M. Robuschi

Prevention of exercise-induced bronchoconstriction by inhaled frusemide.

To determine whether inhaled frusemide, a diuretic able to interfere with ion and water movement across airway epithelium, can modify exercise-induced bronchoconstriction, a three-part randomised, double-blind, placebo-controlled study was done in asthmatic patients who had a fall in FEV1 of at least 20% after running up and down a corridor. In the first part the effect of approximately 28 mg frusemide given as an aerosol was compared with that of a placebo. In the second part two doses of inhaled frusemide (approximately 14 mg and 28 mg) were examined. In the third part the effect of 20 mg oral frusemide was tested. Inhaled frusemide had a good and dose-related protective effect, whereas oral frusemide was ineffective. The mean (95% CI) maximum percentage falls in the FEV1 were: 11.5 (14.3-8.7) with frusemide and 33.8 (39.1-28.5) with placebo in the first part of the study; 13.6 (21.6-6.0) with 28 mg frusemide, 19.7 (28.2-11.3) with 14 mg frusemide, and 34.6 (39.4-30.0) with placebo in the second part of the study; and 15.2 (19.9-10.5) with inhaled frusemide, 38.2 (47.1-29.3) with oral frusemide, and 35.3 (45.9-24.7) with placebo in the last part of the study. The findings lend support to the hyperosmolarity hypothesis of exercise-induced asthma and may have therapeutic implications.

Inhaled frusemide is highly effective in preventing ultrasonically nebulised water bronchoconstriction

A decrease in the osmolarity of the periciliary fluid of central airways is supposed to be the initiating mechanism by which ultrasonically nebulised distilled water (UNH2O) induces bronchoconstriction in asthmatics. It is therefore possible that substances, such as frusemide (F), which, in vitro, interfere with ions and water translocation across the tracheo-bronchial epithelium, can also modify such response. To test this hypothesis, 16 adult asthmatics were challenged with UNH2O after being pretreated with either inhaled F (approximately 28 mg delivered into the mouth) or placebo (the diluent) administered in random order and double-blind by means of a jet nebuliser. F did not modify baseline FEV1 and sRaw but attenuated markedly their changes after UNH2O. Mean max % (95% CI) sRaw increases after placebo and F were 293% (168-419) and 63% (21-104), respectively; mean max % falls in FEV1 were 26% (20-32) and 6% (-1-12). Thus inhaled F is highly effective in preventing UNH2O-induced bronchoconstriction and this unexpected property could have therapeutic implications.

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.

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.

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.

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)

Nimesulide, a Nonsteroidal Anti-Inflammatory Drug, Displays Antianaphylactic and Antihistaminic Activity in Guinea-Pigs

SummaryThe nonsteroidal anti-inflammatory compound nimesulide (4-nitro-2-phenoxymethane sulfonanilide) antagonises the effect of histamine and inhibits the release of this autacoid during immunological reaction in guinea-pigs. The antihistaminic activity of nimesulide, studied in isolated guinea-pig trachea, is specific for the H1-receptor and is of a noncompetitive type. At a concentration of 1 × 10−5 mol/L, the potency of nimesulide is nearly half that of mepyramine (pyrilamine) at 1 × 10−6 mol/L. Furthermore, unlike indomethacin, nimesulide dose-dependently antagonises the effect of histamine on airway resistance of anaesthetised guinea-pigs. In actively ovalbumin-sensitised anaesthetised guinea-pigs, both nimesulide and indomethacin significantly protected the animals from the fatal systemic anaphylactic crisis. However, in perfused sensitised guinea-pig lungs, nimesulide reduced the anaphylactic release of histamine in a concentration-dependent way, whereas indomethacin, in spite of its inhibitory potency on thromboxane A2 formation, potentiated the immune release of histamine. The bronchoconstriction induced by acetaldehyde, administered by aerosol (2.5% in saline) in sensitised anaesthetised guinea-pigs, was substantially reduced by both nimesulide and mepyramine administered by inhalation and by intravenous injection. These data further support the antihistaminic property of nimesulide and also suggest a possible interference of the compound with the degranulation process of sensitised mast cells in response to acetaldehyde. In conclusion, the capacity of nimesulide to control the immunological release of histamine and to attenuate its effect at the receptor level of the airway smooth muscles of the guinea-pig, may have some therapeutic relevance in patients with inflammation of the respiratory tract aggravated by intolerance to aspirin-like drugs.

Inhaled transmembrane ion transport modulators and non-steroidal anti-inflammatory drugs in asthma

Several stimuli which affect the osmolarity of airway surface liquid may induce bronchoconstriction in asthmatic subjects, indicating that in these patients the control of the bronchial calibre is affected by the physicochemical characteristics of the airways lining fluid.1 In the last few years this hypothesis has been confirmed using a number of drugs which are known to affect cellular ion transport.2 Loop diuretics inhibit the bronchial obstructive response to ultrasonically nebulised distilled water (UNW) in a dose dependent fashion.3 It is still unclear, however, whether this protective activity is attributable to the main pharmacological activity of frusemide—the inhibition of the Cl–/Na+/K+ co-transport—since loop diuretics far more potent than frusemide on this mechanism, such as piretanide, torasemide or bumetanide, are markedly less effective than frusemide in preventing UNW induced bronchoconstriction when given by inhalation in equipotent diuretic doses (fig 1).4 In addition to UNW, frusemide was also found to be effective in reducing the bronchoconstriction induced by a variety of “indirect” stimuli including exercise, allergens, hyperosmotic aerosols, metabisulphite, and aspirin.4 5 Figure 1 Protective effect against UNW induced bronchoconstriction of increasing doses of inhaled frusemide, administered from a pressurised metered canister (5 mg/puff) and piretanide administered through a jet nebuliser. Data are expressed as the percentage protection attained in the same patient using an optimal dose of 40 mg frusemide through a jet nebuliser. Values are mean (SE) of 8–12 asthmatic patients. The natriuretic activity of frusemide is known to be partially inhibited by cyclo-oxygenase (COX) inhibitors, and a single study found a complete abrogation of the protective effect …

Protective activity of inhaled frusemide against immunological respiratory changes and mediator release in guinea-pigs

The antianaphylactic activity of inhaled frusemide was studied in ovalbumin-sensitized guinea-pigs. The exposure of the animals to frusemide aerosol (1% solution for 20 min) attenuated the respiratory response to ovalbumin challenge (aerosol 1% solution) and was associated with a significant reduction of blood histamine (70%; P less than 0.01) and thromboxane-B2 (35%; P less than 0.01) compared to control animals. Similar results were obtained in isolated lungs perfused via the trachea excised from ovalbumin-sensitized guinea-pigs exposed to frusemide aerosol (1% solution for 20 min). In this series of experiments frusemide significantly prevented the increase in tracheal perfusion pressure (45%; P less than 0.01) and the concomitant release into the pulmonary effluent of both histamine (75%; P less than 0.01) and thromboxane-B2 (39%; P less than 0.01). In another series of experiments, frusemide (1 x 10(-4) M) significantly reduced the immune release of histamine from mast cells of ovalbumin-sensitized rats. The inhibitory activity of frusemide was in the same range of potency (66%; P less than 0.01) as that of disodium cromoglycate (1 x 10(-4) M). These data taken together indicate that frusemide when given by inhalation prevents histamine release secondary to antigen-antibody reaction.