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Deliberations In Concern with Loss of Asthma Control Following Inhaled Corticosteroid Withdrawal

We evaluated the use of sputum neutrophils and IL-8 as predictors for the development of asthma exacerbations. Our study indicates that neutrophils, rather than eosinophils, are associated with asthma exacerbations following steroid withdrawal. This may result from the increase in sputum IL-8 observed prior to the onset of an exacerbation. Taken together, our findings demonstrated that sequential monitoring of sputum IL-8 and neutrophils might be useful for predicting an episode of severe exacerbation in moderate persistent asthma after corticosteroid withdrawal. This study also confirms that the mechanisms underlying asthma exacerbation are highly variable.

There is growing evidence that reducing asthma exacerbations is achieved by targeting therapy to eosinophilic inflammation. An eosinophilic exacerbation is triggered by allergen exposure. However, several studies, have demonstrated increased neutrophil numbers in airway secretions and airway tissue from patients with acute severe asthma treated with ventolin effectively. Sputum neutrophilia may be mediated by IL-8, a che-mokine that selectively attracts neutrophils. IL-8 is increased in sputum of asthmatic subjects during exacerbations in association with sputum neutrophil-ia. However, there is no clear relationship between the type of airway inflammation and asthmatic exacerbations, possibly due to differences in the methodology, specifically the use of steroid tapering. Furthermore, the pathophysiologic mechanisms underlying asthma exacerbations following abrupt steroid withdrawal in moderate persistent asthmatics may be distinct from those seen with gradual steroid tapering. The neutrophilic airway inflammation in the present study may reflect the sudden withdrawal of inhaled corticosteroids and reflect the kinetics of inflammatory cells in an acute exacerbation when neutrophils are the first cells to infiltrate the airways.

There are several studies suggesting that eosinophilic inflammation is associated with sputum asthma exacerbations in response to controlled withdrawal of steroids. In addition, targeting management based on normalizing sputum eosinophils is able to reduce asthma exacerbations. Unexpectedly, the present study showed that a small number of patients with steroid withdrawal did not have asthma exacerbations, although they had eosinophilic inflammation. The patients in whom the dose of inhaled budesonide was maintained showed a reduction in sputum eosinophils, which may indicate greater compliance with inhaled corticosteroids during the trial period. The difference in the relationship between sputum eosinophils and asthma exacerbation with the majority of current evidence is not easily understood. We suggest that this may be due to the fact that a 10-week period in our study is inadequate to monitor the development of eosinophilic exacerbation. This is supported by the study of Pizzichini and colleagues, who showed that breakthrough eosinophilic inflammation occurred at 4 weeks following steroid reduction and subsequent asthma exacerbations developed within 12 weeks thereafter. Clinical exacerbation depends on the perception of breathlessness that is impaired by eosinophilic inflammation. Patients with eosinophilic inflammation who had no clinical worsening were moderately severe in terms of FEV1 and might have impaired perception of dyspnea and therefore were not aware of worsening asthma. Although the strategy of titrating the inhaled corticosteroid dose against sputum eosinophil counts reduced exacerbations, it by no means eliminated them. It is possible that the residual exacerbations were neutrophilic in nature. Improve your state with asthma inhalers online.

Our results differ from those of Jatakanon et al and in’t Veen and colleagues, who induced loss of control in asthma by gradual tapering of the steroid dose, and both studies showed eosinophil predominance during exacerbations. As suggested above, these results suggest that the pathophysiologic mech-anism(s) of asthma exacerbation induced by complete withdrawal may be different from that induced by steroid tapering. This may have important clinical consequences in that patients with a loss of asthma control as a result of stepping down inhaled corticosteroid dosage should be able to attenuate eosinophil actions by increasing the inhaled steroid dose. In contrast, exacerbations induced after abrupt steroid cessation may need antineutrophilic agents such as long-acting P2-agonists to attenuate the neutrophilic inflammation.

Increases in sputum IL-8 concentrations have been reported to precede an acute asthma attack, but the time course of this increase is unknown. In another study there was a significant elevation of IL-8 levels in sputum samples from asthmatics who had exacerbated compared to IL-8 concentrations after the resolution of the exacerbation. However, the onset of the elevation of IL-8 levels prior to the development of asthma exacerbation has not been previously investigated. The present study demonstrates that a marked increase in IL-8 level occurred 2 weeks before the symptomatic exacerbation (Fig 1, top left, A). Clinically, this may have important implications because there appears to be a window during which it may be possible to adjust asthma treatment, such as the addition of long-acting (32-agonist, in an attempt to suppress IL-8 production and subsequent neutrophilia leading to exacerbation. Although corticosteroids promote neutrophil survival as a result of delay in neutrophil apoptosis in vitro, we did not detect sputum neutrophilia in patients with budesonide treatment despite a failure to suppress sputum IL-8 levels below that seen in the run-in period.

In summary, the findings in this study in contrast to earlier reports suggest that asthma exacerbations following inhaled corticosteroid withdrawal are associated with increased sputum IL-8 and neutrophils. Significant increase in sputum IL-8 and neutrophil influx occurs 2 week prior to an exacerbation. Our results may be used to encourage asthmatic patients who have poor compliance with inhaled corticosteroid therapy are at risk for neutrophilic exacerbation if they abruptly stop their corticosteroid therapy.

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Loss of Asthma Control Following Inhaled Corticosteroid Withdrawal

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Output about Loss of Asthma Control Following Inhaled Corticosteroid Withdrawal

Patient Characteristics

Patient characteristics are shown in Table 1. Two patients in the budesonide treatment group were excluded from the analysis: one was unable to attend for all of the study visits, and the other provided induced-sputum specimens containing squamous cell counts > 80%.

Exacerbations

Eight of 12 patients had an exacerbation over the 10-week period of steroid withdrawal (Table 3). The remaining four subjects did not have an exacerbation during the 10 weeks of follow-up. Only 1 of 10 patients in the budesonide treatment group had an asthma exacerbation at week 2 (Table 2). Buy ventolin, flovent or advair to treat asthma effectively.

Sputum IL-8 and Neutrophils

Overall, the patients with an exacerbation after steroid cessation had significantly increasing levels of sputum IL-8, percentage of neutrophils, and sputum neutrophils 2 weeks prior to an exacerbation and at the onset of exacerbation (Fig 1, top left, A, top right, B, and bottom, C, respectively; Fig 2). The significant increase in IL-8 levels in induced sputum occurred at 2-week prior to an exacerbation and at the onset of exacerbation when compared with nonexacerbation (Table 4) [mean, 1,832.1 ± 151 ng/mL vs 1074.3 ± 111.0 ng/mL, p = 0.001; and 2.690.5 ± 154.7 ng/mL vs 1,420.7 ± 149.2 ng/mL, p < 0.0001, respectively]. The increase in percentage of neutrophils was also observed at the same period of time (Table 4) [mean, 42.0 ± 3.3% vs 23.6 ± 3.5%, p = 0.02; and 51.1 ± 1.9% vs 29.5 ± 4.2%, p = 0.0009, respectively]. Sputum neutrophilia correlated positively with changes in IL-8 levels (Fig 3) [r2 = 0.76, p = 0.01].

No significant differences were observed in baseline total sputum cell and differential cell counts between the budesonide treatment group and steroid withdrawal groups (Tables 2, 3). In contrast, there were significant differences in sputum lymphocyte counts (p = 0.01) and percentage of macrophages (p < 0.0001) at the onset of exacerbation (Table 4; Fig 2, center, right, D, and bottom, left, E).

Sputum Eosinophils

No significant differences in the percentages of eosinophils and absolute eosinophil number in sputum were observed either at the onset of exacerbation or 2 weeks before an exacerbation, compared with nonexacerbation data (Table 4, Fig 2, top, left, A, and top, right, B).

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Loss of Asthma Control Following Inhaled Corticosteroid Withdrawal

Figure 1. Changes in sputum IL-8 (top left, A), percentage of neutrophils (top right, B), and number of neutrophils (bottom, C) in patients with or without an exacerbation (exac). Exacerbation data were derived from those who were treated with placebo (eight cases) and with budesonide (one case), and the nonexacerbation data included asthmatic subjects who were treated with budesonide (nine cases) and with placebo (four cases). Data are shown as mean ± SEM. Comparisons of concentrations of IL-8 and neutrophil numbers in sputum were made between the results 2 weeks prior to an exacerbation and those of nonexacerbation at week 8 and between data at the exacerbation visit and those of the week-10 nonexacerbation.

Figure 2. Changes in percentage of eosinophils (top, left, A) and number of eosinophils (top, right, B), percentage of lymphocytes (center, left, C), number of lymphocytes (center, right, D), percentage of macrophages (bottom, left, E), and number of macrophages (bottom, right, F) in sputum collected from asthmatic subjects with and without an exacerbation. The exacerbation data were derived from those who were treated with placebo (eight cases) and with budesonide (one case), and the nonexacerbation data included asthmatic subjects who were treated with budesonide (nine cases) and with placebo (four cases). All data are shown as mean ± SEM. Comparisons of eosinophil numbers lymphocyte numbers and macrophage numbers in sputum were made between the results 2 weeks prior to an exacerbation and those of nonexacerbation at week 8 and between data on the exacerbation visit and those of the week-10 nonexacerbation. See Figure 1 legend for expansion of abbreviation not used in text.

Figure 3. Relationship between changes in IL-8 concentrations and neutrophil numbers in sputum obtained from the asthmatic patients with severe exacerbations. Symbols represent individual asthmatic patients. IL-8 concentrations correlated positively and significantly with sputum neutrophilia.

Table 3—Changes in Clinical Parameters and Sputum Neutrophils in Asthmatic Subjects Following Inhaled Corticosteroid Withdrawal

Variables Weeks I 0 2 4 6 8 10 Patients, No. 12 12 8 7 6 4 FEVb % predicted 73.5 ± 0.9 66.9 ± 1.1 67.5 ± 1.6 67.7 ± 1.7 67.9 ± 1.7 71.1 ± 0.4 Exacerbations, No. 0 4 1 1 2 0 Total cells, 106/mL 3.7 ± 0.3 6.0 ± 0.8 5.7 ± 0.8 6.9 ± 0.9 7.7 ± 0.7 6.4 ± 0.4 Neutrophils, % 31.0 ± 2.6 39.7 ± 2.3 40.8 ± 3.6 35.6 ± 5.9 28.2 ± 8.4 14.3 ± 1.3 Neutrophils, 106/mL 1.1 ± 0.1 2.5 ± 0.4 2.5 ± 0.5 2.7 ± 0.7 2.4 ± 0.8 0.9 ± 0.1 Eosinophils, % 3.8 ± 0.5 4.2 ± 0.7 5.3 ± 0.9 6.4 ± 1.3 6.4 ± 1.3 8.1 ± 1.1 Eosinophils, 106/mL 0.1 ± 0.02 0.2 ± 0.04 0.3 ± 0.04 0.4 ± 0.06 0.4 ± 0.07 0.5 ± 0.06 Macrophages, % 60.6 ± 2.7 50.9 ± 2.6 50.2 ± 2.9 51.8 ± 5.7 60.9 ± 7.1 73.6 ± 3.0 Macrophages, 106/mL 2.3 ± 0.3 2.9 ± 0.4 2.7 ± 0.3 3.3 ± 0.3 4.5 ± 0.6 4.7 ± 0.5 Lymphocytes, % 4.2 ± 0.7 4.5 ± 0.7 3.8 ± 0.9 4.9 ± 0.8 4.7 ± 0.5 4.5 ± 1.7 Lymphocytes, 106/mL 0.1 ± 0.02 0.2 ± 0.04 0.2 ± 0.05 0.3 ± 0.05 0.4 ± 0.05 0.3 ± 0.1

Table 4—Measurements of Sputum Indices of Exacerbation and Nonexacerbation Groups

Variables Exacerbation (n = 9) Nonexacerbation (n = 13) p Value 95% Confidence Interval of Difference IL-8, ng/mL 2 wk before visit 1,832.1 ± 151 1,074.3 ± 111.0 0.001 – 1,159.4 to – 356.3 Last visit 2,690.5 ± 154.7 1,420.7 ± 149.2 < 0.0001 – 1,753 to – 786.8 Total cell counts, 106 2 wk before visit 5.1 ± 0.9 4.65 ± 0.5 0.69 – 1.77 to 2.61 Last visit 8.5 ± 0.8 4.63 ± 0.5 0.0007 1.84 to 5.89 Neutrophils, % 2 wk before visit 42.0 ± 3.3 23.6 ± 3.5 0.02 – 29.2 to – 7.4 Last visit 51.1 ± 1.9 29.5 ± 4.2 0.0009 – 33.2 to – 9.99 Eosinophils, % 2 wk before visit 4.3 ± 0.4 2.8 ± 1.1 0.24 – 4.1 to 1.1 Last visit 2.7 ± 0.6 2.7 ± 1.0 0.99 – 2.96 to 2.99 Lymphocytes, % 2 wk before visit 5.1 ± 0.7 3.1 ± 0.8 0.09 – 4.5 to 0.36 Last visit 3.6 ± 0.7 1.5 ± 0.8 0.08 – 4.48 to 0.29 Macrophages, % 2 wk before visit 50.3 ± 3.8 70.1 ± 3.5 0.0003 11.2 to 32.0 Last visit 41.6 ± 2.2 68.2 ± 3.2 < 0.0001 17.6 to 35.7

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Research about Loss of Asthma Control Following Inhaled Corticosteroid Withdrawal

Subjects

Twenty-four nonsmoking patients (10 men) with moderate, persistent asthma participated in the study. The inclusion criteria were age 18 to 60 years of age and a history of stable asthma as defined by the American Thoracic Society. Patient characteristics are summarized in Table 1. All patients had a baseline FEVj > 70% of predicted, FEV1 reversibility > 15%, and required regular treatment with moderate doses of inhaled corticosteroids (beclomethasone dipropionate, 800 ^g/d or equivalent) for > 3 months. All patients were hyperresponsive as measured by a provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) < 8 mg/mL. None of the patients had a history of respiratory disease other than asthma, and none required oral glucocorticoid treatment within 3 months before study entry and used any other medication except study medication during the trial. The patients were included during a clinically well-controlled period without symptoms of an upper respiratory tract infection for 4 weeks prior to the study. The study was approved by the Royal Brompton and Harefield NHS Hospital Trust Ethics Committee, and informed consent was given by all patients. All patients suffering from asthma may order asthma inhalers online to treat asthma attacks.

Design

In order to determine the onset of asthma exacerbation after corticosteroid withdrawal, the study was conducted in a randomized, double-blind, placebo-controlled manner by comparing the effects of 10 weeks of treatment with budesonide (400 μg bid or placebo via Turbuhaler; AstraZeneca; Lund, Sweden). The study periods consisted of a 2-week run in phase and a 10-week exacerbation-induction phase. Before the start of the study, patients were screened on 2 separate days. Long-acting P2-agonists and theophylline preparations were discontinued at least 72 h before the first screening visit. On the first day, FEV1 was measured before and after inhalation of 400 μg of albuterol by metered-dose inhaler with a large-volume spacer device, and on the second visit a methacholine challenge test was performed. The patients stopped regular asthma medication for 2 weeks. Thereafter, patients were randomized to receive either matched placebo or budesonide, 400 μg bid, via Turbuhaler. Patients who had exacerbations during the run-in period were excluded from the study. Patients visited the hospital at the end of the run-in period, at 2-week intervals during the exacerbation-induction period, and at the time of an exacerbation to undertake lung function testing and sputum induction. During the study, the patients kept a diary to record morning and evening peak expiratory flow measurements.

Run-in Phase

During the 2-week run-in phase, all patients had to have stable disease without lower respiratory tract infection. Throughout the study, only terbutaline via Turbuhaler was permitted on an on-demand basis as a rescue inhaler. A study physician was accessible by telephone 24 h/d.

Induction of Exacerbation

Steroid withdrawal was performed by inhalation of placebo, and the study was discontinued when an exacerbation developed or when no exacerbation of asthma occurred within the 10-week study period. Order ventolin and treat asthma attacks. Patients undergoing exacerbation during treatment period were withdrawn from the study. Thereafter, inhaled budesonide was increased to 800 |j,g bid, and systemic corticosteroids (prednisolone 30 mg/d) were administered.

An exacerbation was defined as at least one of three crite-ria: (1) a drop in morning peak flow > 20% below baseline (mean of the last 7 days run-in period) on 2 consecutive days; (2) wakening due to asthma on 2 consecutive nights, and requiring rescue medication; (3) > 50% increase in 24-h rescue medication use on at least 2 consecutive days compared to mean use during the last 7 days of the run-in period, which also exceeded the equivalent of four puffs of terbutaline. FEV1 was then measured within 24 h of the exacerbation.

Lung Function Measurements and Methacholine Challenge Tests

FEV1 and FVC were measured using a dry wedge spirometer (Vitalograph; Buckingham, UK). Values are expressed as percentage of predicted. Baseline values were measured after 15 min of rest and taken as the highest of three readings. Single readings only were taken at other times. Airway hyperresponsiveness to methachoHne was assessed using the method of Sterk and colleagues. Methacholine was inhaled by tidal breathing in doubling concentrations (0.015 to 32 mg/mL) for 2 min at 5-min intervals. Measurements of FEV1 were made at baseline and after each dose. The challenge test was discontinued if FEV1 dropped > 20% from baseline. PC20 was calculated by linear interpolation of the log-dose response curves.

Sputum Induction and Processing

Sputum was induced by inhalation for 15 min of 3.5% saline solution via an ultrasonic nebulizer (model 2000; DeVilbis; Heston, UK), as previously described. After each inhalation period, patients were asked to rinse their mouth and were encouraged to expectorate sputum. Briefly, the whole sputum sample was processed with dithiothreitol (Sigma Chemicals; Poole, UK). The homogenized sputum was centrifuged at 1,500g for 10 min. The supernatant was separated and frozen at — 70°C until further analysis. Total cell counts were made on a hemocy-tometer slide, using Kimura stain, and slides were prepared (Cytospin; Shandon; Runcorn, UK) and stained with May-Grun-wald-Giemsa stain. Differential cell counts were made by a blinded observer. Three hundred nonsquamous cells were counted on two slides for each sample in a blind way. Differential cell counts are expressed as percentages of nonsquamous cells. Two of the sputum samples from the same patient in budesonide treatment group at different visits were withdrawn from analysis because of containing > 80% squamous cells (Table 2).

IL-8 Assay

The concentration of IL-8 in sputum supernatant was determined using commercially available enzyme-linked immunosorbent assay (R&D Systems; Minneapolis, MN) according to the manufacturer instructions.

Statistical Analysis

Results are reported as mean ± SEM. We compared patients who lost control of asthma with those who did not after corticosteroid withdrawal. All statistical tests were two sided, and significance was accepted at the level of 95% and p < 0.05 using statistical software (GraphPad Prism; GraphPad Software; San Diego, CA). To determine whether changes in sputum neutrophil counts and sputum IL-8 levels accompanied asthma exacerbation, the differences of the last-visit measurements from baseline were used for analysis of correlation with Pearson product-moment technique. The data from subjects with and without exacerbation at each time point were categorized as a group before analysis. Sputum neutrophil counts, percentage of neutrophils, and IL-8 levels 2 weeks prior to an exacerbation were compared to those of the week-8 inflammatory markers in nonexacerbation group using the unpaired t test. The last-visit measurements of the exacerbation and nonexacerbation groups were also evaluated by the unpaired t test.

Table 1—Patient Characteristics

Characteristics Steroid Withdrawal Budesonide Age, yr 36.9 ± 2.5 38.3 ± 3.1 Male/female gender, No. 4/8 5/7 Atopy, No. 10 9 Postbronchodilator FEVj, L 3.87 ± 0.17 3.75 ± 0.1 Reversibilty, % 20.4 ± 1.0 20.7 ± 1.2 PC20, mg/mL 0.98 ± 0.26 0.99 ± 0.27

Table 2—Total and Specific Sputum Cell Counts After Budesonide

Variables Weeks of Budesonide Treatment 0 2 4 6 8 10 Patients, No. 10 10 10 10 10 10 FEVj, % predicted Exacerbation, No. 72.3 ± 1.5 73.4 ± 2.1 1 71.8 ± 0.9 73.7 ± 0.6 73.2 ± 1.1 72.8 ± 1.7 Total cells, 106/mL 3.4 ± 0.3 3.2 ± 0.3 3.6 ± 0.2 3.2 ± 0.2 3.5 ± 0.4 3.6 ± 0.6 Neutrophils, % 33.9 ± 3.7 41.3 ± 4.1 38.2 ± 2.1 36.4 ± 5.2 37.7 ± 3.8 38.4 ± 4.5 Neutrophils, 106/mL 1.2 ± 0.6 1.3 ± 0.5 1.4 ± 0.4 1.2 ± 0.5 1.3 ± 0.6 1.3 ± 0.7 Eosinophils, % 4.8 ± 1.0 2.6 ± 0.8 1.8 ± 0.6 1.2 ± 0.5 0.45 ± 0.2 0.3 ± 0.1 Eosinophils, 106/mL 0.2 ± 0.03 0.09 ± 0.02 0.06 ± 0.03 0.04 ± 0.01 0.01 ± 0.004 0.02 ± 0.01 Macrophages, % 57.9 ± 3.4 53.3 ± 3.9 57.6 ± 2.7 60 ± 5.5 59.7 ± 4.8 59.5 ± 4.9 Macrophages, 106/mL 1.9 ± 0.2 1.7 ± 0.2 2.1 ± 0.2 2.0 ± 0.2 2.1 ± 0.9 2.2 ± 0.4 Lymphocytes, % 3.3 ± 0.9 2.8 ± 0.7 2.5 ± 0.7 2.4 ± 0.6 2.1 ± 1 2.0 ± 0.7 Lymphocytes, 106/mL 0.1 ± 0.01 0.1 ± 0.01 0.1 ± 0.02 0.07 ± 0.02 0.08 ± 0.03 0.1 ± 0.03

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Loss of Asthma Control Following Inhaled Corticosteroid Withdrawal

Although eosinophilic airway inflammation is recognized as an important feature of some patients with chronic, stable asthma, evidence supports an important role of neutrophils in acute exacerbations. In stable asthma, there is typically an infiltrate of eosinophils, which occurs in response to cytokines such as interleukin (IL)-5, secreted by

T-helper type 2 lymphocytes. In contrast, during acute exacerbations of asthma, the airway inflammatory response is both more intense and heterogeneous. The increased intensity of airway inflammation is reflected by an elevated total cell count in sputum. The heterogeneity of the inflammatory response is reflected by an increase in neutrophils as well as eosinophils, and there are reports of exacerbations without sputum eosinophilia. There is also evidence for increased expression of the potent neutrophil chemoattractant IL-8, in addition to the presence of IL-5. There is heterogeneity in the concentrations of IL-8 in patients with moderate asthma and the strong correlation between the concentration of IL-8 release by peripheral blood mononuclear cells and the frequency of asthma exacerbations. Buy asthma inhalers online to arrest asthma attacks (read about Ventolin and Flovent) .

Leukocytes, particularly neutrophils and eosinophils, are the first cells recruited to the site of tissue damage after an inflammatory insult. These cells are then removed by apoptosis during the resolution of the inflammatory response. Neutrophils are the predominant inflammatory leukocyte characterizing airway inflammation in acute severe asthma, and this may influence the clinical presentation, predisposing to a sudden severe attack. IL-8 is a key chemokine involved in the recruitment of neutrophils to the area of inflammation, but few studies have characterized the kinetics of IL-8 production in sputum over a period of time prior to the onset of a clinical asthma exacerbation. Because it is not possible to obtain this information prospectively with a naturally occurring exacerbation, we induced loss of control of asthma by withdrawing inhaled corticosteroids so that we were able to make prospective measurements of inflammatory indexes in induced sputum. This was done in a double-blind controlled manner so that steroid withdrawal could be compared with continued therapy with inhaled corticosteroids.

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Treatment of Exercise-induced Asthma. Canadian Health&Care Mall Suggests Ventolin Inhalers

The hypothesis of Szentivanyi that bronchial asthma is associated with impaired 0-adrenoceptor function has been tested in several investigations in recent years. Most of these studies have been performed on leukocytes from peripheral blood, since these cells are easily accessible and since they are endowed with 0-adrenoceptors of the 02-subtype, as is human lung tissue. The interpretation of results from some of these studies is confounded by the findings that the (3-adrenoceptors of white blood cells are down-regulated by antiasthmatic therapy with β-adrenoceptor agonists. Such down-regulation of 0-adrenoceptors in white blood cells disappears within one week after discontinuation of treatment.

Some controversy still exists as to whether 0-adrenoceptors in white blood cells are altered or not in asthma. There are reports suggesting a reduced response to 0-adrenergic stimulation in untreated patients or a reduction of 0-adrenoceptor binding sites not ascribed to antiasthmatic therapy. However, most studies indicate that white blood cells from nonmedicated asthmatic patients have normal cyclic AMP (cAMP) responses to 0-adrenoceptor stimulation, normal adenylate cyclase activity, and normal amounts of 0-adrenoceptor binding sites.

Studies of various in vivo responses to 0-adrenergic stimulation in nonmedicated asthmatic patients have also yielded variable results. Shelhamer and co-work-ers showed reduced pulse pressure and plasma cAMP responses to intravenous infusions of isoprenaline both in asthmatic subjects and atopic subjects. Apold and Aksnes showed a diminished plasma cAMP response to adrenaline in untreated asthmatic children. However, Tattersfield and co-workers found no evidence in favor of reduced bronchodilator responses to salbutamol in patients with mild asthma. However, since asthmatic patients usually have at least some degree of (subclinical) bronchoconstriction, it is difficult to evaluate P-adrenoceptor sensitivity in the target organ by comparisons of bronchodilator responses to (3-agonists in asthmatic patients and healthy control subjects due to differences in baseline measurements. The healthy subjects will, of course, dilate their bronchi less readily due to the absence of bronchoconstriction. Other studies of P-adrenoceptor responsiveness in asthma have not clearly stated that the experiments were performed in a drug-free interval. To reduce the risk of asthma attacks you may if you buy asthma ventolin inhalers.

All the above-mentioned studies have been carried out on patients with allergic asthma. We were interested also in studying the subgroup of patients with exercise-induced asthma (EIA), since exercise is a rather effective means of increasing circulating adrenaline, and EIA could be associated either with a blunted adrenaline response to exercise or a diminished bronchodilator response to adrenaline. We have previously reported that EIA patients have a normal plasma adrenaline response to exercise. The possibility that EIA is associated with blunted (mediated responses was therefore examined in the present study. The aim of the study was twofold: first, to examine P-adrenoceptor sensitivity both in lymphocytes in tntro and during isoprenaline infusions in vivo, since few in vivo studies have been performed, and second, to compare the responses of healthy control subjects to those of nonmedicated patients with EIA or nonexercise induced asthma (NEIA). Our in vivo studies with isoprenaline iniusions are performed with a technique, in which the various responses are related to the plasma concentrations of isoprenaline instead of the dose.

Material and Methods

Subjects

The investigation was comprised of two studies. In study I, eight patients with a history of exercise-induced asthma (EIA), eight age-and sex-matched patients with asthma not induced by exercise (NEIA), and eight similarly matched healthy control subjects participated. Details of these subjects have been presented elsewhere. In study 2, eight patients with EIA, selected on the same grounds as the EIA patients in study 1, and seven age- and sex-matched healthy control subjects participated. All EIA patients but none of the control patients or NEIA patients participating in the present investigation had decreases of FEV, of >15 percent following a standardized pretrial exercise test described previously. At this pretrial examination, all subjects had basal pre-exercise FEVj values greater than 75 percent of their predicted values. In study 2, the EIA patients (seven males) were aged 16 to 35 years and the control subjects (six males), 15 to 36 years. Previous ventolin inhalers therapy in study 1 has been presented in detail. Previous therapy in the EIA group of study 2 was terbutaline aerosol when required (three patients), terbutaline aerosol and tablets when required (two), disodium cromoglycate (DSCG) when required (one), DSCG tid and salbutamol aerosol when required (one), and choline theophyllinate tablets when required (one patient). Thus, a total of 16 EIA patients, eight NEIA patients, and 15 healthy control patients participated in the investigation after a period of one week or more without any medication. Fourteen of the 16 EIA patients also had verified allergies. All patients in the present investigation had mild to moderate asthma, since they were required to be free from drug treatment during at least one week before the investigation. All subjects were nonsmokers and were asked to abstain from caffeine containing beverages on the day of the experiment. The subjects gave their informed consent before participating and the study protocol had been approved by the Ethics Committee of the Karolinska Institute.

Analytical Procedures

Lymphocytes: Sixty ml of peripheral venous blood was diluted in an equal volume of balanced salt solution containing 5000 IU heparin. The diluted blood was carefully layered on a solution of Ficoll-Paque (Pharmacia) with a density of1.077 ± 0.001 g/cm. After centrifugation (30 minutes at 400 x g and 18°C), the lymphocyte layer was carefully removed and diluted in the balanced salt solution. The lymphocyte suspension was centrifuged at 250 x g for 10 minutes at 18°C. The supernatant was discarded, and the pellet resuspended and washed using the same procedure. The final pellet was suspended in Dulbeccos phosphate buffered saline (PBS) containing 5.5 mM glucose and kept cold until incubated. The cells were counted in a Burker chamber and diluted with PBS to give a final concentration in the incubation step of 2-3 X106 cells/ml. Only plastic materials or siliconized glassware was used. The procedure yielded a cell preparation consisting of more than 90 percent mononuclear cells of which more than 90 percent were lymphocytes. Viability, as measured by trypan blue dye exclusion, was >95 percent.

To study P-adrenoceptor mediated cyclic AMP (cAMP) accumulation, the cells were incubated with 0 (blank), or 10~-10-4 M isoprenaline. Ascorbic acid (110 μ.М) was present in all incubates to prevent catecholamine oxidation. In study 1, concentration-effect curves for isoprenaline were also performed in the absence and presence of 30 nM (-)-propranolol and 50 jiM atenolol. The shifts of the dose-response curves were used to calculate pA^values for the two р-adrenoceptor antagonists. In these experiments, the isoprenaline response was amplified by the addition of the phosphodiesterase inhibitor 3-isobutyl-l-methyl-xanthine (IBMX, 0.5 mM).

The incubation was started by adding 40 |xl of lymphocyte suspension to 160 ц.1 of ice-cold PBS containing the above-mentioned drugs. The cells were then incubated for 20 minutes at 37°C, after which the incubation was stopped by heating to 85 to 90°C for three minutes. The samples were subsequently cooled and stored at — 20°C until analyzed for cAMP contents by the protein binding method of Brown and co-workers. Incubations were performed in duplicate or triplicate, and cAMP was subsequently determined in duplicate, using 50 \l\ aliquots from each incubate.

Plasma Assays: Venous blood samples were collected in ice-cold centrifuge tubes containing EDTA (10 mM final concentration). Following centrifugation at + 4°C, the plasma was removed and stored at — 80°C until analyzed. Plasma catecholamines were determined by high performance cation exchange liquid chromatography with electrochemical detection. In our laboratory, the sensitivity is better than 0.05 nM (7 to 9 pg/ml) for noradrenaline, adrenaline, and dopamine, and approximately 0.1 nM for isoprenaline in plasma. For the endogenous catecholamines the interassay and intraassay coefficients of variation have been estimated to be 9 to 12 percent at 0.1 to 0.2 nM and 2 to 3 percent above 1 to 2 nM; for isoprenaline these coefficients are 3 to 9 percent at 0.5 nM and 1.4 to 5 percent at 3 nM. Plasma cAMP was determined by the protein binding method of Brown et аl, and glycerol by an enzymatic micromethod.

Experimental Procedure

Venous cannulae were inserted into antecubital veins on both arms (one for blood sampling and one for infusions). After five to ten minutes of rest, 60 ml of blood was taken for the lymphocyte studies. After a further 30 minute rest period, the subjects in study 1 performed an exercise test, the results of which have been reported. Ibirty minutes after this exercise test, an isoprenaline infusion test was performed using two dose levels of isoprenaline (0.02 and 0.1 jig x kg’ x min). During isoprenaline infusions, heart rate was monitored continuously by ECC. Blood pressure was determined with a conventional cuff technique at rest and after six and eight minutes on each isoprenaline dose level. After the eight minute measurements, a 10 ml blood sample was drawn and the isoprenaline infusion interrupted for lung function measurements in a whole-body plethysmograph, followed by spirometric measurements of FEVt and vital capacity. The plethysmographic measurements included lung volumes and airway resistance, from which specific airway conductance (Sgaw) was calculated. Due to the preceding exercise test in study 1, results from the isoprenaline infusion test in that study were only used for exploratory purposes. In study 2, a similar procedure was used, but the subjects were not subjected to the exercise test and three dose levels of isoprenaline (0.02, 0.05 and 0.1 jigxkg_1xmin 4, each step lasting eight minutes) were used.

Statistical Analysis

Results are presented as mean values ± SEM. Plasma concentration-response curves for isoprenaline in the in vivo infusion tests and dose-response curves in the in vitro experiments were compared by analysis of covariance. When appropriate, Students f-test for paired or unpaired variates was used. A value of p<0.05 was considered significant.

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New Post has been published on Flovent Inhaler Online for Asthma Treatment

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Asthma. Main Features. Treatment by Ventolin Inhalers

Twelve subjects were studied. All were wheezing at the time of study and all had moderate-to-severe airways obstruction with an FEV! between 720 ml and 1,500 ml. Table 1 shows the FEV, on pulmonary function tests done before and after bronchodilators, performed within four weeks of the lung sound recording.

Five five-minute periods of observation were studied in each patient. To determine the most efficient number of samples to be randomly chosen, we compared 5, 25, 50, and 75 samples per five-minute period. As shown in Table 2, the ratio for intersubject variation was significantly greater when 50 segments were analyzed rather than five segments. The addition of 25 more segments did not appear to add any additional information. We chose to analyze 50 segments per five-minute period.

Comparing sounds with corresponding spectrums, we found that an audible wheeze was associated with a peak with a narrow frequency band and a frequency between 150 and 1,000 Hz as noted previously. Figure one shows two segments of the sound signal, one with and one without a peak. The FFT of the sound signal associated with a wheeze always had a peak similar to that seen on the left in Figure 1.

The minimum peak height to be considered as a wheeze was studied. Table 3 compares Est Tw/Ttot with FEVb using different criteria for peak height.

Among patients, a significant correlation was found between the FEV! and the percentage of segments with peaks three or more times baseline (Est Tw/Ttot) as shown in Figure 2 (r =.89, p<0.001). Table 4 shows the estimated Tw/Ttot for each subject for all five five-minute segments. All peak heights shown were associated with a significant correlation with FEVb but the use of three times baseline as the minimal peak value was associated with the highest F ratio on analysis of variance comparing intersubject vs intrasubject variation. Asthma sufferers prefer to treat asthma and arrest the attacks with the help of ventolin inhalers – buy-asthma-inhalers-online.com.

Five subjects underwent eight sleep studies. None showed significant desaturation during the night. No patient had apnea. Figure 3 shows the sleep stages and wheezing of one patient. The percentage of wheezing (Est Tw/Ttot) for every five-minute period from 11 pm to 6 am is shown. There are several time intervals during the night when there was little wheezing and other times with a large amount of wheezing.

Previous studies have compared airflow obstruction at midnight and at 4 am. The Est Tw/Ttot from midnight to 12:30 am was compared with that from 4:00 to 4:30 am for the eight sleep studies (Fig 4). More wheezing, and therefore more obstruction, was found between 4:00 and 4:30 am (p<0.05).

Figure 1. Frequency spectrum of 250 ms of sound signal. Left panel reveals a sharp peak at 490 Hz corresponding to an audible wheeze. Right panel has no significant frequency peaks above 150 Hz.

Figure 2. Comparison of FEVi to the estimated Tw/Ttot (r = 0.89, p<0.001).

Figure 3. One subject studied through night. Study began at midnight. Lower panel is estimated Tw/Ttot. Upper panel shows corresponding sleep stage (W is awake; R, REM sleep; 1-4, sleep stages 1 to 4).

Figure 4. Est Tw/Ttot for Midnight to 12:30 am vs 4:00 am to 4:30 am (p<0.05).

Table 1—Results of Pulmonary Function Tests Obtained Within Four Weeks of Study

Before After Bronchodilators Bronchodilators Subject Age FEVj, L FEV„ L 1 42 1.20 1.58 2 50 1.00 1.36 3 23 .81 1.08 4 62 1.58 1.92 5 52 .90 1.25 6 40 .80 1.19 7 22 .97 1.32 8 52 .83 1.02 9 49 .77 1.21 10 50 1.11 1.50 11 55 1.20 1.50 12 31 1.41 1.80

Table 2—Accuracy of Estimated TwITtot Using Analysis of Variance: Effect cf Varying the Number of Samples

No. Samples Intersubject Variation (F ratio) Intrasubject Variation (F ratio) 5 7.27 1 25 10.76* 0.38 50 39.37t 1.28 75 90.13+ .23

Table 3—Accuracy af Estimated TwITtot: Effect of Varying the Minimum Peak Height

Peak Height Compared to Baseline Correlation Est Tw/Ttot vs FEV, Intersubject Variation (F Ratio) 2 times .898* 43.3* 3 times .893* 55.0* 5 times .767* 28.lt 8 times .641t 14.5$

Table 4—Estimated Tw/Ttot for Patients

FEV,, L Estimated Tw/Ttot (%)For Each Five Minute Segment 1.20 20 24 18 26 30 1.20 18 22 30 36 24 1.00 22 36 28 54 32 1.50 4 2 4 4 6 1.36 8 6 4 10 4 .80 56 36 50 48 48 .97 42 42 32 50 32 1.30 18 10 10 4 6 .72 66 60 66 74 72 .85 46 42 40 44 42 1.20 20 22 18 26 16 1.29 32 28 20 18 24

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Asthma Therapy With Ventolin Inhaler

In Europe, as on other continents, bronchial asthma is a common disorder with widely variable clinical features. It is frequently not diagnosed and, if diagnosed, its severity is often underestimated by the medical profession as well as by patients and their families. Failure to diagnose or to correctly estimate the severity leads to considerable undertreatment. Moreover, in few other chronic conditions have more divergent opinions been noted concerning the correct type and order of treatment to be applied to the chronic state of the disease, as well as to its acute exacerbations. This was also brought out by a pilot survey conducted on the basis of a questionnaire among 68 chest physicians from seven European countries during the summer of 1983; although clear patterns of responses emerged among the physicians of each country, there was considerable disagreement among countries on the proper choice and dosage of drugs and ventolin inhalers for asthma therapy. Because of the interest generated by the presentation and the discussion of this survey at the Second Annual Meeting of the European Society of Pneumology in Edinburgh, it was decided to enlarge the scope into a complete European Audit on Diagnosis and Treatment of Asthma, covering all major countries of western Europe and using an improved and extended questionnaire.

Methodology of the 1984 European Audit

The questionnaire now also included questions on diagnosis and management of asthma, as well as on patient information and education. However, the emphasis was on treatment of chronic (stable) asthma, both in adults and in children. The main questions were the following:

1. In patients whose asthma is stable and not acutely deteriorating:

a. what is the considered order (sequence) of treatment for maintenance (8 choices to be numbered 1 to 8);

b. how often are a number of drugs used as “first line” therapy for regular maintenance (never, sometimes, often, always)?

2. For allergic asthma, how often is desensitisation used (same gradations as for lb)?

3. If they are used, what is the recommended metered-dose of inhaled beta-agonists and steroids (in number of puffs daily: 0-5, 5-10, 10-15,15-20, more than 20)?

4. If patients with mild/moderate asthma are unable to satisfactorily use a metered-dose inhaler, what is the order of preference (1 to 4) for an alternative delivery system?

A total of 3,305 questionnaires were mailed in June 1984 (1,075 to members of the European Society of Pneumology and 2,230 to other physicians in 16 countries). The latter were either non-pediatric (adult) specialists, pediatricians, or general practitioners and they were randomly selected within their country by the Glaxo Company. The time comes to purchase ventolin inhaler for asthma treatment via buy-asthma-inhalers-online.com.

French questionnaires were used in France and Portugal, German in western Germany and Austria, and the Spanish version was distributed in Spain. Physicians in the other countries received the English version. In a covering letter, responding physicians were encouraged to express in their answers their average attitude in their average asthma patient.

The present analysis for 16 countries (Table 1) is based on 735 answers from adult specialists (88 percent of whom were chest specialists) and 209 responses from pediatricians. Response rates were 40 percent and 27 percent respectively. Only for seven countries did the number of responses from pediatricians exceed 10, which was considered a minimum for meaningful analysis.

For all possible answers, the percentage of the total picking that answer was calculated. For questions about frequency of use or the order of treatment, a mean score was also calculated (Table 2). Furthermore, for all percentages and scores (provided that the number of responses of all countries exceeded 10), a mean European answer (MEA) was calculated in which the answers of each country were weighted for the population supposedly served by the specialists in that country.

A brief account of the results will be given here. Two preliminary reports have already been published, and a more complete report is in preparation.

Table 1—Responses from 16 Countries

Regions Countries AdultSpecialists Pediatricians British Great Britain (GB) 132 60 Isles Ireland (IRL) 13 (10) Northern Denmark (DK) 39 27 Norway (N) 28 24 Sweden (S) 32 11 Finland (SF) 27 (0) Western France (F) 128 28 Belgium (B) 50 (5) Netherlands (NL) 48 (3) Central Germany (D) 79 11 Switzerland (CH) 53 (7) Austria (A) 27 12 Southern Italy (I) 28 (2) Greece (GR) 14 (4) Spain (E) 23 (2) Portugal (P) 14 (3) Total 735 209

Table 2—Analysis

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Ventolin Inhaler for treatment asthma - Canadian Health&Care Mall Advice

The prevalence of asthma and allergic disease has increased substantially during recent decades, and to a large extent the causes for this increase are still imperfectly understood. It is well recognized that the incidence of asthma is greater in childhood compared to adulthood, and that the male subject/ female subject ratio of incident asthma diminishes with increasing age. However, an interest in adult-onset asthma has emerged, not in the least due to reports coming from several large-scale longitudinal studies from Europe (European Community Respiratory Health Survey2) and the and United States (National Health and Nutrition Examination Study), pointing out the growing impact of adult respiratory allergic disease morbidity. No single hypothesis can explain this widened distribution of disease, but a biologically plausible model is likely to include environmental risk factors associated with a westernized lifestyle interacting with individual susceptibility genotypes. In a search for factors fitting such a model, several environmental determinants have been shown be part of the cause of adult-onset wheezing illness, including female sex, upper airway allergic disease, sensitization to aeroallergens,> obesity, exposures encountered at work, and perhaps hormone replacement therapy. Still, longitudinal data on incident asthma among adults are sparse, and the study of these data may therefore provide new insight into the development and natural history of the disease.

By means of a prospective questionnaire study, the objective of this survey was to determine the incidence of asthma and to examine the age-dependent and sex-dependent risk for adolescent-onset and adult-onset asthma from 1994 through 2002. Furthermore, we wanted to provide risk estimates for incident asthma during the intervening 8-year period given information on hay fever, eczema, body mass index (BMI), smoking, and leisure time physical activity.

Study Design

The study population is based on the birth cohorts from 1953 to 1982 that were ascertained from The Danish Twin Registry. In 1994, a mailed questionnaire was answered by 29,180 twin individuals (86%),n and for an 8-year follow-up analysis in 2002, 21,162 of those twin individuals (73%) participated. We observed similar response rates in the different age and sex groups across surveys. Of those participating in both surveys (21,162 subjects), a total of 19,349 subjects with no reported history of asthma in 1994 were identified, and analyses of incident asthma were based on this sample. It is a known fact asthma should e treated by ventolin inhalers and by nothing more – buy-asthma-inhalers-online.

A questionnaire with items aimed at identifying multiple phenotypes, including identical questions on asthma, was used to assess subjects on both occasions. Affected cases were identified on the basis of responses to the question “Do you have, or have you ever had asthma?” Individuals answering “yes” to that question were classified as having or having had asthma. This procedure has previously been shown to be reliable with respect to identifying subjects with asthma in population-based studies that use questionnaire responses as the sole diagnostic criterion. Similar questions were applied to detect subjects with hay fever and eczema.

Subjects were stratified into the following four separate categories on the basis of answers to questions on smoking history: (1) current daily smokers (subjects who smoked more than one cigarette, one cigar, one cheroot, and/or 1 g of pipe tobacco per day); (2) occasional smokers (subjects who smoked less than one cigarette, one cigar, one cheroot, or 1 g of pipe tobacco per day on average); (3) former smokers (subjects who have stopped smoking any time prior to the date of assessment); and (4) never smokers (subjects who have never smoked).

Subjects were divided into the following three categories owing to the quantity of weekly leisure time physical activity: (1) light physical activity (subjects who spend < 2 h per week on light exercise activities); (2) moderate physical activity (subjects who spend between 2 h per week on light exercise activities and 4 h per week on heavy exercise activities); and (3) heavy physical activity (subjects who spend > 4 h per week on heavy exercise activities).

Statistical Analysis

The data were analyzed with a statistical software package (R: A Language for Data Analysis and Graphics; R. Gentleman, GNU Project, Free Software Foundation; Boston, MA). Overdispersion could be expected to a certain extent due to intrapair correlation of asthma. The overdispersion parameter was estimated to be equal to 1.068, which means that the intrapair correlation of asthma in this cohort is very small. Furthermore, the studied cohort comprised 35% single twins, which also provides us with ample authority to consider the entire sample of twins as if it was composed of single uncorrelated individuals (ie, the confidence intervals [CIs] reported fall 2 to 3% narrow of that ideal situation).

Since we did not know the exact time of the onset of asthma in each subject, we calculated the incidence rates of asthma under the assumption that each incident case of asthma on average acquired asthma in the middle of the study period (ie, after 4 years). This approach gave us a total of 151,440 person-years under observation.

The probability of acquiring asthma depends on age and BMI in a fashion that is still poorly understood. We analyzed the age-dependent and BMI-dependent risk of new asthma by means of a generalized additive model, which allowed us to handle age and BMI as continuous variables when the analyses were performed separately for subjects 12 to 19 and 20 to 41 years of age.

Logistic regression modeling was applied to investigate associations among risk factors for having asthma. Separate analyses were performed for the age groups 12 to 19 years and 20 to 41 years, with incident asthma from 1994 through 2002 as response, and with sex, age, smoking, and leisure time physical activity as explanatory variables. BMI was also included in the older age group. BMI was calculated as weight in kilograms divided by the square of height in meters.

The analyses of incident asthma in relation to eczema and hay fever were done by means of two-way tables stratified on sex, for the entire cohort. Results are reported as odds ratios (ORs). A p value of < 0.05 was considered to be statistically significant. The protocol was evaluated and approved by the local ethics committee.