Prevalence and correlates of echocardiographic determined left ventricular hypertrophy in 2318 asymptomatic middle-aged men: the ECCIS project. Epidemiolgia e Clinica della Cardiopatia Ischemica Silente

BACKGROUND: Serum levels of eosinophil cationic protein are an indirect measure of airway inflammation in asthma. It is proposed that the extent to which broncho-constriction or airway inflammation contributes to airflow obstruction in acute asthma may determine responsiveness to bronchodilator therapy. OBJECTIVE: To test the hypothesis that subjects with acute asthma exacerbations who respond poorly to inhaled bronchodilator treatment may have more marked airway inflammation than those who respond well to identical therapy. METHODS: Forty-eight asthmatic children who visited the emergency room due to acute exacerbations were studied. Serum levels of eosinophil cationic protein were measured at the time of acute exacerbations and of clinical remissions. At acute exacerbation, FEV1 was assessed before and after the administration of aerosolized salbutamol. RESULTS: The mean serum level of eosinophil cationic protein at acute exacerbation (41.1 +/- 12.8 micrograms/L) was significantly higher (P < .01) than that at clinical remission (30.0 +/- 8.5 micrograms/L) in the study population. The level at acute exacerbation was even higher in group A (n = 18: postbronchodilator FEV1 < 75% predicted) than in group B (n = 30: postbronchodilator FEV1 > or = 75% predicted), whereas both groups showed similar levels at clinical remission. The level at acute exacerbation correlated positively with severity of exacerbation (r = .47, P < .01) and negatively with bronchodilator responses (r = -.56, P < .01). This negative correlation was valid among subjects with a similar degree of exacerbation. CONCLUSION: A higher level of eosinophil cationic protein at acute asthma exacerbation was associated not only with more severe exacerbation but also with a lower degree of bronchodilator responsiveness. This suggests that degree of airway inflammation may be one determinant of degree of responsiveness to initial bronchodilator therapy at acute asthma exacerbation.     

The efficacy of inhaled corticosteroids in the management of non asthmatic chronic airflow obstruction

AIMS: The aims of this investigation were to evaluate the efficacy of regular inhaled beclomethasone in the control of symptoms and lung function with non-asthmatic smoking related obstructive pulmonary disease and to evaluate the relationship between clinical responses to a short course of oral prednisone and longer term outcomes using inhaled steroid. METHODS: The study was a randomised, double blind, placebo controlled, crossover investigation in 18 patients. The active treatment was inhaled beclomethasone 1000 micrograms given twice daily for three months by metered dose inhaler. At the end of each treatment period, patients received oral prednisone 30 mg/day for ten days. The two treatment phases were separated by a one month washout interval. Peak flow rates, symptom scores and "rescue" bronchodilator use were recorded twice daily. Lung function (FEV1, FVC and lung volumes) and bronchial hyperresponsiveness (PC20 methacholine) were measured at monthly visits. The number of exacerbations requiring intervention therapy were also recorded. RESULTS: There were no consistent benefits attributable to beclomethasone. Lung function was not significantly better as a result of active treatment. Sputum production improved but other symptom scores were similar during active and placebo therapy. Three patients exhibited an increase in FEV1 of 15% or more during active treatment but did not do so when oral prednisone was administered immediately after the period of placebo treatment. A further three patients showed an improvement in FEV1 of 15% or more with oral prednisone but failed to improve during treatment with inhaled beclomethasone. The predictive value of the "trial of steroid" was 0% and 81.3% for positive and negative outcomes respectively. CONCLUSIONS: Our results indicate that in non-asthmatic chronic obstructive pulmonary disease inhaled corticosteroid fails to achieve significant improvements in either lung function or symptoms. The response to a "trial of steroid" using oral prednisone is not clinically helpful in selecting the small number of patients who may subsequently benefit from this form of therapy.     

Anti-inflammatory effects of inhaled beclomethasone dipropionate in nonatopic asthmatics

The effects of inhaled beclomethasone dipropionate (BDP) on asthma symptoms and infiltration of the bronchial mucosa by inflammatory cells were investigated in an open study of 10 patients with mild-to-moderate nonatopic bronchial asthma. Asthma scores were recorded in an asthma diary. Peak expiratory flow (PEF), PEF diurnal variation (PEF%), forced expiratory volume in one second (FEV1%), methacholine airway hypersensitivity (minimum dose of methacholine) (Dmin) were measured. Biopsy of the bronchial mucosa was performed before and after 8 weeks of treatment with BDP (400 micrograms.day-1). The following inflammatory cells were immunostained: eosinophils with anti-EG2; mast cells with AA1; neutrophils with NP57; T-lymphocytes with anti-CD3, CD4, and CD8; and activated T-lymphocytes with anti-CD25. There was a significant improvement in the asthma symptom score, PEF%, FEV1%, and Dmin after BDP therapy and the number of EG2-, AA1-, CD3-, CD4-, and CD25-positive cells decreased significantly. We conclude that inhaled beclomethasone dipropionate inhibited inflammatory cell infiltration of airway tissue and that associated with this there was an improvement of symptoms in this open study of inhaled beclomethasone dipropionate in a group of nonatopic asthmatic subjects.     

Chemical and pharmacological studies of Phyllanthus caroliniensis in mice

We studied retrospectively the effect of long-term treatment with an inhaled corticosteroid on bronchial hyperresponsiveness (BHR) and clinical asthma in moderate-severe asthmatic subjects. Fifty-eight patients who had used beclomethasone dipropionate (BDP) over one year, were enrolled in this study. BHR was measured before and after treatment with BDP by the methods recommended by Japanese Society of Allergology. Moreover we examined the clinical factors and the frequency of acute exacerbations. The results as follows: 1) The mean age was 48.8 years and the mean asthma history was 9.2 years. The mean dose and mean time of BDP administration was 801 micrograms/day and 28.1 months, respectively. 2) Patients during BDP treatment over one year showed about 6-fold mean improvements in BHR, but there were many patients who showed no improvements in BHR. 3) We retrospectively divided all the patients into two groups. Namely, the improved group (n = 25) showed more than 4 fold improvement in BHR and unchanged group (n = 33), less than 4-fold. But there were no significant differences in clinical characteristics and %FEV1 during treatment with BDP. 4) The unchanged group had more near fatal episodes in the past than the improved group. 5) There was significant decrease in acute exacerbation during treatment with BDP, but the unchanged group had more acute exacerbations than the improved group during treatment with BDP. These results indicates that there are many patients who had no improvement on BHR with long term BDP treatment and they have more acute exacerbations due to various stimuli. In conclusion, asthma is recognized chronic inflammatory disease and inhaled corticosteroid therapy has been recommended as the first line therapy. We must further study the clinical problems and underlying mechanisms concerning about treatment with an inhaled corticosteroid.     

Effect of long-term treatment with salmeterol on asthma control: a double blind, randomised crossover study

OBJECTIVES: To determine the effect of adding salmeterol 50 micrograms twice daily for six months to current treatment in subjects with asthma who control their inhaled corticosteroid dose according to a management plan. DESIGN: A double blind, randomised crossover study. SETTING: Nottingham. SUBJECTS: 101 subjects with mild or moderate asthma taking at least 200 micrograms twice daily of beclomethasone dipropionate or budesonide. INTERVENTIONS: Salmeterol 50 micrograms twice daily and placebo for six months each, with a one month washout. Subjects adjusted inhaled steroid dose according to guidelines. MAIN OUTCOME MEASURE: Reduction in inhaled steroid use, exacerbations of asthma, and use of oral steroids. RESULTS: Data were available for 87 subjects. When compared with placebo salmeterol treatment was associated with a 17% reduction in inhaled steroid use (95% confidence interval 12% to 22%) with no significant difference in the number of subjects who had an exacerbation (placebo 25%, salmeterol 16%) or use of oral steroids. For secondary end points salmeterol treatment was associated with higher morning and evening peak expiratory flow and forced expiratory volume in one second; a reduction in symptoms, bronchodilator use and airway responsiveness to methacholine; and no effect on serum potassium concentration, 24 hour heart rate, or the final forced expiratory volume in one second achieved during a salbutamol dose-response study. CONCLUSIONS: In subjects who adjusted their inhaled steroid treatment according to guidelines the addition of salmeterol 50 micrograms twice daily was associated with a reduction in inhaled steroid use and improved lung function and symptom control.     

Effect of addition of inhaled salmeterol to the treatment of moderate-to-severe asthmatics uncontrolled on high-dose inhaled steroids. European Respiratory Study Group

The aim of this study was to assess the efficacy and safety of inhaled salmeterol 100 micrograms b.d. (SM) versus inhaled salbutamol 400 micrograms q.d.s. (SB), both via the Diskhaler, when added to concurrent treatment, in asthmatic patients who were not controlled on high doses of inhaled steroids (> or = 1,500 micrograms beclomethasone dipropionate (BDP) or equivalent daily). This was a multicentre, parallel group, double-blind study in which 190 patients with a forced expiratory volume in one second (FEV1) or peak expiratory flow rate (PEFR) of 30-75% predicted and 15% reversibility to inhaled bronchodilator were randomized to treatment for 6 weeks. In the SM group, morning PEFR increased from 281 to 315 L-min-1 during treatment and in the SB group from 311 to 315 L.min-1 (p < 0.001). The SM group showed significantly better reduction in diurnal variation, from 39 to 22 L.min-1 during treatment, than the SB group (34 to 37 L.min-1) (p < 0.001). There was a significantly greater improvement in FEV1 in the SM group (from 1.63 to 1.85 L) than in the SB group (from 1.79 to 1.84 L). The SM group had significantly more symptom-free nights than the SB group (p < 0.001), and also more "rescue-free" nights (p = 0.04). The adverse event profile was similar in both groups. This study indicates that in asthmatic patients, not controlled on high-dose inhaled steroids, inhaled salmeterol 100 micrograms b.d. significantly improves lung function and reduces asthma symptoms.     

Are anti-oxidant and anti-inflammatory treatments effective in different subgroups of COPD? A hypothesis

The treatment of chronic obstructive pulmonary disease (COPD) with inhaled corticosteroids or anti-oxidants is still under debate and the identification of sub-groups of COPD patients who may benefit from either anti-inflammatory or anti-oxidant treatment is needed. We re-analysed data from an earlier study of inhaled beclomethasone therapy in COPD (n = 28) and asthma (n = 28) patients in order to determine patient characteristics that predict a favourable inhaled steroid treatment effect. A higher bronchodilatory response, a faster decline of FEV1 prior to the treatment period and a lower Tiffeneau index were significantly related to more beneficial treatment effects. Increased smoking tended to be related to less steroid treatment benefits, though it was not statistically significant. In this paper these findings are presented in light of the available literature on anti-inflammatory and anti-oxidant COPD treatment. On this basis the hypothesis is presented that anti-oxidant treatment might be relatively more effective among those COPD patients who respond less well to inhaled steroids (low reversibility and heavy smoking).     

The effect of nedocromil sodium on the clinical course, ventilatory parameters and nonspecific bronchial hyperreactivity in patients with nonatopic bronchial asthma treated with beclomethasone dipropionate

The efficacy of nedocromil sodium (NED) (8mg twice daily) in controlling the clinical symptoms of asthma (score symptoms), the pulmonary parameters (FEV1, FVC) and bronchial hyperreactivity to histamine was assessed. The study was performed in double-blind, cross-over and placebo-controlled way in 16 patients suffering from nonatopic, stable, moderate asthma treated with beclomethasone dipropionate (from 400 micrograms to 800 micrograms). NED and placebo were administered in a randomized way with 8-week wash-out period. Bronchial reactivity to histamine, was measured as the amount of histamine causing a 20% fall in FEV1 (PC20H in mg/ml). Treatment with NED did not change asthma symptom scores, FVC and FEV1. Decreased usage of beta 2-agonist was observed. NED did not influence bronchial hyperreactivity to histamine (xg PC20H was respectively 0.09 and 0.11 mg/ml after placebo and 0.06 and 0.08 after NED). The authors conclude that studies with NED in nonatopic asthmatics should be continued, but the dosage of the drug ought to be bigger and the time of treatment ought to be longer.     

Salmeterol xinafoate as maintenance therapy compared with albuterol in patients with asthma

OBJECTIVE: To compare the efficacy and safety of inhaled salmeterol xinafoate, a long-acting beta 2-adrenoceptor agonist, with that of albuterol, a short-acting inhaled beta 2-agonist, in the treatment of asthma. DESIGN: Randomized, double-blind, placebo-controlled, parallel-group study. SETTING: Eleven outpatient clinical centers. SUBJECTS: A total of 322 male and female patients at least 12 years of age with chronic symptomatic asthma requiring daily therapy. INTERVENTION: Patients were treated with salmeterol xinafoate (42 micrograms inhaled twice daily), albuterol (180 micrograms inhaled four times daily), or placebo (four times a day) for 12 weeks; patients in all three groups could use inhaled albuterol as backup medication for breakthrough symptoms. MAIN OUTCOME MEASURES: Serial 12-hour forced expiratory flow in 1 second (FEV1), peak expiratory flow (PEF), asthma symptoms, nocturnal awakenings due to asthma, episodes of asthma exacerbations, and electrocardiography. RESULTS: The mean area under the curve for FEV1 throughout each 12-hour period was consistently greater after a single dose of salmeterol than after two doses of albuterol administered 6 hours apart (P < .001), with the difference ranging from 3.1 to 4.3 L.h. Salmeterol produced an average increase in morning and evening PEF of 26 and 29 L/min, respectively, over pretreatment values compared with decreases of -13 and -3 L/min, respectively, in the albuterol group and -2 L/min both in the morning and evening in the placebo group (P < .001). Patients in the salmeterol group had significantly fewer days and nights with symptoms than did either the albuterol or placebo group (P < .001). Responses to salmeterol were similar at day 1 and at week 12. Adverse events in all treatment groups were equally infrequent, and no clinically significant change in cardiac rhythm was observed with salmeterol treatment. CONCLUSION: Salmeterol inhaled twice daily is more effective than albuterol inhaled four times a day (or as needed) in patients with asthma requiring maintenance therapy. No deterioration of asthma control was observed with the use of salmeterol over a 3-month period.     

Efficacy and safety of salmeterol in childhood asthma

In children with asthma, twice daily administration of salmeterol 25 micrograms, salmeterol 50 micrograms and salbutamol 200 micrograms were compared in two, 3-month, double-blind, parallel group studies, one using metered dose inhalers (MDIs), the other using dry powder inhalers (Diskhaler, DPIs). Both studies were continued for a further 9 months during which time exacerbation rates, lung function at the clinic and adverse events were monitored. Similarities in design and methodology of the two studies justified a combined analysis. Eight hundred and forty-seven asthmatic children aged between 4 and 16 (mean 10.1) years, requiring inhaled beta 2-agonist treatment were randomised to treatment. After a 2 week run-in when all bronchodilator therapy was withdrawn, 279 patients received salmeterol 25 micrograms bd, 290 patients salmeterol 50 micrograms bd and 278 patients salbutamol 200 micrograms bd. After 3 months' treatment the change from baseline in daily morning and evening peak expiratory flow (PEF) was significantly greater with salmeterol 50 micrograms bd than with salbutamol 200 micrograms bd (P < 0.001). Salmeterol 50 micrograms bd was also significantly better than salmeterol 25 micrograms bd at improving mean morning PEF (P = 0.017) but both treatments had a similar effect on evening PEF. Analysis of variance showed an interaction between baseline PEF less than 100% predicted normal value and treatment outcome. Analysis of this sub-set of patients with lower lung function revealed similar results to the total population although the improvements in PEF from baseline were greater. Data from both studies, showed that the improvement in lung function was maintained throughout 12 months' treatment. Patients receiving salmeterol 50 micrograms bd had significantly more symptom-free nights (P < 0.01) and a higher percentage of rescue bronchodilator-free days (P = 0.01). The incidence of asthma exacerbations was evenly distributed between the three treatment groups and there was no evidence of any change in the rate of occurrence of exacerbations over the 12 month period. Adverse events were no different across treatment groups or across age groups and were primarily related to the patients' disease state. CONCLUSION: Salmeterol 50 micrograms bd is the appropriate dose for the treatment of children with mild to moderate asthma.     

Treatment of nocturnal asthma with nedocromil sodium

BACKGROUND: The association of nocturnal asthma symptoms with a diurnal increase in inflammatory activity suggests a role for anti-inflammatory therapy in nocturnal asthma. METHODS: Fifty patients with asthma with nocturnal symptoms entered a randomised, double blind, placebo controlled, crossover study. After a two week baseline period patients received nedocromil sodium (4 mg) or placebo four times daily. After eight weeks of treatment patients crossed to the alternative treatment for a further eight weeks. Symptom severity was recorded on a scale of 0-4 and inhaled bronchodilator use and peak flow (PEFR) were also recorded daily by the patients. Asthma severity, pulmonary function (FEV1, PEFR, FVC), and adverse events were recorded at clinic visits (baseline and after four and eight weeks of treatment). Global effectiveness was rated by clinician and patient, and treatment preference was recorded. RESULTS: Efficacy was assessed from data from 28 patients. Night-time asthma (mean (SE) difference between nedocromil sodium and placebo: -0.52 (0.13)), total nocturnal symptom severity defined as night-time asthma plus morning tightness (-0.72 (0.20)), and night-time bronchodilator use (-0.62 (0.23)) were reduced with nedocromil sodium compared with placebo treatment during the primary efficacy period (weeks 5-8) and during weeks 1-4 (-0.36 (0.12), -0.63 (0.20), and -0.55 (0.28), respectively). Morning and evening PEFR values improved slightly--but not significantly--compared with placebo. Patient and clinician opinions favoured nedocromil sodium treatment. Daytime asthma, daytime cough, and clinic assessment of asthma severity (secondary efficacy variables) were improved with nedocromil sodium treatment; day-time bronchodilator use and clinic pulmonary function were not. CONCLUSIONS: Nedocromil sodium was more effective than placebo in reducing nocturnal symptoms of asthma and bronchodilator use in this group of patients.     

Comparison of fluticasone propionate and beclomethasone dipropionate on direct and indirect measurements of bronchial hyperresponsiveness in patients with stable asthma

BACKGROUND: Fluticasone propionate is a new inhaled corticosteroid with a 2:1 efficacy ratio compared with beclomethasone dipropionate with regard to lung function and symptom scores, without increased systemic activity. The aim of this study was to investigate whether this was also the case for bronchial hyperresponsiveness, assessed by both a direct (histamine) and an indirect (ultrasonically nebulised distilled water (UNDW)) provocation test. METHODS: Fluticasone propionate, 750 micrograms/day, and beclomethasone dipropionate, 1500 micrograms/day, were compared in a randomised, double blind, crossover study consisting of two six week treatment periods, each preceded by a three week single blind placebo period. Twenty one non-smoking asthmatics (mean forced expiratory volume in one second (FEV1) 74.7% predicted, mean PC20histamine 0.36 mg/ml) completed the study. RESULTS: Fluticasone propionate and beclomethasone dipropionate improved FEV1, peak flow rates, asthma symptoms, and bronchial hyperresponsiveness to the same extent. Both fluticasone propionate and beclomethasone dipropionate caused an increase in PC20histamine (mean 2.29 [95% confidence interval 1.45 to 3.13] and 1.95 [1.07 to 2.84] doubling doses, respectively) and in PD20UNDW (1.12 [0.55 to 1.70] and 1.28 [0.88 to 1.70] doubling doses, respectively). Neither treatment changed morning serum cortisol levels, but fluticasone propionate decreased the number of peripheral blood eosinophils less than beclomethasone dipropionate, indicating smaller systemic effects of fluticasone propionate. CONCLUSIONS: These findings show that fluticasone propionate is as effective as twice the dose of beclomethasone dipropionate on bronchial hyperresponsiveness, assessed by provocation with both histamine and UNDW, without increased systemic activity.     

Total blood eosinophils, serum eosinophil cationic protein and eosinophil protein X in childhood asthma: relation to disease status and therapy

Blood eosinophils, and serum levels of the eosinophil proteins, eosinophil cationic protein (ECP) and eosinophil protein X (EPX) were measured in childhood asthma. Seventeen patients mean age 11.9 years who were symptomatic with asthma, were enrolled in a study examining the eosinophil counts and eosinophil proteins at the onset of study and after treatment in relation to changes in their baseline forced expiratory volume at 1 second (FEV1) and % predicted FEV1. The patients with symptomatic asthma were compared with 17 patients mean age 12.0 years with asymptomatic asthma maintained on daily inhaled steroid and 13 patients, mean age 12.0 years, without asthma but with urticaria who served as non-asthma controls. Patients with symptomatic asthma did not have significantly higher initial eosinophil counts compared with those with asymptomatic asthma (0.43 x 10(9)/l vs 0.26 x 10(9)/l, P = 0.09) but had higher serum ECP levels (28.9 micrograms/l vs 18.5 micrograms/l). Both asthma patient groups had significantly higher serum ECP levels (P < 0.01) than the controls (9.8 micrograms/l). After therapy consisting of increased dose of inhaled steroids and/or oral steroids, patients in the symptomatic asthma group demonstrated a significant rise in FEV1 (1.67 l/sec at Visit 1 vs 2.08 l/sec at Visit 2, P < 0.001). A similar rise was seen for % predicted FEV1.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of addition of theophylline to inhaled steroid with doubling of the dose of inhaled steroid in asthma

The anti-asthmatic effect of theophylline may supplement those of inhaled steroids in asthma. The aim of the present trial was to study how the addition of theophylline compares to doubling the dose of inhaled steroid in asthmatics who remain symptomatic on beclomethasone dipropionate (BDP) 400 micrograms/day. The trial was designed as a randomized, double-blind, parallel-group study in several European countries. 69 patients were treated for 6 weeks with theophylline plus BDP 400 micrograms/day, compared to 64 patients treated with BDP 800 micrograms/day. The mean +/- SD serum theophylline concentration was 10.1 +/- 4.2 mg/l. Lung function measurements were made throughout the study and patients kept daily records of peak expiratory flow rate (PEF), symptoms and salbutamol usage. Forced expiratory volume in one second and PEF at week 6 were significantly increased by both treatments (p < 0.01). PEF variability was reduced by about 30% in both groups. There were significant improvements in asthma symptoms and rescue medication use (p < 0.001). There were no significant differences between the treatment groups. The study demonstrated clinical equivalence of theophylline plus beclomethasone dipropionate 400 micrograms/day and beclomethasone dipropionate 800 micrograms/day in patients whose asthma is not controlled on beclomethasone dipropionate 400 micrograms/d. The results support the use of theophylline as steroid-sparing agent. The combination of low-dose inhaled steroid plus theophylline is a suitable treatment for moderate 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.     

Inhaled steroids modify bronchial responses to hyperosmolar saline

We investigated the effects of inhaled beclomethasone dipropionate (BDP) on airway sensitivity (provocative dose producing a 20% fall in forced expiratory volume in one second (FEV1) from baseline (PD20)) and reactivity (slope of the dose-response curve) to inhaled aerosols of hyperosmolar (4.5%) saline, and histamine or methacholine. This was an open study on 13 patients referred to the laboratory by their respiratory physician for investigation of their asthma. These challenges were performed on separate days before (initial visit) and 8.8 +/- 0.8 (SD) weeks (range 5.6-12.4 weeks) after (visit 1) a treatment period with BDP (dose range 600-1,500 micrograms.day-1). At visit 1 there was a significant reduction in sensitivity to 4.5% NaCl and histamine/methacholine and in reactivity. The PD20 increased 5.6 fold for 4.5% NaCl and 4.1 fold for histamine/methacholine. All patients remained responsive to histamine/methacholine and a fall in FEV1 > 20% to 4.5% saline was documented in 10 of the 13 patients. We conclude that treatment with BDP reduces sensitivity and reactivity to both osmotic and pharmacological challenge.     

Methotrexate in the management of severe steroid dependent asthma

AIMS: This study was designed to assess the efficacy of low dose methotrexate, 15 mg weekly, as a steroid-sparing agent in asthmatic patients requiring long-term oral prednisone treatment. METHODS: The study was a randomised, double blind, placebo controlled, cross over study of 48 weeks duration. Eleven patients with severe steroid-dependent asthma were included. A successful outcome was defined as a reduction in mean prednisone requirements of 7 mg daily compared to baseline requirements, during active treatment. RESULTS: Two patients were required to be withdrawn owing to methotrexate-related adverse effects. The mean prednisone dose for patients who completed the study was 14.4 mg per day (95% CI; 13.6, 15.1) during active treatment, and 12.9 mg per day (95% CI: 12.2, 13.6) during placebo treatment (NS). Only one patient reduced his individual dose requirements by more than 7 mg per day, whereas in three patients prednisone requirements actually increased during active treatment. There were no significant differences in symptom scores, pulmonary function data, and exacerbations between active and placebo treatments. CONCLUSION: No significant steroid-sparing effect was obtained using low dose methotrexate in this study. This negative outcome may be attributable to the small population of patients studied, low baseline FEV1, and the omission of a steroid minimisation run-in period. Our results highlight the importance of careful patient selection and a painstaking approach in the management of patients with steroid-dependent asthma.     

Is normal bronchial responsiveness in asthmatics a reliable index for withdrawing inhaled corticosteroid treatment?

STUDY OBJECTIVE: Inhaled corticosteroid (ICS) treatment is first-line maintenance therapy in bronchial asthma. However, it is not clear whether and when ICS treatment can be withdrawn. The aim of this open study was to assess whether normalization of bronchial responsiveness could be used as a reliable index to assess the opportunity of ICS treatment withdrawal. DESIGN: Open study at two different points in time. SETTING: Outpatient pulmonary clinic. PATIENTS: Eighteen asthmatic subjects. MEASUREMENTS AND RESULTS: ICS therapy was withdrawn in subjects treated with beclomethasone dipropionate, at the maintenance dose of 889+/-246 microg/d for >3 months. Upon recruitment, all subjects were asymptomatic, had FEV1 >70% of predicted value, and were in treatment with beta2-agonists on an as-needed basis. Eight subjects (group 1) had normal bronchial responsiveness (methacholine provocative dose causing a 20% fall in FEV1 [PD20] >2,000 microg) and 10 subjects (group 2) had bronchial hyperresponsiveness (BHR) (PD20 < or = 2,000 microg). After withdrawal of ICS treatment, subjects were followed up for 3 weeks and were asked to record their asthma symptoms (cough, dyspnea, and wheezing) and their beta2-agonist use. At recruitment and at the end of follow-up, subjects underwent spirometry and a methacholine challenge test. Frequency of asthma exacerbation was similar in subjects with normal bronchial responsiveness (NBR) and in subjects with BHR (50% vs 60%), but subjects with NBR tended to remain asymptomatic for longer than those with BHR (mean+/-SD, 10.7+/-4.4 days vs 5.5+/-3.8 days) (p=0.08). None of the subjects reported any condition that could have triggered exacerbation. Asthma exacerbation was associated with a significant decrease in FEV1 (-105+/-107 mL; p<0.05) and in PD20 (-1,332+/-1,020 microg; p<0.001). CONCLUSIONS: Our study shows that the likelihood of asthma exacerbation is not reduced if ICS treatment is withdrawn when the subjects have NBR, but the exacerbation could be delayed. Further studies in larger populations of asthmatics are needed to confirm these findings.     

Inhalation by nebulization of albuterol-ipratropium combination (Dey combination) is superior to either agent alone in the treatment of chronic obstructive pulmonary disease. Dey Combination Solution Study Group

Combination bronchodilator therapy for chronic obstructive pulmonary disease (COPD) potentially can provide increased benefit over single-agent therapy. The objective of this double-blind, randomized, positive-control trial was to determine the effectiveness of an albuterol-ipratropium solution aerosol combination (Dey combination solution, Dey LP, Napa, Calif., USA) compared with solution aerosols of both component medications administered alone in patients with COPD. The trial consisted of a 6-week, 3-period crossover phase followed by a 6-week parallel phase during which patients self-administered study medications by inhalation from a nebulizer. A total of 863 patients were initially randomized to each of the six possible treatment sequences of the three study medications in the crossover phase and received each study medication in turn for a 2-week period. Patients continued to receive the same treatment administered during the last 2-week period of the crossover phase for an additional 6 weeks in the parallel phase. Assessment of 1-second forced expiratory volume (FEV1) curves before and after dosing on the last day of each 2-week period indicated that the combination was superior to either single agent in peak effect and area under the curve up to 8 h after dosing (FEV1-AUC0-8), in both phases of the trial. The use of Dey combination during the crossover phase resulted in 24% more improvement in peak FEV1 than was seen with albuterol alone (p < 0.001), and 37% more than was seen with ipratropium alone (p < 0.001). Similarly, when examining FEV1-AUC0-8, Dey combination resulted in 30% more improvement than was seen with albuterol alone (p < 0.001), and 32% more than was seen with ipratropium alone (p < 0.001). The combination affords a convenient dosing regimen and incorporates enhanced benefit without compromising the safety profile of either component agent.