Cross-tachyphylactic airway response to inhaled bradykinin, kallidin and [desArg9]-bradykinin in asthmatic subjects

Kinins are oligopeptides that may act as mediators in the pathogenesis of bronchial asthma by interacting with specific cell surface receptors designated B1 and B2. When administered by inhalation to asthmatic subjects, bradykinin and kallidin, but not [desArg9]-bradykinin, provoke potent bronchoconstriction, thus suggesting a specific effect compatible with the stimulation of B2 receptors. To characterize further the receptor(s) mediating this bronchospastic response we have carried out cross-tachyphylactic studies with inhaled bradykinin, kallidin, and [desArg9]-bradykinin, administered in a randomized double-blind fashion in a group of 10 asthmatic subjects. Inhalation of bradykinin and kallidin, but not [desArg9]-bradykinin, elicited concentration-related falls in forced expiratory volume in one second (FEV1) in all the subjects studied. The geometric mean provocation concentrations of inhaled agonists reducing FEV1 by 20% of baseline (PC20) were 0.12 and 0.28 mg.ml-1 for bradykinin and kallidin, respectively. When inhaled at concentrations up to 10.62 mg.ml-1, [desArg9]-bradykinin failed to provoke any significant fall in FEV1 from baseline in any of the subjects studied. Following recovery from the second bradykinin challenge, provocation with kallidin revealed a reduced response to this agonist, the PC20 value increasing from 0.28 to 1.23 mg.ml-1. Similarly, once the airways had recovered from the second kallidin challenge, provocation with bradykinin also showed a reduced response, the PC20Bk increasing from 0.12 to 0.94 mg.ml-1. Surprisingly, despite failing to cause bronchoconstriction, repeated exposures with inhaled [desArg9]-bradykinin reduced the airway response to bradykinin, the PC20Bk increasing from 0.12 to 0.41 mg.ml-1.(ABSTRACT TRUNCATED AT 250 WORDS)     

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

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

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

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

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

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

Ozone effects on the immediate-phase response to allergen in the nasal airways of allergic asthmatic subjects

The human CASP8 gene, whose product is also known as caspase 8 and FLICE, encodes an interleukin-1beta converting enzyme (ICE)-related cysteine protease that is activated by the engagement of several different death receptors. Caspase 8 is immediately recruited to the Fas receptor once it oligomerizes, and its protease activity is crucial for the apoptotic response generated by the resulting death-inducing signaling complex (DISC). We report here that the CASP8 gene contains at least 11 exons spanning approximately 30kb on human chromosome band 2q33-34. This region of human chromosome 2 was previously reported as the location of the CASP10 gene, whose product is closely related to caspase 8. Chromosome 2 band q33-34 is also involved in tumorigenesis, with loss of heterogeneity (LOH) being reported in a number of tumors. We also report EcoRI and HindIII polymorphisms that may prove to be useful in disease analysis. Both caspases 8 and 10 contain long pro-domains with duplicated death effector domains (DEDs), as well as their corresponding cysteine protease catalytic domains. Thus, it appears that CASP8 and CASP10 have evolved by tandem gene duplication, much like the CASP1, CASP4 and CASP5 gene cluster on human chromosome 11q22.2-22.3.     

Loss of normal cyclical beta 2 adrenoceptor regulation and increased premenstrual responsiveness to adenosine monophosphate in stable female asthmatic patients

BACKGROUND: A study was undertaken to investigate the influence of the menstrual cycle on airway responsiveness and beta 2 adrenoceptor function in female asthmatic patients. It has previously been shown that normal women exhibit cyclical changes in beta 2 adrenoceptor function with an increase in beta 2 adrenoceptor density in the luteal phase during the premenstrual period. METHODS: Fifteen women with stable, well controlled asthma (mean forced expiratory volume in one second (FEV1) 2.971 (93.8% predicted)) were evaluated. Measurements were made at the follicular phase (days 1-6) and the luteal phase (days 21-24) of the menstrual cycle. Airway responsiveness was assessed using adenosine 5'-monophosphate (AMP) and expressed as PC20 AMP. Beta 2 adrenoceptor function was evaluated by measuring lymphocyte beta 2 adrenoceptor parameters and constructing dose-response curves to salbutamol (100-1600 micrograms). The levels of female sex hormones were also measured at both phases of the cycle. RESULTS: There were significant increases in serum levels of both oestradiol (2.2-fold, p < 0.001) and progesterone (7.2-fold, p < 0.05) between the follicular and luteal phases. Geometric mean PC20 AMP was 19.0 mg/ml and 7.6 mg/ml during the follicular and luteal phases, respectively (p < 0.05), a 2.51-fold difference (95% CI 1.19 to 5.30) amounting to 1.33 doubling doses of AMP. There was no change in lymphocyte beta 2 adrenoceptor parameters or in airway beta 2 adrenoceptor responses to salbutamol between the two phases. CONCLUSIONS: Despite an appropriate rise in female sex hormones during the luteal period, beta 2 adrenoceptor regulation in female asthmatic subjects shows a loss of the normal cyclical pattern. In addition, there were cyclical changes in airway responsiveness to AMP which was highest during the premenstrual period. Thus, drugs such as theophylline which block adenosine receptors warrant investigation in premenstrual asthma.     

Perception of the role and potential side effects of inhaled corticosteroids among asthmatic patients

BACKGROUND: Misunderstanding of the role of asthma medication and fear of untoward side effects may reduce compliance to therapy, potentially resulting in poor asthma control and increased risk of severe asthma events. METHODS: We report the results of a recent Canadian survey of 603 asthmatic patients recruited from the general population, aimed at determining their perception of the role and potential side effects of inhaled corticosteroids (ICS). RESULTS: The survey revealed that a large proportion of asthmatic patients do not understand the role of their medications and have many misconceptions and fears in regard to ICS, reducing their willingness to use them. Among the most common fears are those concerning troublesome side effects, particularly in regard to corporeal image, bone density, and a reduction in efficacy of medication over time. More than half of the population said they were very or somewhat concerned using ICS on a regular basis; two thirds of patients had not discussed their concerns about ICS with their physicians or other health-care professionals. Finally, in a large number of asthma patients, asthma was not adequately controlled, according to recent asthma consensus guidelines. CONCLUSIONS: These observations stress the importance for those involved in asthma care of questioning patients about their understanding of the role of asthma medications, particularly ICS, their fears and misconceptions, and what they consider to be adequate asthma control, in order to provide appropriate education and counseling.     

Blood markers of early and late airway responses to allergen in asthmatic subjects. Relationship with functional findings

Resistance exercise has been suggested to increase blood volume, increase the sensitivity of the carotid baroreceptor cardiac reflex response (BARO), and decrease leg compliance, all factors that are expected to improve orthostatic tolerance. To further test these hypotheses, cardiovascular responses to standing and to pre-syncopal limited lower body negative pressure (LBNP) were measured in two groups of sedentary men before and after a 12-week period of either exercise (n = 10) or no exercise (control, n = 9). Resistance exercise training consisted of nine isotonic exercises, four sets of each, 3 days per week, stressing all major muscle groups. After exercise training, leg muscle volumes increased (P < 0.05) by 4-14%, lean body mass increased (P = 0.00) by 2.0 (0.5) kg, leg compliance and BARO were not significantly altered, and the maximal LBNP tolerated without pre-syncope was not significantly different. Supine resting heart rate was reduced (P = 0.03) without attenuating the heart rate or blood pressure responses during the stand test or LBNP. Also, blood volume (125I and 51Cr) and red cell mass were increased (P < 0.02) by 2.8% and 3.9%, respectively. These findings indicate that intense resistance exercise increases blood volume but does not consistently improve orthostatic tolerance.     

Cyclic adenosine monophosphate and the development of Polysphondylium

A procedure is described for the quantitative extraction of phenols from human urine. The compounds were chromatographed as the trimethylsilyl derivatives on wall-coated glass capillary columns. A more specific method of extraction involving the formation of acetate derivatives is also described. The acetates were prepared by treating dilute solutions of phenols at room temperature with acetic anhydride in the presence of 4-dimethylaminopyridine, which is a far more powerful catalyst than pyridine. Under these conditions N-acylamino acids are converted to azlactones.     

Effect of inhaled cyclosporin A on the allergen-induced late asthmatic response and increased in airway hyperresponsiveness in a guinea pig model of asthma

Oral administration of cyclosporin (CsA), a potent inhibitor of helper T cell function, prevents the allergen-induced late asthmatic response (LAR) and the increase in airway hyperresponsiveness (AH) seen in actively sensitized guinea pigs. The systemic administration of this agent in humans has been associated with serious side effect, therefore, the effects of inhaled CsA were therefore examined in guinea pigs that were actively sensitized by repeated exposure to nebulized ovalbumin. Respiratory resistance (Rrs) of the animals was measured by an oscillation method and the extent of AH was inferred from the inhaled concentration of histamine required to increase Rrs by 200%. The magnitude of ovalbumin-induced immediate bronchoconstriction after sensitization was similar in CsA-treated and nontreated control animals. However, a LAR was observed in 4/5 control animals but in 0/5 CsA-treated animals. The increase in AH observed 24 hours after antigen exposure in control animals was significantly inhibited by prior CsA inhalation. Significant CsA concentrations were detected by radioimmunoassay in the lungs of CsA-treated animals. Thus, inhaled CsA should be further investigated because it may be useful treating asthma while avoiding side effects.     

Pentobarbital enhances cyclic adenosine monophosphate production in the brain by effects on neurons but not glia

BACKGROUND: Cyclic adenosine monophosphate (cAMP) is an important regulator of neuronal excitability. The effects of barbiturates on cAMP production in intact neurons are not known. This study used cultures of cortical neurons, cultures of glia, and slices of cerebral cortex from the rat to study the effects of barbiturates on cAMP regulation in the brain. METHODS: Primary cultures of cortical neurons or glia were prepared from 17-day gestational Sprague-Dawley rat fetuses and were used after 12-16 days in culture. Cross-cut slices (300 microns) were prepared from cerebral cortex of adult rats. Cyclic AMP accumulation was determined by measuring the conversion of [3H]adenosine triphosphate (ATP) to [3H]cAMP in cells preloaded with [3H]adenine. RESULTS: Pentobarbital enhanced isoproterenol- and forskolin-stimulated, but not basal, cAMP accumulation in cultures of cerebral neurons. Cyclic AMP production was enhanced by pentobarbital in a dose-dependent fashion up to a concentration of 250 microM; This concentration of pentobarbital increased cAMP production by 40-50% relative to that in controls without pentobarbital. At 500 microM pentobarbital, the magnitude of the enhancement was less. Pentobarbital had no effect on isoproterenol-stimulated cAMP production in cultures containing only glia. Pentobarbital also enhanced isoproterenol-stimulated, but not basal, cAMP production in slices of cerebral cortex by approximately 30% at concentrations of 62.5-250 microM and by almost 100% at 500 microM. CONCLUSIONS: Pentobarbital enhances stimulated cAMP accumulation in cultured preparations from brain and fresh cortical slices. Neurons are required for this effect. Because cAMP modulates neuronal excitability, this effect of pentobarbital may be an important mechanism by which this anesthetic influences brain function.     

Site of action of inhaled 6 per cent carbon dioxide in the lungs of asthmatic subjects before and after exercise

We studied 10 nonsmoking young adults before and after inducing asthmatic attacks by treadmill exercise. We used body plethysmography, flow-volume curves with air and a mixture of 80% helium and 20% oxygen, pressure-volume diagrams, and arterial blood gas analyses to characterize the effects of exercise and acute inhalation of 6% CO2. Even when exercise produced no change in arterial CO2 tension, inhalation of 6% CO2 relieved obstruction to airflow. It also altered the volume-pressure ralationship of the lungs so that total lung capacity was reduced within minutes, and elastic recoil was increased at fixed lung volume. A large increase in density dependence of airflow was seen in some cases, suggesting relief of obstruction in peripheral airways. Atropine sulfate did not prevent obstruction after exercise and did not prevent relief during CO2 inhalation. We concluded that CO2 inhalation can relax both central and peripheral airways in young asthmatic adults, both at rest and after exercise, and that both total lung capacity and density dependence of airflow can change acutely in these subjects.     

Differences in airway closure between normal and asthmatic subjects measured with single-photon emission computed tomography and technegas

The absence of a maximal dose-response plateau as well as gas trapping and increases in closing capacity (CC) suggest that increased airway closure is an important mechanical abnormality of asthmatic airways. We compared the extent and distribution of airway closure in 13 normal and in 23 asthmatic subjects. Airway closure (LVclosed) was measured with single-photon emission computed tomography (SPECT) and an inhaled Technegas bolus as the percentage of lung volume without Technegas (LVtrans), and with CC, using nitrogen washout. LVclosed was compared in the apical, middle and lower zones, each being of equal vertical height. Values of mean LVclosed +/- 95% confidence interval (CI) were similar in normal (30 +/- 6.0% LVtrans) and asthmatic subjects (30 +/- 7.8% LVtrans). In normal subjects, LVclosed correlated with both age (r = 0.89, p < 0. 01) and CC (r = 0.86, p < 0.01), was more extensive in the lower zone (58 +/- 18.8% LVtrans, p < 0.01) than in the middle and upper zones (17 +/- 8.7% and 26 +/- 8.2 LVtrans, respectively), and increased with age in both the middle and lower zones (r = 0.94 and r = 0.90, respectively, p < 0.01). In asthmatic subjects, LVclosed did not correlate with age; was greatest in the lower zone, intermediate in the middle zone, and lowest in the apical zone (59 +/- 13.2%, 22 +/- 5.8%, and 12 +/- 4.4% LVtrans, respectively, p < 0. 01); and correlated weakly with age in the middle zone only (r = 0. 46, p < 0.05). We conclude that there is a predictable pattern of airway closure in normal subjects and that it is primarily influenced by pulmonary elastic recoil. This pattern is lost in asthmatic subjects. This may be explained by an increased range of closing pressures and a patchy distribution of airway closure, probably secondary to allergic inflammation.     

Effects of acute and chronic exposure to nicotine aerosol on bronchial reactivity to inhaled methacholine

Normal baboons, like humans, demonstrate a wide range of bronchial reactivity to inhaled methacholine. Cigarette-smoking baboons demonstrate reduced bronchial reactivity to inhaled methacholine compared with sham-smoking controls after 6 pack-yr of smoking. To evaluate the role of nicotine in this blunting of airway reactivity, we studied the effects of both acute and chronic nicotine inhalation on reactivity to methacholine in baboons. Inhalation of 2 mg of nicotine had no acute effect on lung function but blunted bronchial reactivity in highly reactive animals. This effect was not diminished after daily inhalation of nicotine for 90 days. Marked interindividual differences in bronchial reactivity to methacholine were not abolished by propranolol, suggesting that factors other than beta-adrenergic tone account for this intersubject variability.     

Effect of frusemide on cough responses to chloride-deficient solution in normal and mild asthmatic subjects

We studied the tussive effects of a chloride-deficient solution (1.26% sodium bicarbonate). Nine normal volunteers and 10 mild asthmatic subjects were studied. In two double-blind, placebo-controlled, cross-over studies, we assessed the profile of any inhibitory effects that inhaled frusemide had over these responses. Baseline cough challenge was followed by inhalation of either frusemide (40 mg), or 0.15 M NaCl control. Cough was then induced at 0.5, 2, 4 and 6 h after treatment. Forced expiratory volume in one second (FEV1) was measured before and after each challenge. Changes from the baseline cough response due to drug or control were compared nonparametrically at each time point. There was no difference in the sensitivity of normal and asthmatic subjects to the cough challenge (median cough response 15 and 14.5 on control day, 12 and 15 on frusemide day). Frusemide caused sustained inhibition of the cough response in normal subjects (p < 0.05 at 2 h, p < 0.01 at 4 h), but had only a small, nonsignificant effect in asthmatic subjects at 30 min. Falls in FEV1 of asthmatic subjects due to the chloride-deficient solution were not significant, and did not correlate with number of coughs. We conclude that mild asthmatic subjects are less sensitive than normal subjects to the influence of frusemide against low chloride challenge. This observation is not explained by bronchoconstrictor effects of the cough challenge in asthmatic subjects.     

Effect of inhaled interleukin-5 on airway hyperreactivity and eosinophilia in asthmatics

This study examined whether serial cold-water immersions over a 10-h period would lead to fatigue of shivering and vasoconstriction. Eight men were immersed (2 h) in 20 degrees C water three times (0700, 1100, and 1500) in 1 day (Repeat). This trial was compared with single immersions (Control) conducted at the same times of day. Before Repeat exposures at 1100 and 1500, rewarming was employed to standardize initial rectal temperature. The following observations were made in the Repeat relative to the Control trial: 1) rectal temperature was lower and heat debt was higher (P < 0.05) at 1100; 2) metabolic heat production was lower (P < 0.05) at 1100 and 1500; 3) subjects perceived the Repeat trial as warmer at 1100. These data suggest that repeated cold exposures may impair the ability to maintain normal body temperature because of a blunting of metabolic heat production, perhaps reflecting a fatigue mechanism. An alternative explanation is that shivering habituation develops rapidly during serially repeated cold exposures.     

Effects of feedback on the ability of asthmatic subjects to detect increases in the flow-resistive component to breathing.

Improved perception of increases in airflow resistance may have implications in asthma self management. Two experiments that evaluated effects of feedback on the detection of flow-resistive loads are summarized. In the 1st experiment, detection ability of asthma patients who received feedback about the correctness of their responses in a signal-detection task was compared with that of asthma patients who did not receive feedback. Exp 1 showed that Ss in the feedback condition detected the presence of flow-resistive loads more accurately than Ss in the no-feedback condition. In the 2nd experiment, effects of feedback were compared between asthmatic and non asthmatic Ss. Exp 2 showed that effects of feedback training were equivalent in Ss with and without asthma. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Comparison of basophil histamine release, eosinophil cationic protein and non-specific airway responsiveness between mite-sensitive asthmatic and non-asthmatic children and non-allergic controls

To understand the relevance of allergy to the development of asthma in children, we examined basophil histamine release (HR) with Df antigen, blood eosinophil counts, serum eosinophil cationic protein (ECP) levels, and bronchial responsiveness to methacholine (PC20) in three groups of children, including 36 asthmatics with high RAST titre for Df (group 1), 36 non-asthmatics with similarly high RAST titre for Df (group 2) and 21 non-asthmatics with negative RAST titre for Df (group 3). The amount of Df antigen inducing 50% HR from basophils did not vary significantly between group 1 and 2 (P > 0.05), while none of the cells responded to higher concentrations of Df in group 3. The mean number of blood eosinophils and level of serum ECP were highest in group 1, and lowest in group 3, with group 2 being intermediate, and the differences were significant between all three groups (P < 0.01). The mean PC20 value was the lowest in group 1, intermediate in group 2, and the highest in group 3, and the differences were significant between all three groups (P < 0.01). While correlation studies showed that PC20 values of group 2 subjects significantly correlated with their eosinophil numbers (r = -0.48, P < 0.01) and ECP levels (r = -0.49, P < 0.01), such correlations were not found in group 1 subjects. These results suggest that the degree of the eosinophilic inflammation caused by the allergic reaction to mites is an important factor in determining the clinical expression of asthma in atopic subjects.     

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

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

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

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