Long-term comparison of three combinations of albuterol, theophylline, and beclomethasone in children with chronic asthma.

Three combination regimens, (1) inhaled albuterol (ALB) with oral theophylline (THEO), (2) inhaled ALB with inhaled beclomethasone dipropionate (BDP), or (3) inhaled ALB, inhaled BDP, and oral THEO, were evaluated and compared as optimal pharmacotherapy for chronic asthma in 111 children. In this double-blind, parallel-group, multicenter study, children, aged 6 to 16 years with moderately severe asthma (unstable despite daily medications), were treated with one of the combinations for 12 weeks. Patients were evaluated every 4 weeks by spirometry and serum THEO measurement. Patients kept daily symptom diaries, measured peak flow rates twice daily, and recorded adverse events. Treatment groups did not differ in disease or demographic characteristics at study entry. All three combination treatments provided and maintained significant improvement in FVC, FEV1, and FEF25%-75% volume points, and compared with that of pretreatment, with no significant differences between treatments. Throughout the 12-week treatment period, however, patients receiving BDP had lower symptom scores, fewer had more than one asthma attack, fewer required "bursts" of prednisone (p = 0.001), and fewer required rescue medication (p = 0.009). Significantly more patients receiving BDP said that they felt better than they did at the beginning of the study compared with the number of patients not receiving BDP (p = 0.002). Adverse events were similar among treatment groups.     

Cyclosporin for steroid-dependent asthma

We used cyclosporin to treat 12 adult patients with severe bronchial asthma who had been on systemic steroids for an average of 16 years. During the baseline period, lasting 4-6 months, therapy with high doses of inhaled beclamethasone, aminophylline and salbutamol was standardized and a minimum necessary dose of systemic steroids was established. After 9 months' treatment with low-dose cyclosporin (average whole-blood trough levels of 105 ng/ml), in six patients the daily dose of oral prednisone could be reduced from mean 30 mg to mean 11 mg, while daily symptom scores and peak expiratory flows improved significantly. This was accompanied by a reduction in exacerbations of asthma. However, in six other patients attempts to taper the steroid doses were unsuccessful, and cyclosporin was stopped after 4 to 7 months. These preliminary results suggest that cyclosporin might be of benefit in some patients with steroid-dependent asthma.     

Serum rheumatoid factor and peripheral blood eosinophil counts in patients with bronchial asthma]

These days some reports say that bronchial asthma, especially severe asthma, is systemic inflammatory and its severity correlates with eosinophil counts. Some patients with asthma have positive tests for rheumatoid factor (RF) which is detected in systemic hyper immunoreactive desease such as rheumatoid arthritis. So we investigated each of these factors in asthmatic patients. We randomly selected 100 asthmatics from regular outpatients of our hospital. In a positive RF level group (over 21 IU/ml), Eosinophil counts were significantly higher than those in a negative RF level group. RF levels were significantly and positively correlated with the logarithm of eosinophil count. And in severe groups (patients with severe asthma, treated with high dose inhaled steroids, and with history of systemic steroids use for the last one month), RF levels were significantly higher than those in other groups. Our result suggested that RF levels reflect eosinophilia and asthma severity.     

A clinical trial of combined cromolyn/beclomethasone treatment for chronic asthma

Some patients with chronic asthma treated with beclomethasone aerosol (BA) derive significant symptom benefit, yet have persisting adrenal suppression due in part to their BA therapy. The daily dose of BA required is higher in patients with atopy. We therefore assessed the usefulness of ancillary treatment with cromolyn sodium (CS), a drug known to inhibit atopic asthma, to try to improve the balance of risk vs benefit in such patients. Thirty asthmatics, well controlled on high-dose BA (mean, 1,040 micrograms +/- 97 SE) but with morning cortisol levels averaging approximately 10 micrograms/dl, were allocated randomly to placebo or CS inhalant, used in addition to their regular BA and other asthma medications. After 4 wk, their BA dose was halved. Both groups were monitored for greater than 6 mo by daily symptom diaries and peak flows, and by spirograms and morning serum cortisol tests every 4 wk. Mean cortisol levels rose 27% after BA dose reduction (p less than 0.05) but asthma worsened. Risk-benefit assessments 20 wk after reducing the BA showed a general tendency for higher cortisol values to be coupled with worsening of the asthma symptoms and FEF25%-75%. The distributions of good, fair, and poor risk-benefit responses were the same in both CS and placebo-treated groups (p = 0.20). In other asthmatics who may have less associated bronchitis or small airways obstruction than these patients, CS might prove useful, but in these adult chronic asthmatics with this particular therapeutic problem, there was no discernible BA-sparing effect or other clinical advantage from adding CS to their established BA regimen.     

Steroid-sparing effect of subcutaneous SQ-standardised specific immunotherapy in moderate and severe house dust mite allergic asthmatics

BACKGROUND: The present study evaluated the steroid-sparing effect of subcutaneous SQ-standardized specific immunotherapy (SIT) in moderate and severe house dust mite (HDM) allergic asthmatics. METHODS: Fifty-four adult asthmatics allergic to HDM requiring at least inhaled corticosteroids (ICS) doses equivalent to 500 microg fluticasone propionate daily were randomized to subcutaneous SIT or placebo injections for a period of 3 years. The minimum required ICS dose, 4 week diary of asthma symptom score, use of rescue medication, peak expiratory flow (PEF) measurements and visual analog scale for asthma symptoms were assessed before start of treatment and after 1, 2 and 3 years of treatment. RESULTS: In patients with moderate and severe asthma, the reduction in ICS was statistical significant after 2 years of treatment (P = 0.03) but not after 3 years. The median reductions were 82% and 42% after the third year for active and placebo respectively. In patients with moderate persistent asthma the reduction was statistical significant larger for those treated with SIT compared with placebo after year 2 and year 3. The median reductions after 3 years were 90% for SIT and 42% for placebo (P = 0.04). Despite significant steroid reduction, there was no difference in asthma assessments between the two groups. No serious reactions related to SIT injections were seen. CONCLUSION: This study shows that SIT with a SQ-standardized HDM extract is safe. An ICS sparing effect was evident in patients with moderate persistent asthma.     

The effect of repirinast on airway responsiveness to methacholine and allergen.

Repirinast, a novel ingested antiallergic asthma medication from Japan, was compared versus placebo on airway responsiveness to methacholine and was compared versus placebo and cromolyn on airway responses to allergen. In 14 patients with mild, stable, atopic asthma, we performed a double-blind, double-dummy, random-order trial with ingested repirinast 300 mg twice daily for 7 days, inhaled cromolyn 40 mg spincaps single dose, and double placebo on allergen-induced early (EAR) and late (LAR) asthmatic responses and increased airway responsiveness. In the 14 subjects, no difference occurred in methacholine PC20 after 6 days of repirinast or 6 days of placebo. In the 13 subjects who completed the allergen study, single-dose cromolyn significantly reduced the EAR by 63% and the LAR by 65% versus placebo (p < 0.02); repirinast was not significantly different from placebo, both the EAR and LAR being reduced by less than 10%. Allergen-induced increase in methacholine responsiveness was borderline (p = 0.052), and no significant drug effects occurred. In these models, a 1-week treatment period with repirinast, like other oral antiallergic asthma medications (e.g., ketotifen, fumarate), provides no protection against airway responses to methacholine or allergen.     

Long-term treatment with oral sustained-release theophylline

The treatment of chronic asthma with a sustained-release rheophylline preparation was evaluated in a placebo controlled, 2 × 4 week, randomised, double-blind study. The dose which would give serum theophylline levels in the range of 10–20 meg/ml had been previously determined for each patient. This individualization of dosage resulted in 80% of the patients having scrum content rations within the 10–20 meg/ml therapeutic range. The average daily close taken by males was 998.55 mg (range 700–1175 mg) and by females 778.1 (range 500–1000 mg).
Of the 33 patients who completed the study 28 had less asthma during the theophylline period, lour did not respond and one did better during the placebo period. No serious side effects were reported. During theophylline therapy. patient's requirements for aerosol bronchodilators were significantly reduced.     

Combination drug therapy in children with exercise-induced bronchospasm

Fifty-three children with moderately severe asthma were studied to determine the capacity of drugs to block exercise-induced bronchospasm (EIB). All 53 children demonstrated EIB (as defined by a 20% fall in FEV1 or 30% fall in FEF25-75) while receiving therapeutic theophylline (serum level 10-20 micrograms/ml). EIB was completely blocked in 47 children by an inhaled metaproterenol 10 minutes prior to exercise, in addition to the theophylline. In six children, EIB was only partially blocked when either metaproterenol or cromolyn was added to the theophylline, but was completely blocked when all three drugs were used. A small group of children may benefit from combination therapy for EIB.     

A randomized,double-blinded,placebo-controlled study of the use of viscous oral cromolyn sodium for the treatment of eosinophilic esophagitis

Background

There is a need for effective, nonsteroid pharmacologic therapies for eosinophilic esophagitis (EoE). Cromolyn sodium offers an option because mast cells have been implicated in the symptomatology of EoE and cromolyn has been shown to have some anti-eosinophilic properties.

Short- and long-term effects of cromolyn sodium on the airway reactivity of asthmatics

To study the effects of cromolyn sodium on the airway reactivity of asthmatics, we performed a randomized, double-blind, crossover study in which 11 atopic asthmatics inhaled 20 mg of cromolyn sodium or a matching placebo four times daily for 4 wk each, while in their allergy season. Bronchial challenges consisting of either eucapnic hyperventilation with frigid air or methacholine were performed before, in the middle, and at the end of each treatment period. Stimulus-response relationships were assessed with the forced expiratory volume in I sec (FEV1). The level of ventilation (VE) and the provocative dose of methacholine (meth) required to reduce the FEV1 20% from control were recorded as the PD20VE and PD20meth, respectively. There were no significant differences in the baseline FEV1 on any study day. The short-term administration of cromolyn brought about a significant increase In PD20VE prior to both the placebo and active phases of the study. Placebo had no effect on airway reactivity. After 2 wk of cromolyn, PD20VE rose significantly and stayed elevated during the course of the study. Neither the short- nor long-term administration of cromolyn had any effect on the responsiveness to methacholine. These results demonstrated that long-term therapy can attenuate the responsiveness to naturally occurring asthmogenic stimuli even when nonspecific reactivity is unchanged.     

Single-dose inhaled budesonide in subjects with chronic asthma

In 30 stable asthmatics, a comparison was made between the changes in pulmonary function (FEV1, FVC, PEF, MEF75, MEF50 and MEF25) hourly for 9 h after a single dose of inhaled budesonide 1,600 micrograms, and placebo. All subjects used inhaled steroids daily; this medication was, however, withheld 8 days prior to the study. For all parameters of pulmonary function, a significant difference in favour of budesonide was demonstrated. The effect tended to decrease after 9 h, and had abated within 24 h. FEV1 age, sex, smoking habits, or results of an inhaled beta 2-agonist reversibility test could not be demonstrated as predictors of those subjects to react with the most pronounced responses to budesonide. In conclusion, our results demonstrate an effect 3 h after administration of an inhaled glucocorticosteroid in adult outpatients with chronic asthma. These results parallel previous findings in highly selected asthmatics and after systemic administration of glucocorticosteroids. Single-dose administration and subsequent monitoring for 8-9 h may therefore prove valuable in evaluating new prophylactic agents for the treatment of asthma.     

Steroid sparing effect of nedocromil sodium in asthmatic patients on high doses of inhaled steroids

Nedocromil sodium is a non-steroidal prophylactic agent developed for the management of asthma. We have assessed the steroid sparing potential of inhaled nedocromil sodium 4 mg four limes daily in a randomized, double blind, placebo controlled study in 69 asthmatic subjects controlled on inhaled beclomethasone dipropionate in the dose range 1000 2000 μg daily. Following a 4 week run-in period subjects added nedocromil sodium or placebo by metered dose inhaler to their usual medication for a further 4 weeks. The dose of inhaled steroid was then reduced at fortnightly intervals according to a predetermined schedule, with monitoring of asthma severity, symptom scores, bronchodilator use and peak flow recordings. Sixty subjects entered the steroid reduction phase and achieved median (range) % decreases in steroid dose of 80 (17-100)% with nedocromil sodium compared to 65 (0-100)% with placebo (P = 0.34) with 14 patients in the nedocromil sodium group and 10 in the placebo group being withdrawn completely from inhaled steroids. Subjective global assessment scores were significantly better with nedocromil sodium (mean 2.14) than with placebo (2.93; P<0.02) though there was no difference between individual daily symptom scores. In this study therefore in asthmatic patients controlled on high doses of inhaled steroids, nedocromil sodium was well tolerated but the smalt differences in steroid sparing effect between nedocromil and placebo were not statistically significant.     

A review of the hospital course of asthmatic children and adults

We reviewed 82 consecutive hospital admitted patients treated for acute severe asthma over a seven-month period at a University medical center and an additional 25 patients at an affiliated community hospital. Those asthmatics treated on the adult medical service had a significantly longer length of hospitalization when compared to those treated on the pediatric service (t = 5.12; p less than 0.005). In addition, longer hospitalization periods were noted for those asthmatics who smoked (t = 2.98; p less than 0.005) and for those with a history of chronic bronchitis (t = 2.32; p less than 0.025). Drug regimens were frequently suboptimal; 30% of the patients reviewed were receiving no therapeutic agents prior to admission. Of those patients receiving theophylline 53% had serum levels of less than 10 mcg/ml on their post admission assessment. Although frequently suboptimal, inadequate drug regimens prior to admission did not lengthen hospital stay. Poor compliance with medications was recorded as a major cause of decompensation in nine patients whose mean age was 13 years. Finally, occupational exposure to airway irritants was elicited from 24% of the adult population at the University medical center. Increased length of stay in the hospital for adult asthmatics may reflect relatively fixed airway disease among these patients since a significant proportion of them related a history compatible with chronic bronchitis or were smokers. Occupational histories should be evaluated in adult asthmatics to rule out workplace exposures as a cause for severe decompensation. In addition, the importance of educational efforts addressing therapeutic non-compliance is evident from this study.     

A Canadian multicenter study with Zaditen (ketotifen) in the treatment of bronchial asthma in children aged 5 to 17 years

One hundred thirty-eight children with chronic asthma, requiring daily treatment with bronchodilators, took part in a 7-month, double-blind, multicenter clinical study. Patients were randomized into two groups, and after a 1-month baseline, were administered Zaditen (ketotifen), 1.0 mg twice daily, or an identical placebo for a period of 6 months. After 10 weeks of receiving the study medication, bronchodilator use was reduced or stopped. In the Zaditen-treated group, 60% of the children taking theophylline were able to stop its use completely, compared to 34% of the patients taking placebo (p less than 0.05). Of the patients who were unable to stop taking theophylline, the Zaditen-and placebo-treated groups recorded average dosage reductions of 62% and 26%, respectively. These differences were statistically significant (p less than 0.05). Thus, a high percentage of patients in the placebo-treated group maintained asthma symptom control with theophylline, whereas most of the Zaditen-treated patients could stop using this medication. Although pulmonary function readings improved in both groups, those patients taking Zaditen demonstrated earlier improvement and greater changes from baseline. Significant differences (p less than 0.05) in favor of Zaditen were found for reduction of concomitant medications, patient's global evaluation, physician's clinical evaluations, incidence of emergency room visits for asthma, and upper respiratory tract infections. No unexpected side effects were observed. It is concluded that Zaditen is an effective medication for long-term control of asthma in children.     

Cromolyn sodium in the management of systemic mastocytosis

A multicenter, double-blind, placebo-controlled trial of the efficacy of oral cromolyn sodium (200 mg orally four times per day) was conducted in 11 patients with systemic mastocytosis who had been maintained with the drug on an individualized compassionate-need basis. Efficacy was measured by physician assessment of overall disease severity based on history and physical examination at specified intervals and by the average daily patient symptom diary scores for each of three mastocytosis-related symptoms that had previously appeared to be alleviated by the use of this drug. Efficacy variables were compared for a 4-week baseline period, during which patients received open-labeled cromolyn sodium, and at 4-week intervals during a 16-week period of random assignment to cromolyn sodium or placebo. Overall disease severity and symptoms recorded in patient diaries were graded on a scale of 0 (absent) to 5 (incapacitating). The average physician assessment of disease severity and symptom scores of the patients in the placebo-treated group increased significantly during the randomization phase relative to patients in the cromolyn sodium-treated group, reflecting an exacerbation of symptoms with drug withdrawal (p less than 0.05 and less than 0.028, respectively). When the symptom scores were analyzed separately for gastrointestinal manifestations of disease (diarrhea, abdominal pain, nausea, and vomiting), cromolyn sodium treatment was significantly beneficial relative to placebo (p less than 0.02), whereas the benefit for nongastrointestinal manifestations did not reach statistical significance.     

Inhaled albuterol powder for the treatment of asthma--a dose-response study

Many patients are unable to obtain optimal benefit from inhaled bronchodilators as delivered by metered-dose aerosol spray because of difficulty in synchronizing release of medication with the start of inspiration. The Rotahaler is a flow-activated device that avoids this problem since the act of inspiration itself delivers medication to the lungs. In this randomized, double-blind, crossover study, each of 20 male patients with moderate to severe asthma, ages 12 to 23 yr, received a single treatment with 100, 200, or 400 mcg of albuterol powder or placebo by Rotahaler on 4 study days separated by 2 to 10 days. All patients stopped theophylline and inhaled beta-agonists as needed 24 and 12 hr, respectively, before study days. All patients emptied the Rotahaler with a single inhalation. Pulmonary functions were followed for 8 hr after medication. Statistical analyses of FEV1, FEF25-75, and FVC revealed that all doses of albuterol powder were superior to placebo within 5 min with a log dose-response trend for both degree and duration of bronchodilation.     

Treatment of asthma with nebulized lidocaine: a randomized, placebo-controlled study

BACKGROUND: In 2 prior uncontrolled studies, nebulized lidocaine reduced oral glucocorticoid use in patients with severe glucocorticoid-dependent asthma. OBJECTIVE: We tested the safety and efficacy of nebulized lidocaine in a randomized, placebo-controlled study in patients with mild-to-moderate asthma. METHODS: We recruited 50 subjects (25 receiving lidocaine and 25 receiving placebo); all had a prebronchodilator FEV(1) of 64% to 125% of predicted normal value and were treated with daily inhaled glucocorticoids (but not systemic glucocorticoids) and bronchodilators for at least 2 months. Before treatment, subjects monitored their symptoms and peak flow values and maintained their medications for 2 weeks. At initiation, subjects inhaled either nebulized placebo (saline) or lidocaine (4%, 100 mg) 4 times daily. All subjects were instructed to reduce their inhaled glucocorticoid dosage by one half each week for 3 weeks and to discontinue glucocorticoid treatment at week 4. The subjects continued the nebulized lidocaine or placebo for a total of 8 weeks, monitored their symptoms, and used bronchodilators to control symptoms. RESULTS: Indicators of asthma severity showed benefit for the lidocaine-treated group: changes in FEV(1) (P < or =.001), nighttime awakenings (P < or =.02), symptoms (P < or =.010), bronchodilator use (P < or =.010), and blood eosinophil counts (P < or =.020). Subjects in both groups reduced use of inhaled glucocorticoids comparably. Subjects receiving nebulized placebo showed increases in their symptom scores, bronchodilator use (P < or =.05 for both), and blood eosinophil counts (P < or =.01) and decreases in FEV(1) (P < or =.001). CONCLUSION: Nebulized lidocaine provided effective and safe therapy in subjects with mild-to-moderate asthma.     

Cromolyn in extrinsic and intrinsic asthma

Cromolyn sodium was evaluated in 30 patients with intrinsic bronchial asthma and in 29 patients with extrinsic bronchial asthma using a double-blind crossover method. Each patient was studied during a base line, placebo, and cromolyn period. Daily evaluation was performed with regard to upper respiratory tract symptoms, lower respiratory tract symptoms, oral medication scores, use of sympathomimetic agents by aerosolization and peak expiratory flow rates measured 5 times a day. Weekly evaluation consisted of a physician's evaluation and a timed vital capacity. At the end of each test period spirometry, airway resistance and an exercise tolerance test were performed. Evaluation of the intrinsic asthmatic patients revealed significant improvement during the cromolyn period as compared to the placebo and base line periods with regard to the daily recorded variables and the physician's evaluation. Study of the other parameters showed no significant trend. Evaluation of the use of cromolyn in extrinsic bronchial asthma revealed no general trends for any of the parameters measured.     

A research method to induce and examine a mild exacerbation of asthma by withdrawal of inhaled corticosteroid

This study evaluated a research method to examine an exacerbation of asthma induced by corticosteroid withdrawal. Ten non-smoking adult asthmatics who were stable on treatment with inhaled steroid underwent a graded reduction of the daily dose by 200 micrograms at weekly intervals until an exacerbation of symptoms occurred. A daily symptom, peak expiratory flow rate (PEF) and medication diary was kept. Weekly clinic visits were used to assess symptoms, spirometry, methacholine airway responsiveness (expressed as the provocative concentration to cause a fall in FEV1 of 20%, PC20), circulating eosinophils, basophils and their progenitors (Eo/B-CFU), and sputum inflammatory cells. The laboratory tests were performed blind to the clinical details. Each subject developed an exacerbation of symptoms, on average at 16 (7-26) days after the onset of steroid reduction. This was accompanied by a deterioration in each of the objective measures. There was a fall in FEV1 by 320 ml (s.e.m. 9.5) and in PC20 from 0.8 to 0.43 mg/ml. Circulating eosinophils rose from 114 (24) x 10(3)/ml to 227 (50) x 10(3)/ml and Eo/B-CFU rose from 31 (5.6) to 44 (11.3)/10(6) cells. Sputum developed in five subjects and contained 36 (5.2)% eosinophils and 1.98 (0.21)% metachromatic cells (mast cells or basophils). The symptom diary and weekly questionnaire were demonstrated to be valid and responsive to change. A deterioration indicated by the daily symptom score preceded changes in PEF. Treatment by an increase in steroid was followed by reversal of each of the changes.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhaled mometasone furoate reduces oral prednisone requirements while improving respiratory function and health-related quality of life in patients with severe persistent asthma

BACKGROUND: Inhaled corticosteroid therapy in severe persistent asthma has been shown to reduce or eliminate oral corticosteroid (OCS) use while retaining effective asthma control. OBJECTIVE: We sought to evaluate the ability of mometasone furoate (MF) delivered by means of dry powder inhaler to reduce daily oral prednisone requirements in OCS-dependent patients with severe persistent asthma. METHODS: We performed a 12-week, double-blind, placebocontrolled trial (21 centers, 132 patients) comparing 2 doses of MF (400 and 800 microg administered twice daily) with placebo, followed by a 9-month open-label phase in which 128 patients received treatment with MF. RESULTS: At the endpoint of the double-blind trial, MF 400 and 800 mg twice daily reduced daily OCS requirements by 46.0% and 23.9%, respectively, whereas placebo increased OCS requirements by 164.4% (P <.01). Oral steroids were eliminated in 40%, 37%, and 0% of patients in the MF 400 and 800 mg twice daily and placebo groups, respectively. Pulmonary function and quality of life significantly increased for MF-treated patients. Further reductions in OCS requirements were achieved with long-term MF treatment in the open-label phase. CONCLUSION: MF inhaled orally as a dry powder is an effective alternative to systemic corticosteroids in patients with severe persistent asthma.