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Theophylline in Chronic Obstructive Pulmonary Disease

New Horizons

Department of Thoracic Medicine, National Heart and Lung Institute, London, United Kingdom

Correspondence and requests for reprints should be addressed to P. J. Barnes, M.A., D.M., D.Sc., F.R.C.P., Department of Thoracic Medicine, National Heart and Lung Institute, Imperial College, Dovehouse Street, London SW3 6LY, UK. E-mail: p.j.barnes{at}imperial.ac.uk

	ABSTRACT

TOP ABSTRACT CURRENT USE OF THEOPHYLLINE... BRONCHODILATOR ACTION ANTIINFLAMMATORY EFFECTS MOLECULAR MECHANISMS AT HIGHER... MOLECULAR MECHANISM AT... INTERACTION WITH STEROIDS SIDE EFFECTS FUTURE DEVELOPMENTS REFERENCES

 
Although theophylline has side effects when used in bronchodilator doses, increasing evidence shows that it has significant antiinflammatory effects in chronic obstructive pulmonary disease at lower plasma concentrations. These antiinflammatory effects are unlikely to be accounted for by phosphodiesterase inhibition or adenosine receptor antagonism, which require higher concentrations. There is now evidence that theophylline at low therapeutic concentrations is an activator of histone deacetylases and that this activation enhances the antiinflammatory effect of corticosteroids. There appears to be a marked reduction in histone deacetylase-2 in macrophages and peripheral lung of patients with chronic obstructive pulmonary disease, which accounts for amplified inflammation and steroid resistance. Theophylline has been shown to restore steroid sensitivity in vitro. The effect of theophylline on histone deacetylase activity appears to be enhanced by oxidative stress. The mechanism whereby theophylline activates histone deacetylase is not yet known, but it does not involve other known actions of theophylline that account for its side effects. Better understanding of the molecular basis for the action of theophylline might lead to the development of novel drugs.

Key Words: alveolar macrophage • histone acetylation • histone deacetylase • oxidative stress • phosphodiesterase

Theophylline has been used in the treatment of chronic obstructive airway diseases, including chronic obstructive pulmonary disease (COPD), for more than 70 years. It is still widely prescribed worldwide, because it is inexpensive. In many industrialized countries, the frequency of side effects and the relatively low efficacy of theophylline have led to reduced usage, because inhaled ß₂-agonists are far more effective as bronchodilators and, in asthma, inhaled corticosteroids have a greater antiinflammatory effect. There has been considerable uncertainty about the mode of action of theophylline in the management of airway diseases and its logical place in therapy. Because of the problems with side effects, there have been attempts to improve on theophylline, and there has been increasing interest in the development of selective phosphodiesterase (PDE) inhibitors. Selective PDE4 inhibitors have the potential to improve the beneficial effects of theophylline and reduce its adverse effects, although existing inhibitors appear to be limited by the same side effects as theophylline (1).

	CURRENT USE OF THEOPHYLLINE IN COPD

TOP ABSTRACT CURRENT USE OF THEOPHYLLINE... BRONCHODILATOR ACTION ANTIINFLAMMATORY EFFECTS MOLECULAR MECHANISMS AT HIGHER... MOLECULAR MECHANISM AT... INTERACTION WITH STEROIDS SIDE EFFECTS FUTURE DEVELOPMENTS REFERENCES

 
In international guidelines, theophylline has been relegated to third-line therapy in COPD (2). Theophylline is still used as a bronchodilator, but inhaled anticholinergics and ß₂-agonists are preferred therapy (3, 4). Theophylline tends to be added to these inhaled bronchodilators for patients with more severe disease and has been shown to give additional clinical improvement when added to a long-acting ß₂-agonist (5). As in asthma, patients with severe COPD deteriorate when theophylline is withdrawn from their treatment regimen (6). 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 (7). It does not appear to be of value in treatment of acute exacerbations of COPD, however (8).

	BRONCHODILATOR ACTION

TOP ABSTRACT CURRENT USE OF THEOPHYLLINE... BRONCHODILATOR ACTION ANTIINFLAMMATORY EFFECTS MOLECULAR MECHANISMS AT HIGHER... MOLECULAR MECHANISM AT... INTERACTION WITH STEROIDS SIDE EFFECTS FUTURE DEVELOPMENTS REFERENCES

 
When theophylline was 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 set at 20 mg/L because of 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 airway smooth muscle in vitro and, like ß₂-agonists, acts as a functional antagonist, preventing and reversing the effects of all bronchoconstrictor agonists (9). The molecular mechanism of bronchodilatation is likely explained by PDE inhibition, resulting in an increase in cyclic adenosine 3',5'-monophosphate (cAMP) by inhibition of PDE3 and PDE4 and an increase in cyclic guanosine 3',5'-monophosphate (cGMP) by inhibition of PDE5 (10). 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 (11). Theophylline is a relatively weak bronchodilator with a median effective concentration of 1.5 x 10^–4 M in vitro, which equates to a plasma concentration of 67 mg/L, assuming 60% protein binding (12, 13).

	ANTIINFLAMMATORY EFFECTS

TOP ABSTRACT CURRENT USE OF THEOPHYLLINE... BRONCHODILATOR ACTION ANTIINFLAMMATORY EFFECTS MOLECULAR MECHANISMS AT HIGHER... MOLECULAR MECHANISM AT... INTERACTION WITH STEROIDS SIDE EFFECTS FUTURE DEVELOPMENTS REFERENCES

 
There is increasing evidence that theophylline has antiinflammatory effects in asthma and COPD (14). In patients with COPD, low doses of theophylline reduce the total number and proportion of neutrophils in induced sputum, the concentration of interleukin (IL)-8, and myeloperoxidase and neutrophil chemotactic responses, suggesting that it may have an antiinflammatory effect (15). In another placebo-controlled study of patients with COPD, a significant reduction in myeloperoxidase and neutrophil elastase occurred after 4 weeks of treatment with theophylline (16). This is in sharp contrast to the lack of effect of high doses of inhaled corticosteroids in a similar population of patients (17–19). The antiinflammatory effects of theophylline are seen at concentrations less than 10 mg/L, which is below the dose at which significant clinically useful bronchodilatation is evident.

	MOLECULAR MECHANISMS AT HIGHER DOSES

TOP ABSTRACT CURRENT USE OF THEOPHYLLINE... BRONCHODILATOR ACTION ANTIINFLAMMATORY EFFECTS MOLECULAR MECHANISMS AT HIGHER... MOLECULAR MECHANISM AT... INTERACTION WITH STEROIDS SIDE EFFECTS FUTURE DEVELOPMENTS REFERENCES

 
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 (13). Although several plausible molecular mechanisms of action have been proposed, most appear to occur only with higher concentrations of theophylline than are clinically effective (often more than 20 mg/L) (Table 1). There is little evidence that these mechanisms occur at plasma concentrations of 5 to 10 mg/L, levels at which clinical benefit and antiinflammatory effects are seen.

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 (21). 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 (22). The receptor involved appears to be an A_2B receptor in humans (although an A₃ receptor serves a similar role in rats) (23). A novel AMP receptor, P2Y₁₅, has been identified that is more potently inhibited by theophylline (24), although the function of these receptors is not yet established. Adenosine antagonism is likely to account for some of the serious side effects of theophylline, such as seizures and cardiac arrhythmias through blockade of A₁ receptors.

IL-10 Release
IL-10 has a broad spectrum of antiinflammatory effects, and there is evidence that its secretion is reduced in COPD (25). IL-10 release is increased by theophylline. This effect may be mediated via PDE inhibition (26), although this has not been seen at the low doses that are effective in asthma (27).

Effect on Transcription
Theophylline prevents the translocation of the proinflammatory transcription factor nuclear factor (NF)-B into the nucleus, thus potentially reducing the expression of inflammatory genes in asthma and COPD (28). Inhibition of NF-B appears to be due to a protective effect against the degradation of the inhibitory protein IB-, so that nuclear translocation of activated NF-B is prevented (29). However, these effects are seen at high concentrations and may be mediated by inhibition of PDE.

Effect on Kinases
Theophylline directly inhibits phosphoinositide 3-kinases, with greatest potency for the phosphoinositide 3-kinase (p110) subtype (median inhibitory concentration, 75 µM) (30), a subtype of the enzyme that has been implicated in responses to oxidative stress (31). However, theophylline has a relatively weak effect against the phosphoinositide 3-kinase subtype (median inhibitory concentration, 800 µM), which is involved in chemotactic responses of neutrophils and monocytes. This does not provide an explanation for the inhibitory effect of theophylline on chemotactic responses.

Effects on Apoptosis
Prolonged survival of granulocytes due to a reduction in apoptosis may be important in perpetuating chronic inflammation in COPD. Theophylline promotes apoptosis in neutrophils in vitro (32). Theophylline-induced apoptosis of eosinophils is associated with a reduction in the antiapoptotic protein Bcl-2 (33). This effect is not mediated via PDE inhibition, but apoptosis in neutrophils may be mediated by antagonism of adenosine A_2A receptors (34). Theophylline also induces apoptosis of T lymphocytes, thus reducing their survival. This effect appears to be mediated via PDE inhibition (35).

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-. These effects are generally seen only at high concentrations of theophylline that are above the therapeutic range, and they are, therefore, unlikely to contribute to the antiinflammatory actions of theophylline.

	MOLECULAR MECHANISM AT THERAPEUTIC DOSES

TOP ABSTRACT CURRENT USE OF THEOPHYLLINE... BRONCHODILATOR ACTION ANTIINFLAMMATORY EFFECTS MOLECULAR MECHANISMS AT HIGHER... MOLECULAR MECHANISM AT... INTERACTION WITH STEROIDS SIDE EFFECTS FUTURE DEVELOPMENTS REFERENCES

 
A novel mechanism of action involving activation of histone deacetylases (HDACs) has been described that, in contrast to the proposed molecular mechanisms discussed above, is seen at therapeutically relevant concentrations (13).

Histone Acetylation and Deacetylation
Acetylation of core histones is associated with activation and transcription of inflammatory genes and is regulated by coactivator molecules that have intrinsic histone acetyltransferase activity (36). Proinflammatory transcription factors such as NF-B and activator protein-1 bind to coactivator molecules and activate this enzyme. In COPD there is an increase in NF-B activation in macrophages in induced sputum and peripheral lung, as well as in airway epithelial cells, which is further increased during exacerbations (37, 38). Histone acetylation is reversed by HDACs. There are at least 11 distinct subtypes of mammalian HDACs known to deacetylate histones (39, 40). They have been classified into two classes: Class I includes HDAC1, 2, 3, 8, and 11, which are localized to the nucleus, whereas Class II includes HDAC4, 5, 6, 7, 9, and 10, which shuttle between nucleus and cytoplasm. There is a marked reduction in HDAC activity in COPD alveolar macrophages, bronchi, and peripheral lung (41, 42). Decreased HDAC activity also results in increased NF-B–mediated inflammatory gene expression without affecting NF-B DNA binding (43).

Role of HDAC in Corticosteroid Actions
Corticosteroids suppress the expression of inflammatory genes by binding to and activating glucocorticoid receptors, which recruit HDAC2 to the transcription complex of inflammatory genes that is activated, thereby reversing histone acetylation and silencing genes that have been activated by inflammatory stimuli (44). These mechanisms appear to account for most of the antiinflammatory effects of corticosteroids in asthma (45). In COPD the marked reduction in HDAC activity and expression may account for the characteristic resistance to the antiinflammatory effects of steroids seen in this disease (46). Steroid resistance may be the result of oxidative stress leading to peroxynitrite formation and nitration of critical tyrosine residues in HDAC2, which impair its function and target it for destruction by the proteasome (47).

Effect of Theophylline
Theophylline activates HDAC activity and therefore suppresses the expression of inflammatory genes (48) (Figure 1). This effect is seen at therapeutic concentrations of theophylline (10^–6–10^–5 M), is lost at higher concentrations (10^–4 M), and is blocked by the nonselective HDAC inhibitor trichostatin A. A significant increase in HDAC activity is seen in bronchial biopsies after patients with asthma are treated with low doses of theophylline (mean plasma concentration, about 5 mg/L), indicating that low therapeutic concentrations are sufficient to activate HDAC in vivo.

View larger version (42K): [in this window] [in a new window]   Figure 1. Theophylline directly activates histone deacetylases (HDACs), which deacetylate core histones that have been acetylated by the histone acetyltransferase (HAT) activity of coactivators such as CBP (cAMP-responsive element-binding [CREB] protein). This results in suppression of inflammatory genes and proteins, such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-8, that have been switched on by proinflammatory transcription factors, such as NF-B. Corticosteroids also activate HDACs but through a different mechanism, resulting in the recruitment of HDACs to the activated transcriptional complex via activation of the glucocorticoid receptors (GRs), which function as a molecular bridge. This predicts that theophylline and corticosteroids may have a synergistic effect in repressing inflammatory gene expression. TNF- = tumor necrosis factor-.

Molecular Mechanisms
The mechanism whereby low concentrations of theophylline activate HDAC is not yet known, but it is not mediated by either PDE inhibition or adenosine receptor antagonism, because PDE inhibitors (nonselective and PDE3, PDE4, and PDE5 inhibitors) and adenosine A₁ and A₂ receptor antagonists do not mimic this action of theophylline (48).

The effect of theophylline on HDAC activity appears to be potentiated under conditions of oxidative stress. This is partly because baseline HDAC activity is lower, but it is possible that theophylline interferes with signal transduction pathway(s) activated by oxidative stress. There is a marked reduction in HDAC activity in COPD alveolar macrophages, and it is restored to above normal by low concentrations of theophylline (49). Current studies are investigating nuclear signal transduction pathways that regulate HDAC2 activity and the effect of theophylline on these pathways.

	INTERACTION WITH STEROIDS

TOP ABSTRACT CURRENT USE OF THEOPHYLLINE... BRONCHODILATOR ACTION ANTIINFLAMMATORY EFFECTS MOLECULAR MECHANISMS AT HIGHER... MOLECULAR MECHANISM AT... INTERACTION WITH STEROIDS SIDE EFFECTS FUTURE DEVELOPMENTS REFERENCES

 
HDACs are not effective in switching off inflammatory genes unless recruited to the active inflammatory site by activated glucocorticoid receptors. The novel action of theophylline predicts that theophylline alone would have a relatively weak antiinflammatory action, whereas theophylline should potentiate the antiinflammatory actions of corticosteroids. We have shown that the combination of low concentrations of theophylline (10^–5 M) and low concentrations of dexamethasone (10^–10 M) increases the repression of inflammatory cytokine release in both macrophages and epithelial cells, whereas neither alone had any effect (51). In vitro, low concentrations of theophylline potentiate the antiinflammatory effects of corticosteroids by 100- to 1,000-fold (49), which may underlie the benefit of adding low-dose theophylline to low or high doses of inhaled corticosteroids, as seen in clinical studies of patients with asthma (52–54). As discussed above, increased oxidative stress in COPD reduces HDAC activity, which may account for the resistance to the antiinflammatory actions of corticosteroids seen in patients with COPD and in alveolar macrophages from patients with COPD (55). Theophylline, through direct activation of HDACs, is able to reverse the effect of oxidative stress and cigarette smoke extract and thus restore corticosteroid responsiveness in cell lines and in alveolar macrophages from smokers and patients with COPD (49, 51). This effect of theophylline is completely reversed by trichostatin A, a nonselective inhibitor of HDACs, thereby confirming that the enhancement of corticosteroid responsiveness by theophylline is mediated via HDAC.

These findings suggest that theophylline has the potential to "unlock" the resistance to corticosteroids that is seen in patients with COPD. In vivo studies in mice have now confirmed that theophylline can reverse the steroid-resistant inflammation induced by cigarette smoking (P. J. Barnes, unpublished observations). Clinical studies to determine whether theophylline allows corticosteroids to exert an antiinflammatory effect in patients with COPD are now in progress.

	SIDE EFFECTS

TOP ABSTRACT CURRENT USE OF THEOPHYLLINE... BRONCHODILATOR ACTION ANTIINFLAMMATORY EFFECTS MOLECULAR MECHANISMS AT HIGHER... MOLECULAR MECHANISM AT... INTERACTION WITH STEROIDS SIDE EFFECTS FUTURE DEVELOPMENTS REFERENCES

 
A major limitation to the use of theophylline is the frequency of adverse effects (56). Unwanted effects of theophylline are usually related to plasma concentration and tend to occur when plasma levels exceed 20 mg/L. Side effects may be reduced by gradually increasing the dose until therapeutic concentrations are achieved.

Theophylline is metabolized in the liver by the P-450 isoenzyme CYP1A2 (57). 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 most common 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 antagonism (predominantly A₁ receptor antagonism) and may therefore be avoided by selective PDE inhibitors. However, the most common side effects of theophylline are nausea, gastrointestinal symptoms, and headaches, which may be due to inhibition of certain PDEs (e.g., PDE4 in the vomiting center) (58). 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 were relatively common and often led to discontinuation of therapy. 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).

	FUTURE DEVELOPMENTS

TOP ABSTRACT CURRENT USE OF THEOPHYLLINE... BRONCHODILATOR ACTION ANTIINFLAMMATORY EFFECTS MOLECULAR MECHANISMS AT HIGHER... MOLECULAR MECHANISM AT... INTERACTION WITH STEROIDS SIDE EFFECTS FUTURE DEVELOPMENTS REFERENCES

 
Although theophylline has been used much less in industrialized countries, the appreciation of its antiinflammatory effects at low doses has rekindled interest in this drug. There are particular reasons to explore this drug further in patients with COPD, because corticosteroids are ineffective as an antiinflammatory treatment and PDE4 inhibitors have relatively frequent side effects. The fact that antiinflammatory effects occur at low plasma concentrations (5–10 mg/L) that largely avoid side effects makes theophylline an attractive treatment. It is the only therapy currently available that is antiinflammatory in patients with COPD.

Now that the molecular mechanisms for the antiinflammatory effects of theophylline are better understood, there is a strong scientific rationale for combining low-dose theophylline with inhaled corticosteroids, particularly in patients with COPD. The molecular mechanisms of theophylline on HDAC activity discussed here predict that, although the antiinflammatory effects of corticosteroids mediated through HDAC recruitment might be enhanced by theophylline, steroid side effects are likely to be avoided. This is because corticosteroid side effects are largely mediated by gene induction by corticosteroids, whereas antiinflammatory effects are mediated via HDAC. Thus, it may be possible to increase the therapeutic ratio of corticosteroids. If theophylline is able to restore corticosteroid sensitivity in patients with COPD, as we have demonstrated in cells in vitro and animals in vivo, then the use of low-dose theophylline combined with a low dose of inhaled or even oral steroids may be effective as an antiinflammatory therapy and may even reduce the progression of the disease. What is particularly attractive about this approach is that theophylline becomes more effective as oxidative stress increases, making it perfectly adaptable to treating all stages of COPD without having to change the dose.

New Drugs
It has been established that HDAC activation is an important mechanism of action of theophylline and that it is independent of the probable molecular mechanisms for most side effects. Hence, there is the potential for designing novel theophylline-like molecules that mimic HDAC activation but avoid PDE inhibition or adenosine receptor antagonism and are therefore free of the side effects that have previously limited clinical doses. Theophylline has an activating effect on HDAC at low concentrations but an inhibitory effect at high concentrations, which might mean that it is acting as a partial agonist. This makes it important to search for fuller agonists that might have greater efficacy. There may also be novel structures that mimic the effect of theophylline that could be discovered by high-throughput screening, using HDAC activation as a read-out. Their identification could lead to the development of novel oral antiinflammatory drugs that could be used alone or in combination with corticosteroids in the treatment of COPD. These novel drugs would have the potential to unlock the steroid resistance that limits the clinical usefulness of corticosteroids in this disease (59). Such drugs might also have a place in the management of chronic inflammatory diseases that require systemic antiinflammatory treatments such as severe asthma, rheumatoid arthritis, inflammatory bowel disease, and even atherosclerosis. There is now a search for the molecular basis for the action of theophylline to identify novel intracellular targets.

	FOOTNOTES

 
Research supported by GlaxoSmithKline, Mitsubishi Pharma, and the British Lung Foundation.

Conflict of Interest Statement: P.J.B. has received funding and has served on scientific advisory boards for GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim, Novartis, Altana, Pfizer, and Millennium.

(Received in original form April 5, 2005; accepted in final form May 3, 2005)

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42. To Y, Elliott WM, Ito M, Hayashi S, Adcock IM, Hogg JC, Barnes PJ, Ito K. Total histone deacetylase activity decreases with increasing clinical stage of COPD. Am J Respir Crit Care Med 2004;169:A276.
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45. Barnes PJ, Adcock IM. How do corticosteroids work in asthma? Ann Intern Med 2003;139:359–370.[Free Full Text]
46. Barnes PJ, Ito K, Adcock IM. Corticosteroid resistance in chronic obstructive pulmonary disease: inactivation of histone deacetylase. Lancet 2004;363:731–733.[CrossRef][Medline]
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49. Cosio BG, Tsaprouni L, Ito K, Jazrawi E, Adcock IM, Barnes PJ. Theophylline restores histone deacetylase activity and steroid responses in COPD macrophages. J Exp Med 2004;200:689–695.[Abstract/Free Full Text]
50. Waterborg JH. Steady-state levels of histone acetylation in Saccharomyces cerevisiae. J Biol Chem 2000;275:13007–13011.[Abstract/Free Full Text]
51. Ito K, Lim S, Chung KF, Barnes PJ, Adcock IM. Theophylline enhances histone deacetylase activity and restores glucocorticoid function during oxidative stress. Am J Respir Crit Care Med 2002;165:A625.
52. 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.[Abstract/Free Full Text]
53. 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.[Abstract]
54. Lim S, Tomita K, Caramori 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.[Abstract/Free Full Text]
55. Culpitt SV, Rogers DF, Shah P, de Matos C, Russell REK, Donnelly LE, Barnes PJ. Impaired inhibition by dexamethasone of cytokine release by alveolar macrophages from patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003;167:24–31.[Abstract/Free Full Text]
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58. Howell RE, Muehsam WT, Kinnier WJ. Mechanism for the emetic side effect of xanthine bronchodilators. Life Sci 1990;46:563–568.[CrossRef][Medline]
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