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Theophylline (dimethyxanthine) has been used to treat airway diseases for over 80 years. It was originally used as a bronchodilator but the relatively high doses required are associated with frequent side effects, so its use declined as inhaled β2-agonists became more widely used. More recently it has been shown to have anti-inflammatory effects in asthma and COPD at lower concentrations. The molecular mechanism of bronchodilatation is inhibition of phosphodiesterase(PDE)3, but the anti-inflammatory effect may be due to inhibition of PDE4 and histone deacetylase(HDAC)-2 activation, resulting in switching off of activated inflammatory genes. Through this mechanism theophylline also reverses corticosteroid resistance and this may be of particular value in severe asthma and COPD where HDAC2 activity is reduced. Theophylline is given systemically (orally as slow-release preparations for chronic treatment and intravenously for acute exacerbations of asthma). Efficacy is related to blood concentrations, which are determined mainly by hepatic metabolism that may be increased or decreased in several diseases and by concomitant drug therapy. Theophylline is now usually used as an add-on therapy in asthma patients not well controlled on inhaled corticosteroids with or without long-acting β2-agonists and in COPD patients with severe disease not controlled by bronchodilator 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 A1-receptor antagonism. In the future low dose theophylline may be useful in reversing corticosteroid-resistance in COPD and severe asthma.
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Pulmonary Perspectives
Theophylline
Peter J. Barnes
1
1
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
2
-agonists be-
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
2
-agonists and
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
1
-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;
histone deacetylase
HISTORICAL INTRODUCTION
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
2
-agonists are
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
25
M) than are clinically effective.
Phosphodiesterase Inhibition
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
1
and A
2
receptors at ther-
apeutic concentrations but is less potent at A
3
receptors, suggesting
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
2B
recep-
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
1
receptors.
Increased IL-10
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: p.j.barnes@imperial.ac.uk
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
of PDE.
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
26
M)
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).
PHARMACOKINETICS
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,soitispreferabletoredene
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.
PHARMACODYNAMICS
Theophylline has several cellular effects that may contribute to its
clinical efficacy in the treatment of asthma and COPD (Figure 3).
Bronchodilator Action
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).
Antiinflammatory Effects
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
1
,A
2A
,A
2B
receptors)
Inhibition of nuclear factor-kB(nuclear translocation)
Histone deacetylase 2 via Inhibition of phosphoinositide 3-kinase-d
IL-10 secretion
Apoptosis of inflammatory cells (neutrophils, T cells)
Poly(ADP-ribose)polymerase-1 (PARP-1)
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
in CD4
1
and CD8
1
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
1
and
CD8
1
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-
ways (27).
Extrapulmonary Effects
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.
CLINICAL USE
Acute Exacerbations
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
2
-agonists for
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
2
-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).
Chronic Asthma
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
2
-agonists (LABAs)
(34). In an open study of adolescent patients with severe asthma
controlled with oral and inhaled steroids, nebulized b
2
-agonists,
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
2
-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
1
, 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
Increased clearance
P450 enzyme induction by drugs (rifampicin, phenobarbitone,
carbamazepine, ethanol)
Smoking (tobacco, marijuana)
High-protein, low-carbohydrate diet
Barbecued meat
Childhood
Decreased clearance
P450 enzyme inhibition by drugs (cimetidine,* erythromycin,
fluoroquinolone
antibiotics, allopurinol, zileuton, fluvoxamine, phenytoin, fluconazole,
ketoconazole, acyclovir, ritonavir, diltiazem, verapamil, interferon-a,
estrogens, pentoxifylline)
Congestive heart failure
Liver disease
Pneumonia
Viral infection
Vaccination (influenza immunization)
High carbohydrate diet
Old age
* Not ranitidine.
y
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).
Chronic COPD
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
1
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).
DOSING STRATEGIES
Intravenous
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
2
-agonists. The
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.
Oral
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.
Other Routes
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.
COST-EFFECTIVENESS
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.
COMBINATION THERAPY
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
1
, which
occurs rapidly with a bronchodilator effect (43) but may occur more
slowly due to an antiinflammatory effect (37). Typically, the increase
in FEV
1
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).
ADVERSE EFFECTS
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
achieved.
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
1A
-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).
SAFETY SYSTEMS
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.
GUIDELINES
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.
FUTURE DEVELOPMENTS
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.
References
1. Weinberger M, Hendeles L. Theophylline in asthma. N Engl J Med 1996;
334:1380–1388.
2. Rabe KF, Magnussen H, Dent G. Theophylline and selective PDE
inhibitors as bronchodilators and smooth muscle relaxants. Eur Respir
J1995;8:637–642.
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;
10:565–572.
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
Immunol 1996;77:34–38.
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
2005;338:1805–1810.
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–
371.
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
2006;61:761–766.
16. Zhang ZY, Kaminsky LS. Characterization of human cytochromes P450
involved in theophylline 8-hydroxylation. Biochem Pharmacol 1995;
50:205–211.
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
1988;297:1506–1510.
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.
Lancet 1994;343:1006–1008.
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
Immunol 1996;97:1242–1246.
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
2002;165:1371–1376.
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
2004;9:249–254.
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
Ther 2008;21:874–878.
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–
1914.
28. Aubier M, De Troyer A, Sampson M, Macklem PT, Roussos Ch.
Aminophylline improves diaphragmatic contractility. N Engl J Med
1981;305:249–252.
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
Rev 2005;CD001276.
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
1988;18:143–150.
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–
332.
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
Med 1997;337:1412–1418.
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
steroidinasthma.EurRespirJ1997;10:2754–2760.
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–
1918.
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
2006;11:603–610.
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:
CD000140.
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:
2343–2356.
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
... Относительно точного механизма действия теофиллина сохраняются разногласия, но этот препарат обладает и бронходилатационной, и противовоспалительной активностью. При назначении теофиллина значимо улучшается легочная функция при ХОБЛ и, возможно, улучшается функция дыхательной мускулатуры, но при этом повышается риск НЯ [103]. Есть данные о том, что при использовании низких доз теофиллина (100 мг 2 раза в сутки) статистически значимо уменьшается частота обострений ХОБЛ [104]. ...
... Теофиллин рекомендуется для лечения ХОБЛ в качестве дополнительной терапии у пациентов с тяжелыми симптомами [103][104][105][106]. ...
... При назначении теофиллина рекомендуется контролировать его концентрацию в крови и корректи-ровать дозу препарата в зависимости от полученных результатов [103]. ...
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Currently, chronic obstructive pulmonary disease (COPD) is a global health issue and one of the leading causes of death in the world. COPD therapy includes pharmacological and non-pharmacological approaches that can significantly improve clinical symptoms and reduce frequency of exacerbations of the disease. Methodology . The target audience of these clinical recommendations are therapists, general practitioners, and pulmonologists. Each thesis-recommendation about diagnostic and therapeutic procedures was graded according to the scales of classes of recommendations from 1 to 5 and the A, B, C scale of the levels of evidence. The clinical recommendations also contain comments and explanations to the theses together with algorithms for the diagnosis and treatment of COPD. Conclusion . The presented clinical guidelines cover the latest information about the etiology and pathogenesis, clinical manifestations, diagnosis, treatment, and prevention of chronic obstructive pulmonary disease. These guidelines were approved by the Scientific and Practical Council of the Ministry of Health of the Russian Federation in 2021.
... It also consists of the preparation of the desired product from pure substances [1]. Theophylline (TPH) is a widely used bronchodilator for the treatment of asthma and chronic obstructive pulmonary disease in humans [2]. It is also currently used off-label for the treatment of asthma in cats and dogs due to the lack of approved veterinary TPH products [2,3], but the marketed doses are often too high to suit the therapeutic needs of animals. ...
... Theophylline (TPH) is a widely used bronchodilator for the treatment of asthma and chronic obstructive pulmonary disease in humans [2]. It is also currently used off-label for the treatment of asthma in cats and dogs due to the lack of approved veterinary TPH products [2,3], but the marketed doses are often too high to suit the therapeutic needs of animals. Furthermore, animals are not small humans, and therefore human dosage forms cannot always be scaled down according to the weight of the animal [4], nor does the dosage form allow for precise down-scaling. ...
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Certain patient populations receive insufficient medicinal treatment due to a lack of commercially available products. The number of approved veterinary products is limited, making animals a patient population with suboptimal medicinal treatments available. To answer to this unmet need, compounding and off-label use of human-marketed products are practiced. Both of which have a significant risk of preparation errors. Hence, there is a dire demand to find and implement a more automated approach to the accurate, precise, and rapid production of veterinary dosage forms close to the point-of-care. This study aimed to assess the use of semi-solid extrusion-based 3D printing for the preparation of tailored doses of theophylline in the form of a chewable dosage form suitable for veterinary use. This study proved that semi-solid extrusion-based 3D printing could successfully be utilized to manufacture pet-friendly, chewable theophylline-loaded tablets. The prepared dosage forms showed a high correlation (R2 = 0.9973) between the designed size and obtained drug amount and met the USP and Ph. Eur. content uniformity criteria. Furthermore, the stability study showed the dosage form being stable and able to be used for up to three months after printing.
... It has been widely used as an antiasthmatic and chronic obstructive pulmonary disease drug at high doses, where it acts as an inhibitor of phosphodiesterases, increasing intracellular cAMP levels and protein kinase A activity. At high doses, Theophylline also antagonizes adenosine receptors [38]. Theophylline is also a potent activator of HDAC2, and low doses are sufficient to activate HDAC2 [38]; thus, its therapeutic use as HDAC2 activator would present the advantage of strongly reduced risk of potential adverse events as compared to its use in the treatment of chronic lung diseases. ...
... At high doses, Theophylline also antagonizes adenosine receptors [38]. Theophylline is also a potent activator of HDAC2, and low doses are sufficient to activate HDAC2 [38]; thus, its therapeutic use as HDAC2 activator would present the advantage of strongly reduced risk of potential adverse events as compared to its use in the treatment of chronic lung diseases. ...
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Charcot-Marie-Tooth disease (CMT) is a large group of inherited peripheral neuropathies that are primarily due to demyelination and/or axonal degeneration. CMT type 1A (CMT1A), which is caused by the duplication of the peripheral myelin protein 22 (PMP22) gene, is a demyelinating and the most frequent CMT subtype. Hypermyelination, demyelination, and secondary loss of large-caliber axons are hallmarks of CMT1A, and there is currently no cure and no efficient treatment to alleviate the symptoms of the disease. We previously showed that histone deacetylases 1 and 2 (HDAC1/2) are critical for Schwann cell developmental myelination and remyelination after a sciatic nerve crush lesion. We also demonstrated that a short-term treatment with Theophylline, which is a potent activator of HDAC2, enhances remyelination and functional recovery after a sciatic nerve crush lesion in mice. In the present study, we tested whether Theophylline treatment could also lead to (re)myelination in a PMP22-overexpressing mouse line (C22) modeling CMT1A. Indeed, we show here that a short-term treatment with Theophylline in C22 mice increases the percentage of myelinated large-caliber axons and the expression of the major peripheral myelin protein P0 and induces functional recovery. This pilot study suggests that Theophylline treatment could be beneficial to promote myelination and thereby prevent axonal degeneration and enhance functional recovery in CMT1A patients.
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Theophylline, a methylxanthine drug, has been used as a therapy for respiratory diseases. Recently, it has also been shown to have a potential in treating different cancers. Also, it has shown promising results in clinical trials for AML in combination therapy. Subsequently, studies have shown theophylline to kill breast cancer cells but not normal breast cells. Therefore, in this study, we have explored the molecular mechanism underlying the cytotoxic effect of theophylline on breast cancer cells. Theophylline-treated cancer cells were analyzed for the transcript and protein expression of candidate apoptotic genes such as TNFR1, caspase-8, -9, -3 using qPCR and immunoblotting, respectively. Cell viability and apoptosis was measured in the presence or absence of TNFR1 inhibitor, R7050, using AO/EtBr staining and MTT assay, respectively. Similarly, oxidative stress was studied by analyzing ROS in the presence or absence of ROS inhibitor, NAC, using DCFDA assay. Theophylline caused reduced cell viability in cancer but not normal cells. Theophylline-treated breast cancer cells showed increased expression of death receptor, TNFR1, along with elevated levels of active caspase-8, -9 and -3. Inhibition of TNFR1 reduced caspase-dependent apoptosis even in the presence of theophylline. Theophylline further caused increased ROS generation, inhibition of which resulted in reduced TNFR1-mediated apoptosis. Theophylline also increased cathepsin activity, which was reduced on exposure of cells to TNFR1 inhibitor, R7050. We conclude that ROS-mediated activation of TNFR1 is responsible for caspase-3 and cathepsin-dependent cell death in breast cancer cells on exposure to theophylline.
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The major reason for development of new drug delivery system is based largely on promoting therapeutic outcome and minimizing toxic effect of a drug by increasing the amount and persistence of a drug in target cells areas, while reducing exposure of the drug to non-target cells. In this study, Grewia spp gum obtained from Grewia spp pods was extracted and used as binder and release retardant in the formulation of controlled release theophylline tablets. A total of six (6) batches of the tablets were produced with carried concentrations of the test gum by wet granulation technique. To produce the tablets, various granules were formulated via wet granulation and characterized by measuring flow and packing properties. Granules with adequate flow properties were compressed to tablets. Tablets so formed were evaluated for hardness, percentage friability, weight variability and drug release profiles. The percentage yield was 18.64% and the pH of the test gum was 6.15. The angle of repose, bulk density, tapped density and Carr’s index of the formulated granules ranged from 22.48±0.00 to 24.90±0.00˚, 0.53±0.03 to 0.67±0.00g/ml, 0.67±0.02 to 0.82±0.00g/ml and 18.29±0.00 to 22.06±0.26% respectively. Resultant tablets hardness values of 3.69±0.45 to 13.39±0.65kgF and friability percentage of 0.40± 0.00 to 2.56%±0.01% were also obtained. The formulated theophylline granules showed good flow properties and compressibility. Thus, the study revealed that the test gum has comparable binding effect to Eudragit RS 100 at a ratio of 2:1. We recommend further studies to rule out any interaction of Grewia spp gum with theophylline in controlled release theophylline tablets.
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Background: Aminophylline injection has been on an intermittent nation-wide shortage due to manufacturing delays leaving a need for an alternative reversal agent for regadenoson-associated side effects. Intravenous theophylline should be a logical acceptable pharmacological alternative; however, data regarding its safety and efficacy as a reversal agent are lacking. Methods: Utilizing electronic medical records at the University of Colorado hospital, we identified patients ≥ 18 years of age who had a pharmacologic stress test using regadenoson during periods of aminophylline shortage (3/1/2013 to 5/31/2013 and 4/1/2018 to 8/30/2018) in which theophylline was used as an alternative antidote for side effect reversal. Intravenous theophylline was prepared by the inpatient pharmacy to a concentration of 0.8 mg/mL in a total volume of 100 mL D5W. Specific side effects and side effect resolution were evaluated. Results: Of the 122 patients evaluated, theophylline was administered in doses ranging from 40 to 75 mg with the majority receiving 40 mg. Complete resolution of regadenoson side effects occurred in 98 patients with 12 experiencing partial resolution and 1 without resolution. No adverse effects or events were reported. Conclusion: Due to limited availability of aminophylline, theophylline may be a safe and effective alternative to reverse regadenoson-associated side effects.
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Chronic obstructive pulmonary disease (COPD) is a global health problem and since 2001 the Global Initiative for Chronic Obstructive Lung Disease (GOLD) has published its strategy document for the diagnosis and management of COPD. This executive summary presents the main contents of the second 5-year revision of the GOLD document that has implemented some of the vast knowledge about COPD accumulated over the last years. Today, GOLD recommends that spirometry is required for the clinical diagnosis of COPD in order to avoid misdiagnosis and to ensure proper evaluation of severity of airflow limitation. The document highlights that the assessment of the COPD patient should always include assessment of 1) symptoms, 2) severity of airflow limitation, 3) history of exacerbations, and 4) comorbidities. The first three points can be used to evaluate level of symptoms and risk of future exacerbations and this is done in a way that split COPD patients into 4 categories - A, B, C and D. Non-pharmacologic and pharmacologic management of COPD match this assessment in an evidence-based attempt to relieve symptoms and reduce risk of exacerbations. Identification and treatment of comorbidities must have high priority and a separate chapter in the document addresses management of comorbidities as well as COPD in the presence of comorbidities. The revised document also contains a new chapter on exacerbations of COPD. The GOLD initiative will continue to bring COPD to the attention of all relevant shareholders and will hopefully inspire future national and local guidelines on the management of COPD.
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Many patients with chronic obstructive pulmonary disease continue to experience significant functional limitation despite the use of both long-acting anticholinergic and beta-agonist inhalers. Theophylline is a widely available medication which may further improve lung function and exercise performance. Previous studies evaluating the effects of theophylline on exercise capacity in chronic obstructive pulmonary disease (COPD) have demonstrated heterogeneous results. We performed a randomized placebo-controlled double-blind pilot study assessing the effects of theophylline on constant load exercise duration and lung function, involving 24 COPD patients already treated with long-acting inhaled beta-agonist and long-acting anti-cholinergic bronchodilator therapy. Analyzable data was available in 10 of 12 subjects in the treatment arm and 11 of 12 subjects in the control arm. Theophylline was associated with a 26.1% (95% confidence interval [CI]: -17.3-69.5) improvement in exercise duration compared to placebo. Four of 10 treated patients demonstrated an improvement in exercise duration exceeding the minimum clinically important difference of 33%, compared to 1 of 11 controls (P = 0.15). Furthermore, peak ventilation was reduced by 11.1%, (95% CI: 0.77-21.5) which may suggest improvements in gas exchange. There were no significant observed differences in resting lung function nor measures of dyspnea between the two treatment groups. Our study demonstrated a trend, but not a statistically significant improvement in exercise duration and a reduction in peak ventilation with theophylline. Based on the observed mean differences and standard deviations in this pilot study, a randomized controlled trial would require 45 subjects in each arm to detect a significant change in exercise duration.
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Previous studies demonstrated that theophylline modulates NF-κB activation in mast cells and pulmonary epithelial cells. We examined whether or not this modulation of NF-κB activation by theophylline is due to inhibition of the degradation of the IκBα protein, which suppresses NF-κB activation. TNF-α-induced NF-κB activation in a human pulmonary epithelial cell line (A549) was evaluated by Western blotting and a chloramphenicol acetyltransferase (CAT) assay. Expression of the IκBα protein was evaluated by Western blotting. Western blotting of nuclear extracts of A549 cells demonstrated that theophylline suppresses NF-κB-p65 nuclear translocation. The CAT assay indicated that NF-κB-dependent reporter gene expression is inhibited in A549 cells pretreated with theophylline. Western blotting of cytoplasmic extracts of A549 cells revealed that this inhibition was linked to theophylline-induced protection of expression of the IκBα protein. Moreover, theophylline inhibited interleukin-6 production induced by TNF-α in A549 cells. These findings are consistent with the idea that theophylline suppresses the production of proinflammatory cytokines via inhibition of NF-κB activation through protection of the IκBα protein.
Article
Concern about side-effects of theophylline prompted us to investigate whether this drug could be eliminated from the multi-medication regimen of severe asthmatics. We studied patients with a demonstrated requirement for systemic steroids who were taking most other available anti-asthma medications in an attempt to reduce systemic steroids while maintaining clinical stability. Five in-patients, 12–15 years old, completed a double-blind, cross-over trial of theophylline vs placebo. All were stable for 4 weeks prior to the study with normal spirometry and mildly elevated lung volumes. Regular medications consisted of long-acting theophylline with levels between 12 mcg/ml and 16 mcg/ml, and prednisone 10–30 mg on alternate days. In addition, they were all taking inhaled metaproterenol, cromolyn sodium, atropine sulphate, and beclomethasone dipropionate four times daily (qid). Patients received either theophylline or placebo during two drug periods. All other medications were unchanged. Parameters measured were symptom score, number of extra respiratory treatments (prn RTs), increase in steroid dosage, and daily spirometry. During the placebo period, all five patients required increased steroids, daily spirometry decreased and three patients developed severe exacerbations unrelated to viral infection. A marked increase in symptom score occurred within 48 hr of discontinuing theophylline in all. These findings emphasize that theophylline is beneficial in a subset of severe asthmatics who cannot be controlled with all other available bronchodilators, cromolyn, and inhaled and systemic steroids.
Article
There is abundant evidence for T-lymphocyte recruitment into the airways in allergic inflammatory responses. This study has tested the hypothesis that T-cell chemotaxis induced by platelet-activating factor (PAF) and human recombinant interleukin-8 (hrIL-8) can be attenuated by inhibition of phosphodiesterase activity and raised intracellular 3′,5′-cyclic adenosine monophosphate (cAMP) levels.This study used theophylline, a nonselective phosphodiesterase (PDE) inhibitor, and rolipram, a selective PDE4 inhibitor, to study the effect of PDE inhibition on T-cell chemotaxis. The β2-adrenoceptor agonist, salbutamol, the adenylyl cyclase activator, forskolin, and the cAMP analogue, dibutyryl cAMP (db-cAMP), were used to demonstrate a role for raised cAMP levels. T-cells were obtained from 10 atopic asthmatics, and the phenotype of migrating cells was examined by flow cytometry.Theophylline caused an inhibition of both PAF-and hrIL-8-induced chemotaxis (mean±sem maximum inhibition at 1 mM: 73±4% and 48±8% for hrIL-8 and PAF, respectively) that was not specific for the CD4+, CD8+, CD45RO+ or CD45RA+ T-cell subsets. T-cell chemotaxis was more sensitive to treatment with rolipram whose effect was already significant from 0.1 µM on hrIL-8-induced chemotaxis. Both a low concentration of salbutamol (0.1 mM) and forskolin (10 µM) potentiated the inhibitory effect of a low concentration of theophylline (25 µM) on responses to PAF but not to hrIL-8. Finally, T-cell chemotaxis was also inhibited by db-cAMP.It is concluded that attenuation of T-cell chemotaxis to two chemoattractants of relevance to asthma pathogenesis can be achieved via phosphodiesterase inhibition and increased intracellular 3′, 5′-cyclic monophosphate using drugs active on cyclic nucleotide phosphodiesterase. This action may explain the anti-inflammatory effects of theophylline and related drugs in asthma.
Article
Phosphodiesterases (PDEs) are important modulators of inflammation and wound healing. In this capacity, specific targeting of PDEs for the treatment of many diseases, including chronic obstructive pulmonary disease (COPD), has been investigated. Currently, treatment of COPD is suboptimal. PDE4 modulates the inflammatory response of the lung, and inhibition of PDE4 may be a novel, COPD-specific approach toward more effective treatment strategies. This review describes the state of PDE4-inhibitor therapy for use in COPD treatment.
Article
Recurrent apnoea is common in preterm infants, particularly at very early gestational ages. These episodes of ineffective breathing can lead to hypoxaemia and bradycardia that may be severe enough to require the use of positive pressure ventilation. Methylxanthines (such as caffeine, theophylline or aminophylline) have been used to stimulate breathing and reduce apnoea and its consequences. To determine the effects of methylxanthine treatment on the incidence of apnoea and the use of intermittent positive pressure ventilation (IPPV) and other clinically important outcomes in preterm infants with recurrent apnoea. Searches were made of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2010), the Oxford Database of Perinatal Trials, MEDLINE (1966 to June 2010), EMBASE (1982 to June 2010), previous reviews including cross references, abstracts, conferences and symposia proceedings, expert informants, journal hand searching mainly in the English language. All trials utilizing random or quasi-random patient allocation in which methylxanthine (theophylline, caffeine or aminophylline) as treatment for apnoea was compared with placebo or no treatment for apnoea in preterm infants were included. Methodological quality was assessed independently by the review authors. Data were extracted independently by the review authors. Analysis was done in accordance with the recommendations of the Cochrane Neonatal Review Group. Six trials reported on the effect of methylxanthine in the treatment of apnoea (three trials of theophylline and three trials of caffeine). Five trials that enrolled a total of 192 preterm infants with apnoea evaluated short term outcomes; in these studies, methylxanthine therapy led to a reduction in apnoea and use of IPPV in the first two to seven days. The post-hoc analysis of the large CAP Trial comparing caffeine to control in a subgroup of infants being treated for apnoea reported significantly reduced rates of PDA ligation; postmenstrual age at last oxygen treatment, last endotracheal tube use, last positive pressure ventilation; and reduced chronic lung disease at 36 weeks. Methylxanthine is effective in reducing the number of apnoeic attacks and the use of mechanical ventilation in the two to seven days after starting treatment. Caffeine is also associated with better longer term outcomes. In view of its lower toxicity, caffeine would be the preferred drug for the treatment of apnoea.