Sebastiano Bianco

Protective effect of inhaled furosemide on allergen-induced early and late asthmatic reactions.

The movement of ions and water across the membranes of bronchial cells is part of the control of the bronchial obstructive response to physical stimuli. In a double-blind, randomized, crossover study, we compared the effect of an aerosol of the loop diuretic furosemide with that of a placebo on the early (within 60 minutes) and late (4 to 12 hours) asthmatic responses to a specific inhaled allergen. We studied 11 subjects with mild allergic asthma, who had both early and late asthmatic responses to a specific inhaled allergen in a preliminary challenge. After placebo administration, the maximal changes (mean +/- SE) from base line in the forced expiratory volume in one second (FEV1) and specific airway resistance were, respectively, a decrease of 35 +/- 4 percent and an increase of 288 +/- 56 percent between 0 and 60 minutes after inhalation of the allergen (early response) and a decrease of 35 +/- 5 percent and an increase of 301 +/- 40 percent between 4 and 12 hours (late response). After furosemide administration (4 ml; 10 mg per milliliter), the early response to inhaled allergen was markedly attenuated in all the subjects, and the late response in all but one. The maximal changes in the FEV1 and specific airway resistance were, respectively, a decrease of 11 +/- 2 percent and an increase of 61 +/- 2 percent between 0 and 60 minutes and a decrease of 20 +/- 4 percent and an increase of 178 +/- 25 percent between 4 and 12 hours (P less than 0.05 for all comparisons). No significant differences were seen in the bronchoconstrictor response to inhaled methacholine after furosemide or placebo administration. We conclude that a furosemide-sensitive mechanism in the airways is involved in the pathogenesis of the reactions of patients with allergic asthma. Whether inhaled furosemide might be useful in the treatment of allergic asthma is uncertain and will require further study.

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.

Improvement of pulmonary function after lobectomy for non-small cell lung cancer in emphysematous patients

OBJECTIVE Pulmonary emphysema is frequently associated with lung cancer and, because of the impaired pulmonary function involved, it may contraindicate surgical treatment. However, improvement of pulmonary function has been observed after surgical resection in patients with advanced emphysema. The aim of this study was to evaluate whether pulmonary emphysema, as assessed by pulmonary function tests and radiological evaluation, can influence postoperative respiratory function after lobectomy for non-small cell lung cancer (NSCLC). METHODS Respiratory function was evaluated before and after lobectomy for NSCLC. Radiological evaluation of emphysema was performed on chest X-ray and CT scan. Patients that had undergone chemo- or radiotherapy or had segmental or lobar atelectasis were excluded from the study. RESULTS Thirty-five patients entered the study. A decrease in static lung volumes was observed after surgery. Total lung capacity (TLC) decreased from 6.58+/-0.92 to 5.46+/-0.77 l; functional residual capacity (FRC) from 3.70+/-0.88 to 2.96+/-0.73 1 and residual volume (RV) from 2.93+/-0.78 to 2.2+/-0.53 l. However, in a subgroup of 10 patients (Group 1), dynamic volumes after surgery were unchanged or slightly increased (forced vital capacity (FVC) from 3.23+/-0.65 to 3.3+/-0.68 l; forced expiratory volume in 1 s (FEV1) from 2.14+/-0.51 to 2.25+/-0.54 l), and airway resistances (sRaw) decreased from 15.58+/-5.18 to 11.42+/-5.25 cm H2O/s. Preoperative data showed that these patients had a greater obstruction, with FEV1 changing from 69+/-12.42 to 72.70+/-13.72% of predicted, as compared with a change from 87+/-12.7 to 72.08+/-13.10% in the other group of 25 patients (Group 2). Correlation analysis reached statistical significance between FEV1% variation (deltaFEV1%) and preoperative FEV1 and FVC% (r = -0.49, P = 0.002 and r = -0.5, P = 0.001, respectively) and between delta (FEV1)% and radiological scores for 3-level CT (r = 0.39, P = 0.04) and the sum of chest X-ray, single and 3-level CT scores (r = 0.49, P = 0.01). CONCLUSIONS Pulmonary function may remain unchanged or even increase after lobectomy in patients with a pronounced emphysematous component of airway obstruction. The identification of preoperative parameters that identify this group of patients could extend the indications for the treatment of lung cancer in patients with pulmonary emphysema.

Aspects of bronchial reactivity to prostaglandins and aspirin in asthmatic patients.

The behaviour of bronchial reactivity to PGF2alpha was studied in asthmatic patients under various experimental conditions. Premedication with aminophylline, i.v., and, to a lesser extent, with DSCG afforded a partial protection, while beclomethasone dipropionate was inactive under this point of view. Diftalone, a new non-steroid anti-inflammatory agent, was well tolerated in 9 aspirin-intolerant asthmatic patients, and did not modify the bronchial response to PGF2alpha which was found to be generally lower then that of other aspirin-tolerant asthmatic patients. PGE 1-2 and DSCG prevented the bronchospasm induced by inhalation or ingestion of acetylsalicylic acid in a small group of patients. Good protection was also reached with PGE1-2 in the exercise-induced bronchospasm.

Prevention of antigen-induced early obstructive reaction by inhaled furosemide in (atopic) subjects with asthma and (actively sensitized) guinea pigs

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.

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.

Bronchial Inflammation and NSAIDs

SummaryA wide range of experimental evidence shows that bronchial eosinophilic inflammation plays a major role in the pathogenesis of the asthmatic syndromes characterised by reversible airway obstruction and bronchial hyperresponsiveness. A treatment aimed at controlling inflammation is therefore of primary importance in these pathological conditions. To date, corticosteroids have been routinely used for this purpose, but their administration is often accompanied by serious side effects. Cromoglycate and cromoglycate-like compounds have been proposed as alternative anti-inflammatory agents, but because their anti-inflammatory activity is relatively low, they can replace corticosteroids only in mild asthma. In the most severe forms of asthma, gold salts and methotrexate have demonstrated a steroid-sparing effect, but at the cost of a high incidence of toxic effects.Little attention has been devoted to the use of NSAIDs in asthma for 2 principal reasons. In acute studies, NSAIDs such as aspirin (acetylsalicylic acid) and indomethacin have not shown satisfactory bronchodilator or antireactive activity. More importantly, NSAIDs have traditionally been associated with a relatively high frequency of severe obstructive reactions in patients with asthma.However, nimesulide, a recently developed NSAID, has proven to be safe in NSAID-sensitive patients. Moreover, in guinea-pigs, the drug exhibits good antianaphylactic activity and an impressive antihistaminic effect that is not shared by other NSAIDs such as indomethacin. On the basis of these findings, nimesulide can be considered as a potential antireactive-antiasthmatic agent, of which further clinical investigation is justified.