Theophylline: Recent Advances in the Understanding of Its Mode of Action and Uses in Clinical Practice
1998; Elsevier BV; Volume: 73; Issue: 4 Linguagem: Inglês
10.1016/s0025-6196(11)63701-4
ISSN1942-5546
AutoresRobert Vassallo, James J. Lipsky,
Tópico(s)Pharmacological Receptor Mechanisms and Effects
ResumoTheophylline, a drug that has been used for several decades, has several different actions at a cellular level, including inhibition of phosphodiesterase isoenzymes, antagonism of adenosine, enhancement of catecholamine secretion, and modulation of calcium fluxes. Recently, theophylline was found to have several immunomodulatory and anti-inflammatory properties, and thus interest in its use in patients with asthma has been renewed. The use of theophylline in the treatment of asthma and chronic obstructive pulmonary disease has diminished with the advent of new medications, but theophylline remains beneficial, especially in the patient with difficult refractory symptoms. In the future, theophylline may be used as treatment for bradyarrhythmias after cardiac transplantation, prophylactic medication to reduce the severity of nephropathy associated with intravenous administration of contrast material, therapy for breathing problems during sleep, and treatment for leukemias. Theophylline, a drug that has been used for several decades, has several different actions at a cellular level, including inhibition of phosphodiesterase isoenzymes, antagonism of adenosine, enhancement of catecholamine secretion, and modulation of calcium fluxes. Recently, theophylline was found to have several immunomodulatory and anti-inflammatory properties, and thus interest in its use in patients with asthma has been renewed. The use of theophylline in the treatment of asthma and chronic obstructive pulmonary disease has diminished with the advent of new medications, but theophylline remains beneficial, especially in the patient with difficult refractory symptoms. In the future, theophylline may be used as treatment for bradyarrhythmias after cardiac transplantation, prophylactic medication to reduce the severity of nephropathy associated with intravenous administration of contrast material, therapy for breathing problems during sleep, and treatment for leukemias. Theophylline and caffeine are drugs that are related in chemical structure and pharmacologic action.1Goodman LS Gilman A The Pharmacological Basis of Therapeutics. MacMillan, New York1941: 274-285Google Scholar Henry Hyde Salter, a sufferer of asthma, made detailed observations on the usefulness of caffeine in the treatment of asthma in 1859 and reported that up to two-thirds of his patients with asthma received benefit from the regular intake of coffee.2Persson CG On the medical history of xanthines and other remedies for asthma: a tribute to HH Salter.Thorax. 1985; 40: 881-886Crossref PubMed Scopus (46) Google Scholar More than 80 years later, the first reports2Persson CG On the medical history of xanthines and other remedies for asthma: a tribute to HH Salter.Thorax. 1985; 40: 881-886Crossref PubMed Scopus (46) Google Scholar on the efficacy of theophylline in the treatment of severe bronchospasm were published separately by Hermann and Greene. What is important about a review of an "old" drug that some investigators claim is obsolete? In the past 15 years, our understanding of the mode of action of theophylline and its use have expanded substantially. Controversy about the use of this drug possibly stems from failure to understand its actions and appropriate use in clinical practice. The aims of this article are to provide a brief review of the recent advances in the understanding of the mode of action of theophylline and to outline its role in clinical practice. The mode of action of theophylline and the chemically related xanthines is poorly defined despite the fact that these drugs have been used for more than 80 years. Several mechanisms of action have been suggested to explain the effectiveness of theophylline. At a cellular level, four main theories relate to the molecular mechanisms involved in the action of theophylline. Of importance, all the hypotheses subsequently outlined have flaws, and the exact mode of action is unclear. Possibly, several mechanisms participate in producing the effects of theophylline.3Barnes PJ Pauwels RA Theophylline in the management of asthma: time for reappraisal?.Eur Respir J. 1994; 7: 579-591Crossref PubMed Scopus (237) Google Scholar The traditional understanding was that theophylline exerts its bronchodilator effect by inhibition of phosphodiesterase isoenzymes (PDEs), which cause breakdown of cyclic adenosine monophosphate (cAMP) and cyclic guanine monophosphate (cGMP). PDEs are found in several tissues including airway smooth muscle and inflammatory cells.4Torphy TJ Livi GP Phosphodiesterase isozymes in airways.Lung Biol Health Dis. 1993; 67: 177-222Google Scholar Inhibition of PDEs in the airway smooth muscle and the resultant accumulation of cAMP and cGMP were thought to cause relaxation of airway smooth muscle and bronchodilation.3Barnes PJ Pauwels RA Theophylline in the management of asthma: time for reappraisal?.Eur Respir J. 1994; 7: 579-591Crossref PubMed Scopus (237) Google Scholar, 5Torphy TJ Undem BJ Phosphodiesterase inhibitors: new opportunities for the treatment of asthma.Thorax. 1991; 46: 512-523Crossref PubMed Scopus (348) Google Scholar This theory was challenged because of the observation that therapeutic doses of theophylline produce only slight inhibition of PDE activity6Poison JB Krzanowski JJ Goldman AL Szentlvanyl A Inhibition of human pulmonary phosphodiesterase activity by therapeutic levels of theophylline.Clin Exp Pharmacol Physiol. 1978; 5: 535-539Crossref PubMed Scopus (91) Google Scholar and that theophylline-induced smooth muscle relaxation in isolated organ preparations did not correlate with pronounced changes in either cAMP or cGMP.7Miech RP Stein M Respiratory pharmacology: methylxanthines.Clin Chest Med. 1986 Sep; 7: 331-340PubMed Google Scholar Despite these findings, results of recent studies and a better understanding of PDEs suggest that inhibition of these isoenzymes may be the main mechanism involved in the bronchodilatory effect of theophylline and its alteration of immune cell function.3Barnes PJ Pauwels RA Theophylline in the management of asthma: time for reappraisal?.Eur Respir J. 1994; 7: 579-591Crossref PubMed Scopus (237) Google Scholar, 5Torphy TJ Undem BJ Phosphodiesterase inhibitors: new opportunities for the treatment of asthma.Thorax. 1991; 46: 512-523Crossref PubMed Scopus (348) Google Scholar PDE is not just one enzyme but rather a family of several isoenzymes (PDE I to VII) that differ in structure, molecular weight, and sensitivity to pharmacologic inhibitors.4Torphy TJ Livi GP Phosphodiesterase isozymes in airways.Lung Biol Health Dis. 1993; 67: 177-222Google Scholar, 5Torphy TJ Undem BJ Phosphodiesterase inhibitors: new opportunities for the treatment of asthma.Thorax. 1991; 46: 512-523Crossref PubMed Scopus (348) Google Scholar, 8Bergstrand H Lundqulst B Partial purification and characterization of cyclic nucleotide phosphodiesterases from human bronchial tissue.Mol Cell Biochem. 1978; 21: 9-15Crossref PubMed Scopus (13) Google Scholar, 9Banner KH Page CP Anti-inflammatory effects of theophylline and selective phosphodiesterase inhibitors.Clin Exp Allergy. 1996; 26: 2-9Crossref PubMed Google Scholar Inflammatory cells express predominantly type IV PDEs and to a lesser extent type III PDEs,4Torphy TJ Livi GP Phosphodiesterase isozymes in airways.Lung Biol Health Dis. 1993; 67: 177-222Google Scholar, 9Banner KH Page CP Anti-inflammatory effects of theophylline and selective phosphodiesterase inhibitors.Clin Exp Allergy. 1996; 26: 2-9Crossref PubMed Google Scholar, 10Schudt C Tenor H Hatzelmann A PDE isoenzymes as targets for anti-asthma drugs.Eur Respir J. 1995; 8: 1179-1183Crossref PubMed Scopus (125) Google Scholar whereas human airway smooth muscle contains at least five known types of PDEs,5Torphy TJ Undem BJ Phosphodiesterase inhibitors: new opportunities for the treatment of asthma.Thorax. 1991; 46: 512-523Crossref PubMed Scopus (348) Google Scholar, 11Torphy TJ Undem BJ Ciesllnski LB Luttmann MA Reeves MK Hay DWP Identification, characterization and functional role of phosphodiesterase isozymes in human airway smooth muscle [abstract].Am Rev Respir Dis. 1993; 147: A184Google Scholar of which type III seems to be the main one in mediating bronchodilation.3Barnes PJ Pauwels RA Theophylline in the management of asthma: time for reappraisal?.Eur Respir J. 1994; 7: 579-591Crossref PubMed Scopus (237) Google Scholar Several in vitro and in vivo animal studies have demonstrated the bronchorelaxant activity of selective type III, IV, and mixed III-IV PDE inhibitors,5Torphy TJ Undem BJ Phosphodiesterase inhibitors: new opportunities for the treatment of asthma.Thorax. 1991; 46: 512-523Crossref PubMed Scopus (348) Google Scholar and theophylline seems to relax human bronchial smooth muscle through nonselective PDE inhibition involving at least type III and IV PDEs.12Rabe KF Tenor H Dent G Nakashima M Schudt C Magnussen H Theophylline relaxes human airways and pulmonary arteries in vitro through phosphodiesterase inhibition [abstract].Am Rev Respir Dis. 1993; 147: A184Crossref Google Scholar The inhibition of PDEs in inflammatory cells eventuates in a wide range of immunomodulatory effects4Torphy TJ Livi GP Phosphodiesterase isozymes in airways.Lung Biol Health Dis. 1993; 67: 177-222Google Scholar, 9Banner KH Page CP Anti-inflammatory effects of theophylline and selective phosphodiesterase inhibitors.Clin Exp Allergy. 1996; 26: 2-9Crossref PubMed Google Scholar that occur as a result of an inhibitory effect of cAMP on immune cell function.13Kammer GM The adenylate cyclase-cAMP-protein kinase A pathway and regulation of the immune response.Immunol Today. 1988; 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This theory could explain why some of the older in vitro studies performed on nonasthmatic smooth muscle showed only slight PDE inhibition.6Poison JB Krzanowski JJ Goldman AL Szentlvanyl A Inhibition of human pulmonary phosphodiesterase activity by therapeutic levels of theophylline.Clin Exp Pharmacol Physiol. 1978; 5: 535-539Crossref PubMed Scopus (91) Google Scholar This is supported by the clinical observation that theophylline produces no appreciable bronchodilator response in normal subjects in contrast to patients with asthma.16Estenne M Yernault JC De Troyer A Effects of parenteral aminophylline on lung mechanics in normal human.Am Rev Respir Dis. 1980; 121: 967-971PubMed Google Scholar Another consideration is that there may be PDEs, which are as yet undiscovered, that are sensitive to inhibition from theophylline. Adenosine, a naturally occurring purine nucleoside, is generated by dephosphorylation of adenosine monophosphate17Church MK Featherstone RL Cushley MJ Mann JS Holgate ST Relationships between adenosine, cyclic nucleotides, and xanthines in asthma.J Allergy Clin Immunol. 1986; 78: 670-675Abstract Full Text PDF PubMed Scopus (34) Google Scholar and has been shown to cause bronchospasm when inhaled by patients with asthma18Cushley MJ Tattersfleld AE Holgate ST Inhaled adenosine and guanosine on airway resistance in normal and asthmatic subjects.Br J Clin Pharmacol. 1983; 15: 161-165Crossref PubMed Scopus (323) Google Scholar and smokers.19Pin I Hepperle MJ Wong BJO Ramsdale EH Hargreave FE Methacholine (M) and adenosine monophosphate (AMP) airway hyperresponsiveness (AHR) in asthmatics and smokers with chronic airflow limitation (CAL) [abstract].Am Rev Respir Dis. 1991; 143: A413Google Scholar At therapeutic concentrations, theophylline acts as a competitive antagonist at adenosine receptors,20Rail TW Drugs used in the treatment of asthma: the methylxanthines, cromolyn sodium, and other agents.in: Gilman AG Rail TW Nies AS Taylor P Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. 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Xanthines have a stimulatory effect on the adrenal medulla, causing release of catecholamines, predominantly epinephrine.27Higbee MD Kumar M Galant SP Stimulation of endogenous catecholamine release by theophylline: a proposed additional mechanism of action for theophylline effects.J Allergy Clin Immunol. 1982; 70: 377-382Abstract Full Text PDF PubMed Scopus (75) Google Scholar Theophylline has been shown to cause a statistically significant increase in epinephrine levels in healthy nonasthmatic subjects.27Higbee MD Kumar M Galant SP Stimulation of endogenous catecholamine release by theophylline: a proposed additional mechanism of action for theophylline effects.J Allergy Clin Immunol. 1982; 70: 377-382Abstract Full Text PDF PubMed Scopus (75) Google Scholar A similar response is observed in children with asthma who are treated with intravenously administered aminophylline,28Ishizaki T Minegishi A Morishita M Odajima Y Kanagawa S Nagai T et al.Plasma catecholamine concentrations during a 72-hour aminophylline infusion in children with acute asthma.J Allergy Clin Immunol. 1988; 82: 146-154Abstract Full Text PDF PubMed Scopus (7) Google Scholar an indication that, at least in the acute phase, theophylline could produce bronchodilation through epinephrine release and stimulation of adenyl cyclase.28Ishizaki T Minegishi A Morishita M Odajima Y Kanagawa S Nagai T et al.Plasma catecholamine concentrations during a 72-hour aminophylline infusion in children with acute asthma.J Allergy Clin Immunol. 1988; 82: 146-154Abstract Full Text PDF PubMed Scopus (7) Google Scholar, 29Krzanowski JJ Poison JB Mechanism of action of methylxanthines in asthma.J Allergy Clin Immunol. 1988; 82: 143-145Abstract Full Text PDF PubMed Scopus (8) Google Scholar The increase in cAMP production from epinephrine release and the decrease in cAMP breakdown from PDE inhibition may result in a synergistic effect.30Nielson CP Crowley JJ Cusack BJ Vestal RE Therapeutic concentrations of theophylline and enprofylline potentiate catecholamine effects and inhibit leukocyte activation.J Allergy Clin Immunol. 1986; 78: 660-667Abstract Full Text PDF PubMed Scopus (29) Google Scholar Theophylline has the ability to increase diaphragm muscle contractility, an effect thought to be due to altered calcium fluxes in muscle cells.31Kolbeck RC Speir WA Diltiazem, verapamil, and nifedipine inhibit theophylline-enhanced diaphragmatic contractility.Am Rev Respir Dis. 1989; 139: 139-145Crossref PubMed Scopus (18) Google Scholar This effect is inhibited by calcium channel blockers and by the removal of extracellular calcium, an indication that theophylline produces this effect through alteration of transmembrane calcium flux.31Kolbeck RC Speir WA Diltiazem, verapamil, and nifedipine inhibit theophylline-enhanced diaphragmatic contractility.Am Rev Respir Dis. 1989; 139: 139-145Crossref PubMed Scopus (18) Google Scholar In the foreshortened diaphragm (70% of optimal length), however, the addition of the calcium blocker verapamil did not affect theophylline-induced twitch potential, whereas the addition of ryanodine, which blocks calcium release from the sarcoplasmic reticulum, inhibited theophyllineinduced increase in twitch potential.32Gayan-Ramirez G Janssens S Himpens B Decramer M Mechanism of theophylline-induced inotropic effects on foreshortened canine diaphragm.Eur Respir J. 1995; 8: 1915-1921Crossref PubMed Scopus (7) Google Scholar The data on the effect on calcium channels are difficult to interpret, but theophylline seems to act at a cellular level on muscle cells through alterations in the calcium environment, an outcome that results in increased force of contractility of some muscle groups like the diaphragm. In the past decade, several studies have demonstrated effects of theophylline on immune function that may be relevant in the treatment of asthma. The anti-inflammatory effects are thought to be partly due to inhibition of PDEs9Banner KH Page CP Anti-inflammatory effects of theophylline and selective phosphodiesterase inhibitors.Clin Exp Allergy. 1996; 26: 2-9Crossref PubMed Google Scholar, 10Schudt C Tenor H Hatzelmann A PDE isoenzymes as targets for anti-asthma drugs.Eur Respir J. 1995; 8: 1179-1183Crossref PubMed Scopus (125) Google Scholar, 33Hatzelmann A Tenor H Schudt C Differential effects of non-selective and selective phosphodiesterase inhibitors on human eo-sinophil functions.Br J Pharmacol. 1995; 114: 821-831Crossref PubMed Scopus (98) Google Scholar, 34Bousquet J Chanez P Lacoste JY Barnéon G Ghavanian N Enander I et al.Eosinophilic inflammation in asthma.N Engt J Med. 1990; 323: 1033-1039Crossref PubMed Scopus (2098) Google Scholar and probably through other mechanisms that are not yet clearly defined. Theophylline exerts several effects on the eosinophil, a cell that has a pivotal role in the pathophysiology of asthma.35Frigas E Gleich GJ The eosinophil and the pathophysiology of asthma.J Allergy Clin Immunol. 1986; 77: 527-537Abstract Full Text PDF PubMed Scopus (477) Google Scholar, 36Gleich GJ The eosinophil and bronchial asthma: current understanding.J Allergy Clin Immunol. 1990; 85: 422-436Abstract Full Text PDF PubMed Scopus (583) Google Scholar Interleukin (IL)-5-induced prolongation of eosinophil survival is inhibited in vitro by clinically relevant levels of theophylline, albeit somewhat high at 18 μg/mL.37Ohta K Sawamoto S Nakajima M Kubota S Tanaka Y Mlyasaka T et al.The prolonged survival of human eosinophils with interleukin-5 and its inhibition by theophylline via apoptosis.Clin Exp Allergy. 1996; 26: 10-15Crossref PubMed Google Scholar Possibly, theophylline achieves this effect by inducing apoptosis in IL-5-stimulated eosinophils.37Ohta K Sawamoto S Nakajima M Kubota S Tanaka Y Mlyasaka T et al.The prolonged survival of human eosinophils with interleukin-5 and its inhibition by theophylline via apoptosis.Clin Exp Allergy. 1996; 26: 10-15Crossref PubMed Google Scholar Suppression of platelet activating factor-induced up-regulation of the adhesion molecule Mac-1 on eosinophils has also been demonstrated,38Sagara H Fukuda T Okada T Ishikawa A Makino S Theophylline at therapeutic concentration suppresses PAF-induced upregulation of Mac-1 on human eosinophils.Clin Exp Allergy. 1996; 26: 16-21Crossref PubMed Google Scholar and this may have the effect of reducing eosinophil migration into the bronchial mucosa. Antigen-induced eosinophil infiltration is decreased in the airways of patients treated with low doses of theophylline.39Sullivan P Bekir S Jaffar Z Page C Jeffery P Costello J Anti-inflammatory effects of low-dose oral theophylline in atopic asthma [published errata appears in Lancet 1994;343:1512].Lancet. 1994; 343: 1006-1008Abstract PubMed Scopus (370) Google Scholar Data suggest that theophylline at therapeutic concentrations impairs the release of eosinophil cationic protein and eosinophil-derived neurotoxin, which are thought to contribute to the damage observed in the epithelial lining of the airways of patients with asthma.33Hatzelmann A Tenor H Schudt C Differential effects of non-selective and selective phosphodiesterase inhibitors on human eo-sinophil functions.Br J Pharmacol. 1995; 114: 821-831Crossref PubMed Scopus (98) Google Scholar, 35Frigas E Gleich GJ The eosinophil and the pathophysiology of asthma.J Allergy Clin Immunol. 1986; 77: 527-537Abstract Full Text PDF PubMed Scopus (477) Google Scholar, 40Kita H Abu-Ghazaleh RI Gleich GJ Abraham RT Regulation of Ig-induced eosinophil degranulation by adenosine 3′,5′-cyclic mono-phosphate.J Immunol. 1991; 146: 2712-2718PubMed Google Scholar Of note, Hatzelmann and associates33Hatzelmann A Tenor H Schudt C Differential effects of non-selective and selective phosphodiesterase inhibitors on human eo-sinophil functions.Br J Pharmacol. 1995; 114: 821-831Crossref PubMed Scopus (98) Google Scholar showed that, whereas theophylline inhibits complement component C5a-stimulated human eosinophil granule release, this effect was not reproduced with selective PDE type IV inhibitors like rolipram (type IV PDE is the predominant isoenzyme in eosinophils).33Hatzelmann A Tenor H Schudt C Differential effects of non-selective and selective phosphodiesterase inhibitors on human eo-sinophil functions.Br J Pharmacol. 1995; 114: 821-831Crossref PubMed Scopus (98) Google Scholar This implies that PDE inhibition is not the only reason for some of the effects of theophylline on eosinophil function. Theophylline has several effects on T-lymphocyte function. Reduced T-cell proliferation after antigenic41Scordamaglia A Ciprandi G Ruffoni S Caria M Paolferi F Venuti D et al.Theophylline and the immune response: in vitro and in vivo effects.Clin Immunol Immunopathol. 1988; 48: 238-246Crossref PubMed Scopus (47) Google Scholar and mitogenic42Bruserud O The effect of theophyllamine on T-lymphocyte activation in vitro.Clin Immunol Immunopathol. 1984; 32: 111-118Crossref PubMed Scopus (24) Google Scholar stimulation as well as diminished E-rosette formation43Limatibul S Shore A Dosch HM Gelfand EW Theophylline modulation of E-rosette formation: an indicator of T-cell maturation.Clin Exp Immunol. 1978; 33: 503-513PubMed Google Scholar have been demonstrated. Phytohemagglutininstimulated IL-2 production and IL-2-dependent proliferation of T lymphocytes are diminished by theophylline in vitro.42Bruserud O The effect of theophyllamine on T-lymphocyte activation in vitro.Clin Immunol Immunopathol. 1984; 32: 111-118Crossref PubMed Scopus (24) Google Scholar, 44Mary D Aussei C Ferrua B Fehlmann M Regulation of interleukin 2 synthesis by cAMP in human T cells.J Immunol. 1987; 139: 1179-1184PubMed Google Scholar Long-term theophylline therapy in patients with asthma increases the number of CD8+ or suppressor T cells in the peripheral blood and also impairs the graft-versushost reaction of these lymphocytes.41Scordamaglia A Ciprandi G Ruffoni S Caria M Paolferi F Venuti D et al.Theophylline and the immune response: in vitro and in vivo effects.Clin Immunol Immunopathol. 1988; 48: 238-246Crossref PubMed Scopus (47) Google Scholar, 45Fink G Mittelman M Shohat B Spitzer SA Theophylline-induced alterations in cellular immunity in asthmatic patients.Clin Allergy. 1987; 17: 313-316Crossref PubMed Scopus (29) Google Scholar Theophylline also acts as an anti-inflammatory drug through modulation of cytokine production. 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Although the use of theophylline in the management of asthma is common worldwide, its use in the United States is declining. The narrow therapeutic index fo
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