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RATIONALE: Asthma exacerbations are unpredictable, disruptive, and frightening, and are therefore important to prevent. OBJECTIVES: We investigated whether a policy of quadrupling the dose of inhaled corticosteroid when asthma control starts to deteriorate reduces asthma exacerbations requiring treatment with oral corticosteroids. METHODS: A total of 403 people with asthma were given a self-management plan and randomized to take an active or placebo corticosteroid inhaler in addition to their usual asthma treatment when their PEF fell by 15% on 2 consecutive days or by 30% on 1 day. The study inhalers provided a quadrupling or no change in corticosteroid dose. MEASUREMENTS AND MAIN RESULTS: Eighteen of 197 (9%) and 29 of 203 (14%) participants had an exacerbation of asthma requiring treatment with oral corticosteroids in the active and placebo groups, respectively, giving a risk ratio of 0.64 (95% confidence interval, 0.37-1.11, P = 0.11). Of the 94 participants who started the study inhaler far fewer required treatment with oral corticosteroids in the active compared with the placebo group: 12 of 56 (21%) in the active group and 19 of 38 (50%) in the placebo group, giving a risk ratio of 0.43 (95% confidence interval, 0.24-0.78, P = 0.004). CONCLUSIONS: Although our primary outcome did not reach statistical significance, quadrupling the dose of inhaled corticosteroid when asthma control starts to deteriorate appears to reduce acute exacerbations of asthma and deserves further investigation. Clinical trial registered with www.controlled-trials.com (ISRCTN 46018181). [ABSTRACT FROM AUTHOR]

BACKGROUND: Poor adherence with inhaled corticosteroids is an important problem in asthma management. Previous approaches to improving adherence have had limited success. AIM: To determine whether treatment with a single inhaler containing a long-acting beta(2)-agonist and a corticosteroid for maintenance treatment and symptom relief can overcome the problem of poor adherence with inhaled corticosteroids. DESIGN OF STUDY: Randomised, parallel group, open-label trial. SETTING: Forty-four general practices in Nottinghamshire. METHOD: Participants who used less than 70% of their prescribed dose of inhaled corticosteroid and had poorly controlled asthma were randomised to budesonide 200 microg one puff twice daily plus their own short-acting beta(2)-agonist as required (control group), or budesonide/formoterol 200/6 microg one puff once daily and as required (active group) for 6 months. The primary outcome was inhaled corticosteroid dose. RESULTS: Seventy-one participants (35 control, 36 active group) were randomised. Adherence with budesonide in the control group was approximately 60% of the prescribed dose. Participants in the active group used approximately 80% more budesonide than participants in the control group (448 versus 252 microg/day, mean difference 196 mug, 95% confidence interval 113 to 279; P<0.001) and were less likely to withdraw from the study (3 versus 13; P<0.01). No safety issues were identified. CONCLUSION: Using a single inhaler for both maintenance treatment and symptom relief approximately doubled the dose of inhaled corticosteroid taken, suggesting this could be a useful strategy to overcome the problems related to poor adherence with inhaled corticosteroids. [ABSTRACT FROM AUTHOR]

1. The inadvertent administration of timolol to asthmatic patients continues to cause occasional severe and even fatal attacks of asthma. The (R)-enantiomer of timolol, L-714,465, is four times less potent than timolol in reducing intraocular pressure in man. It is 49 times less potent than timolol on beta 2-adrenoceptors in animals and 13 times less potent on the airways of normal subjects. These findings suggested that L-714,465 might be a safer alternative for the treatment of glaucoma. 2. Ten subjects with mild asthma who bronchoconstricted to timolol eye drops (0.25 or 0.5%) were studied. Airway dose-response curves to timolol (0-2%), L-714,465 (0-4%), and placebo (methyl cellulose) eye drops were performed in a double-blind randomised study in which airway response was measured as change in FEV1 and specific airway conductance (sGaw). 3. L-714,465 and timolol caused dose dependent falls in sGaw and FEV1 with L-714,465 being approximately four times less potent than timolol. The geometric mean dose ratio was 3.89 for FEV1 (95% confidence interval (CI) 1.7-8.7) and 3.93 (95% CI 2- 7.8) for sGaw. Since the difference in potency is similar to the reported difference in potency of the two drugs on intraocular pressure we conclude that L-714,465 would not have a greater safety margin than timolol. 4. After completion of the dose-response study eight subjects inhaled ipratropium bromide (72 micrograms) and this caused an increase in FEV1 from 74% to 80% of baseline.(ABSTRACT TRUNCATED AT 250 WORDS) [ABSTRACT FROM AUTHOR]

The R-enantiomer of timolol, L-714,465, is considerably less potent as a beta 1- and beta 2-adrenoceptor antagonist in animals than timolol, whilst only slightly less potent in reducing intraocular pressure. If the same was true in man L-714,465 would have potential benefits over timolol in the treatment of glaucoma. The extent of bronchial beta- adrenoceptor blockade following one eyedrop in each eye of timolol 1% and L-714,465 1% was compared in six normal subjects, by measuring the displacement of the bronchodilator dose-response curve to isoprenaline following each drug compared to the isoprenaline dose-response curve after placebo eyedrops (methyl-cellulose). There was no significant difference between the dose-response curves to L-714,465 and placebo, but a significant displacement of the dose-response curve following timolol. The geometric mean dose ratio following timolol (21) differed significantly from that following L-714,465 (1.6). Heart rate at the end of the isoprenaline dose-response study was lower after timolol, despite the fact that subjects had received higher doses of isoprenaline. The trend was in the same direction after L-714,465 when compared with placebo though less marked. L-714,465 clearly causes less beta-adrenoceptor blockade than timolol when given as 1% eyedrops. The effects of L-714,465 1% on the airways and heart rate did not differ significantly from placebo in these six subjects but the pattern of response would be most consistent with L-714,465 having some beta- adrenoceptor blocking activity though considerably less than timolol. [ABSTRACT FROM AUTHOR]

Bisoprolol is a new beta-adrenoceptor antagonist which has shown beta- adrenoceptor selectivity in studies in isolated tissues. Bronchial and cardiac beta-adrenoceptor blockade were assessed in eight normal subjects before and after oral ingestion of placebo, bisoprolol 20 and 40 mg, metoprolol 200 mg and propranolol 80 mg in random order. Bronchial beta-adrenoceptor blockade was assessed as the displacement of the bronchodilator dose-response curve to inhaled isoprenaline after each beta-adrenoceptor blocking drug compared to placebo and expressed as the dose ratio. Bronchodilatation was measured as change in specific airway conductance (sGaw) in the body plethysmograph. Cardiac beta- adrenoceptor blockade was assessed as the percentage reduction in exercise heart rate during the fifth minute of exercise at 70% of the subject's maximum work rate. Bisoprolol 20 and 40 mg caused a 24 and 25% reduction in exercise heart rate respectively, compared to 26% with metoprolol 200 mg and 20% with propranolol 80 mg. The dose ratios for the airway dose-response curves for the four beta-adrenoceptor blocking drugs were 1.04 and 3.4 for bisoprolol 20 and 40 mg, 1.4 for metoprolol 200 mg and 30 for propranolol 80 mg. Both doses of bisoprolol produced considerably less bronchial beta-adrenoceptor blockade than propranolol 80 mg despite causing a greater reduction in exercise heart rate. Bisoprolol 20 mg caused a similar amount of bronchial beta-adrenoceptor blockade and a similar reduction in exercise heart rate as metoprolol 200 mg, confirming that it is cardio-selective in man. [ABSTRACT FROM AUTHOR]

To determine whether the beta 2-selectivity of ICI 118551 extended to human airways, we measured bronchial beta-adrenoceptor blockade and the reduction in exercise heart rate in six normal subjects on different occasions after ingestion of ICI 118551 20 or 50 mg, propranolol 40 mg or placebo in random order. Bronchial beta-adrenoceptor blockade after each active drug was measured as the displacement of the airway dose- response curve to salbutamol and expressed as a dose ratio. Exercise heart rate was measured during the fifth minute of steady state exercise at 70% of the subject's maximum work load. The mean dose ratios for the salbutamol airway dose-response curves following ICI 118551 20 and 50 mg and propranolol 40 mg were 11, 55 and 48 respectively. The mean reductions in exercise heart rate for the three drugs were 0.6, 6.6 and 16.6% respectively. These results confirm that the beta 2-selectivity of ICI 118551 includes airway beta 2- adrenoceptors in man. [ABSTRACT FROM AUTHOR]

1 The airway response to inhaled prostaglandin E2 (PGE2) and the effect of oral propranolol on this response was studied in eight normal subjects in a double-blind randomised trial. The airway response was measured as specific airway conductance (sGaw). 2 Inhalation of PGE2 caused retrosternal soreness, coughing and an awareness of mucus production. Despite this, PGE2 caused bronchodilatation and reproducible dose-response curves were obtained, with a maximum increase in sGaw of 53%. 3 Inhalation of the diluent of PGE2, an ethanol/saline mixture, did not cause irritation nor did it alter sGaw. 4 Prior administration of propranolol 80 mg did not alter baseline sGAW, nor the response to PGE2, indicating that the action of PGE2 in vivo is unaffected by bronchial beta-adrenoceptor blockade. 5 This technique should be of value in studying bronchodilator prostaglandins and their interaction with other drugs. [ABSTRACT FROM AUTHOR]

Bronchial and cardiac beta-adrenoceptor blockade have been compared in six normal subjects after three beta-adrenoceptor antagonists. Single and double doses of atenolol (50 and 100 mg), acebutolol (100 and 200 mg) and labetalolol (150 and 300 mg) were studied on separate occasions. 2 Salbutamol airway dose-response curves were obtained by measuring the airway response as the change in specific airway conductance (sGaw) after increasing doses of inhaled salbutamol. Bronchial beta-adrenoceptor blockade was assessed after each drug as the dose of salbutamol needed to cause a 50% increase in sGaw (sGaw D50). 3 Cardiac beta-adrenoceptor blockade was assessed after the same doses of each beta-adrenoceptor antagonist, by measuring the percentage reduction in exercise heart rate from control, after exercise for 5 min at 70% of the subject's maximum work rate. 4 Atenolol 50 and 100 mg caused least bronchial beta-adrenoceptor blockade and the greatest reduction in exercise heart rate. 5 Acebutolol 100 and 200 mg and labetalol 150 and 300 mg produced more bronchial beta-adrenoceptor blockade than atenolol. 6 With this approach new beta-adrenoceptor antagonists can be assessed without putting asthmatic patients at risk. [ABSTRACT FROM AUTHOR]

To determine the role of Na/K ATPase in determining bronchial reactivity in man, we studied the effect of 1 mg inhaled ouabain on histamine reactivity in six normal and 10 asthmatic subjects in a placebo controlled, crossover study. sGaw was measured before and up to 2 h after drug, followed by a histamine challenge test to estimate the dose of histamine causing a 35% reduction in sGAW (PD35). sGAW values after ouabain and placebo did not differ significantly. Ouabain did not affect bronchial reactivity, geometric mean (95% CI) PD35 histamine values following ouabain and placebo were 8.98 (3.8-21.2) and 7.75 (3.2- 18.7) mumol respectively in normal subjects and 0.46 (0.18-1.21) and 0.69 (0.22-2.13) in asthmatic subjects. We were thus unable to demonstrate a role for Na/K ATPase in determining bronchial reactivity to histamine in man. [ABSTRACT FROM AUTHOR]

The objective of this study was to examine the relationship between descriptors of breathlessness and its underlying cause in patients with lung cancer and cardiopulmonary diseases to see whether descriptors might be used to help determine the cause of breathlessness, particularly in patients with lung cancer. We studied 131 patients with primary or secondary lung cancer, whose breathlessness was attributed to tumor mass, pleural effusion, lung collapse, metastases, pleural thickening or lymphangitis carcinomatosis, and 130 patients with breathlessness attributed to asthma, chronic obstructive pulmonary disease (COPD), interstitial lung disease or cardiac failure. Patients selected statements (descriptors) that described the quality of their breathlessness from a 15-item questionnaire and the relationship between the descriptors and the attributed cause of breathlessness was evaluated by cluster analysis. All patient groups were characterized by more than one cluster and several clusters were shared between groups. Specific sets of clusters were associated with breathlessness due to asthma, COPD and cardiac failure, and to cancer causing collapse, metastases or pleural thickening. The association of different sets of clusters with the different diagnostic groups suggests that patients are describing qualitatively different experiences of breathlessness, but the relationship does not appear to be sufficiently robust for the questionnaire to aid differential diagnosis. [ABSTRACT FROM AUTHOR]