Comparison of three inhaled non-steroidal anti-inflammatory drugs on the airway response to sodium metabisulphite and adenosine 5'-monophosphate challenge in asthma.
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BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are used to assess the role of prostaglandins in asthma but their effects on bronchoconstrictor challenges have been inconsistent. The effects of three nebulised nonsteroidal anti-inflammatory drugs on the airway response to inhaled sodium metabisulphite (MBS) and adenosine 59-monophosphate (AMP) were compared in the same asthmatic subjects to see whether contractile prostaglandins were involved in MBS or AMP induced bronchoconstriction. A possible protective effect of the osmolarity or pH of the inhaled solutions was also assessed. METHODS: Two double blind placebo controlled studies were carried out. In study 1, 15 non-aspirin sensitive patients with mild asthma attended on four occasions and inhaled 5 ml of lysine aspirin (L-aspirin) 900 mg, indomethacin 50 mg, sodium salicylate 800 mg, or saline 20 minutes before an inhaled MBS challenge. On four further occasions 14 of the patients inhaled the same solutions followed by an inhaled AMP challenge. In study 2, 10 of the patients attended on four additional occasions and inhaled 5 ml of 0.9%, 3%, 10%, or 9.5% saline with indomethacin 50 mg 20 minutes before an inhaled MBS challenge. RESULTS: In study 1 inhaled lysine aspirin had a similar effect on MBS and AMP induced bronchoconstriction, increasing the provocative dose causing a 20% fall in FEV1 (PD20) by 1.29 (95% CI 0.54 to 2.03) and 1.23 (95% CI 0.53 to 1.93) doubling doses, respectively. Indomethacin increased the MBS PD20 and AMP PD20 by 0.64 (95% CI -0.1 to 1.38) and 0.99 (95% CI 0.29 to 1.69) doubling doses, respectively. Sodium salicylate had no significant effect on either challenge. The two solutions causing most inhibition were the most acidic and the most alkaline. In study 2 inhaled 9.5% saline with indomethacin (osmolarity 3005 mOsm/kg) increased the MBS PD20 by 1.1 doubling doses (95% CI 0.2 to 2.0) compared with only 0.09 (95% CI -0.83 to 1.0) and 0.04 (95% CI -0.88 to 0.95) doubling doses with 3% saline (918 mOsm/kg) and 10% saline (2994 mOsm/ kg), respectively. CONCLUSIONS: Inhaled L-aspirin and indomethacin have broadly similar protective effects against MBS and AMP induced bronchoconstriction in the doses given, although the effect of indomethacin on MBS was not quite statistically significant. The osmolarity and pH of the solutions did not appear to be important determinants of the response. The effect of L-aspirin and indomethacin is likely to be the result of cyclooxygenase inhibition reducing the production of contractile prostaglandins during MBS and AMP challenge.Keywords:
Sodium salicylate
Adenosine monophosphate
Abstract Background: Dairy products have often been implicated as a cause of exacerbation of asthma, but there is little scientific evidence to support this hypothesis. Objective: We sought to determine whether dairy products induce bronchoconstriction in a group of adults with asthma. Methods: Twenty subjects with asthma (13 women and 7 men) were recruited from respondents who had previously completed a food and asthma questionnaire. Ten subjects perceived that their asthma became worse with ingestion of dairy products (positive perceivers), whereas ten were negative perceivers. None of the subjects had positive skin prick test results with cow's milk. The study was a randomized, cross-over, double-blind, placebo-controlled trial. Subjects complied with a dairy-free diet throughout the study. The active challenge was a single-dose drink equivalent to 300 ml of cow's milk. A positive reaction was defined as a 15% reduction in both FEV 1 and peak expiratory flow (PEF) on the active challenge day compared with results obtained at the same time on the placebo day. Results: For both FEV 1 and PEF there were no statistically significantly differences in group means between active challenge and placebo challenge, between sequence of administration, or between perceptions. Nine subjects showed FEV 1 or PEF changes that were greater than 15% of baseline values: four patients showed changes after both active and placebo treatment; two after treatment with placebo only; and three after active treatment alone. Of the latter group, two subjects showed changes only in PEF, and when one of these subjects underwent a further detailed study, no asthmatic reaction could be demonstrated. Conclusion: It is unlikely that dairy products have a specific bronchoconstrictor effect in most patients with asthma, regardless of their perception. (J Allergy Clin Immunol 1998;101:45-50.)
Chocolate milk
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Methacholine
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Rationale. Bronchoconstriction after deep inhalation is associated with increased severity of asthma and is also a predictor of length of hospital stay in individuals admitted with asthma exacerbations. We hypothesized that this effect may represent a new non-invasive method to assess bronchial reactivity and other measures of asthma control. Methods. We used a cross-sectional study design recruiting participants 18 to 65 years of age with a physician diagnosis of asthma. All participants were asked to provide three serial peak expiratory flow rate (PEFR) measurements in the morning, and bronchial reactivity was measured up to a maximum inhaled dose of 24.5 μ moL methacholine on the same day. Participants also recorded their asthma symptoms score and bronchodilator use during the 7 days before measuring bronchial reactivity. Results. A total of 127 people provided data for analysis. There was no significant relationship between bronchoconstriction after deep inhalation (as measured by three serial PEFR measurements) and either bronchial reactivity to methacholine, asthma symptoms, or bronchodilator use. Conclusions. Bronchoconstriction induced by deep inspiration does not appear to be a valid marker of airway hyperresponsiveness or asthma severity in adults with mild to moderate asthma.
Methacholine
Bronchial hyperresponsiveness
Bronchodilator Agents
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To diagnose Aspirin-induced asthma (AIA) safely and steadily, we performed an inhalation challenge test with a solution of Aspirin DL-lysine (Venopyrin®) in 35 bronchial asthmatics. This test was positive in 15 asthmatics including 12 symptomatic AIA cases. Three of the 23 symptomatic non-AIA patients, showed a positive reaction by aspirin inhalation. All 4 patients, who had a positive result in the aspirin oral challenge test, also showed a positive reaction in the aspirin inhalation challenge test. However, during the inhalation experiment there was no evidence of large attacks provoked by the aspirin oral challenge test, indicating the safety of the inhalation challange test. These findings suggest that the test may be important for prevention of progression of intractable asthma by detection of latent AIA patients.
Pathogenesis
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We wished to determine whether the refractory period after hypertonic saline (HS) challenge is due to mast cell mediator depletion. Therefore, the airway responsiveness to adenosine 5' monophosphate (AMP), which induces bronchoconstriction via mast cell histamine release, was determined after the inhalation of HS aerosol. Nine asthmatic subjects attended the laboratory on three occasions. On day 1 HS challenge was performed followed one hour later by a second HS challenge. On day 2 an AMP challenge was performed. On day 3 an HS challenge was performed followed one hour later by an AMP challenge. Airway responsiveness (PD35 sGaw) to an initial HS challenge ranged from 12 to 315 l of aerosol (mean 47 l). Airway responsiveness to a second HS challenge ranged from 8 to 800 l (mean 102 l p = 0.035, n = 9). Airway responsiveness to AMP increased from 0.44 to 14.0 mumol (mean 2.37 mumol) at baseline to 0.3 to 15.5 (mean 1.3 mumol) (p = 0.05) after HS challenge. There was a linear correlation between baseline AMP responsiveness and baseline HS responsiveness (r = 0.911, p = 0.001). There was no correlation between the degree of refractoriness and the change in AMP responsiveness (r = 0.1, p = 0.9). Thus airway responsiveness to AMP increased significantly after inhalation of HS aerosol and this increase was independent of refractory behaviour. Our results suggest that the refractory period to HS is not due to mediator depletion.
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Adenosine monophosphate
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Inhalation of aerosolized lysine-aspirin (L-ASA) has been described as an alternative diagnostic method in aspirin-sensitive asthma. To further understand the pathogenetic mechanism of aspirin-sensitive asthma, we performed L-ASA (Inyesprin) bronchoprovocation test (BPT) in 51 asthmatic patients (45 non-atopic and six atopic asthma). Twenty-six patients showed significant bronchoconstriction after the inhalation of L-ASA. Bronchoprovocation test produced immediate asthmatic responses in 13 cases as well as dual asthmatic responses in four cases, whose late onset asthmatic response was noted at 4-7 h after L-ASA inhalation. We conclude that L-ASA bronchoprovocation might be a useful method for the diagnosis and investigation of aspirin-sensitive asthma. However, L-ASA inhalation can also induce late onset asthmatic responses.
Methacholine
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In order to determine the mechanism of bronchoconstriction induced by the inhalation of adenosine in asthmatics, we measured, by the astograph method, cyclic nucleotides, leukotrienes and thromboxane B2 before and after the inhalation, and we studied the relationship between serum theophylline concentration and Rrs cont, Dmin and S Grs/Grs cont of the astogram obtained by inhaled adenosine. Plasma TXB2 level was significantly raised (p less than 0.05) after inhalation, but cAMP, cGMP, LTB4 and LTC4 did not change. In the astogram, Dmin was significantly elevated (p less than 0.01) when plasma theophylline concentration was raised to the therapeutic level, but Rrs cont and S Grs/Grs cont showed no remarkable change. We confirmed that inhaled adenosine caused bronchoconstriction in asthmatic patients, and that Dmin was elevated after the administration of theophylline. These results suggest that TXB2, a metabolic product of arachidonic acid, may be one of the most important mediators in the bronchoconstriction mechanism of inhaled adenosine.
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Asthma is currently a worldwide problem. Worldwide deaths from this condition have reached over 250,000 annually. Aspirin or Acetylsalicylic acid (ASA), has remained one of the world's safest, least expensive and most consumed analgesics. Aspirin (other Nonsteroidal anti-inflammatory drugs; NSAIDs) is contra-indicated for asthmatics because aspirin (other NSAIDs) precipitate asthmatic attacks in patients with bronchial asthma. Aspirin-induced asthma (AIA) refers to the development of acute bronchoconstriction, profuse rhinorrhea and skin flushing in asthmatic individuals following the ingestion of aspirin. The prevalence of AIA is 4.3, 8.8 and 10.5% in Poland, Finland and Australia, respectively. AIA is more common in women. The biochemical pathways involved in aspirin-sensitive asthma are not fully established. In this review, we try to provide an overview of pathogenesis, clinical symptoms, diagnosis & treatment of AIA.
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