Adriano Vaghi

Efficacy and Tolerability of Nimesulide in Asthmatic Patients Intolerant to Aspirin

SummaryInflammation of the airways accompanied by eosinophil infiltration appears to play a fundamental role in the pathogenesis of bronchial asthma. Therefore, anti-inflammatory agents (at present corticosteroids, cromoglycate and nedocromil) are the first-line treatment for this condition. Nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin (acetylsalicylic acid) and indomethacin, however, have never been used in this setting, mainly for fear of adverse effects (e.g. severe obstructive reactions); these can occur, in a consistent number of patients as a consequence (according to the most widely accepted theory) of inhibition of prostaglandin synthesis. In a double-blind crossover placebo-controlled study involving 20 aspirin-sensitive patients with asthma, we found that oral nimesulide 100mg was well tolerated both clinically and functionally (no significant changes in forced expiratory volume in 1 second and specific airway resistance after drug intake). In a more recent study, we observed a mild obstructive reaction (easily controlled with inhaled bronchodilators) after oral administration of nimesulide 400mg to 3 patients who had previously tolerated a 100mg dose. On the basis of clinical experience, nimesulide (unlike most other NSAIDs) in the recommended doses appears to be well tolerated in aspirin-sensitive asthmatic patients. Furthermore, this distinctive anti-inflammatory agent might provide a novel approach to the treatment of bronchial asthma.

Prevention of fog-induced bronchospasm by nedocromil sodium

A single dose double‐blind crossover study was performed to compare the efficacy of nedocromil sodium (4 mg) and placebo administered from pressurized aerosols against bronchoconstriction induced by the inhalation of ultrasonically nebulized distilled water (fog) in twelve asthmatic subjects. Neither active nor placebo pre‐treatment produced any significant change in baseline FEV1 and SRaw. Nedocromil sodium significantly attenuated fog‐induced falls in FEV1 (P < 0.001) and increased specific airways resistance (SRaw, P < 0.01). The results provide further evidence of the potential therapeutic usefulness of nedocromil sodium in the management of chronic obstructive airways disease.

Steroid-sparing effect of inhaled lysine acetylsalicylate and furosemide in high-dose beclomethasone–dependent asthma

BACKGROUND Inhaled lysine acetylsalicylate and furosemide exert a mutually potentiating protective activity on experimentally induced bronchoconstriction in asthma. OBJECTIVE Our purpose was to investigate the clinical effectiveness of combined treatment of asthma with inhaled lysine acetylsalicylate and furosemide. METHODS We performed a randomized, double-blind, crossover study in nine patients with chronic asthma requiring a high dose (2 mg/day) of inhaled beclomethasone for clinical control. Patients were treated with a combination of 720 mg inhaled lysine acetylsalicylate and 40 mg furosemide twice daily, or with matched placebo in addition to inhaled steroids. The dose of inhaled steroids was reduced by half every 15 days and eventually suspended unless a patients respiratory condition worsened. RESULTS During treatment with placebo, all patients had worsening of asthma at dosages of 1 or 0.5 mg/day beclomethasone (mean +/- SE, 833 +/- 83 micrograms/day). During combined treatment complete suspension of inhaled steroids in two patients and reduction to 0.5 to 0.25 mg in the remaining seven patients (mean, 250 +/- 72 micrograms/day) was achieved, with a mean reduction of 71% +/- 7%. Forced expiratory volume in 1 second, weekly peak expiratory flow rate, symptom score, and bronchodilator intake remained significantly better with combined treatment than with placebo. CONCLUSIONS Treatment with inhaled lysine acetylsalicylate and furosemide allows a considerable sparing of inhaled steroids without significant side effects in patients with severe asthma.

Protective activity of inhaled nonsteroidal antiinflammatory drugs on bronchial responsiveness to ultrasonically nebulized water

Relatively high doses of oral aspirin are needed to afford a significant protective effect against the bronchial obstructive reaction to ultrasonically nebulized distilled water (UNDW) in asthmatic patients. Sodium salicylate at similar doses and indomethacin at normal dose afford no protection. The present study was undertaken to assess the protective activity of these drugs taken by inhalation. Thirteen asthmatic patients performed two UNDW challenges 20 minutes and 24 hours after inhalation of 900 mg lysine acetylsalicylate (L-ASA) or placebo. The volume of UNDW causing a 20% fall in FEV1 (UNDW PD20) was calculated by linear interpolation on the dose-response curve. UNDW response after placebo was not significantly different from the preliminary test (PD20 4.3 +/- 0.7 and 4.1 +/- 04 ml, respectively, mean +/- SE), whereas after L-ASA, UNDW PD20 increased to 17 +/- 2.7 ml (p < 0.01 vs placebo) and remained significantly increased after 24 hours. In another group of 12 patients under the same experimental conditions, an equivalent dose of inhaled sodium salicylate caused no effect. Finally, in a third group of asthmatic patients pretreatment with inhaled indomethacin at two dose levels (6 patients, 25 mg; 10 patients, 50 mg) resulted in a significant dose-related protective effect. These findings indicate that inhaled indomethacin and especially L-ASA exert against UNDW-induced bronchoconstriction a potent protective effect, which appears to be mediated by inhibition of local prostaglandin synthesis in the airways. This fact could have therapeutic implications.

Potentiation of the antireactive, antiasthmatic effect of inhaled furosemide by inhaled lysine acetylsalicylate.

Nonsteroid antiinflammatory drugs interfere with the diuretic activity of furosemide, implying that this effect is at least partially dependent on renal prostaglandin synthesis. To investigate whether prostaglandin production could also modulate the bronchial antireactive activity of this diuretic drug, we investigated the effect of inhaled Iysine acetylsalicylate (162 mg) and of furosemide (18 mg), alone and in combination, on the bronchial obstructive response to ultrasonically nebulized water in asthmatic patients. The study was also prompted by the conflicting results obtained in previous studies of oral nonsteroid antiinflammatory drugs. Fifteen asthmatic patients underwent bronchial challenge with a mist of ultrasonically nebulized distilled water at the same time of day on four occasions, 2–4 days apart, 15 min after premedication according to a double‐blind, randomized protocol. After placebo, mean PD15 to water mist did not differ from a preliminary test (2.1 ± 0.2 and 2.5 ± 0.4 ml, M ± SE, respectively). After lysine acetylsalicylate, mean PD., rose to 5.0 ± 0.7 ml (2.8 ± 0.6 times higher than placebo); after furosemide, to 9.0± 1.5 ml (4.4 ± 0.9 times over placebo); and after the two drugs in combination, to 32.2 ± 5.6 ml (16.3 ± 3.0 times higher than placebo). Similar results were obtained with inhaled indomethacin, whereas sodium salicylate had no effect. These data indicate that the bronchial antireactive activity of inhaled furosemide is greatly enhanced by inhaled lysine acetylsalicylate through a mechanism which probably involves inhibition of the local synthesis of prostaglandins, and could have therapeutic implications.

Protective effect of inhaled lysine acetylsalicylate on allergen-induced early and late asthmatic reactions ☆ ☆☆ ★

Conflicting results have been reported on the effect of non-steroidal antiinflammatory drugs on allergen-induced asthmatic responses. The aim of this study was to investigate the effect of inhaled lysine acetylsalicylate (LASA) on the early and late allergen-induced responses. We studied 16 patients with mild, stable asthma who had an early asthmatic response and 10 patients with a dual (early and late) response. Each patient underwent two challenges with a single dose of allergen assessed in a preliminary test, after inhalation of either 720 mg of LASA in 4 ml of saline solution or placebo, according to a randomized, double-blind protocol. Allergen-induced hyperreactivity to methacholine was measured in six patients from each of the early and the dual response groups 2 hours and 24 hours after the challenge, respectively. In the patients with early response, the maximum fall in FEV1 after challenge was 24% +/- 1% after inhalation of placebo and 14% +/- 2% after inhalation of LASA (p < 0.005). No protection was observed in four patients who received the drug orally instead of by inhalation. In the patients with a dual response, the maximum FEV1 decrease during the early response was 27% +/- 2% after placebo and 21% +/- 2% after LASA (p < 0.025). During the late response (between 3 and 8 hours), the maximum decrease in FEV1 was 28% +/- 4% after placebo and 16% +/- 4% after LASA (p < 0.005). In both groups allergen challenge caused a significant reduction in methacholine PD20 after treatment with placebo but not with LASA. Without allergen challenge, LASA had no effect on methacoline reactivity. We conclude that inhaled LASA significantly reduces both the early and the late asthmatic response to allergen challenge and that it prevents the allergen-induced airway hyperresponsiveness that follows these responses.

Time-limited protective effect of inhaled frusemide against aspirin-induced bronchoconstriction in aspirin-sensitive asthmatics

Inhaled frusemide effectively prevents the bronchial obstructive response to allergens and to a number of nonallergic stimuli. In most of the experimental models in which it has been tested, the protective effect of frusemide has been evaluated for only a short time after administration. In aspirin-sensitive patients, acetylsalicylic acid causes an asthmatic reaction which typically lasts for 2 h or more after exposure. We investigated the presence and duration of the protective effect of inhaled frusemide against the bronchial response to aspirin in sensitive patients, using a specific inhalation challenge with lysine acetylsalicylate (LASA). In the first study, eight subjects with aspirin-asthma underwent two bronchial challenges with a single dose of lysine acetylsalicylate administered through a jet nebulizer, after treatment with 40 mg inhaled frusemide or placebo, according to a randomized, double-blind protocol. Forced expiratory volume in one second (FEV1) was monitored for 120 min after challenge. In the second study in eight patients, the protocol was modified by the use of a dosimeter for delivery of lysine acetylsalicylate, by reducing the dose of lysine acetylsalicylate to avoid intense reactions, and by extending the follow-up to 4 h. In the first study, after placebo, FEV1 gradually decreased, reaching a maximum decrement of 39 +/- 3% at 120min. Inhaled frusemide exerted a significant protection at all time-points, although this activity appeared to decrease with time. In the second study, after placebo, inhaled lysine acetylsalicylate caused a gradual decrease in FEV1, which reached a maximum decrement at 180 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term macrolides in diffuse interstitial lung diseases

In the present review we provide currently available evidence for the use of macrolides in the treatment of diffuse interstitial lung diseases (ILDs). Up to now, research on macrolides has mainly focused on three areas. First, macrolides have shown some promising results in cellular models and case reports as antifibrotic agents, by promoting autophagy and clearance of intracellular protein aggregates and acting as regulators of surfactant homeostasis. Secondly, macrolides have an immunomodulatory effect, which has been applied in some organising pneumonia cases. In particular, macrolides have been tested in association with systemic corticosteroids as steroid-sparing agents and alone as either first-line agents in mild cases or second-line agents where steroids were poorly tolerated or had failed. Thirdly, a recent area of research concerns the possible role of macrolides as modulators of lung microbiota and the host–microbiota interaction. This function has been particularly studied in idiopathic pulmonary fibrosis patients, in whom changes in microbiota have been proved to be associated with disease progression. However, the lack of high-quality studies makes the application of macrolide therapy in ILDs a field in which research should be conducted on a large scale. Macrolides may act as microbiota modulators as well as anti-inflammatory and antifibrotic agents in ILDs http://ow.ly/stlc30gB3je

Comparison between anticholinergic and beta-2 agonist treatments by using pletismography and impulse oscillometry

COPD (chronic obstructive pulmonary disease) treatment includes both anticholinergic and beta-2 agonist inhaled bronchodilators which can relieve symptoms and reduce exacerbations. To evaluate the effect of bronchodilator drugs, FEV1 (forced expiratory volume in 1 second) and FVC (forced vital capacity) are routinely measured, even if they don9t often fully identify important mechanical modifications of the lung, e.g. hyperinflation. Body plethysmography and impulse oscillometry (IOS) can better evaluate lung function. We recruited 32 patients: 16 with COPD, 10 with ACOS (asthma COPD overlap syndrome) and 6 with bronchial asthma. Patients underwent spirometry, body pletismography and IOS on 1st day, then they received 100 µg dose of salmeterol on 2nd day and 322 µg dose of aclidinium bromide on 3rd day, repeating functional tests each day. All values bettered, reaching statistical significance, after both salmeterol and aclidinium treatment in bronchial asthma and in ACOS patients, while in COPD patients only sGaw, R5, R20 and AX reached statistical significance, even if all values improved. The percentage of improvement obtained with aclidinium was higher than that obtained with salmeterol in functional tests. Data correlation was then performed. High association was found between FEV1 and R5 and between R5, R20 and VR. Values of ACOS patients showed the strongest association. IOS can adequately measure lung resistance changes caused by inhaled bronchodilators, related to changes in lung volumes. Absolute values of bronchodilation and of reduction of both peripheral and central resistances obtained with aclidinium were greater than those got with salmeterol.

Which Mask for Noninvasive Ventilation in Acute Respiratory Failure

www.chestpubs.org a better survival rate. 5 Although all patients received antiviral treat ment, in the seasonal outbreak, a 1-day delay (5 days instead of 4 days) in the antiviral administration was observed. This apparent treatment delay could be associated with a corresponding difference in the time from symptoms onset to hospital (4.9 days vs 4.3 days, P , .01) or ICU admission (2.3 days vs 1.8 days, P , .01). 5 All of these variables must be considered to explain the higher mortality rate observed in patients undergoing invasive mechanical ventilation during the seasonal outbreak of An(H1N1) (42.6%) compared with patients with A(H1N1) (34.2%, P , .001). 5 APACHE II score (OR 5 1.1; 95% CI, 1.06-1.12), invasive mechanical ventilation (OR 5 8.3; 95% CI, 4.32-15.91), hematologic disease (OR 5 3.0; 95% CI, 1.66-5.49), HIV infection (OR 5 3.9; 95% CI, 1.38-11.51), and antiviral therapy (OR 5 0.45; 95% CI, 0.28-0.73) were variables independently associated with mortality. Finally, only 6.2% of patients admitted to the ICU during the seasonal outbreak were vaccinated, and they seemed to have a more favorable outcome with shorter ICU stay (3 days) and fewer days under invasive mechanical ventilation (3 days). Seasonal fl u during the winter of 2010 to 2011 was dominated by the An(H1N1) virus and survival of intubated patients was , 60%. Delay in diagnosis, a low rate of vaccination, and suboptimal antiviral therapy indicate the need to improve educational measures and public information management for the coming years.