Peter J. Barnes
National Heart and Lung Institute, Imperial College, London, United Kingdom
Theophylline (dimethylxanthine) has been used to treat airway dis-
eases for more than 80 years. It was originally used as a bronchodi-
lator, but the relatively high doses required are associated with
frequent side effects, so its use declined as inhaled b
came more widely used. More recently it has been shown to have
antiinﬂammatory effects in asthma and chronic obstructive pulmo-
nary disease (COPD) at lower concentrations. The molecular mech-
anism of bronchodilatation is inhibition of phosphodiesterase (PDE)
3, but the antiinﬂammatory effect may be due to inhibition of
PDE4 and histone deacetylase-2 activation, resulting in switching
off of activated inﬂammatory genes. Through this mechanism, the-
ophylline also reverses corticosteroid resistance, and this may be
of particular value in severe asthma and COPD, wherein histone
deacetylase-2 activity is reduced. Theophylline is given systemically
(orally as slow-release preparations for chronic treatment and intra-
venously for acute exacerbations of asthma). Efﬁcacy is related to
blood concentrations, which are determined mainly by hepatic me-
tabolism, which may be increased or decreased in several diseases
and by concomitant drug therapy. Theophylline is now usually used
as an add-on therapy in patients with asthma not well controlled on
inhaled corticosteroids with or without long-acting b
in patients with COPD with severe disease not controlled by bron-
chodilator therapy. Side effects are related to plasma concentrations
and include nausea, vomiting, and headaches due to PDE inhibition
and at higher concentrations to cardiac arrhythmias and seizures
due to adenosine A
-receptor antagonism. In the future, low-dose
theophylline may be useful in reversing corticosteroid resistance in
COPD and severe asthma.
Keywords: methylxanthine; phosphodiesterase; adenosine receptor;
Theophylline is still one of the most widely prescribed drugs for
the treatment of asthma and chronic obstructive pulmonary dis-
ease (COPD) worldwide, because it is inexpensive and widely
available. Theophylline (dimethylxanthine) occurs naturally in
tea and cocoa beans in trace amounts. It was ﬁrst extracted from
tea and synthesized chemically in 1895 and initially used as a di-
uretic. Its bronchodilator property was later identiﬁed, and it was
introduced as a clinical treatment for asthma in 1922. Despite its-
widespread global use, in industrialized countries theophylline
has become a third-line treatment as anadd-on therapy in patients
with poorly controlled disease, because inhaled b
far more effective as bronchodilators, and inhaled corticosteroids
have a greater antiinﬂammatory effect. Theophylline is used as
an oral therapy (rapid or slow-release tablets) or as more soluble
aminophylline, an ethylenediamine salt, which is suitable for oral
and intravenous use (1).
MECHANISMS OF ACTION
Several molecular mechanisms of action have been proposed for
theophylline (Table 1), although many of these occur only at
higher concentrations (.10
M) than are clinically effective.
Theophylline is a weak nonselective inhibitor of phosphodiester-
ase (PDE) isoenzymes, which break down cyclic nucleotides in
the cell, leading to increased intracellular concentrations of
cAMP and cyclic 39,59guanosine monophosphate concentra-
tions (Figure 1). However, the degree of inhibition is small at
therapeutic concentrations. Theophylline relaxes airway smooth
muscle by inhibition mainly of PDE3 activity, but relatively
high concentrations are needed for maximal relaxation (2),
and its inhibitory effect on mediator release from alveolar mac-
rophages is mediated by inhibition of PDE4 activity (3). Inhi-
bition of PDE should lead to synergistic interaction with
b-agonists, but this has not been convincingly demonstrated
in vivo or in clinical studies. Inhibition of PDEs accounts for
the most frequent side effects of theophylline.
Adenosine Receptor Antagonism
Theophylline antagonizes adenosine A
receptors at ther-
apeutic concentrations but is less potent at A
that this could be the basis for its bronchodilator effects. 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 mast cells of patients with asthma via A
tors (4). Inhaled adenosine causes bronchoconstriction in subjects
with asthma via release of histamine from airway mast cells, and
this is prevented by therapeutic concentrations of theophylline,
although this does not signify that this is important for its anti-
asthma effect. However, adenosine antagonism is likely to account
for the serious side effects of theophylline, such as seizures and
cardiac arrhythmias, via blockade of A
IL-10 has a broad spectrum of antiinﬂammatory effects, and its
secretion is reduced in asthma and COPD. IL-10 release is in-
creased by relatively high concentrations of theophylline medi-
ated though PDE inhibition (5), although this has not been seen
at the low doses that are effective in asthma (6).
Effects on Transcription
Theophylline prevents the translocation of the proinﬂammatory
transcription factor nuclear factor-kB (NF-kB) into the nucleus
(Received in original form February 26, 2013; accepted in ﬁnal form May 3, 2013)
Correspondence and requests for reprints should be addressed to Peter J. Barnes,
D.M., D.Sc., National Heart and Lung Institute, Imperial College School of Med-
icine, Dovehouse Street, London SW3 6LY, UK. E-mail: firstname.lastname@example.org
Am J Respir Crit Care Med Vol 188, Iss. 8, pp 901–906, Oct 15, 2013
Copyright ª2013 by the American Thoracic Society
Originally Published in Press as DOI: 10.1164/rccm.201302-0388PP on May 14, 2013
Internet address: www.atsjournals.org
through preventing the degradation of the inhibitory I-kBa,
thus potentially reducing the expression of inﬂammatory genes
in asthma and COPD (7). However, these effects are seen at
high concentrations and are likely to be mediated by inhibition
Effects on Cell Survival
Theophylline promotes apoptosis in neutrophils in vitro through
a reduction in the antiapoptotic protein Bcl-2 (8). Theophylline
also induces apoptosis of T lymphocytes, thus reducing their
survival, and this effect appears to be mediated via PDE inhi-
bition (9). Theophylline also inhibits the enzyme poly(ADP-
ribose)polymerase-1 (PARP-1), which is activated by oxidative
stress and leads to a reduction in NAD levels, resulting in an
energy crisis that leads to cell death (10).
Histone Deacetylase Activation
Theophylline in low therapeutic concentrations (z5 mg/L) acti-
vates histone deacetylases, especially when their activity is re-
duced by oxidative stress (11, 12). In COPD cells, in which HDAC2
activity and expression are markedly reduced, theophylline (10
restores HDAC2 activity to normal and thus reverses the cortico-
steroid resistance in these cells, an effect that is blocked by an
inhibitor of HDAC activity trichostatin A (12) (Figure 2). This
action of theophylline is independent of PDE inhibition and
adenosine receptor antagonism but due to selective inhibition
of phosphoinositide-3-kinase-d(PI3K-d) that is activated by ox-
idative stress and involved in the inhibition of HDAC2 activity
via phosphorylation (13). Increased reactive oxygen species and
nitric oxide from increased expression of inducible nitric oxide
synthase result in the formation of peroxynitrite radicals, which
nitrate tyrosine residues in HDAC2, resulting in its inactivation
and degradation (14). Theophylline reduces the formation of
peroxynitrite, thus providing a further mechanism for increasing
HDAC2 function in asthma and COPD (15).
There is a close relationship between the acute improvement in
airway function and serum theophylline concentrations. Below
10 mg/L bronchodilator effects are small, and above 25 mg/L ad-
ditional beneﬁts are outweighed by side effects, so that the thera-
peutic range was usually taken as 10 to 20 mg/L (55–110 mM).
Nonbronchodilator effects of theophylline may be seen at plasma
concentrations of less than 10 mg/L,soitispreferabletoredeﬁne
the therapeutic range as 5 to 15 mg/L. The dose of theophylline
required to achieve therapeutic concentrations varies among
patients, largely because of differences in clearance. For children
(6–12 yr), one-half of the adult dose should be used. Theophylline
is rapidly and completely absorbed, but there are large interindi-
vidual variations in clearance, due to differences in its hepatic
metabolism (Table 2). Theophylline is metabolized in the liver
by the cytochrome P450 microsomal enzyme system, and a large
number of factors may inﬂuence hepatic metabolism. Theophyl-
line is predominantly metabolized by CYP1A2, whereas at higher
plasma concentrations CYP2E1 is also involved (16). Increased
clearance is seen in children (1–16 yr) and in cigarette and mar-
ijuana smokers. Concurrent administration of phenytoin, pheno-
barbitone, or rifampicin, which increase P450 activity, increases
metabolic breakdown, so that higher doses may be required. Re-
duced clearance is found in liver disease, pneumonia, and heart
failure, and doses need to be reduced to one-half and plasma levels
monitored carefully. Decreased clearance is also seen with several
drugs, including erythromycin, quinolone antibiotics (ciproﬂoxacin,
but not oﬂoxacin), allopurinol, cimetidine (but not ranitidine), se-
rotonin uptake inhibitors (ﬂuvoxamine), and the 5-lipoxygenase
inhibitor zileuton, all of which interfere with CYP1A2 function.
Thus, if a patient on maintenance theophylline requires a course
of erythromycin, the dose of theophylline should be halved. Al-
though there is a similar interaction with clarithromycin, there is
nointeractionwithazithromycin(17). Viral infections and vaccina-
tions (inﬂuenza immunizations) may also reduce clearance, and this
may be particularly important in children. Because of these varia-
tions in clearance, individualization of theophylline dosage is re-
quired, and plasma concentrations should be measured 4 h after
thelastdosewithslow-release preparations, when steady state has
usually been achieved.
Theophylline has several cellular effects that may contribute to its
clinical efﬁcacy in the treatment of asthma and COPD (Figure 3).
Theophylline was primarily used as a bronchodilator, and it relaxes
large and small human airways in vitro, acting as a functional an-
tagonist by increasing intracellular cAMP concentrations. However,
it is a relatively weak bronchodilator at therapeutic concentrations,
with little bronchodilator effect at plasma concentrations of less
than 10 mg/L. In vivo intravenous aminophylline has an acute bron-
chodilator effect in patients with asthma, which is most likely to be
due to a relaxant effect on airway smooth and has a small protective
effect of theophylline on histamine-, methacholine-, or exercise-
induced bronchospasm. Oral theophylline reduces air trapping in
patients with COPD, indicating an effect on peripheral airways (18).
Theophylline has several antiinﬂammatory effects in asthma and
COPD, and these may be seen at lower plasma concentrations
Figure 1. Effect of phosphodiesterase (PDE) inhibitors in the break-
down of cyclic nucleotides in airway smooth muscle and inﬂammatory
cells. AC ¼adenylyl cyclase; cGMP ¼cyclic guanosine monophos-
phate; G ¼stimulatory G-protein; GC ¼guanylyl cyclase; GTP ¼gua-
nosine triphosphate; R ¼receptor.
TABLE 1. PROPOSED MECHANISMS OF ACTION OF THEOPHYLLINE
Phosphodiesterase inhibition (nonselective)
Adenosine receptor antagonism (A
Inhibition of nuclear factor-kB(↓nuclear translocation)
↑Histone deacetylase 2 via Inhibition of phosphoinositide 3-kinase-d
↑Apoptosis of inﬂammatory cells (neutrophils, T cells)
902 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 188 2013
than are required for its bronchodilator actions (19). In vitro
theophylline inhibits mediator release from mast cells and reac-
tive oxygen species from neutrophils, although this is signiﬁcant
only at relatively high concentrations. Low-dose theophylline
reduces the late response and airway eosinophil inﬂux after in-
haled allergen (20) and reduces the numbers of eosinophils in
bronchial biopsies, bronchoalveolar lavage, and induced sputum
in patients with mild asthma (21). It also reduces bronchoalveolar
lavage neutrophil inﬂux in patients with nocturnal asthma (22).
In patients with COPD, theophylline reduces the proportion of
neutrophils in induced sputum and reduces the concentration of
CXCL8, suggesting an antiinﬂammatory effect unlike corticosteroids
(23–25). At high concentrations, theophylline inhibits proliferation
lymphocytes and inhibits the chemotactic re-
sponse of T lymphocytes, effects that are mediated through PDE
inhibition (26). In patients with asthma, low-dose theophylline
treatment results in an increase in activated circulating CD4
T cells but a decrease in these cells in the airways, suggesting
that it may reduce the trafﬁcking of activated T cells into the air-
Aminophylline increases diaphragmatic contractility and reverses
diaphragm fatigue (28), but this effect has not been observed by all
investigators. However, there are doubts about the relevance of
these observations to the clinical beneﬁt provided by theophylline
(29). Whether theophylline has any effects on systemic effects or
comorbidities in patients with COPD has not yet been established.
Intravenous aminophylline was previously widely used in the
management of acute exacerbations of asthma and COPD. How-
ever, in patients with acute asthma a systematic review showed
no evidence of beneﬁt when added to nebulized b
any outcome measure, whereas there was an increased risk of
side effects (30), and similar results were found in children (31).
Intravenous aminophylline should be reserved for the few
patients with acute severe asthma who fail to show a satisfactory
response to nebulized b
-agonists. When intravenous aminoph-
ylline is used, it should be given as a slow intravenous infusion
with careful monitoring of vital signs, and plasma theophylline
concentrations should be measured before and after infusion.
Aminophylline similarly has no place in the routine manage-
ment of COPD exacerbations (32, 33).
Currently, theophylline is recommended as an additional bron-
chodilator if asthma remains difﬁcult to control after high doses
of inhaled corticosteroids plus long-acting b
(34). In an open study of adolescent patients with severe asthma
controlled with oral and inhaled steroids, nebulized b
inhaled anticholinergics, and sodium cromoglycate, in addition
to regular oral theophylline, withdrawal of the theophylline resulted
in a marked deterioration of asthma control, which only responded
to reintroduction of theophylline (35). In a placebo-controlled trial
of theophylline withdrawal in patients with severe asthma con-
trolled on high doses of inhaled corticosteroids, there was a signif-
icant deterioration in symptoms and lung function when placebo
was substituted for the relatively low maintenance dose of theoph-
ylline (27). Addition of theophylline improves asthma control to
a greater extent than b
-agonists in patients with severe asthma
treated with high-dose inhaled corticosteroids (36). Several studies
have demonstrated that adding low-dose theophylline to inhaled
corticosteroids in patients whose asthma is not controlled gives
better asthma control than doubling the dose of inhaled cortico-
steroids (37–39). Interestingly, there is a greater degree of improve-
ment in FVC than in FEV
, suggesting an effect on air trapping and
peripheral airways. The improvement in lung function is relatively
slow, suggesting an antiinﬂammatory rather than a bronchodilator
effect of theophylline. These studies suggest that low-dose theoph-
ylline may be preferable to increasing the dose of inhaled steroids
when asthma is not controlled on moderate doses of inhaled ste-
roids; such a therapeutic approach would be less expensive than
adding a LABA, although it is less effective (34). Low-dose the-
ophylline is also effective in smoking patients with asthma, who
have a poor response to inhaled steroids, and this may be through
TABLE 2. FACTORS AFFECTING CLEARANCE OF THEOPHYLLINE
P450 enzyme induction by drugs (rifampicin, phenobarbitone,
Smoking (tobacco, marijuana)
High-protein, low-carbohydrate diet
P450 enzyme inhibition by drugs (cimetidine,* erythromycin,
antibiotics, allopurinol, zileuton, ﬂuvoxamine, phenytoin, ﬂuconazole,
ketoconazole, acyclovir, ritonavir, diltiazem, verapamil, interferon-a,
Congestive heart failure
Vaccination (inﬂuenza immunization)
High carbohydrate diet
* Not ranitidine.
Also clarithromycin but not azithromycin.
Figure 2. Theophylline increases histone deacetylase-2 (HDAC2) via
inhibition of phosphoinositide-3-kinase-d(PI3Kd), which is activated
by oxidative stress to phosphorylate and reduce HDAC2. HDAC2
deacetylates core histones that have been acetylated by the histone
acetyltransferase (HAT) activity of coactivators, such as CREB-binding
protein (CBP). This results in suppression of inﬂammatory genes and
proteins, such as granulocyte-macrophage colony stimulating factor
(GM-CSF) and CXCL8, that have been switched on by proinﬂammatory
transcription factors, such as nuclear factor-kB (NF-kB). Corticosteroids
also activate HDAC2, but through a different mechanism, resulting in
the recruitment of HDAC2 to the activated transcriptional complex via
activation of glucocorticoid receptors (GR), which function as a molec-
ular magnet. This explains how theophylline may reverse corticosteroid
resistance due to reduced HDAC2 activity.
Pulmonary Perspectives 903
increasing HDAC2 activity, which is reduced in the airways
patients with asthma who smoke (40); this has been conﬁrmed
in vitro (41).
Theophylline increases exercise tolerance in patients with COPD
(42) and reduces air trapping (18). In high doses (with plasma
concentration 10–20 mg/L) it is a useful additional bronchodilator
in patients with severe COPD and has an added effect to a LABA
(43). Low-dose theophylline reduces exacerbations in patients with
COPD by approximately 50% when used as single therapy over 1
year (44). In COPD macrophages, theophylline restores HDAC2
activity to normal and thus reverses corticosteroid resistance (12).
Low-dose theophylline increases the recovery from acute exacer-
bations of COPD, and this is associated with reduced inﬂammation
and increased HDAC activity (45). In patients with moderate
COPD, low-dose theophylline has a greater antiinﬂammatory effect
and improvement in FEV
when added to an inhaled corticosteroid
than either drug alone (46). This suggests that theophylline may be
useful in reversing corticosteroid resistance in patients with COPD,
and long-term clinical trials are currently underway in patients with
COPD to investigate this.
Apnea in Preterm Infants
Theophylline has been used to prevent recurrent apnea and bra-
dycardia in preterm infants by stimulating breathing. It is effective
in reducing episodes and the need for mechanical ventilation, al-
though less effective than caffeine (47).
Intravenous aminophylline has long been used in the treatment
of acute exacerbations of asthma and COPD but is used much
less now as it is less effective than nebulized b
recommended dose is 6 mg/kg given intravenously over 20 to 30
minutes, followed by a maintenance dose of 0.5 mg/kg/h. If the
patient is already taking theophylline, or there are any factors
that decrease clearance, these doses should be halved and the
plasma level checked more frequently.
Plain theophylline tablets or elixir are rapidly absorbed but give
wide ﬂuctuations in plasma concentrations and are not recom-
mended. Several sustained-release preparations of theophylline
and aminophylline that are absorbed at a constant rate provide
steady plasma concentrations over a 12- to 24-hour period (1).
The recommended doses for bronchodilatation are 200 to 400 mg
twice daily, but one-half of these doses may be effective as an anti-
inﬂammatory treatment. Although there are differences between
preparations, these are relatively minor. Once optimal doses have
been established, plasma concentrations usually remain stable, pro-
viding no factors that alter clearance are introduced.
Aminophylline may be given as a suppository, but rectal absorp-
tion is unreliable and proctitis may occur, so this route should be
avoided. Inhalation of theophylline is irritating and ineffective
(48). Intramuscular injections of theophylline are very painful
and should never be given.
Slow-release theophylline preparations are less expensive than
LABA as an add-on therapy, although less effective. Plain the-
ophylline is very inexpensive but not recommended because of
ﬂuctuation in plasma concentrations.
At present there are no ﬁxed combination therapies available. In
the future, a combination of low-dose theophylline and an oral
corticosteroid might be useful in COPD.
MEASURING EFFECTS AND OUTCOMES
Assessment of the effect of adding theophylline to existing ther-
apy usually involves demonstrating an increase in FEV
occurs rapidly with a bronchodilator effect (43) but may occur more
slowly due to an antiinﬂammatory effect (37). Typically, the increase
is accompanied by a decrease in symptoms. In COPD,
theophylline may reduce air trapping and improve exercise perfor-
mance, although its effects are small (49). The reduction in exacer-
bations reported in patients with COPD is difﬁcult to monitor in
clinical practice (44).
The main limitation to the use of theophylline in conventional
doses has been the relatively high frequency of adverse
effects. Unwanted effects of theophylline are usually related
to plasma concentration and tend to occur when plasma levels
exceed 20 mg/L, although patients develop side effects at low
pla sm a concentrations. Side effects may initially be reduced by
gradually increasing the dose until therapeutic concentrations are
The most frequent side effects are headache, nausea and vom-
iting, increased acid secretion, and gastroesophageal reﬂux,
which may be explained by PDE inhibition. Diuresis may be
due to adenosine receptor antagonism. At high concentrations,
convulsions and cardiac arrhythmias may occur and may be due
to adenosine A
-receptor antagonism. Doxofylline, which is
available in some countries, is another methylxanthine deriva-
tive that has similar efﬁcacy to theophylline but appears to have
less effect on adenosine receptors so may be safer (50).
It is important to recognize the factors that both increase and
decrease plasma theophylline concentrations, as these may affect
efﬁcacy and safety. Drug interactions are particularly important
and are listed in Table 2. Plasma theophylline concentrations
Figure 3. Cellular effects of theophylline.
904 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 188 2013
should be checked if there are any adverse effects or if there are
concerns about compliance. Theophylline should never be given
with roﬂumilast, as both inhibit PDE4.
The Global Initiative for Asthma recommends that theophylline
should be considered as additional treatment when asthma is not
controlled on inhaled corticosteroids (step 3) but is less preferred
than a LABA and may be added for patients not controlled on
inhaled corticosteroids and LABA (steps 4 and 5) (51). In chil-
dren, low-dose theophylline may be used as a controller at step
2 but is less effective than inhaled corticosteroids. Intravenous
aminophylline is not recommended for acute severe asthma.
The Global Initiative for Chronic Obstructive Lung Disease
recommends that theophylline be used as a bronchodilator only
if inhaled long-acting bronchodilators are unavailable or unaf-
fordable (52). Intravenous aminophylline is not recommended
for acute exacerbations.
Theophylline is a relativelypoor bronchodilator, as adverse effects
limit the dose and make it less effective than inhaled bronchodila-
tors. However, there is interest in exploring its antiinﬂammatory
effects and its potential to reverse corticosteroid resistance at lower
doses that would largely avoid side effects. Low concentrations of
theophylline restore reduced HDAC2 to normal and therefore may
reverse corticosteroid resistance in COPD and in severe asthma
and in smokers with asthma. This effect is achieved by inhibition
of phosphoinositidePI3Kd(13), suggesting that PI3Kdinhibitors
may be developed in the future to treat corticosteroid-resistant
airway obstruction. Theophylline is also a nonselective inhibitor
of PDE isoenzymes, which may account for the effects of theoph-
ylline at higher doses. PDE4 inhibition may mediate antiinﬂam-
matory effects but also the common side effects. The selective
PDE4 inhibitor roﬂumilast is now marketed in several countries
as an antiinﬂammatory treatment for COPD, but its clinical efﬁ-
cacy is limited by side effects such as diarrhea, nausea, and head-
aches, which also occur with high doses of theophylline (53). Other
PDE4 inhibitors are in clinical development, although several have
failed, including inhaled PDE4 inhibitors. An inhaled PDE3/4
inhibitor, which has a bronchodilator effect due to PDE3 inhibi-
tion, is also in clinical development (54). However, PDE inhibitors
do not have any effect on HDAC2 so have no potential to reverse
corticosteroid resistance. Currently, clinical trials are in progress to
assess the potential of low-dose theophylline to reverse corticoste-
roid resistance in COPD.
Author disclosures are available with the text of this article at www.atsjournals.org.
1. Weinberger M, Hendeles L. Theophylline in asthma. N Engl J Med 1996;
2. Rabe KF, Magnussen H, Dent G. Theophylline and selective PDE
inhibitors as bronchodilators and smooth muscle relaxants. Eur Respir
3. Dent G, Giembycz MA, Rabe KF, Wolf B, Barnes PJ, Magnussen H.
Theophylline suppresses human alveolar macrophage respiratory burst
through phosphodiesterase inhibition. Am J Respir Cell Mol Biol 1994;
4. Polosa R, Blackburn MR. Adenosine receptors as targets for therapeutic
intervention in asthma and chronic obstructive pulmonary disease.
Trends Pharmacol Sci 2009;30:528–535.
5. Mascali JJ, Cvietusa P, Negri J, Borish L. Anti-inﬂammatory effects of
theophylline: modulation of cytokine production. Ann Allergy Asthma
6. 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 al-
veolar macrophages. Allergy 2001;56:1087–1090.
7. Ichiyama T, Hasegawa S, Matsubara T, Hayashi T, Furukawa S. Theophylline
inhibits NF-kB activation and I kBadegradation in human pulmonary
epithelial cells. Naunyn Schmiedebergs Arch Pharmacol 2001;364:558–561.
8. 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.
9. Ohta K, Yamashita N. Apoptosis of eosinophils and lymphocytes in
allergic inﬂammation. J Allergy Clin Immunol 1999;104:14–21.
10. Moonen HJ, Geraets L, Vaarhorst A, Bast A, Wouters EF, Hageman
GJ. Theophylline prevents NAD1depletion via PARP-1 inhibition
in human pulmonary epithelial cells. Biochem Biophys Res Commun
11. 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.
12. 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.
13. To Y, Ito K, Kizawa Y, Failla M, Ito M, Kusama T, Elliot M, Hogg JC,
Adcock IM, Barnes PJ. Targeting phosphoinositide-3-kinase-dwith
theophylline reverses corticosteroid insensitivity in COPD. Am J
Respir Crit Care Med 2010;182:897–904.
14. Osoata GO, Yamamura S, Ito M, Vuppusetty C, Adcock IM, Barnes PJ,
Ito K. Nitration of distinct tyrosine residues causes inactivation of
histone deacetylase 2. Biochem Biophys Res Commun 2009;384:366–
15. Hirano T, Yamagata T, Gohda M, Yamagata Y, Ichikawa T, Yanagisawa
S, Ueshima K, Akamatsu K, Nakanishi M, Matsunaga K, et al.
Inhibition of reactive nitrogen species production in COPD airways:
comparison of inhaled corticosteroid and oral theophylline. Thorax
16. Zhang ZY, Kaminsky LS. Characterization of human cytochromes P450
involved in theophylline 8-hydroxylation. Biochem Pharmacol 1995;
17. Nahata M. Drug interactions with azithromycin and the macrolides: an
overview. J Antimicrob Chemother 1996;37:133–142.
18. Chrystyn H, Mulley BA, Peake MD. Dose response relation to oral
theophylline in severe chronic obstructive airways disease. BMJ
19. Barnes PJ. Theophylline: new perspectives for an old drug. Am J Respir
Crit Care Med 2003;167:813–818.
20. Sullivan P, Bekir S, Jaffar Z, Page C, Jeffery P, Costello J. Anti-
inﬂammatory effects of low-dose oral theophylline in atopic asthma.
21. 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.
22. Kraft M, Torvik JA, Trudeau JB, Wenzel SE, Martin RJ. Theophylline:
potential antiinﬂammatory effects in nocturnal asthma. J Allergy Clin
23. 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
24. Kobayashi M, Nasuhara Y, Betsuyaku T, Shibuya E, Tanino Y, Tanino
M, Takamura K, Nagai K, Hosokawa T, Nishimura M. Effect of low-
dose theophylline on airway inﬂammation in COPD. Respirology
25. Kanehara M, Yokoyama A, Tomoda Y, Shiota N, Iwamoto H, Ishikawa
N, Taooka Y, Haruta Y, Hattori N, Kohno N. Anti-inﬂammatory
effects and clinical efﬁcacy of theophylline and tulobuterol in mild-
to-moderate chronic obstructive pulmonary disease. Pulm Pharmacol
26. Hidi R, Timmermans S, Liu E, Schudt C, Dent G, Holgate ST, Djukanović
R. Phosphodiesterase and cyclic adenosine monophosphate-dependent
inhibition of T-lymphocyte chemotaxis. EurRespirJ2000;15:342–349.
Pulmonary Perspectives 905
27. 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–
28. Aubier M, De Troyer A, Sampson M, Macklem PT, Roussos Ch.
Aminophylline improves diaphragmatic contractility. N Engl J Med
29. Moxham J. Aminophylline and the respiratory muscles: an alternative
view. Clin Chest Med 1988;9:325–336.
30. Nair P, Milan SJ, Rowe BH. Addition of intravenous aminophylline
to inhaled beta(2)-agonists in adults with acute asthma. Cochrane
Database Syst Rev 2012;12:CD002742.
31. Mitra A, Bassler D, Goodman K, Lasserson TJ, Ducharme FM.
Intravenous aminophylline for acute severe asthma in children over
two years receiving inhaled bronchodilators. Cochrane Database Syst
32. Duffy N, Walker P, Diamantea F, Calverley PM, Davies L. Intravenous
aminophylline in patients admitted to hospital with non-acidotic
exacerbations of chronic obstructive pulmonary disease: a prospec-
tive randomised controlled trial. Thorax 2005;60:713–717.
33. Barr RG, Rowe BH, Camargo CA Jr. Methylxanthines for exacerbations
of chronic obstructive pulmonary disease: meta-analysis of rando-
mised trials. BMJ 2003;327:643.
34. Wilson AJ, Gibson PG, Coughlan J. Long acting beta-agonists versus
theophylline for maintenance treatment of asthma. Cochrane Data-
base Syst Rev 2000;2:CD001281.
35. Brenner MR, Berkowitz R, Marshall N, Strunk RC. Need for
theophylline in severe steroid-requiring asthmatics. Clin Allergy
36. 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–
37. 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
38. 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
39. Lim S, Groneberg D, Fischer A, Oates T, Caramori G, Mattos W,
Adcock I, Barnes PJ, Chung KF. Expression of heme oxygenase
isoenzymes 1 and 2 in normal and asthmatic airways: effect of
inhaled corticosteroids. Am J Respir Crit Care Med 2000;162:1912–
40. Spears M, Donnelly I, Jolly L, Brannigan M, Ito K, McSharry C, Lafferty
J, Chaudhuri R, Braganza G, Adcock IM, et al. Effect of low-dose
theophylline plus beclometasone on lung function in smokers with
asthma: a pilot study. Eur Respir J 2009;33:1010–1017.
41. Marwick JA, Wallis G, Meja K, Kuster B, Bouwmeester T, Chakravarty
P, Fletcher D, Whittaker PA, Barnes PJ, Ito K, et al. Oxidative stress
modulates theophylline effects on steroid responsiveness. Biochem
Biophys Res Commun 2008;377:797–802.
42. Murciano D, Auclair MH, Pariente R, Aubier M. A randomized,
controlled trial of theophylline in patients with severe chronic
obstructive pulmonary disease. N Engl J Med 1989;320:1521–1525.
43. 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.
44. Zhou Y, Wang X, Zeng X, Qiu R, Xie J, Liu S, Zheng J, Zhong N, Ran
P. Positive beneﬁts of theophylline in a randomized, double-blind,
parallel-group, placebo-controlled study of low-dose, slow-release
theophylline in the treatment of COPD for 1 year. Respirology
45. Cosio BG, Iglesias A, Rios A, Noguera A, Sala E, Ito K, Barnes PJ,
Agusti A. Low-dose theophylline enhances the anti-inﬂammatory
effects of steroids during exacerbations of chronic obstructive pul-
monary disease. Thorax 2009;64:424–429.
46. Ford PA, Durham AL, Russell REK, Gordon F, Adcock IM, Barnes PJ.
Treatment effects of low-dose theophylline combined with an inhaled
corticosteroid in COPD. Chest 2010;137:1338–1344.
47. Henderson-Smart DJ, De Paoli AG. Methylxanthine treatment for
apnoea in preterm infants. Cochrane Database Syst Rev 2010;12:
48. Cushley MJ, Holgate ST. Bronchodilator actions of xanthine derivatives
administered by inhalation in asthma. Thorax 1985;40:176–179.
49. Voduc N, Alvarez GG, Amjadi K, Tessier C, Sabri E, Aaron SD. Effect
of theophylline on exercise capacity in COPD patients treated with
combination long-acting bronchodilator therapy: a pilot study. Int J
Chron Obstruct Pulmon Dis 2012;7:245–252.
50. Shukla D, Chakraborty S, Singh S, Mishra B. Doxofylline: a promising
methylxanthine derivative for the treatment of asthma and chronic
obstructive pulmonary disease. Expert Opin Pharmacother 2009;10:
51. Bateman ED, Hurd SS, Barnes PJ, Bousquet J, Drazen JM, FitzGerald
M, Gibson P, Ohta K, O’Byrne P, Pedersen SE, et al. Global strategy
for asthma management and prevention: GINA executive summary.
Eur Respir J 2008;31:143–178.
52. Vestbo J, Hurd SS, AgustíAG, Jones PW, Vogelmeier C, Anzueto A,
Barnes PJ, Fabbri LM, Martinez FJ, Nishimura M, et al. Global
strategy for the diagnosis, management, and prevention of chronic
obstructive pulmonary disease: GOLD executive summary. Am J
Respir Crit Care Med 2013;187:347–365.
53. Michalski JM, Golden G, Ikari J, Rennard SI. PDE4: a novel target in
the treatment of chronic obstructive pulmonary disease. Clin
Pharmacol Ther 2012;91:134–142.
54. Banner KH, Press NJ. Dual PDE3/4 inhibitors as therapeutic agents for
chronic obstructive pulmonary disease. Br J Pharmacol 2009;157:892–906.
906 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 188 2013