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Sleep Breath (2012) 16:10271032

DOI 10.1007/s11325-011-0639-1

REVIEW

The actual role of sodium cromoglycate in the treatment


of asthmaa critical review
Nikolaus C. Netzer & T. Kpper & Hans W. Voss &
Arn H. Eliasson

Received: 6 April 2011 / Revised: 30 October 2011 / Accepted: 15 December 2011 / Published online: 6 January 2012
# Springer-Verlag 2012

Abstract
Introduction Despite international consensus and clearly
written guidelines urging wider use of corticosteroids or
combinations of inhaled short- and long-acting -agonists
(SABA and LABA) and corticosteroids in persistent asthma,
prescribing patterns and compliance rates fall far short of
recommendations.
Objectives The failure to use steroids more aggressively is
due, in part, to their side effects, even with inhaled forms of
the drug. There is a role for expanded use of sodium cromolyn
in asthma. Its potent anti-inflammatory effects, lack of side
N. C. Netzer
Hermann Buhl Institute for Hypoxia and Sleep Medicine Research,
Paracelsus Medical University,
Salzburg, Austria
N. C. Netzer
Department of Internal Medicine, University Hospital Ulm,
Ulm, Germany
T. Kpper
Institute of Occupational and Social Medicine,
RWTH Aachen University,
Aachen, Germany
H. W. Voss
Clin Research Inc.,
Cologne, Germany
A. H. Eliasson
Pulmonary Division, Department of Medicine, Uniformed
Services University of the Health Sciences,
Bethesda, MD, USA

effects, and acceptable dosing and method of delivery, as well


as its special role in exercise-induced asthma, make it a very
suitable choice in the initial therapy for control of asthma.
Conclusion Compared to SABA and LABA, cromoglycates
alone are unsuspicious of being used to enhance physical
performance.
Keywords Asthma . Anti-inflammatory therapy . Sodium
cromoglycate . Inhaled corticosteroids . Leukotriene
antagonists

The status quo of guideline recommendations


According to the National Asthma Education and Prevention
Program, asthma that is more severe than the mild intermittent
category warrants treatment using a controller medication
with anti-inflammatory properties [1]. The choices of controller medication include corticosteroids and sodium cromoglycates (SCG). Because of a smaller inflammatory effect than
steroids in several studies, SCG has been taken of the list from
inhaled asthma drugs reimbursed by the public health care
insurances in several European countries. The efficacy of
steroids has been clearly demonstrated [2-4], but their use
has not been fully embraced because of side effectsboth
real and perceived. The problem of side effects with steroids,
including inhaled corticosteroids (ICS), points to the need for
effective alternatives.

ICS side effects versus SCG


N. C. Netzer (*)
Fachklinik Ghersburg fr Geriatrische Rehabilitation,
Ghersburgstr. 9,
83043 Bad Aibling, Germany
e-mail: nikinetzer@yahoo.com

Side effects from ICS have been experienced in all age


categories of patients. Potential toxicities in children are
magnified by the implied lifelong duration of treatment

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and the possible impact on developmental growth and maturation. Recent research has demonstrated decreased bone mineral density and decreased standing height with the use of
potent ICS in children with asthma [5]. Diminished growth in
children on ICS has been shown to be as much as a centimeter
over a 12-month period in a dose-dependent fashion [6], and
this side effect may explain the hesitation of pediatricians to
prescribe steroids freely. While some studies do show good
safety data [7, 8], concerns regarding effects of ICS on growth
have led the Food and Drug Administration to convene a joint
meeting to review the data and to release new class labeling
for ICS that notes this potential side effect [9].
Studies on suppression of the hypothalamuspituitary
adrenal (HPA) axis have been reassuring, but such considerations continue to concern physicians when using higher than
recommended doses or newer, more potent forms of inhaled
steroids [10, 11]. When sensitive measures of basal adrenal
activity are used, dose-related suppressive HPA effects can be
detected with specific drugs and application systems [5,
12-14]. Diminished bone mineral density has been demonstrated with even moderate dose ICS in children and adults
[14, 15]. Eye problems are associated with ICS, including
ocular hypertension, open-angle glaucoma, and cataract formation, though toxicity is much less than with oral doses
required to achieve the same benefit [14, 16, 17]. Local side
effects of cough, hoarseness, pharyngeal thrush, and throat
irritation [18] remind clinicians and patients of the potency of
inhaled steroids. Even the perception of harmful side effects is
a strong deterrent to compliance with any regimen. All of
these problems with ICS, both real and perceived, make it
clear that there is a need for other effective asthma therapies.

Inflammatory effects of SCG


In the past 20 years, the anti-inflammatory and anti-allergic
effect of SCG was shown to work through inhibition of IgEstimulated mediator release from human mast cells in a
dose-dependent fashion [19]. At the molecular level, recent
research has specifically demonstrated that the cromoglycates (both cromolyn disodium and nedocromil sodium) are
potent G-protein-coupled receptor 35 (GPR35) agonists and
that GPR35 is expressed in human mast cells, basophils, and
eosinophils [20]. GPR35 mRNA is upregulated upon challenge with IgE antibodies, and cromoglycates may work by
dampening the effects of this interaction. In other recent investigations, SCG demonstrated a cell-selective and mediatorselective suppressive effect on macrophages, eosinophils, and
monocytes [21]. Hoshino and Nakamura demonstrated antiinflammatory effects of SCG by performing biopsies of bronchial mucosa in nine patients with asthma before and after
treatment with inhaled SCG from a metered-dose inhaler
(MDI) [22]. The numbers of eosinophils, mast cells, T-

Sleep Breath (2012) 16:10271032

lymphocytes, and macrophages were significantly reduced as


a result of SCG, and the expressions of intercellular adhesion
molecule-1 (ICAM-1), vascular cell adhesion molecule-1
(VCAM-1), and endothelial leukocyte adhesion molecule-1
(ELAM-1) were also significantly reduced.
Head to head comparison of SCG with beclomethasone
diproprionate (BDP) further verifies the anti-inflammatory
effect of SCG. Each medication similarly reduced mucosal
populations of eosinophils, mast cells, and T-lymphocytes
[23].
Other in vivo studies have been performed to evaluate the
effect of SCG on the early and late phase reactions to
allergens. Cockcroft and Murdock compared SCG with
beclomethasone and albuterol in a placebo-controlled trial
[24]. They found that SCG was as effective as beclomethasone in blocking both early and late phase responses, while
albuterol effectively blocked bronchospasm only in the early
phase.
A question arises regarding the duration of the antiinflammatory effects of SCG and its ability to attenuate
bronchial hyper-reactivity. Hoag and McFadden reviewed
all original investigations done concerning this question
from 1969 to 1991 and concluded that SCG has a protective
effect in reducing bronchial hyper-reactivity if it is used for
longer than 12 weeks continuously [25]. Because this effect
was observed in children and adults and independent of an
allergic background, they concluded that the effect of SCG on
bronchial hyper-responsiveness may result not only from its
ability to stabilize mast cells but from other anti-inflammatory
properties as well.
Several studies have revealed that early use of antiinflammatory therapy can prevent increasing asthma severity especially in children [26-28]. This has led to a change in
the actual guidelines for asthma treatment from a first step
treatment with inhaled beta agonists alone to a dual approach with inhaled beta agonists and anti-inflammatory
drugs or single therapy with inhaled anti-inflammatory
drugs at initiation of therapy [1, 29]. The dual approach
has been further validated in a recent study in which the
combination of nebulized sodium cromoglycate and salbutamol produced much better asthma scores compared to
each agent alone in the treatment of moderate to severe
asthma in children [30]. On the other hand, the addition of
montelukast to SCG provides minimal additional benefit
against the airway response to mannitol [31]. It is evident
that not all combinations are superior to a single agent.

Good results with SCG in asthma in children


Regarding prevention of the development of asthma, one
study followed up on children less than 2 years of age who
were hospitalized for wheezing. Results showed a markedly

Sleep Breath (2012) 16:10271032

lower rate of asthma development in these children at school


age with SCG therapy compared to therapy with budesonide
[32]. The mechanism of this protective effect against the
development of asthma remains speculative, but one recent
study demonstrated that DSCG may be an effective agent
for the prevention of RSV-induced disease and the relief of
symptoms of RSV infection [33]. Such anti-viral qualities
would build an acceptable theory for a preventive effect for
asthma development in children.
The expectation for early treatment with anti-inflammatory
inhalers was that inhaled corticosteroids would be more effective than SCG or nedocromil. Several investigations, however,
have shown that cromolyn is as effective as inhaled steroids
when used as first treatment in adults and children with mild to
moderate asthma [27, 28, 34-36]. In severe asthma, corticosteroids have been clearly shown to be a more effective antiinflammatory treatment than SCG [37, 38]. Two investigations demonstrate superiority of ICS in moderate asthma in
children as well [39, 40]. However, when added to high-dose
ICS, inhaled SCG improved morning peak flows in atopic
adults with severe, refractory asthma, providing support for
the role of SCG as a secondary agent in such cases [41].
Furthermore, when evaluating the clinical effects of SCG
and ICS, caution must be applied to the conclusions of various
meta-analyses because these studies have not taken adequate
account of changes in the formulations used and newer studies
examining different age groups [42].
If the risk profile of ICS is taken into consideration,
caution must be used when prescribing them in the treatments at initiation of therapy, and SCG must be considered
as an attractive alternative.

SCG in exercise-induced asthma and as a combination


drug with -mimetics
In addition to their use as an anti-allergic drug, one of the major
applications for SCG and nedocromil has been in patients with
exercise-induced asthma [43-45]. SCG appears to prevent one
of the major potential causes for exercise-induced bronchoconstriction, which is heat and water loss of the mucosa [46]. To
this end, SCG has comparable effects in a similar time frame
compared to furosemide and heparin [47-49].
SCG shows at least equivalent effects to ICS in the
attenuation of exercise-induced bronchoconstriction. Furthermore, SCG in a fixed combination with reproterol
showed superior protection against exercise-induced bronchoconstriction compared to 3 days of the leukotriene inhibitor montelukast [50]. However, the onset of drug effect
is shorter for SCG than for ICS [51], and data from our own
investigations suggest that the onset of action for SCG is
faster than that for one of the leukotriene antagonists (montelukast) [52]. However, the effect of leukotriene antagonists

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seems to persist longer, lasting throughout an entire day [51,


52]. The longer duration of action of montelukast may be
desirable if exercise is to be repeated during the day.
In view of the fact that most patients with exercise-induced
asthma are children and adolescents, SCG therapy would be
favored over ICS because of their advantageous safety profile.
In recent years, there has been controversy about the
doseresponse related effects of SCG in asthma and
exercise-induced asthma. Studies indicated that a single
dosage of 5 mg may be more effective than the 1-mg/puff
single dosage in the available metered dose inhalers (MDI)
[53-55]. Consequently, a consensus statement on the management of childhood asthma recommended SCG as a firstline anti-inflammatory drug with a minimum daily dose of
10 mg given three to four times daily [56].
However, several studies have shown that this recommendation may not be justified. In a double-blind, randomized design, Storm et al. studied 26 children with exerciseinduced asthma to evaluate the effect of different doses and
the timing of administration of SCG on exercise challenge
[57]. On day one, study subjects performed a baseline
exercise challenge with no medication and demonstrated at
least a 15% fall in FEV1 to qualify for the study. On
subsequent days, the subjects received either 1 or 5 mg of
SCG at 20 or 120 min before the exercise challenge. The
data convincingly showed that both doses and both timing
regimens were equally protective and reduced the fall in
FEV1 as a response to exercise. Comparable results were
previously shown in another study comparing different dosages of the fixed combination of 1-mg SCG+0.5-mg reproterol [58]. Furthermore, in the recently completed study
called Adults with ExeRcise-Induced Asthma (AERIA), a
10% beneficiary effect on the FEV1 after 5,10, and 30 min
after a 10-min submaximal exercise on a treadmill of a fixed
combination of SCG and reproterol over the individual drugs
and an 80% beneficiary effect over placebo were validated in
adults with exercise-induced asthma, specifically demonstrating a preventive effect for bronchospasm in this population
[59]. However, a closer analysis of a subgroup from this
multicenter study, the group of one center, did not confirm
this 10% better FEV1 over the single drugs (manuscript by
Kpper, T., Goebbels, K., Kennes, L., Netzer, NC. Chromoglycate, reproterol, or bothwhats best for exercise-induced
asthma? Submitted to Sleep and Breath in 2011).

Could there be a possible renaissance of sodium


cromoglycate and other mastcell stabilizing drugs
in pediatric or adult asthma treatment in the second
and third decades of the twenty-first century?
Recent publications show that scientists in pharmaceutical
research look at mastcell stabilizers like SCG, montelucast,

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and maybe new versions of chloride channel influencing


drugs from different angles probably in order to find alternatives to the actual common anti-inflammatory treatment with
inhaled steroids. This could of course, on one side, be driven
by financial interest because steroid inhalers are still expensive, but patents are running out, and generic drug producers
are on the doorstep. On the other side, researchers could think
that they underestimated the potential of these drugs or the
delivery method of these substances was just wrong. One
publication driving in that direction is a more recent Cochrane
database review, which still denies a major potent role of SCG,
nedocromil, and montelucast, but states that publications regarding these drugs could have been biased in both directions
pro- and contra-mastcell stabilizers, which could still leave
room for speculations[60]. Another publication reports that in
many European countries, Canada, and Australia, SCG is still
used in childhood asthma more than in the USA and UK
because pediatricians and pulmonary physicians trust the drug
[61].
One of the speculations that derivates from recent investigations is that the delivery of SCG and nedocromil in the
widely used inhalers with flour-chloride containing propelling gases has been the wrong application method for these
drugs and that this would have decreased the drugs potency
significantly [62]. With the used inhalers, the drug reached
the mucosa too dry, and molecules could not interact. Thus,
there could be a much higher potency with a drug delivery
in saline solution using regular inhalation.
This would explain why SCG in vitro has a high potential
to block CL-influx into the human mastcell as shown in a
new study with a microelectrode array and completely
inhibits mastcell degranulation [63], but isnt as clinically
potent with propelled aerosol inhalers. Pharmaceutical
researchers have also picked up on SCG- and nedocromillike drugs as mastcell degranulation inhibitors. One promising substance is deriving from SCG is zaprinast, which has
a higher potency as G-protein-coupled receptor 35 (GPR35)
agonist in rat and mouse cells than SCG but has also a
higher phosphodiesterase-inhibitor potency in human cells
than SCG and nedocromil [21]. Future will show if really a
new drug will evolve from this substance.
An important argument for nonsteroidal anti-inflammatory
asthma drugs could be asthma during pregnancy. For the
actually growing group of pregnant asthma patients, maybe
due to a later onset of pregnancy in life, obstetricians rather
recommend nonsteroidal asthma drugs such as SCG [64].

Conclusion
There is still an important role for SCG in the treatment of
mild to moderate asthma especially in children as initial antiinflammatory treatment due to its lower risk profile compared

Sleep Breath (2012) 16:10271032

to inhaled corticosteroids and its potent anti-inflammatory


effects [65]. SCG also has a useful role in the treatment of
exercise-induced asthma in patients of all ages. However, the
drug has to compete with other nonsteroidal anti-inflammatory
drugs with a low-risk profile such as the leukotriene antagonists. Its clinical effects measured as FEV1 before and after
exercise compared to modern long-acting -agonist or combinations of -agonists and corticosteroids are probably inferior.
The decision to choose SCG as preventive asthma drug may
be driven by factors of stabilization which are not easily
measurable via simple lung function tests.
Acknowledgement The authors wish to thank Prof. Rudolfo Alvarez
Sala MD, Madrid, for the helpful information on the role of sodium
cromoglycates in Spain and for proofreading this article. Another thank
you goes to Wilfried Darlath Ph.D., Cologne, for his chemical and
pharmacological information at all times
Disclosure The authors have performed studies on different aerosol
asthma drugs in the past including sodium cromoglycates, steroids,
leukotriene antagonists, and -agonists for different drug producers
such as Rhone Poulenc Rohrer, 3 M, MSD, Glaxo, and others. The
actual paper has been written independent of any of these studies. None
of the authors has had any financial or otherwise personal interest in
this publication and therefore nothing to disclose.

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