Therapeutic novelties of inhaled corticosteroids and bronchodilators in asthma

Therapeutic novelties of inhaled corticosteroids and bronchodilators in asthma

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Therapeutic novelties of inhaled corticosteroids and bronchodilators in asthma

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Fabio L.M. Ricciardolo a, *, Francesco Blasi b, Stefano Centanni c, Paola Rogliani d a

Department of Clinical and Biological Sciences, University of Torino, Torino, Italy  Granda, Milano, Italy Department of Pathophysiology and Transplantation, University of Milano, IRCCS Fondazione Ca c  degli Studi di Milano, Milan, Italy Respiratory Unit, San Paolo Hospital, Dipartimento di Scienze della Salute, Universita d Unit of Respiratory Clinical Pharmacology, Department of System Medicine, University of Rome Tor Vergata, Roma, Italy b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 30 April 2015 Accepted 15 May 2015 Available online xxx

Orally inhaled agents are a key therapeutic class for treatment of asthma. Inhaled corticosteroids (ICS) are the most effective anti-inflammatory treatment for asthma thus representing the first-line therapy and bronchodilators complement the effects of ICSs. A significant body of evidence indicates that addition of a b2-agonist to ICS therapy is more effective than increasing the dose of ICS monotherapy. In this paper, pharmacological features of available ICSs and bronchodilators will be reviewed with a focus on fluticasone propionate/formoterol fumarate combination which represents the one of the most powerful ICS acting together with the most rapid active LABA. © 2015 Published by Elsevier Ltd.

Keywords: Asthma Inhaled corticosteroid Bronchodilator Long-acting b2 agonist

1. Introduction Over the past decade, orally inhaled fixed-dose agents have emerged as an important therapeutic class for treatment of asthma. The conceptual simplicity of inhaled agents belies both the complexity of their development, and the profound advantages they offer patients. The therapeutic revolution in asthma management first occurred in the 1950s, when Riker Laboratories (now subsidiary of 3M Healthcare) launched on the market the first metered dose inhaler (MDI), delivering isoprenaline, a non-selective specific badrenergic agonist, propelled by chlorofluorocarbons (i.e. Freon™) [1]. These inhalers were widely used for asthma treatment, however in the second half of twentieth century a real epidemic of deaths attributable to asthma was recorded in UK, with a 400% increase of death rate [2]. Data analysis suggested a link of deaths due to asthma to the widespread use of the non-selective b agonist drugs [3]. In the 1960s and 1970s, relatively specific b-adrenergic agonists were developed for use by inhalation (e.g. fenotreol, salbutamol, metaproterenol, isoetherine, terbutaline) and several studies demonstrated that this novel class of drugs was superior in

* Corresponding author. Department of Clinical and Biological Sciences, University of Torino, San Luigi Hospital, Regione Gonzole 10, 10043 Orbassano, Torino, Italy. E-mail address: [email protected] (F.L.M. Ricciardolo).

term cardiovascular adverse effects, compared with intravenous administration [4,5]. The inhaled selective b-bronchodilators with rapid and long lasting bronchodilation action became the primary treatment of acute asthmatic airway obstruction. However, in the 1980s, a peak in asthma deaths in New Zealand was linked to the use of potent selective short-acting b2 agonist (SABA) fenoterol [6], and confirmed by case-control studies [6,7]. A second revolution in asthma therapy was introduced in the early 1970s by the use of inhaled corticosteroid (ICS), whose efficacy as anti-inflammatory treatment for asthma control was subsequently proved [8,9]. Nowadays ICSs have an established and recognized position in the management of asthma patients morbidity and mortality, and are recommended in all national and international guidelines [10,11]. Meanwhile, the therapeutic tools available - based on inhaled bronchodilator agents e has been implemented and improved by developing selective b2 agonists engineered for a prolonged activity. The first of these long-acting b2 agonists (LABA), salmeterol, has been launched in the market at the end of 1980s. The results of a study published in 1994 first demonstrated that the addition of LABA to ICSs in inadequately controlled patients was superior to dosage increase of the steroids [12]. This study was followed by a substantial body of evidence from randomized control trials indicating that addition of a LABA to existing ICS therapy was clinically more effective than increasing the dose of ICS monotherapy [13]. However, some skepticism and fear still remained on

http://dx.doi.org/10.1016/j.pupt.2015.05.006 1094-5539/© 2015 Published by Elsevier Ltd.

Please cite this article in press as: F.L.M. Ricciardolo, et al., Therapeutic novelties of inhaled corticosteroids and bronchodilators in asthma, Pulmonary Pharmacology & Therapeutics (2015), http://dx.doi.org/10.1016/j.pupt.2015.05.006

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the possibility that the bronchodilator prolonged activity could mask the inflammatory status, with the consequent possible worsening of asthma episodes. The pivotal Formoterol And Corticosteroid Establishing Therapy Trial (FACET), which required a bronchodilator responsiveness of 15% or more as an inclusion criterion, used the arguably more appropriate endpoint of (predefined) exacerbations as the primary endpoint. Addition of a LABA to low-dose or high-dose ICS reduced exacerbations compared with the identical dose of ICS alone and in all groups the LABA-containing regimens provided greater improvement in expiratory flow rates [14]. A further study, designed to compare frequency and severity of asthma exacerbations during budesonide and LABA formoterol treatment, confirmed that the LABA-ICS combination is an effective therapy for asthma control with no masking effects on bronchial inflammation [15]. This evidence decisively dispelled all doubts on the matter. The addition of leukotriene receptor antagonists (LTRA) may be an alternative to ICS/LABA combination for management of asthma which is not controlled with ICS low-medium dose monotherapy. ICS/LTRA combination resulted in a valid option in view of the heterogeneity of patient response to asthma treatment [16]. However, several randomized controlled trials demonstrated that LABA is superior to LTRA as add-on therapy to ICS for chronic asthma management for preventing exacerbations requiring systemic steroids administration, and for improving lung function, and the use of rescue b2-agonists [17,18]. 2. Mechanisms of actions and efficacy of inhaled corticosteroids Corticosteroids (CSs) are by far the most effective antiinflammatory treatment for asthma and have now become the first-line therapy in all patients with persistent asthma. The predominant effect of CSs is to switch-off multiple inflammatory genes activated during the inflammatory process. Moreover, CSs also act on anti-inflammatory proteins synthesis and exert post-genomic effects [19]. 2.1. Corticosteroid effects on inflammatory genes expression CSs act by binding and activating specific cytosolic CS receptors (CSRs) held mainly in the cytosol in a resting state. Once activated CSRs translocate into the cell nucleus where regulate inflammatory genes expression The activated CSR can either induce the expression of anti-inflammatory genes by direct or indirect binding of transcription factors AP-1 and NF-kB or repress the transcription of inflammatory genes by interacting with pro-inflammatory transcriptional factors, thereby preventing their binding to specific DNA sites and consequently inhibiting inflammatory genes expression [20]. The molecular pathways regulating inflammation-related gene expression are quite delineated, and it clearly appears that chromatin remodeling plays a critical role in the gene transcription control. Several stimuli switch on inflammatory genes by changing the chromatin structure and CSs can reverse this process. It has been demonstrated that histones, the basic units of chromatin, are involved in regulation of gene expression determining which genes are active or inactive. The resting “closed” chromatin structure is associated with suppression of gene expression, while the activated “open” chromatin is the key and mandatory step to initiate gene transcription. The transition between the two conformations of chromatin is mediated by histone acetyltransferase activity: histone acetylation and deacetylation are respectively associated with gene transcription and gene silencing. These mechanisms apply

also to the regulation of inflammatory genes in asthma [19]. Both in vitro experiments on lung adenocarcinoma A549 cells and ex vivo studies on bronchial biopsies from asthma patients showed an increase in acetylation and a reduction in deacetylation activities. Moreover, increased deacetylation and decreased acetylation are observed in asthma patients on CS therapy [21,22]. 2.2. Corticosteroid effects on airway vasculature Tracheobronchial vasculature alterations such those occurring in neoangiogenesis, increased blood flow and vascular permeability, leukocyte recruitment and edema formation in the airway wall are hallmarks of asthma disease. The CS anti-inflammatory activity exerted by regulating gene expression requires hours to be effective, because of the multiple steps of intracellular events required to modulate protein expression. Therefore, the genomic data on CS regulation of inflammatory genes expression, do not fully explain the rapid effects observed on airway vasculature upon administration of CS, such as acute reduction in bronchial blood flow and the blanching skin outcome, representing itself an acute vasoconstrictor effect [23]. It is widely demonstrated that ICSs acutely suppress airway hyperperfusion associated with asthma. Evidence suggests that CSs modulate sympathetic control of vascular tone thus decreasing airway blood flow. It has been shown that inhaled fluticasone propionate decreases airway mucosal blood flow, both in healthy and asthmatic subjects, with a maximal effect 30 min after treatment [24] and that a pretreatment with a selective a1-adrenoreceptor antagonist (5 mg terazosin), inhibits the effect of fluticasone propionate [23]. These data suggest that CSs facilitate the transmission of noradrenergic signals o stimulate neurogenic vasoconstriction [25]. On the contrary, CSs inhibit the uptake of norepinephrine [26] increasing both sympathetic signal transmission and vascular tone [23,27]. This effect reduces the reuptake of norepinephrine released from the airway nerves and it may explain the a1-adrenoreceptordependent vasoconstrictor action of CSs. 2.3. Corticosteroid effects on phosphorylation pathways CSs exert their activity within minutes, by means of signaling mechanisms that do not require CSR-mediated transcription or translation (both processes taking a few hours to be accomplished). These actions are mediated by the activation of CSR signal transduction pathways such as the mitogen-activated protein kinase (MAPK) pathway. CSR (both cytosolic and membrane-bound) is a phosphoprotein with several phosphorylation sites specific for ERK, p38 MAPK, protein kinase C, and protein kinase A. Altered CSR phosphorylation status can affect GR-ligand binding [28] as well as CS-CSR complex translocation from the cytosol to the nucleus [29], thus affecting CS actions on target cells. Indeed, cells respond differently to CSs during the cell cycle phases, being less sensitive to CS activity during G2/M, when CSR are hyperphosphorylated [29]. Data from patients on CS treatment for asthma showed a negative correlation between p38 MAPK activity and patients' response to CS therapy [30]. 2.4. Corticosteroid effects on cells and mediators of inflammation CSs have direct inhibitory effects on many cell types involved in asthma-related airway inflammation, including macrophages, Tlymphocytes, eosinophils, mast cells, and airway smooth muscle and epithelial cells [31]. Humoral (bronchoalveolar lavage; BAL), bioptic (endobronchial tissue) and necroptic specimens have clearly shown that mast cells

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and eosinophils are the primary effector cells of the inflammatory component of asthma, with T lymphocytes playing a coordination role [8]. Clinical data have clearly shown that ICS treatment reduces the number of mast cells, macrophages, T-lymphocytes and eosinophils in sputum, bronchoalveolar lavage and bronchial wall sample in asthma patients [8,9,32]. Moreover, ICSs reverse epithelial cells shedding, goblet-cell hyperplasia, basementmembrane thickening [9,33] and reduce the increased airway wall vascularization observed in the airway mucosa of asthmatics [34]. Eosinophils appear as the inflammatory component of asthmatic airways most responsive to CS treatment. In vitro data show that CSs decrease cytokineemediated survival of eosinophils by stimulating apoptosis [35]. This process may explain the reduction in the number of eosinophils in the circulation and airways of patients with asthma during CS therapy [8,9]. Importantly, in patients with well-controlled persistent asthma, tapering of ICSs induces exacerbation within a few months, associated with a reversible increase of eosinophils-mediated airway inflammation [36]. Clinical studies showed a wane in PEF and FEV1, with a flare-up of eosinophils in sputum during corticosteroid-tapering phase [36], together with suppression of eosinophilic airway inflammation upon ICS treatment [36]. Comparison of CS withdrawal-induced exacerbations with the spontaneous ones, showed that only induced exacerbations are associated with increased eosinophils percentages in sputum and airway responsiveness to indirect stimuli [8,9,36e40]. The number of other inflammatory cells, including total T lymphocytes or CD4þ and CD8þ subsets is not affected by CSs. However, even though the absolute number of T lymphocytes is invariant in asthmatic patients, a significant increase in the expression of HLA-DR and CD25 (both established markers of T cell activation) has been shown on T cells recovered by BAL, but not in peripheral lymphocytes [41]. On the other hand, ICS administration normalizes the expression levels of these markers on BAL T cells [42]. In contrast, CSs either have no effect on, or may even augment neutrophil-mediated inflammation through negligible (if any) suppression of leukotriene production, increased superoxide production, as well as inhibition of cell apoptosis [43]. In vitro and in vivo data on inflammatory cells with a prominent role in asthma suggest that CSs may substantially reduce the inflammatory pathways driven by eosinophils and lymphocytes, while are neglecting or even enhancing the neutrophil-mediated pathways. Beside the analysis of induced sputum, the nitric oxide (NO) level in exhaled air (fractional exhaled NO, FENO) is considered a useful biomarker for monitoring disease control in asthma [44]. NO is produced by inducible nitric oxide synthase (iNOS) in a variety of cells of the respiratory tract, both in health and disease, including inflammatory conditions [45e48]. NO concentration is raised in asthmatic patients, while CSs inhibit the activation of iNOS in epithelial cells of asthmatic patients both in vitro and in vivo [49]. In particular, the cells of airway epithelium in asthmatics patients express an increased amount of iNOS and consequently the percentage of exhaled NO in these patients is higher than in normal subjects. These data suggest that the CS-mediate reduction of exhaled NO is due, at least in part, to suppression of epithelial iNOS expression [50]. Clinical studies have demonstrated a correlation between ICS administration and FENO value, showing a reduction in exhaled NO in asthmatic patients after oral or inhaled steroids [49]. Interactions of innate and adaptive immune cells and the related cytokines play an important role in airway inflammation. It was reported that airway inflammation in asthma was orchestrated

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mainly by T helper (Th) 2 cells [45e47], through secretion of a cluster of cytokines, including interleukins IL-3, IL-4, IL-5, IL-9, IL13 and granulocyte macrophage colonyestimulating factor (GMCSF) [51]. However, some recent studies have shown potential collaboration from other Th cells and the related cytokines: Th17 [52,53], Th9, Th22 and Th25 are also important to initiate allergic reactions and start developing the airway inflammation process [54]. Therapeutic effects of CSs can be ascribed to the strong inhibitory effect on the production of pro-inflammatory cytokines and chemokines [55]. 3. Inhaled corticosteroid and bronchial hyperresponsiveness in asthma Bronchial hyperresponsiveness (BHR) and airway inflammation are established features of asthma. Airway hyperresponsiveness is characterized by the increase of sensitivity and maximal response of airways to bronchoconstrictor agents [56e58]. Increased sensitivity is associated with epithelial damage or dysfunction [59], abnormal autonomic control [58], or increased number and/or activity of inflammatory cells [60]. Increased maximal response may be related to enhanced shortening of airway smooth muscle [58,61] or thickening of the airway wall as a consequence of inflammatory processes [58]. Therefore an increased maximal response can determine excessive airway narrowing, the potentially hazardous component of BHR, in asthmatic patients [58] and adequate treatment of asthma should limit or even prevent this feature [56,58]. Bronchodilators, such as b2-agonists, are the most effective agents reducing hypersensitivity [62] but they do not affect excessive airway narrowing [63]. On the other hand, ICSs have only a modest long-term effect on airway hypersensitivity but significantly decrease excessive airway narrowing in mild asthma [38,58,64]. Several data support the hypothesis that inflammatory processes in the airway wall are responsible for airway narrowing in asthma. Therefore, according to the available data, an adequate therapy for asthma should include anti-inflammatory drugs such as ICS. Moreover, the results from a study in 1991 showed for the first time that anti-inflammatory treatment with ICSs can reduced airway narrowing in asthmatic patients to levels similar to those of healthy subjects [58]. ICS treatment constantly decreases AHR [55] and long-term therapy with this class of inhaled drugs reduce airway responsiveness to both direct and indirect stimuli (cholinergic agonists, allergens, bradykinin, histamine, adenosine, exercise, fog, cold air, and irritants) [55,57]. Improvements occur quickly within a few hours, even though for reaching the maximum effect, several months of therapy may be needed to obtain maximal reduction in airway hyperresponsiveness. Therapy discontinuation usually reverts the positive therapeutic effect to pre-treatment levels [55,65,66]. 4. Intrinsic properties of inhaled corticosteroids Inhalation is the preferred route of CS administration for treatment of asthma. Inhaled drugs reach the lung directly, where they can exert action locally, thus minimizing potential systemic sideeffects associated with oral or parenteral administration. Beclomethasone dipropionate (BDP), budesonide, fluticasone propionate (FP), ciclesonide, flunisonide, triamcinolone acetate and mometasone furoate (MF) are topical, inhaled, corticosteroids available for asthma treatment. Bioavailability, receptor-binding and half-life, contribute to pharmacokinetics and pharmacodynamics profiles, thus determining efficacy and safety features of an ICS (Table 1) [55,67,68].

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Potency of CSs is usually measured in vitro by binding affinity tests to CS receptors in lung tissue cells and by CS ability to induce cutaneous vasoconstriction. However, other factors need to be evaluated when assessing ICSs in clinical practice. The pharmacological characteristics contributing to optimization of the therapeutic profile of an ICS include low oral bioavailability, high pulmonary bioavailability, high receptor and a long pulmonary retention time. Because of these characteristics, the efficacy of an ICS is influenced also by the delivery device and by the mechanism of action of the drug. The effect exerted by an ICS depends on its deposition in the airways. The systemic absorption of CSs determines the systemic bioavailability and therefore the potential systemic side effects. The fraction of drug that enters directly into the systemic circulation depends on the efficiency of absorption of the dose deposited in the lower airways, and on the efficiency of the first-pass liver metabolism of the portion absorbed from the gastrointestinal tract. A low oral bioavailability reduces the systemic bioavailability. Accordingly, the newest class of ICS has a reduced oral bioavailability: beclomethasone dipropionate and budesonide has 41% and 11% respectively of oral bioavailability, while fluticasone propionate, ciclesonide and mometasone furoate score less than 1% [55,67]. Moreover, fluticasone propionate has a clearance rate similar to the normal rate of liver blood flow (69 and 81 L/h, respectively) [69,70]. This systemic clearance rate allows fluticasone propionate to undergo a high level of first-pass metabolism, thus contributing to maintain a low systemic availability [68]. Lipophylicity of ICSs positively correlates to pulmonary retention and duration of action [67,69]: the more lipophylic an ICS is, the more slowly it is released from the lung. Among available ICSs, fluticasone propionate is the most lipophylic, thus exerting a long lasting anti-nflammatory action [67,68]: budesonide takes 6 min to diffuse into bronchial fluid, while fluticasone propionate needs up to 8 h [55]. According to CSR-binding affinity, high ligand-receptor capacity associates with decreased risk of systemic effects, because the systemic availability of the drug is reduced [68] Among the ICSs currently used in asthma therapy, fluticasone, ciclesonide and mometasone have the highest CSR-binding properties [69]. The relative receptor-binding affinity (versus dexamethasone) of fluticasone is second only to mometasone however, the inhalation halflife of mometasone is much lower than that of fluticasone [71]. According to the glucocorticoid receptor affinity, the relative potencies of ICS are: fluticasone propionate > budesonide > beclomethasone propionate > triamcinolone acetonide > flunisolide [50].

ICS may improve control of symptoms, but worsen the tolerability profile of the drug. Studies on fluticasone propionate did not show statistically significant differences between 400 and 500 mg and 800e1000 mg, and between 50 and 100 mg and 800e1000 mg [73]. However, in some case of severe asthma, the use of high doses of FP may allow for a reduction in oral prednisolone administration. Table 2 reports the clinical equivalent doses divided of ICS [55].

5. Inhaled corticosteroid dose-response

6.2. Corticosteroid receptor-mediated mechanisms

All ICSs show a dose-response relationship in terms of efficacy, however, most of the therapeutic benefits are obtained with lowmoderate dose of each ICS [72]. In some patients, high doses of

Increased expression of the beta isoform of CSR (CSRb), might be involved in CS resistance in asthma, as it has been observed that CSRb acts as a competitor of the a isoform of CSR (CSRa)

6. CS resistance Approximately 5e10% of asthmatic patients do not get beneficial response to high doses of CSs [55]. One-third of patients of these patients is on daily oral dose of CS for their asthma [55,74] and are classified as ‘corticosteroid-dependent’. In corticosteroiddependent patients a reduction of the maintenance CS dose worsens asthma control, while a dose escalation improves asthma symptoms. The dose of oral CS needed to satisfactorily control asthma contributes to significant side-effects such as osteoporosis, skin bruising, diabetes and obesity, but may not completely reverse chronic airflow limitation [55,74]. Multicentre trials were conducted on patients with severe asthma, which were dependent on oral CS (on top of ICS therapy) for asthma control, aimed at testing the effect of ICSs as OCSsparing agents [72,75]. The results of these studies showed that inhaled fluticasone propionate 2000 mg/day in patients receiving prednisolone 9.5e10.2 mg/d resulted in either discontinuation or reduction of oral CS treatment [72]. There is a range of steroid responsiveness, spanning from the very rare resistance to the relative resistance observed in asthmatic patients requiring high doses of ICS (steroid-dependent asthma). It is conceivable that several different mechanisms may contribute to the resistance to CS effects, with a possible variability of these mechanisms among patients [19,76,77]. 6.1. Mitogen-activated protein kinase mechanisms Several cytokines, namely IL-2, IL-4 and IL-13, which are present at increased levels in patients with steroid-resistant asthma, are likely to induce a reduction of the affinity of CS-CSR complex T lymphocytes, thus causing resistance to the anti-inflammatory actions of CS [78,79]. IL-2 and IL-4 have been shown to induce steroid resistance through p38 MAP kinase activation, with consequent phosphorylation of CSRs reducing CS binding affinity [28]. Based on this evidence, p38 MAP kinase inhibitors have been developed to reverse this form of steroid resistance.

Table 1 Pharmacological profiles of inhaled corticosteroids (ICSs) available for asthma treatments (Chung 2009, Tamm 2012, Cazzola 2014). ICS

Relative receptor binding affinityc

Protein binding (%)

Oral bioavailability (%)

Pulmonary bioavailability (%)

Systemic clearance (L/h)

Half-life (h)

Distribution volume (L)

Beclometasonea Beclometasone 17 mono propionateb Budesonide Ciclesonidea Desciclesonideb Fluticasone propionate Mometasone furoate

53 1345 935 12 1200 1800 2300

87 na 88 99 99 90 99

15e20 26e40 11 <1 <1 1 <1

50e60 na 15e30 50 na 20 11

150e230 120 84 152 228e396 66e69 54

0.1 2.7 2.0e2.8 0.4e0.5 3.6e5.1 14.4 4.5

20 424 183e280 207 897e1190 318e859 152e332

a b c

This agent is activated to its active metabolite in the airway. Active metabolite. Receptor-binding affinity is relative to dexamethasone ¼ 100.

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Table 2 Pharmacological profiles of b2-agonists available for asthma treatments [98]. Class of b2-agonist

Agent

Intrinsic activitya (% isoprenaline)

SABA LABA

Albuterol Formoterol

LABA

Salmeterol

ULTRA LABA

Indicaterol

ULTRA LABA ULTRA LABA

Olodaterol Vilanterol

47 90 95 100 38 41 73 99 86 88 70

a

± ± ± ± ± ± ± ± ± ± ±

1 1 0.04 3 1 0.01 1 5 0.02 2 3

Onseta t1/2 (min)

Duration of actiona (min)

11.0 ± 4.0 6±1 5.8 ± 0.7

14.6 ± 3.7 76 ± 14 35.3 ± 8.8

19 ± 5 8.3 ± 0.8 14 ± 1 7.8 ± 0.7

230 ± 55 >720 449 ± 62 >720

na 3.1 ± 0.3

na na

Different values refers to different sources of data na, not available.

[80]. However, patients with reduced responsiveness to CS do not over express CSRb [81e83]. Furthermore, IL-2/IL-4 which are known to induce CS resistance, do not upregulate CSRb expression in mononuclear cells of asthmatic patient. Therefore it is unlikely that this receptor is responsible for CS resistance in asthma [83]. 6.3. Oxidative stress and deacethylase activity In some COPD patients resistant to CS therapy it has been shown that this resistance is due to CS failure in IL-8 and TNF-a inhibition [84,85]. In vitro studies demonstrate that alveolar macrophages from smokers patients are far more resistant to anti-inflammatory agents compared with those from non-smoker ones [86,87]. This can be partially explained by the inhibitory effect of cigarette smoking/oxidative stress on histone deacetylase function, interfering with CS anti-inflammatory action [88]. Since oxidative stress is increased also in patients with severe asthma and during exacerbations [89e91], it is conceivable that the impaired histone deacetylase function may be one of the mechanisms accounting for the CS resistance in these patients. 7. Adverse effects of ICS Several factors are important in determining the topical and systemic effects and therapeutic index of ICS: dose delivered to the patient, potency, deposition, receptor affinity and local retention, distribution, elimination and individual differences in steroid response. 7.1. Local side effects Candidiasis, hoarseness and dysphonia are the major local side effects of ICS treatment. Cough can also be a potential side effect, albeit independent of the administered drug. However, this adverse effect is related to the inhaler device, therefore manageable by switching dry powder inhaler to a metered dose inhaler. Gargling and washes are useful to prevent oral candidiasis and when needed topical antimycotic treatments may be administered. Hoarseness and dysphonia are caused by the local action of ICS deposited on the vocal cords [55]. 7.2. Systemic side effects The systemic side effects are related to the fraction of ICS absorbed from the lung mucosa (ICSs absorbed from gastrointestinal tract are metabolized by the liver). Therefore, incidence and severity of systemic side effects depend on the amount deposited in the lower airways, and hence on the inhaler device [92] The

ideal ICS should settle in the airways for a sufficient period of time to exert the anti-inflammatory function (2e3 h), and then be metabolized in inactive forms before entering the systemic circulation. An high protein binding coefficient in the blood flow is also important, as this minimizes tissue exposure to CS [92] The main issues for systemic side effects are reduction in adrenal function, bone mineral density and growth in children [50]. CSs affect bone turnover by increasing bone resorption and decreasing bone formation thus inducing osteoporosis. Data on monitoring of bone activity markers show that ICS >800e1000 mg/ day (budesonide equivalent) may have systemic effects. However, benefits of ICS therapy prevail over the risks of uncontrolled asthma, having a good safety profile when administered at the recommended dosage [55]. Since bone modeling is higher in children than in adults, particular attention need to be paid on CS treatment in the former. However no effects on bone formation/ degradation rate have been reported at standard pediatric doses of ICS. Treatment with high dose ICSs can cause significant changes in bone turnover, but the effects of these changes during short term treatment are not yet clear [50]. Long term ICS treatment in asthmatic children, may potentially influence somatic growth by reducing collagen turnover [93]. The ICS portion entering the systemic circulation may acutely decrease growth in children, however the effect is temporary and does not seem to affect adult height [94]. Data from a meta-analysis comparing attained height with expected height in asthmatic children treated with oral CSs or ICSs showed a weak, although significant growth impairment in children receiving oral CS, while children treated with ICS attained normal height [50]. Furthermore, there was no statistical evidence of associations between ICS therapy and growth impairment at higher doses or with longer therapy duration. Finally, poor control of asthma may also retard growth [50]. Moderate-high doses of exogenous CSs affect the hypothalamicpituitary-adrenal (HPA) axis, as the presence of exogenous CSs reduces the need for endogenous production [95]. However, the risk of insufficient endogenous adrenalin production due to ICS treatment is very low [95] and dynamic tests of adrenal function have shown no effects of ICSs on adrenal gland responsiveness [50,96]. Patients treated with low-moderate doses (<400 mg/d) of ICS do not require routine monitoring of the HPA axis. Conversely, when highdose ICS therapy is needed or when disease severity require CS administration by additional routes, the morning plasma cortisol levels should be monitored periodically [50] (Ricciardolo 2007). Noteworthy, although ICSs affect the HPA axis: (i) adequate antiinflammatory action is essential for treatment of severe asthma, (ii) ICSs are the most effective anti-inflammatory agents available, and (iii) the effects of ICSs on the HPA axis are fewer than those exerted by equivalent doses of oral CS [95].

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8. Mechanisms of actions and efficacy of inhaled b2-agonists Ephedrine (adrenaline), a non-selective beta-adrenoceptor agonist, was firstly isolated at the end of the 1800s from ma huang, a chinese herb, which has been used for over 5000 thousand years to treat asthma [97]. In 1900s subcutaneous administration of ephedrine was introduced into clinical practice for treatment of acute asthma, then salbutamol and terbutaline appeared as the first truly b2-selective adrenoceptor agonists. The first b2-agonists agents used for asthma treatment had a short duration of action (4e6 h), and are still referred to as short-acting b2-agonists (SABAs). A further step was the development of long-acting b2agonists (LABAs): salmeterol and formoterol, whose duration of action is approximately 12 h [98]. More recently, ultra-LABAs (indacaterol, vilanterol, olodaterol, and abediterol) have been developed, which have a daylong duration of action (24 h) [98,99]. Because of the short half-life, SABAs are currently used only as rescue medications. On the contrary, LABAs and ultra-LABAs provide sustained bronchodilation and therefore are used in maintenance therapies [98]. Usually treatment of acute asthma includes repetitive administration of inhaled SABAs, however it has been reported that high-dose formoterol provides rapid and effective bronchodilation, similar to high-dose SABAs, and diminish the need for repeated rescue medications [100]. b2-agonists act by binding to the b2-adrenergic receptors (ARs). b2 ARs are coupled to a stimulatory G protein, which stimulates adenylyl cyclase. The signaling resulting upon receptor engagement generates intracellular cyclic adenosine monophosphate (cAMP) that in turn activates downstream effectors like protein kinase A (PKA) or Epac, the guanine nucleotide exchange factors for the small G protein Rap [98]. The activation of these pathways leads to a fall in intracellular Ca2þ levels and the activation of Kþ channels, with the consequent hyperpolarization of airway smooth muscle cell membranes, producing muscle relaxation [97]. There are three types of b ARs: b1, b2 and b3. b2 ARs are highly represented in lung tissue: about 70% of pulmonary b-ARs are of the b2 subtype [97]. Essential features for LABA include onset of action, duration of action, selectivity for b2 over b1 (b1/b2 ratio) and intrinsic efficacy (namely the extent to which they activate the receptor) evaluated by means of cAMP production assay (Table 2) [98] Pharmacologically, intrinsic efficacy is the clearest distinguishing feature among available b2-agonists [98,101]. Between the two available inhaled LABA, formoterol demonstrates higher intrinsic efficacy than salmeterol when stimulating cAMP synthesis. Having salmeterol a far lower intrinsic efficacy, it appears as a partial agonist [71]. Highefficacy agonists (e.g. formoterol) cause more phosphorylation and internalization of the receptor than low efficacy agonists (e.g. salmeterol) [71]. However, high-efficacy agonists do not necessarily cause desensitization, as once assumed [101]. Moreover, lowefficacy ligands have a reduced capability of receptor activation, which may not be sufficient to generate a full response, even at full occupancy of available receptors. High efficacy agonists instead allow even a small percentage of receptors to generate a full response, thus leaving a sufficient amount of spare receptors available [71]. Ultra LABA vilanterol and indicaterol showed a comparable level of intrinsic efficacy in stimulating cAMP synthesis with a significantly greater efficacy than salmeterol, being however significantly less effective than formoterol [102]. As regards the secondary effects of b-agonists in the airways, such as tolerance to the functional antagonist effect, two studies on asthmatic patients treated with salmeterol and either low- or moderate-dosage of ICSs reported control of symptoms and lung function, but also increased rate of treatment failure, asthma

exacerbations, and airway inflammation [103,104]. Although the researchers concluded that LABAs enabled a 50% reduction of ICS in most patients, the data suggested treatment failure. This indicates that LABA provide positive effects on symptoms and lung function but have a negative impact on inflammation and exacerbations occurrence [105]. Tolerance to bronchodilation/bronchoprotection occurs both more rapidly and at higher degree with LABAs than with SABAs [105]. Pharmaceutical companies marketing LABAs in USA have been asked by the US Food and Drug Administration (FDA), to provide supportive data from randomized controlled trials, because of the concern on safety profile of LABAs. The results of the FDA metaanalysis, presented to three FDA advisory panels [105], showed that LABAs when administered in combination with ICS, are not associated with an increased risk of death, intubations, or hospital admission for exacerbations. Moreover, when symptom control is achieved, the withdrawal of LABA is associated with consequent symptom exacerbation [105]. 9. Interactions between inhaled corticosteroids and LABAs 9.1. ICS/LABA synergistic effects Combined administration of ICS and LABA has been shown to increase both in vitro and in vivo b2-receptor number and activity. Several studies reported that fluticasone and budesonide enhance retention of LABAS in the airways. This effect is greater with more cationic LABAs such as formoterol than with more lipophylic compounds such as salmeterol [68,106]. 9.2. LABA steroid-sparing effects LABAs, besides acting as bronchodilators themselves, complement the effects of ICSs by interacting with CS signal transduction pathways and thus enhancing transcription of anti-inflammatory mediators. It has been observed that the maximal CS-related responses occur at 10-fold lower concentrations of ICS when administered together with a LABA [68]. The anti-inflammatory effects of LABAs have also been demonstrated in vitro; budesonide combined with either formoterol or salmeterol inhibited inflammatory cytokine release in bronchial epithelial cells by 85% [68], while monotherapy with LABA does not provide important anti-inflammatory effects and it is ineffective in control asthma symptoms compared with ICS alone [68]. Together with the anti-inflammatory effects, ICSs and LABAs exert also anti-proliferative functions on airway smooth muscle cells in vitro. Recent studies suggest that this effect could be different in asthmatic and healthy airway cells [68]. For example, formoterol reduces smooth muscle cell proliferation both in asthmatic and healthy cells; however, signal transduction pathways are different: in the asthmatic cells signaling is delivered via p27Kip (cyclin-dependent kinase inhibitor), while in healthy cells it occurs via p21Waf1. Interestingly, with the addition of a CS, the antiproliferative effects of formoterol doubled in the asthmatic cells [68]. 9.3. ICS/LABA-mediated airway remodeling Bradykinin is a peptide known to mediate several proinflammatory effects. In asthmatic patients bradykinin is involved in the ICS/LABA-sensitive extracellular matrix remodeling of the airways [107]. Combination therapy of the ICS budesonide and the LABA formoterol decrease the thickness of reticular basement membrane

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and bronchial wall in patients with asthma [108]. Moreover, in vitro results underline the impact of LABA on collagen deposition, (a key feature of airway remodeling), therefore highlighting the complementary effects of LABAs and ICSs in asthmatic patient management [68]. It has been shown that in the presence of a CS, formoterol further reduces collagen levels, revealing that LABAs can reduce airway remodeling in asthma and that this effect is enhanced by combination with a CS [68]. 9.4. LABA effect on corticosteroid insensitivity Corticosteroid insensitivity represents a considerable problem in the management of asthmatic patients. Data in vitro demonstrate that some isoforms of p38 MAPK (mitogen-activate protein kinase) inhibit inflammation-induced CSR phosphorylation [109]. p38 MAPKg isoform is involved in CS insensitivity by means of hyperphosphorylation of CSR [109]. Also oxidative stress plays a role in corticosteroid insensitivity via reduction of both expression and activity of HDAC2 enzyme, with consequent reduction of CSR nuclear translocation after steroid binding or by enhanced degradation of the ligand-receptor CSCSR complex [110]. Formoterol is able to inhibit p38 MAPK-g with the consequence of inhibition of CSR phosphorylation. Moreover, it was reported that formoterol, but not salmeterol, inhibited PI3K-dependent phosphorylation induced by oxidative stress (being PI3K another pathway of CSR desensitization). These data suggest that formoterol, alone and in combination with ICS, may induce higher clinical advantages compared with salmeterol for the treatment of respiratory diseases with high level of oxidative stress, like chronic asthma of smoker and COPD [109,111]. 10. LABA/LAMA combination The combination of LABA and ICS is, at present, the most commonly used for asthma treatment. However, LABA/LAMA combination tiotropium þ formoterol has recently been reported to improve FEV1 and FVC more than the ICS/LABA combination salmeterol þ fluticasone [112] and to improve symptom scores and rescue medicine use, compared with tiotropium alone [113]. Treatment with the LABA/LAMA combination has been associated with a greater improvement of the above mentioned parameters than both LABA or LAMA monotherapy [113]. Moreover, LABA/ LAMA combination may be readily coupled with ICS in a single inhaler device [114]. 11. Long-acting anti-muscarinic agents It has been shown that another class of drugs, the long-acting anti-muscarinic agents (LAMA), provide improvements in asthma when added to ICS treatment as an alternative to dose increase in ICS monotherapy. However, atropine (a competitive muscarinic acetylcholine receptor antagonist extracted from deadly nightshade Atropa belladonna) and atropine-derivatives are readily absorbed across the blood-brain barrier, thus causing anti-cholinergic systemic side effects that limit their clinical use [98]. Several synthetic analogs of atropine have been generated and formulated as bromide salts (as tiotropium). These drugs are not delivered efficiently through biological membranes like the bloodbrain barrier. As a consequence, a lower systemic exposure occurs and side effects are reduced [115]. LABAs stimulate b2-adrenergic receptors while LAMAs block the effects of acetylcholine on muscarinic receptors to reverse airway obstruction [116].

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Five distinct muscarinic receptor subtypes have been identified so far (M1-M5), and three of them (M1-M3) are localized in airway smooth muscle [115]. M1 receptors enhance cholinergic reflex bronchoconstriction, M2 receptors act as feedback inhibitors of acetylcholine release, and M3 receptors located on airway smooth muscle cells, lead to bronchoconstriction in response to acetylcholine. Therefore, M2 blockade results in unregulated acetylcholine release (i.e. bronchoconstriction), while M3 blockade prevents acetylcholine-induced bronchoconstriction [115]. Muscarinic receptors are not located only in the airways, therefore anticholinergic agents may potentially generate systemic effects: M2 receptors are also placed on cardiac tissue [117], therefore this receptor subtype may be involved in some cardiac toxicities associated with nonselective or M2-selective anticholinergic agents. Muscarinic antagonists specifically targeting the M3 receptor subtype would be ideal for providing effective bronchodilation and symptom relief with a favorable safety profile [115]. For the treatment maintenance in stable COPD, LAMAs are commonly recommended. Moreover, for the treatment of asthma LAMAs are currently used in parallel to anti-inflammatory therapy, even if they are not indicated by GINA guidelines [115]. Several LAMAs are clinically tested in monotherapy or in combination with known or novel b2-agonists for COPD and a number of these drugs are being under investigation for asthma as well. 12. Adverse effects of LABAs and LAMAs All b2-agonists can possibly induce vasodilation and reflex tachycardia because some of the b2-agonist receptors are present in the heart cells [98,118]. Moreover, b2-agonists administration also induces a small and transient decrease in the partial pressure and b2-agonist receptors engagement in liver cells induces glycogenolysis and raises blood sugar levels [98]. Hypokalemia is also a risk with b2-agonist treatment because of stimulation of the Naþ/Kþ pump coupled to b-agonist receptors in skeletal muscle cells. This results in an increased amount of intracellular potassium and in a reduction of Kþ plasma levels. Such hypokalemia has been correlated both to arrhythmias and the dose-related tremor, being the latter one of the most characteristic b-agonist-related adverse events [98]. Some of the effects of b2-agonists tend to be lost when these drugs are extensively and recurrently used. In particular, upon prolonged use, desensitization to b2-agonists may occur with consequent tolerance to their bronchoprotective effects [98]. The therapeutic margin and the tolerability of the approved LAMAs are quite large, also due to their poor absorption once inhaled. However, the accidental contact with eyes may result in dilation of the pupil and blurred vision. Angle-closure glaucoma worsening has been reported upon ipratropium bromide and tiotropium bromide aerosol treatment [97,119]. LAMAs can cause urinary retention and therefore they should be used with caution in men with prostatic hyperplasia. Because of the same reason, patients with renal impairment should be closely monitored when treated with this class of drugs [97]. Paradoxical bronchoconstriction after LAMA administration has been observed, however it has been associated to the hypotonic and antibacterial features of nebulizer solution. Concerns have been raised about possible associations of LAMA with higher cardiovascular morbidity and mortality [120,121]. According to a systematic review and meta-analysis, a significantly increased mortality risk is associated with the use of the tiotropium bromide mist inhaler. The possible cause may be the more effective drug delivery to the lungs and to systemic circulation, by the novel drug formulation and the characteristics of the specific associated device [122].

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13. Conclusions and discussion According to the recommendations of the International guidelines for asthma management, a LABA should be administered with an ICS in case of not well controlled symptoms upon low dosage of ICS monotherapy [10e11]. The potential efficacy of any ICS/LABA combination depends on the pharmacological properties of the individual component and the characteristics of the delivery device [68]. Anti-inflammatory power of ICS and rapid bronchodilator activity of LABA are mentioned by physicians as two of the most important properties for asthma treatment [71]. Among the available agents, fluticasone propionate and formoterol appear to offer excellent pharmacokinetic and pharmacodynamic profiles when compared with those of the other available ICS and LABA for inhalation therapy [67]. Fluticasone propionate is one of the most powerful ICS [68]. It has a low oral and consequently systemic bioavailability, reducing the incidence of adverse events. It has a significantly stronger antiinflammatory activity due to its high receptor binding and lipophylic properties. Moreover, fluticasone propionate has a pulmonary half-life lung ensuring adequate efficacy and duration of action [67,71]. Formoterol is the most rapid active LABA by inhalation [123] with the bronchodilator activity lasting over 12 h [124]. At present, the use of the combination fluticasone/formoterol is currently viewed as the best therapy for asthma, due both to the beneficial effects of each active principle and to their ability of synergistic interaction, as outlined above. In the future, the possibility of combining Ultra LABA and/or LAMA to ICS (as a triple combined therapy) might lead to additional effects for the control of severe asthma. Moreover, targeting bitter taste receptors with specific drugs may propose a novel scenario and make available additional therapeutic options for asthma management [125]. Disclosure All authors participated to an Editorial meeting hosted by Mundipharma S.r.l., Italy in order to discuss topics to be included in the paper. The paper was completed independently with no funding. Editorial assistance for the publication of this manuscript was provided by HPSdHealth Publishing & Services S.r.l., Milan, Italy with a limited contribution by MundiPharma S.r.l., Italy. Conflict of interest None declared. References [1] J. Swarbrick, Encyclopedia of Pharmaceutical Technology, 3rd illustrated ed, 2007, p. 1170. [2] G. Crompton, A brief history of inhaled asthma therapy over the last fifty years, Prim. Care Respir. J. 15 (2006) 326e331. [3] W.H. Inman, A.M. Adelstein, Asthma mortality and pressurised aerosols, Lancet 2 (1969) 693. [4] T.H. Rossing, C.H. Fanta, D.H. Goldstein, et al., Emergency therapy of asthma: comparison of the acute effects of parenteral and inhaled sympathomimetics and infused aminophylline, Am. Rev. Respir. Dis. 122 (1980) 365e371. [5] D.A. Warrell, D.G. Robertson, J.N. Howes, et al., Comparison of cardiorespiratory effects of isoprenaline and salbutamol in patients with bronchial asthma, Br. Med. J. 1 (1970) 65e70. [6] J. Crane, N. Pearce, A. Flatt, et al., Prescribed fenoterol and death from asthma in New Zealand, 1981-83: case-control study, Lancet 1 (1989) 917e922. [7] J. Grainger, K. Woodman, N. Pearce, et al., Prescribed fenoterol and death from asthma in New Zealand, 1981-7: a further case-control study, Thorax 46 (1991) 105e111. [8] R. Djukanovic, J.W. Wilson, K.M. Britten, et al., Effect of an inhaled corticosteroid on airway inflammation and symptoms in asthma, Am. Rev. Respir.

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