Failure of ipratropium bromide to modify the diurnal variation of asthma in asthmatic children.

Thirty one children with asthma were given 40 micrograms of ipratropium bromide and identical placebo by inhalation three times a day in a double blind, randomised crossover study to test the ability of an anticholinergic drug to modify the diurnal variation in airway calibre and bronchial reactivity. Subjects measured peak expiratory flow rate approximately eight hourly, before and after inhaled salbutamol, for four week periods. Paired t tests and cosinor analysis were used to assess the diurnal variation in airway calibre from the peak expiratory flow rate recorded before salbutamol and to assess the diurnal variation in bronchodilator responsiveness from the increase in peak expiratory flow rate after salbutamol. Maintenance treatment with ipratropium bromide 40 micrograms three times daily reduced the provocative dose of histamine which caused a 20% fall in FEV1 (geometric mean PD20 = 0.78 v 0.49 mg/ml, p less than 0.05), despite an eight to 12 hour gap between the last dose of ipratropium and histamine challenge. It did not, however, diminish the diurnal variation in airway calibre (mean amplitude = 12.7 v 10.1) or in bronchodilator responsiveness (mean amplitude = 62.4 v 63.5). There was no improvement in the clinical state of subjects while they were taking ipratropium bromide.     

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.     

Regional lung clearance during cough and forced expiration technique (FET): effects of flow and viscoelasticity.

BACKGROUND--In vitro studies have suggested that both the viscoelastic properties of lung secretions and the peak flow attained during simulated cough influence clearance. This study examines the possible association of the viscoelastic properties of sputum and maximum expiratory flow with measured effectiveness of mucus clearance induced by instructed cough and by forced expiration technique (FET) in patients with airways obstruction. METHODS--Nineteen patients (11 men and eight women) of mean (SE) age, % predicted FEV1, and daily sputum wet weight of 64 (2) years, 52 (6)%, and 37.5 (7.9) g respectively participated in the study. Mucus movement from proximal and peripheral lung regions was measured by an objective non-invasive radioaerosol technique. Each patient underwent three assessments: control, cough, and FET. During cough and FET, maximum expiratory flow was measured at the mouth level. Apparent viscosity and elasticity of the expectorated sputum samples were measured with a viscometer. RESULTS--Compared with the control run (mean (SE) clearance: 16 (3)%) there was an increase in clearance from the whole lung during cough (44 (5)%) and FET (42 (5)%), and also an enhanced clearance of inhaled, deposited radioaerosol from the trachea, inner and intermediate regions of the lungs, but not from the outer region. There were, however, no differences in regional clearance between cough and FET. Neither regional nor total clearance correlated with maximum expiratory flow, apparent viscosity, elasticity, or daily sputum wet weight. CONCLUSIONS--These results confirm that cough and FET both promote effective clearance but suggest that, unlike in vitro studies, sputum production and viscoelasticity, as well as maximum expiratory flow, provide no guide to clearance efficacy in humans.     

Cholinergic blockade in the prevention of exercise-induced asthma.

The contribution of vagal mechanisms to exercise-induced asthma has been studied in 10 adult asthmatic patients using the anticholinergic drug ipratropium bromide. Exercise tests were performed for eight minutes on a cycle ergometer and each individual's tests were standardised by matching oxygen uptake. Two tests were done on each of three study days, the first being without previous medication, and the second preceded by inhalation of ipratropium bromide, 0.1, or 1 mg or saline placebo given 90 minutes beforehand. The mean falls in FEV1 and PEFR after the initial tests were very similar on the three study days. The mean falls in FEV1 after the second test were 22.3%, 19.5%, and 12.5% with placebo, 0.1 mg, and 1 mg ipratropium bromide respectively. Only the higher dose was significantly better than placebo. The results were also analysed using a protection index to compare the first and second tests each day and 1 mg ipratropium bromide was significantly better than both 0.1 mg and placebo. Similar results were obtained using PEFR. Equal bronchodilatation was produced by the two doses of drug. We conclude that conventional doses of anticholinergic drugs are not effective in preventing exercise-induced asthma, while large doses may do so in the same group of subjects.     

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 response study of ipratropium bromide aerosol on maximum exercise performance in stable patients with chronic obstructive pulmonary disease.

BACKGROUND: Although the bronchodilating effect of inhaled anticholinergics has been established in patients with chronic obstructive pulmonary disease (COPD), their effects on exercise capacity are still controversial. Previous studies have suggested that the standard dosage hardly affects exercise tolerance, whereas higher doses might elicit an improvement. The aim of the present study was to determine the dose of ipratropium bromide aerosol that improves exercise performance using progressive cycle ergometry in patients with stable COPD. METHODS: Twenty men with stable COPD of mean (SD) age 69.2 (4.6) years and forced expiratory volume in one second (FEV1) 1.00 (0.37) 1 were studied in a randomised double blind manner. Each patient received ipratropium bromide in doses of 240 micrograms, 160 micrograms, 80 micrograms, 40 micrograms, and placebo from a metered dose inhaler (MDI) with an InspirEase spacer on five separate days. Spirometric parameters were assessed before and at 30, 60, 90, and 120 minutes after each inhalation, and pulse rate and blood pressure were also measured immediately before each spirometric measurement. Symptom limited progressive (20 watts/min) cycle ergometer exercise tests were performed 90 minutes after each inhalation. RESULTS: Ipratropium bromide in doses of 160 micrograms and 240 micrograms produced a greater increase in FEV1 than 40 micrograms or 80 micrograms ipratropium bromide at all time points. Doses of 160 micrograms and 240 micrograms ipratropium bromide also produced greater increases in maximal work load and maximal oxygen consumption than placebo, whereas 40 micrograms and 80 micrograms ipratropium bromide did not. There was a weak correlation between the change in FEV1 and the change in maximal work load (r = 0.45). No differences were found in pulse rate or blood pressure between the treatment and placebo groups, and no side effects were noted throughout the study. CONCLUSIONS: A dose of at least four times the standard dose of ipratropium bromide from an MDI with a spacer device was necessary to improve maximal cycle exercise capacity in patients with stable COPD. Although the data from cycle ergometry cannot be directly applied to exercise performed during day to day activities, it is conceivable that the recommended doses of ipratropium bromide do not elicit the optimal clinical benefits.     

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.     

Relationship between bronchial reversibility and tracheobronchial clearance in patients with chronic bronchitis

BACKGROUND: Patients with chronic bronchitis show a large intersubject variation in sputum rheology, tracheobronchial clearance, and reversibility of airflow obstruction to beta 2 agonists. The bronchial mediators which are known to cause bronchoconstriction, mucosal oedema, mucus hypersecretion, and cough can also affect mucociliary transport. The aim of this study was to ascertain whether changes in tracheobronchial clearance and sputum rheological properties in patients with chronic bronchitis were associated with a specific degree of airflow reversibility assessed as the bronchial response to an inhaled beta 2 agonist (fenoterol 400 micrograms). METHODS: Bronchial reversibility (percentage change in baseline forced expiratory volume in one second (FEV1)) was measured in 26 patients with chronic bronchitis on three separate occasions, at least one week apart. Tracheobronchial clearance was evaluated by a non-invasive radioaerosol technique, and an oscillatory viscometer was used for measuring sputum apparent viscosity and elasticity. The number of coughs (productive and nonproductive coughs), the wet weight of sputum, and its radioaerosol content were recorded during the six hour clearance period, as well as the 24 hour sputum production. RESULTS: The change in FEV1 after fenoterol was less than 15% in 12 patients and more than 15% in 14. Patients with airways reversibility of more than 15% had faster tracheobronchial clearance, more coughs, lower sputum viscosity and elasticity, and larger 24 hour sputum production than those with airways reversibility of less than 15%. CONCLUSIONS: In patients with chronic bronchitis a large bronchodilator response is associated with faster clearance of mucus by mucociliary transport and coughing.




     

Effects of inhaled budesonide on spirometric values, reversibility, airway responsiveness, and cough threshold in smokers with chronic obstructive lung disease.

Inhaled corticosteroids are known to reduce respiratory symptoms and airway responsiveness in allergic patients with asthma. The aim of the present randomised, double blind study was to assess the effect of eight weeks' treatment with inhaled budesonide in non-allergic smokers with chronic obstructive lung disease. Twenty four subjects (23 male) entered the study. Their ages ranged from 40 to 70 (mean 57) years, with a mean of 35 (range 9-80) pack years of smoking; the mean FEV1 was 53% (range 32-74%) predicted and geometric mean PC20 (histamine concentration causing a 20% fall in FEV1) 0.96 (range 0.07-7.82) mg/ml. After a two week washout, single blind, placebo period, 12 patients were allocated to treatment with budesonide 1600 microgram/day and 12 to placebo for eight weeks. The only additional drug to be taken was ipratropium bromide "if needed." Twenty one patients completed the study, 10 in the budesonide group and 11 in the placebo group. The standard deviation of the difference between duplicate measurements of PC20 histamine and citric acid cough threshold made two weeks apart was below one doubling dose step. There was a significant reduction in dyspnoea in the budesonide group, but otherwise no change in symptom scores or use of ipratropium bromide over the eight weeks of treatment within or between the two groups. No significant differences in spirometric values, peak expiratory flow, PC20 histamine, or citric acid cough threshold were found between the groups. Although differences were not significant, some of the changes showed a trend in favour of budesonide. Whether a longer observation period would show a significant influence of inhaled corticosteroids in patients with chronic obstructive lung disease remains to be determined.     

Comparison of the efficacy of preservative free ipratropium bromide and Atrovent nebuliser solution.

The paradoxical bronchoconstriction observed with commercially available isotonic ipratropium bromide nebuliser solution (Atrovent) in patients with asthma results from an adverse reaction to the preservatives, benzalkonium chloride and ethylenediaminetetra-acetic acid (EDTA). The airway response to inhaled Atrovent and preservative free ipratropium bromide nebuliser solutions has been examined in a double blind study. On separate occasions 30 asthmatic subjects inhaled 2 ml of the solutions and airway calibre was measured in terms of FEV1 for 45 minutes. Atrovent nebuliser solution provoked a greater than 20% fall in FEV1 in five of the 30 subjects, whereas this did not occur after preservative free ipratropium bromide. Inhalation of the preservative free solution resulted in more rapid and greater overall bronchodilatation than Atrovent, with mean maximum increases in FEV1 of 29.2% and 18.5% respectively. It is concluded that the risk of paradoxical bronchoconstriction with ipratropium bromide is considerably reduced by removal of benzalkonium chloride and EDTA and that preservative free ipratropium bromide is a more potent bronchodilator than the currently available Atrovent solution.     

Effect of long term treatment with oxitropium bromide on airway secretion in chronic bronchitis and diffuse panbronchiolitis.

BACKGROUND--Anticholinergic bronchodilator drugs improve lung function in chronic bronchitis but less is known of their effects on the volume and physical properties of sputum in conditions associated with excessive airway secretions. This study examines the effects of the regular use of oxitropium bromide in such patients. METHODS--The study was conducted in a parallel, double blind, placebo controlled fashion. Patients were divided into two groups: the first group (n = 17) received oxitropium bromide from a metered dose inhaler (two puffs three times daily; 100 micrograms/puff) for eight weeks, and the second group (n = 16) received placebo. Lung function was measured as forced expiratory volume in one second (FEV1) and vital capacity. In evaluating airway secretion, daily amount of expectorated sputum, percentage solid composition, viscoelastic properties including elastic modulus and dynamic viscosity, and sputum microbiology were determined. RESULTS--Oxitropium bromide increased FEV1 and decreased the mean (SE) sputum production from 61(4) to 42(3) g/day after treatment, whereas placebo had no effect. Bacterial density and sputum flora were unchanged, but solid composition and elastic modulus increased from 2.52(0.43)% to 3.12(0.34)%, and 68(12) dyne/cm2, respectively, in the group taking oxitropium bromide. CONCLUSIONS--Regular treatment with oxitropium bromide not only improves airflow limitation but also reduces sputum production, probably through the inhibition of both mucus secretion and water transport, the latter component being predominant.     

Comparative dose-response study of three anticholinergic agents and fenoterol using a metered dose inhaler in patients with chronic obstructive pulmonary disease.

BACKGROUND--Inhaled anticholinergics and beta agonists are widely used in the treatment of patients with chronic obstructive pulmonary disease (COPD). However, dosage requirements have not been thoroughly evaluated and comparative dose-response data for these agents are limited. METHODS--Twenty men with stable COPD of mean (SD) age 69.4 (5.8) years and FEV1 0.93 (0.38) litres were studied in randomised, double blind, crossover, placebo controlled experiments. All of the patients received two, four, eight, and 16 puffs of ipratropium bromide (20 micrograms/puff), flutropium bromide (30 micrograms/puff), oxitropium bromide (100 micrograms/puff), fenoterol (200 micrograms/puff), or placebo in random order on five separate days. Doses were administered by a metered dose inhaler at intervals of 60 minutes to give cumulative doses of two, six, 14, and 30 puffs. Five mg of nebulised salbutamol was administered 60 minutes after the patient had received the final 16 puffs of each regimen. Forced expiratory volume in one second (FEV1), forced vital capacity (FVC), heart rate, and blood pressure were measured five minutes before each treatment and 30 minutes after treatment with nebulised salbutamol. RESULTS--FEV1 and FVC reached a plateau after administration of a cumulative dose of 14 puffs of ipratropium bromide (280 micrograms) or flutropium bromide (420 micrograms), and after six puffs of oxitropium bromide (600 micrograms). There were no differences with respect to maximum increases in FEV1 and FVC amongst the three anticholinergic agents. However, after six puffs oxitropium bromide produced a greater increase in FEV1 than either ipratropium bromide or flutropium bromide. Fenoterol caused a greater increase in both FEV1 and FVC than the three anticholinergic agents after six puffs, as well as a greater increase in pulse rate. Oxitropium bromide produced a greater increase in pulse rate than the other anticholinergics after 14 puffs. The incidence of side effects was dose-related and notable adverse effects were reported after 30 puffs of ipratropium bromide, 14 puffs of oxitropium bromide, and two puffs of fenoterol. CONCLUSIONS--Oxitropium bromide produced a greater bronchodilator effect than either ipratropium bromide or flutropium bromide when used at doses of less than six puffs, without apparent side effects. There were, however, no differences in maximal response between these drugs. Fenoterol may have a greater peak bronchodilator effect than the anticholinergic agents but it causes more adverse effects, even at lower doses. Depending upon the balance between efficacy and side effects, oxitropium bromide may be preferred in the treatment of patients with COPD.     

Effect of ipratropium bromide on mucociliary clearance and pulmonary function in reversible airways obstruction.

The effects of (a) regular use for one week and (b) a single dose of a synthetic anticholinergic (ipratropium bromide) on lung mucociliary clearance and as a bronchodilator was ascertained in a controlled, double-blind, cross-over study in 12 patients with reversible airways obstruction (mean increase in FEV after isoprenaline: 17% range 10-50%). Two puffs from a metered dose inhaler of either placebo (propellants only) or drug (40 microgram) were administered four times a day for one week (regular use), and mucociliary clearance was measured, by radioaerosol tracer, at the end of each treatment period and after a control period in which no treatment was given. On the mornings of the measurements after the placebo and drug periods one final dose (single dose) of ipratropium (40 microgram) or placebo was given 2.5 hours before the start of the test. There was no statistically significant difference between the three mean mucociliary clearance curves (control, placebo, and drug) for the group; however, there was a significantly greater penetration towards the periphery of the lung of the tracer in the test after drug administration compared with the other two. This increased penetration was attributed to bronchodilatation caused by the drug. Ipratropium bromide does not appear to impair mucociliary clearance, and it acts an effective bronchodilator.     

Acute effect of pretreatment with single conventional dose of salmeterol on dose-response curve to oxitropium bromide in chronic obstructive pulmonary disease

BACKGROUND: An earlier study documented that, in patients with chronic obstructive pulmonary disease (COPD), addition of ipratropium bromide at the clinically recommended dose (40 microg) does not produce any further bronchodilation than that achieved with salmeterol 50 microg alone. However, the dose of ipratropium bromide needed to produce near maximal bronchodilation is several times higher than the customary dosage. The full therapeutic potential of combined salmeterol plus an anticholinergic drug can therefore only be established using doses higher than those currently recommended in the marketing of these agents. A study was undertaken to examine the possible acute effects of higher than conventional doses of an anticholinergic agent on the single dose salmeterol induced bronchodilation in patients with stable and partially reversible COPD. METHODS: Thirty two outpatients received 50 microg salmeterol or placebo. Two hours after inhalation a dose-response curve to inhaled oxitropium bromide (100 microg/puff) or placebo was constructed using one puff, one puff, two puffs, and two puffs-that is, a total cumulative dose of 600 microg oxitropium bromide. Dose increments were given at 20 minute intervals with measurements being made 15 minutes after each dose. On four separate days all patients received one of the following: (1) 50 microg salmeterol + 600 microg oxitropium bromide; (2) 50 microg salmeterol + placebo; (3) placebo + 600 microg oxitropium bromide; (4) placebo + placebo. RESULTS: Salmeterol induced a good bronchodilation (mean increase 0.272 l; 95% CI 0.207 to 0.337) two hours after its inhalation. Oxitropium bromide elicited an evident dose-dependent increase in forced expiratory volume in one second (FEV(1)) and this occurred also after pretreatment with salmeterol with a further mean maximum increase of 0.152 l (95% CI of differences 0.124 to 0.180). CONCLUSIONS: This study shows that acute pretreatment with 50 microg salmeterol does not block the possibility of inducing more bronchodilation with an anticholinergic agent when a higher than normal dosage of the muscarinic antagonist is used.     

In vivo effects of recombinant human DNase I on sputum in patients with cystic fibrosis.

BACKGROUND: Viscoelastic secretions in cystic fibrosis cause impaired mucus clearance and persistence of bacteria within the lung. The abnormal rheology is partly due to the presence of high molecular weight deoxyribonucleic acid (DNA). Recombinant human DNase I (rhDNase) has been shown to depolymerise DNA and thereby reduce the in vitro viscoelasticity of sputum in patients with cystic fibrosis. A phase II double blind placebo controlled study showed that rhDNase improved pulmonary function in patients with cystic fibrosis. The object of the present study was to evaluate the in vivo effects of rhDNase on sputum rheology and to determine whether these were correlated with changes in pulmonary function. METHODS: Patients were randomised to receive either placebo or rhDNase 2.5 mg twice daily for 10 days. Sputum samples were collected in sterile containers during screening and during treatment with the study drug. Pulmonary function and rheological analysis were the primary outcomes evaluated. Other parameters assessed were quantitative sputum bacteriology, sputum DNA concentration, and change in molecular mass of DNA polymers. RESULTS: The viscoelasticity of the sputum in untreated patients with cystic fibrosis was high and treatment with rhDNase reduced all the rheological parameters measured: dynamic storage modulus (a measure of elasticity), dynamic loss modulus (a measure of viscosity), and log complex modulus (a measure of mucus rigidity). The calculated cough clearance index was also improved following treatment with rhDNase. These rheological parameters showed a correlation with forced expiratory volume in one second (FEV1) which was improved by a mean (SE) of 13.3 (5.6)% on day 10 of treatment with rhDNase compared with a change of 0.2 (3.1)% in the placebo group. There was no change in bacterial colony counts or sputum DNA concentrations following treatment with rhDNase, but a small decrease in high molecular weight DNA was observed. CONCLUSIONS: Patients with cystic fibrosis treated with rhDNase show an improvement in rheological properties and pulmonary function, one of the mechanisms being a reduction in the proportion of high molecular weight DNA.     

Prostaglandin F2 alpha enhancement of capsaicin induced cough in man: modulation by beta 2 adrenergic and anticholinergic drugs.

The effect of inhaled prostaglandin (PG) F2 alpha on the response to the inhaled tussive agent capsaicin was investigated in normal subjects. Seven subjects inhaled three breaths of four doses of capsaicin (0.3, 0.6, 1.2, and 2.4 nmol) before and immediately after inhaling PGF2 alpha (0.1 mumol) or placebo (0.15M NaCl) on separate days. The numbers of capsaicin induced coughs were greater after PGF2 alpha (mean 42.3 coughs) than after 0.15M sodium chloride (30.1). Visual analogue scores (0-10 on a 10 cm continuous scale) showed that capsaicin was more irritant after PGF2 alpha than after saline. Total respiratory resistance (Rrs), measured by the forced oscillation technique, was unaltered throughout the study. A double blind, placebo controlled study of the effects of inhaled salbutamol (200 micrograms, 0.6 mumol) and ipratropium bromide (40 micrograms, 0.1 mumol) on cough induced by capsaicin (2.4 nmol) and by PGF2 alpha (0.1 mumol) and on PGF2 alpha augmented, capsaicin induced coughing was performed in seven subjects. Neither drug had any effect on capsaicin induced coughing. Salbutamol reduced coughing due to PGF2 alpha (mean 7.7 coughs after salbutamol, 9.3 after placebo) but ipratropium bromide did not (mean 6.9 coughs after ipratropium bromide, 6.6 after placebo). Salbutamol also inhibited the augmentation of the capsaicin induced cough that followed inhalation of PGF2 alpha (mean augmentation 1.9 coughs after salbutamol, 4.1 after placebo), whereas ipratropium bromide did not (augmentation 1.7 coughs after ipratropium bromide, 2.7 after placebo). No changes in Rrs were seen after PGF2 alpha or either drug. Thus salbutamol reduces PGF2 alpha induced cough and the augmentation of capsaicin induced cough that follows PGF2 alpha.     

Effect of differing doses of inhaled budesonide on markers of airway inflammation in patients with mild asthma

BACKGROUND: It is desirable to prescribe the minimal effective dose of inhaled steroids to control asthma. To ensure that inflammation is suppressed whilst using the lowest possible dose, a sensitive and specific method for assessing airway inflammation is needed. METHODS: The usefulness of exhaled nitric oxide (NO), sputum eosinophils, and methacholine airway responsiveness (PC20) for monitoring airway inflammatory changes following four weeks of treatment with an inhaled corticosteroid (budesonide via Turbohaler) were compared. Mild stable steroid naive asthmatic subjects were randomised into two double blind, placebo controlled studies. The first was a parallel group study involving three groups receiving either 100 micrograms/day budesonide (n = 8), 400 micrograms/day budesonide (n = 7), or a matched placebo (n = 6). The second was a crossover study involving 10 subjects randomised to receive 1600 micrograms budesonide or placebo. The groups were matched with respect to age, PC20, baseline FEV1 (% predicted), exhaled NO, and sputum eosinophilia. RESULTS: There were significant improvements in FEV1 following 400 micrograms and 1600 micrograms budesonide (11.3% and 6.5%, respectively, p < 0.05). This was accompanied by significant reductions in eosinophil numbers in induced sputum (0.7 and 0.9 fold, p < 0.05). However, levels of exhaled NO were reduced following each budesonide dose while PC20 was improved only with 1600 micrograms budesonide. These results suggest that exhaled NO and PC20 may not reflect the control of airway inflammation as accurately as the number of eosinophils in sputum. There were dose dependent changes in exhaled NO, sputum eosinophils, and PC20 to inhaled budesonide but a plateau response of exhaled NO was found at a dose of 400 micrograms daily. CONCLUSION: Monitoring the number of eosinophils in induced sputum may be the most accurate guide to establish the minimum dose of inhaled steroids needed to control inflammation. This, however, requires further studies involving a larger number of patients.     

No demonstrable effect of S-carboxymethylcysteine on clearance of secretions from the human lung.

The mucolytic efficacy of S-carboxymethylcysteine has been assessed in a double-blind crossover trial in 16 patients with chronic obstructive bronchitis. No significant difference was found between drug and placebo after four or seven days' treatment in the rate of clearance of secretions from the lung. This was measured by external counting of previously inhaled polystyrene tracer particles tagged with technetium-99m (99mTc). Lateral scans across the right chest after inhaling the aerosol showed equal penetration of particles towards the periphery of the lung in drug and placebo runs; this indicated that the airways had not been cleared of mucus by the drug. There was no significant difference between drug and placebo runs in the number of coughs or the weight and radioactive content of sputum voided or raised at the end of the run by chest percussion and postural drainage. Ventilatory capacity was not significantly changed nor was there any subjective improvement in the patients as a result of taking the drug.     

Effects of allergy and age on responses to salbutamol and ipratropium bromide in moderate asthma and chronic bronchitis.

The bronchodilating responses to 400 micrograms salbutamol and 80 micrograms ipratropium bromide were studied in 188 patients with chronic bronchitis (n = 113) or asthma (n = 75) and mild to moderate airflow obstruction (forced expiratory volume in one second (FEV1) above 50% but below 2 SD of predicted value) in a crossover study on two days a week apart. Both the patients with asthma and the patients with chronic bronchitis varied considerably in their responses to the salbutamol and the ipratropium bromide. The mean increase in FEV1 in the subjects with asthma was higher after salbutamol (0.371 or 18% of the prebronchodilator value) than after ipratropium bromide (0.26 1 or 13%). In chronic bronchitis there was no difference between the increase in FEV1 after salbutamol (0.161 or 7%) and after ipratropium bromide (0.191 or 8%). When patients were categorised into those with a better response to salbutamol 400 micrograms and those with a better response to ipratropium bromide 80 micrograms, patients with chronic bronchitis responded better in general to ipratropium bromide whereas asthmatic patients responded better to salbutamol. The response pattern was also related to allergy and age, allergic patients and patients under 60 being more likely to respond better to salbutamol 400 micrograms than non-allergic patients and older patients, who benefited more from ipratropium bromide 80 micrograms. The response pattern was not related to sex, smoking habits, lung function, bronchial reactivity, respiratory symptoms, or number of exacerbations during the preceding year.     

Effects of cessation of terbutaline treatment on airway obstruction and responsiveness in patients with chronic obstructive pulmonary disease.

BACKGROUND: Cessation of regular therapy with inhaled beta 2 agonists in patients with asthma may lead to a temporary deterioration of lung function and airway responsiveness. Few such studies have been reported in patients with chronic obstructive pulmonary disease (COPD), so an investigation was carried out to determine whether rebound airway responsiveness and rebound bronchoconstriction also occurs in COPD and if there is any relationship with the dose of beta 2 agonist being used. METHODS: Lung function (forced expiratory volume in one second (FEV1) and peak expiratory flow (PEF)), airway responsiveness (PC20 methacholine (PC20)) and symptoms were assessed in a double blind, placebo controlled crossover study during and after cessation of two weeks regular treatment with placebo, and low dose (250 micrograms) and high dose (1000 micrograms) inhaled terbutaline via a dry powder inhaler (Turbohaler) all given three times a day. Sixteen non-allergic patients with COPD of mean (SD) age 58.7 (6.5) years, FEV1 57.1 (12.8)% of predicted, and reversibility on 1000 micrograms terbutaline of 4.5 (3.5)% predicted were studied. PC20 and FEV1 were measured 10, 14, 34 and 82 hours after the last inhalation of terbutaline or placebo. Measurements performed at 10, 14, and 34 hours were expressed relative to 82 hour values in each period, transformed into an area under the curve (AUC) value and analysed by ANOVA. RESULTS: Mean morning and evening PEF increased during terbutaline treatment. PC20 and FEV1 did not change after cessation of terbutaline treatment. CONCLUSIONS: Cessation of regular treatment with both low and high dose inhaled terbutaline does not result in a rebound bronchoconstriction and rebound airway responsiveness in patients with COPD.