Abstract
Methylxanthines represent a unique class of drugs for the treatment of asthma. The methylxanthine theophylline has demonstrated efficacy in attenuating the three cardinal features of asthma – reversible airflow obstruction, airway hyperresponsiveness, and airway inflammation. At doses achieving relatively high serum levels in which toxic side effects are sometimes observed, direct bronchodilatory effects of theophylline are recognized. At lower serum concentrations, theophylline is a weak bronchodilator but retains its capacity as an immunomodulator, anti-inflammatory, and bronchoprotective drug. Intense investigation into the molecular mechanisms of action of theophylline has identified several different points of action. Phosphodiesterase inhibition and adenosine receptor antagonism have both been implicated in promoting airway smooth muscle relaxation and bronchodilation. Similar mechanisms of action may explain the inhibitory effects of theophylline on immune cells. At lower concentrations that fail to inhibit phosphodiesterase, effects on histone deacetylase activity are believed to contribute to the immunomodulatory actions of theophylline. Since anti-inflammatory and immunomodulatory effects of methylxanthines are realized at lower serum concentrations than are required for bronchodilation, theophylline’s predominant role in asthma treatment is as a controller medication for chronic, persistent disease.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Abbreviations
- ASM:
-
Airway smooth muscle
- cAMP:
-
Cyclic AMP
- cGMP:
-
Cyclic GMP
- HDAC:
-
Histone deacetylase
- ICS:
-
Inhaled corticosteroids
- PDE:
-
Phosphodiesterase
- PPARγ:
-
Peroxisome-proliferator-activated receptor γ
- RyR:
-
Ryanodine receptor
References
Abebe W, Mustafa SJ (1998) A1 adenosine receptor-mediated Ins(1,4,5)P3 generation in allergic rabbit airway smooth muscle. Am J Physiol 275:L990
Ali S, Mustafa SJ, Metzger WJ (1992) Adenosine-induced bronchoconstriction in an allergic rabbit model: antagonism by theophylline aerosol. Agents Actions 37:165
Ali S, Mustafa SJ, Metzger WJ (1994a) Adenosine receptor-mediated bronchoconstriction and bronchial hyperresponsiveness in allergic rabbit model. Am J Physiol 266:L271
Ali S, Mustafa SJ, Metzger WJ (1994b) Adenosine-induced bronchoconstriction and contraction of airway smooth muscle from allergic rabbits with late-phase airway obstruction: evidence for an inducible adenosine A1 receptor. J Pharmacol Exp Ther 268:1328
Aubier M, De Troyer A, Sampson M, Macklem PT, Roussos C (1981) Aminophylline improves diaphragmatic contractility. N Engl J Med 305:249
Auchampach JA, Jin X, Wan TC, Caughey GH, Linden J (1997) Canine mast cell adenosine receptors: cloning and expression of the A3 receptor and evidence that degranulation is mediated by the A2B receptor. Mol Pharmacol 52:846
Baehr G, Pick EP (1913) Pharmakologische Studien an der Bronchialmuskulatur der uberlebenden Meerschweinchenlunge. Arch Exp Pathol Pharmakol 74:40
Bailly S, Ferrua B, Fay M, Gougerot-Pocidalo MA (1990) Differential regulation of IL 6, IL 1 A, IL 1 beta and TNF alpha production in LPS-stimulated human monocytes: role of cyclic AMP. Cytokine 2:205
Barrington K, Finer N (1991) The natural history of the appearance of apnea of prematurity. Pediatr Res 29:372
Bateman ED, Hurd SS, Barnes PJ, Bousquet J, Drazen JM, FitzGerald M, Gibson P, Ohta K, O’Byrne P, Pedersen SE, Pizzichini E, Sullivan SD, Wenzel SE, Zar HJ (2008) Global strategy for asthma management and prevention: GINA executive summary. Eur Respir J 31:143
Bergstrand H, Lundquist B (1978) Partial purification and characterization of cyclic nucleotide phosphodiesterases from human bronchial tissue. Mol Cell Biochem 21:9
Berkowitz BA, Spector S (1971) Effect of caffeine and theophylline on peripheral catecholamines. Eur J Pharmacol 13:193
Calhoun WJ, Stevens CA, Lambert SB (1991) Modulation of superoxide production of alveolar macrophages and peripheral blood mononuclear cells by beta-agonists and theophylline. J Lab Clin Med 117:514
Cheek TR, Moreton RB, Berridge MJ, Stauderman KA, Murawsky MM, Bootman MD (1993) Quantal Ca2+ release from caffeine-sensitive stores in adrenal chromaffin cells. J Biol Chem 268:27076
Cortijo J, Bou J, Beleta J, Cardelus I, Llenas J, Morcillo E, Gristwood RW (1993) Investigation into the role of phosphodiesterase IV in bronchorelaxation, including studies with human bronchus. Br J Pharmacol 108:562
Cosio BG, Mann B, Ito K, Jazrawi E, Barnes PJ, Chung KF, Adcock IM (2004) Histone acetylase and deacetylase activity in alveolar macrophages and blood mononocytes in asthma. Am J Respir Crit Care Med 170:141
Cushley MJ, Tattersfield AE, Holgate ST (1983a) Inhaled adenosine and guanosine on airway resistance in normal and asthmatic subjects. Br J Clin Pharmacol 15:161
Cushley MJ, Tattersfield AE, Holgate ST (1983b) Adenosine antagonism as an alternative mechanism of action of methylxanthines in asthma. Agents Actions Suppl 13:109
D’Avila RS, Piva JP, Marostica PJ, Amantea SL (2008) Early administration of two intravenous bolus of aminophylline added to the standard treatment of children with acute asthma. Respir Med 102:156
Dettbarn C, Gyorke S, Palade P (1994) Many agonists induce “quantal” Ca2+ release or adaptive behavior in muscle ryanodine receptors. Mol Pharmacol 46:502
Dowdell WT, Javaheri S, McGinnis W (1990) Cheyne-Stokes respiration presenting as sleep apnea syndrome. Clinical and polysomnographic features. Am Rev Respir Dis 141:871
Eason J, Markowe HL (1989) Aminophylline toxicity–how many hospital asthma deaths does it cause? Respir Med 83:219
Eldridge FL, Millhorn DE, Waldrop TG, Kiley JP (1983) Mechanism of respiratory effects of methylxanthines. Respir Physiol 53:239
Espinoza H, Antic R, Thornton AT, McEvoy RD (1987) The effects of aminophylline on sleep and sleep-disordered breathing in patients with obstructive sleep apnea syndrome. Am Rev Respir Dis 136:80
Evans DJ, Taylor DA, Zetterstrom O, Chung KF, O’Connor BJ, Barnes PJ (1997) A comparison of low-dose inhaled budesonide plus theophylline and high-dose inhaled budesonide for moderate asthma. N Engl J Med 337:1412
Fanta CH, Rossing TH, McFadden ER Jr (1986) Treatment of acute asthma. Is combination therapy with sympathomimetics and methylxanthines indicated? Am J Med 80:5
Feoktistov I, Biaggioni I (1995) Adenosine A2b receptors evoke interleukin-8 secretion in human mast cells. An enprofylline-sensitive mechanism with implications for asthma. J Clin Invest 96:1979
Feoktistov I, Polosa R, Holgate ST, Biaggioni I (1998) Adenosine A2B receptors: a novel therapeutic target in asthma? Trends Pharmacol Sci 19:148
Feoktistov I, Garland EM, Goldstein AE, Zeng D, Belardinelli L, Wells JN, Biaggioni I (2001) Inhibition of human mast cell activation with the novel selective adenosine A(2B) receptor antagonist 3-isobutyl-8-pyrrolidinoxanthine (IPDX)(2). Biochem Pharmacol 62:1163
Finnerty JP, Lee C, Wilson S, Madden J, Djukanovic R, Holgate ST (1996) Effects of theophylline on inflammatory cells and cytokines in asthmatic subjects: a placebo-controlled parallel group study. Eur Respir J 9:1672
Finney MJ, Karlsson JA, Persson CG (1985) Effects of bronchoconstrictors and bronchodilators on a novel human small airway preparation. Br J Pharmacol 85:29
Fredholm BB (1984) Effects of methylxanthines on skeletal muscle and on respiration. Prog Clin Biol Res 158:365
Fredholm BB, Persson CG (1982) Xanthine derivatives as adenosine receptor antagonists. Eur J Pharmacol 81:673
Fredholm BB, Brodin K, Strandberg K (1979) On the mechanism of relaxation of tracheal muscle by theophylline and other cyclic nucleotide phosphodiesterase inhibitors. Acta Pharmacol Toxicol (Copenh) 45:336
Godfrey RW, Manzi RM, Gennaro DE, Hoffstein ST (1987) Phospholipid and arachidonic acid metabolism in zymosan-stimulated human monocytes: modulation by cAMP. J Cell Physiol 131:384
Greene JA, Paul WD, Faller AE (1937) The action of theophylline with ethylenediamine on intrathecal and venous pressures in cardiac failure and on bronchial obstruction in cardiac failure and in bronchial asthma. J Am Med Assoc 109:1712
Guilleminault C, Hayes B (1983) Naloxone, theophylline, bromocriptine, and obstructive sleep apnea. Negative results. Bull Eur Physiopathol Respir 19:632
Guillot C, Fornaris M, Badier M, Orehek J (1984) Spontaneous and provoked resistance to isoproterenol in isolated human bronchi. J Allergy Clin Immunol 74:713
Henderson-Smart DJ, Steer P (2001) Methylxanthine treatment for apnea in preterm infants. Cochrane Database Syst Rev CD000140
Herrmann G, Aynesworth MB, Martin J (1937) Successful treatment of persistent extreme dyspnea status asthmaticus: use of theophylline ethylene diamine (aminophylline, USP) intravenously. J Lab Clin Med 23:135
Herrmann-Frank A, Luttgau HC, Stephenson DG (1999) Caffeine and excitation-contraction coupling in skeletal muscle: a stimulating story. J Muscle Res Cell Motil 20:223
Higbee MD, Kumar M, Galant SP (1982) Stimulation of endogenous catecholamine release by theophylline: a proposed additional mechanism of action for theophylline effects. J Allergy Clin Immunol 70:377
Hirsch S (1922) Klinischer und experimenteller Beitrag zur krampflosenden Wirkung der Purinderivate. Klin Wochschr 1:615
Hua X, Erikson CJ, Chason KD, Rosebrock CN, Deshpande DA, Penn RB, Tilley SL (2007) Involvement of A1 adenosine receptors and neural pathways in adenosine-induced bronchoconstriction in mice. Am J Physiol Lung Cell Mol Physiol 293:L25
Ishizaki T, Minegishi A, Morishita M, Odajima Y, Kanagawa S, Nagai T, Yamaguchi M (1988) Plasma catecholamine concentrations during a 72-hour aminophylline infusion in children with acute asthma. J Allergy Clin Immunol 82:146
Ito K, Caramori G, Lim S, Oates T, Chung KF, Barnes PJ, Adcock IM (2002a) Expression and activity of histone deacetylases in human asthmatic airways. Am J Respir Crit Care Med 166:392
Ito K, Lim S, Caramori G, Cosio B, Chung KF, Adcock IM, Barnes PJ (2002b) A molecular mechanism of action of theophylline: induction of histone deacetylase activity to decrease inflammatory gene expression. Proc Natl Acad Sci USA 99:8921
Jaffar ZH, Sullivan P, Page C, Costello J (1996) Low-dose theophylline modulates T-lymphocyte activation in allergen-challenged asthmatics. Eur Respir J 9:456
Javaheri S, Guerra L (1990) Lung function, hypoxic and hypercapnic ventilatory responses, and respiratory muscle strength in normal subjects taking oral theophylline. Thorax 45:743
Javaheri S, Parker TJ, Wexler L, Liming JD, Lindower P, Roselle GA (1996) Effect of theophylline on sleep-disordered breathing in heart failure. N Engl J Med 335:562
Kelly DH, Shannon DC (1981) Treatment of apnea and excessive periodic breathing in the full-term infant. Pediatrics 68:183
Kolbeck RC, Speir WA Jr, Carrier GO, Bransome ED Jr (1979) Apparent irrelevance of cyclic nucleotides to the relaxation of tracheal smooth muscle induced by theophylline. Lung 156:173
Kong H, Jones PP, Koop A, Zhang L, Duff HJ, Chen SR (2008) Caffeine induces Ca2+ release by reducing the threshold for luminal Ca2+ activation of the ryanodine receptor. Biochem J 414:441
Kraft M, Torvik JA, Trudeau JB, Wenzel SE, Martin RJ (1996) Theophylline: potential antiinflammatory effects in nocturnal asthma. J Allergy Clin Immunol 97:1242
Lakshminarayan S, Sahn SA, Weil JV (1978) Effect of aminophylline on ventilatory responses in normal man. Am Rev Respir Dis 117:33
Levy BD, Kitch B, Fanta CH (1998) Medical and ventilatory management of status asthmaticus. Intensive Care Med 24:105
Lim S, Jatakanon A, Gordon D, Macdonald C, Chung KF, Barnes PJ (2000) Comparison of high dose inhaled steroids, low dose inhaled steroids plus low dose theophylline, and low dose inhaled steroids alone in chronic asthma in general practice. Thorax 55:837
Littenberg B (1988) Aminophylline treatment in severe, acute asthma. A meta-analysis. JAMA 259:1678
Louis RE, Radermecker MF (1990) Substance P-induced histamine release from human basophils, skin and lung fragments: effect of nedocromil sodium and theophylline. Int Arch Allergy Appl Immunol 92:329
Macht DI, Ting G-C (1921) A study of antispasmodic drugs on the bronchus. J Pharmacol Exp Ther 18:373
Magnussen H, Reuss G, Jorres R (1987) Theophylline has a dose-related effect on the airway response to inhaled histamine and methacholine in asthmatics. Am Rev Respir Dis 136:1163
Magnussen H, Reuss G, Jorres R (1988) Methylxanthines inhibit exercise-induced bronchoconstriction at low serum theophylline concentration and in a dose-dependent fashion. J Allergy Clin Immunol 81:531
Manzini S, Perretti F, Abelli L, Evangelista S, Seeds EA, Page CP (1993) Isbufylline, a new xanthine derivative, inhibits airway hyperresponsiveness and airway inflammation in guinea pigs. Eur J Pharmacol 249:251
McFadden ER Jr (1985) Methylxanthine therapy and reversible airway obstruction. Am J Med 79:1
McWilliams BC, Menendez R, Kelly HW, Howick J (1984) Effects of theophylline on inhaled methacholine and histamine in asthmatic children. Am Rev Respir Dis 130:193
Mitenko PA, Ogilvie RI (1973a) Rational intravenous doses of theophylline. N Engl J Med 289:600
Mitenko PA, Ogilvie RI (1973b) Pharmacokinetics of intravenous theophylline. Clin Pharmacol Ther 14:509
Mulloy E, McNicholas WT (1992) Theophylline in obstructive sleep apnea. A double-blind evaluation. Chest 101:753
Murciano D, Aubier M, Lecocguic Y, Pariente R (1984) Effects of theophylline on diaphragmatic strength and fatigue in patients with chronic obstructive pulmonary disease. N Engl J Med 311:349
Murciano D, Aubier M, Viires N, Mal H, Pariente R (1987) Effects of theophylline and enprofylline on diaphragmatic contractility. J Appl Physiol 63:51
Numao T, Fukuda T, Akutsu I, Makino S (1991) Effects of anti-asthmatic drugs on human eosinophil chemotaxis. Nihon Kyobu Shikkan Gakkai Zasshi 29:65
Pal J (1912) Über toxische Reaktionen der Koronararterien und Bronchien. Dtsch Med Wochenschr 38:5
Pauwels R (1987) The effects of theophylline on airway inflammation. Chest 92:32S
Pauwels R, Van Renterghem D, Van der Straeten M, Johannesson N, Persson CG (1985) The effect of theophylline and enprofylline on allergen-induced bronchoconstriction. J Allergy Clin Immunol 76:583
Peach MJ (1972) Stimulation of release of adrenal catecholamine by adenosine 3′:5′-cyclic monophosphate and theophylline in the absence of extracellular Ca2+. Proc Natl Acad Sci USA 69:834
Pearce FL, Befus AD, Gauldie J, Bienenstock J (1982) Mucosal mast cells. II. Effects of anti-allergic compounds on histamine secretion by isolated intestinal mast cells. J Immunol 128:2481
Persson CG, Andersson KE, Kjellin G (1986) Effects of enprofylline and theophylline may show the role of adenosine. Life Sci 38:1057
Phillips GD, Rafferty P, Beasley R, Holgate ST (1987) Effect of oral terfenadine on the bronchoconstrictor response to inhaled histamine and adenosine 5′-monophosphate in non-atopic asthma. Thorax 42:939
Phillips GD, Polosa R, Holgate ST (1989a) The effect of histamine-H1 receptor antagonism with terfenadine on concentration-related AMP-induced bronchoconstriction in asthma. Clin Exp Allergy 19:405
Phillips GD, Scott VL, Richards R, Holgate ST (1989b) Effect of nedocromil sodium and sodium cromoglycate against bronchoconstriction induced by inhaled adenosine 5′-monophosphate. Eur Respir J 2:210
Poisner AM (1973) Direct stimulant effect of aminophylline on catecholamine release from the adrenal medulla. Biochem Pharmacol 22:469
Polson JB, Krzanowski JJ, Fitzpatrick DF, Szentivanyi A (1978) Studies on the inhibition of phosphodiesterase-catalyzed cyclic AMP and cyclic GMP breakdown and relaxation of canine tracheal smooth muscle. Biochem Pharmacol 27:254
Prabhakar U, Lipshutz D, Truneh A (1993) Inhibition of CD44, CD45 and LFA-3 mediated cytokine release from human monocytes by SK&F 86002 and pentoxifylline. Int J Immunopharmacol 15:205
Prieur AM, Granger GA (1975) The effect of agents which modulate levels of the cyclic nucleotides on human lymphotoxin secretion and activity in vitro. Transplantation 20:331
Rabe KF, Magnussen H, Dent G (1995) Theophylline and selective PDE inhibitors as bronchodilators and smooth muscle relaxants. Eur Respir J 8:637
Ream RS, Loftis LL, Albers GM, Becker BA, Lynch RE, Mink RB (2001) Efficacy of IV theophylline in children with severe status asthmaticus. Chest 119:1480
Rosenthal LA, Taub DD, Moors MA, Blank KJ (1992) Methylxanthine-induced inhibition of the antigen- and superantigen-specific activation of T and B lymphocytes. Immunopharmacology 24:203
Rossing TH, Fanta CH, Goldstein DH, Snapper JR, McFadden ER Jr (1980) Emergency therapy of asthma: comparison of the acute effects of parenteral and inhaled sympathomimetics and infused aminophylline. Am Rev Respir Dis 122:365
Ryzhov S, Goldstein AE, Biaggioni I, Feoktistov I (2006) Cross-talk between G(s)- and G(q)-coupled pathways in regulation of interleukin-4 by A(2B) adenosine receptors in human mast cells. Mol Pharmacol 70:727
Salter H (1860) Asthma. Its pathology and treatment. London
Schultze-Werninghaus G, Meier-Sydow J (1982) The clinical and pharmacological history of theophylline: first report on the bronchospasmolytic action in man by S. R. Hirsch in Frankfurt (Main) 1922. Clin Allergy 12:211
Scordamaglia A, Ciprandi G, Ruffoni S, Caria M, Paolieri F, Venuti D, Canonica GW (1988) Theophylline and the immune response: in vitro and in vivo effects. Clin Immunol Immunopathol 48:238
Self TH, Redmond AM, Nguyen WT (2002) Reassessment of theophylline use for severe asthma exacerbation: is it justified in critically ill hospitalized patients? J Asthma 39:677
Siegel D, Sheppard D, Gelb A, Weinberg PF (1985) Aminophylline increases the toxicity but not the efficacy of an inhaled beta-adrenergic agonist in the treatment of acute exacerbations of asthma. Am Rev Respir Dis 132:283
Singer JW, Bianco JA, Takahashi G, Simrell C, Petersen J, Andrews DF 3rd (1992) Effect of methylxanthine derivatives on T cell activation. Bone Marrow Transplant 10:19
Spatafora M, Chiappara G, Merendino AM, D’Amico D, Bellia V, Bonsignore G (1994) Theophylline suppresses the release of tumour necrosis factor-alpha by blood monocytes and alveolar macrophages. Eur Respir J 7:223
Spears M, Donnelly I, Jolly L, Brannigan M, Ito K, McSharry C, Lafferty J, Chaudhuri R, Braganza G, Adcock IM, Barnes PJ, Wood S, Thomson NC (2009) Effect of low-dose theophylline plus beclometasone on lung function in smokers with asthma: a pilot study. Eur Respir J 33:1010
Stephens CG, Snyderman R (1982) Cyclic nucleotides regulate the morphologic alterations required for chemotaxis in monocytes. J Immunol 128:1192
Sullivan P, Bekir S, Jaffar Z, Page C, Jeffery P, Costello J (1994) Anti-inflammatory effects of low-dose oral theophylline in atopic asthma. Lancet 343:1006
Sydbom A, Fredholm BB (1982) On the mechanism by which theophylline inhibits histamine release from rat mast cells. Acta Physiol Scand 114:243
Takeuchi M, Hayakawa A, Takagi K, Hiramatsu K, Shimizu Y, Matsumoto S, Hiramatsu T, Ito Y, Kume H, Suzuki R, Yamaki K (1999) Theophylline induces apoptosis of the IL-3 activated eosinophils of patients with bronchial asthma. Apoptosis 4:461
Tenor H, Hatzelmann A, Church MK, Schudt C, Shute JK (1996) Effects of theophylline and rolipram on leukotriene C4 (LTC4) synthesis and chemotaxis of human eosinophils from normal and atopic subjects. Br J Pharmacol 118:1727
Tilley SL, Tsai M, Williams CM, Wang ZS, Erikson CJ, Galli SJ, Koller BH (2003) Identification of A3 receptor- and mast cell-dependent and -independent components of adenosine-mediated airway responsiveness in mice. J Immunol 171:331
Trendelenburg P (1912) Physiologische und pharmakologische Untersuchungen an der isolierten Bronchialmuskulatur. Arch Exp Pathol Pharmakol 69:79
Ukena D, Harnest U, Sakalauskas R, Magyar P, Vetter N, Steffen H, Leichtl S, Rathgeb F, Keller A, Steinijans VW (1997) Comparison of addition of theophylline to inhaled steroid with doubling of the dose of inhaled steroid in asthma. Eur Respir J 10:2754
Usami A, Ueki S, Ito W, Kobayashi Y, Chiba T, Mahemuti G, Oyamada H, Kamada Y, Fujita M, Kato H, Saito N, Kayaba H, Chihara J (2006) Theophylline and dexamethasone induce peroxisome proliferator-activated receptor-gamma expression in human eosinophils. Pharmacology 77:33
Weinberger M, Hendeles L (1996) Theophylline in asthma. N Engl J Med 334:1380
Weston MC, Anderson N, Peachell PT (1997) Effects of phosphodiesterase inhibitors on human lung mast cell and basophil function. Br J Pharmacol 121:287
Wrenn K, Slovis CM, Murphy F, Greenberg RS (1991) Aminophylline therapy for acute bronchospastic disease in the emergency room. Ann Intern Med 115:241
Yasui K, Agematsu K, Shinozaki K, Hokibara S, Nagumo H, Yamada S, Kobayashi N, Komiyama A (2000a) Effects of theophylline on human eosinophil functions: comparative study with neutrophil functions. J Leukoc Biol 68:194
Yasui K, Agematsu K, Shinozaki K, Hokibara S, Nagumo H, Nakazawa T, Komiyama A (2000b) Theophylline induces neutrophil apoptosis through adenosine A2A receptor antagonism. J Leukoc Biol 67:529
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
Copyright information
© 2011 Springer Berlin Heidelberg
About this chapter
Cite this chapter
Tilley, S.L. (2011). Methylxanthines in Asthma. In: Methylxanthines. Handbook of Experimental Pharmacology, vol 200. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-13443-2_17
Download citation
DOI: https://doi.org/10.1007/978-3-642-13443-2_17
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-13442-5
Online ISBN: 978-3-642-13443-2
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)