Dose-response study of sodium cromoglycate in exercise-induced asthma.

Ten patients with exercise-induced asthma participated in a single-blind dose-response study comparing the protective effect of inhaled sodium cromoglycate in increasing concentrations from 2 to 40 mg/ml. Saline was used as a control. Effects were assessed from the mean maximal percentage fall in forced expiratory volume in one second (FEV1) after the patients had run on a treadmill for eight minutes. There was slight bronchodilation evident from the increase in baseline FEV1 after inhalation of sodium cromoglycate, the difference reaching statistical significance with the highest concentration (5.7%, p less than 0.05). After exercise the maximal percentage falls in FEV1 (means and SEM) after saline and after sodium cromoglycate at 2, 10, 20, and 40 mg/ml were 37.3 +/- 4.7, 17.3 +/- 4.1, 10 +/- 3.3, 7.6 +/- 2.4, and 12 +/- 2.9. Sodium cromoglycate inhibited the exercise-induced fall in FEV1 at all the concentrations used in the study (p less than 0.001) and its inhibitory effect increased from 2 to 20 mg/ml. The mean FEV1 returned to baseline values within 15 minutes at higher concentrations of sodium cromoglycate (20 and 40 mg/ml) and a small bronchodilator effect was noted at 30 minutes. The findings suggest that the protective effect of sodium cromoglycate in exercise asthma is dose related. At higher concentration the drug suppresses chemical mediator release from the lung mast cells and may also modify the bronchial reactivity to release mediators.     

Perception of breathlessness during bronchoconstriction induced by antigen, exercise, and histamine challenges.

Perception of breathlessness was studied in eight patients with mild, stable asthma after a histamine and exercise challenge performed before and 24 and 48 hours respectively after an antigen challenge. FEV1 and perception of breathlessness, evaluated by Borg's 10 point category scale, were measured after each administration of doubling antigen or histamine concentrations to achieve a greater than 20% fall in FEV1, and after six minutes of steady state exercise at 80% of maximal oxygen consumption (VO2max). The geometric mean provocative concentration of histamine causing a 20% fall in FEV1 (PC20) fell from 1.67 mg/ml before antigen challenge to 0.52 mg/ml 24 hours after the challenge. The median maximal % fall in FEV1 with exercise was 24.9% (range 10.5-40.5%) before and 30.6% (range 13.8-52.3%) 48 hours after antigen challenge. The median maximum % fall in FEV1 after antigen inhalation was 20.1% (range 13.3-35.2%) within the first hour; only two subjects had a late fall in FEV1 (23% and 58%). The median (range) of Borg scores obtained when FEV1 was reduced by 20% did not differ significantly for the three types of acute challenges: 1.25 (0.5-2.5) and 1.0 (0.5-3.0) after histamine tests, 1.0 (0.5-4.1) and 1.55 (0.5-2.0) after exercise, and 1.5 (0-3.0) after antigen challenge. In the two subjects who had a late response to antigen the Borg score was reduced for the same % fall in FEV1 as with the early response. It is concluded that the perception of breathlessness does not differ appreciably during the early response to histamine, antigen exposure, or exercise, but that it is reduced during the late asthmatic response. It was not influenced by previous antigen exposure, despite an increase in airway responsiveness.     

Sodium cromoglycate and atropine block the fall in FEV1 but not the cough induced by hypotonic mist.

In a group of patients with mild asthma the inhalation of mist derived from ultrasonically nebulised distilled water caused an increase in cough and a fall in FEV1. Double blind administration for five minutes of sodium cromoglycate (from an original solution containing 30 mg/ml) or atropine (2 mg/ml) by inhalation from a Minineb nebuliser, 30 minutes before the mist challenge, caused a significant reduction in the fall in FEV1 (p less than 0.05), but not in cough, by comparison with the protection afforded by placebo (saline). In a second study the fall in FEV1 caused by the inhalation of distilled water was not significantly different from that seen in response to hypotonic sodium chloride (1.7 g/l, 58 mmol/l), but both produced a significantly greater fall than did a similar mist containing sodium cromoglycate at an original concentration of 10 mg/ml (58 mmol/l). The results show that both atropine and sodium cromoglycate can block the fall in FEV1 due to mist and that protection by sodium cromoglycate is immediate. These results suggest that sodium cromoglycate blocks the nervous reflexes concerned in the response to mist, probably in the afferent limb of the reflex.     

Effect of cetirizine on exercise induced asthma.

The effect of oral and inhaled cetirizine, a potent and specific H1 receptor antagonist, was studied in patients with exercise induced asthma. Twelve patients (five male; mean age 35.2 years) were given oral placebo or cetirizine 10 mg twice daily for one week, double blind and in randomised order, and exercised on a treadmill for six to eight minutes at a submaximal work load two hours after the final dose. There was no significant change in baseline FEV1 after treatment and cetirizine failed to inhibit exercise induced bronchoconstriction (maximum falls in FEV1 28% and 27% of baseline). In a further eight patients (four male; mean age 40.8 years) the effect of 1 ml cetirizine (5 and 10 mg/ml) given through a Wright nebuliser was compared with that of placebo in a double blind trial. The fall in FEV1 after exercise was reduced after both concentrations of cetirizine by 15.2% of baseline after 5 mg/ml and by 10.2% after 10 mg/ml, compared with 23.7% after placebo. In two patients cetirizine had no effect. In a further study cetirizine (10 mg/ml) given by inhalation displaced the geometric mean PC20 histamine 13.1 fold to the right by comparison with placebo. The reason for the difference between the effects of oral and of inhaled cetirizine on exercise asthma is not clear but may be related to differences in local concentration in the airway.     

Influence of diltiazem on bronchoconstriction induced by cold air breathing during exercise.

Since the calcium antagonists nifedipine and verapamil have been shown to diminish exercise induced asthma, the effect of oral diltiazem, a calcium channel blocker not previously investigated in this context, was studied. Ten patients with bronchial asthma were given 60 mg diltiazem or placebo four hours before the challenge in a double blind, randomised, crossover fashion. Exercise was performed on a cycle ergometer while the subjects were breathing cold air, resulting in a respiratory heat exchange which was similar at the two study sessions. FEV1 and specific conductance (sGaw) were recorded before and three, 10, 15, and 30 minutes after the challenge. No significant differences were found between placebo and diltiazem days in the fall of FEV1 or sGaw after exercise. Thus unlike other calcium antagonists diltiazem, in a dose of 60 mg given orally four hours before exercise, failed to protect against exercise induced asthma.     

Dose-response effect of sodium cromoglycate pressurised aerosol in exercise induced asthma.

The effects of 2, 10, and 20 mg of sodium cromoglycate delivered by aerosol were compared with those of placebo in a double blind study in 11 patients with extrinsic and exercise induced asthma. The effect of nebulised sodium cromoglycate delivered through a Wright nebuliser (estimated dose 12 mg) was also studied. Patients exercised on a treadmill for six to eight minutes at submaximal work loads on five days, 30 minutes after inhaling placebo or sodium cromoglycate. The FEV1 was recorded before treatment, before exercise, and up to 30 minutes after exercise. Mean baseline values of FEV1 before and after placebo or sodium cromoglycate did not differ significantly on the five days. After exercise the mean (SEM) maximal percentage fall in FEV1 after placebo; 12 mg sodium cromoglycate nebuliser solution; and 2, 10, and 20 mg sodium cromoglycate aerosol were 31.1 (3.8); 9.4 (2.1); and 19.4 (4.6), 13.7 (3.5), and 9.4 (1.9). Sodium cromoglycate inhibited exercise induced asthma at all doses used; the protective effect of the aerosol increased from 2 to 20 mg. The protective effect of 20 mg sodium cromoglycate aerosol was similar to that seen with 12 mg nebulised solution. Our results suggest that the effect of sodium cromoglycate aerosol in exercise induced asthma is dose related.     

Inhaled frusemide and exercise-induced bronchoconstriction in children with asthma.

BACKGROUND--Nebulised frusemide has been shown to be protective against bronchoconstricting stimuli in adult asthmatic subjects and against cold air challenge in children. Animal studies suggest that inhaled frusemide may be more effective in the young. METHODS--A double blind placebo, controlled, crossover study on the effect on exercise of pretreatment with frusemide (20 mg) from a metered dose inhaler via a large volume spacer (Volumatic) was performed in 12 asthmatic children. Exercise testing consisted of eight minutes of running on a treadmill in an environmentally controlled laboratory. RESULTS--Deterioration in lung function was less after frusemide than after the placebo exercise tests. The mean (95% CI) maximum percentage falls in forced expiratory volume in one second (FEV1) were 14.4% (7.7 to 21.0) for placebo and 5.7% (2.3 to 9.0) for frusemide. CONCLUSIONS--Inhaled frusemide via a metered dose inhaler reduces exercise-induced bronchoconstriction in children.     

Effect of inhaled frusemide on the early response to antigen and subsequent change in airway reactivity in atopic patients.

The purpose of this study was to investigate whether inhaled frusemide was able to inhibit the increase in nonspecific bronchial reactivity that occurs after the early response to allergen exposure in subjects with allergic rhinitis or asthma (or both). Ten symptom free patients initially underwent a challenge with methacholine, to determine the dose of methacholine that caused a 15% fall in FEV1 (PD15 FEV1 meth) and a challenge with a specific allergen, to determine the concentration of allergen that caused a fall in FEV1 of at least 15%. On two further occasions they inhaled allergen concentration that had caused the greater than or equal to 15% fall in FEV1 preceded by inhaled frusemide (40 mg frusemide in 4 ml buffered saline) or placebo (4 ml of diluent solution), according to a randomised, double blind, crossover design. All allergen studies were separated by at least seven days. A methacholine challenge was performed two hours after the allergen challenge, a time when the early response to allergen had completely resolved. Frusemide inhibited the early response to antigen, causing mean (95% confidence interval) protection of 87.6% (96-80%) for the maximum fall in FEV1. The increase in non-specific airway reactivity that occurred after antigen when this was preceded by placebo was reduced by frusemide. The mean (95% CI) difference in PD15 values between the placebo and the frusemide days was 1.73 (2.30-1.16) doubling doses of methacholine. These results confirm that frusemide is highly effective in preventing the early response to allergen, and show that it inhibits the increase in reactivity to methacholine that follows the early response.     

Effect of GR32191, a potent thromboxane receptor antagonist, on exercise induced bronchoconstriction in asthma.

Previous work suggests a role for mast cell derived mediators in exercise induced asthma. The contribution of newly generated contractile prostaglandins to exercise induced asthma was assessed by using a potent and orally active thromboxane (TP1) receptor antagonist, GR32191. The effect of 120 mg GR32191 on exercise induced asthma was observed in 12 asthmatic subjects. For the exercise challenge the subjects performed six minutes of treadmill exercise, breathing dry air at a work load that had previously been shown to induce a fall in FEV1 of 25% or more from the pre-exercise baseline. No effect of GR32191 on pre-exercise baseline airway calibre was evident. There was no significant difference in the mean maximum percentage fall in FEV1 from baseline after exercise between drug and placebo (placebo 30.2%, GR32191 day 31.6%). It is concluded that the thromboxane antagonist GR32191 has no effect on exercise induced asthma. This suggests that prostaglandins, including PGD2, that act via the thromboxane receptor do not have an important role in exercise induced asthma.     

Comparison of terbutaline and placebo from a pressurised metered dose inhaler and a dry powder inhaler in a subgroup of patients with asthma.

BACKGROUND--Reversibility after administration of an inhaled bronchodilator is not always demonstrable in patients with asthma. Bronchodilator aerosol-induced bronchoconstriction has also been reported to occur in some patients. METHODS--Fifteen selected patients showing < 10% improvement in forced expiratory volume in one second (FEV1) when tested with four doses of salbutamol (0.1 mg/dose) or terbutaline (0.25 mg/dose) from a pressurised metered dose inhaler (MDI) participated in two randomised, double blind studies. They received 2.0 mg terbutaline (4 x 2 doses of 0.25 mg) or a corresponding placebo from an MDI connected to a 750 ml spacer, and 1.0 mg (2 x 0.5 mg) terbutaline or placebo from a multidose dry powder inhaler free of additives (Turbohaler). RESULTS--Inhalation of placebo MDI resulted in a mean (SD) decrease in FEV1 of 20.5 (14.1)% (range -42.9% to +2.6%). In 14 patients inhalation of 2.0 mg terbutaline MDI with spacer resulted in < 10% improvement (mean increase 3.1 (6.0)%). One mg of terbutaline via a Turbohaler resulted in improvements in FEV1 of > 15% in eight patients (mean increase 16.0 (9.7)%). The improvement was < 10% in four patients. Use of placebo Turbohaler did not affect airway calibre (mean change 0.2 (2.9)%). CONCLUSIONS--Additives of MDIs may cause bronchoconstriction in some patients with asthma. In these patients inhalation from a pressurised metered dose inhaler is more likely to decrease the bronchodilator response than inhalation from an additive-free inhaler. The frequency of this phenomenon is unknown.     

Inhaled frusemide and exercise induced asthma: evidence of a role for inhibitory prostanoids.

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.     

Increased urinary excretion of LTE4 after exercise and attenuation of exercise-induced bronchospasm by montelukast, a cysteinyl leukotriene receptor antagonist

BACKGROUND: A study was undertaken to determine whether montelukast, a new potent cysteinyl leukotriene receptor antagonist, attenuates exercise-induced bronchoconstriction. The relationship between the urinary excretion of LTE4 and exercise-induced bronchoconstriction was also investigated. METHODS: Nineteen non-smoking asthmatic patients with a forced expiratory volume in one second (FEV1) of > or = 65% of the predicted value and a reproducible fall in FEV1 after exercise of at least 20% were enrolled. Subjects received placebo and montelukast 100 mg once daily in the evening or 50 mg twice daily, each for two days, in a three-period, randomised, double blind, crossover design. In the evening, approximately 20-24 hours after the once daily dose or 12 hours after the twice daily dose, a standardised exercise challenge was performed. Data from 14 patients were available for complete analysis. RESULTS: The mean (SD) maximal percentage decrease in FEV1 after exercise was 29.6 (16.0), 17.1 (8.2), and 14.0 (9.4) for placebo, once daily, and twice daily regimens, respectively. The mean (95% CI) percentage protection was 37 (15 to 59) for the group who received 50 mg twice daily and 50 (31 to 69) for those who received 100 mg once daily. Active treatments were not different from each other. The mean (SD) plasma concentrations of montelukast were higher after the twice daily regimen (1.27 (0.81) microgram/ml) than after the once daily regimen (0.12 (0.09) microgram/ml); there was no correlation between the percentage protection against exercise-induced bronchoconstriction and plasma concentrations. After exercise urinary excretion of LTE4 increased significantly during placebo treatment (from 34.3 to 73.7 pg/mg creatinine; p < 0.05) but did not correlate with the extent of exercise-induced bronchoconstriction. CONCLUSIONS: Montelukast protects similarly against exercise-induced bronchoconstriction between plasma concentrations of 0.12 and 1.27 micrograms/ml. The increase in the urinary excretion of LTE4 after exercise and the protection from exercise-induced bronchoconstriction with a cysteinyl leukotriene receptor antagonist provide further evidence of the role of leukotrienes in the pathogenesis of exercise-induced bronchoconstriction.


     

Effect of nebulised salbutamol on maximal exercise performance in men with mild asthma.

The effect of 5 mg nebulised salbutamol on the cardiorespiratory responses to a progressive maximal exercise test was investigated in eight asthmatic (mean forced expiratory volume in one second (FEV1) 3.48 (1.0) litres) and eight non-asthmatic men. Exercise tests were performed on a bicycle ergometer after administration of nebulised salbutamol or matched saline placebo. In the asthmatic subjects salbutamol increased the resting FEV1 by 11%. The mean (SD) percentage fall in FEV1 after exercise did not change significantly (salbutamol 9.4 (12.8); placebo 15.0 (8.0], but because the FEV1 before exercise was increased the lowest FEV1 after exercise was also significantly higher after salbutamol than placebo (3.60 (1.13) v 2.85 (0.80) litres). Despite the improvement in FEV1 before exercise there was no significant difference in maximal workload, oxygen uptake, heart rate, or ventilation during exercise after salbutamol compared with placebo in the asthmatic patients. Tidal volume was higher at maximal exercise after salbutamol but there was no change in perception of breathlessness or exertion in the asthmatic subjects. During submaximal progressive exercise the perceived rate of exertion was reduced in the asthmatic patients and oxygen pulse was reduced in both groups owing to a small and non-significant increase in heart rate. The FEV1 and cardiorespiratory response to the progressive maximal exercise test in the non-asthmatic subjects were otherwise unchanged after salbutamol. The results suggest that 5 mg nebulised salbutamol has little effect on the cardiorespiratory responses to progressive maximal exercise in patients with mild asthma and in non-asthmatic subjects. Salbutamol in this dose may reduce the severity of exercise induced asthma, but no ergogenic effect on maximal exercise performance was shown.     

Effect of caffeine on histamine bronchoprovocation in asthma.

It was recently reported that caffeine may reduce the clinical symptoms of asthma and may prevent the clinical manifestations of this disease. The effect of caffeine on histamine responsiveness is unknown. The effect of caffeine (5 mg/kg) and placebo on histamine responsiveness (the provocation concentration causing a 20% fall in FEV1, PC20) was studied in 10 subjects with mild asthma (prechallenge FEV1 84% of predicted value). The PC20 for histamine bronchoprovocation after caffeine ingestion was 2.65 (95% confidence limits 0.99, 7.10) mg/ml. After placebo the PC20 was 1.89 (0.96, 3.71) mg/ml. It is concluded that caffeine in a dose equivalent to about three cups of coffee has a very small effect, if any, on histamine bronchoprovocation in those with mild asthma. Specific instructions about not having drinks containing caffeine before histamine challenge are therefore not necessary.     

Effect of nedocromil sodium on sulphur dioxide induced bronchoconstriction.

Nedocromil sodium is a pyranoquinoline derivative that has been developed for the treatment of asthma. We report the results of a double blind randomised study of the effect of two doses of nedocromil sodium (2 and 4 mg) and matched placebo, delivered by metered dose pressurised aerosol, on bronchoconstriction induced by sulphur dioxide in six asthmatic subjects. Nedocromil sodium had no effect on baseline lung function. The magnitude of sulphur dioxide induced bronchoconstriction monitored by partial forced expiratory flow at 30% of reference vital capacity was significantly inhibited by nedocromil sodium 4 mg (p less than 0.05) but not by 2 mg. The maximum changes after placebo and after nedocromil 2 mg and 4 mg were -44.7, -32.7, and -11.8 l min-1. The area under the curve monitoring the effect over 6 minutes was significantly inhibited by both doses to the same extent, the mean changes after placebo and after nedocromil 2 mg and 4 mg being -349.3, -31.2, and 44.6 l. Dyspnoea was monitored by visual analogue scale and showed a significant reduction over 6 minutes with both doses of nedocromil. After placebo and after nedocromil 2 mg and 4 mg the mean maximum changes were 31.5, 13.7, and 15.7 mm, and the mean changes in area under the visual analogue scale-time curve were 289, 194, and 151 mm.min respectively.     

Inhibition of sodium metabisulphite induced bronchoconstriction by frusemide in asthma: role of cyclooxygenase products.

BACKGROUND--Inhaled frusemide inhibits airway responses to sodium metabisulphite and other indirect bronchial challenges in asthma by undetermined mechanisms which may relate to its ability to stimulate prostaglandin release. Inhalation of sodium metabisulphite provokes indirect bronchoconstriction, possibly by activating sensory nerves. To investigate the role of cyclooxygenase products in the airway actions of frusemide and sodium metabisulphite, the effects of a potent cyclooxygenase inhibitor, flurbiprofen, alone and in combination with frusemide were investigated against airway responsiveness to sodium metabisulphite. METHODS--In a double blind double placebo controlled study, 12 mild asthmatic subjects attended on four occasions to undergo three inhalation challenges with sodium metabisulphite. A baseline challenge was performed one hour before oral intake of flurbiprofen 200 mg or matched placebo, and two hours before inhalation of frusemide 40 mg or matched placebo. A second challenge was performed immediately after inhalation of frusemide (two hours after flurbiprofen) with a further challenge three hours later. The log concentration provoking a 20% fall in FEV1 (log PC20) was used to assess airway responsiveness to sodium metabisulphite. RESULTS--Frusemide caused an immediate 1.9 doubling dose protection and a lesser 0.7 doubling dose protection at three hours. This protection was enhanced by flurbiprofen at both time points to 2.7 (early) and 1.9 (late) doubling doses. In addition, flurbiprofen alone significantly reduced airway responsiveness to sodium metabisulphite by 1.1 doubling doses at both two and five hours. CONCLUSIONS--The generation of bronchoprotective prostaglandins is unlikely to underlie the inhibitory action of frusemide against airway responsiveness to sodium metabisulphite. Endogenous contractile prostaglandins within the airways may be involved in the bronchoconstrictor response to sodium metabisulphite.     

Effect of acetazolamide and amiloride against sodium metabisulphite-induced bronchoconstriction in mild asthma.

BACKGROUND--Inhaled frusemide but not bumetanide, another loop diuretic, reduces bronchial responsiveness to sodium metabisulphite (MBS). To investigate whether the effect of frusemide could be mediated through mechanisms other than Na+/K+/Cl- cotransporter inhibition, the effects of amiloride--an inhibitor of sodium channels in the airway epithelium--and of acetazolamide--a specific inhibitor of carbonic anhydrase--against MBS challenge were studied. METHODS--In two separate randomised double blind placebo controlled studies, 10 subjects with mild asthma attended on four separate occasions to inhale 7.5 mg amiloride or matched placebo, and 500 mg acetazolamide or placebo, immediately before MBS challenge. The concentration of MBS required to cause a 20% fall in baseline FEV1 (PC20) was measured. RESULTS--Amiloride and acetazolamide had no effect on baseline FEV1. Amiloride had no effect against MBS challenge, but acetazolamide increased -log PC20 from a mean (SE) of 0.75 (0.09) to 0.98 (0.06) representing a 0.77 (0.24) doubling dose increase. CONCLUSIONS--These results suggest that carbonic anhydrase activity in the airways, but not sodium flux, modulates bronchial responsiveness to MBS challenge. The action of frusemide is not likely to involve inhibition of carbonic anhydrase activity.     

Histamine reactivity during the refractory period after exercise induced asthma

An episode of exercise induced asthma will usually be followed by a period during which further exercise will not induce asthma. Postulated mechanisms include persistence of catecholamines released during exercise, development of tolerance to released mediators, and mediator depletion. To investigate the underlying mechanism further eight asthmatic men underwent three experimental protocols as follows: two treadmill runs of eight minutes; two incremental challenges with histamine inhalation; and a treadmill run of eight minutes followed by an incremental challenge with histamine inhalation. In each case the two challenges began 40 minutes apart. Patients performed the paired exercise trial first. Refractoriness to bronchoconstriction was shown in the repeated exercise studies but did not occur with repeated histamine challenge. The geometric mean histamine concentrations required to produce a 20% fall in forced expiratory volume in one second (FEV1) were 1.53 mg/ml and 0.93 mg/ml for the first and second challenges respectively (NS) and 1.4 mg/ml (NS) for the histamine challenge after exercise. It is concluded that refractoriness to exercise induced asthma is not explained by the development of smooth muscle tolerance to repeated histamine exposure or by the persistence of catecholamines released during exercise. The data are consistent with the theory of mediator depletion as the cause of refractoriness.     

Bronchodilator actions of xanthine derivatives administered by inhalation in asthma.

The airway response to the inhalation of four alkyl xanthines was studied in 17 subjects with moderately severe asthma (mean FEV1 1.19 litres, 42% predicted). Theophylline (10 mg/ml), glycine theophyllinate (50 mg/ml), theophylline ethylenediamine (aminophylline 50 mg/ml), and diprophylline (125 mg/ml) were administered by nebulisation and the airway response was measured as percentage change from baseline of specific airway conductance (sGaw). All xanthine derivatives had an unpleasant taste and produced coughing at the onset of nebulisation. All four xanthines produced a significant increase in sGaw by comparison with saline placebo, with a maximum mean increase from baseline of 35% for theophylline, 40% for glycine theophyllinate, 60% for aminophylline, and 32% for diprophylline. Inhalation of 200 micrograms salbutamol from a metered dose inhaler produced an additional increase in sGaw of 149%. Thus alkyl substituted xanthines administered by inhalation to patients with asthma cause significant short lived bronchodilatation, but this effect is small compared with that of a conventional dose of an inhaled beta 2 adrenoceptor agonist.     

Role of cysteinyl leukotrienes in adenosine 5'-monophosphate induced bronchoconstriction in asthma

BACKGROUND: Adenosine induced bronchoconstriction in patients with asthma is thought to be mediated by the synthesis and release of autacoids from airway mast cells. In vitro, adenosine induced constriction of asthmatic bronchi is blocked by a combination of specific histamine and cysteinyl leukotriene receptor antagonists, but the relative contribution of these mediators in vivo is unclear. We hypothesised that adenosine induced bronchoconstriction in asthmatic patients may be blocked by pretreatment with the orally active selective cysteinyl leukotriene-1 (CysLT(1)) receptor antagonist, montelukast. METHODS: In a randomised, double blind, crossover study, oral montelukast (10 mg) or placebo was administered once daily on two consecutive days to 18 patients with mild to moderate persistent atopic asthma. Incremental doses of adenosine 5'-monophosphate (AMP) from 0.39 to 400 mg/ml were inhaled by dosimeter and the dose producing a 20% fall in FEV(1) (PC(20)AMP) after AMP inhalation was recorded. Leukotriene E(4) (LTE(4)) urinary concentrations were measured by enzyme immunoassay 4 hours after AMP challenge. RESULTS: Montelukast pretreatment provided highly significant protection against adenosine induced bronchoconstriction, with geometric mean PC(20)AMP values of 52.6 mg/ml (95% CI 35.2 to 78.7) after placebo and 123.9 mg/ml (95% CI 83.0 to 185.0) after montelukast (p=0.006). The geometric mean of the montelukast/placebo PC(20)AMP ratio was 2.4 (95% CI 1.3 to 4.2). Montelukast had no significant effect on 4 hour urinary excretion of LTE(4) compared with placebo. CONCLUSIONS: Selective CysLT(1) receptor antagonism with montelukast provides highly significant protection against AMP induced bronchoconstriction in patients with atopic asthma, implying that cysteinyl leukotrienes are generated from airway mast cells through preferential activation of their A(2B) receptors.