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.     

Upregulation of alpha GM-CSF-receptor in nonatopic asthma but not in atopic asthma

BACKGROUND: Intrinsic asthma is characterized by an increased number of activated eosinophils and macrophages and an increased expression of the hematopoietic growth factor granulocyte-macrophage colony-stimulating factor (GM-CSF) in the bronchial mucosa. OBJECTIVE: This study was carried out to investigate the expression of alpha GM-CSF receptor (alpha GM-CSFr) messenger RNA and protein in the bronchial mucosa of patients with intrinsic or atopic asthma and of control subjects and to correlate the expression of alpha GM-CSFr to the number of EG2+ cells (eosinophils) and CD68+ cells (macrophages) and pulmonary function. METHODS: Nineteen patients with stable asthma (9 with atopic and 10 with intrinsic asthma) and 22 normal control subjects (12 atopic and 10 nonatopic subjects) were recruited, and FEV1 (percent predicted) and PC20 were measured before bronchoscopy. Endobronchial biopsy specimens were obtained and examined for membrane-bound alpha GM-CSFr by using in situ hybridization and immunocytochemistry. RESULTS: alpha GM-CSFr mRNA- and protein-positive cells were identified in biopsy specimens from all four groups studied. There was no significant difference in the number of cells expressing alpha GM-CSFr mRNA and protein in patients with atopic asthma compared with atopic and nonatopic control subjects. However, the numbers of alpha GM-CSFr mRNA- and protein-positive cells were significantly higher in nonatopic patients with asthma compared with atopic patients with asthma and atopic and nonatopic control subjects (p < 0.001). In the patients with intrinsic asthma, the number of alpha GM-CSFr mRNA-positive cells per millimeter of basement membrane correlated with numbers of CD68+ cells (r2 = 0.87, p < 0.001) but not with EG2+ cells, and colocalization studies demonstrated that 80% of the cells expressing alpha GMCSFr mRNA were CD68+. The expression of GM-CSF was also significantly increased in patients with intrinsic asthma compared with those with atopic asthma and control subjects (p < 0.05). In addition, in intrinsic asthma, there was a correlation between alpha GM-CSFr mRNA and FEV1 (r2 = 0.61, p < 0.05). CONCLUSION: These results demonstrate that elevated numbers of cells expressing alpha GM-CSFr can be detected in nonatopic asthma but not in atopic asthma and suggest that this increased expression is predominantly macrophage-associated and may play an important pathophysiologic role in intrinsic asthma.     

Effectiveness of nedocromil sodium in preventing exercise-induced asthma in children

Exercise-induced asthma is a well-known phenomenon, particularly affecting children, with an important social impact. In order to assess the usefulness of nedocromil sodium in the prevention of exercise-induced asthma, we studied 49 (15 females, 34 males) children who suffered from asthma; their mean +/- SD age was 9.2 +/- 3.0 (range: 3.3-19.1) years. On the first day respiratory function was evaluated by spirometry, basally and after 6 minutes. The inhalation of nedocromil sodium had a great influence on post-exercise lung function measurements; in fact on the day of nedocromil sodium pretreatment, our patients showed an increase of respiratory function, significantly different from the parameters recorded during the first day. Our findings suggest that nedocromil sodium is effective in the prevention of exercise-induced asthma, in pediatric age.     

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Eosinophil differentiation is thought to occur by the action of interleukin (IL)-5 on CD34(+) progenitor cells. The allergen-induced increase in eosinophil numbers in isolated airway preparations in vitro, and detection of increased numbers of circulating CD34(+) cells in atopic subjects, led us to the hypothesis that the eosinophil infiltration of the airway in asthma may result from local mucosal differentiation, in addition to recruitment from the bone marrow. We examined CD34(+) cell numbers by immunohistochemistry and IL-5 receptor alpha (IL-5Ralpha) messenger RNA (mRNA) expression by in situ hybridization in bronchial biopsies from atopic asthmatic patients, and from atopic and nonatopic control subjects. CD34(+) cell numbers were increased in the airway in atopic asthmatic and atopic nonasthmatic subjects. In contrast, CD34(+)/ IL-5Ralpha mRNA+ cells were increased in asthmatic subjects when compared with both atopic and nonatopic control subjects. Airway numbers of CD34(+)/IL-5Ralpha mRNA+ cells were correlated to airway caliber in asthmatic subjects and to eosinophil numbers. These findings support the concept that eosinophils may differentiate locally in the airway in asthma.     

Nedocromil sodium in obstructive airways disease: effect on symptoms and plasma protein leakage in sputum

In patients with asthma or chronic obstructive pulmonary disease, there is chronic airway inflammation with increased leakage of plasma proteins into the airway lumen, which can be reduced by inhaled glucocorticosteroids. Nedocromil sodium is an anti-inflammatory drug, and we questioned whether it also affects the leakage of plasma proteins. In a double-blind placebo-controlled study we investigated the effect of 12 weeks of treatment with nedocromil on forced expiratory volume in one second (FEV1), provocative concentration of histamine causing a 20% fall in FEV1 (PC20), peak flow, symptom scores, and plasma protein leakage in sputum, in 31 patients with obstructive airways disease and sputum production (mean (range) FEV1 61% of predicted (42-87%); geometric mean (range) PC20 0.39 (0.04-2.9) mg x mL(-1)). As a measure for plasma protein leakage we calculated the relative coefficients of excretion (RCE) of proteins from serum to the soluble phase of sputum. There was a small increase in morning and evening peak flow (p<0.05) and a decrease in night-time bronchodilator use (p<0.02) in favour of nedocromil. The RCE of alpha2-macroglobulin to albumin significantly decreased after treatment with nedocromil (p=0.03). The results show limited clinical efficacy of nedocromil in our study group. They further suggest that the anti-inflammatory properties of nedocromil extend to inhibition of plasma protein leakage into the airways.     

Inhaled furosemide prevents ultrasonically nebulized water bronchoconstriction in children with both atopic and nonatopic asthma

To determine whether inhaled furosemide can modify the bronchoconstriction induced by ultrasonically nebulized distilled water (UNDW) in children with both atopic and nonatopic asthma, a single-blind, randomized, placebo-controlled study was undertaken. The UNDW inhalation challenge was performed in 21 asthmatic children (atopic, 14; nonatopic, 7; mean +/- SEM age, 11.5 +/- 0.5 years), who had a fall in FEV1 of at least 20 percent after distilled water inhalation. On separate days, these subjects underwent UNDW challenge test after inhalation of furosemide (10 mg/body square meters) or placebo (saline solution). Inhaled furosemide exerted a protective effect against bronchoconstriction induced by UNDW in children with both atopic and nonatopic asthma (p < 0.01, p < 0.05, respectively). These results indicate that the protective action of furosemide against UNDW-induced bronchoconstriction may be independent of its direct inhibitory effect on airway mast cell activation.     

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.     

Nedocromil sodium (Tilade)

Nedocromil sodium is a well-tolerated antiasthmatic agent for initial therapy in patients with mild or moderate asthma not well controlled with inhaled beta-2 agonists and/or where methylxanthines are indicated. Like cromolyn sodium, nedocromil sodium offers a potential alternative to inhaled corticosteroids as maintenance therapy in patients with mild or moderate asthma not adequately controlled by bronchodilators. Furthermore, cromolyn sodium and nedocromil sodium may also reduce the usage of corticosteroids and provide some additional symptom control in patients whose asthma is not suitably controlled by optimal doses of inhaled corticosteroids. Both nedocromil sodium and cromolyn sodium are more efficacious than placebo for controlling of asthma, however, few studies have compared the effectiveness of cromolyn versus nedocromil at this time. Further experience and comparison studies of nedocromil sodium with cromolyn sodium in children are required before the role of nedocromil sodium as maintenance treatment in young asthmatic patients can be defined.     

A retrospective assessment of cost avoidance associated with the use of nedocromil sodium metered-dose inhaler in the treatment of patients with asthma

A retrospective analysis of patient charts was performed for a single, multioffice pulmonary practice in Toronto, Ontario. Canada, to assess hospital care utilization and associated cost reductions after asthma prophylaxis with nedocromil sodium inhalation aerosol. Data were obtained from 310 adult patients with mild, moderate, or severe asthma who were treated in the practice between January 1988 and June 1994 and who had been placed on nedocromil sodium for at least 1 year. The number of office visits increased with nedocromil sodium therapy due to initial surveillance of the new medication, but no other changes were made in the usual protocol for each visit. After initiation of nedocromil sodium therapy, patients showed better asthma control as measured by improvements in pulmonary function scores and by reduced hospital utilization (both emergency department visits and hospital admissions). It is likely that the improvements in asthma control could result in cost savings, and savings projections for the Canadian health care system were made using the retrospective data collected for asthma-related hospital services. Prospective data are needed to confirm our findings.     

The influence of salmon calcitonin on the soluble form of VCAM-1 (CD 106) and E-selectin (CD 62E) in serum of patients with atopic bronchial asthma

The aim of the study was to evaluate the effect of salmon calcitonin (CT) on serum level of soluble form of VCAM-1 (sVCAM-1 = soluble vascular cell adhesion molecule-1) and E-selectin (sE-selectin = soluble E-selectin) in patients with atopic bronchial asthma. Twenty-four individuals divided into 4 groups (6 persons each) were investigated. The first group consisted of patients with chronic moderate bronchial asthma, the second and third groups consisted of patients with mild bronchial asthma and the fourth group K consisted of healthy individuals. The patients of the first and second group were treated with CT at a dose of 100 i.v./days s.c. for three days. The patients of the third group were given placebo (phychological saline) in similar way as CT. The indices were measured before the treatment with CT or placebo and on the 4th day of the treatment. It was found that CT treatment decreased sVCAM-1 in serum only in the patients of the first group (p < 0.05) but had no effect upon sE-selectin level. The obtained results suggest that CT interfered into mechanisms of inflammation involving adhesion molecules in patients with bronchial asthma.     

Focal lesion in the splenium of the corpus callosum in epileptic patients: antiepileptic drug toxicity?

Although the prevalence of asthma has risen significantly during the last 30 yr, it is not clear whether this has occurred primarily in persons with a strong genetic predisposition to asthma and atopy or in other sections of the population. We have investigated outcomes in children of nuclear families selected through probands previously characterized by studies in 1964 and 1989 as having histories of persistent childhood onset atopic asthma, transient childhood wheezy bronchitis, and no respiratory symptoms or atopy. Children of wheezy bronchitic probands had a significantly better symptomatic outcome in adolescence, irrespective of the atopic status of the parent proband, than do children of either asthmatic or asymptomatic probands, suggesting that this may be a syndrome that shows familial aggregation and is distinct from asthma. Total serum IgE levels were significantly lower in children of nonatopic asymptomatic probands, including those with wheezing symptoms. In contrast children of nonatopic asymptomatic probands had an unexpectedly high prevalence of wheezing (33%), positive skin prick tests (56%), and positive specific serum IgE to common allergens (48%) that was similar to that found in children of atopic asthmatic probands. Our findings support the concept that wheezy bronchitis is a separate syndrome from atopic asthma. High total serum IgE levels within our population appear to be an important marker of genetic predisposition to atopy. Our data also suggest that much of the increase in asthma prevalence is associated with specific IgE sensitization and is occurring in persons previously considered to be at low risk of developing asthma or atopy.     

Comparison of the protective effects of cromolyn sodium and nedocromil sodium in the treatment of exercise-induced asthma in children

Seventeen children with asthma were studied in a double-blind, crossover, placebo-controlled study designed to compare the efficacy of cromolyn sodium with that of nedocromil sodium in preventing exercise-induced asthma. All drugs were delivered through a metered-dose inhaler (cromolyn sodium, 10 mg; nedocromil sodium, 4 mg; placebo, two puffs). Nedocromil sodium and cromolyn sodium provided significant, comparable protection from exercise-induced asthma, and both drugs were better than placebo. We conclude that nedocromil sodium and cromolyn sodium administered by a pressurized aerosol provide equal protection against exercise-induced asthma in children.     

Apheresis platelets: emerging issues related to donor platelet count, apheresis platelet yield, and platelet transfusion dose

The prevalence of atopic dermatitis and other allergic diseases is increasing in industrialized countries. Today we know that atopy is conditioned genetically, but the development of the atopic phenotype requires environmental factors. It is believed that the genetic factors have not changed and that the increased prevalence is due to the increase in exposure to allergenic and non-specific environmental factors. The potential for sensitization is greater in the early years of life, so it is necessary to reduce harmful environmental exposure at these ages. Atopic clinical manifestations develop sequentially, in many cases beginning with atopic dermatitis in the early months of life. We know that children with atopic dermatitis present non-specific bronchial hyperreactivity (58 to 82%), which is a risk factor for the later development of asthma. The presence of specific bronchial hyperreactivity for mites in atopic dermatitis with mite sensitization also has been described, and it has been demonstrated that signs of eczema can develop or become exacerbated by airway exposure during bronchial challenge tests. The evolution from atopic dermatitis to asthma is a possibility that must be kept in mind. Patients should be followed-up and study of hyperreactivity and sensitization to allergens should be carried out in order to prevent the development of clinical symptoms. Prevention should include pneumoallergens, food allergens, and non-specific environmental risk factors, such as parental smoking (particularly mothers), pollution inside and outside the home, etc. Prevention is particularly important in children at risk of allergy, as determined by a family history among first-degree relatives, as well as the presence of atopic dermatitis, particularly of early onset, because these patient are most at risk of developing bronchial asthma in later years. At present, pharmacological prevention is being studied, without overlooking environmental prevention, in children at high risk of atopic disease for the purpose of preventing chronic inflammations that will condition their future as adults. In our daily clinical experience, atopic dermatitis is responsible for 8% of visits to a pediatric allergology unit. We emphasize that 62.5% of our patients with dermatitis are referred when they already have bronchial asthma, which represents an important delay in diagnosis with respect to the onset of symptoms.     

Frequencies of T cells expressing interleukin-4 and interleukin-5 in atopic asthmatic children. Comparison with atopic asthmatic adults

T-cell-derived cytokines have been implicated in the pathogenesis of asthma and it has been suggested that Th2-type cytokines (interleukin-4 [IL-4], interleukin-5 [IL-5]) are pivotal in the allergic inflammation. However, there are little data on human cytokine production by individual T cells at the protein level, in particular in asthmatic children. In this study we analyzed the cytokine production at the single cell level in peripheral blood from mild atopic asthmatic (AA) children and adults and age-matched atopic nonasthmatic (AN) and nonatopic nonasthmatic (NN) control subjects (n = 9 in each group) using the technique of intracellular cytokine detection by flow cytometry. Comparing asthmatic children with atopic and nonatopic control subjects, an increased percentage of IL-5-producing T cells (AA: median 4.9% [range 1.1 to 8.9%]; AN: 0.3% [0.2 to 0.9%], p = 0.003; NN: 0.4% [0.1 to 3.8%], p = 0.001) was detectable, with a positive correlation to the number of peripheral eosinophils and to bronchial hyperresponsiveness. The frequency of IL-4-producing T cells was increased in both atopic groups compared with nonatopic controls (AA: 1.2% [0.2 to 2.6%], p = 0.011; AN: 0.8% [0.4 to 3.7%], p = 0.007; NN: 0.4% [0.2 to 0.9%]) with a positive correlation to total IgE concentration. In adults there were no differences in IL-5- or IL-4-producing T cells between all three groups. A substantial proportion of T cells coproducing IL-4 and IL-5 was not detectable in children and adults. These findings indicate that in asthmatic children the frequencies of Th2-type-producing T cells are increased and that expression of IL-4 and IL-5 is regulated independently.     

Analysis of ventilation parameters before and after fiber optic bronchoscopy in patients with atopic bronchial asthma and chronic obstructive pulmonary diseases

Bronchial asthma and chronic bronchitis in a stable period of the disease could be an indication for diagnostic bronchofiberoscopy. The aim of the authors of this article is to assess whether bronchoscopy may be safely used either as diagnostic or therapeutic procedure. 21 patients (age 33-46), 13 with atopic bronchial asthma and 8 with COPD took part in this study. The measurements were carried out one day before and 3 hours after the bronchoscopy. The following parameters: Forced Vital Capacity (FVC), Forced Expiratory Volume (FEV1), Forced Expiratory Flow (FEF25, FEF50, FEF75) and Resistance of Airways (R aw) were taken into consideration. It was shown that bronchofiberoscopy could be performed safely in these patients and did not lead to woersing ventilation parameters. Bronchospasm was not observed during the study. Moreover the increase in FEF50, FEF75 and R aw were observed. This significant decrease of amount of bronchial discharge could serve as an explanation of this phenomenon.     

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.     

Characteristic features of cockroach hypersensitivity in Turkish asthmatic patients

Exposure to cockroach has been reported to cause asthma in many parts of the world. Although house-dust-mite is known to be the most important indoor allergen in Turkey, there are few data on the prevalence of allergy to cockroaches. Therefore, we evaluated the prevalence of cockroach sensitivity in asthmatic Turkish patients to see whether it is also an important source of asthma in addition to house-dust mites. A total of 206 patients demonstrating the characteristic features of asthma were included in the study. Sixty-three percent of the patients were considered atopic, and 37% were found to be nonatopic by skin prick tests. Mite allergens were the most common cause of indoor allergy (50%), while cockroach sensitivity was detected in 25.7% of all the asthmatics. Among all cockroach-sensitive patients, 70% were also positive for mites. A female predominance was observed in cockroach-sensitive patients, as 44% of atopic women and 34% of atopic men had positive skin tests with cockroach allergen. The average duration of asthma was 7.1+/-5.6 years in cockroach-sensitive asthmatics, and there was no difference between groups in average duration of asthma (P>0.05). Mild, moderate, and severe asthmatics constituted 73.6%, 20.7%, and 5.7% of the cockroach-sensitive patients, respectively. These data indicate that cockroach is also an important source of domestic infestation in Turkey. Thus, it seems reasonable to suggest the need for cockroach allergen in the routine battery of inhalant skin tests in this geographic location. However, possible cross-reactivity with mites has to be taken into consideration during the clinical evaluation of subjects with cockroach sensitivity, especially in our patient population with such high rates of house-dust-mite allergy.