183–91
Gozzard N, Herd CM, Blake AM, et al. Effect of theophylline and rolipram on antigen-induced airway responses in neonatally immunised rabbits. BrJ Pharmacol 1996; 117: 1405–12
Turner CR, Andreson CJ, Smith WB, et al. Effects of rolipram on responses to acute and chronic antigen exposure in monkeys. Am J Respir Crit Care Med 1994; 149: 1153–9
Turner CR, Cohan VL, Cheng JB, et al. The in vivo pharmacology of CP-80,633, a selective inhibitor of phosphodiesterase 4. J Pharmacol Exp Ther 1996; 278: 1349–55
Nagai H, Takeda H, Iwama T, et al. Studies on anti-allergic activity of AH-21-132, a novel isozyme-selective phosphodiesterase inhibitor in airways. Jap J Pharmacol 1995; 67: 149–56
Danahay H, Broadley KJ. Effects of inhibitors of phosphodiesterase, on antigen-induced bronchial hyperreactivity in conscious sensitized guinea-pigs and airway leukocyte infiltration. Br J Pharmacol 1997; 120: 289–97
Danahay H, Broadley KJ. PDE4 inhibition and a corticosteroid in chronically antigen exposed conscious guinea-pigs. Clin Exp Allergy 1998; 28: 513–22
Elwood W, Sun J, Barnes PJ, et al. Inhibition of allergen-induced lung eosinophilia by type IV and combined type III-and IV-selective phosphodiesterase inhibitors in Brown Norway rats. Inflammation Res 1995; 44: 83–6
Howell RE, Jenkins LP, Fielding LE, et al. Inhibition of antigen-induced pulmonary eosinophilia and neutrophilia by selective inhibitors of phosphodiesterases types 3 or 4 in Brown Norway rats. Pulmon Pharmacol 1995; 8: 83–9
Sturm RJ, Osborne MC, Heaslip RJ. The effect of phosphodiesterase inhibitors on pulmonary inflammatory cell influx in ovalbumin-sensitized guinea-pigs. J Cell Biochem 1990; 14: 337
Underwood DC, Matthews JK, Osborn RR, et al. The influence of endogenous catecholamines on the inhibitory effects of rolipram against early- and late-phase response to antigen in the guinea pig. J Pharmacol Exp Ther 1997; 280: 210–9
Underwood DC, Bochnowicz S, Osborn RR, et al. Anti-asthmatic activity of the second-generation phosphodiesterase 4 (PDE4) inhibitor SB 207499 (Ariflo) in the guinea pig. J Pharmacol Exp Ther 1998; 287: 988–95
Lagente V, Moodley I, Perrin S, et al. Effects of isozyme-selective phosphodiesterase inhibitors on eosinophil infiltration in the guinea-pig lung. Eur J Pharmacol 1994; 255: 253–6
Lagente V, Pruniaux MP, Junien JL, et al. Modulation of cytokine-induced eosinophil infiltration by phosphodiesterase inhibitors. Am J Respir Crit Care Med 1995; 151: 1720–4
Santing RE, Olymulder CG, Van der Molen K, et al. Phosphodiesterase inhibitors reduce bronchial hyperreactivity and airway inflammation in unrestrained guinea pigs. Eur J Pharmacol 1995; 275: 75–82
Howell RE, Woeppel SL, Howell DE, et al. Pulmonary antiallergic and antiinflammatory effects of a novel, orally-active phosphodiesterase IV inhibitor (WAY-127093B) in guinea pigs and rats. Inflamm Res 1995; 44 Suppl. 2: S172–3
Holbrook M, Gozzard N, James T, et al. Inhibition of bronchospasm and ozone-induced airway hyperresponsiveness in the guinea-pig by CDP840, a novel phosphodiesterase type 4 inhibitor. Br J Pharmacol 1996; 118: 1192–200
Raeburn D, Karlsson J-A. Effect of isoenzyme-selective inhibitors of cyclic nucleotide phosphodiesterase on microvascular leak in guinea-pig airways in vivo. J Pharmacol Exp Ther 1993; 267: 1147–52
Ortiz J, Cortijo J, Valles JM, et al. Rolipram inhibits airway microvascular leakage induced by platelet-activating factor, histamine and bradykinin in guinea-pig. J Pharmacol 1993; 45: 1090–2
Ortiz JL, Valles JM, Marticabrera M, et al. Effects of selective phosphodiesterase inhibitors on platelet-activating factor-and antigen-induced airway hyperreactivity, eosinophil accumulation, and microvascular leakage in guinea pigs. Naunyn-Schmiedeberg’s Arch Pharmacol 1996; 353: 200–6
Souness JE, Giembycz MA. Cyclic nucleotide phosphodiesterases in airways smooth muscle. In: Raeburn D, Giembycz MA, editors. Airways smooth muscle: biochemical control of contraction and relaxation. Basel: Birkhauser Verlag AG, 1994:271–308
Myou S, Fujimura M, Kamio Y, et al. Bronchodilator effect of inhaled olprinone, a phosphodiesterase 3 inhibitor, in asthmatic patients. Am J Resir Crit Care Med 1999; 160: 817–20
Foster RW, Rakshi K, Carpenter JR, et al. Trials of the bronchodilator activity of the isoenzyme-selective phosphodiesterase inhibitor, AH 21-132 in healthy volunteers during methacholine challenge test. Br J Clin Pharmacol 1992; 34: 527–34
Brunnee T, Engelstatter R, Steinijans VW, et al. Bronchodilatory effect of inhaled zardaverine, a phosphodiesterase III and IV inhibitor, in patients with asthma. Eur Respir J 1992; 5: 982–5
Ukena D, Rentz K, Reiber C, et al. Effects of the mixed phosphodiesterase III/IV inhibitor, zardaverine, on airway function in patients with chronic airflow obstruction. Respir Med 1995; 89: 441–4
Evans DJ, Aikman SL, Kharitanov SA, et al. Inhaled tolafentrine, a PDE III/TV inhibitor: acute effect on histamine- and AMP-induced bronchoconstriction and exhaled NO in mild asthma [Abstract]. Am J Respir Crit Care Med 1996; 153: A347
Israel EP, Mathur PN, Tashkin D, et al. LY 186655 prevents bronchospasm in asthma of moderate severity. Chest 1988; 91: 715–8
Jonker GJ, Tijhuis GJ, De Monchy JGR. RP73401 (aphospho-diesterase IV inhibitor) single dose does not prevent allergen-induced bronchoconstriction during the early phase reaction in asthma [abstract]. Eur Respir J 1996; 9: 82S
McGrath JL, Aikman SL, Cook RM, et al. Six weeks treatment with inhaled RP 73401, a PDE IV inhibitor: effect on airway hyperresponsiveness and exhaled nitric oxide in mild to moderate asthma [abstract]. Am J Respir Crit Care Med 1997; 155: A660
Perry MJ, O’Connell J, Walker C, et al. CDP840: a novel inhibitor of PDE-4. Cell Biochem Biophys 1998; 29: 113–32
Harbinson PL, MacLeod D, Hawksworth R, et al. The effect of a novel orally active selective PDE4 isoenzyme inhibitor (CDP840) on allergen-induced responses in asthmatic subjects. Eur Respir J 1997;10: 1008–14
Norman P. PDE4 Inhibitors 1998. Exp Opin Ther Pat 1998; 8: 771–84
Nieman RB, Fisher BD, Amit O, et al. SB 207499 (Ariflo™), a second generation, selective oral phosphodiesterase type 4 (PDE4) inhibitor, attenuates exercise-induced bronchoconstriction in patients with asthma [abstract]. Am J Respir Crit Care Med 1998; 157: A413
Compton CH, Cedar E, Nieman RB, et al. Ariflo™improves pulmonary function in patients with asthma: results of a study in patients taking inhaled corticosteroids [abstract]. Am J Respir Crit Care Med 1999; 159: A522
Krause W, Kuhne G. Pharmacokinetics of rolipram in the rhesus and cynomolgous monkeys, the rat and the rabbit: studies on species differences. Xenobiotica 1988; 18: 561–71
Data on file (WO9723460). Celltech Therapeutics Ltd, 1997
Data on file (WO9723461). Celltech Therapeutics Ltd, 1997
Rogers DF, Giembycz MA. Asthma therapy for the 21st century. Trends Pharmacol Sci 1998; 19: 160–4
Society for Medicines Research. Trends in Medicinal Chemistry Meeting Report. London: Society for Medicines Research, December 1996
Escott KJ, Birrell M, Webber SE, et al. Efficacy versus toxicity of PDE4 inhibitors [abstract]. Am J Respir Crit Care Med 1998; 157: A413
Duplantier AJ, Biggers MS, Chambers RJ, et al. Biarylcarboxylic acids and -amides: inhibition of phosphodiesterase type IV versus [3H]rolipram binding activity and their relationship to emetic behavior in the ferret. J Med Chem 1996; 39: 120–5
Gale DD, Landells LJ, Spina D, et al. Pharmacodynamic-pharmacokinetic (PD/PK) profile of the phosphodiesterase (PDE) 4 inhibitor, V11294A, in human volunteers [Abstract]. Am J Respir Crit Care Med 1999; 159: A108
Muller T, Engels P, Fozard JR. Subtypes of the type 4 cAMP phosphodiesterases: structure, regulation and selective inhibition. Trends Pharmacol Sci 1996; 17: 294–8
Bushnik T, Conti M. Role of multiple cAMP-specific phosphodiesterase variants. Biochem Soc Trans 1996; 24: 1014–9
Manning CD, Burman M, Christensen SB, et al. Suppression of human inflammatory cell function by subtype-selective PDE4 inhibitors correlates with inhibition of PDE4A and PDE4B. Br J Pharmacol 1999; 128: 1393–8
Torphy TJ, Christensen SB, Barnette MS, et al. Molecular basis for an improved therapeutic index of SB 207499, a second generation phosphodiesterase 4 inhibitor [abstract]. Eur Respir J 1997; 10: S313
Cavalla D, Gale DD, Spina D, et al. Activity of V11294A, a novel phosphodiesterase 4 (PDE4) inhibitor, in cellular and animal models of asthma [abstract]. Am Rev Respir Crit Care Med 1997; 155: A660
Cavalla D, Gale D. A case history in successful virtual research. Drugs News Perspect 1997; 10: 470–6
Robichaud A, Tattersall FD, Choudhury I, et al. Emesis induced by inhibitors of type IV cyclic nucleotide phosphodiesterase (PDE TV) in the ferret. Neuropharmacol 1999; 38: 289–97
Engels P, Fichtel K, Lubbert H. Expression and regulation of human and rat phosphodiesterase type IV isogenes. FEBS Lett 1994; 350: 291–5
Gantner F, Tenor H, Gekeler V, et al. Phosphodiesterase profiles of highly purified human peripheral blood leukocyte populations from normal and atopic individuals: a comparative study. J Allergy Clin Immunol 1997; 100: 527–35
Gantner F, Gotz C, Gekeler V, et al. Phosphodiesterase profile of human B lymphocytes from normal and atopic donors and the effects of PDE inhibition on B cell proliferation. Br J Pharmacol 1998; 123: 1031–8
Verghese MW, McConnell RT, Lenhard JM, et al. Regulation of distinct cyclic AMP-specific phosphodiesterase (phosphodiesterase type 4) isozymes in human monocytic cells. Mol Pharmacol 1995; 47: 1164–71
Fuhrmann M, Jahn HU, Seybold J, et al. Identification and function of cyclic nucleotide phosphodiesterase isoenzymes in airway epithelial cells. Am J Respir Cell Mol Biol 1999; 20: 292–302
Wright LC, Seybold J, Robichaud A, et al. Phosphodiesterase expression in human epithelial cells. Am JPhysiol 1998; 275: L694–700
Jin S-LC, Richard FJ, Kuo W-P, et al. Impaired growth and fertility of cyclic AMP-specific phosphodiesterase PDE4D-deficient mice. Proc Natl Acad Sci U S A 1999; 96: 11998–12003
Conti M, Jin C, Hansen G. Role of PDE4 in cell signalling: new insights from PDE4 Knockout mice. William Harvey Research Conferences — PDE inhibitors: drugs with an expanding range of therapeutic uses. Nice, 1999
Engels P, Abdel’ Al S, Hulley P, et al. Brain distribution of four rat homologues of the Drosophila dunce cAMP phosphodiesterase. J Neurosci Res 1995; 41: 169–78
Souness JE, Rao S. Proposal for pharmacologically distinct conformers of PDE4 cyclic AMP phosphodiesterases. Cell Signal 1997; 9: 227–36
Barnette MS, Christensen SB, Underwood DC, et al. Phosphodiesterase 4: biological underpinnings of the design of improved inhibitors. Pharmacol Rev Commun 1997; 8: 65–73
Hughes B, Owens R, Perry M, et al. PDE4 inhibitors: the use of molecular cloning in the design and development of novel drugs. Drug Disc Today 1997; 2: 89–101
Barnette MS, Manning CD, Cieslinski LB, et al. The ability of phosphodiesterase IV inhibitors to suppress Superoxide production in guinea pig eosinophils is correlated with inhibition of phosphodiesterase IV catalytic activity. J Pharmacol Exp Ther 1995; 273: 674–9
Souness JE, Houghton C, Sardar N, et al. Evidence that cyclic AMP phosphodiesterase inhibitors suppress interleukin-2 release from murine splenocytes by interacting with a “low affinity” phosphodiesterase 4 conformer. Br J Pharmacol 1997; 121: 743–50
Souness JE, Griffin M, Maslen C, et al. Evidence that cyclic AMP phosphodiesterase inhibitors suppress TNFα generation from human monocytes by interacting with a ‘low-affinity’ phosphodiesterase 4 conformer. Br J Pharmacol 1996; 118: 649–58
Barnette MS, Grous M, Cieslinski LB, et al. Inhibitors of phosphodiesterase IV (PDE IV) increase acid secretion in rabbit isolated gastric glands: correlation between function and interaction with a high-affinity rolipram binding site. J Pharmacol Exp Ther 1995; 273: 1396–402
Harris AL, Connell MJ, Ferguson EW, et al. Role of low Km cyclic AMP phosphodiesterase inhibition in tracheal relaxation and bronchodilation in the guinea pig. J Pharmacol Exp Ther 1989; 251: 199–206
Christensen SB, Guider A, Forster CJ, et al. 1,4-Cyclohexa-necarboxylates: potent and selective inhibitors of phosphodiesterase 4 for the treatment of asthma. J Med Chem 1998; 41: 821–35
Murdoch RD, Cowley H, Upward J, et al. The safety and tolerability of Ariflo™ (SB 207499), a novel and selective phosphodiesterase 4 inhibitor, in healthy male volunteers [abstract]. Am J Respir Crit Care Med 1998; 157: A409
Masamune H, Cheng JB, Cooper K, et al. Discovery of micromolar PDE IV inhibitors that exhibit much reduced affinity for the [3H] rolipram binding site; 3-Norboryl-4-methoxy-phenylmethylene oxindoles. Bioorganic Med Chem Letts 1995; 5: 1965–8
Cheng JB, Cooper K, Duplantier AJ, et al. Synthesis and in vitro profile of a novel series of catechol benzimidazoles: the discovery of potent, selective phosphodiesterase type IV inhibitors with greatly attenuated affinity for the [3H] rolipram binding site. Bioorganic Med Chem Letts 1995; 5: 1969–72
Hulme C, Moriarty K, Huang FC, et al. Quaternary substituted PDE IV inhibitors II: the synthesis and in vitro evaluation of a novel series of y-lactams. Bioorg Med Chem Lett 1998; 8: 399–404
Souness JE, Foster M. Potential of phosphodiesterase type 4 inhibitors in the treatment of rheumatoid arthritis. Curr Res Rheum Arthr 1998; 2: 255–68
Ward A, Clissold SP. Pentoxifylline: a review of its pharmacokinetic properties, and its therapeutic efficacy. Drugs 1987; 34: 50–97
Data on file (Eur.Pat. 3200032). Kamijo S, Imai J, 1989
Data on file (Eur.Pat. 319902). KamijoS,ImaiJ,KodairaH, 1989
Data on file (Eur.Pat. 350913). Masakatsu K, Ohashi M, 1990
Robicsek SA, Blanchard DK, Djeu JY, et al. Multiple high affinity cyclic AMP phosphodiesterases in human T-lymphocytes. Biochem Pharmacol 1991; 42: 869–77
Tenor H, Schudt C. Analysis of PDE isoenzyme profiles in cells and tissues by pharmacological methods. In: Schudt C, Dent G, Rabe K, editors. Handbook of immunopharmacology: phosphodiesterase inhibitors. London: Academic Press, 1996: 21–40
Wood MA, Hess ML. Long term therapy of congestive heart failure with phosphodiesterase inhibitors. J Am Med Sei 1989; 297: 105–13
Naccarelli GV, Goldstein RA. Electrophysiology of phosphodiesterase inhibitors. Am J Cardiol 1989; 63: 35A-40A
Masuoka H, Ito M, Sugioka M, et al. Two isoforms of cGMP-inhibited cyclic nucleotide phosphodiesterases in human tissues distinguished by their responses to vesnarinone, a new cardiotonic agent. Biochem Biophys Res Commun 1993; 190: 412–7
Larson JL, Pino MV, Geiger LE, et al. The toxicity of repeated exposures to rolipram, a type IV phosphodiesterase inhibitor, in rats. Pharmacol Toxicol 1996; 78: 44–9
Alousi A, Fabian RJ, Baker JF, et al. Milrinone. In: Scriabine A, editor. New drugs annual: cardiovascular drugs. New York: Raven Press, 1985: 245–83
Westwood FR, Iswaran TJ, Greaves P. Pathologic changes in blood vessels following administration of an inotropic vasodilator (ICI 153,110) to the rat. Fund Appl Toxicol 1990; 14: 797–809
Han P, Fletcher CF, Copeland NG, et al. Assignment of the mouse PDE7A gene to the proximal region of chromosome 3 and of the human PDE7A gene to chromosome 8ql 3. Genomics 1998; 48: 275–6
Bloom TJ, Beavo JA. Identification of PDE VII in HUT78 T-lymphocyte cells [abstract]. FASEB J 1994; 8: A372
Li L, Yee C, Beavo JA. CD3- and CD28-dependent induction of PDE7 required for T cell activation. Science 1999; 283: 848–51
Hayashi M, Matsushima K, Ohashi H, et al. Molecular cloning and characterization of human PDE8B, a novel thyroid-specific isozyme of 3′,5′-cyclic nucleotide phosphodiesterase. Biochem Biophys Res Commun 1998; 250: 751–6
Markham A, Faulds D. Theophylline: a review of its potential steroid sparing effects in asthma. Drugs 1998; 56: 1081–91
Chung KF. Theophylline in chronic asthma: evidence for disease-modifying properties. Clin Exp Allergy 1996; 26 Suppl. 2: 22–7
LaHat N, Nir E, Horenstein L, et al. Effect of theophylline on the proportion and function of T-suppressor cells in asthmatic children. Allergy 1985; 40: 453–7
Shohat B, Volovitz B, Varsano I. Induction of suppressor T-cells in asthmatic children by theophylline treatment. Clin Allergy 1983; 13: 487–93
Brenner M, Berkowitz R, Marshall N, et al. Need for theophylline in severe steroid-requiring asthmatics. Clin Allergy 1988; 18: 143–50
Kidney JC, Dominguez M, Taylar P, et al. Immunomodulation by theophylline: demonstration by withdrawal of therapy. Am J Respir Crit Care Med 1995; 151: 1907–14
Evans DJ, Taylor DA, Zetterstrom O, et al. A comparison of low-dose inhaled budesonide plus theophylline and high-dose inhaled budesonide for moderate asthma. N Engl J Med 1997; 337: 1412–8
O’Neill SJ, Sitar DS, Klass DJ, et al. The pulmonary disposition of theophylline and its influence on human macrophage bactericidal function. Am Rev Respir Dis 1986; 134: 1225–8
Condino-Neto A, Vilela MM, Cambiucci EC, et al. Theophylline therapy inhibits neutrophil and mononuclear cell chemotaxis from chronic asthmatic children. Br J Clin Pharmacol 1991; 32: 557–61
Jaffar Z, Sullivan P, Page C, et al. Low-dose theophylline modulates T-lymphocyte activationin allergen-challenged asthmatics. Eur Respir J 1996; 9: 456–62
Ohta K, Sawamoto S, Nakajima M, et al. The prolonged survival of human eosinophils with interleukin-5 and its inhibition by theophylline via apoptosis. Clin Exp Allergy 1996; 26: 10–5
Finnerty JP, Lee C, Wilson S, et al. Effects of theophylline on inflammatory cells and cytokines in asthmatic subjects: a placebo-controlled parallel group study. Eur Respir J 1996; 9: 1672–7
Mascali JJ, Cvietusa P, Negri J, et al. Anti-inflammatory effects of theophylline: modulation of cytokine production. Ann Allergy Asthma Immunol 1996; 77: 34–8
Coward WR, Sagara H, Church MK. Asthma, adenosine, mast cells and theophylline. Clin Exp Allergy 1998; 28 Suppl. 3: 42–6
Blackwell TS, Christman JW. The role of nuclear factor-KB in cytokine gene regulation. Am J Respir Cell Mol Biol 1997; 17: 3–9
LAS 31025. Clin Trials Monitor 1997; 69: 25-6
Ferrer P, Dihn-Xuan T, Chanal I, et al. Bronchodilator activity of LAS 31025, a new selective phosphodiesterase inhibitor [abstract]. Am J Respir Crit Care Med 1997; 155: A660
Hanifin JM, Chan SC, Cheng JB, et al. Type 4 phosphodiesterase inhibitors have clinical and in vitro anti-inflammatory effects in atopic dermatitis. J Invest Dermatol 1996; 107: 51–6
Barnes PJ. Chronic obstructive pulmonary disease: new opportunities for drug development. Trends Pharmacol Sci 1998; 19: 415–23
Compton CH, Gubb J, Cedar E, et al. The efficacy of Ariflo™ (SB 207499), a second generation, oral PDE4 inhibitor, in patients with COPD [abstract]. Am J Respir Crit Care Med 1999; 159: A806
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The author gratefully acknowledges the Medical Research Council (UK), the National Asthma Campaign (UK), the British Lung Foundation [BLF] and Glaxo-Wellcome Research and Development for financial support.
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Giembycz, M.A. Phosphodiesterase 4 Inhibitors and the Treatment of Asthma. Drugs 59, 193–212 (2000). https://doi.org/10.2165/00003495-200059020-00004
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DOI: https://doi.org/10.2165/00003495-200059020-00004