Different effects of inhaled aspirinlike drugs on allergen-induced early and late asthmatic responses.

Little is known about the anti-asthmatic effects of powerful anti-inflammatory agents such as aspirin-like drugs. We compared the effects of two aspirin-like drugs with different pharmacologic activities, sodium salicylate (SSA) and indomethacin, with the effect of lysine acetylsalicylate (LASA), inhaled 30 min before challenge, on the early and the late asthmatic response induced by a single dose of allergen causing a 25% decrease in FEV1 in a preliminary challenge. Inhaled SSA partially prevented both the early and late response, providing a protection with respect to placebo of 22 +/- 6% in the early phase and 23 +/- 9% in the late phase of the response. These values were lower (but not significantly) than those of LASA (41 +/- 9% and 39 +/- 11%, respectively). In a second group of patients, indomethacin failed to affect the early response, while LASA provided a protection of 31 +/- 7%. However, these two drugs were equally effective in reducing the late response (44 +/- 18% and 39 +/- 17% protection for LASA and indomethacin, respectively). In subjects with an early response, despite being ineffective in preventing allergen-induced bronchoconstriction, indomethacin blocked the allergen-induced increase in bronchial hyperresponsiveness measured 2 h after challenge. We conclude that inhaled salicylates, but not indomethacin, exert a protective activity against the early allergic response. This difference is not explained by the different pattern of cyclooxygenase inhibitory activity of these drugs.

Combined lung volume reduction surgery and thoracic aortic aneurysm resection.

Postoperative improvement of respiratory function has been reported with lung volume reduction surgery (LVRS) in patients with severe emphysema. Since smoking is an established risk factor for lung cancer, vascular diseases and emphysema, it is not infrequent to find these diseases associated in the same patient. Combined treatment of lung cancer and emphysema has already been reported. Surgical treatment of vascular diseases in emphysematous patients could also benefit from the application of LVRS techniques. We report resection of an aortic aneurysm combined with LVRS in a patient with concomitant thoracic aortic aneurysm and severe emphysema. Respiratory function improved in the postoperative period.

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.

Attenuation of aspirin-induced bronchoconstriction by sodium cromoglycate and nedocromil sodium.

The protective activity of nedocromil sodium and of sodium cromoglycate against aspirin-induced asthma has never been investigated in controlled studies. Because it has been reported that aspirin-induced platelet-mediated cytotoxic activity in vitro is inhibited after treatment in vivo with nedocromil but not with cromoglycate, we investigated whether these compounds also exhibit a different protective activity against aspirin-induced bronchoconstriction. Ten patients with aspirin-induced asthma underwent three bronchial challenges with a single dose of lysine acetylsalicylate (LASA) that caused a decrease in FEV1 of 25% or more in a preliminary dose-response test 30 min after inhalation of 4 mg nedocromil sodium, 10 mg sodium cromoglycate, or placebo. FEV1 and SRaw were recorded at intervals for 195 min. After placebo, LASA caused a maximal decrease in FEV1 of 42 +/- 4% of baseline. After cromoglycate and nedocromil the maximal decrease in FEV1 was reduced to 20 +/- 3% and 18 +/- 4%, respectively (p < 0.01 versus placebo for both treatments), without significant differences between the two treatments. Similar results were observed with SRaw. We conclude that, at the recommended therapeutic doses, sodium cromoglycate and nedocromil sodium are equally effective in attenuating aspirin-induced bronchoconstriction and that it is unlikely that platelet activation participates in the pathogenesis of aspirin-induced asthma.

Inhaled PGE2 prevents aspirin-induced bronchoconstriction and urinary LTE4 excretion in aspirin-sensitive asthma.

Bronchial overproduction of leukotrienes and inhibition of prostaglandin synthesis are involved in the pathogenesis of aspirin-induced asthma. We investigated whether inhaled prostaglandin E2 (PGE2) attenuates the response to bronchial challenge with lysine acetylsalicylate (LASA) and the associated increase in urinary leukotriene E4 (u-LTE4) in seven aspirin-sensitive subjects with asthma. Each subject performed two challenges with a single dose of LASA that caused a decrease in FEV1 of 20% or more in a preliminary test, immediately after inhaling 100 micrograms PGE2 in 4 ml saline or placebo, according to a randomized double-blind protocol. FEV1 was recorded at 30-min intervals for 4 h. u-LTE4 was measured by combined high-performance liquid chromatography enzyme immunoassay at 2-h intervals. After placebo, LASA caused an obstructive reaction in all patients, with a maximum decrease in FEV1 of 35 +/- 5% with respect to baseline. u-LTE4 rose from 911 +/- 261 picograms (pg)/mg creatinine at baseline to a maximum value of 2249 +/- 748 after challenge. Inhaled PGE2 provided almost complete protection in all patients. Baseline u-LTE4 was 883 +/- 243 pg/mg creatinine and did not change significantly during the test, reaching a maximum value of 864 +/- 290 (p < 0.05 versus placebo). These results confirm that PGE2 is highly effective in preventing aspirin-induced asthma and suggest that this effect is mediated by inhibition of sulfidopeptide leukotriene production.

Protective effect of furosemide combined with non-steroidal anti-inflammatory drugs administered by inhalation route on guinea-pigs anaphylaxis model.

The exposure of ovalbumin sensitized guinea-pig to an areosol of the specific antigen causes a respiratory crisis in approximately 100 s (dispnoea time) associated with a substantial increase in blood concentration of both histamine (from 27.5 +/- 1.8 ng/ml to 1570 +/- 26 ng/ml; n = 8) and thromboxane B2 (TXB2, from 0.52 +/- 0.03 ng/ml to 18.1 +/- 0.6 ng/ml; n = 8). The aerosol treatment of the animals (20 min) with furosemide (CAS 54-31-9, frusemide, FRU), nimesulide (CAS 51803-78-2, NIM), acetylsalicylic acid (CAS 50-78-2, ASA) and indometacin (CAS 53-86-1, INDO) at the concentrations of 1-3-10 and 30 mg/ml, before ovalbumin challenge, brought about an attenuation of anaphylactic response. The rank order of potency for the prolongation of dyspnoea time was FRU > NIM > ASA > INDO. In these experiments blood evaluation performed at the peak of the dyspnoea time for histamine concentration in the treated animals indicated that whereas FRU (ED25 = 2.14 mg/ml (1.97-2.38) and NIM (ED25 = 2.74 mg/ml (2.37-3.19)) were equiactive in reducing the release of histamine, ASA and INDO were devoid of this activity. On the contrary, the results obtained with ASA and INDO indicated a greater intrinsic activity in antagonizing TXB2 formation than that shown by the log-dose response curves of NIM and FRU. In another series of experiments the interaction of FRU with the other anti-inflammatory drugs in protecting guinea-pig from immune bronchoconstriction has been evaluated using the combination of two equiactive doses. The mixture considered were FRU+NIM, FRU+INDO and FRU+ASA. The results obtained indicated that FRU interacts positively with the three non-steroidal anti-inflammatory drugs in delaying the onset of the dyspnoeic crisis in guinea-pig. However, when FRU was combined with NIM the gain obtained (209%) appeared superior to that reached when FRU was combined with ASA (180%) or INDO (126%). Taken together these results suggest that non-steroidal anti-inflammatory compounds given by aerosol may represent a valid pharmacological intervention in protecting guinea-pig from anaphylactic bronchoconstriction.

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 patient's 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.

The efficacy and safety of moguisteine in comparison with codeine phosphate in patients with chronic cough.

We conducted a multicentre, double-blind, parallel group study to compare the clinical efficacy of a new antitussive drug, moguisteine (100 mg t.i.d.), to that of a reference standard, codeine (15 and 30 mg, t.i.d.). Both drugs were given orally for a period of two days. A group of 119 patients (mean age 54 yrs; 61 females and 58 males) with chronic, dry or slightly productive cough, associated with various respiratory disorders (including chronic obstructive pulmonary disease, respiratory malignancies and pulmonary fibrosis) were enrolled at six participating centres. The percentage reduction in the number of morning coughs over a period of 6 h after the first administered dose compared to baseline assessment, was 21% with moguisteine (n = 39), 28% with codeine 15 mg (n = 38), and 29% with codeine 30 mg (n = 36). Differences between treatments were not significant. The percentage reduction in the number of nocturnal coughs per hour, after the last evening dose compared to baseline assessment, was 33, 46 and 52%, respectively. Subjective assessments (patients' visual analogue scale scores of cough frequency, cough intensity and sleep disturbance, and investigators' ranking of cough severity) indicated that there was a similar improvement in cough symptoms in all treatment groups. Adverse events were observed in two patients on moguisteine, three on codeine 15 mg, and five on codeine 30 mg. No event was serious, but discontinuation of treatment was required in two patients on codeine 30 mg. The results of our study suggest that moguisteine 100 mg t.i.d. is safe, and seems to have an antitussive activity similar to that of codeine 15-30 mg t.i.d.

Influence of acetaldehyde on airway resistance and plasma exudation in the guinea-pig.

In anaesthetized ventilated guinea-pig, acetaldehyde (CAS 75-07-0) (40-80 mg/kg i.v.) elicits a dose-dependent increase in intratracheal pressure accompanied by an increase in circulating histamine. When acetaldehyde is injected repeatedly at 15 min intervals in capsaicin-desensitized animals, it already loses its activity at the second administration (50% reduction; p < 0.01); this does not happen in control animals. This phenomenon is even more marked when acetaldehyde is given at the dose of 80 mg/kg i.v., since at the third injection both the bronchoconstriction and the increase in blood histamine are almost completely reduced to baseline values. The increase in intratracheal pressure caused by acetaldehyde (20, 40, 80 mg/kg i.v.) is associated with a dose related increase in microvascular permeability and leakage of protein-bound Evans blue in lower tracheal tissue. This event and the bronchoconstrictor response caused by acetaldehyde (40 mg/kg i.v.) are 87% and 35% inhibited, respectively, (p < 0.01) in tachykinin-depleated animals. On the contrary, thiorphan (2 mg/kg i.v.) remarkably potentiates both the rise in intratracheal pressure (110%; p < 0.01) and Evans blue extravasation (215%; p < 0.01) induced by acetaldehyde (20 mg/kg i.v.) in normal guinea-pigs. Furthermore, treatment with CP-96,345, a selective tachykinin NK1-receptor antagonist, only prevents plasma extravasation in lower tracheal tissue (82% inhibition; p < 0.01) without affecting the bronchoconstriction caused by acetaldehyde (40 mg/kg i.v.).(ABSTRACT TRUNCATED AT 250 WORDS)

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)

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 lysine 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 PD15 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 piretanide on the bronchial obstructive response to ultrasonically nebulized H2O. A dose-response study.

Inhaled furosemide prevents the obstructive response to several bronchoconstrictor stimuli in asthma. To verify whether this protective effect is also shared by other loop diuretics, we investigated the effect of inhaled piretanide on the bronchial obstructive response to ultrasonically nebulized distilled water (UNW) in ten patients with moderate, stable asthma. In a randomized, single-blind dose-response study, each subject performed an UNW test immediately after nebulization of different doses of piretanide between 12 and 48 mg or placebo. The effect of a single 40-mg dose of inhaled furosemide was also investigated in six subjects. Piretanide caused a significant, dose-dependent increase in UNW PD20 with respect to placebo, corresponding to 0.6 +/- 0.2 doubling doses (mean +/- SE) after 12 mg, 1.3 +/- 0.2 after 24 mg, and 2.0 +/- 0.2 after 48 mg, and had a remarkable diuretic effect; 40 mg of furosemide increased UNW PD20 by 2.3 +/- 0.3 doubling doses (p < 0.01), but showed only a modest diuretic activity. These data indicate that inhaled piretanide is as effective as furosemide in preventing UNW-induced asthma, and this effect is unrelated to their diuretic potency.

Efficacy and tolerability of nimesulide in asthmatic patients intolerant to aspirin.

Inflammation 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.

Inhaled loop diuretics as potential new anti-asthmatic drugs.

The observation that changes in bronchial osmolarity can induce bronchoconstriction in asthma inspired the experimental studies which, unexpectedly, revealed that frusemide is an effective bronchoprotective agent against a variety of osmotic and non osmotic stimuli. Although the mechanism of this protective effect is not fully understood, studies in vivo and in vitro suggest that frusemide may inhibit the activation of different cell types induced by bronchoconstrictor stimuli. Other loop diuretics also exert bronchoprotective activity, but frusemide appears to be the more effective bronchoprotective agent of this family, regardless of their diuretic potency and lipid solubility. Despite the relatively large amount of experimental evidence, there is currently little information on the clinical effectiveness of frusemide in asthma and a long-term controlled study is currently in progress. The observations that treatment with a combination of inhaled acetylsalicylate and frusemide results in a markedly increased bronchoprotective effect compared to either drug alone, opens a new perspective in the possible clinical use of these drugs. Preliminary studies suggest that the association of these drugs is well tolerated and may result in a remarkable steroid sparing effect in patients with steroid dependent asthma, for whom a convenient alternative to long-term steroid therapy is not currently available.

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.

Prevention of exercise-induced bronchoconstriction by a new leukotriene antagonist (SK&F 104353). A double-blind study versus disodium cromoglycate and placebo.

The effects of 800 micrograms of inhaled SK&F 104353, a peptidoleukotriene receptor antagonist, and of 20 mg disodium cromoglycate (DSCG) on exercise-induced bronchoconstriction were compared in 18 asthmatic patients. The study was conducted according to a double-blind, crossover, randomized, placebo-controlled design. Two baseline exercise tests were carried out, and pulmonary function tests were done before and at 1, 5, 10, 15, 20, and 30 min after completion of the exercise. Patients showing a 20% or greater decrease in FEV1 in both exercise challenges entered the blinded portion of the study. When placebo was administered before exercise, FEV1 fell to the same extent as during the baseline phase. After SK&F 104353 and DSCG, the bronchoconstriction was attenuated. The mean maximal percentage fall in FEV1 after exercise was 29% after placebo and 20% after SK&F 104353 and DSCG. The differences between the two active treatments did not reach the 5% level of statistical significance, though at 20 min SK&F 104353 showed a more pronounced effect than DSCG. The protective effect suggests an important role of leukotrienes in the pathogenesis of exercise-induced bronchoconstriction.