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The kinetics of changes in inflammatory indices in induced sputum from eight prednisone dependent asthmatics whose minimum clinical maintenance and exacerbation doses were known were investigated. The study began on the last day of a course of 30 mg prednisone daily for one week. Thereafter, the daily prednisone was reduced in a structured way to below the maintenance dose. This treatment was continued until a clinical exacerbation occurred. Prednisone 30 mg daily was then given again for one week. The mean duration of prednisone reduction was 7.4 weeks and the median dose was 7.5 mg x day(-1). Increases in sputum eosinophils preceded increases in blood eosinophils by 4 weeks and worsening of symptoms and forced expiratory volume in one second by 6 weeks. The clinical exacerbation was also accompanied by sputum neutrophilia and increases in sputum eosinophil cationic protein (ECP), fibrinogen and interleukin (IL)-5. Treatment with prednisone suppressed median sputum eosinophilia (from 16.3 to 0%, p<0.001), decreased sputum ECP (from 7,480 to 700 microg x L(-1), p = 0.01), but did not improve neutrophil numbers, fibrinogen or IL-5. The results show that the reduction of prednisone treatment in prednisone-dependent asthmatics evokes a severe airway eosinophilic inflammatory response. Clinical and blood indices deteriorate later than those in sputum suggesting that sputum examination may be useful to identify the minimum regular dose of prednisone required in these patients.

Aims: We investigated whether the deterioration in asthma control reported following cessation of theophylline was due to tolerance to theophylline., Methods: Eighteen subjects with mild stable asthma were given oral theophylline 10 mg kg(-1) day(-1) or placebo for 2 weeks in a double-blind crossover study. FEV1 and PD20 histamine were measured before and 8 h after the first dose of treatment and 8, 32 and 56 h after the final dose. PD20 AMP was measured before treatment and 9 h after the final dose., Results: Six patients did not tolerate theophylline. In the other 12 subjects there were no differences between treatments in daily PEF, symptom scores, rescue bronchodilator use, PD20 histamine or FEV1 up to 8 h post treatment. Following withdrawal of theophylline there were significantly lower values for mean FEV1 (mean difference 0.151, 95% CI 0.03, 026) and PD20 AMP compared to placebo but no difference in other end points., Conclusions: The small rebound deterioration in lung function following regular treatment with therapeutic doses of oral theophylline is consistent with the development of tolerance.

Researchers are increasingly looking for reliable non-invasive methods of assessing blood gas concentrations, and several new techniques have recently become available. Values derived using arterialized earlobe samples have been found to be comparable with conventional arterial samples, and recent studies have compared transcutaneous blood gas analysis with the traditional arterial samples and found a reasonable level of agreement in particular for the partial pressure of carbon dioxide. There are no data comparing oxygen and carbon dioxide partial pressures (pO2, pCO2) derived from arterialized samples with one of the newer transcutaneous techniques. We therefore simultaneously studied arterialized earlobe blood gas samples and values for pO2 and pCO2 obtained by a transcutaneous monitor (TINA, Radiometer, Copenhagen) in 26 subjects with varying blood gas values. There was a close agreement between the two methods for assessment of pCO2 [mean difference (95% C.I.) between transcutaneous and earlobe values 0.25 kPa (-0.004, 0.5 kPa)], but not for pO2 [1.71 kPa (0.35, 3.07 kPa)]. Similarly, the limits of agreement were narrow for pCO2 compared to those for pO2 (-0.98, 1.47 kPa and -6.44, 3.02 kPa respectively). We conclude that transcutaneous measurement of pCO2 using the TINA is acceptable in the research setting, whereas assessment of pO2 cannot reliably be made using this technique.

Background: Inhaled adenosine monophosphate (AMP) is thought to cause bronchoconstriction in asthmatic patients indirectly through mast cell mediator release. It may therefore be a more sensitive marker of airway inflammation in asthma and hence more specific for epidemiological surveys of asthma than challenges that act directly on airway smooth muscle such as histamine. There is some uncertainty as to how repeatable the measurement is and this is important if it is to be used for epidemiological studies., Methods: The response to histamine and AMP challenges and the protection afforded by terbutaline (500 micrograms) against these two challenges was measured on two occasions two weeks apart in 20 subjects with asthma (19 completed the study). The response to histamine and AMP was measured as the provocative dose causing a 20% fall in forced expiratory volume in one second (PD20) and the protection afforded by terbutaline in doubling doses (DD). Repeatability was assessed as the limits of agreement., Results: Although terbutaline had a slightly greater protective effect against AMP than histamine on both the first (delta PD20 = 2.66 versus 2.11 DD) and second occasion (2.56 and 2.15 DD), the differences were not statistically significant. The limits of agreement for the two histamine and two AMP challenges after placebo were from 3.06 to -3.5 and from 3.78 to -4.54 DD respectively, and these values did not differ significantly. The agreement limits between the first PD20 histamine and PD20 AMP values after placebo were similar, being from 3.73 to -3.72 DD after allowing for the 17.8-fold higher PD20 values for AMP compared with histamine., Conclusions: Terbutaline caused a slightly greater inhibition of the bronchoconstrictor response to AMP than histamine but the differences were small and non-significant. Any differences in repeatability between AMP and histamine challenges are small and in this study were not significant. The fact that the agreement between histamine and AMP PD20 values was similar to the agreement between repeat histamine or repeat AMP PD20 values suggests that, within an asthmatic population, PD20 AMP may not be providing different information from that provided by PD20 histamine.

In the case reported, serial evaluation of sputum inflammatory cell counts made it possible to identify an unusual series of events in a man with eosinophilic bronchitis. The patient initially presented with a productive cough, which did not respond to treatment with antibiotics or high-dose inhaled corticosteroids. A diagnosis of eosinophilic bronchitis was made after demonstration of intense sputum eosinophilia. When inhaled corticosteroids were stopped, symptoms and sputum eosinophilia became worse and airway hyperresponsiveness developed. Both abnormalities were reversed by a course of prednisone. When the prednisone was stopped the productive cough recurred but on this occasion sputum examination suggested a different disease process and the symptoms resolved after a course of co-trimoxazole. The patient has subsequently remained well on no treatment with little or no sputum eosinophilia.

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 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., 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.

Regular exposure to antimuscarinic drugs would be expected to upregulate airway muscarinic receptors and could cause a transient increase in airways obstruction if treatment was stopped or omitted. We have examined peak expiratory flow rate (PEFR) during treatment and forced expiratory flow in one second (FEV1) and airway responsiveness to three constrictor agonists (as the provocative dose of agonist causing a 20% fall in FEV1, (PD20)) following cessation of regular inhaled ipratropium bromide, in 13 subjects with mild stable asthma. Subjects inhaled placebo and ipratropium bromide, 80 microg q.i.d. for 14 days in a cross-over fashion with a 1 week run-in/wash-out period before and after each treatment period. Subjects recorded symptom scores and PEFR throughout the study, and FEV1 and PD20 to histamine, methacholine and metabisulphite were measured before and after cessation of treatment. When compared to baseline, FEV1 was lower after cessation of ipratropium than after placebo, with a significant difference 30 h after the last dose (difference 190 mL; 95% confidence interval (95% CI) 310-70 mL; p<0.02). FEV1 measured 6-10 days later, did not differ significantly. PEFR was significantly lower after cessation of ipratropium than after placebo on Day 15 (19-37 h after the last dose) (mean difference 4.6%; 95% CI 1.6-7.5%; p<0.01) but not on Day 16. There were no significant changes in PD20 histamine, methacholine and metabisulphite, symptom scores or rescue bronchodilator use after cessation of treatment. Thus, transient bronchoconstriction was found around 30 h after cessation of regular therapy with inhaled ipratropium for 2 weeks. The mechanism is unclear, as no evidence of muscarinic receptor upregulation was found. Although the changes were small and unlikely to be important for most patients, the results of this study indicate that the timing of lung function measurements relative to the last dose of ipratropium is important when interpreting the course of lung function in long-term studies.

Inhaled heparin inhibits the early response to allergen and exercise-induced asthma, probably by inhibiting mast cell mediator release. Recent animal studies suggest that heparin might also inhibit cholinergic neurotransmission in asthma by restoring inhibitory M2 receptor function. We have tested the hypothesis that heparin inhibits neurally-mediated bronchoconstriction in asthma by examining the effect of inhaled heparin on bronchial reactivity to sodium metabisulphite. We also examined the effect of inhaled heparin on methacholine-induced bronchoconstriction to exclude a direct effect on airway smooth muscle. Eleven patients with mild asthma inhaled nebulized heparin (1,000 U.kg-1) or placebo (normal saline) in a randomized, double-blind fashion, 10 min before a challenge with sodium metabisulphite. Nine patients were also challenged with methacholine after the same dose of heparin or placebo. Inhaled heparin did not significantly change forced expiratory volume in one second (FEV1), nor did it alter the provocative dose of sodium metabisulphite or methacholine required to cause a 20% fall in FEV1 (PD20). Geometric mean sodium metabisulphite PD20 was 2.54 and 2.15 mumol after placebo and heparin, respectively (mean difference -0.24 doubling doses; 95% confidence interval (95% CI) -0.64-0.17). Geometric mean methacholine PD20 was 1.00 and 1.51 mumol after placebo and heparin, respectively (mean difference 0.6 doubling doses; 95% CI -0.25-1.5). Thus, heparin inhaled at doses sufficient to inhibit allergen and exercise-induced bronchoconstriction has no effect on the response to sodium metabisulphite and methacholine challenge in asthma. This argues against an inhibitory effect on neural pathways or airway smooth muscle.

Inhaled furosemide has been shown to protect subjects with asthma from bronchoconstriction induced by a wide variety of stimuli, including allergen, but the mechanism of action is controversial. We have used an in vitro model of allergen-induced bronchoconstriction to examine the effects of furosemide and other ion transport inhibitors. Human bronchial rings were passively sensitized by incubation with serum from an atopic donor and were challenged with Dermatophagoides pteronyssinus. Allergen-challenged bronchial rings developed bronchoconstriction which was effectively inhibited by the cysteinyl-leukotriene antagonist ICI 198,615 (10(-7) M) and to a lesser extent by terfenadine (10(-5) M). Assessed over 60 min furosemide 10(-6), 10(-5), and 10(-4) M inhibited contractions by a mean (95% confidence interval [CI]) 7.9% (-23.5, 39.3%, p > 0.05), 44.2% (12.9, 75.2%, p < 0.01), and 86.9% (55.5, 118.3%, p < 0.001) respectively (n = 5). The same concentrations of bumetanide inhibited contractions by 21.5% (-8.4, 51.4%, p > 0.05), 13.6% (-16.3, 43.4%, p > 0.05) and 51.6% (21.7, 81.4%, p < 0.01) respectively (n = 5). The sodium transport inhibitor amiloride and the anion transport inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) were without effect (both 10(-4) M; n = 4). Furosemide increased PGE2 production by the bronchial rings by 134% (95% CI 53, 259%). Indomethacin (3 x 10(-6) M) blocked the furosemide-induced increase in PGE2 production and reduced the protection afforded by 10(-4) M furosemide against allergen-induced contractions from 67.9% to 34.7% (mean difference 33.2%; 95% CI 9.7, 56.6%; p < 0.01; n = 8).(ABSTRACT TRUNCATED AT 250 WORDS)

We have investigated the relation between lung function and dietary intake of the antioxidant vitamins C and E in the general population in a cross-sectional survey of a random sample of adults from the electoral register of an administrative area of Nottingham. In 2,633 subjects 18 to 70 yr of age, we measured FEV1 and FVC, allergen skin sensitivity to grass pollen, cat fur, and Dermatophagoides pteronyssinus, pack-years smoking exposure by personal recall, and usual dietary intake of vitamins C and E by semiquantitative food frequency questionnaire. After adjustment for the effects of age, sex, height, mean allergen skin wheal diameter, and pack-years smoking history, both FEV1 and FVC were significantly and independently related to mean daily intake of vitamin C, such that a standard deviation (40 mg/d) higher vitamin C intake was associated with a 25.0 (95% CI, 5.2 to 44.8; p = 0.01) ml higher FEV1 and a 23.3 (0.94 to 45.7, p = 0.04) ml higher FVC. There was also an association between vitamin E intake and lung function, such that a standard deviation (2.2 mg) higher intake of vitamin E was associated with a 20.1 (1.3 to 40.4, p = 0.04) ml higher FEV1 and a 23.1 (1.0 to 45, p = 0.04) ml higher FVC. However, vitamin C and vitamin E intakes were significantly correlated (r = 0.29, p < 0.001), and after allowing for the effects of vitamin C there was no additional independent effect of vitamin E on either FEV1 or FVC.(ABSTRACT TRUNCATED AT 250 WORDS)

The possibility that impaired production of bronchoprotective factors contributes to the pathogenesis of asthma cannot be excluded. Prostaglandin E2 (PGE2) could be such a factor. It is a dominant cyclo-oxygenase product of airway epithelium and smooth muscle; it has inhibitory effects on inflammatory cells and pathways involved in bronchoconstriction at concentrations known to occur in the airway; inhalation of PGE2 has considerable bronchoprotective effects in patients with asthma; and manoeuvres that increase or decrease endogenous production of PGE2 have beneficial and deleterious effects on airway function.

Inhaled furosemide prevents bronchoconstriction induced by a number of challenges in asthma. One approach to determine the mechanism underlying this protection has been to examine the effects of diuretics with different or overlapping pharmacologic effects. We have compared the effects of furosemide on sodium metabisulfite-induced bronchoconstriction with those of equivalent diuretic doses of ethacrynic acid, a loop diuretic that, unlike furosemide, does not interact directly with the membrane Na/K/Cl cotransporter protein or inhibit carbonic anhydrase. Eight subjects with mild asthma were studied on five occasions, receiving nebulized furosemide (20 and 40 mg), ethacrynic acid (25 and 50 mg), or placebo (normal saline) in random order and double-blind 10 min before a cumulative dose challenge with inhaled sodium metabisulfite. After placebo the geometric mean sodium metabisulfite PD20 was 7.9 mumol. Furosemide 20 mg and 40 mg increased the PD20 by a mean 1.1 (95% confidence interval, -0.2-2.4; p > 0.05) and 1.6 (0.4-2.9; p < 0.02) doubling doses to 17.1 and 24.7 mumol, respectively. After inhaled ethacrynic acid 25 mg and 50 mg, the geometric mean PD20 was increased by 0.9 (-0.4-2.2; p > 0.05) and 1.5 (0.2-2.8; p < 0.05) doubling doses to 14.5 and 22.4 mumol, respectively. Thus, equivalent diuretic doses of furosemide and ethacrynic acid have a similar inhibitory effect on sodium metabisulfite-induced bronchoconstriction in asthma. This suggests that interaction with the Na/K/Cl cotransporter protein, or carbonic anhydrase inhibition, is not relevant to the effects of furosemide in asthma.

Prostaglandin E2 (PGE2) is thought to be an important inhibitory modulator of inflammatory processes in the airway. Previous studies have shown that it is produced by bovine cultured airway smooth muscle (ASM) cells in large quantities, but its regulation by second messengers has not been studied in this tissue. To determine whether PGE2 production by ASM might be an important action of beta-adrenoceptor agonists in asthma, the regulation of PGE2 production by adenosine 3',5'-cyclic monophosphate (cAMP) was assessed using dibutyryl cAMP (DBcAMP), forskolin, and albuterol. DBcAMP increased PGE2 production over a 24-h time course. Forskolin and albuterol both increased PGE2 production over control cells to similar levels after 24 h. Incubation of albuterol-treated cells with propranolol significantly (70%) reduced the stimulatory effect of albuterol on PGE2 production. Incubation of forskolin-treated cells with Rp-cAMP, a cAMP antagonist, inhibited the PGE2 response evoked by forskolin by 80%. Ro-20-1724, a selective inhibitor of type IV phosphodiesterase, stimulated PGE2 production (P = 0.02). Cycloheximide, a protein-synthesis inhibitor, did not inhibit the response to DBcAMP. The effects of DBcAMP were additive with the effects of bradykinin, a proinflammatory mediator known to increase PGE2 production (P < 0.05). These studies suggest that cAMP may play an important regulatory role in stimulating PGE2 production by ASM. This may be a novel beneficial action of beta-adrenoceptor agonists in asthma.

Background: The effect of adrenergic agonists in asthma depends on their net effect on microvascular leakage, mucosal oedema, vascular clearance of spasmogens, inhibition of cholinergic neurotransmission, and airway smooth muscle contractility. It has been postulated that adrenaline, by virtue of its alpha effects on the vasculature and cholinergic neurotransmission, may have additional useful properties in asthma compared with selective beta agonists such as salbutamol., Methods: The airway effects of adrenaline (a non-selective adrenoreceptor agonist) were compared with the selective beta 2 agonist salbutamol. Their airway smooth muscle relaxant potencies and effect on histamine contraction in human bronchi in vitro were compared with their effects on airway calibre and histamine reactivity in asthmatic subjects in vivo. For the in vitro studies changes in tension were measured in response to these agents in thoracotomy specimens of human airways. In vivo the effects of adrenaline and salbutamol on airway calibre and histamine reactivity were measured in eight subjects with mild to moderate asthma in a randomised crossover study., Results: Salbutamol and adrenaline had approximately equivalent airway smooth muscle relaxant potencies in vitro and bronchodilator potency in vivo. However, their effects on histamine induced contraction in vitro were significantly different from their effects on histamine reactivity in vivo. Salbutamol was less potent in vitro producing a mean (SE) 2.4 (0.15) doubling dose increase in the histamine EC20 and adrenaline a 5.2 (0.18) doubling dose increase (mean difference between salbutamol and adrenaline 2.8 doubling doses; 95% CI 1.1 to 4.5). Salbutamol had no effect on the maximal response to histamine whereas adrenaline reduced it by 54%. In contrast, salbutamol was more potent in vivo producing a mean (SE) increase in PD20 histamine of 1.84 (0.5) doubling doses whereas adrenaline was without effect increasing PD20 by only 0.06 (0.47) doubling doses (mean difference between adrenaline and salbutamol 1.78, 95% CI 0.26 to 3.29 doubling doses)., Conclusions: These findings suggest that the alpha adrenergic airway effects of non-selective adrenoreceptor agonists such as adrenaline offer no additional protection against histamine-induced broncho-constriction in vivo than beta 2 selective drugs such as salbutamol, despite adrenaline providing greater protection against histamine-induced contraction in vitro. The differences between the effects of these agents in vitro and in vivo may be related to their opposing vascular effects in vivo.

There is a transient rebound increase in bronchial reactivity to histamine and methacholine following regular treatment with an inhaled beta 2-agonist. We set out to determine whether the response to allergen was increased after cessation of regular inhaled terbutaline and whether concomitant inhaled budesonide modifies this response. In a double-blind, double-dummy, parallel group design we studied 41 subjects (37 evaluable) with mild asthma who were allergic to Dermatophagoides pteronyssinus, grass pollen, or cat fur. Following a 2 wk run-in period, subjects underwent a fixed three-dose allergen challenge based on their previously determined provocative concentration of allergen producing a 20% fall in FEV1 (PC20) before starting terbutaline 1,000 micrograms or placebo three times daily and budesonide 800 micrograms or placebo twice daily for a period of 2 to 4 wk (mean 18 d). The same three-dose allergen challenge was repeated 33 h after stopping treatment. During treatment evening peak flow values were highest in the terbutaline plus budesonide group. Following regular terbutaline there was no rebound increase in bronchial reactivity to allergen. Following budesonide there was a significantly smaller response to allergen and an increased FEV1 compared with the other three groups, including the budesonide plus terbutaline group. The changes in median (95% CI) allergen PC20 after budesonide, terbutaline, budesonide plus terbutaline, and placebo were 0.79 (0.3, 2.3), 0.11 (-0.4, 0.6), 0.24 (-0.4, 0.5) and -0.47 (-1.5, 0.1) doubling doses (p < 0.01). The respective changes in mean FEV1 were 0.34, -0.16, -0.01, and 0.06 L (p < 0.005). Thus bronchial reactivity to allergen was not increased after regular inhaled terbutaline.(ABSTRACT TRUNCATED AT 250 WORDS)

Background: 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., Methods: 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., Results: 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., Conclusions: 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.

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.

Background: Knowing the extent of the systemic effects of a new beta 2 agonist relative to an established drug is important for the prediction and interpretation of side effects. A recent study in which the effect of cumulative doses of salbutamol was compared with single doses of salmetreol suggested that, weight for weight, salmeterol may be up to 10 times more potent than salbutamol. This current study was designed to investigate further the dose equivalence of salmeterol and salbutamol., Methods: Twelve patients with mild asthma inhaled cumulative doses of placebo, salmeterol 25, 50, 100, and 200 micrograms, and salbutamol 100, 500, 1000, and 1000 micrograms on separate days at hourly intervals in a randomised double blind crossover study. Changes in forced expiratory volume in one second (FEV1), heart rate, plasma potassium concentration, systolic and diastolic blood pressure were measured. Dose equivalence was determined as the dose ratio of salmeterol to salbutamol for the 50% maximum response to salbutamol., Results: No important changes occurred in any measurements following placebo. Salmeterol and salbutamol caused a near maximum increase in FEV1 following the first dose so the dose equivalence for the airway effects could not be estimated. Heart rate increased and plasma potassium concentration and diastolic blood pressure decreased in a dose dependent manner following salmeterol and salbutamol, with median dose equivalences for salmeterol compared with salbutamol of 17.7, 7.8, and 7.6, respectively., Conclusions: These results confirm that the systemic activity of salmeterol compared with salbutamol is higher than would be expected from in vitro data, particularly for heart rate. Whether this is because of the relatively high dose of salmeterol used or pharmacokinetic differences between the two drugs is uncertain.

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)

1. Prostaglandin E2 (PGE2) is thought to be an important inhibitory modulator of inflammatory processes in the airway. It inhibits inflammatory cell function and cholinergic neurotransmission in vitro and roles have been postulated in vivo in refractoriness and in the mechanism of action of the diuretic agent, frusemide. 2. The production of PGE2 by bovine cultured airway smooth muscle cells has been studied under a range of conditions. The effects of cyclo-oxygenase inhibitors (flurbiprofen, indomethacin, acetyl salicylic acid) on serum-induced production of PGE2 were assessed over a range of concentrations (10(-7)-10(-4) M). 3. Serum-stimulated production of PGE2 in control wells ranged from 350 to 800 ng PGE2 ml-1 in cells from different animals. All three cyclo-oxygenase inhibitors inhibited PGE2 production with an order of potency, flurbiprofen > indomethacin > acetyl salicylic acid. Log IC50 values were -6.24 for flurbiprofen, -5.23 for indomethacin and -3.50 for acetyl salicylic acid. 4. PGE2 production was stimulated by arachidonic acid (10(-5) M) or addition of the proinflammatory mediator, bradykinin (10(-8)-10(-5) M). 5. Incubation of cells for 24 h with 5 bromo deoxyuridine (BRDU) (10(-4) M) to prevent DNA synthesis did not alter PGE2 production in response to serum, suggesting that it was not a function of proliferation per se. 6. Our study suggests that airway smooth muscle may be an important source of PGE2. Production of PGE2 may be a novel feedback mechanism whereby airway smooth muscle cells can negatively modulate airways inflammation. The differing potencies of the cyclo-oxygenase inhibitors may explain the contrasting effect of these drugs in recent studies in asthma.

Background: Exercise and inhaled sodium metabisulphite are thought to cause bronchoconstriction in asthma through different mechanisms. The response to both stimuli becomes refractory with repeat challenge. The mechanism of refractoriness is unclear, although depletion of mast cell derived mediators or neurotransmitters has been suggested. Recent studies suggest a common mechanism involving release of inhibitory prostaglandins. If this is true, exercise and sodium metabisulphite induced bronchoconstriction should show cross refractoriness., Methods: Thirteen subjects with mild asthma and previously established exercise and sodium metabisulphite induced bronchoconstriction performed two sodium metabisulphite challenges (giving a single dose previously shown to cause a 20% fall in FEV1) on one study day, and two exercise tests on another. The second challenge proceeded after recovery (FEV1 > 95% baseline) from the first. Subjects then attended on two further occasions when an exercise test was performed after sodium metabisulphite and a sodium metabisulphite challenge after exercise., Results: When expressed as the percentage reduction in the area under the change in percentage FEV1 curve over 20 minutes (AUC) the response to exercise was reduced by a mean 62.3% (95% CI 46.5% to 78.1%) following a first exercise challenge, and by 50.7% (95% CI 27.8% to 73.6%) following a sodium metabisulphite challenge. The response to a sodium metabisulphite challenge was reduced by a mean of 80.2% (95% CI 68.9% to 91.5%) when it followed a sodium metabisulphite challenge, and by 37.3% (95% CI 15.1% to 59.5%) following an exercise challenge., Conclusion: This study shows some cross refractoriness between exercise and sodium metabisulphite induced bronchoconstriction, in keeping with a partially shared mechanism of refractoriness.

Stimulation of exposed C-fibre afferent nerve endings by inflammatory mediators may contribute to airway inflammation and bronchoconstriction in asthma through the release of neuropeptides from collateral nerve endings. The polar opioid peptide 443c81 is a mu-opioid receptor agonist which inhibits C-fibre activation and non-cholinergic neurally mediated bronchoconstriction in animal models. We have compared the effect of 443c81 (5 ml of a 4 mg/ml solution nebulized) four times daily for 7 days with placebo on asthma control in a double-blind parallel group study of 40 subjects with mild asthma. Twenty subjects (12 male, mean FEV1 83% predicted) received placebo and 20 (15 male, mean FEV1 91% predicted) 443c81 after a 1 week run-in. Efficacy was assessed by comparing changes from baseline values in FEV1, provocative dose of histamine causing a 20% fall in FEV1 (PD20), symptom scores, bronchodilator use and home peak flow readings. 443c81 had no acute effect on FEV1 and the mean changes in FEV1 after 1 week of treatment were not significantly different (placebo -0.9%; 443c81-3.8%). One hour after the first dose of 443c81 PD20 increased from a geometric mean of 0.88 to 1.48 mumol (mean change 0.76 doubling doses; 95% CI 0.23, 1.29) but this did not differ significantly from the change with placebo (mean difference between 443c81 and placebo 0.63 doubling doses; 95% CI -0.2, 1.5; P = 0.095). After 1 week's treatment, PD20 was similar to baseline values with 443c81 (0.78 mumol) and placebo (baseline 0.71, post-treatment 0.93 mumol).(ABSTRACT TRUNCATED AT 250 WORDS)

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)

It has been suggested that regular treatment with high doses of beta 2-agonists might result in poorer control of asthma and increased bronchial responsiveness. We have examined change in FEV1 (delta FEV1), bronchial reactivity, peak expiratory flow (PEF), and symptoms during and after 3 wk of regular treatment with a relatively low dose of albuterol and broxaterol, a new beta 2-agonist. Eleven subjects 18 to 50 yr of age with mild asthma inhaled albuterol (200 micrograms), broxaterol (400 micrograms), or placebo three times a day for 3 wk with a 2- to 4-wk run-in/washout period between treatments. Ipratropium bromide was allowed for symptomatic relief. The PD20 (dose of histamine causing a 20% fall in FEV1) was measured before and 11, 35, and 59 h after cessation of treatment and a bronchodilator dose-response study before and 83 h after cessation of treatment. Change from baseline after albuterol and broxaterol are compared with change after placebo. Diurnal change in PEF (amplitude % mean) increased during treatment with albuterol by 6.5% (95% CI, 1.7-12.3; p < 0.02) mainly because of a fall in morning PEF. Cessation of treatment with both beta 2-agonists was associated with a fall in FEV1 and PD20 compared with placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

The recognition that asthma has a large inflammatory component has led to the use of steroids in its treatment. The adverse systemic effects of the drugs have promoted the development of inhaled steroids with a high topical to systemic potency ratio. The 2 most widely used agents are beclomethasone dipropionate and budesonide. Budesonide has a longer plasma elimination half-life than beclomethasone dipropionate but a higher topical to systemic potency ratio. These agents have been shown to be equipotent with respect to their anti-asthma effects but budesonide may have a slightly more favourable adverse effect profile. At low dosages (up to 400 micrograms/day) these drugs are well tolerated. At higher dosages (> 1000 micrograms/day) adverse effects on bone metabolism and adrenal function have been noted. Other agents such a triamcinolone or flunisolide have no obvious advantages. We recommend that inhaled steroids should be prescribed at the lowest dose required to control symptoms, with the dose being increased or decreased in a stepwise manner in parallel with asthma severity.

Prostaglandin E2 (PGE2) is produced in the lung but unlike most other lipid mediators has potentially important antiallergic effects. Whether these properties are relevant to asthma has not been established. The effect of inhaled PGE2 on allergen-induced asthma was examined in a double-blind crossover study of eight subjects with asthma. In Study 1 subjects inhaled 100 micrograms PGE2 or placebo 5 min before a normal saline challenge, and FEV1 and bronchial reactivity to methacholine was measured at intervals for 7 h. In Study 2, which had a similar design, subjects inhaled the same dose of PGE2 or placebo followed by a dose of allergen previously shown to cause a fall in FEV1 of 20% or more. On the normal saline challenge day inhaled PGE2 caused a small increase in FEV1 that lasted for around 60 min; there was no difference in the provocative dose of methacholine causing a 20% fall in FEV1 (PD20) at 4 and 7 h compared with placebo. PGE2 caused marked inhibition of the early and late response to allergen. The mean maximum fall in FEV1 0 to 2 h after allergen was 37.8 and 7.7% with placebo and PGE2 pretreatment, respectively (mean difference 30%; 95% CI 15, 45%; p < 0.005). The mean maximum fall in FEV1 from 4 to 7 h after allergen was 25.5 and 8.8% respectively (mean difference 16.7%; 95% CI 4, 29%; p < 0.02). The methacholine PD20 fell significantly after allergen with placebo but not with PGE2. The difference was 1.5 doubling doses at both 4 and 7 h (p < 0.01 and p < 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Objective: To examine the pharmacological interaction of salmeterol and salbutamol and to derive an estimate of dose equivalence of salmeterol for airway and systemic effects in patients with asthma., Design: Randomised double blind crossover study., Subjects: 12 patients with mild asthma., Intervention: Placebo or salmeterol 50, 100, 200 micrograms given on separate days followed two hours later by inhaled salbutamol in cumulative doses up to 3600 micrograms., Main Outcome Measures: Change in forced expiratory volume in one second (FEV1), heart rate, plasma potassium concentration, QTc interval, tremor amplitude, and creatine kinase myocardial isoenzyme concentration., Results: Compared with placebo, the mean (95% confidence interval) changes in FEV1 and heart rate after salmeterol 200 micrograms were 0.61 (0.32 to 0.90) l and 7.0 (3.8 to 10.2) beats/min. Adding salbutamol caused a large increase in FEV1 after placebo (0.69 l) with progressively smaller changes after increasing doses of salmeterol (0.19 l after salmeterol 200 micrograms). Heart rate and QTc interval increased and plasma potassium concentration decreased roughly in parallel on the four study days with a suggestion of convergence at higher doses of salbutamol. Geometric mean dose equivalences for salmeterol 50 micrograms and 100 micrograms compared with salbutamol were 4.9 and 7.8 (mean 6.4) for FEV1 and ranged from 7.1 (2.9 to 17.0) to 12.6 (4.4 to 36.4) for heart rate, plasma potassium, and tremor (mean 9.5)., Conclusions: The effect of adding salbutamol to salmeterol is largely additive. Weight for weight salmeterol may be up to 10 times more potent than salbutamol. Considering its longer duration of action salmeterol 50 micrograms twice daily could be equivalent to salbutamol in doses up to 500 micrograms four to six hourly.

Frusemide, a loop diuretic, has been shown to potently inhibit several indirect bronchoconstrictor challenges in asthma. The mechanism by which nebulized frusemide protects against indirect bronchoconstrictor stimuli in asthma is not known. One mechanism could be related to inhibition of sodium transport. If this is the case, then amiloride, another inhibitor of sodium transport, should also protect against indirect bronchoconstrictor challenges. Ten subjects with mild asthma were administered either 10(-2) M amiloride or placebo, by nebulizer, in a double-blind crossover fashion. After each inhalation, forced expiratory volume in one second (FEV1) was recorded at 10 min intervals for 30 min, after which a metabisulphite challenge was performed. No significant difference in the response to metabisulphite was seen between placebo and amiloride treatment. The mean difference in provocative dose of metabisulphite producing a 20% fall in FEV1 (PD20) between placebo and amiloride was 1.015 doubling doses, 95% confidence interval (95% CI) -0.201 to 2.231, (p = 0.09). This result does not support the hypothesis that frusemide is acting to protect against bronchoconstrictor challenges in asthma by an effect on sodium transport.

Background: 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., Methods: 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)., Results: 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., Conclusion: These findings support a role for inhibitory prostanoids, such as PGE2, in the beneficial effects of frusemide as a protection against exercise induced asthma.

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.

The airway response and cardiovascular and hypokalaemic effects of fenoterol, salbutamol, and terbutaline given in multiples of standard doses from metered-dose inhalers were studied in ten patients with mild asthma. In a double-blind, crossover, placebo-controlled study the subjects received 2, 6, and 18 puffs of each drug with intervals of 90 min, and forced expiratory volume in 1 s, heart rate, QTc interval, plasma potassium concentration, tremor, and bronchial reactivity to histamine were measured. All three drugs produced similar bronchodilatation. However, the rises in heart rate, QTc interval, and tremor and the fall in plasma potassium were greater after fenoterol than after salbutamol or terbutaline. The maximum mean (SD) increases in heart rate for fenoterol, salbutamol, and terbutaline were 29 (24) bpm, 8 (9) bpm, and 8 (14) bpm, respectively; falls in plasma potassium were 0.76 (0.62) mmol/l, 0.46 (0.32) mmol/l, and 0.52 (0.39) mmol/l, respectively. Fenoterol afforded no additional protection against histamine compared with salbutamol. These findings suggest that at doses based on those used in clinical practice fenoterol causes more adverse effects than salbutamol or terbutaline. The most likely explanation for these effects is that fenoterol has been marketed at a higher dose than the other beta 2-agonists; fenoterol may in addition be less selective for beta 2 receptors.

Heart disease responsive to steroids is well described in many disorders, including sarcoidosis, systemic lupus erythematosus, polyarteritis nodosa, myocarditis and Churg-Strauss syndrome. The underlying disorder is often obvious and the response is usually slow. We describe a woman who had severe left ventricular failure, cardiac dilatation and pericardial effusion which were rapidly rectified by steroid therapy. Steroid withdrawal led to recurrence of signs, which were reversed by recommencing steroids. The aetiology was not determined.