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Mario Cazzola,1 Paola Rogliani,1 Rossella Laitano,1 Luigino Calzetta,2 Maria Gabriella Matera3 1Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy; 2Unit of Respiratory Diseases and Lung Function, Department of Medicine and Surgery, University of Parma, Parma, Italy; 3Unit of Pharmacology, Department of Experimental Medicine, University of Campania Luigi Vanvitelli, Naples, ItalyCorrespondence: Mario Cazzola Email mario.cazzola@uniroma2.itAbstract: Although pharmacological treatment of COPD is codified in different guidelines and strategy documents, there is abundant evidence of discrepancy between what they suggest and what health professionals prescribe, especially in low-risk groups where there is widespread overprescription of triple therapy. It is therefore necessary to clarify when the use of triple therapy is indicated in COPD patients and when it is preferable to maintain treatment with dual bronchodilation. In this article, we discuss our views based on our experience and what is reported in the literature and try to give answers to these two questions. The evidence generated by pivotal RCTs supports the use of triple therapy in patients who present for the first time and have severe airway obstruction, are symptomatic, have had frequent moderate or severe exacerbations in the previous year, and have peripheral eosinophilia. However, it is difficult to determine whether step-up is useful in all other cases because the available data are quite conflicting. It is likely that the inconsistency in the information generated by the various available studies may explain the prescribing behaviour of many physicians who do not adhere to recommendations of guidelines and strategies. However, it is necessary to establish whether and when the addition of an ICS to the LAMA/LABA combination is effective, to determine whether triple therapy can induce an additional clinical benefit over dual bronchodilation, irrespective of a preventive effect on COPD exacerbations, to establish its value, and to examine whether cost differences can support the use of triple therapy over combined LAMA/LABA therapy in real life.Keywords: dual bronchodilation, triple therapy, ICSs, LABs, LAMAs

Objectives: The recent publication of additional data retrieval for patients missing week 52 vital status in the original analyses of the ETHOS study provides the urgent need of updating previous network meta-analyses (NMA) to produce stronger evidence on mortality in patients receiving dual and triple FDCs according with the level of ICS dose. Methods: A NMA was performed to compare the effect of ICS/LABA/LAMA, ICS/LABA, and LABA/LAMA FDCs administered via the same inhaler device in COPD patients. The number need to treat (NNT) was also calculated. Results: When considering on-treatment all-cause of death (analyzed patients: 18,864), MD ICS/LABA/LAMA and MD ICS/LABA FDCs significantly reduced the risk of mortality vs. LABA/LAMA FDC (RR 0.59 95%CrI 0.35–0.97 and 0.61 95%CrI 0.38–0.99 respectively, P

The management of chronic obstructive pulmonary disease (COPD) is fundamentally still heavily dependent on the use of bronchodilators and corticosteroids. Therefore, there is a need for alternative, more effective and safer therapeutic approaches. In particular, since inflammation in COPD lungs is often poorly responsive to corticosteroid treatment, novel pharmacological anti-inflammatory approaches are needed to optimally treat COPD patients. There have been multiple attempts to develop drugs that inhibit recruitment and activation of inflammatory cells, such as macrophages, neutrophils and T-lymphocytes, in the lungs of patients with COPD or target inflammatory mediators that are important in the recruitment or activation of these inflammatory cells or released by such cells. This review article focuses on novel classes of anti-inflammatory drugs that have already been tested in humans as possible treatments for patients with COPD.

There is no justification for a therapeutic nihilism in clinical practice because current management (pharmacological and non-pharmacological) of the patients with chronic obstructive pulmonary disease (COPD) according to treatable traits is effective in decreasing their respiratory symptoms, increasing their exercise tolerance and capacity, improving their quality of life, preventing (and treating) many of their exacerbations and decreasing their mortality.

Currently, there is much controversy surrounding the therapeutic approach to pulmonary function abnormalities in patients with bronchiectasis and, consequently, whether and when to use bronchodilators in these patients. National and international guidelines on the treatment of bronchiectasis in adults do not recommend the routine use of bronchodilators because there is no evidence that a significant response to a bronchodilator or the presence or hyperresponsiveness of the airway are good predictors of future effective clinical response. However, some guidelines recommend them in the presence of airway obstruction and/or special conditions, which vary according to the guideline in question, although there are no recommendations on optimal dosing and bronchodilator treatment combined with or without inhaled corticosteroids. Nonetheless, in contrast with guideline recommendations, bronchodilators are overused in real-world patients with bronchiectasis even in the absence of airway obstruction, as demonstrated by analysis of national and international registries. This overuse can be explained by the awareness of the existence of a solid pharmacological rationale that supports the use of bronchodilators in the presence of chronic airway obstruction independent of its aetiology. We performed a systematic review of the literature and were able to verify that there are no randomised controlled trials (apart from a small study with methodological limitations and a very recent trial involving a not-very-large number of patients), or any long-term observational studies on the short- or long-term effect of bronchodilators in patients with bronchiectasis. Therefore, we believe that it is essential and even urgent to evaluate the effects of bronchodilators in these patients with appropriately designed studies.

Background The usefulness of bronchodilators in coronavirus diseases 2019 (COVID-19) survivors is still uncertain, especially for patients with a concomitant obstructive lung disease. We aimed at verifying the level of bronchodilator reversibility in COVID-19 patients undergoing multidisciplinary pulmonary rehabilitation after the acute phase. Methods We enrolled 105 consecutive patients referring to the Pulmonary Rehabilitation Unit of Istituti Clinici Scientifici Maugeri Spa SB, IRCCS of Telese Terme, Benevento, Italy after being discharged from the COVID-19 acute care ward and after recovering from acute COVID-19 pneumonia. All subjects performed a spirometry before and after inhalation of salbutamol 400 μg to determine the bronchodilation response within 48 h of admission to the unit. Results All patients had suffered from a moderate to severe COVID-19, classified 3 or 4 according to the WHO classification, Seventeen patients had concomitant obstructive lung disease (14 suffering from COPD and 3 from asthma). FEV1 after salbutamol improved on average by 41.7 mL in the entire examined sample, by 29.4 mL in subjects without concomitant obstructive lung diseases, by 59.3 mL in COPD patients and by 320.0 mL in asthma patients. Mean FVC after salbutamol improved by 65.7 mL in the entire examined sample, by 52.5 mL in subjects without concomitant obstructive lung diseases, by 120.0 mL in COPD patients, and by 200.0 mL in asthma patients. Conclusions This study suggests that a treatment with bronchodilators must always be taken into consideration in post-COVID-19 patients because it can induce a functional improvement that, even if small, can facilitate the breathing of these patients.

LABA/ICS and LABA/LAMA/ICS combinations elicit beneficial effects in asthma. Specific evidence concerning the impact of combining indacaterol acetate (IND), glycopyrronium bromide (GLY), and mometasone furoate (MF) on human airway hyperresponsiveness (AHR) and airway inflammation is still missing. The aim of this study was to characterize the synergy of IND/MF and IND/GLY/MF combinations, both once-daily treatments for asthma, in hyperresponsive airways. Passively sensitized human medium and small airways were stimulated by histamine and treated with IND/MF (molar ratio: 100/45, 100/90) and IND/GLY/MF (molar ratio: 100/37/45, 100/37/90). The effect on contractility and airway inflammation was tested. Drug interaction was assessed by Bliss Independence equation and Unified Theory. IND/MF 100/90 elicited middle-to-very strong synergistic relaxation in medium and small airways (+≈20–30% vs. additive effect, P < 0.05), for IND/MF 100/45 the synergy was middle-to-very strong in small airways (+≈20% vs. additive effect, P < 0.05), and additive in medium bronchi (P > 0.05 vs. additive effect). IND/GLY/MF 100/37/45 and 100/37/90 induced very strong synergistic relaxation in medium and small airways (+≈30–50% vs. additive effect, P < 0.05). Synergy was related with significant (P < 0.05) reduction in IL-4, IL-5, IL-6, IL-9, IL-13, TNF-α, TSLP, NKA, SP, and non-neuronal ACh, and enhancement in cAMP. IND/MF and IND/GLY/MF combinations synergistically interact in hyperresponsive medium and small airways and modulate the levels of cytokines, neurokinins, ACh, and intracellular cAMP. The concentrations of MF in the combinations modulate the effects in the target tissue.

Introduction: The role of long-acting muscarinic antagonists (LAMAs) is well established in uncontrolled asthma, but not in milder stages. Areas covered: This review examines the main randomized controlled trials (RCTs) that have investigated LAMAs administered as monotherapy or in combination to asthmatic patients, according to the different phenotypes. It offers an overview of the role of LAMAs or their fixed dose combinations (FDCs) in the treatment across all the different stages of asthma. Expert opinion: Tiotropium is now widely recognized as treatment for moderate to severe uncontrolled asthma (step 4–5) in adults and children. The most recent new evidence is: a) in adults, three different LAMA/long-acting β2-agonist (LABA)/inhaled corticosteroid (ICS) FDCs have been recently approved, extending the treatment options for these patients; b) therapy with LAMAs does not depend on patient’s Th2 status and justifies the indication regardless of patient’s phenotyping; c) in the milder stages, the high variability of response to LAMAs and the lack of a good phenotyping of patients represents the main obstacle in prescribing LAMAs. A better characterization of parasympathetic tone activity could improve LAMAs prescription.

Dual bronchodilation therapy is becoming the cornerstone for the treatment of COPD because the clinical benefits of LABA/LAMA fixed-dose combinations (FDCs) are now extensively established. Therefore, it not surprising that a number of LAMA/LABA combinations in a single inhaler have now been approved for clinical use as treatments for patients with COPD. Regrettably, very few head-to-head studies between all of the available LABA/LAMA FDCs have been carried out. This makes choosing the most appropriate FDC difficult. Comparative effectiveness research that also uses conventional meta-analyses to compare different care strategies can help generate useful information. A bidimensional comparative analysis across LAMA/LABA FDCs has suggested constant superiority for tiotropium/olodaterol. However, considering that there is not an equivalent amount of evidence on efficacy outcomes for all LAMA/LABA FDCs, a proper comparison between the different LAMA/LABA FDCs cannot be made yet, and the information available is still rather inconsistent.

Objective: This study analysed whether the persistence of both reversible airway obstruction (RAO) and elevated BE counts was associated to reduced asthma control and accelerated lung function decline in treated severe asthmatics. Methods: About 202 severe asthmatics were studied after 12–120months of step-5 treatment associated to anti-IgE therapy. Following treatments, reversibility tests, after inhaling 400 mcg of Salbutamol, were performed. FEV1>12% or ≤12% changes differentiated RAO+ from RAO− subjects. Blood eosinophil (BE) counts after treatment were considered. Results: Pre-/post-treatment bronchodilator FEV1% and ACT were lower (61% [50–71], 74.4% [62.5–83.7] and 20[18–22]), whereas BE were higher (380 cells/µl [170–590]) in RAO+ compared to RAO− subjects (77% [64–88], p=0.0001, 81.8% [66.1–94.3], p=0.0001, 21[18–23], p=0.045 and 230 cells/µl [80–360], p=0.003). A negative relationship between SABA-induced FEV1% changes and pre-bronchodilator FEV1% (β=−0.551%; p=0.0001) and ACT (β=−0.059; p=0.038) was found. Conversely, post-treatment BE levels were positively related (β=145.565 cells/µl; p=0.003) to FEV1>12% increases. A rising trend of pre-/post-bronchodilator FEV1% in time was observed in RAO− subjects with BE300 cells/µl reaching lower values after more than 36months of step-5 treatment (59.6% [39.9–72.1] vs 74[66.5–89.2] of RAO+ individuals with BE300 cells/µl [p=0.009]). Conclusion: Persistent SABA-induced FEV1>12%, especially when associated to BE>300 cells/ml, may be a marker of accelerated lung function decline in severe asthmatics despite maximal step-5 treatment. The highest bronchodilation associated to the lowest BE levels should be the main goal of asthma treatment to prevent such decline.

The ultra long-acting β2-adrenoceptor agonist olodaterol plus the ultra long-acting muscarinic antagonist tiotropium bromide are known to relax equine airways. In human bronchi combining these drugs elicits a positive interaction, thus we aimed to characterize this information further in equine isolated airways stimulated by electrical field stimulation (EFS) and using the Concentration-Reduction Index (CRI) and Combination Index (CI) equations. The drugs were administered alone and together by reproducing ex vivo the concentration-ratio delivered by the currently available fixed-dose combination (1:1). The single agents elicited a significant (p&nbsp

Background Chronic obstructive pulmonary disease (COPD) is a heterogeneous disorder characterized by usually progressive development of airflow obstruction that is not fully reversible. While most patients will experience symptoms throughout the day or in the morning upon awakening, many patients do not experience their symptoms as constant but report variability in symptoms during the course of the day or over time. Symptom variability adversely affects patients' health status and increases the risk of COPD exacerbations. Methods We examined data from the literature on symptom variability and control in patients with COPD, with focus on the use of inhaled bronchodilator therapy with long-acting muscarinic antagonist agents (LAMA) plus long-acting β 2 -agonists (LABA); in particular twice-daily fixed-dose combination LAMA/LABA therapy with aclidinium/formoterol. Results Correct diagnosis and assessment of COPD requires comprehensive clinical and functional evaluation and consideration of individual needs to support the clinical decisions necessary for effective long-term management. Combining bronchodilators from different and complementary pharmacological classes with distinct mechanisms of action can increase the magnitude of bronchodilation as opposed to increasing the dose of a single bronchodilator. Conclusions The use of inhaled bronchodilator therapy with LAMA/LABA fixed-dose combinations in patients with stable COPD is supported by current evidence. This treatment approach provides robust effects on lung function and symptom control and may improve patients' adherence to treatment. Administration of the long-acting bronchodilators aclidinium and formoterol as twice daily fixed-dose aclidinium/formoterol 400/12 μg has the potential to control symptoms throughout the 24 h in patients with stable moderate-to-severe COPD.

Marco Contoli,1 Paolo Solidoro,2 Fabiano Di Marco,3,4 Nicola Scichilone,5 Angelo Corsico,6 Fulvio Braido,7 Pierachille Santus4,8 1Research Centre on Asthma and COPD, Department of Medical Sciences, University of Ferrara, Ferrara, Italy; 2Cardiovascular and Thoracic Department, Città della Salute, Turin, Italy; 3Department of Health Sciences, University of Milan, Milan, Italy; 4Respiratory Unit, San Paolo Hospital, Milan, Italy; 5Department of Internal Medicine, Section of Pulmonology (DIBIMIS), University of Palermo, Palermo, Italy; 6Department of Molecular Medicine, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; 7Allergy and Respiratory Diseases Clinic, DIMI, University of Genoa, IRCS AOU San Martino-IST, Genoa, Italy; 8Pulmonary Rehabilitation Unit, Fondazione Salvatore Maugeri, Scientific Institute of Milan-IRCCS, Milan, Italy Abstract: The pathophysiology of chronic obstructive pulmonary disease (COPD) includes persistent airflow limitation, altered gas exchange, and enhanced chronic inflammatory response. According to disease severity in individual patients, exacerbations and comorbidities frequently occur. The overall nocturnal and daily symptoms have a strong impact on patient quality of life and clinical outcomes. Bronchodilators, by targeting two important aspects of COPD pathophysiology, ie, bronchoconstriction and lung hyperinflation, are the mainstay of therapy for COPD. Aclidinium bromide in particular is an anticholinergic molecule, approved for maintenance bronchodilator treatment of stable COPD, that combines high antimuscarinic activity with strong kinetic selectivity for the M3 receptor subtype. Moreover, the elevated plasma clearance of aclidinium has been related to low systemic bioavailability and low incidence of anticholinergic adverse events, whereas the reduced residence time at M2 receptors provides good cardiovascular safety. Altogether, these characteristics result in a high safety and tolerability profile. This review aims to reappraise the contribution of symptoms and of the level of quality of life determinants on COPD severity and to evaluate how therapeutic strategies with aclidinium may positively impact on these specific determinants of disease severity. Keywords: COPD, quality of life, daily symptoms, LAMA, aclidinium

Introduction: The appropriate drug management of COPD is still based on the use of bronchodilators, possibly associated with an anti-inflammatory agent. However, there are still fundamental questions that require clarification to optimise their use and major unmet clinical needs that must be addressed.Areas covered: The advances obtained with the pharmacological options currently consolidated and the different approaches that are often used in an attempt to respond to unmet therapeutic needs are reviewedExpert opinion: In view of the unsatisfactory status of current treatments for COPD, there is an urgent need for alternative and more effective therapeutic approaches that will help to relieve patient symptoms and affect the natural course of COPD, inhibiting chronic inflammation and reversing the disease process or preventing its progression. However, new pharmacologic options have proved difficult to develop. Therefore, it is mandatory to optimize the use of the treatment options at our disposal. However, there are still fundamental questions regarding their use, including the step-up and step-down pharmacological approach, that require clarification to optimise the use of these drugs. It is likely that phenotyping COPD patients would help in identifying the right treatment for each COPD patient and improve the effectiveness of therapies.

Fabiano Di Marco,1 Piero Balbo,2 Francesco de Blasio,3 Vittorio Cardaci,4 Nunzio Crimi,5 Giuseppe Girbino,6 Girolamo Pelaia,7 Pietro Pirina,8 Pietro Roversi,9 Pierachille Santus,10,11 Nicola Scichilone,12 Alessandro Vatrella,13 Patrizio Pasqualetti,14 Mauro Carone15 1Department of Health Sciences, University of Milan, Respiratory Unit, Papa Giovanni XXIII Hospital, Bergamo, Italy; 2SC Malattie dell’Apparato Respiratorio, AOU Maggiore della Carità, Novara, Italy; 3Respiratory Medicine and Pulmonary Rehabilitation Section, Clinic Center S.p.A. Private Hospital, Department of Medicine and Health Sciences “V Tiberio”, University of Molise, Campobasso, Italy; 4Unit of Pulmonary Rehabilitation, IRCCS “San Raffaele Pisana”, Rome, Italy; 5Unità Operativa Complessa di Pneumologia e Allergologia, Policlinico Rodolico Vittorio Emanuele, Università di Catania, Catania, Italy; 6Dipartimento di Scienze Biomediche, Odontoiatriche e delle Immagini Morfologiche e Funzionali (BIOMORF), Università degli Studi di Messina, Messina, Italy; 7Department of Medical and Surgical Sciences, Unit of Respiratory Diseases, University Magna Graecia of Catanzaro, Catanzaro, Italy; 8Respiratory Unit, AOU Sassari, Sassari, Italy; 9Azienda Ospedaliera Universitaria, Policlinico di Modena, Modena, Italy; 10Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy; 11Division of Respiratory Diseases “L. Sacco” Hospital, ASST Fatebenefratelli Sacco, Milan, Italy; 12Dipartimento Biomedico di Medicina Interna e Specialistica (DIBIMIS), University of Palermo, Palermo, Italy; 13Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Salerno, Italy; 14Fondazione Fatebenefratelli per la Ricerca e la Formazione Sanitaria e Sociale, Rome, Italy; 15Istituti Clinici Scientifici Maugeri, IRCCS di Cassano delle Murge, Cassano delle Murge (BA), Italy Purpose: There is a lack of consensus on the most appropriate early diagnostic strategy, criteria for early access to treatment and follow-up approach for patients with COPD. Materials and methods: A Delphi consensus project investigated the early management of COPD. We formulated two questionnaires for completion by pneumologists in Italy. Results: A total of 207 specialists completed questionnaire 1 and 184 of them questionnaire 2, between November 2016 and October 2017. Early diagnosis of COPD was considered uncommon for 93.2% of the expert panel. Regardless of the definition of “early diagnosis” – a diagnosis made before the clinical manifestation of the disease for most responders (60.4%) – experts were confident of the positive effects of early disease management, which they consider is effective in modifying the natural history of the disease. Lack of awareness of the disease was considered the first limiting factor to early COPD management for 78% of respondents. The most effective steps to reduce functional decline were considered to be smoking cessation, followed by long-acting β2-agonist (LABA)/long-acting muscarinic antagonist (LAMA), LAMA, LABA, and finally inhaled corticosteroid/LABA(P

Purpose: Unlike in the outpatient setting, delivery of aerosols to critically ill patients may be considered complex, particularly in ventilated patients, and benefits remain to be proven. Many factors influence aerosol delivery and recommendations exist, but little is known about knowledge translation into clinical practice. Methods: Two-week cross-sectional study to assess the prevalence of aerosol therapy in 81 intensive and intermediate care units in 22 countries. All aerosols delivered to patients breathing spontaneously, ventilated invasively or noninvasively (NIV) were recorded, and drugs, devices, ventilator settings, circuit set-up, humidification and side effects were noted. Results: A total of 9714 aerosols were administered to 678 of the 2808 admitted patients (24 %, CI95 22–26 %), whereas only 271 patients (10 %) were taking inhaled medication before admission. There were large variations among centers, from 0 to 57 %. Among intubated patients 22 % (n = 262) received aerosols, and 50 % (n = 149) of patients undergoing NIV, predominantly (75 %) inbetween NIV sessions. Bronchodilators (n = 7960) and corticosteroids (n = 1233) were the most frequently delivered drugs (88 % overall), predominantly but not exclusively (49 %) administered to patients with chronic airway disease. An anti-infectious drug was aerosolized 509 times (5 % of all aerosols) for nosocomial infections. Jet-nebulizers were the most frequently used device (56 %), followed by metered dose inhalers (23 %). Only 106 (

Aim of our study was to understand if the interaction between aclidinium and formoterol administered at therapeutic doses leads to a synergistic rather than additive broncholytic effect. We tested the type of effect ex vivo on isolated human bronchi and then in vivo in COPD patients. The analysis of the interaction between aclidinium and formoterol in vitro was measured by applying the Unified Theory, whereas that in COPD patients was measured by applying the Bliss Independence criterion. Aclidinium and formoterol administered alone completely relaxed human isolated bronchial tissues sub-maximally pre-contracted with ACh in a concentration-dependent manner with similar potency (EC50: aclidinium 4.64 ± 0.78 nM, formoterol 2.71 ± 0.21), whereas the interaction of aclidinium plus formoterol produced moderate to strong synergism. Changes in FEV1 values showed that inhaled aclidinium and formoterol induced a significant and time-dependent bronchodilatory effect during the study time. The inhalation of aclidinium and formoterol in combination significantly anticipated at 5 min post-administration the bronchodilatory effect of FEV1, compared with the effect of drugs administered alone. There was a synergistic interaction for FEV1 at 5 min and from 120 min to 240 min post-inhalation, whereas from 30 min to 60 min post-administration the drug interaction was additive. This study shows that aclidinium and formoterol can produce a significant synergistic interaction that may have a role also in the clinic setting.

In order to clarify the possible role of N-acetylcysteine (NAC) in the treatment of patients with chronic bronchitis and chronic obstructive pulmonary disease (COPD), we have carried out a meta-analysis testing the available evidence that NAC treatment may be effective in preventing exacerbations of chronic bronchitis or COPD and evaluating whether there is a substantial difference between the responses induced by low (≤600 mg per day) and high (>600 mg per day) doses of NAC.The results of the present meta-analysis (13 studies, 4155 COPD patients, NAC n=1933; placebo or controls n=2222) showed that patients treated with NAC had significantly and consistently fewer exacerbations of chronic bronchitis or COPD (relative risk 0.75, 95% CI 0.66–0.84; pThe strong signal that comes from this meta-analysis leads us to state that if a patient suffering from chronic bronchitis presents a documented airway obstruction, NAC should be administered at a dose of ≥1200 mg per day to prevent exacerbations, while if a patient suffers from chronic bronchitis, but is without airway obstruction, a regular treatment of 600 mg per day seems to be sufficient.

Long-acting β 2 -adrenoceptor agonists, formoterol and salmeterol, represent a milestone in the treatments of chronic obstructive lung diseases. Although no specific indications concerning the choice of one molecule rather than another are provided by asthma and COPD guidelines, they present different pharmacological properties resulting in distinct clinical employment possibilities. In particular, salmeterol has a low intrinsic efficacy working as a partial receptor agonist, while formoterol is a full agonist with high intrinsic efficacy. From a clinical perspective, in the presence of low β 2 -adrenoceptors availability, like in inflamed airways, a full agonist can maintain its bronchodilatory and non-smooth muscle activities while a partial agonist may be less effective. Furthermore, formoterol presents a faster onset of action than salmeterol. This phenomenon, combined with the molecule safety profile, leads to a prompt amelioration of the symptoms, and allows using this drug in asthma as an "as needed" treatment in patients already on regular treatment. The fast onset of action and the full agonism of formoterol need to be considered in order to select the best pharmacological treatment of asthma and COPD.

Background Corticosteroids increase the expression of β2-adrenoceptors (β2-ARs) and protect them against down-regulation. Conversely, β2-AR agonists improve the anti-inflammatory action of corticosteroids. Nevertheless, it is still uncertain whether adding a long-acting β2-AR agonist (LABA) to an inhaled corticosteroid (ICS) results in an additive effect, or there is true synergy. Therefore, the aim of this study was to pharmacologically characterize the interaction between the ICS beclomethasone diproprionate (BDP) and the LABA formoterol fumarate (FF) in a validated human ex vivo model of bronchial asthma. Methods Human medium and small airways were stimulated by histamine and treated with different concentrations of BDP and FF, administered alone and in combination at concentration-ratio reproducing ex vivo that of the currently available fixed-dose combination (FDC; BDP/FF 100:6 combination-ratio). Experiments were performed in non-sensitized (NS) and passively sensitized (PS) airways. The pharmacological interaction was assessed by using Bliss Independence and Unified Theory equations. Results BDP/FF synergistically increased the overall bronchorelaxation in NS and PS airways (+ 15.15% ± 4.02%; P

Introduction: Long-acting β2-adrenoceptor (β2-AR) agonists (LABAs) plus long-acting muscarinic antagonists (LAMAs) is the cornerstone for treating chronic obstructive pulmonary disease (COPD). LABA/LAMA combinations elicit clinical and functional synergistic interaction, and such an interaction should permit to reduce the dose of each monocomponent in the drug mixture to minimize the risk of adverse events (AEs). Overall, currently available LABA/LAMA fixed-dose combinations (FDCs) combine the drugs at the same doses of formulations designed for a single drug. Therefore, concerns regarding the possible risk of cardiovascular AEs have been raised related to the use of LABA/LAMA FDCs in COPD patients. Areas covered: LABAs and LAMAs have a high potential to induce cardiovascular AEs by stimulating the β2-AR receptors and inhibiting the muscarinic M2receptors expressed in the heart. This review will explore the data published on the cardiovascular safety of dual bronchodilation therapy in COPD patients. Expert opinion: LABA/LAMA FDCs are characterized by an acceptable cardiovascular safety profile, at least in the COPD population enrolled in randomized clinical trials. Nevertheless, large real life studies suggest that dual bronchodilation therapy may increase the risk of cardiovascular AEs. Post-marketing surveillance and observational studies are needed to adequately define the real cardiovascular safety profile of LABA/LAMA FDCs.

Background Acute asthma attack is a frequent condition in children. It is one of the most common reasons for emergency department (ED) visit and hospitalization. Appropriate care is fundamental, considering both the high prevalence of asthma in children, and its life-threatening risks. Italian Society of Pediatrics recently issued a guideline on the management of acute asthma attack in children over age 2, in ambulatory and emergency department settings. Methods The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was adopted. A literature search was performed using the Cochrane Library and Medline/PubMed databases, retrieving studies in English or Italian and including children over age 2 year. Results Inhaled ß2 agonists are the first line drugs for acute asthma attack in children. Ipratropium bromide should be added in moderate/severe attacks. Early use of systemic steroids is associated with reduced risk of ED visits and hospitalization. High doses of inhaled steroids should not replace systemic steroids. Aminophylline use should be avoided in mild/moderate attacks. Weak evidence supports its use in life-threatening attacks. Epinephrine should not be used in the treatment of acute asthma for its lower cost / benefit ratio, compared to β2 agonists. Intravenous magnesium solphate could be used in children with severe attacks and/or forced expiratory volume1 (FEV1) lower than 60% predicted, unresponsive to initial inhaled therapy. Heliox could be administered in life-threatening attacks. Leukotriene receptor antagonists are not recommended. Conclusions This Guideline is expected to be a useful resource in managing acute asthma attacks in children over age 2.

TGF-beta-targeting structural and inflammatory cells has been implicated in the mechanisms leading to the inflammatory and restructuring processes in asthma, suggesting an impact of TGF-beta1 signaling on the development and persistency of this disease. We investigated the potential early involvement of TGF-beta1 activity in the immunological and molecular mechanisms underlying progression of inflammation in childhood asthma. We evaluated the levels of TGF-beta1 in induced sputum supernatants (ISSs) and the expression of small mother cell against decapentaplegic (Smad) 2 and Smad7 proteins in induced sputum cells (ISCs) from children with intermittent asthma (IA), moderate asthma (MA) and control subjects (C). Furthermore, we investigated the regulatory role of TGF-beta1 activity on eosinophil and neutrophil adhesion to epithelial cells using adhesion assay, and on the granulocyte expression of adhesion molecule CD11b/CD18 Macrophage-1 antigen (MAC-1), by flow cytometry. We found that the levels of TGF-beta1 are increased in ISSs of IA and MA in comparison to C, concomitantly to the activation of intracellular signaling TGFbeta/Smads pathway in ISCs. In MA, TGF-beta1 levels correlated with the number of sputum eosinophils and neutrophils. Furthermore, we showed the ability of sputum TGF-beta1 to promote eosinophil and neutrophil adhesion to epithelial cells, and to increase the expression of MAC-1 on the granulocyte surface. This study shows the activation of TGFbeta/Smad signaling pathway in the airways of children with IA and, despite the regular ICS treatment, in children with MA, and provides evidence for the contribution of TGF-beta1 in the regulation of granulocyte activation and trafficking.

Chronic obstructive pulmonary disease (COPD) is a major cause of mortality worldwide, whose burden is expected to increase in the next decades, because of numerous risk factors, including the aging of the population. COPD is both preventable and treatable by an effective management including risk factor reduction, prevention, assessment, and treatment of acute exacerbations and co-morbidities. The available agents approved for COPD treatment are long-acting or ultra-long-acting β2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) bronchodilators, as well as inhaled corticosteroids (ICS) in combination with LABAs. ICS use has been restricted only to selected COPD patients by the most recent documents, mainly based on the risk of exacerbations. However, several observational studies showed a high rate of prescription of ICS in COPD, irrespective of clinical recommendations, questioning the efficacy of these compounds in unselected patients with COPD and leading to possible increase risk of side effects related to ICS use. After examining the low levels of adherence in primary care and in the clinical settings to national and international recommendations for the treatment of COPD in different countries, the most common drivers of the prevailing use of ICS are critically reviewed here by examining their pros and cons, aimed at identifying evidence-based drivers for a proper selection of patients who may benefit from the proper use of ICS.

BACKGROUND The safe and appropriate use of long-acting beta-agonists (LABAs) for the treatment of asthma has been widely debated. In two large clinical trials, investigators found a potential risk of serious asthma-related events associated with LABAs. This study was designed to evaluate the risk of administering the LABA salmeterol in combination with an inhaled glucocorticoid, fluticasone propionate. METHODS In this multicenter, randomized, double-blind trial, adolescent and adult patients (age, ≥12 years) with persistent asthma were assigned to receive either fluticasone with salmeterol or fluticasone alone for 26 weeks. All the patients had a history of a severe asthma exacerbation in the year before randomization but not during the previous month. Patients were excluded from the trial if they had a history of lifethreatening or unstable asthma. The primary safety end point was the first serious asthma-related event (death, endotracheal intubation, or hospitalization). Noninferiority of fluticasone–salmeterol to fluticasone alone was defined as an upper boundary of the 95% confidence interval for the risk of the primary safety end point of less than 2.0. The efficacy end point was the first severe asthma exacerbation. RESULTS Of 11,679 patients who were enrolled, 67 had 74 serious asthma-related events, with 36 events in 34 patients in the fluticasone–salmeterol group and 38 events in 33 patients in the fluticasone-only group. The hazard ratio for a serious asthmarelated event in the fluticasone–salmeterol group was 1.03 (95% confidence interval [CI], 0.64 to 1.66), and noninferiority was achieved (P = 0.003). There were no asthma-related deaths; 2 patients in the fluticasone-only group underwent asthmarelated intubation. The risk of a severe asthma exacerbation was 21% lower in the fluticasone–salmeterol group than in the fluticasone-only group (hazard ratio, 0.79; 95% CI, 0.70 to 0.89), with at least one severe asthma exacerbation occurring in 480 of 5834 patients (8%) in the fluticasone–salmeterol group, as compared with 597 of 5845 patients (10%) in the fluticasone-only group (P

A solid scientific rationale and an increasing body of clinical evidence for combining a β2-agonist with an antimuscarinic agent in COPD fully support the opinion that patients not controlled by a single bronchodilator should be given two bronchodilators with different mechanisms of action. Tiotropium is an established choice for the management of patients with stable COPD, and olodaterol is a new effective and safe once-daily long-acting β2-agonist. The parallel bronchodilating modes of action of olodaterol and tiotropium make them an attractive combination in COPD. The large ongoing TOviTO Phase III trial program is documenting the efficacy and safety of olodaterol/tiotropium fixed dose combination delivered via the Respimat Soft Mist Inhaler as maintenance therapy in patients with moderate to very severe COPD. However, we must still know whether this fixed-dose combination will affect exacerbations and hospitalizations, and ultimately death, and also the precise estimates of its relative cardiovascular safety.

Background To date there is emerging clinical evidence to add long-acting anti-muscarinic agents (LAMAs) with inhaled corticosteroid (ICSs) in asthma, but the pharmacological rationale that supports the use of such a combination has not yet been explained. The aim of this study was to pharmacologically investigate the interaction between the ICS beclomethasone and the LAMA glycopyrronium on the human airway smooth muscle (ASM) tone. Methods We investigated the rapid non-genomic bronchorelaxant effect of beclomethasone and glycopyrronium, administered alone and in combination, in human isolated bronchi and bronchioles. Experiments were carried out also in passively sensitized airways and the pharmacological analysis of drug interaction was performed by Bliss Independence method. Results The acute administration of beclomethasone and glycopyrronium induced a significant relaxation of passively sensitized ASM pre-contracted with histamine, by causing submaximal/maximal inhibition of the contractile tone in both medium bronchi and bronchioles. Beclomethasone was characterized by a rapid non-genomic and epithelium independent bronchorelaxant effect. In passively sensitized airways, this effect seemed to be dependent by the activation of a Gsα – cyclic adenosine monophosphate (cAMP) – protein kinase A cascade. While no synergistic interaction was detected in non-sensitized bronchi, the beclomethasone/glycopyrronium combination synergistically enhanced the relaxation of passively sensitized medium and small bronchi. The synergistic interaction between beclomethasone and glycopyrronium was associated with an increase of cAMP concentrations. Conclusions Our study provides for the first time the pharmacological rationale for combining low doses of an ICS plus a LAMA.

The major influencing factors on persistent asthma control are the selected treatment(s), the drug delivery route and patient's adherence to therapy, together with the influence of lifestyle (i.e. sedentary habit), comorbid conditions and specific asthma phenotypes. Inhaled corticosteroids (ICS) in combination with a long-acting β2-agonist (LABA) are the gold standard for management of persistent asthma, with maximal local targeting and minimal systemic side effects. Several innovative inhaler devices have been developed for effective local drug administration and good patient compliance to therapy. Recently, a new ICS/LABA fixed combination, formulated with fluticasone propionate (FP) and formoterol fumarate (FF), has been proposed for maintenance treatment of asthma in adults and adolescent patients. FP/FF combines the anti-inflammatory and bronchodilating properties of powerful compounds in a single inhaler. Its pharmacological characteristics allow rapid speed of onset and dosage flexibility required for step-up and step-down strategies, improving adherence to treatment of asthmatic patients. The efficacy of the FP/FF fixed combination at all dosages in controlling asthma symptoms and the reduced rate of discontinuation have been demonstrated by all randomized trials conducted so far.

To evaluate the relationship between inflammatory markers and severity of asthma in children, the amount of interleukin-8 (IL-8) and granulocyte/macrophage colony-stimulating factor (GM-CSF) released by peripheral blood mononuclear cells, exhaled nitric oxide (FE NO) levels, p65 nuclear factor-kappaB subunit, and phosphorylated IkBalpha expression by peripheral blood mononuclear cells were assessed in six control subjects, 12 steroid-naives subjects with intermittent asthma, and 17 children with moderate asthma. To investigate their predictive value, biomarker levels were correlated with the number of exacerbations during a 18-month follow-up period. We found that GM-CSF release was higher in moderate and intermittent asthmatics than in control subjects, whereas IL-8 release was higher in moderate than in intermittent asthmatics and control subjects. FE NO levels were similar among study groups. In moderate asthmatics, IL-8, GM-CSF, and FE NO significantly correlated with the exacerbation numbers. Moreover, p65 and phosphorylated IkBalpha levels were greater in moderate than in intermittent asthmatics and control subjects. According to GM-CSF, IL-8, and FE NO levels, two distinct subgroups of moderate asthmatics (low and high producers) were identified. High producers experienced more exacerbations than low producers. This study shows ongoing inflammation associated with biological and clinical heterogeneity in moderate asthmatics despite regular treatment and proposes that large prospective studies confirm the importance of biomarkers to assess inflammation and asthma control in children with asthma.

Summary Background Treatment guidelines for patients with moderate persistent asthma recommend regular therapy with a combination of an inhaled corticosteroid and a longacting β 2 agonist plus as-needed rapid-acting bronchodilators. We investigated whether symptom-driven budesonide and formoterol combination therapy administered as needed would be as effective as regular treatment with this combination plus as-needed symptom-driven terbutaline for patients with moderate asthma. Methods In this non-inferiority randomised clinical trial, we recruited adult patients (18–65 years of age) with stable moderate persistent asthma, according to 2006 Global Initiative for Asthma guidelines. Patients were recruited from outpatient clinics of secondary and tertiary referral hospitals and university centres. After a 6-week run-in period of inhaled regular budesonide and formoterol plus as-needed terbutaline, the patients were randomly assigned in a 1:1 ratio to receive placebo twice daily plus as-needed treatment with inhaled 160 μg budesonide and 4·5 μg formoterol (as-needed budesonide and formoterol therapy) or twice-daily 160 μg budesonide and 4·5 μg formoterol combination plus symptom-driven 500 μg terbutaline (regular budesonide/formoterol therapy) for 1 year. Randomisation was done according to a list prepared with the use of a random number generator and a balanced-block design stratified by centre. Patients and investigators were masked to treatment assignment. The primary outcome was time to first treatment failure measured after 1 year of treatment using Kaplan-Meier estimates, and the power of the study was calculated based on the rate of treatment failure. Analyses were done on the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00849095. Findings Between April 20, 2009, and March 31, 2012, we screened 1010 patients with moderate asthma and randomly assigned 866 eligible patients to the two treatment groups (424 to as-needed budesonide and formoterol therapy and 442 to regular budenoside and formoterol therapy). Compared with regular budesonide and formoterol therapy, as-needed budesonide and formoterol treatment was associated with a lower probability of patients having no treatment failure at 1 year (Kaplan-Meier estimates 53·6% for as-needed treatment vs 64·0% for regular treatment; difference 10·3% [95% CI 3·2–17·4], at a predefined non-inferiority limit of 9%). Patients in the as-needed budesonide and formoterol group had shorter time to first treatment failure than those in the regular therapy group (11·86 weeks vs 28·00 weeks for the first quartile [ie, the time until the first 25% of patients experienced treatment failure]). The difference in treatment failures was largely attributable to nocturnal awakenings (82 patients in the as-needed treatment group vs 44 in the regular treatment group). Both treatment regimens were well tolerated. Interpretation In patients with moderate stable asthma, as-needed budesonide and formoterol therapy is less effective than is the guideline-recommended regular budesonide and formoterol treatment, even though the differences are small. Funding Italian Medicines Agency.

Background Limited data are available on eosinophilic oesophagitis in Italy. Aim To evaluate typical features of eosinophilic oesophagitis patients in a tertiary centre. Methods 973 consecutive patients with dysphagia and/or bolus impaction were prospectively enrolled and underwent upper endoscopy for eosinophilic oesophagitis (≥15 eosinophils in at least one high-power field [hpf] and no response to acid suppressants). Demographic and multiple clinical factors were collected. Results 45 patients (80% males, mean age 35 ± 16) with incident eosinophilic oesophagitis (mean eosinophil peak count 57.2 ± 40.6/hpf) were enrolled. 32 patients complained of solids dysphagia (71%), and 29 of bolus impaction (64%). Endoscopy found rings in 20 (44%), furrows in 9 (20%), whitish exudates/plaques in 12 (27%), crepe paper in 7 (13%) and normal findings in 14 patients (31%). Endoscopic and radiologic stenosis occurred in 20 (44%) and 23 (51%), respectively. Ten patients had proton pump inhibitor-oesophageal eosinophilia (22%). Topic fluticasone was effective in 28 of the remaining cases (62%), while 7 required additional treatments (16%). Conclusion Eosinophilic oesophagitis prevalence was 12% in patients with dysphagia and/or bolus impaction, emphasizing the importance of this disease in Italy. Despite different environmental factors and dietary habits, Italian patients with eosinophilic oesophagitis present similar characteristics to those of other Western counties.

Post-viral cough is a type of cough originating from upper respiratory tract infections that persists after the infection is resolved. Although it was hypothesized that bronchodilators might have a role in the management of post-viral cough, a clear demonstration of their efficacy is missing. Therefore, we tested the efficacy of a combination of a β-agonist and an anticholinergic agent in reducing post-viral cough with a randomized, double blind, placebo controlled clinical trial. Patients were treated for 10 days with either a nebulized combination of salbutamol 1.875 mg/0.5 mL and ipratropium bromide 0.375 mg/0.5 mL, or a placebo, and followed up for another 10 days. Daytime and nighttime cough severity and spirometry testing were assessed before starting treatment, after 10 and 20 days. Ninety-two patients were randomized to receive placebo (n = 46) or the active treatment (n = 46); nine of them (4 in the placebo group, 5 in the active treatment group) dropped out from the study. Daytime and nighttime cough severity were significantly reduced in both groups during the study period, but the reduction was more prominent in the active treatment group vs. placebo after 10 days of treatment (P = 0.003 for day cough; P = 0.061 for night cough), whereas at the end of follow-up period cough severity was comparable between the two groups. Small but significant increases in spirometric parameters were observed in the active treatment vs. placebo group, although at the end of follow-up these values returned to be comparable to placebo. The frequency of adverse events was not significantly different between the two groups of patients. We concluded that a combination of a β-agonist and an anticholinergic agent can effectively reduce post-viral cough, and can thus represent a valid option for this type of cough.

BACKGROUND AND OBJECTIVES The European Union Nitric Oxide trial was designed to assess the potential benefits of inhaled nitric oxide (iNO) compared with placebo in infants with respiratory failure. This follow-up study evaluated respiratory, neurodevelopmental, and other outcomes for infants entered into the European Union Nitric Oxide trial to age 2 years. METHODS: In a multicenter, randomized, double-blind study, preterm infants born at RESULTS: At 36 weeks’ postmenstrual age, 696 of 792 infants were alive; 4 in the iNO arm subsequently died before age 2 years compared with 7 in the control arm. We evaluated 95% of the survivors at 12 months and 90% at 2 years. In the iNO arm, 244 of 363 (67.2%) infants had survived without disability at age 2 years compared with 270 of 374 (72.2%) who received placebo (P = .094). Mean (SD) cognitive composite scores (Bayley Scales of Infant and Toddler Development, third edition) were 94 (13) in the iNO group and 95 (14) in the placebo group; in the iNO group, 19% scored CONCLUSIONS: At 2 years of age, low-dose (5 ppm) iNO started early (

Background and aims: Bronchiectasis is defined as an abnormal and irreversible dilatation of the bronchi, often associated with chronic productive cough, airway obstruction, and recurrent infections. Methods: MEDLINE data from 1978 to November 2008 was analysed. Search was limited to randomized control trials, clinical trials, meta-analysis, reviews published in English, using the keyword bronchiectasis. Results: The prevalence of bronchiectasis is unknown. However, prevalence seems to increase with age from 4.2 per 100 000 persons aged 18–34 years to 271.8 per 100 000 among those aged 75 years or older. Therapy is aimed to limit the cycle of infection and inflammation and to reduce the number of exacerbations, in order to improve quality of life. Conclusions: Bronchiectasis still remain a significant health problem. Further research is required to improve the management of this herterogeneous condition. Please cite this paper as: Pappalettera M, Aliberti S, Castellotti P, Ruvolo L, Giunta V and Blasi F. Bronchiectasis: an update. The Clinical Respiratory Journal 2009; 3: 126–134.

Co-administration of a long-acting β2-agonist and a long acting muscarinic antagonist produces superior bronchodilation compared with their individual effects. Our preclinical data indicated that combining aclidinium bromide (ACLI) and formoterol fumarate (FORM) provides synergistic benefit on smooth muscle relaxation of both large and small human airways. Data from more than 2,000 patients in eleven clinical trials documented that ACLI/FORM, a twice- daily fixed-dose combination, produces a greater degree of bronchodilation than ACLI or FORM monotherapy alone and is safe and well tolerated. Two large key trials have shown that there is a benefit in using ACLI/FORM when the clinical target is the variability of symptoms and mainly nighttime and/or early morning symptoms. ACLI/FORM is the only long acting muscarinic antagonist/long acting β2-agonist fixed-dose combination that has been studied for this therapeutic indication.

Objectives: Our objectives were to test the hypothesis that, in the geriatric population, chronic airway obstruction is associated with a higher prevalence of sleep disturbances; to identify the main correlates of sleep disturbances, and to verify whether asthma and COPD patients have different patterns of sleep disturbances. Methods: The EPESE questionnaire was administered to 734 patients aged 65 years and over with asthma or chronic obstructive pulmonary disease (cases) and 1237 individuals of comparable age who were free of respiratory disease but not of other chronic conditions (controls). Four sleep disturbances were quantified: difficulty in falling asleep, nocturnal awakening, morning tiredness, and early awakening. Multidimensional assessment of demographic data, personal history, clinical, and functional status was performed. Independent correlates of sleep disturbances were identified by logistic regression analysis. Results: One or more sleep disturbances were reported by 445 cases and 697 controls (60.6% vs. 56.4%, ns). Morning tiredness and early awakenings were more prevalent among cases (38% vs. 27.8%, p

Bronchodilators represent one of the most important therapeutic weapons for the treatment of airway obstructive diseases and the inhaled route of administration is very often employed due to the greater drug availability and reduced magnitude of side effects. During acute exhacerbations, it is not unfrequent that the elastic and resistive loads imposed on the ventilatory pump overcome the force sustainable by the respiratory muscles and the patient requires ventilatory assistance, in order to relieve fatigue and to optimize alveolar gas exchange. During these episodes, inhaled bronchodilators, far from being discontinued, sometime must be administered during mechanical ventilation, that, in hypercapnic ventilatory failure can be frequently applied noninvasively with a good rate of success. While in the current literature there are a lot of data about inhaled drug administration during invasive mechanical ventilation, very few data are available on the topic of aerosol therapy during noninvasive mechanical ventilation. With the present paper we want to analyze the rationale, the feasibility and the current data dealing with the administration of inhaled drugs during noninvasive mechanical ventilation.

Acute exacerbations are frequent complications of chronic obstructive pulmonary disease (COPD). Individuals developing COPD exacerbations usually increase the rescue use of bronchodilators (short-acting β-2 agonist and anticholinergic drugs) and are prescribed systemic corticosteroids if they do not respond. Systemic corticosteroids significantly reduce treatment failure,shorten hospital stay,and improve symptoms and lung function. Although available evidence suggests that patients with COPD who are given antibiotics receive moderate benefit,current guidelines recommend antibiotic treatment only in patients with increased dyspnea,sputum volume,and purulence (Anthonisen criteria). The most frequent causes of COPD exacerbations are believed to be viral and/or bacterial infections. However,in most cases,the etiology of a COPD exacerbation is unknown,and clinical features are of limited help in identifying the cause and particularly in distinguishing between viral and bacterial infections. Several biomarkers (e.g.,procalcitonin) have been used to diagnose acute exacerbations of COPD due to bacterial infections,with the aim of reducing the exposure of patients to antibiotics,but their role is controversial and their use is not yet recommended by guidelines.

Bamifylline, a 7-8 disubstituted theophylline derivative, reduces in a dose dependent way (1 x 10(-5) M, 1 x 10(-4) M and 1 x 10(-3) M) the release of histamine, TXB2 (measured also as TXA2-like material) and SRS-A (as LTD4-like material) during the immunological challenge of actively sensitized guinea-pig lungs perfused in vitro. Theophylline was significantly less potent than bamifylline and particularly, at the higher concentrations used (1 x 10(-3) M), bamifylline was 2.7 times more potent than theophylline in reducing the immunological release of histamine and 1.6 and 1.5 times more potent in inhibiting the production of TXB2 and SRS-A, respectively. These data suggest that the ability of the two xanthine derivatives to control the immunological release of histamine represents an important point in understanding the mechanism of their anti-anaphylactic activity.

The present study was undertaken to determine the effect of furosemide on antigen-induced bronchoconstriction. Ten patients with stable asthma (eight men and two women), aged 17 to 48 years, were challenged with the same dose of allergen (Dermatophagoides pteronissinus, Parietaria, and grass mix) that had induced an FEV1 fall of at least 20% in a preliminary study on two occasions: immediately after placebo and furosemide (approximately 28 mg) administered by inhalation in random order and double-blind. Furosemide did not demonstrate any direct bronchodilator effect but markedly attenuated allergen-induced bronchoconstriction. The mean (95% confidence interval) maximum fall in FEV1 was 31.5% (40.2% to 22.8%) after placebo and 8.4% (11.8% to 4.9%) after furosemide administration. Furosemide, administered by aerosol to anesthetized guinea pigs actively sensitized to ovalbumin, dose dependently protected the animals from anaphylactic reaction. Infusion of furosemide (10 mg/kg for 10 minutes) failed to protect the animals from the anaphylactic response. In nonsensitized guinea pigs, the cardiovascular and pulmonary changes induced by histamine (10 micrograms/kg intravenously [i.v.]), leukotriene C4 (1 micrograms/kg i.v.), and platelet-activating factor (0.1 microgram/kg i.v.) were not modified by aerosol administration of furosemide (10 mg/ml for 10 minutes). In conclusion, inhaled furosemide induces a clear-cut protection against immediate obstructive reaction caused by areoallergerns and ovalbumin, both in subjects with asthma and actively sensitized guinea pigs, respectively.