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.     

Effect of antihistamines and antiallergic drugs on responses to allergen and histamine provocation tests in asthma.

The inhibition of immediate allergen or histamine induced airflow obstruction by inhaled ketotifen, clemastine, sodium cromoglycate, and placebo was studied in two groups of asthmatic subjects. Single doses of ketotifen (0.5 mg), clemastine (0.5 mg), sodium cromoglycate (20 mg), or placebo were administered by inhalation 45 minutes before bronchial provocation testing at weekly intervals, double blind and in random order. Inhalation of ketotifen and clemastine, but not sodium cromoglycate, caused an increase in the amount of histamine which had to be administered to cause a 20% fall in FEV1 from control levels (PD20-FEV1) compared with placebo. The PD20-FEV1 for allergen increased significantly after inhalation of clemastine and sodium cromoglycate. Clemastine, primarily an H1 receptor antagonist, inhibited airflow obstruction after inhalation of both histamine and allergen. Its inhibitory effect on allergen induced asthma did not differ significantly from that of sodium cromoglycate. Ketotifen, when inhaled in a single dose of 0.5 mg before bronchial provocation testing, showed potent antihistamine activity, but there was no evidence of any additional "antianaphylactic" activity.     

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.     

Inhibition of the bronchial response to respiratory heat exchange by increasing doses of terbutaline sulphate

Ten asthmatic patients inhaled terbutaline sulphate (250, 500, or 1000 micrograms) or placebo on separate days, double blind and in random order, 30 minutes before isocapnic hyperventilation induced by cold air inhaled in doses that increased in a precisely controlled manner. The respiratory heat exchange (RHE) was calculated for each level of ventilation and the results were expressed as the RHE causing a fall in FEV1 of 10% (PD10RHE). The PD10RHE after placebo was highly reproducible. After terbutaline inhalation there was a highly significant shift in the RHE dose-response curves to the right and a trend towards a linear increase in PD10RHE with increasing doses of terbutaline. The subjects who were most responsive to the RHE required more terbutaline to inhibit the response completely. The results indicate that RHE dose-response curves are a precise method to examine the effects of drugs on hyperventilation-induced asthma, that increasing doses of terbutaline can produce increasing protection, and that the degree of protection is dependent on the level of increased bronchial responsiveness to RHE.     

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.     

Pressurised aerosol deposition in the human lung with and without an "open" spacer device

A radiotracer technique has been used to assess aerosol delivery from a pressurised metered dose inhaler, used both with and without a 10 cm cylindrical spacer attachment (Syncroner), which has an open section in its upper surface. The radionuclide technetium-99m (99mTc) was added to sodium cromoglycate in a canister (Intal inhaler; 1 mg/puff); in vitro studies with a multistage liquid impinger showed that the radiolabel acted as a marker for the presence of drug over a wide range of particle sizes. Ten healthy volunteers were studied after they had inhaled from (1) a metered dose inhaler alone (slow inhaled flow rate, about 25 l/min); (2) metered dose inhaler plus spacer (slow flow rate); and (3) metered dose inhaler plus spacer (fast inhaled flow rate, about 100 l/min). Inhalation was coordinated with firing the spray and was followed by 10 seconds' breath holding. With the metered dose inhaler alone a mean 11.0% (SEM 1.4%) of the dose reached the lungs, compared with significantly higher doses for slow (16.1% (2.2%] and fast (13.3% (1.7%] inhalations through the spacer. The distribution pattern within the lungs was significantly more peripheral after slow inhalation. Oropharyngeal deposition was halved by the spacer. The open spacer should teach patients good coordination and delivers more aerosol to the lungs than a correctly used metered dose inhaler.     

Comparison of two high dose corticosteroid aerosol treatments, beclomethasone dipropionate (1500 micrograms/day) and budesonide (1600 micrograms/day), for chronic asthma.

Twenty eight patients with chronic asthma took part in a double blind single crossover controlled trial of inhaled budesonide and inhaled beclomethasone dipropionate, using high doses of 1600 micrograms and 1500 micrograms daily respectively. Both drugs were administered by pressurised aerosol inhaler; the inhaler containing budesonide and its matching placebo were fitted with a collapsible spacer device. There was no significant difference in the control of asthma during the two six week treatment periods. There was no significant difference in FEV1 and forced vital capacity after four and six weeks of treatment or in mean morning and evening peak expiratory flow rates for the last 21 days of treatment. There was a small but statistically significant reduction in the daytime wheeze score while they were taking high dose budesonide but there was no difference for daytime activity, cough, and night symptoms. The mean basal cortisol concentrations were significantly lower after six weeks of high dose treatment than before treatment (budesonide p less than 0.01, beclomethasone p less than 0.05). There was no difference between mean basal cortisol values after six weeks of high dose treatment, and there was no effect on the rise of cortisol obtained after a short tetracosactrin test. High dose inhaled corticosteroids produced few side effects and were well tolerated.     

Comparison of bronchodilator responses and deposition patterns of salbutamol inhaled from a pressurised metered dose inhaler, as a dry powder, and as a nebulised solution.

The lung dose and deposition patterns of drug delivered by dry powder inhaler are not known. The effects of inhaling 400 micrograms salbutamol delivered by dry powder inhaler (two 200 micrograms salbutamol Rotacaps), by pressurised metered dose inhaler, and by Acorn nebuliser were studied in nine subjects with chronic stable asthma. Technetium-99m labelled Teflon particles were mixed with micronised salbutamol in the pressurised metered dose inhaler and in the capsules; technetium-99m labelled human serum albumin was mixed with the salbutamol solution for the nebuliser study. The pressurised metered dose inhaler deposited 11.2% (SEM 0.8%) of the dose within the lungs; this was significantly more than the dose deposited by the dry powder inhaler (9.1% (0.6%], but did not differ significantly from the dose delivered by the nebuliser (9.9% (0.7%]. Distribution within the peripheral third of the lung was significantly greater with the nebuliser than with the other two systems; FEV1 improved to a significantly greater extent after inhalation of 400 micrograms salbutamol from the pressurised metered dose inhaler (35.6% from baseline) than from the nebuliser (25.8%) or dry powder inhaler (25.2%). Thus after inhalation of similar doses of salbutamol a larger proportion of drug was deposited within the lungs when it was inhaled from a metered dose inhaler than from a dry powder system; the nebuliser achieved the greatest peripheral deposition. The bronchodilator response seems to depend on the amount of drug within the lungs rather than its pattern of distribution.     

Evaluation of ultrasonically nebulised solutions for provocation testing in patients with asthma.

The airway response to the inhalation of ultrasonically nebulised distilled water was determined in 55 asthmatic patients and 16 normal subjects. We calculated the dose of water required to induce a 20% reduction (PD20) in forced expiratory volume in one second (FEV1) by measuring the output of the nebuliser and the volume ventilated by each subject. Forty-eight of the asthmatic patients had a PD20 of 9 ml or less but three patients required as much as 24 ml. A PD20 was not recorded in the normal subjects and the challenge was stopped after 33 ml. In 12 patients the challenge was repeated within six months and the airway response was shown to be reproducible at equivalent doses of water. In a separate group of 11 patients there was, however, a highly significant reduction in the percentage fall in FEV1 when equivalent doses of water were given on two occasions 40 minutes apart. When the temperature of the inhaled water was increased from 22 degrees C to 36 degrees C eight of 10 patients had a similar change in FEV1 with equivalent doses of water. The airways obstruction induced by the inhalation of water was readily reversed with salbutamol administered by aerosol. In some patients a challenge with water or 3.6% saline was repeated after pretreatment with sodium cromoglycate, atropine methonitrate, and verapamil hydrochloride, all given as aerosols. The airway response to the equivalent dose of water or saline was significantly reduced after treatment with sodium cromoglycate but not atropine or verapamil.     

Effect of azelastine on bronchoconstriction induced by histamine and leukotriene C4 in patients with extrinsic asthma.

Azelastine, a new oral agent with antiallergic and antihistamine properties, has been shown to inhibit the effect of histamine and leukotriene (LT) in vitro, though not a specific leukotriene receptor antagonist. The effect of both a single dose (8.8 mg) and 14 days' treatment (8.8 mg twice daily) with azelastine on bronchoconstriction induced by LTC4 and histamine has been examined in 10 patients with mild asthma in a placebo controlled, double blind, crossover study. LTC4 and histamine were inhaled in doubling concentrations from a dosimeter and the results expressed as the cumulative dose (PD) producing a 20% fall in FEV1 (PD20FEV1) and 35% fall in specific airways conductance (PD35sGaw). The single dose of azelastine produced a significantly greater FEV1 and sGaw values than placebo at 3 hours, but this bronchodilator effect was not present after 14 days of treatment. Azelastine was an effective H1 antagonist; after a single dose and 14 days' treatment with placebo the geometric mean PD20FEV1 histamine values (mumol) were 0.52 (95% confidence interval 0.14-1.83) and 0.54 (0.12-2.38), compared with 22.9 (11.5-38.3) and 15.2 (6.47-35.6) after azelastine (p less than 0.01 for both). LTC4 was on average 1000 times more potent than histamine in inducing bronchoconstriction. Azelastine did not inhibit the effect of inhaled LTC4; the geometric mean PD20FEV1 LTC4 (nmol) after a single dose and 14 days' treatment was 0.60 and 0.59 with placebo compared with 0.65 and 0.75 with azelastine. The PD35sGaw LTC4 was also unchanged at 0.66 and 0.73 for placebo compared with 0.83 and 0.74 for azelastine. Thus prolonged blockade of H1 receptors did not attenuate the response to LTC4, suggesting that histamine and LTC4 act on bronchial smooth muscle through different receptors. Four patients complained of drowsiness while taking azelastine but only one who was taking placebo and three patients complained of a bitter, metallic taste while taking azelastine.     

Effect of terbutaline on mucociliary clearance in asthmatic and healthy subjects after inhalation from a pressurised inhaler and a dry powder inhaler.

BACKGROUND: beta Agonists have been shown to increase mucociliary clearance in some studies but not all. Whether the formulation of beta agonists affects mucociliary clearance is not known but may be important as the use of dry powder inhalers increases. METHODS: The effect of different methods of administration of inhaled terbutaline on mucociliary clearance and forced expiratory volume in one second (FEV1) was assessed in 10 patients with asthma and 10 healthy subjects. Terbutaline (1 mg) was administered through a metered dose inhaler with a spacer (Nebuhaler) or a dry powder inhaler (Turbuhaler), or both treatments were given, in a four way double blind, double dummy trial. Mucociliary clearance was measured by bronchoscintigraphy. RESULTS: Clearance of radioactivity from the lobar bronchi increased in the asthmatic patients by a median of 32% after terbutaline was given by metered dose inhaler and 55% after a combined dose of 2 mg from both inhalers (1 mg from each) compared with placebo but by only 9% after 1 mg of terbutaline was given by a dry powder inhaler. In the healthy subjects mucociliary clearance increased by 51% when terbutaline was given by a dry powder inhaler, by 66% when given by a metered dose inhaler, and by 66% when given by both inhalers combined. The effect of terbutaline on FEV1 was the same with each of the inhalers. CONCLUSION: Despite similar changes in FEV1 with the two formulations terbutaline increased mucociliary clearance significantly in asthmatic and healthy subjects when inhaled from a metered dose inhaler whereas when it was inhaled from a dry powder inhaler its effect was significant only in healthy subjects. The reason for the difference in asthmatic subjects is unclear, but may be associated with differences in the deposition of terbutaline.     

Use of sequential quadrupling dose regimens to study efficacy of inhaled corticosteroids in asthma

BACKGROUND: Inhaled corticosteroids are widely used to treat asthma. There is a need to be able to compare different inhaled corticosteroids and different doses of an inhaled corticosteroid to determine potency and dose equivalence, but measuring efficacy in a dose related manner is difficult because of their slow onset of action. There is uncertainty about the role of sequential dosing regimens and the best end point for such studies. We have explored the use of sequential quadrupling dose regimens and a range of end points to assess the response to budesonide in subjects with asthma. METHODS: 21 subjects with mild asthma, aged 18-65, took part in a randomised three way crossover study comparing two sequential and one non-sequential regimen, separated by at least 3 weeks. The sequential regimens consisted of increasing doses of inhaled budesonide (100, 400 1600 microg/day) with each dose being given for 1 or 2 weeks; the non-sequential regimen consisted of 1600 microg/day for 2 weeks with end points measured after 1 and 2 weeks. The end points studied included the provocative dose of adenosine monophosphate causing a 20% fall in forced expiratory volume in 1 second (PD20AMP), lung function, symptoms, and bronchodilator use. RESULTS: There was a dose related increase in PD20AMP with both sequential dose regimens. The increase in PD20AMP ranged from 1.49 doubling doses (DD) following the lowest dose (100 microg/day) to 3.1 DD following the highest dose (1600 microg/day) in the 1 week sequential regimen and from 1.98 to 4.03 DD in the 2 week sequential regimen; standard deviations (SD) for the changes in PD20AMP ranged from 1.3 to 2.6 DD. Changes in forced expiratory volume in 1 second (FEV1) and morning peak expiratory flow rate (PEFR) were dose related but small and more variable (maximum change in FEV1=148 ml, SD 228 ml), while changes in evening PEFR, symptoms, and bronchodilator use were small and not dose related. Change in PD20AMP after budesonide 1600 microg did not differ significantly between regimens. CONCLUSION: Combining PD20AMP measurements with a sequential regimen of three quadrupling doses of an inhaled corticosteroid given for 1 or 2 weeks provides clear dose-response curves for comparative studies. PD20AMP is a more sensitive end point for this purpose than FEV1, PEFR, symptoms, or relief inhaler use.     

Dose-response comparison of ipratropium bromide from a metered-dose inhaler and by jet nebulisation

The dose-response relationships of the anticholinergic bronchodilator drug ipratropium bromide were studied. Cumulative doses totalling 288 micrograms ipratropium were given by inhalation of a liquid aerosol from a Wright nebuliser to each of 10 patients with stable, moderately severe airflow obstruction. Up to 80% of the maximum achievable bronchodilator response, as assessed by a rise in the patients' mean forced expiratory volume in one second (FEV1), was obtained with a cumulative total dose of 72 micrograms; with additional doses beyond 72 micrograms there was no significant further improvement. In the same patients the effects of administration of cumulative doses of ipratropium to a total of 72 micrograms from a Wright nebuliser were compared with those achieved with a metered-dose inhaler. Bronchodilatation was assessed by measurement of peak expiratory flow rate, FEV1, forced vital capacity, thoracic gas volume and specific airways conductance (sGaw). No significant difference was observed in the response at any dose level between the wet and the dry aerosols. By fitting a curve to the mean values of FEV1 and sGaw an estimate was made of the dose of ipratropium bromide required to produce 99% of the achievable bronchodilator response. For FEV1 this dose was 78 micrograms when ipratropium was inhaled as a nebulised solution from the Wright nebuliser and 82 micrograms when it was inhaled from the metered-dose inhaler; for sGaw the respective values were 54 and 58 micrograms. In these patients with stable airflow obstruction there was no therapeutic advantage in the use of ipratropium bromide as a wet aerosol.     

Dose related effects of salbutamol and ipratropium bromide on airway calibre and reactivity in subjects with asthma.

The relationship between change in airway calibre and change in airway reactivity after administration of bronchodilator drugs has been investigated by comparing the effect of increasing doses of inhaled salbutamol and ipratropium bromide on the forced expiratory volume in one second (FEV1), specific airways conductance (sGaw), and the dose of histamine causing a 20% fall in FEV1 (PD20) in six subjects with mild asthma. On each of 10 occasions measurements were made of baseline FEV1, sGaw, and PD20 after 15 minutes' rest, and followed one hour later, when the FEV1 had returned to baseline, by a single nebulised dose of salbutamol (placebo, 5, 30, 200 and 1000 micrograms) or ipratropium (placebo, 5, 30, 200 and 1000 micrograms) given in random order. Measurements of FEV1, sGaw, and PD20 were repeated 15 minutes after salbutamol and 40 minutes after ipratropium. Salbutamol and ipratropium caused a similar dose related increase in FEV1 and sGaw, with a mean increase after the highest doses of 0.76 and 0.69 litres for FEV1 and 1.15 and 0.96 s-1 kPa-1 for sGaw. Salbutamol also caused a dose related increase in PD20 to a maximum of 2.87 (95% confidence interval 2.18-3.55) doubling doses of histamine after the 1000 micrograms dose, but ipratropium bromide caused no significant change in PD20 (maximum increase 0.24 doubling doses, 95% confidence interval -0.73 to 1.22). Thus bronchodilatation after salbutamol was associated with a significantly greater change in airway reactivity than a similar amount of bronchodilatation after ipratropium bromide. This study shows that the relation between change in airway reactivity and bronchodilatation is different for two drugs with different mechanisms of action, suggesting that change in airway calibre is not a major determinant of change in airway reactivity with bronchodilator drugs.     

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.     

Rapid effect of inhaled steroids on nocturnal worsening of asthma

BACKGROUND: Inhaled steroids are the most commonly used anti-inflammatory agents for asthma and are increasingly recognised as having a more rapid onset of action than was previously thought. We have investigated the effect of a single dose of inhaled steroid on nocturnal worsening of asthma. METHODS: Ten patients with steroid naive moderate asthma and nocturnal asthma participated in a randomised, double blind, placebo controlled, crossover trial. Participants spent three nights in the laboratory, one week apart. On each night they underwent spirometric testing at 16.00 hours and received one of the three treatments (placebo, beclomethasone 1000 micro g, or fluticasone 1000 micro g) delivered by metered dose inhaler. Spirometric tests were repeated at 04.00 hours the following morning. RESULTS: Following placebo administration the mean (SE) overnight fall in FEV(1) was 0.65 (0.27) l compared with -0.02 (0.13) l following fluticasone (p=0.019) and 0.23 (0.12) l following beclomethasone (p=0.048 v placebo). CONCLUSION: A single dose of inhaled steroid (within the therapeutic range) reduced the fall in FEV(1) in patients with nocturnal asthma when administered at 16.00 hours. Nocturnal worsening of asthma is a useful model for testing inhaled steroid activity in a single night study.     

Attenuation of propranolol-induced bronchoconstriction by frusemide

BACKGROUND: Inhaled propranolol causes bronchoconstriction in asthmatic subjects by an indirect mechanism which remains unclear. Inhaled frusemide has been shown to attenuate a number of indirectly acting bronchoconstrictor challenges. The aim of this study was to investigate whether frusemide could protect against propranolol-induced bronchoconstriction in patients with stable mild asthma. METHODS: Twelve asthmatic subjects were studied on three separate days. At the first visit subjects inhaled increasing doubling concentrations of propranolol (0.25-32 mg/ml), breathing tidally from a jet nebuliser. The provocative concentration of propranolol causing a 20% reduction in FEV1 (PC20FEV1 propranolol) was determined from the log concentration- response curve for each subject. At the following visits nebulised frusemide (4 ml x 10 mg/ml) or placebo (isotonic saline) was administered in a randomised, double blind, crossover fashion. FEV1 was measured immediately before and five minutes after drug administration. Individual PC20FEV1 propranolol was then administered and FEV1 was recorded at five minute intervals for 15 minutes. Residual bronchoconstriction was reversed with nebulised salbutamol. RESULTS: Frusemide had no acute bronchodilator effect but significantly reduced the maximum fall in FEV1 due to propranolol: mean fall 18.2% after placebo and 11.8% after frusemide. The median difference in maximum % fall in FEV1 within individuals between study days was 3.6% (95% CI 1.2 to 11.7). CONCLUSIONS: Frusemide attenuates propranolol-induced bronchoconstriction, a property shared with sodium cromoglycate. Both drugs block other indirect challenges and the present study lends further support to the suggestion that frusemide and cromoglycate share a similar mechanism of action in the airways.


     

The effect of inhaled frusemide on airway sensitivity to inhaled 4.5% sodium chloride aerosol in asthmatic subjects.

BACKGROUND: Frusemide inhaled by asthmatic subjects before a variety of indirect bronchial challenges inhibits the airway response to these challenges. Since inhalation of hyperosmolar saline is an indirect bronchial challenge, the effect of inhaled frusemide and its vehicle on airway sensitivity to a 4.5% sodium chloride (NaCl) aerosol challenge was investigated. METHODS: Eleven asthmatic subjects (five females, six males) who had a 20% fall in forced expiratory volume in one second after 4.5% NaCl challenge were enrolled in this double blind controlled crossover trial. Sensitivity was measured as the dose of aerosol required to provoke a 20% fall in FEV1. Frusemide (33.2 mg) or its vehicle was delivered through a Fisoneb ultrasonic nebuliser and inhaled 10 minutes before challenge with 4.5% NaCl. A Mistogen ultrasonic nebuliser was used to generate the 4.5% NaCl aerosol and FEV1 was measured before and one minute after each challenge period of 0.5, one, two, four, eight, eight and eight minutes. The doubling dose difference for PD20 was calculated. RESULTS: Frusemide or vehicle had no effect on baseline lung function. The geometric mean PD20 after vehicle was 1.3 ml with a 95% confidence interval of 0.7-2.3 and after frusemide was 8.2 ml with a 95% confidence interval of 4.7-14.1. This represented a 2.6 doubling dose increase in PD20 after frusemide inhalation. In five of the 11 subjects an increase from baseline FEV1 occurred after exposure to 4.5% NaCl challenge in the presence of frusemide. This transient bronchodilatation may be caused by the release of prostaglandin E2. CONCLUSION: Inhalation of frusemide is very effective in delaying airway narrowing induced by an aerosol of 4.5% NaCl in asthmatic subjects.     

Repeatability of bronchial hyperresponsiveness to adenosine-5'-monophosphate (AMP) by a short dosimeter protocol

BACKGROUND: To study bronchial responsiveness to adenosine 5'-monophosphate (AMP) in population surveys, repeatability of a rapid dosimetric method with quadrupling doses was evaluated. METHODS: Volunteers with symptoms of airway respiratory allergy or asthma were invited for AMP challenges on two occasions. After each dose the fall in forced expiratory volume in one second (FEV(1)) compared with the post-saline value was determined. The cumulative doses of AMP needed to cause a fall in FEV(1) of 20% (PD(20)), 15% (PD(15)), and 10% (PD(10)) were calculated. Agreement was evaluated by means of kappa values. After excluding systematic differences in PD values on two occasions (t test), repeatability of a single estimation of the chosen PD values was calculated and expressed in doubling doses (DD). RESULTS: In 28 of 76 subjects a PD(20) was estimated on the two visits, in 29 subjects a PD(15) was estimated, and in 32 a PD(10) was obtained. Kappa values for a positive threshold were 0.89 for a cut off level for a 20% fall in FEV(1), 0.78 for a 15% fall in FEV(1), and 0.76 for a fall in FEV(1) of 10%. The PD values did not differ between the two visits and 95% repeatability of a single estimation was +/-1.7 DD for PD(20), +/-2.2 DD for PD(15), and +/-2.4 DD for PD(10). The quadrupling dose method reduced time by 40% in non-hyperresponsive subjects and no adverse effects were observed. CONCLUSION: The short dosimeter protocol with quadrupling doses for AMP challenges is a rapid, reproducible tool for estimating bronchial responsiveness in population surveys.