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So.druck beeh_umbruchvorlage
Reprint from European Journal of Medical Research Official Organ » Deutsche AIDS-Gesellschaft« I. Holzapfel Verlag GmbH, Munich, Germany I. Holzapfel Verlag GmbH, Harthauser Str. 105, 81545 Munich, Germany Tel. +49-89/13 99 87 30, Fax +49-89/13 99 87 31, e-mail [email protected]
EU RO PE AN JOUR NAL OF MED I CAL RE SEARCH
Eur J Med Res (2008) 13: 557-562 I. Holzapfel Publishers 2008
K. M. Beeh1, J. Beier1, A. Esperester2, L. D. Paul3
1insaf Respiratory Research Institute, Wiesbaden, Germany, 2Boehringer Ingelheim, Ingelheim, Germany,
3Institute of Forensic Medicine, Forensic Toxicology, Ludwig Maximilians University, Munich, Germany
Abstract
piratory diseases associated with increased mucus pro-
Ambroxol is frequently used as mucolytic agent in res-
duction, such as chronic bronchitis. Due to its ability to
piratory diseases associated with increased mucus pro-
pro mote bronchial secretion and clearance, ambroxol is
duction like acute or chronic bronchitis. Further, am-
used as a mucolytic or expectorant. Further, ambroxol
broxol is used topically (lozenges) for the treatment of
has been used for the prophylaxis or treatment of res-
sore throat and pharyngitis associated with common
piratory distress syndrome, bronchopulmonary dyspla-
cold. In addition to the effects of ambroxol on mucus
sia, alveolar proteinosis, and postoperative pulmonary
regulation and local anaesthetic effects, a wide range of
complications after major surgery [1, 2, 3, 4, 5]. More
pharmacological antiinflammatory properties of am-
recently, a topical application of ambroxol (ambroxol
broxol have been described in vitro and in vivo, includ-
lozenges) has been approved for the treatment of sore
ing inhibition or scavenging of oxidative and nitro -
throat and pharyngitis associated with acute oropha-
sative stress, increase of local defense molecules in-
ryngeal infections. The pharmacological effects of am-
volved in respiratory virus replication, reduction of
broxol cover a wide range, including mucus regulation
proinflammatory cytokines and arachidonic acid meta -
on gland cells, increased production of pulmonary
bolites, inflammatory cell chemotaxis, and lipid peroxi-
surfactant, neutralization of oxidative and nitrosative
dation of tissues. The present review summarizes the
stress, suppression of respiratory virus replication, re-
antiinflammatory effects of ambroxol and relates these
duction of proinflammatory cytokines, chemotaxis,
properties to results from controlled clinical trials in
respiratory burst of inflammatory cells, and tissue
targeted diseases such as chronic bronchitis, chronic
lipid peroxidation, as well as, noticeably, local anaes-
obstructive pulmonary disease and sore throat.
In particular when used topically, some of the clini-
Key words: Ambroxol, inflammation, COPD, bronchi-
cal effects seen with ambroxol, namely reduction of
pain and swelling, appear to be attributable to local
aneasthetic properties of ambroxol [6]. However,
there is also evidence to suggest that the antiinflam-
matory properties of ambroxol play a major role in its
effects on sore throat and pharyngitis, as well as inter-
Ambroxol, (2-amino-3,5-dibromo-N-(trans-4-hydroxy-
action of ambroxol with viral replication per se. This
cyclohexyl)benzylamine), a bromhexin metabolite, is
review summarizes the anti-inflammatory properties
widely used for the treatment of acute or chronic res-
Table 1. Summary of antiinflammatory effects of ambroxol in the literature. Mediator Ambroxol effect Reference LTB4 ↓ release in vitro 17 cys-LT ↓ release in vitro 17 IL-1 ↓ expression and secretion in vitro 27, 30 IL-2 ↓ release in vitro 28 IL-4 ↓ release in vitro 17 IL-6 ↓ release and concentration in vitro / in vivo 22, 29, 30 IL-8 ↓ release and concentration in vitro / in vivo 21, 22 IL-12 ↓ release in vivo 47 IL-13 ↓ release in vitro 17 IFN-γ ↓ release in vitro 28, 47 TNF-α ↓ secretion in vitro 27, 28, 30, 47 Histamine ↓ release in vitro 17, 24 Oxidative metabolites ↓ release in vitro / in vivo 30, 39, 40, 41, 42 Surfactant proteins increased concentration and expression in vivo 46, 47
shown that ambroxol at therapeutic concentrations in-
hibits the neutrophil chemotactic response to various
Inflammation is generally defined as a distinct re-
sponse of the immune system to noxious stimuli. Re-
Alongside LTB4, interleukin (IL) -8, a CXC-chemo -
cruitment of inflammatory cells involves a series of
kine, has potent neutrophil and macrophage chemoat-
regulated events including chemotactic stimuli like cy-
tractant activities [8, 19]. IL-8 is consistently associated
tokines or lipid mediators, transendothelial migration
with, in particular neutrophil dominated, inflamma-
of leukocytes through selectin-mediated tethering,
tion, and IL-8 concentrations in tissues, blood or other
rolling and subsequent adhesion by integrin-depen-
biological samples are often directly correlated with
dent mechanisms [7, 8]. At the respective site of in-
neutrophilia. Epithelial cells and macrophages are ma-
flammation, inflammatory cells become activated
jor sources of IL-8, and IL-8 is released following a
through multiple stimuli, which lead to release of pro-
number of inflammatory stimuli [20]. The release of
teolytic enzymes, cytokines, nitric oxide and superox-
IL-8 from bronchial epithelial cells was reduced after
ide anion. In inflamed tissues, clearing of inflammato-
pre treatment of cells with ambroxol [21]. A further
ry cells may also be delayed by survival-promoting fac-
investigation in subjects with COPD showed that
tors, such as granulocyte-macrophage colony stimulat-
blood and salivary IL-8 was reduced after 10 days
While the physiological role of the inflammatory
In addition to neutrophils and monocytes, other ef-
response is generally to eliminate potential noxious
fector cells play an important role in certain types of
agents or stimuli, the cellular response itself may act as
inflammation, e.g. basophils and eosinophils in allergic
a stimulus for inflammation to persist, thus forming a
conditions. These cells are particularily responsive to
vicious cycle in such chronic inflammatory diseases,
T(helper)2 or mast-cell derived chemoattractant cy-
even after the initial trigger has been eliminated. How-
tokines like IL-4, IL-13, or IL-5, and chemotactic me-
ever, this phenomenon may also be observed in acute
diators like cysteinyl leukotrienes or vasoactive pep-
disease states such as the systemic inflammatory re-
tides (e.g. histamines) [23]. In a study by Gibbs et al.,
sponse syndrome (SIRS) or acute rhinovirus infection,
ambroxol reduced both basophil release of cys-
where it has been shown that not infection or viral cy-
leukotrienes, IL-4, IL-13 and histamine, while also de-
totoxicity per se, but rather the inflammatory response
creasing mast cell release of histamine in human skin
to viral infection causes the majority of tissue damage
mast cells 17.Mast cell release of histamine was also
and – consecutively – symptoms [10]. Numerous stud-
reduced by ambroxol in a different study using human
ies have evaluated the effect of ambroxol on inflam-
matory mechanisms, and these involve initiation, am-
plification and persistence of inflammation.
In addition to chemotaxis, the initiation of the inflam-
matory cascade is mediated by a sequence of signalling
In acute inflammation, chemoattractants and/or cy-
events directing effector cells into sites of inflamma-
tokines with chemoattractant properties are the prima-
tion. Leukocytes tethering, rolling and transmigration
ry initiators of an inflammatory response. Among the
along endothelial walls of blood vessels is mediated by
various chemoattractants, the lipid mediator
cell adhesion molecules [25], and their expression is
leukotriene (LT) B4 is one of the most potent and im-
among other mechanisms induced by classical proin-
portant chemoattractants in acute responses, such as
flammatory cytokines like IL-1β, IL-4, IL-6, IL-13 or
viral infections. LTB4 exerts its main effects on mono-
tumor necrosis factor (TNF) [26]. The release or pro-
cytes / macrophages and neutrophils, which are key
duction of some of these cytokines has been shown
players in the initiation of various acute inflammatory
diseases [11]. After binding to its neutrophil receptor,
Bianchi et al. demonstrated a significant reduction
LTB4 elicits calcium influx, transmembrane potential
of IL-1 secretion from lipopolysaccharide (LPS)-treat-
changes, degranulation, increased expression of the
ed human macrophages in vitro by ambroxol [27]. In
CD11b/CD18 adhesion molecule and, as a result,
their study, it was also shown that ambroxol signifi-
chemotaxis. In many chronic inflammatory diseases
cantly inhibited IL-1β mRNA expression, indicating
there is evidence of CD11b/CD18 upregulation on
an effect not only on cytokine release, but also pro-
neutrophils together with increased levels of LTB4 in
duction. Similar effects were observed by Pfeifer et al.
serum or respiratory secretions [12, 13]. For example
who investigated the effects of ambroxol on IL-2 re-
in COPD, LTB4 accounts for a large part of the total
lease from human bronchoalveolar lavage (BAL) and
neutrophil chemotactic activity of airway secretions
peripheral blood mononuclear cells [28]. In addition
[14, 15]. Interestingly, LTB4 also inhibits neutrophil
to IL-2, interferon (IFN)-γ release was also reduced by
apoptosis which may delay the resolution of inflam-
ambroxol, indicating a more general antiinflammatory
mation in tissues [16]. Epithelial cells, but also inflam-
matory cells like mast cells, basophils, eosinophils,
In a rat model of LPS-induced acute lung injury,
macrophages/monocytes, and neutrophils themselves
ambroxol also potently reduced proinflammatory cy-
represent a major source of LTB4. In models of acute
tokines IL-6 and TNF-alpha compared to saline-treat-
inflammation, ambroxol effectively reduced the release
ed animals [29]. In this study, the inhibitory effect of
of LTB4 from monocytes and neutrophils after stimu-
ambroxol was comparable to dexamethasone. Salivary
lation [17]. Further in this regard, Stockley et al. have
levels of IL-6 were also significantly reduced by am-
broxol treatment in COPD patients after 10 days 22.
peroxide (H2O2) promote both epithelial and par -
Jang et al. [30] reported that ambroxol decreased the
enchymal tissue damage through formation of toxic
production of IL-1β, IL-6, and TNF-alpha in alveolar
hypochlorous acides (HClO), activation and increased
macrophages activated by LPS, while also reducing the
release of cytokines [38]. Further, the interaction of
production of superoxide anion, hydrogen peroxide,
reactive oxygen intermediates with nitric oxide (NO)
and nitric oxide and the release of cellular granular en-
metabolites generated by NO-synthases (NOS), which
are activated or induced by proinflammatory cy-
TNF-alpha, besides its general function as proin-
tokines, promotes the formation of highly reactive ni-
flammatory cytokine, also promotes the chemotactic
trogen species, in particular peroxynitrite (ONOO-).
response of inflammatory cells to chemoattractants in
Therefore, the restoration of the oxidant/antioxidant
various ways [19]. Therefore, it seems noticeable in
imbalance and counteraction of nitrosative stress has
this regard, that Bianchi et al. demonstrated an in vitro
been a desirable therapeutic option in various chronic
suppression of approximately 90% by ambroxol on
the production of TNF from human macrophages af-
Ambroxol has been shown to have beneficial thera-
ter stimulation with lipopolysaccharide (LPS) [27].
peutic effects on markers of oxidative stress in a num-
TNF production by BAL cells and peripheral blood
ber of investigations. Gillisen et al. showed that am-
mononuclear cells PBMCs was also significantly re-
broxol at therapeutic concentrations reduced the re-
duced by ambroxol in another study by Pfeifer et al.
lease of reactive oxygen species (ROS) by polymor-
phonuclear cells in a time-dependent manner, suggest-
Finally, Aihara et al. studied the effect of ambroxol
ing that ambroxol did not only have the potential to
on LPS-induced secretion of IL-12 and IL-10 by hu-
directly scavenge free radicals, but also alter the proox-
man alveolar macrophages [31]. In particular, they in-
idative metabolism in inflammatory cells [39]. Further,
vestigated the ratio of IL-12/IL-10, since it is as-
Stetinova et al. demonstrated that ambroxol inhibited
sumed that the particular ratio of these cytokines reg-
hyaluronic acid degradation induced by hydroxy radi-
ulates T-cell responses rather than their mere concen-
cals and lipid peroxidation by hydroperoxide both in
trations per se. In their study, ambroxol increased the
vitro and in vivo [40]. Ambroxol also inhibited perox-
secretion of IL-12, but not IL-10, thus shifting the IL-
ynitrite- and hypochlorous acid induced damage of al-
12/IL-10 ratio in favour of IL-12. This observation
pha-1—antiproteinase, an important endogenous inac-
would indicate a possible role of ambroxol in en-
tivator of neutrophil-derived tissue degrading elastase,
hancement of T-cell mediated immunity. However,
in a study by Lee et al. [41]. In the same study by Lee
one needs to take into account that macrophage-de-
et al., ambroxol also significantly reduced the produc-
rived TNF negatively regulates IL-12 secretion of
tion of superoxide, hydrogen peroxide, HClO, and ni-
macrophages, thus the observed increase of IL-12 se-
tric oxide in IL-1 activated phagocytic cells. These ob-
cretion could also be a direct consequence of the pre-
servations have also been confirmed by Jang et al. [30]
viously described inhibitory effect of ambroxol on
and Ottonello et al. using activated human neutrophils
The mechanisms by which ambroxol elicits antiin-
flammatory effects on release and production of vari-
ous cytokines are as yet incompletely understood. One
possible explanation is a direct inhibition of phospho-
Although ambroxol is often used in the treatment of
diesterases (PDE), including PDE-4, by ambroxol, as
acute upper and lower respiratory tract infection, few
reported by Ferretti et al. [32]. Moreover, ambroxol
studies have investigated the direct effect of ambroxol
could also interact with the transcription factor NF-
on infectious agents, e.g. human respiratory viruses.
kappa B, thus reducing intracellular production of
Acute viral respiratory infections are mainly caused by
proinflammatory cytokines [21]. Finally, Kim et al. ob-
rhinovirus (30-50%), corona virus (10-15%), parain-
served an inhibition of cellular activation processes in-
fluenza (5%) and respiratory syncytial virus (5%) [43].
volving proteine kinase C and protein tyrosine kinases
While studies indicate that cytopathic effects of rhi-
novirus on epithelial cells are weak and neutrophilic
inflammatory infiltrates appear relatively mild [44],
adenoviruses and, in particular, influenza A virus
cause significant epithelial damage in the human respi-
Oxidative stress results from the increased presence
ratory tract. Entry and replication of influenza A in
and activation of inflammatory cells, in particular neu-
respiratory cells is facilitated by epithelial proteases,
trophils, which generate vast amounts of reactive oxy-
e.g. trypsin-like protease, or tryptase clara, which inter-
gen intermediates as part of their innate antibacterial
act with viral envelope membrane glycoproteins, thus
defense. Several cellular and non-cellular defense
further promoting viral cell entry. These host proteas-
mechanisms protect resident cells from injury due to
es in turn underly regulation by endogenous cellular
oxidative stress. However, in chronic inflammatory
suppressors, such as secretory leukoprotease inhibitor,
conditions, there is ample evidence that endogenous
human mucus protease inhibitor, or, in the lower air-
defense mechanisms are insufficient to counteract ox-
ways, pulmonary surfactant [45]. Hence, upregulation
idative injury [34-37]. Inflammatory cell-derived oxi-
of natural inhibitors of proteases represents a poten-
dants can also interact with other cellular mediators to
tial therapeutic approach to suppress viral airway repli-
enhance their cytotoxic effects. For example, neu-
cation. Seifart et al. studied the effect of ambroxol on
trophil-derived myeloperoxidase (MPO) and hydrogen
surfactant proteins in rats. In their investigation, am-
broxol increased protein and mRNA content of pneu-
preventive effect on acute viral upper respiratory tract
mocytes or clara cells of surfactant proteins -C and
-D [46]. Yang et al. demonstrated also in rats, that
More recently, a topical preparation of ambroxol
treatment of animals with increasing concentrations of
was introduced into the treatment of pharyngitis and
ambroxol prior to infection with influenza A virus
sore throat associated with acute viral cold. In a proof-
caused a significant suppression of virus multiplica-
of-concept trial, 20 mg ambroxol lozenges led to a re-
tion and improved overall survival [47]. This beneficial
duction of sore throat pain superior to placebo in 218
effect was accompanied by an increase of virus repli-
patients [56]. In two further confirmatory trials, 20 or
cation inhibitors mucus protease inhibitor, surfactant
30 mg of ambroxol also relieved pain in sore throat
protein A, and immunoglobulines –A and –G, while
over placebo, although the higher dose was no more
ambroxol simultaneously reduced inflammatory cy-
effective than the lower dose [57]. Although local
tokines TNF-alpha, IFN-γ, and IL-12. The mecha-
anaesthetic effects for ambroxol have been described
nisms underlying the stimulation of immunoglobu-
[6], the reduction of mucosal hyperemia and redness
lines and inhibitory proteins by ambroxol are, again,
observed in clinical studies suggests, that the clinical
not understood. However, the observed effect on sev-
benefits of ambroxol lozenges in sore throat are at
eral target cells in the upper and lower airways again
least partially mediated by antiinflammatory properties
suggest a more general effect on central regulatory cel-
of ambroxol (de Mey C, Peil H., Koelsch, S., Bubeck
lular mechanisms, like the PDEs or NF-kappa B as
J., Vix J.M., EBM-based clinical documentation of the
discussed above. Interestingly, a protective effect of
efficacy and safety of lozenges containing ambroxol in
ambroxol on the number of acute upper respiratory
treating acute uncomplicated sore throat, manuscript in
disease episodes was recently demonstrated in a con-
CLINICAL STUDIES WITH AMBROXOL SUPPORTING AN
Ambroxol is widely used as a mucolytic in respiratory
diseases associated with increased mucus production,
Numerous clinical studies have been performed with
e.g. acute or chronic bronchitis. Further, ambroxol is
ambroxol, either in its oral, inhaled, or topical prepara-
used topically for the treatment of sore throat and
tion. Indications for therapeutic long-term use includ-
pharyngitis associated with common cold. In addition
ed asthma, chronic bronchitis /COPD, and viral infec-
to the effects of ambroxol on mucus regulation and
tions / common cold, in particular sore throat.
local anaesthetic effects, a wide range of pharmaco-
In asthmatic subjects, ambroxol reduced airway re-
logical antiinflammatory properties of ambroxol have
activity to methacholine after 14 days of oral treat-
been described in vitro and in vivo, including inhibi-
ment (90 mg) [49]. However, ambroxol had no effect
tion or scavenging of oxidative and nitrosative stress,
on the cough threshold to capsaicin in asthmatics with
increase of local defense molecules involved in respi-
cough-variant asthma [50]. To date, no long-term stud-
ratory virus replication, reduction of proinflammatory
ies have evaluated a potential efefct of ambroxol in
cytokines and arachidonic acid metabolites, inflamma-
tory cell chemotaxis, and lipid peroxidation of tissues,
In chronic bronchitis and / or COPD, Poole et al.
while some of these antiinflammatory effects are also
described a protective effect of mucolytics usage in-
supported by results from controlled clinical trials, e.g.
cluding ambroxol on the overall frequency of exacer-
in chronic bronchitis / COPD and virally induced sore
bations, by means of a systematic review [51]. The
meta-analysis included a placebo-controlled clinical
study by Olivieri et al. who demonstrated an increase
of exacerbation free intervals with ambroxol [45].
These observations were – at least partially – support-
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On a recent bus trip to Toronto, following the route of the 1837 rebels from Lloydtown, we were asked to re-create the experience in our mind'seye. To imagine the effort of a 35 mile hike, to pass farmers’ fields andsmall inns, to feel the privation of thirst or hunger and the anxiety of potential conflict that they must have experienced on this long walk. A tough task,considering the amo
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