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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].
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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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