[show abstract][hide abstract] ABSTRACT: 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 5'-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.
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.
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.
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.
[show abstract][hide abstract] ABSTRACT: High dietary sodium intake has been identified as a potential cause of asthma and airway hyperreactivity. This study was designed to test the hypothesis that dietary sodium intake is an independent determinant of the risk of hyperreactivity in the general population, and to assess the role of atopy in the association between these factors.
Airway reactivity to methacholine, atopy, 24 hour urinary sodium excretion, and self-reported smoking and symptom history were measured in a random sample of 1702 adults aged 18-70 from an administrative district of Nottingham. Hyperreactivity was defined as a PD20FEV1 of 12.25 mumol or less, and atopy was defined quantitatively as the mean allergen skin weal response to Dermatophagoides pteronyssinus, cat fur, and grass pollen, and categorically as the occurrence of any allergen response 1 mm or greater than the saline control. Multiple logistic regression analysis was used to estimate the independent relative odds of hyperreactivity, atopy, or symptoms in relation to sodium excretion in all 1702 subjects, and multiple linear regression to assess the independent relation between sodium excretion and mean allergen skin weal diameter, and the PD20 value amongst hyperreactive subjects.
There was no relation between the relative odds of hyperreactivity to methacholine and 24 hour urinary sodium excretion, either before or after adjustment for age, smoking, allergen skin weal diameter, and sex, and similarly no relation if the analysis was restricted to men or women only. The relative odds of having at least one allergen skin test response 1 mm greater than the saline control were increased in relation to sodium excretion after adjustment for age, sex, and smoking by a ratio of 2.08 (95% CI 1.04 to 4.15) per log10 unit increase in sodium excretion, but there was no evidence of an association between sodium excretion and the occurrence of self-reported wheeze, hay fever, eczema, or asthma. There was no relation between 24 hour sodium excretion and the magnitude of the mean allergen skin weal response or the PD20 value.
These findings do not support the hypothesis that a high dietary sodium intake is a risk factor for airway hyperreactivity or atopic disease in the general adult population.
[show abstract][hide abstract] ABSTRACT: Magnesium is involved in a wide range of biological activities, including some that may protect against the development of asthma and chronic airflow obstruction. We tested the hypothesis that high dietary magnesium intake is associated with better lung function, and a reduced risk of airway hyper-reactivity and wheezing in a random sample of adults. In 2633 adults aged 18-70 sampled from the electoral register of an administrative area of Nottingham, UK, we measured dietary magnesium intake by semiquantitative food-frequency questionnaire, lung function as the 1-sec forced expiratory volume (FEV1), and atopy as the mean skin-prick test response to three common environmental allergens. We measured airway reactivity to methacholine in 2415 individuals, defining hyper-reactivity as a 20% fall in FEV1 after a cumulative dose of 12.25 mumol or less. Mean (SD) daily intake of magnesium was 380 (114) mg/day. After adjusting for age, sex, and height, and for the effects of atopy and smoking, a 100 mg/day higher magnesium intake was associated with a 27.7 (95% CI, 11.9-43.5) mL higher FEV1, and a reduction in the relative odds of hyper-reactivity by a ratio of 0.82 (0.72-0.93). The same incremental difference in magnesium intake was also associated with a reduction in the odds of self-reported wheeze within the past 12 months, adjusted for age, sex, smoking, atopy, and kilojoule intake, by a ratio of 0.85 (0.76-0.95). Dietary magnesium intake is independently related to lung function and the occurrence of airway hyper-reactivity and self-reported wheezing in the general population. Low magnesium intake may therefore be involved in the aetiology of asthma and chronic obstructive airways disease.
The Lancet 09/1994; 344(8919):357-62. · 39.06 Impact Factor
[show abstract][hide abstract] ABSTRACT: The factors that determine the occurrence of airway hyperreactivity in the general population are not clearly understood. This study was designed to assess the independent effects of age, atopy, smoking and airway calibre. In a random sample of 2,415 adults aged 18-70 yrs we measured reactivity to methacholine as the dose provoking a 20% fall (PD20) in one-second forced expiratory volume (FEV1), atopy as the mean skin wheal response to three common environmental allergens, and airway calibre as the baseline FEV1 in absolute terms, as percent predicted (FEV1 % predicted) and as percent forced vital capacity (FEV1 % FVC). Hyperreactivity, defined as a PD20 < or = 12.25 mumol, was present in 314 (13%) of the sample, and before adjustment for FEV1 was more common in females (independent odds ratio (OR) = 2.05 (95% confidence interval 1.6-2.7)), current smokers (OR = 1.89 (1.3-2.6)), atopics (OR = 1.39 (1.3-1.5) per mm skin wheal), and in older age groups (OR for age 60-70 yrs relative to 18-29 yrs = 2.70 (1.7-4.3)). However, the odds of hyperreactivity were also strongly and independently related to absolute FEV1 (OR = 0.46 (0.27-0.77) per litre), FEV1 % predicted (OR = 0.96 (0.94-0.98) per percent), and FEV1 % FVC (OR = 0.92 (0.90-0.94) per percent; combined chi-square on 3 df = 312, p < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)
European Respiratory Journal 06/1994; 7(5):881-7. · 6.36 Impact Factor
[show abstract][hide abstract] ABSTRACT: Refractoriness occurs after challenges causing mediator release in asthma, by a mechanism which may involve inhibitory prostaglandins. Bronchoconstriction due to inhaled sodium metabisulphite is thought to involve neural pathways and to be independent of mediator release; whether it shows refractoriness is uncertain. We have sought evidence of refractoriness to the bronchoconstrictor response to inhaled sodium metabisulphite in subjects with mild asthma, and have tested the hypothesis that the development of refractoriness involves inhibitory prostaglandins. Twelve subjects were challenged twice with a dose of sodium metabisulphite, previously shown to cause a 20% fall in forced expiratory volume in one second (FEV1); the second challenge proceeded after recovery from the first. The response to sodium metabisulphite was expressed as the maximum % fall in FEV1 and area under the change in FEV1 curve over 20 min (AUC). Nine subjects were studied after double-blind treatment with oral indomethacin, 50 mg t.d.s., or placebo, for 3 days. The second sodium metabisulphite challenge caused significantly less bronchoconstriction than the first (mean maximum fall in FEV1 13.1 and 24.3%, respectively). Nine subjects showed a greater than 50% reduction in the response to the second challenge (mean reduction in AUC 73.7%). In these subjects, indomethacin did not alter the response to the first sodium metabisulphite challenge, or the mean maximum fall in FEV1 in response to the second challenge (placebo 9.7%, indomethacin 11.2%), but significantly increased the AUC of the second challenge (placebo 55, indomethacin 114). The mean reduction in AUC from first to second challenge was 78% with placebo and 48% with indomethacin.(ABSTRACT TRUNCATED AT 250 WORDS)
European Respiratory Journal 02/1994; 7(1):50-4. · 6.36 Impact Factor
[show abstract][hide abstract] ABSTRACT: Inhaled frusemide protects subjects with asthma against a wide range of bronchoconstrictor challenges, including allergen, exercise and inhaled sodium metabisulphite. An investigation was designed to determine whether this protection is related to the production of inhibitory prostaglandins, such as prostaglandin E2 (PGE2), by studying the effect of the cyclooxygenase inhibitor indomethacin on the protection afforded by inhaled frusemide against exercise induced asthma.
In a double blind crossover study 10 subjects with mild asthma were pretreated with indomethacin (50 mg thrice daily) or placebo capsules for three days; they then inhaled frusemide (40 mg) or placebo 10 minutes before an exercise test previously shown to cause a 20-30% fall in forced expiratory volume in one second (FEV1).
After inhalation of placebo exercise caused a similar maximum fall in FEV1 whether pretreatment was with placebo (26%) or indomethacin (25.2%). After inhalation of frusemide the maximum fall in FEV1 was reduced to 14.3% after placebo pretreatment and to 21.8% after indomethacin pretreatment; the difference between placebo and indomethacin pretreatment was significant (mean difference 7.5%, 95% limits 0.6%, 14.4%). The inhibitory effect of frusemide on the response to exercise, assessed as change in FEV1 over 30 minutes, was significantly greater with placebo (62%) than indomethacin (13%) pretreatment.
These findings support a role for inhibitory prostanoids, such as PGE2, in the beneficial effects of frusemide as a protection against exercise induced asthma.
[show abstract][hide abstract] ABSTRACT: Circulating epinephrine concentrations are altered in certain pathophysiological states, but whether such changes in epinephrine concentrations can alter bronchial responsiveness in subjects with asthma has not been studied. We studied 10 subjects with asthma in a double-blind crossover study on 4 nonconsecutive days. After measurement of baseline forced expiratory volume in 1 s (FEV1) and plasma epinephrine concentration, subjects were given placebo or 4, 16, or 64 ng.kg-1.min-1 epinephrine by intravenous infusion for 45 min. Blood was taken for plasma epinephrine concentration before the infusion and at 30 min, when a histamine challenge test was performed. Mean plasma epinephrine concentrations ranged from 0.37 nmol/l on placebo to 3.76 nmol/l with the 64-ng/kg infusion. FEV1 increased progressively with increasing concentrations of infused epinephrine, the mean change ranging from -0.051 on placebo to 0.331 after the highest concentration of epinephrine. The provocative dose of histamine causing a 20% fall in FEV1 increased progressively with increasing concentrations of infused epinephrine, geometric mean values ranging from 0.61 mumol with placebo to 1.7 mumol after the highest dose of epinephrine. Thus epinephrine, at physiological plasma concentrations, can modify bronchial reactivity.
Journal of Applied Physiology 10/1992; 73(3):1004-7. · 3.48 Impact Factor
[show abstract][hide abstract] ABSTRACT: It has been suggested that inhaled corticosteroids may provide greater protection against constrictor stimuli that act indirectly such as exercise than those that act directly such as histamine.
The effects of six weeks treatment with inhaled budesonide (800 micrograms twice daily) on bronchial reactivity to histamine, exercise, and eucapnic voluntary hyperventilation of dry air were compared in a double blind, placebo controlled, non-crossover study in 40 subjects with asthma. Change in bronchial reactivity to histamine and eucapnic hyperventilation over the six weeks was measured as change in the provocative dose of histamine or dry air causing a 20% fall in FEV1 (PD20 histamine and PV20 eucapnic hyperventilation (EVH) of dry air); this was not possible for exercise because of the development of refractoriness. To enable the change in response to all three stimuli to be compared, the response (percent fall in FEV1) to a fixed dose was measured for all three challenge tests.
After budesonide there was an increase in PD20 histamine from 0.48 to 2.81 mumol and in PV20 EVH from 364 to 639 litres, and a significant correlation between the changes in PD20 histamine and PV20 EVH (r = 0.63). The median percentage fall in FEV1 in response to eucapnic hyperventilation, exercise, and histamine was similar before budesonide (25.5%, 26.6%, and 24.5%); the reduction in the percentage fall in FEV1 with budesonide was also similar for the three challenges (18.9%, 17.5%, and 16.6%), and all differed significantly from the changes following placebo. There was a significant correlation between change in percentage fall in FEV1 after budesonide with the three stimuli (histamine v exercise: r = 0.48; histamine v eucapnic hyperventilation: r = 0.46; exercise v eucapnic hyperventilation: r = 0.63).
The similar magnitude of change in bronchial reactivity to all three stimuli after budesonide and the within subject correlation obtained between these changes suggest that corticosteroids act by a common mechanism to protect against eucapnic hyperventilation, exercise, and histamine.
[show abstract][hide abstract] ABSTRACT: We have studied the effect of RG 12525, an oral leukotriene D4 (LTD4) antagonist, on LTD4-induced bronchoconstriction in eight male subjects with mild asthma (baseline FEV1 greater than 80% predicted) in a double-blind, placebo-controlled fashion. RG 12525 800 mg displaced the dose-response curve for LTD4 to the right. The mean (95% confidence intervals) difference in log PC20FEV1 following RG 12525 and placebo was 2.88 (1.61, 4.17) doubling doses of LTD4 (P less than 0.01), a 7.5 fold difference. We conclude that RG 12525 when administered orally is an effective LTD4 antagonist in subjects with mild asthma.
British Journal of Clinical Pharmacology 11/1991; 32(4):512-5. · 3.58 Impact Factor
[show abstract][hide abstract] ABSTRACT: Inhaled frusemide protects against the bronchoconstrictor response to a wide range of stimuli that cause bronchoconstriction by indirect mechanisms. One possible explanation for this protection relates to the known ability of frusemide to enhance synthesis of prostaglandin E2 (PGE2). Studies in vitro suggest that PGE2 might protect against indirectly acting bronchoconstrictor challenges rather than those that act directly on airway smooth muscle, though little is known about the effects of PGE2 in vivo. The effect of inhaled PGE2 on the bronchoconstrictor response to inhaled sodium metabisulphite (a stimulus with an indirect action) and methacholine (which acts directly on airway smooth muscle) was studied in nine patients with asthma. Subjects were studied on four days, inhaling PGE2 (100 micrograms) or placebo in a double blind fashion followed immediately by a cumulative dose challenge with sodium metabisulphite or methacholine. The response to the constrictor stimuli was measured as the provocative dose causing a 20% fall in FEV1 (PD20). There was no significant change in FEV1 after inhaled PGE2 compared with placebo, nor any significant change in the response to methacholine; the geometric mean methacholine PD20 was 0.9 mumol after PGE2 and 0.56 mumol after placebo (mean difference 0.7 (95% confidence limits--0.1, 1.5) doubling doses). PGE2, however, protected against sodium metabisulphite, the geometric mean sodium metabisulphite PD20 being 11.8 mumol after PGE2 and 1.8 mumol after placebo (mean difference 2.5 (95% CL 1.9, 3.1) doubling doses). PGE2 conferred significantly greater protection against sodium metabisulphite than methacholine (mean difference 1.8 (95% CL 0.8, 2.8) doubling doses). This suggests that PGE2, like frusemide, has an inhibitory effect on pathways relevant to the bronchoconstriction induced by sodium metabisulphite, with little or no effect on those relevant to methacholine.
[show abstract][hide abstract] ABSTRACT: The time course of change in FEV1, bronchial reactivity, and daily measures of asthma control (peak expiratory flow, symptoms, and beta 2-agonist inhaler use) was determined during 6 wk of treatment with inhaled budesonide, 800 micrograms twice a day, and for 2 wk following cessation of treatment in 40 asthmatic subjects in a double-blind, placebo-controlled, parallel group study. Histamine reactivity, expressed as the provocative dose of histamine causing a 20% fall in FEV1 (PD20), was measured at intervals during the 8 wk of the study, with more frequent measurements after the first and last dose of drug to provide a detailed profile of change at the start and end of treatment. The first dose of budesonide caused a small increase in median values of FEV1 (0.2 L) and PD20 (1.0 doubling dose of histamine), which was maximum at 6 h. There was a further increase in FEV1 and PD20 over the 6 wk in the budesonide group relative to placebo, the maximum increases (0.53 L, 3.4 doubling doses of histamine) being recorded 6 h after the last dose on Day 42. Following cessation of treatment, FEV1 and PD20 declined and PD20 returned to placebo values at 1 wk. Median PEF increased by 40 and 30 L/min in the morning and evening, respectively, with budesonide treatment. Symptom scores and beta 2-agonist inhaler use were lower in the budesonide group than the placebo group during treatment but tended to be similar (symptom scores) or higher (beta 2-agonist) in the 2 wk following cessation of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
The American review of respiratory disease 07/1991; 143(6):1317-21. · 10.19 Impact Factor
[show abstract][hide abstract] ABSTRACT: Bronchial reactivity is being measured with increasing frequency in epidemiological studies, but there debate continues about the relative merits of the different methods used to measure reactivity, particularly for subjects with no previous experience of reactivity testing as is the case in epidemiological studies. Repeatability is likely to improve with practice, and laboratory based studies on experienced subjects may overestimate the repeatability of a test in inexperienced subjects. We have compared the repeatability of the Yan method with a dosimeter (Mefar) method of administering methacholine to 40 asthmatic subjects: 20 with experience of methacholine challenge on at least six previous occasions and 20 with no previous experience. Subjects attended the laboratory on four days within a two week period, at the same time of day. A methacholine challenge was performed on two occasions using the Yan method and on two occasions using the dosimeter. Methacholine responsiveness was measured as the provocative dose causing a 20% reduction in forced expiratory volume in one second (PD20FEV1). Geometric mean PD20FEV1 values with the Yan method were 1.14 doubling doses (DD) of methacholine higher than with the dosimeter method. In the experienced subjects, the 95% range for a single estimate was +/- 1.56 DD for the Yan method and +/- 1.37 DD for the dosimeter method. In the inexperienced subjects, the 95% ranges were +/- 2.65 and +/- 1.87 DD for the Yan and dosimeter methods, respectively. Thus, the differences in repeatability between the Yan and dosimeter methods, were small; experienced subjects gave more repeatable values than inexperienced subjects.
European Respiratory Journal 05/1991; 4(4):497-502. · 6.36 Impact Factor
[show abstract][hide abstract] ABSTRACT: The effects of two pranayama yoga breathing exercises on airway reactivity, airway calibre, symptom scores, and medication use in patients with mild asthma were assessed in a randomised, double-blind, placebo-controlled, crossover trial. After baseline assessment over 1 week, 18 patients with mild asthma practised slow deep breathing for 15 min twice a day for two consecutive 2-week periods. During the active period, subjects were asked to breathe through a Pink City lung (PCL) exerciser--a device which imposes slowing of breathing and a 1:2 inspiration:expiration duration ratio equivalent to pranayama breathing methods; during the control period, subjects breathed through a matched placebo device. Mean forced expiratory volume in 1 s (FEV1), peak expiratory flow rate, symptom score, and inhaler use over the last 3 days of each treatment period were assessed in comparison with the baseline assessment period; all improved more with the PCL exerciser than with the placebo device, but the differences were not significant. There was a statistically significant increase in the dose of histamine needed to provoke a 20% reduction in FEV1 (PD20) during pranayama breathing but not with the placebo device. The usefulness of controlled ventilation exercises in the control of asthma should be further investigated.
The Lancet 07/1990; 335(8702):1381-3. · 39.06 Impact Factor