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.     

Comparison of inhaled corticosteroids

OBJECTIVE: To review the comparative studies evaluating both efficacy and safety of inhaled corticosteroids in the management of asthma. Specifically, comparative clinical trials are evaluated that allow clinicians to determine relative potencies of the various inhaled corticosteroids. METHODS: A critical review was performed of the published clinical trials, either as articles or abstracts, comparing the clinical efficacy or systemic activity of inhaled corticosteroids. No a priori criteria were applied, as this was not a meta-analysis. FINDINGS: In vitro measures of antiinflammatory activity of corticosteroids consistently demonstrate potency differences among the various corticosteroids. Traditionally, these in vitro measures have been used to develop new corticosteroids with greater topical activity. While no accepted direct measure of antiasthmatic antiinflammatory activity exists, clinical trials using surrogate measures (e.g., forced expiratory volume in 1 second, peak expiratory flow, bronchial hyperresponsiveness, symptom control) indicate that in vitro measures provide a relatively accurate assessment of antiasthmatic potency. The relative antiinflammatory potency of the inhaled corticosteroids is in the following rank order. flunisolide = triamcinolone acetonide < beclomethasone dipropionate = budesonide < fluticasone. Studies of systemic activity appear to confirm this relative order of potency. Currently, no evidence exists for greater efficacy for any of the inhaled corticosteroids when administered in their relative equipotent dosages. The preponderance of current data suggests that when administered in equipotent antiinflammatory doses as a metered-dose inhaler plus spacer or as their respective dry-powder inhaler, the existing inhaled corticosteroids have similar risks of producing systemic effects. CONCLUSIONS: Delivery systems can significantly affect both topical and systemic activity of inhaled corticosteroids. More direct comparative studies between agents are required to firmly establish comparative topical to systemic activity ratios. The preponderance of evidence suggests that the agents are not equipotent on a microgram basis.     

Tolerance to the protective effects of salmeterol on methacholine-induced bronchoconstriction: influence of inhaled corticosteroids

Long-acting beta2-adrenoceptor agonists such as salmeterol reduce airway responsiveness for at least 12 h, but this effect seems to decrease with regular use. We evaluated the time-course of the protective effects of salmeterol on methacholine-induced bronchoconstriction, its modulation by inhaled corticosteroids (ICS) and its influence on asthma control. Thirty two subjects (13 males and 19 females) with mild to moderate stable asthma were divided into two groups according to their medication needs: bronchodilators (BD) alone (n=16) or with ICS (n=16). After a 2 week run-in period, a double-blind crossover study was conducted. Subjects from both groups received salmeterol 50 microg b.i.d. or a placebo for 4 weeks each in random order, separated by a 2 week washout period. The provocative concentration of methacholine causing a 20% fall in forced expiratory volume in one second (PC20) was measured before and after each treatment period, 1 h prior to inhalation of salmeterol or placebo and 1 and 12 h after. Baseline forced expiratory volume in one second (FEV1) increased significantly after salmeterol, both after the first dose and at 4 weeks (BD group: 19 and 17%; ICS: 22 and 13%). On the first day of administration, salmeterol provided significant protection in both groups up to 12 h with a PC20 before and 1 and 12 h postdose of 2.2, 21.7 and 12.4, mg x mL(-1), respectively, in the BD group and 2.1, 11.6 and 55 mg x mL(-1), respectively, in the ICS group. After 4 weeks, this effect was significantly attenuated in both groups with a PC20 before, 1 and 12 h postdose of 3.3, 10.9 and 7.1 mg x mL(-1), respectively, in the BD group and 2.1, 5.0 and 2.3 mg x mL(-1), respectively, in the ICS group. This loss of protective effect was of similar magnitude in both groups. Respiratory symptoms, rescue beta2-agonist use and baseline FEV1 did not change significantly throughout the study in both groups. In conclusion, the bronchoprotective effect of salmeterol decreased with regular use both 1 and 12 h postdose; inhaled corticosteroids did not prevent this reduction. However, the development of tolerance was not associated with loss of asthma control.     

The role of "fear of corticosteroids" in nonparticipation in early intervention with inhaled corticosteroids in asthma and COPD in general practice

Treatment of chronic airflow obstruction with inhaled corticosteroids at an early stage has been shown to preserve the lung function. We tested the hypothesis that "fear of corticosteroids" may be an important reason for nonparticipation in the Detection, early Intervention and Monitoring programme on Chronic obstruction pulmonary disease (COPD) and Asthma ("DIMCA") project. One thousand seven hundred and forty nine adult subjects from 10 general practices were invited to participate in the several parts of the "DIMCA" programme. Refusers were questioned about the reason(s) for nonparticipation. Together the screening, monitoring and three drug interventions of the study showed on average 25-35% refusers. The most frequent reasons for nonparticipation were absence of pulmonary symptoms and lack of time. For those invited to take part in one of the three drug interventions, "dislike of medication" was the most important reason for nonparticipation (33, 45 and 67% of the refusers). "Fear of corticosteroids" specifically was the reason for nonparticipation in 8% of the refusers on the basis of "dislike of medication". We concluded that a specific fear of corticosteroids was not a major obstacle for early intervention with inhaled corticosteroids.     

Studies of the effects of inhaled magnesium on airway reactivity to histamine and adenosine monophosphate in asthmatic subjects

HLA class II DRB1-DQA1-DQB1 haplotypic polymorphism was determined in 120 Liberian and 230 Gabonese individuals. In our study groups, the number of allelic variants observed for each locus was similar to that found in non-African populations. However, 39 novel haplotypes and several yet unrecognized DRB1-DQA1 and DQA1-DQB1 combinations were identified. The extent of HLA-haplotypic variability in Africans appears to result from the high degree of allele combinations rather than from allelic polymorphism.     

Effect of short- and long-acting inhaled beta2-agonists on exhaled nitric oxide in asthmatic patients

Increased concentrations of exhaled nitric oxide (NO) occur in patients with asthma, and exhaled NO may be useful for assessing the effect of drug therapy on airway inflammation. Beta2-agonists have been proposed to have both proinflammatory and anti-inflammatory effects. We therefore assessed exhaled NO after beta2-agonists in asthmatic patients. Two randomized, double-blind, placebo-controlled studies were conducted. Firstly, exhaled NO was measured in 18 asthmatics (9 taking inhaled glucocorticosteroids (GCS)) before and after nebulized salbutamol (5 mg), or identical placebo (0.9% saline). Exhaled NO and forced expiratory volume in one second (FEV1) were measured at 15 min intervals for 1 h (Study 1). Secondly, the effect of 1 week of treatment with the long-acting beta2-agonist, salmeterol (50 microg b.i.d.), added to either budesonide (800 microg b.i.d.) or placebo, was studied in eight mild asthmatic subjects (Study 2). Exhaled NO was measured by a chemiluminescence analyser, adapted for on-line recording. In Study 1, exhaled NO showed no significant change at any time-point in patients not taking inhaled GCS. In asthmatics on inhaled GCS, exhaled NO increased compared to placebo at 15 and 30 min, but this did not reach statistical significance. In Study 2, treatment with salmeterol increased FEV1, but exhaled NO levels were not significantly changed, either after budesonide treatment (143+/-35 to 179+/-67 ppb), or after placebo (201+/-68 to 211+/-65 ppb). Our results confirm that single high dose salbutamol does not increase exhaled nitric oxide in asthmatics not taking inhaled glucocorticosteroids. Salbutamol may increase exhaled nitric oxide in asthmatics taking inhaled glucocorticosteroids. However, regular use of salmeterol resulted in no change in exhaled nitric oxide, either used alone or in combination with inhaled glucocorticosteroids.     

Influence of inhaled corticosteroids and dietary intake on bone density and metabolism in patients with moderate to severe asthma

OBJECTIVES: Compare the effect of high doses of inhaled corticosteroids on bone loss in subjects with moderate to severe asthma or mild asthma, and examine the influence of dietary intake on bone metabolism. DESIGN: A survey on the effects of corticotherapy and nutrition on bone density was conducted in 74 subjects currently being treated for asthma in the asthma clinic of H?pital Laval (Sainte-Foy, Quebec, Canada). Fifty-eight subjects completed the study (attrition rate = 15%). MAIN OUTCOME MEASURES: In all subjects expiratory volumes were determined and urinary analysis was conducted for hydroxyproline, calcium, phosphorus, and cortisol levels. Osteocalcin, calcium, phosphorus, cortisol, alkaline phosphatase, and gamma-glutamyltransferase levels were measured in blood samples. Bone density of the lumbar spine was determined by means of dual-energy x-ray absorptiometry. Nutrition evaluation was based on a 3-day food diary analyzed using progiciel Nutri 91. The nutritional parameters examined were calcium; phosphorus; magnesium; zinc; vitamins A, C, and D; protein; total fiber; oxalates; energy; caffeine; and alcohol in relation to bone density. SUBJECTS: Thirty-one patients with moderate to severe asthma who had been taking more than 1,000 micrograms beclomethasone per day or the equivalent for more than 2 years and 27 patients with mild asthma who were taking less than 500 micrograms beclomethasone per day or the equivalent. STATISTICAL ANALYSES PERFORMED: Four-factor analysis of variance with hierarchized interactions of four levels, Duncan's test, Pearson correlation coefficients. RESULTS: Blood levels of osteocalcin and protein intake were lower in patients with moderate to severe asthma than in those with mild asthma (P < .05). Significant correlations (P < .02) were observed between bone density and calcium intake (r = .40), phosphorus intake (r = .35), protein intake (r = .30), and serum alkaline phosphatase level (r = -.30). Bone density was not significantly different between the two groups of patients with asthma. APPLICATIONS: A follow-up of patients with asthma who are taking inhaled corticosteroids is needed to assess bone density, osteocalcin levels, and dietary intakes of calcium. Verify if osteocalcin level decreases over time in patients with moderate to severe asthma, monitor possible modifications in bone density, and verify if the correlation between dietary calcium and bone density is maintained.     

Effect of inhaled PGE2 on exercise-induced bronchoconstriction in asthmatic subjects

Previous studies have suggested that the endogenous release of inhibitory prostanoids limits the bronchoconstrictor response to repeated exercise. The aim of our study was to determine whether inhaled prostaglandin (PG)E2 attenuates exercise-induced bronchoconstriction or methacholine airway responsiveness in asthmatic subjects. Eight subjects with mild stable asthma and exercise bronchoconstriction were studied on 4 separate days, 48 h apart. Subjects inhaled PGE2 or placebo in a randomized, crossover, double-blind fashion, 30 min prior to an exercise challenge or a methacholine challenge. PGE2 inhalation significantly attenuated exercise bronchoconstriction. The mean maximal %fall in FEV1 after exercise was 26% (SEM 3.7%) after placebo, and was 9.7% (SEM 2.7%) after PGE2 (p < 0.001). PGE2 also significantly reduced the duration of exercise bronchoconstriction (p = 0.034). However, PGE2 did not significantly attenuate methacholine airway responsiveness. The geometric mean methacholine provocative concentration causing a 20% fall in FEV1 (PC20) was 0.77 (%SEM 1.48) after placebo day, and 1.41 (%SEM 2.20) after PGE2 (p = 0.30). These results demonstrate that inhaled PGE2 markedly attenuates exercise bronchoconstriction in asthmatic subjects and suggest that this effect is not occurring through functional antagonism of airway smooth muscle.     

The response of asthmatic subjects to isoproterenol inhaled at differing lung volumes

Asthmatics are usually instructed to use pressurized bronchodilator aerosols by delivering a bolus of drug at the beginning of a full inspiration. Because airways are better dilated near total lung capacity, the delivery of the drug near the end of a full breath might allow better penetration of particles into the lung and greater bronchodilatation. To test this hypothesis, 13 asthmatic subjects inhaled 400 mug of isoproterenol at 20 per cent (low) and at 80 per cent (high) vital capacity. The studies were done on 2 separate days when the severity of asthma was the same. Forced vital capacity, 1-sec forced expiratory volume, specific airway conductance and maximal flow at 50 per cent of viral capacity were measured at frequent intervals after drug administration. Ten min after drug delivery, there was a significantly greater (P less than 0.05) improvement in 1-sec forced expiratory volume after the drug was inhaled at the high lung volume compared to the response after delivery at the low lung volume. The differences in forced vital capacity, specific conductance, and maximal flow at 50 per cent of vital capacity were not significant. We concluded that inhaling a bronchodilator drug at the end of a full inspiration causes relatively greater bronchodilatation than inhaling the same dose at the beginning of inspiration.     

Serum concentrations and side effects in psychiatric patients during risperidone therapy

PURPOSE: Evaluation of fluoroscopic stent placement as an emergency therapeutical approach for treatment of acute large bowel obstruction due to colorectal neoplasm. METHODS AND MATERIAL: From January to December 1996 in 11 patients suffering from colorectal stenosis due to known or supposed malignancy the indication for the fluoroscopic placement of self-expanding metal stents was established. All patients showed clinical and radiological signs of an acute mechanical large bowel obstruction. Elective single-stage surgery was planned if the decompression had been carried out successfully. RESULTS: Stent placement was successful in 8 cases. Functional success in respect of resolving the acute large bowel obstruction was seen in 7 out of 11 patients. Elective surgery was possible in all 7 cases creating a primary end-to-end anastomosis without major complications during the perioperative period. CONCLUSION: Fluoroscopic placement of self-expanding metal stents in malignant colorectal stenosis is a promising method to avoid emergency surgery.     

One year follow-up study of endocrine and lung function of asthmatic children on inhaled budesonide

Inhaled corticosteroids have become a mainstay in the management of chronic asthma. Their use had been considered safe, although some degree of adrenal suppression has been demonstrated after 2 and 4 weeks of treatment with either 400 microg x day(-1) of beclomethasone dipropionate or budesonide. To weigh the benefits and risks of long-term treatment, 12 children with moderately severe asthma were assessed in a follow-up study on budesonide 200 microg b.i.d. After 1 yr, the nocturnal cortisol production was significantly reduced by 19%, but no greater compared to 2 and 4 weeks of treatment. Growth and growth hormone levels were normal. Lung function tests were significantly better, not only versus baseline values but also versus 2 and 4 weeks of treatment. We conclude that systemic effects of inhaled corticosteroids in conventionally low doses do not accumulate with length of treatment, whilst lung function parameters will continue to improve. Therefore, inhaled corticosteroids once started in asthmatic children not controlled on other medications should be continued, but their use should be carefully considered and the minimal dose required to control the asthma employed.     

Potentiating effect of inhaled acetaldehyde on bronchial responsiveness to methacholine in asthmatic subjects

BACKGROUND: It has recently been reported that acetaldehyde induces bronchoconstriction indirectly via histamine release. However, no study has been performed to assess whether acetaldehyde worsens bronchial responsiveness in asthmatic subjects so this hypothesis was tested. METHODS: Methacholine provocation was performed on three occasions: (1) after pretreatment with oral placebo and inhaled saline (P-S day), (2) after placebo and inhaled acetaldehyde (P-A day), and (3) after a potent histamine H1 receptor antagonist terfenadine and acetaldehyde (T-A day) in a double blind, randomised, crossover fashion. Nine asthmatic subjects inhaled 0.8 mg/ml acetaldehyde or saline for four minutes. After each inhalation a methacholine provocation test was performed. RESULTS: Methacholine concentrations producing a 20% fall in FEV1 (PC20-MCh) on the P-A day (0.48 mg/ml, 95% CI 0.21 to 1.08) and T-A day (0.41 mg/ml, 95% CI 0.22 to 0.77) were lower than those on the P-S day (0.85 mg/ml, 95% CI 0.47 to 1.54). There was no change in the PC20-MCh between the P-A and T-A days. A correlation was observed between the logarithmic values of PC20-MCh (log PC20-MCh) on the P-S day and the potentiating effect of acetaldehyde on the methacholine responsiveness [(log PC20-MCh on P-A day)-(log PC20-MCh on P-S day)] (rho = 0.82). CONCLUSIONS: Acetaldehyde induces bronchial hyperresponsiveness in patients with asthma by mechanisms other than histamine release.     

Gastrointestinal side effects associated with clinidamycin. 1,000 consecutive patients

The incidience and parameters associated with diarrhea related to clindamycin usage were studied in a population of both inpatients and outpatients. Diarrhea occurred in 66 (6.6%) of the 1,000 patients. In three of them, substantial morbidity was associated with the diarrhea. Of the multiple parameters that were evaluated, significant association with diarrhea was found only for age (patients over the age of 20 years) (P less than .01) and sex (females) (P less than .005). Interestingly, dose, duration, and route of administration showed no significant relationship to diarrhea (P greater than .05).