Dose-response study of nebulised nedocromil sodium in exercise induced asthma.

Ten patients with exercise induced asthma, in whom inhaled nedocromil sodium 4 mg by metered dose inhaler attenuated the exercise fall in forced expiratory volume in one second (FEV1) by at least 40%, participated in a double blind dose response study to compare the protective effect of nedocromil sodium given 15 minutes before exercise challenge via a nebuliser (Wright) in concentrations of 0.5, 5, 10, and 20 mg/ml with that of placebo (saline). Response was assessed as the maximum fall in FEV1 after the patient had run on a treadmill for six to eight minutes. Plasma concentrations of nedocromil sodium were measured at the time of challenge. After exercise challenge the mean (SEM) maximum percentage falls in FEV1 were 30.3 (1.6) for the control run and 28.0 (4.1) after placebo. The percentage fall was attenuated by pretreatment with all concentrations of nedocromil sodium to 12.8 (2.8), 11.2 (2.1), 12.8 (2.1), and 14.1 (3.5) for the 0.5, 5, 10, and 20 mg/ml concentrations respectively (p less than 0.001). There were no significant differences between the different nedocromil concentrations. Mean plasma concentrations of nedocromil were proportional to dose. Thus concentrations of nebulised nedocromil sodium that ranged from 0.5 to 20 mg/ml gave a similar degree of protection (50-60%) against exercise induced asthma. This appears to be the maximum protection that can be achieved with nedocromil sodium and is similar to the protection obtained with 4 mg nedocromil administered by metered dose aerosol.     

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.     

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.     

Effects of corticosteroids on bronchodilator action in chronic obstructive lung disease.

BACKGROUND: Short term treatment with corticosteroids does not usually reduce airflow limitation and airway responsiveness in patients with chronic obstructive lung disease. We investigated whether corticosteroids modulate the effects of inhaled salbutamol and ipratropium bromide. METHODS: Ten non-allergic subjects with stable disease were investigated; eight completed the randomised, double blind, three period cross over study. Treatment regimens consisted of 1.6 mg inhaled budesonide a day for three weeks, 40 mg oral prednisone a day for eight days, and placebo. After each period cumulative doubling doses of salbutamol, ipratropium, a combination of salbutamol and ipratropium, and placebo were administered on separate days until a plateau in FEV1 was reached. A histamine challenge was then performed. RESULTS: At the end of placebo treatment mean FEV1 was 55.5% predicted after inhaled placebo, 67.9% predicted after salbutamol and 64.0% predicted after ipratropium. Compared with the results after the placebo period the FEV1 with salbutamol increased by 0.7% predicted after treatment with budesonide and by 0.7% predicted after treatment with prednisone; the FEV1 with ipratropium increased by 0.7% predicted after budesonide and by 4.8% predicted after prednisone; none of these changes was significant. After placebo treatment the geometric mean PC20 was 0.55 mg/ml after placebo, 1.71 mg/ml after salbutamol and 0.97 mg/ml after ipratropium. Compared with the placebo period the PC20 with salbutamol was increased by 0.86 doubling concentrations after treatment with budesonide, and by 0.67 doubling concentrations after prednisone; the PC20 with ipratropium increased by 0.03 and 0.34 doubling concentrations after budesonide and after prednisone respectively compared with placebo; none of these changes was significant. CONCLUSIONS: In non-allergic subjects with chronic obstructive lung disease short term treatment with high doses of inhaled or oral corticosteroids does not modify the bronchodilator response to salbutamol or ipratropium or the protection provided by either drug against histamine. Salbutamol produces greater protection from histamine induced bronchoconstriction than ipratropium.     

Effect of an inhaled neutral endopeptidase inhibitor, phosphoramidon, on baseline airway calibre and bronchial responsiveness to bradykinin in asthma.

BACKGROUND--Bradykinin is a potent vasoactive peptide which has been proposed as an important inflammatory mediator in asthma since it provokes potent bronchoconstriction in asthmatic subjects. Little is known at present about the potential role of lung peptidases in modulating bradykinin-induced airway dysfunction in vivo in man. The change in bronchial reactivity to bradykinin was therefore investigated after treatment with inhaled phosphoramidon, a potent neutral endopeptidase (NEP) inhibitor, in a double blind, placebo controlled, randomised study of 10 asthmatic subjects. METHODS--Subjects attended on six separate occasions at the same time of day during which concentration-response studies with inhaled bradykinin and histamine were carried out, without treatment and after each test drug. Subjects received nebulised phosphoramidon sodium salt (10(-5) M, 3 ml) or matched placebo for 5-7 minutes using an Inspiron Mini-neb nebuliser 5 minutes before the bronchoprovocation test with bradykinin or histamine. Agonists were administered in increasing concentrations as an aerosol generated from a starting volume of 3 ml in a nebuliser driven by compressed air at 8 1/min. Changes in airway calibre were measured as forced expiratory volume in one second (FEV1) and responsiveness as the provocative concentration causing a 20% fall in FEV1 (PC20). RESULTS--Phosphoramidon administration caused a transient fall in FEV1 from baseline, FEV1 values decreasing 6.3% and 5.3% on the bradykinin and histamine study days, respectively. When compared with placebo, phosphoramidon elicited a small enhancement of the airways response to bradykinin, the geometric mean PC20 value (range) decreasing from 0.281 (0.015-5.575) to 0.136 (0.006-2.061) mg/ml. In contrast, NEP blockade failed to alter the airways response to a subsequent inhalation with histamine, the geometric mean (range) PC20 histamine value of 1.65 (0.17-10.52) mg/ml after placebo being no different from that of 1.58 (0.09-15.21) mg/ml obtained after phosphoramidon. CONCLUSIONS--The small increase in bronchial reactivity to bradykinin after phosphoramidon exposure suggests that endogenous airway NEP may play a modulatory role in the airways response to inflammatory peptides in human 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 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.     

Effects of montelukast (MK-0476); a potent cysteinyl leukotriene receptor antagonist, on bronchodilation in asthmatic subjects treated with and without inhaled corticosteroids

BACKGROUND: Cysteinyl leukotriene release in association with airway inflammation is a feature of clinical asthma. The acute effects of montelukast (MK-0476), a potent, orally administered, specific cysteinyl leukotriene receptor antagonist, on airways obstruction was assessed in patients with mild to moderately severe asthma. METHODS: Twenty two asthmatic subjects were randomised to receive montelukast, 100 mg or 250 mg, or placebo in a double blind, three period, crossover trial. Ten of the patients were using concomitant inhaled corticosteroids. RESULTS: Montelukast increased the forced expiratory volume in one second (FEV1) from predose baseline values compared with placebo, the percentage point differences between montelukast and placebo being 8.6% (95% CI 3.6 to 13.6) and 8.5% (95% CI 3.5 to 13.5) for the 100 mg and 250 mg doses, respectively. CONCLUSION: Single oral doses of montelukast 100 mg and 250 mg produced significant increases in FEV1 irrespective of the concurrent use of inhaled corticosteroids in asthmatic subjects with airflow limitation.


     

Pranlukast, a novel leukotriene receptor antagonist: results of the first European, placebo controlled, multicentre clinical study in asthma

BACKGROUND: Leukotriene receptor antagonists have been shown to protect against bronchoconstriction induced by antigens, exercise, and cold air. There are relatively few clinical studies reported in patients with asthma. The present study is the first clinical evaluation of pranlukast (SB 205312, ONO-1078) outside Japan in patients with asthma. METHODS: A randomised, double blind, placebo controlled, parallel group, multicentre four week study of the safety and tolerability of oral pranlukast, 225 or 337.5 mg twice daily, was performed in patients with mild to moderate asthma. Preliminary efficacy data were obtained; the main efficacy variables evaluated were forced expiratory volume in one second (FEV1) and morning domiciliary (home) peak expiratory flow rates (PEFR). Clinic PEFR and daytime and night-time asthma symptom scores were also recorded. RESULTS: Compared with the placebo group the improvement in morning home PEFR was statistically significant at all time points for patients receiving pranlukast 337.5 mg twice daily and at weeks 1 and 2 for those treated with pranlukast in a dose of 225 mg twice daily. Mean morning home PEFR increased by 10.8 to 18.61/min (95% CI 0.2 to 29.3 l/min) in patients treated with pranlukast compared with a slight deterioration in those given placebo. FEV1 significantly increased within one hour after the first dose of pranlukast compared with baseline and this increase was maintained for eight hours. Improvements in trough FEV1-that is, at the end of the dosing interval- were statistically significant for the group treated with pranlukast 225 mg twice daily compared with placebo at week 4. Mean increases in FEV1 ranged from 210 ml to 340 ml (95% CI 60 to 500 ml) at trough in the pranlukast group. Patients treated with pranlukast also showed improvements in summary symptom and night-time asthma scores. Pranlukast was well tolerated, and no drug related changes in haematological and biochemical variables were observed. CONCLUSIONS: Pranlukast, an oral leukotriene receptor antagonist, is well tolerated and is effective for the treatment of asthma. It increased FEV1 within one hour of dosing, improved patient summary symptom and night-time asthma scores, and reduced the use of rescue bronchodilators, thus providing further evidence of a role for leukotrienes in the pathogenesis of 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.     

Effect of low dose nebulised morphine on exercise endurance in patients with chronic lung disease.

Low dose nebulised morphine may relieve dyspnoea through a direct effect on lung afferent nerves. To study this further 11 adult patients with advanced chronic lung disease (FEV1 range 0.4-1.41), whose exercise endurance was limited by dyspnoea, were entered into a double blind, randomised, crossover study in which low dose morphine or a placebo was inhaled. The effects were assessed by an endurance exercise test at 80% of maximum work load. One hour after a control endurance test patients inhaled 5 ml of morphine 1 mg/ml or isotonic saline for 12 minutes from a jet nebuliser. An endurance exercise test was repeated 15 minutes later and change in endurance time recorded. The two endurance tests were repeated on a separate day, before and after inhalation of the alternative solution. In all tests 100% oxygen was inhaled from a demand valve. The mean (SD) increase in endurance time was significantly greater after the subjects had inhaled morphine (64.6 (115) s, 35%) than after placebo (8.9 (55) s, 0.8%; p less than 0.01). The mean dose of morphine nebulised was 1.7 (0.66) mg, giving a mean inhaled dose of about 0.6 mg, on the assumption of 30% retention of the nebulised dose by each patient. No side effects were reported. Possibly small amounts of morphine delivered to the lungs act directly on lung afferent nerves to reduce dyspnoea.     

Changes in neurokinin A (NKA) airway responsiveness with inhaled frusemide in asthma

BACKGROUND: Inhaled frusemide exerts a protective effect against bronchoconstriction induced by several indirect stimuli in asthma which could be due to interference of airway nerves. A randomised, double blind, placebo controlled study was performed to investigate the effect of the potent loop diuretic, frusemide, administered by inhalation on the bronchoconstrictor response to neurokinin A (NKA) and histamine in 11 asthmatic subjects. METHODS: Subjects attended the laboratory on four separate occasions to receive nebulised frusemide (40 mg) or matched placebo 10 minutes prior to bronchial challenge with NKA and histamine in a randomised, double blind order. Changes in airway calibre were followed as forced expiratory volume in one second (FEV1) and responsiveness to the agonists was expressed as the provocative concentration causing a 20% fall in FEV1 from baseline (PC20). RESULTS: Compared with placebo, inhaled frusemide reduced the airway responsiveness to NKA in all the subjects studied, the geometric mean (range) values for PC20NKA increasing significantly (p < 0.001) from 130.3 (35.8-378.8) to 419.9 (126.5-1000) micrograms/ml after placebo and frusemide, respectively. Moreover, a small but significant change in airway responsiveness to histamine was recorded after frusemide, their geometric mean (range) PC20 values being 0.58 (0.12-3.80) and 1.04 (0.28-4.33) mg/ml after placebo and frusemide, respectively. CONCLUSIONS: The decrease in airway responsiveness to NKA after administration of frusemide by inhalation suggests that this drug may interfere with the activation of neurotransmission in human asthma.




     

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.     

Comparison of the effects of intravenous and oral montelukast on airway function: a double blind, placebo controlled, three period, crossover study in asthmatic patients

BACKGROUND: Montelukast, a leukotriene receptor antagonist, improves parameters of asthma control including forced expiratory volume in one second (FEV(1)) when given orally to patients aged six years or older. This study was undertaken to compare the effect on FEV(1) of intravenous and oral montelukast and placebo during the 24 hour period following administration. METHODS: Fifty one asthmatic patients (FEV(1) 40-80% predicted and > or =15% improvement after inhaled beta agonist) were enrolled in a double blind, single dose, three period, crossover study to receive intravenous montelukast (7 mg), oral montelukast (10 mg), or placebo in a randomised fashion. The primary end point was area under the curve (AUC)(0-24 h) of the percentage change from baseline in FEV(1). Additional end points were maximum percentage change in FEV(1) and percentage change at different time points. RESULTS: Compared with placebo, intravenous and oral montelukast significantly increased the AUC(0-24 h) (means of 20.70%, 15.72%, and 7.75% for intravenous, oral and placebo, respectively; no statistical difference between intravenous and oral). The difference in least square means from placebo for intravenous montelukast was 13.27% (95% CI 7.07 to 19.46), p<0.001 and for oral montelukast was 7.44% (95% CI 1.20 to 13.68), p = 0.020. The maximum percentage change in FEV(1) was not significantly different for intravenous and oral montelukast (difference in least square means 6.78% (95% CI -0.59 to 14.15), p = 0.071). The mean percentage change in FEV(1) for intravenous montelukast was greater than for oral montelukast within the first hour (15.02% vs 4.67% at 15 min, p< or =0.001; 18.43% vs 12.90% at one hour, p<0.001 for intravenous and oral montelukast, respectively (placebo 3.05% at 15 minutes, 7.33% at one hour). Intravenous and oral montelukast were similar to placebo in the frequency of adverse events. CONCLUSIONS: The onset of action for intravenous montelukast was faster than for oral montelukast and the improvement in airway function lasted over the 24 hour observation period for both treatments. Although not well understood, there was a trend toward a greater improvement in FEV(1) with intravenous than with oral montelukast. These findings suggest that leukotriene receptor antagonists should be investigated as a treatment for acute severe asthma.     

Effects of high dose inhaled beclomethasone dipropionate, 750 micrograms and 1500 micrograms twice daily, and 40 mg per day oral prednisolone on lung function, symptoms, and bronchial hyperresponsiveness in patients with non-asthmatic chronic airflow obstruction.

BACKGROUND--The effect of treatment with inhaled corticosteroids in patients with non-asthmatic chronic airflow obstruction is still disputed. Whether any physiological improvements seen are accompanied by changes in bronchial responsiveness and symptoms and quality of life is also still unclear. METHODS--A sequential placebo controlled, blinded parallel group study investigating the effect of three weeks of treatment with inhaled beclomethasone dipropionate (BDP), 750 micrograms or 1500 micrograms twice daily, and oral prednisolone, 40 mg per day, was carried out in 105 patients with severe non-asthmatic chronic airflow obstruction (mean age 66 years, mean forced expiratory volume in one second (FEV1) 1.05 litres [40% predicted], geometric mean PD20 0.52 mumol). End points assessed were FEV1, forced vital capacity (FVC), and peak expiratory flow (PEF), bronchial responsiveness to inhaled histamine, and quality of life as measured by a formal quality of life questionnaire. RESULTS--Both doses of BDP produced equivalent, small, but significant improvements in FEV1 (mean 48 ml), FVC (mean 120 ml), and PEF (mean 12.4 l/min). The addition of oral prednisolone to the treatment regime in two thirds of the patients did not produce any further improvement in these parameters. Inhaled BDP produced a treatment response in individual patients (defined as an improvement in FEV1, FVC, or mean PEF of at least 20% compared with baseline values) more commonly than placebo (34% v 15%). The two doses of BDP were equally effective in this respect and again no further benefit of treatment with oral prednisolone was noted. Treatment with BDP for up to six weeks did not affect bronchial responsiveness to histamine. Small but significant improvements were seen in dyspnoea during daily activities, and the feeling of mastery over the disease. CONCLUSIONS--High dose inhaled BDP is an effective treatment for patients with chronic airflow obstruction not caused by asthma. Both objective and subjective measures show improvement. Unlike asthma, no improvement in bronchial responsiveness was detected after six weeks of treatment.     

Effect of montelukast added to inhaled budesonide on control of mild to moderate asthma

BACKGROUND: Proinflammatory leukotrienes, which are not completely inhibited by inhaled corticosteroids, may contribute to asthmatic problems [corrected]. A 16 week multicentre, randomised, double blind, controlled study was undertaken to study the efficacy of adding oral montelukast, a leukotriene receptor antagonist, to a constant dose of inhaled budesonide. METHODS: A total of 639 patients aged 18-70 years with forced expiratory volume in 1 second (FEV(1)) > or =55% predicted and a minimum predefined level of asthma symptoms during a 2 week placebo run in period were randomised to receive montelukast 10 mg (n=326) or placebo (n=313) once daily for 16 weeks. All patients received a constant dose of budesonide (400-1600 microg/day) by Turbuhaler throughout the study. RESULTS: Mean FEV(1) at baseline was 81% predicted. The median percentage of asthma exacerbation days was 35% lower (3.1% v 4.8%; p=0.03) and the median percentage of asthma free days was 56% higher (66.1% v 42.3%; p=0.001) in the montelukast group than in the placebo group. Patients receiving concomitant treatment with montelukast had significantly (p<0.05) fewer nocturnal awakenings and significantly (p<0.05) greater improvements in beta agonist use and morning peak expiratory flow rate (PEFR). CONCLUSIONS: For patients with mild airway obstruction and persistent asthma symptoms despite budesonide treatment, concomitant treatment with montelukast significantly improves asthma control.     

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.     

Effect of inhaled thiorphan, a neutral endopeptidase inhibitor, on the bronchodilator response to inhaled atrial natriuretic peptide (ANP).

BACKGROUND: The hormone atrial natriuretic peptide (ANP) causes bronchodilation and partially protects against direct and indirect bronchial challenges. Both in vitro and in vivo studies have found that the protective effect of ANP against bronchoconstriction is enhanced by inhibition of the enzyme neutral endopeptidase (NEP). It was hypothesised that pretreatment with thiorphan, an NEP inhibitor, might enhance the bronchodilator response to inhaled ANP. METHODS: In a randomised double blind placebo controlled crossover study, six asthmatic patients (one woman) of mean (SD) age 47.3 (3.8) years and forced expiratory volume in one second (FEV1) 1.91 (0.42) 1, 55 (3.8)% predicted, were studied. All were shown at screening to have at least a 25% improvement in FEV1 to inhaled salbutamol. On five study visits the patients received either thiorphan 1 mg (in 2 ml) followed by ANP 5 mg or placebo (saline), or placebo (saline) followed by ANP (5 mg), placebo or salbutamol 5 mg. Spirometric parameters were measured after each inhalation and thereafter for the next two hours. RESULTS: ANP alone caused a bronchodilator response up to 15 minutes when compared with placebo or thiorphan alone with a mean (SE) change in FEV1 of 16.8 (8.1)% and 16.1 (6.8)% at 10 and 15 minutes from baseline, respectively. Prior inhalation of thiorphan prolonged the duration of the bronchodilator effect of ANP up to 60 minutes with a mean (SE) change in FEV1 of 23.1 (3.4)% at 60 minutes. There was no difference in the maximum degree of bronchodilation following the administration of ANP alone compared with the combination of thiorphan and ANP. The degree and duration of the bronchodilator response produced by ANP, or the combination of the NEP inhibitor and ANP, were less than that produced by salbutamol. CONCLUSIONS: These results confirm that, at least in part, the bronchodilator response to inhaled ANP is modulated by NEP. Analogues of ANP which are stable to NEP may have greater bronchodilator activity than ANP in the treatment of asthma.     

Decrease of histamine induced bronchoconstriction by caffeine in mild asthma.

BACKGROUND--While high doses of caffeine may affect pulmonary function and bronchial challenge tests in patients with mild asthma, the effects of lower doses (< or = 5 mg/kg) are less well documented. Specific recommendations exist for withholding theophylline, but not caffeine, before bronchoprovocation and pulmonary function testing. METHODS--To assess the effect of a single oral dose of caffeine (5 mg/kg) on FEV1 and bronchial responsiveness to histamine a double blind, placebo controlled study was performed in eight patients with mild stable asthma. RESULTS--While caffeine had no effect on FEV1, mean (95% confidence interval) log PC20 histamine was significantly higher 150 minutes [caffeine = 0.99 (0.2) mg/ml, placebo = 0.53 (0.29)] and 240 minutes [caffeine = 0.89 (0.24), placebo = 0.44 (0.26)] after administration of caffeine than after placebo. CONCLUSIONS--Caffeine should be excluded from the diet for a period of more than four hours before bronchial provocation testing. The exact length of time for which it must be excluded requires further study.     

Inhibition by sodium cromoglycate of bronchoconstriction stimulated by respiratory heat loss: comparison of pressurised aerosol and powder

The protective effect was examined of three doses (2, 10, and 20 mg) of sodium cromoglycate inhaled from a pressurised metered dose inhaler on the response to isocapnic hyperventilation of cold dry air in 10 asthmatic subjects. This was compared with the effect of cromoglycate powder (20 mg) inhaled from a Spincap and with placebo given on two occasions. The medications were inhaled on separate days, in random order and with the use of a double blind double dummy technique, 20 minutes before isocapnic hyperventilation of two fold increasing volumes of air (-15 degrees C, 0% humidity) to produce a 20% fall in the post-treatment FEV1. The response was expressed as the provocative dose of respiratory heat loss required to cause a fall in FEV1 of 15% (PD15, kcal/min). The mean baseline spirometric indices exceeded 85% of predicted normal values on each test day; both placebo treatments reduced the baseline FEV1 by comparison with all active treatments (p less than 0.0001). Comparison of the PD15 on the two placebo days confirmed excellent reproducibility. All doses of cromoglycate shifted the respiratory heat loss dose-response curve to the right of the placebo curve; PD15 after all active treatments exceeded PD15 after placebo (p less than 0.0001). There was no cromoglycate dose-response relationship between the three doses of aerosol (p greater than 0.05), or between any dose of aerosol and powder (p greater than 0.05). It is concluded that cromoglycate aerosol inhaled from a pressurised inhaler in a dose of 2 mg gives the same magnitude of protection against bronchoconstriction stimulated by airway cooling as 20 mg of pressurised aerosol or powder from a Spincap.