American Journal of Respiratory and Critical Care Medicine

Theophylline has been used in the treatment of asthma and chronic obstructive pulmonary disease (COPD) for over 60 years and remains one of the most widely prescribed drugs for the treatment of airway diseases worldwide as it is inexpensive. In many industrialized countries, however, theophylline has recently become a third-line treatment that is only used in some poorly controlled patients. This has been reinforced by various guidelines to therapy. It has even been suggested that theophylline is not indicated in any patients with asthma (1). The frequency of side effects and the relatively low efficacy of theophylline have recently led to reduced usage because inhaled β2-agonists are far more effective as bronchodilators and inhaled corticosteroids have a greater antiinflammatory effect. Despite the long history of theophylline in asthma therapy, there has been considerable uncertainty about its mode of action in the management of airway diseases and its logical place in therapy. Because of problems with side effects, there have been attempts to improve on theophylline, and recently there has been increasing interest in the development of selective phosphodiesterase (PDE) inhibitors (2). Selective PDE4 inhibitors have the possibility of improving the beneficial and reducing the adverse effects of theophylline, although existing inhibitors appear to be limited by the same side effects as theophylline (2).

According to recent international guidelines, theophylline has been relegated to third-line therapy in asthma (Global Initiative for Asthma Guidelines 2002) (3) and COPD (Global Initiative in Chronic Obstructive Lung Disease 2001) (4).


The Global Initiative for Asthma Guidelines 2002 guidelines for asthma recommend that theophylline can be used as an add-on therapy to patients not controlled by low doses of inhaled corticosteroids but recommend long-acting β2-agonists as more effective and with fewer adverse effects (5). Several clinical studies have demonstrated that adding theophylline to inhaled corticosteroids in patients with mild to moderate asthma who are not controlled gives equivalent or better asthma control than doubling the dose of inhaled corticosteroids (68). Studies have also documented steroid-sparing effects of theophylline (9). Slow-release theophylline is useful in the management of nocturnal asthma but has now been largely superceded by long-acting inhaled β2-agonists. Nevertheless, theophylline is still useful in the management of patients with severe asthma. Its benefits have been demonstrated by clinical improvement after addition of theophylline in patients not controlled even on high doses of inhaled corticosteroids (10) and by the worsening of asthma when theophylline is withdrawn, despite the continued use of high doses of inhaled and even oral corticosteroids (11, 12).

Theophylline has also been used as a controller in the management of mild persistent asthma (13), although it is usually found to be less effective than low doses of inhaled corticosteroids (14, 15). Theophylline is currently a less preferred option than inhaled corticosteroids recommended as a second-line choice of controller in management of patients with asthma at Step 2 of the Global Initiative for Asthma Guidelines 2002 guidelines. Although long-acting inhaled β2-agonists are more effective as an add-on therapy at Steps 3 and 4 of the Global Initiative for Asthma Guidelines 2002 guidelines, theophylline is considerably less expensive and may be the only affordable add-on treatment when the costs of medication are limiting.

In the management of acute severe asthma, intravenous aminophylline has been superceded by the use of high doses of short-acting β2-agonists delivered by nebulizer or metered dose inhaler with spacer, as this is more effective and safer. Aminophylline does not appear to confer any additional benefit when added to nebulized β2-agonists (16) and is now usually reserved for the rare patients with severe exacerbations who do not respond adequately to β2-agonist therapy (17).


Theophylline is still used as a bronchodilator in COPD, but inhaled anticholinergics and β2-agonists are preferred (Global Initiative in Chronic Obstructive Lung Disease 2001) (4). Theophylline tends to be added to these inhaled bronchodilators in more patients with more severe COPD and has been shown to give additional clinical improvement when added to a long-acting β2-agonist (18). As in asthma, patients with severe COPD deteriorate when theophylline is withdrawn from their treatment regimen (19). A theoretical advantage of theophylline is that its systemic administration may have effects on small airways, resulting in reduction of hyperinflation and thus a reduction in dyspnea (20).

When theophylline was first introduced into asthma therapy it was used as a bronchodilator, and early dose–response studies showed an increasing acute bronchodilator response above plasma concentrations of 10 mg/L (55 μM). The upper recommended plasma concentration was 20 mg/L due to unacceptable side effects above this level. The therapeutic range for plasma concentrations was therefore established at 10 to 20 mg/L, and doses were adjusted in individual patients to achieve this. Theophylline directly relaxes human airways smooth muscle in vitro and, like β2-agonists, acts as a functional antagonist, preventing and reversing the effects of all bronchoconstrictor agonists (21). The molecular mechanism of bronchodilatation is likely explained by PDE inhibition, resulting in an increase in cAMP by inhibition of PDE3 and PDE4 and in cyclic guanosine 3′,5′-monophosphate by inhibition of PDE5 (22). The bronchodilator effect of theophylline in human airways is reduced by charybdotoxin, which selectively inhibits large conductance Ca2+-activated K+ channels (maxi-K channels), suggesting that theophylline opens these maxi-K channels via an increase in cAMP (23). Theophylline is a relatively weak bronchodilator with an effective concentration giving 50% response of 1.5 × 10−4 M in vitro, which equates to a plasma concentration of 67 mg/L, assuming 60% protein binding (24).

Theophylline may also have an additional effect on mucociliary clearance through a stimulatory effect on ciliary beat frequency and water transport across the airway epithelium. However, relatively high doses of theophylline are needed, as this effect is likely to be due to an increase in cAMP as a result of PDE inhibition (25).

It has long been suggested that theophylline may exert its effects in asthma and COPD via an action outside the airways. It may be relevant that theophylline is ineffective when given by inhalation until therapeutic plasma concentrations are achieved (26). This may indicates that theophylline may have some has effects on cells other than those in the airway, although it is likely that systemic administration will also have effects on cells in the airways via the bronchial circulation. The lack of effect of the inhaled drug may reflect a poor pharmacokinetic profile, with lack of retention in the airways.

An effect of theophylline that remains controversial is its action on respiratory muscles. Aminophylline increases diaphragmatic contractility and reverses diaphragm fatigue (27). However, this effect has not been observed by all investigators, and there are doubts about the relevance of these observations to the clinical benefit provided by theophylline in COPD (28).

There is increasing evidence that theophylline has antiinflammatory effects in asthma (29). In allergen challenge studies in patients with asthma intravenous theophylline inhibits the late response to allergen, although having relatively little effect on the early response (30). A similar finding with allergen challenge has been reported after chronic oral treatment with theophylline (31). Oral theophylline also inhibits the late response to toluene diisocyanate in toluene diisocyanate–sensitive individuals with asthma (32). This has been interpreted as an effect on the chronic inflammatory response, and this is supported by a reduced infiltration of eosinophils and CD4+ lymphocytes into the airways after allergen challenge subsequent to low doses of theophylline (33, 34). In patients with nocturnal asthma, low-dose theophylline inhibits the influx of neutrophils and, to a lesser extent, eosinophils in the early morning (35). In patients with mild asthma, low doses of theophylline (mean plasma concentration ∽ 5 mg/L) reduce the numbers of eosinophils in bronchial biopsies, bronchoalveolar lavage, and induced sputum (36), whereas in severe asthma, withdrawal of theophylline results in increased numbers of activated CD4+ cells and eosinophils in bronchial biopsies (12).

In patients with COPD, theophylline reduces the total number and proportion of neutrophils in induced sputum, the concentration of interleukin-8, and neutrophil chemotactic responses, suggesting that it may have an antiinflammatory effect (37). This is in sharp contrast to the lack of effect of high doses of inhaled corticosteroids in a similar population of patients (38).

These antiinflammatory effects of theophylline in asthma and COPD are seen at concentrations that are usually less than 10 mg/L, which is below the dose where significant clinically useful bronchodilatation is evident. Until recently it has been difficult to find a molecular mechanism that is significant at these low concentrations.

Although theophylline has been in clinical use for many years, its mechanism of action at a molecular level and its site of action remain uncertain. Although several plausible molecular mechanisms of action have been proposed, most of these appear to occur only with higher concentrations of theophylline than are clinically effective (often > 20 mg/L) (Table 1)

TABLE 1. Proposed mechanisms of action of theophylline

Phosphodiesterase inhibition (nonselective)
Adenosine receptor antagonism (A1-, A2A-, A2B-receptors)
Increased interleukin-10 release
Stimulation of catecholamine (epinephrine) release
Mediator inhibition (prostaglandins, tumor necrosis factor-α)
Inhibition of intracellular calcium release
Inhibition of nuclear factor-κB (↓ nuclear translocation)
Increased apoptosis
↑ Histone deacetylase activity (↑ efficacy of corticosteroids)
. Although these proposed mechanisms might contribute to the antiinflammatory actions of theophylline at low plasma concentrations, based on the absence or trivial effects of theophylline on these mechanisms at concentrations less than 10 mg/L this seems unlikely.

PDE Inhibition

Theophylline is a weak and nonselective inhibitor of PDEs, which break down cyclic nucleotides in the cell, thereby leading to an increase in intracellular cAMP and cyclic guanosine 3′,5′-monophosphate concentrations. There is convincing in vitro evidence that theophylline relaxes airway smooth muscle by inhibition of PDE activity (PDE3, PDE4, and PDE5), but relatively high concentrations are needed for maximal relaxation (22). The degree of PDE inhibition is very small at concentrations of theophylline that are therapeutically relevant. Thus, total PDE activity in human lung extracts are inhibited by only 5 to 10% by therapeutic concentrations of theophylline (39). There is no evidence that theophylline has any selectivity for any particular isoenzyme, such as PDE4, which is the predominant PDE isoenzyme in inflammatory cells that mediates antiinflammatory effects in the airways. PDE inhibition may be important for the common side effects of theophylline, such as nausea and headaches, as plasma concentration increases.

Adenosine Receptor Antagonism

Theophylline is a potent inhibitor of adenosine receptors at therapeutic concentrations, with antagonism of A1- and A2-receptors, although it is less effective against A3-receptors (40). Although adenosine has little effect on normal human airway smooth muscle in vitro, it constricts airways of patients with asthma via the release of histamine and leukotrienes, suggesting that adenosine releases mediators from sensitized mast cells (41). The receptor involved appears to be an A2b-receptor in humans (although an A3-receptor subserves a similar role in rats) (42). Inhaled adenosine monophosphate causes bronchoconstriction in subjects with asthma, and this is prevented by therapeutic concentrations of theophylline (43). This only confirms that theophylline at therapeutic concentrations is capable of antagonizing the effects of adenosine, and this does not necessarily prove that adenosine receptor antagonism is important for its antiasthma effect. However, adenosine antagonism is likely to account for some of the serious side effects of theophylline, such as seizures and cardiac arrhythmias. One report indicates that theophylline may inhibit eosinophils by activating (rather than blocking) A3-receptors, but this is seen only at high concentrations that are not therapeutically relevant (44).

Interleukin-10 Release

Interleukin-10 has a broad spectrum of antiinflammatory effects, and there is evidence that its secretion is reduced in asthma (45). Interleukin-10 release is increased by theophylline and this effect may be mediated via PDE inhibition (46), although this has not been seen at the low doses that are effective in asthma (47).

Effect on Transcription

Theophylline prevents the translocation of the proinflammatory transcription factor nuclear factor-κB into the nucleus, thus potentially reducing the expression of inflammatory genes in asthma and COPD (48). Inhibition of nuclear factor-κB appears to be due to a protective effect against the degradation of the inhibitory protein I-κBα, so that nuclear translocation of activated nuclear factor-κB is prevented (49). However, these effects are seen at high concentrations and may be mediated by inhibition of PDE.

Effects on Apoptosis

Prolonged survival of granulocytes due to a reduction in apoptosis may be important in perpetuating chronic inflammation in asthma (eosinophils) and COPD (neutrophils). Theophylline promoted inhibition of apoptosis in eosinophils and neutrophils in vitro (50). This is associated with a reduction in the antiapoptotic protein Bcl-2 (51). This effect is not mediated via PDE inhibition but in neutrophils may be mediated by antagonism of adenosine A2A-receptors (52). Theophylline also induces apoptosis of T-lymphocytes, thus reducing their survival, and this effect appears to be mediated via PDE inhibition (53).

Other Effects

Several other effects of theophylline have been described, including an increase in circulating catecholamines, inhibition of calcium influx into inflammatory cells, inhibition of prostaglandin effects, and antagonism of tumor necrosis factor-α. These effects are generally seen only at high concentrations of theophylline that are above the therapeutic range in asthma and are therefore unlikely to contribute to the antiinflammatory actions of theophylline.

Despite intense efforts, it has been difficult to find any molecular mechanisms that can account for the antiinflammatory effects of theophylline in asthma and COPD. Although several potential mechanisms have been demonstrated in vitro, there is little evidence that these occur at plasma concentrations of 5 to 10 mg/L where clinical benefit is seen. Recently a novel mechanism of action has been described that, in contrast to the proposed molecular mechanisms discussed previously, is seen at therapeutically relevant concentrations.

Acetylation of core histones is associated with activation and transcription of inflammatory genes and is regulated by coactivator molecules that have intrinsic histone acetytransferase activity (54). Proinflammatory transcription factors, such as nuclear factor-κB and activator protein-1, bind to coactivator molecules and activate this enzyme. In asthmatic airways there is an increase in nuclear factor-κB activation and an increase in histone acetyltransferase activity (55, 56). Histone acetylation is reversed by histone deacetylases (HDAC), and there is a reduction in HDAC activity in asthmatic airways and in COPD (5658). Corticosteroids suppress the expression of inflammatory genes by binding to and activating glucocorticoid receptors that recruit HDAC to the transcription complex of inflammatory genes that is activated, thereby reversing histone acetylation and silencing genes that have been activated by inflammatory stimuli (59). Treatment of patients with asthma with inhaled corticosteroids reduces histone acetyltransferase and increases HDAC activity, restoring the balance to normal (56).

Theophylline activates HDAC activity and therefore suppresses the expression of inflammatory genes (60) (Figure 1)

. This effect is seen at therapeutic concentrations of theophylline (10−6–10−5 M) but is lost at higher concentrations (10−4 M). The effect is blocked by the HDAC inhibitor trichostatin A. A significant increase in HDAC activity is seen in bronchial biopsies after treatment of patients with asthma with low doses of theophylline (mean plasma concentration ∼ 5 mg/L). The effect is different from that of corticosteroids, as there appears to be a relatively direct activation of HDAC because the effect of theophylline is observed in immunoprecipitated inflammatory gene complexes immunoprecipitated from nuclear extracts by antibodies to HDAC2. It is not yet certain whether HDAC are the direct target of theophylline as several other nuclear proteins are coprecipitated in these inflammatory gene complexes (59). By contrast, the effects of corticosteroids are due to recruitment of HDAC to the active transcription site, and there is no direct effect on HDAC activation. The mechanism whereby low concentrations of theophylline activate HDAC are not yet known, but it is not mediated by either PDE inhibition or adenosine receptor antagonism because PDE inhibitors (nonselective, PDE4 and PDE3 inhibitors) and adenosine A1- and A2-receptor antagonists do not mimic this action of theophylline.

HDAC are not effective in switching off inflammatory genes unless recruited to the active inflammatory site by activated glucocorticoid receptors. This novel action of theophylline predicts that theophylline alone would have a relatively weak antiinflammatory action, whereas there should be potentiation of the antiinflammatory actions of corticosteroids. Low concentrations of theophylline markedly potentiate the antiinflammatory effects of corticosteroids in vitro, with a potentiation of 100-fold to 1,000-fold (60), and this may underlie the benefit of low-dose theophylline added to low or high doses of inhaled corticosteroids seen in clinical studies of patients with asthma (6, 7, 36). Oxidative stress reduces HDAC activity and that this may account for the resistance to the antiinflammatory actions of corticosteroids seen in patients with COPD (57, 58). Theophylline, through direct activation of HDAC is able to reverse the effect of oxidative stress and cigarette smoke and thus restore corticosteroid responsiveness (61). This suggests that theophylline may “unlock” the resistance to corticosteroids that is seen in patients with COPD and in severe asthma, where impaired responsiveness to corticosteroids therapy is also seen.

Despite its clinical benefit in obstructive airway disease, the main limitation to the use of theophylline is the frequency of adverse effects (62). Unwanted effects of theophylline are usually related to plasma concentration and tend to occur when plasma levels exceed 20 mg/L. To some extent side effects may be reduced by gradually increasing the dose until therapeutic concentrations are achieved. Several factors affect the metabolism of theophylline, which is metabolized in the liver by CYP1A2 (63). Thus drugs that inhibit CYP1A2, such as macrolide and quinolone antibiotics, cimetidine and fluvoxamine, may increase plasma theophylline concentrations to levels that produce side effects. The commonest side effects are headache, nausea and vomiting, abdominal discomfort, and restlessness. There may also be increased acid secretion, gastroesophageal reflux, and diuresis. At high concentrations, convulsions, cardiac arrhythmias, and death may occur.

Some of the side effects of theophylline (central stimulation, gastric secretion, diuresis, and arrhythmias) may be due to adenosine receptor (predominantly A1-receptor) antagonism, and these may therefore be avoided by selective PDE inhibitors. However, the commonest side effects of theophylline are nausea and headaches, which may be due to inhibition of certain PDEs (e.g., PDE4 in the vomiting center) (64). When theophylline was used as a bronchodilator at doses that give plasma concentrations of 10 to 20 mg/L, side effects due to PDE inhibition and adenosine antagonism are relatively common.

Use of low doses of theophylline that give plasma concentrations of 5 to 10 mg/L largely avoids side effects and drug interactions and makes it unnecessary to monitor plasma concentrations (unless checking for compliance).

Although theophylline has recently been used much less in developed countries, there are reasons for believing that it may come back in to fashion for the treatment of chronic asthma, with the recognition that it may have an antiinflammatory and immunomodulatory effect when given in low doses (plasma concentration, 5–10 mg/L) (29). At these low doses the drug is easier to use, side effects are uncommon, and the problems of drug interaction are less of an issue, thus making the clinical use of theophylline less complicated. Theophylline appears to have an effect that is different from those of corticosteroids, and it may therefore be a useful drug to combine with low-dose inhaled steroids. In addition, its low cost makes low-dose theophylline in combination with a generic inhaled corticosteroid the most cost effective way to manage persistent asthma in developing countries.

Now that the molecular mechanisms for the antiinflammatory effects of theophylline are better understood and elucidated, there is a strong scientific rationale for combining low-dose theophylline with inhaled enhanced corticosteroids, particularly in patients with more severe asthma. The synergistic effect of low-dose theophylline and corticosteroids on inflammatory gene expression may account for the add-on benefits of theophylline in asthma. The marked potentiation of the antiinflammatory actions of corticosteroids in asthma may result in the use of lower doses of inhaled corticosteroids or even combined therapy with low-dose theophylline and a low dose of oral corticosteroids that does not have significant systemic side effects. The molecular mechanisms of theophylline on HDAC activity discussed here predict that, although the antiinflammatory effects of corticosteroids mediated through HDAC recruitment may be enhanced by theophylline, the side effects that are largely mediated by gene induction are likely to be avoided, thus increasing the therapeutic ratio of corticosteroids.

In COPD, low-dose theophylline is the first drug to demonstrate clear antiinflammatory effects, and thus it may even have a role in preventing progression of the disease. Furthermore, the reversal of the steroid resistance induced by oxidative stress suggests that theophylline may increase responsiveness to corticosteroids. This may mean that theophylline could “unlock” steroid resistance that is characteristic of COPD and allow corticosteroids to suppress the chronic inflammation. Clinical trials to explore the interactions of theophylline and corticosteroids, both in asthma and in COPD are now needed and these could lead to changes in the way theophylline is used in the future in clinical practice underway.

New Drugs

Now that an important mechanism of action of theophylline activate is established as HDAC activation, and that this is independent of the probable molecular mechanisms for the major of side effects (PDE inhibition and adenosine receptor blockade), so there is now the potential for designing novel theophylline-like molecules that are free of these side effects that have previously limited clinical doses. There may also be novel structures that mimic the effect of theophylline that could be discovered by high throughput screening and using HDAC activation as a readout. This could lead to the development of new oral antiinflammatory drugs that may be used alone or in combination with corticosteroids in the treatment of asthma and COPD. In COPD, these novel drugs have the potential for unlocking the steroid resistance that limits the clinical useful ness of corticosteroids in this disease. These drugs also may also have a place in the management of other chronic inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease, and even atherosclerosis that require systemic antiinflammatory treatments.

Dr. Barnes has received research funding from GlaxoSmithKline, AstraZeneca, Novartis, Millenium, Scios, and Aerocrine. He serves as a consultant to GlaxoSmithKline, and serves on Scientific Advisory Boards for the pharmaceutical companies listed above, and also Altana, Aventis, Epigenesis, Genaissance, and EirX.

1. Lam A, Newhouse MT. Management of asthma and chronic airflow limitation: are methylxanthines obsolete? Chest 1990;98:44–52.
2. 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.
3. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. NHLBI/WHO Workshop Report; 2002. NIH Publication 02-3659.
4. Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med 2001;163:1256–1276.
5. Wilson AJ, Gibson PG, Coughlan J. Long acting beta-agonists versus theophylline for maintenance treatment of asthma. Cochrane Database Syst Rev 2000; CD001281.
6. Evans DJ, Taylor DA, Zetterstrom O, Chung KF, O'Connor BJ, Barnes PJ. A comparison of low-dose inhaled budesonide plus theophylline and high-dose inhaled budesonide for moderate asthma. N Engl J Med 1997;337:1412–1418.
7. Ukena D, Harnest U, Sakalauskas R, Magyar P, Vetter N, Steffen H, Leichtl S, Rathgeb F, Keller A, Steinijans VW. Comparison of addition of theophylline to inhaled steroid with doubling of the dose of inhaled steroid in asthma. Eur Respir J 1997;10:2754–2760.
8. Lim S, Jatakanon A, Gordon D, Macdonald C, Chung KF, Barnes PJ. 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 2000;55:837–841.
9. Markham A, Faulds D. Theophylline: a review of its potential steroid sparing effects in asthma. Drugs 1998;56:1081–1091.
10. Rivington RN, Boulet LP, Cote J, Kreisman H, Small DI, Alexander M, Day A, Harsanyi Z, Darke AC. Efficacy of slow-release theophylline, inhaled salbutamol and their combination in asthmatic patients on high-dose inhaled steroids. Am J Respir Crit Care Med 1995;151:325–332.
11. Brenner MR, Berkowitz R, Marshall N, Strunk RC. Need for theophylline in severe steroid-requiring asthmatics. Clin Allergy 1988;18:143–150.
12. Kidney J, Dominguez M, Taylor PM, Rose M, Chung KF, Barnes PJ. Immunomodulation by theophylline in asthma: demonstration by withdrawal of therapy. Am J Respir Crit Care Med 1995;151:1907–1914.
13. Tinkelman DG, Reed CE, Nelson HS, Offord KP. Aerosol beclomethasone diprionate compared with theophylline as primary treatment of chronic, mild to moderately severe asthma in children. Pediatrics 1993;92:64–77.
14. Reed CE, Offord KP, Nelson HS, Li JT, Tinkelman DG. Aerosol beclomethasone dipropionate spray compared with theophylline as primary treatment for chronic mild-to-moderate asthma: The American Academy of Allergy, Asthma and Immunology Beclomethasone Dipropionate-Theophylline Study Group. J Allergy Clin Immunol 1998;101:14–23.
15. Dahl R, Larsen BB, Venge P. Effect of long-term treatment with inhaled budesonide or theophylline on lung function, airway reactivity and asthma symptoms. Respir Med 2002;96:432–438.
16. Littenberg B. Aminophylline treatment in severe acute asthma: a metaanalysis. JAMA 1988;259:1678–1689.
17. Parameswaran K, Belda J, Rowe BH. Addition of intravenous aminophylline to beta2-agonists in adults with acute asthma. Cochrane Database Syst Rev 2000; CD002742
18. ZuWallack RL, Mahler DA, Reilly D, Church N, Emmett A, Rickard K, Knobil K. Salmeterol plus theophylline combination therapy in the treatment of COPD. Chest 2001;119:1661–1670.
19. Kirsten DK, Wegner RE, Jorres RA, Magnussen H. Effects of theophylline withdrawal in severe chronic obstructive pulmonary disease. Chest 1993;104:1101–1107.
20. Chrystyn H, Mulley BA, Peake MD. Dose response relation to oral theophylline in severe chronic obstructive airway disease. BMJ 1988;297:1506–1510.
21. Finney MJB, Karlson JA, Persson CGA. Effects of bronchoconstriction and bronchodilation on a novel human small airway preparation. Br J Pharmacol 1985;85:29–36.
22. Rabe KF, Magnussen H, Dent G. Theophylline and selective PDE inhibitors as bronchodilators and smooth muscle relaxants. Eur Respir J 1995;8:637–642.
23. Miura M, Belvisi MG, Stretton CD, Yacoub MH, Barnes PJ. Role of potassium channels in bronchodilator responses in human airways. Am Rev Respir Dis 1992;146:132–136.
24. Guillot C, Fornaris M, Badger M, Orehek J. Spontaneous and provoked resistance to isoproterenol in isolated human bronchi. J Allergy Clin Immunol 1984;74:713–718.
25. Wanner A. Effects of methylxanthines on airway mucociliary function. Am J Med 1985;79:16–21.
26. Cushley MJ, Holgate ST. Bronchodilator actions of xanthine derivatives administered by inhalation in asthma. Thorax 1985;40:176–179.
27. Aubier M, De Troyer A, Sampson M, Macklem PT, Roussos Ch. Aminophylline improves diaphragmatic contractility. N Engl J Med 1981;305:249–252.
28. Moxham J. Aminophylline and the respiratory muscles: an alternative view. Clin Chest Med 1988;9:325–340.
29. Barnes PJ, Pauwels RA. Theophylline in asthma: time for reappraisal? Eur Respir J 1994;7:579–591.
30. Pauwels R, van Revterghem D, van der Straeten M, Johanesson N, Persson CGA. The effect of theophylline and enprophylline on allergen-induced bronchoconstriction. J Allergy Clin Immunol 1985;76:583–590.
31. Ward AJM, McKenniff M, Evans JM, Page CP, Costello JF. Theophylline: an immunomodulatory role in asthma? Am Rev Respir Dis 1993;147:518–523.
32. Mapp C, Boschetto P, Dal Vecchio L, Crescioli S, De Marzo N, Paleari N, Fabbri LM. Protective effect of antiasthma drugs on late asthmatic reactions and increased airway responsiveness induced by toluene diisocyanate in sensitized subjects. Am Rev Respir Dis 1987;136:1403–1407.
33. 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.
34. Jaffar ZH, Sullivan P, Page C, Costello J. Low-dose theophylline modulates T-lymphocyte activation in allergen-challenged asthmatics. Eur Respir J 1996;9:456–462.
35. Kraft M, Torvik JA, Trudeau JB, Wenzel SE, Martin RJ. Theophylline: potential antiinflammatory effects in nocturnal asthma. J Allergy Clin Immunol 1996;97:1242–1246.
36. Lim S, Tomita K, Carramori G, Jatakanon A, Oliver B, Keller A, Adcock I, Chung KF, Barnes PJ. Low-dose theophylline reduces eosinophilic inflammation but not exhaled nitric oxide in mild asthma. Am J Respir Crit Care Med 2001;164:273–276.
37. Culpitt SV, de Matos C, Russell RE, Donnelly LE, Rogers DF, Barnes PJ. Effect of theophylline on induced sputum inflammatory indices and neutrophil chemotaxis in COPD. Am J Respir Crit Care Med 2002;165:1371–1376.
38. Culpitt SV, Nightingale JA, Barnes PJ. Effect of high dose inhaled steroid on cells, cytokines and proteases in induced sputum in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999;160:1635–1639.
39. Poolson JB, Kazanowski JJ, Goldman AL, Szentivanyi A. Inhibition of human pulmonary phosphodiesterase activity by therapeutic levels of theophylline. Clin Exp Pharmacol Physiol 1978;5:535–539.
40. Pauwels RA, Joos GF. Characterization of the adenosine receptors in the airways. Arch Int Pharmacodyn Ther 1995;329:151–156.
41. Bjorck T, Gustafsson LE, Dahlen SE. Isolated bronchi from asthmatics are hyperresponsive to adenosine, which apparently acts indirectly by liberation of leukotrienes and histamine. Am Rev Respir Dis 1992;145:1087–1091.
42. Feoktistov I, Polosa R, Holgate ST, Biaggioni I. Adenosine A2B receptors: a novel therapeutic target in asthma? Trends Pharmacol Sci 1998;19:148–153.
43. Cushley MJ, Tattersfield AE, Holgate ST. Adenosine-induced bronchoconstriction in asthma: antagonism by inhaled theophylline. Am Rev Respir Dis 1984;129:380–384.
44. Ezeamuzie CI. Involvement of A(3) receptors in the potentiation by adenosine of the inhibitory effect of theophylline on human eosinophil degranulation: possible novel mechanism of the anti-inflammatory action of theophylline. Biochem Pharmacol 2001;61:1551–1559.
45. Barnes PJ. IL-10: a key regulator of allergic disease. Clin Exp Allergy 2001;31:667–669.
46. Mascali JJ, Cvietusa P, Negri J, Borish L. Anti-inflammatory effects of theophylline: modulation of cytokine production. Ann Allergy Asthma Immunol 1996;77:34–38.
47. Oliver B, Tomita K, Keller A, Caramori G, Adcock I, Chung KF, Barnes PJ, Lim S. Low-dose theophylline does not exert its anti-inflammatory effects in mild asthma through upregulation of interleukin-10 in alveolar macrophages. Allergy 2001;56:1087–1090.
48. Tomita K, Chikumi H, Tokuyasu H, Yajima H, Hitsuda Y, Matsumoto Y, Sasaki T. Functional assay of NF-kappaB translocation into nuclei by laser scanning cytometry: inhibitory effect by dexamethasone or theophylline. Naunyn Schmiedebergs Arch Pharmacol 1999;359:249–255.
49. Ichiyama T, Hasegawa S, Matsubara T, Hayashi T, Furukawa S. Theophylline inhibits NF-κB activation and IκBα degradation in human pulmonary epithelial cells. Naunyn Schmiedebergs Arch Pharmacol 2001;364:558–561.
50. Yasui K, Hu B, Nakazawa T, Agematsu K, Komiyama A. Theophylline accelerates human granulocyte apoptosis not via phosphodiesterase inhibition. J Clin Invest 1997;100:1677–1684.
51. Chung IY, Nam-Kung EK, Lee NM, Chang HS, Kim DJ, Kim YH, Park CS. The downregulation of bcl-2 expression is necessary for theophylline-induced apoptosis of eosinophil. Cell Immunol 2000;203:95–102.
52. Yasui K, Agematsu K, Shinozaki K, Hokibara S, Nagumo H, Nakazawa T, Komiyama A. Theophylline induces neutrophil apoptosis through adenosine A2A receptor antagonism. J Leukoc Biol 2000;67:529–535.
53. Ohta K, Yamashita N. Apoptosis of eosinophils and lymphocytes in allergic inflammation. J Allergy Clin Immunol 1999;104:14–21.
54. Urnov FD, Wolffe AP. Chromatin remodeling and transcriptional activation: the cast (in order of appearance). Oncogene 2001;20:2991–3006.
55. Hart LA, Krishnan VL, Adcock IM, Barnes PJ, Chung KF. Activation and localization of transcription factor, nuclear factor-kB, in asthma. Am J Respir Crit Care Med 1998;158:1585–1592.
56. Ito K, Caramori G, Lim S, Oates T, Chung KF, Barnes PJ, Adcock IM. Expression and activity of histone deacetylases (HDACs) in human asthmatic airways. Am J Respir Crit Care Med 2002;166:392–396.
57. Ito K, Watanabe S, Kharitonov S, Hanazawa T, Adcock IM, Barnes PJ. Histone deacetylase activity and gene expression in COPD patients. Eur Respir J 2001;18:316S.
58. Ito K, Lim S, Caramori G, Chung KF, Barnes PJ, Adcock IM. Cigarette smoking reduces histone deacetylase 2 expression, enhances cytokine expression and inhibits glucocorticoid actions in alveolar macrophages. FASEB J 2001;15:1100–1102.
59. Ito K, Barnes PJ, Adcock IM. Glucocorticoid receptor recruitment of histone deacetylase 2 inhibits IL-1β-induced histone H4 acetylation on lysines 8 and 12. Mol Cell Biol 2000;20:6891–6903.
60. Ito K, Lim S, Caramori G, Cosio B, Chung KF, Adcock IM, Barnes PJ. A molecular mechanism of action of theophylline: induction of histone deacetylase activity to decrease inflammatory gene expression. Proc Natl Acad Sci USA 2002;99:8921–8926.
61. Ito K, Lim S, Chung KF, Barnes PJ, Adcock IM. Theophylline enhances histone deacetylase activity and restores glucocorticoid function during oxidative stress [abstract]. Am J Respir Crit Care Med 2002;165:A625.
62. Barnes PJ. Current therapies for asthma: promise and limitations. Chest 1997;111:17S–22S.
63. Zhang ZY, Kaminsky LS. Characterization of human cytochromes P450 involved in theophylline 8-hydroxylation. Biochem Pharmacol 1995;50:205–211.
64. Howell RE, Muehsam WT, Kinnier WJ. Mechanism for the emetic side effect of xanthine bronchodilators. Life Sci 1990;46:563–568.
Correspondence and requests for reprints should be addressed to P. J. Barnes, D.M., Department of Thoracic Medicine, National Heart and Lung Institute, Imperial College, Dovehouse Street, London SW3 6LY, UK. E-mail:


No related items
American Journal of Respiratory and Critical Care Medicine

Click to see any corrections or updates and to confirm this is the authentic version of record