In vitro evaluation of the immunomodulatory activity of the nutraceutical formulation AminoDefence.

Immune system (IS) functionality is warranted by inter-dependent processes that balance body defences without exceeding in inflammation. An ideal nutraceutical approach should sustain the protective IS activity while controlling inflammation. The potential immunomodulatory activity of the food supplement (FS) AminoDefence was studied in resting macrophages RAW264.7 and following stimulation of bacterial- and viral-associated inflammation trough LPS and PolyI:C treatments, respectively. In unstimulated macrophages, the formulation exerted a dose-dependent immunostimulant activity by up-regulating NO, IL-6, TNF-α and MCP-1 release, while it dampened the aberrant release of these factors induced by pro-inflammatory stimuli. Exploring the contribution of single components Echinacea purpurea (E. purpurea) extract and quercetin, used at proportional concentrations than in whole formulation, a more pronounced immunostimulant effect was observed for E. purpurea, and an anti-inflammatory activity for quercetin. Hence, AminoDefence exerts an immunomodulatory activity in macrophages by effectively stimulating a protective inflammatory response and limiting it in cases of excessive inflammation.

Morniflumate in the treatment of upper airways affections in adults: a review and meta-analysis.

INTRODUCTION: We compared, by a meta-analytic process, the antipyretic and symptomatic activity, and the safety profile of morniflumate (ATC code: M01AX22) with those of other commonly used non-steroidal anti-inflammatory drugs (NSAIDs) in acute ear, nose and throat (ENT) diseases. EVIDENCE ACQUISITION: Our search strategy was performed in various database, included Google Scholar, PubMed and Embase, the key word was "morniflumate". Interventional studies in adults with ENT or lower airway inflammatory diseases were compared in a meta-analysis for the number of symptom-free and fever-free patients at day 3 of therapy, and of drug interruptions due to adverse events (AEs). For symptoms, we included only studies on ENT inflammatory diseases; for fever and AEs, we also considered studies on lower airway inflammatory diseases. Of 33 studies retrieved, 8 (24.2%) met the inclusion criteria and compared morniflumate to placebo, nimesulide, paracetamol and other NSAIDs. EVIDENCE SYNTHESIS: On day 3, the number of symptom-free patients was significantly higher with morniflumate vs placebo and nimesulide (+20% and +30%, respectively) and similar to the other comparators. The number of fever-free patients significantly increased (up to 70%) with morniflumate vs all comparators except paracetamol (similar). No difference was found in the number of AE-related interruptions. CONCLUSIONS: morniflumate showed good antipyretic and symptomatic activity and a short-term safety profile at least comparable to that of other NSAIDs.

Why small particle fixed dose triple therapy? An excursus from COPD pathology to pharmacological treatment evolution.

Although bronchodilators are the cornerstone in chronic obstructive pulmonary disease (COPD) therapy, the treatment with a single-agent bronchodilator may not provide adequate symptoms control in COPD. The combination of drugs with different mechanisms of action may be more effective in inducing bronchodilation and preventing exacerbations, with a lower risk of side-effects in comparison with the increase of the dose of a single molecule. Several studies comparing the triple therapy with the association of long-acting ß2 agonist (LABA)/inhaled corticosteroid (ICS) or long-acting muscarinic antagonist (LAMA)/LABA reported improvement of lung function and quality of life. A significant reduction in moderate/severe exacerbations has been observed with a fixed triple combination of beclometasone dipropionate (BDP), formoterol fumarate (FF) and glycopyrronium (G) in a single inhaler. The TRILOGY, TRINITY and TRIBUTE studies have provided confirming evidence for a clinical benefit of triple therapy over ICS/LABA combination treatment, LAMA monotherapy and LABA/LAMA combination, with prevention of exacerbations being a key finding. A pooled post hoc analysis of the published clinical studies involving BDP/FF/G fixed combination demonstrated a reduction in fatal events in patients treated with ICS-containing medications, with a trend of statistical significance [hazard ratio = 0.72, 95% confidence interval (CI) 0.50-1.02, p = 0.066], that becomes significant if we consider reduction in fatal events for non-respiratory reasons (hazard ratio = 0.65, 95% CI 0.43-0.97, p = 0.037). In conclusion, a fixed combination of more drugs in a single inhaler can improve long-term adherence to the therapy, reducing the risk of exacerbations and hospital resources utilization. The twice a day administration may provide a better coverage of night, particularly in COPD patients who are highly symptomatic. The inhaled extrafine formulation that allows drug deposition in both large and small - peripheral - airways, is the value added.

Beclomethasone/Formoterol in Extra-Fine Formulation Improves Small Airway Dysfunction in COPD Patients.

INTRODUCTION: In patients with chronic obstructive pulmonary disease (COPD), small airway dysfunction (SAD) is a key element and a functional consequence of the pathology. The exact role of SAD as a specific 'pharmacological target' represents an important research topic. Our objective was to ascertain whether an extra-fine formulation of beclomethasone dipropionate/formoterol fumarate (BDP/FF) NEXThaler® 100/6 µg b.i.d. could improve SAD and, consequently, the quality of life of COPD patients. METHODS: We enrolled COPD patients with severe airflow obstruction and at least one moderate exacerbation in the previous year, having started treatment with BDP/FF NEXThaler® for no more than 1 week. Patients underwent three visits: at the start of the treatment (V1), 6 weeks (V2), and 12 weeks later (V3). At each visit, we evaluated the fall in resistance from 5 to 20 Hz (R5-R20) and residual volume/total lung capacity (RV/TLC) ratio by impulse oscillometry, spirometry, and plethysmography. The COPD Assessment Test (CAT) and the modified Medical Research Council (mMRC) questionnaire were also administered to assess the disease's impact on quality of life. RESULTS: We enrolled 43 COPD patients (mean age 69 years, FEV1 43%). R5-R20 significantly changed from baseline [0.23 ± 0.09 kPa/(l/s)] to V2 [0.16 ± 0.09 kPa/(l/s)] and V3 [0.16 ± 0.08 kPa/(l/s)] (p < 0.05). Clinical status was also significantly improved compared to baseline; in fact, CAT score changed from an average baseline value of 13-6 and 4 (V2 and V3, respectively) (p < 0.05). A correlation was found between CAT percentage change values and the corresponding ones of R5-R20 (r = - 0.329, p = 0.045) and RV/TLC (r = 0.354, p = 0.029). CONCLUSIONS: In COPD patients, treatment with BDP/FF extra-fine formulation improved functional parameters related to small airway disease as well as the disease impact on health status. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04421742.

Consequences of not-shaking and shake-fire delays on the emitted dose of some commercial solution and suspension pressurized metered dose inhalers.

BACKGROUND: Pressurized metered-dose inhalers (pMDIs) include hydrofluoroalkane (HFA) propellant to generate a drug aerosol upon actuation and drugs can be formulated as solution or suspension. Suspended particles can cream or sediment depending on density differences between drug and propellant and shaking the pMDI is an essential step to ensure a uniform drug dose release. RESEARCH DESIGN AND METHODS: The effect of the delay (0, 10, 30, 60 seconds) in pMDI actuation after shaking and the effect of no-shaking during the canister life on the emitted dose (ED) for commercial solution and suspension pMDIs was investigated. RESULTS: The ED for solutions was unaffected by no-shaking or by the progressive increasing delay in actuation after shaking (between 77% and 97%). For all the suspension products, shaking was demonstrated to be critical to assure the close to nominal drug delivery. In detail, the actuation delay after shaking led to an increase up to 380% or a drop to 32% of ED in relation to the label claim with high variability. CONCLUSION: The drug delivered can vary widely for no-shaking and over different shake-fire delays with suspension pMDIs while solution formulations appear to remain stable.

Small airway inflammation and extrafine inhaled corticosteroids plus long-acting beta2-agonists formulations in chronic obstructive pulmonary disease.

OBJECTIVES: To summarize the evidence of small airways involvement in chronic obstructive pulmonary disease (COPD) pathophysiology, and to evaluate the efficacy of extrafine formulations of inhaled corticosteroids (ICS) in combination with long-acting beta2-agonists (LABAs) in the treatment of COPD. DATA SOURCE: A search of the PubMed database was conducted using the keywords "COPD", "small airways", "inflammation" and "extrafine formulation." The search was limited to entries published in English before August 2016. Only studies conducted in humans were considered. STUDY SELECTION: Publications were included on the basis of relevance. RESULTS: COPD is a common preventable and treatable disease, characterized by persistent and progressive airflow limitation. With improved understanding of COPD pathophysiology, small airways (internal diameter <2 mm), a well-known major site of COPD-associated inflammation and remodeling, have emerged as a potential target for COPD pharmacologic therapies. The ability of extrafine formulations of ICS in combination with LABAs to achieve central and peripheral lung deposition, and the implications of the enhanced efficacy that this may bring, are discussed by examining findings from the development trials plan of the extrafine formulation of beclometasone dipropionate/formoterol fumarate (Foster®, Chiesi Farmaceutici, Italy) in patients with COPD. CONCLUSION: There is an urgent need for improved and reliable techniques for small airways assessment in order to detect early damage, disease progression and response to treatment. Evidence from randomized clinical trials supports the benefits of extrafine ICS/LABA formulations in COPD, real world studies are necessary to confirm this.

Maintaining Control of Chronic Obstructive Airway Disease: Adherence to Inhaled Therapy and Risks and Benefits of Switching Devices.

Asthma and chronic obstructive pulmonary disease (COPD) are major obstructive airway diseases that involve underlying airway inflammation. The most widely used pharmacotherapies for asthma and COPD are inhaled agents that have been shown to be effective and safe in these patients. However, despite the availability of effective pharmacologic treatment and comprehensive treatment guidelines, the prevalence of inadequately controlled asthma and COPD is high. A main reason for this is poor adherence. Adherence is a big problem for all chronic diseases, but in asthma and COPD patients there are some additional difficulties because of poor inhalation technique and inhaler choice. Easier-to-use devices and educational strategies on proper inhaler use from health caregivers can improve inhaler technique. The type of device used and the concordance between patient and physician in the choice of inhaler can also improve adherence and are as important as the drug. Adherence to inhaled therapy is absolutely necessary for optimizing patient control. If disease control is not adequate despite good adherence, switching to a more appropriate inhaled therapy is recommended. By contrast, uninformed switching or switching to less user-friendly inhaler may impact disease control negatively. This critical review of the available literature is aimed to provide a guidance protocol on when a switch may be recommended in individual patients.

Small airway dysfunction and flow and volume bronchodilator responsiveness in patients with chronic obstructive pulmonary disease.

BACKGROUND: We investigated whether a relationship between small airways dysfunction and bronchodilator responsiveness exists in patients with chronic obstructive pulmonary disease (COPD). METHODS: We studied 100 (20 female; mean age: 68±10 years) patients with COPD (forced expiratory volume in 1 second [FEV1]: 55% pred ±21%; FEV1/forced vital capacity [FVC]: 53%±10%) by impulse oscillometry system. Resistance at 5 Hz and 20 Hz (R5 and R20, in kPa·s·L(-1)) and the fall in resistance from 5 Hz to 20 Hz (R5 - R20) were used as indices of total, proximal, and peripheral airway resistance; reactance at 5 Hz (X5, in kPa·s·L(-1)) was also measured. Significant response to bronchodilator (salbutamol 400 µg) was expressed as absolute (≥0.2 L) and percentage (≥12%) change relative to the prebronchodilator value of FEV1 (flow responders, FRs) and FVC (volume responders, VRs). RESULTS: Eighty out of 100 participants had R5 - R20 >0.03 kPa·s·L(-1) (> upper normal limit) and, compared to patients with R5 - R20 ≤0.030 kPa·s·L(-1), showed a poorer health status, lower values of FEV1, FVC, FEV1/FVC, and X5, along with higher values of residual volume/total lung capacity and R5 (P<0.05 for all comparisons). Compared to the 69 nonresponders and the 8 FRs, the 16 VRs had significantly higher R5 and R5 - R20 values (P<0.05), lower X5 values (P<0.05), and greater airflow obstruction and lung hyperinflation. CONCLUSION: This study shows that peripheral airway resistance is increased in the vast majority of patients with COPD, who showed worse respiratory reactance, worse spirometry results, more severe lung hyperinflation, and poorer health status. Small airway dysfunction was also associated with the bronchodilator responsiveness in terms of FVC, but not in terms of FEV1.

Effect of Ambroxol and Beclomethasone on Lipopolysaccharide-Induced Nitrosative Stress in Bronchial Epithelial Cells.

BACKGROUND: Nitrosative stress is involved in different airway diseases. Lipopolysaccharide (LPS) induces neutrophil-related cytokine release and nitrosative stress in human bronchial epithelial (BEAS-2B) cells alone or with human polymorphonuclear neutrophils (PMNs). Ambroxol protects against oxidative stress, and beclomethasone dipropionate is an anti-inflammatory drug. OBJECTIVES: We evaluated the ability of ambroxol and/or beclomethasone dipropionate to inhibit LPS-induced expression/release of RANTES, IL-8, inducible NO synthase (iNOS), myeloperoxidase (MPO) and 3-nitrotyrosine (3-NT: nitrosative stress biomarker) in BEAS-2B ± PMNs stimulated with LPS (1 µg/ml). METHODS: The effect of ambroxol and/or beclomethasone dipropionate on IL-8, RANTES and iNOS levels was assessed by Western blot analysis; IL-8, MPO and 3-NT levels were measured by ELISA. Cell viability was assessed by the trypan blue exclusion test. RESULTS: In BEAS-2B alone, LPS (at 12 h) increased RANTES/iNOS expression and IL-8 levels (p < 0.001). Ambroxol suppressed LPS-induced RANTES expression and IL-8 release (p < 0.001), whilst inhibiting iNOS expression (p < 0.05). Beclomethasone dipropionate had no effect on RANTES but halved iNOS expression and IL-8 release. Coculture of BEAS-2B with PMNs stimulated IL-8, MPO and 3-NT production (p < 0.001), potentiated by LPS (p < 0.001). Ambroxol and beclomethasone dipropionate inhibited LPS-stimulated IL-8, MPO and 3-NT release (p < 0.05). Ambroxol/beclomethasone dipropionate combination potentiated the inhibition of IL-8 and 3-NT production in BEAS-2B with PMNs (p < 0.05 and p < 0.01, respectively). Ambroxol and/or beclomethasone dipropionate inhibited nitrosative stress and the release of neutrophilic inflammatory products in vitro. CONCLUSION: The additive effect of ambroxol and beclomethasone dipropionate on IL-8 and 3-NT inhibition suggests new therapeutic options in the treatment of neutrophil-related respiratory diseases such as chronic obstructive pulmonary disease and respiratory infections.

Assessing and accessing the small airways; implications for asthma management.

Despite the wealth of experience in the management of asthma, the disease remains inadequately controlled in some patients, who face long-term respiratory impairment and disability. The disease has been characterised as an inflammatory condition affecting first the larger airways and eventually the smaller airways, but there is evidence that peripheral airway involvement defines a particular and more severe phenotype of asthma. For this reason, assessing functional and biological parameters reflective of small airways involvement is important prognostically. No assessment method is universally and directly representative of peripheral airway function, but the traditional spirometric tests, including vital capacity, residual volume and forced vital capacity, are somewhat correlated with this function; useful methods for further assessment include the single-breath nitrogen wash-out test, impulse oscillometry, nitrous oxide and exhaled breath concentrate measurements, as well as computed tomography to reflect air trapping and response to treatment. Formulation advancements have made for easier treatment access to the smaller airways, with the new extrafine formulations resulting in better asthma control compared with non-extrafine formulations.

Ambroxol: a multifaceted molecule with additional therapeutic potentials in respiratory disorders of childhood.

INTRODUCTION: Mucoactive drugs are currently used to cleanse the respiratory tract following disturbance of the normal mucociliary clearance due to mucous hyperproduction and/or modification of its physicochemical characteristics. However, in addition to possessing the ability to perform specific actions on airway secretion, these compounds have the capability to modulate the mechanisms involved in abnormal secretions. Indeed, over the years, in the postmarketing phase, a large number of studies have been published showing interesting pharmacological activities in addition to their secretagogue activity. AREAS COVERED: This article collates available data on ambroxol (2-amino-3,5-dibromo-N-[trans-4-hydroxycyclohexyl]benzylamine), a metabolite of bromhexine, used as a secretagogue in the treatment of childhood airway diseases. This article goes beyond the mucoactive aspects of the drug covering its multiple pharmacological properties. EXPERT OPINION: The non-mucoactive functions exhibited by the compound may provide beneficial effects on airway structure and function in health and disease. Beyond the mucokinetic and secretagogue effects, ambroxol showed great antioxidant, anti-inflammatory, local anesthetic and surfactant synthesis stimulatory activities. Moreover, some antiviral and antibacterial activities were shown. These findings may better explain the clinical results observed in a variety of airway disorders and suggest additional therapeutic potential. Further studies are needed to better define the clinical relevance of these non-mucolytic activities.