Effects of inhaled salbutamol in exercising non-asthmatic athletes

BACKGROUND: Beta-2 agonists such as salbutamol are used, not only by asthmatic athletes to prevent exercise induced asthma, but also by non-asthmatic athletes as a potentially ergogenic agent. We have investigated whether inhaled salbutamol enhances endurance performance in non-asthmatic athletes. METHODS: A prospective double blind, randomised, three way crossover design was used to study the effects of 200 microg and 800 microg inhaled salbutamol versus a placebo in 12 trained triathletes. The treatments were compared in three identical cycle ergometer sessions at 85% of the predetermined maximal oxygen uptake. Lung function, endurance time, metabolic parameters (glucose, potassium, lactate, free fatty acid, and glycerol), and psychomotor performance were evaluated. RESULTS: Neither endurance time nor post-exercise bronchodilation were significantly different between the treatments. Metabolic parameters were affected by exercise but not by treatment. CONCLUSIONS: Inhaled salbutamol, even in a high dose, did not have a significant effect on endurance performance in non-asthmatic athletes, although the bronchodilating effect of the drug at the beginning of exercise may have improved respiratory adaptation. Our results do not preclude an ergogenic effect of beta2 agonists given by other routes or for a longer period.     

Effect of regular terbutaline on the airway response to inhaled budesonide.

BACKGROUND: The rebound increase in bronchial reactivity and fall in forced expiratory volume in one second (FEV1) following treatment with beta agonists seen in several studies has occurred regardless of concurrent steroid therapy. Little is known about the effect of adding beta agonists to corticosteroids, but in a recent study regular treatment with terbutaline appeared to reduce some of the beneficial effects of budesonide. The effects of budesonide alone and in combination with regular terbutaline treatment on lung function, symptom scores, and bronchial reactivity were therefore examined. METHODS: Sixteen subjects with mild stable asthma inhaled budesonide 800 micrograms twice daily for two periods of 14 days with terbutaline 1000 micrograms three times daily or placebo in a double blind crossover fashion. FEV1 and the dose of histamine or adenosine monophosphate (AMP) causing a 20% fall in FEV1 (PD20) were measured before and 12 hours after the final dose of treatment, and changes from baseline were compared. Seven day mean values for daily morning and evening peak expiratory flow (PEF) values, symptom scores, and rescue medication were compared before and during treatment. RESULTS: Morning and evening PEF rose more with budesonide plus terbutaline than with budesonide alone, with a mean difference of 19 l/min occurring in the evening (95% confidence interval (CI) 2 to 36). There was no difference in symptom scores during treatment. Following treatment the mean increase in FEV1 was 150 ml higher with budesonide alone (95% CI-10 to 300). There was no difference between treatments in change in histamine and AMP PD20. CONCLUSIONS: Evening PEF was greater when budesonide was combined with regular terbutaline. There was no evidence of a difference in bronchial reactivity following the two treatment regimens. The findings of a previous study were not confirmed as the reduction in FEV1 after budesonide and terbutaline was smaller and not statistically significant. Further work is needed to determine whether this disparity in findings in the two studies is due to a type 2 statistical error in this study or a spurious finding in the previous study.     

Asthma control during long term treatment with regular inhaled salbutamol and salmeterol

BACKGROUND: The adverse effects of long term treatment of asthma with the short acting beta agonist fenoterol have been established in both epidemiological and clinical studies. A study was undertaken to investigate the efficacy and safety of long term treatment with salbutamol and salmeterol in patients with mild to moderate bronchial asthma. METHODS: In a two centre double dummy crossover study 165 patients were randomly assigned to receive salbutamol 400 micrograms q.i.d., salmeterol 50 micrograms b.i.d., or placebo via a Diskhaler. All patients used salbutamol as required for symptom relief. The study comprised a four week run in and three treatment periods of 24 weeks, each of which was followed by a four week washout. Asthma control was assessed by measuring mean morning and evening peak expiratory flow rate (PEFR), a composite daily asthma score, and minor and major exacerbation rates. Washout assessments included methacholine challenge and bronchodilator dose response tests. Analysis was by intention to treat. RESULTS: Data from 157 patients were analysed. Relative to placebo, the mean morning PEFR increased by 30 l/min (95% CI 26 to 35) for salmeterol but did not change for salbutamol. Evening PEFR increased by 25 l/min (95% CI 21 to 30) and 21 l/min (95% CI 17 to 26), respectively (p < 0.001). Salmeterol improved the asthma score compared to placebo (p < 0.001), but there was no overall difference with salbutamol. Only daytime symptoms were improved with salbutamol. The minor exacerbation rates were 0.29, 0.88, and 0.97 exacerbations/patient/year for salmeterol, salbutamol and placebo, respectively (p < 0.0001 for salmeterol). The corresponding major exacerbation rates were 0.22, 0.51 and 0.40, respectively (p < 0.03 for salmeterol). For salbutamol the asthma score deteriorated over time (p < 0.01), and the time spent in major exacerbation was significantly longer compared with placebo (12.3 days (95% CI 4.2 to 20.4) versus 8.4 days (95% CI 5.2 to 11.6), p = 0.02). There was no evidence of rebound deterioration in asthma control, lung function, or bronchial hyper-responsiveness following cessation of either active treatment, and no evidence of tolerance to salbutamol or salmeterol. CONCLUSIONS: Regular treatment with salmeterol is effective in controlling asthma symptoms and reduces minor more than major exacerbation rates. Salbutamol was associated with improved daytime symptoms but subtle deterioration in asthma control occurred over time. Salbutamol should therefore be used only as required.     

Effect of nedocromil sodium on the airway response to inhaled capsaicin in normal subjects.

In six normal subjects treatment with 4 mg nedocromil sodium failed to alter the cough and bronchoconstriction induced by inhaled capsaicin. Because nedocromil has previously been shown to inhibit reflex bronchoconstriction provoked by inhaled sulphur dioxide and inhaled bradykinin, the results suggest that inhaled capsaicin acts on different nerve fibres.     

Acute effects of inhaled salbutamol on the metabolic rate of normal subjects.

BACKGROUND--This study was designed to investigate the contribution of inhaled salbutamol to the increase in resting metabolic rate found in patients with chronic airflow limitation who were receiving bronchodilator therapy. METHODS--The resting metabolic rate of 10 normal subjects (age 20-47 years, weight 42-105 kg, seven men) was studied after inhalations of salbutamol or placebo. An open canopy method of indirect calorimetry was used to measure resting oxygen consumption (VO2) and resting carbon dioxide production (VCO2). Subjects inhaled two, four, eight, or 12 puffs (100 micrograms/puff) of salbutamol or placebo in a double blind manner. Recordings of VO2 and VCO2 were made after inhalation of the four doses of salbutamol or placebo, integrated over one hour, and compared. RESULTS--VO2 and VCO2 increased in a dose dependent manner after inhaled salbutamol with a maximum effect at five minutes after inhalation. After four puffs, VO2 was 203 and 188 ml/kg/h for salbutamol and placebo respectively. After eight puffs, VO2 was 207 and 185 and VCO2 was 167 and 155 ml/kg/h. After 12 puffs, VO2 was 220 and 190 with a VCO2 of 181 and 168 ml/kg/h. Twelve puffs of salbutamol increased the mean (SE) respiratory quotient from 0.85 (0.01) to 0.93 (0.04) at five minutes indicating an increase in ventilation in excess of metabolic demand. Mean heart rate increased in parallel with VO2. CONCLUSION--Inhaled salbutamol significantly increases resting metabolic rate in a dose dependent manner.     

Bronchial responsiveness to inhaled histamine and isoprenaline in patients with airway obstruction

In order to examine the hypothesis that bronchial reactivity to non-specific constrictor stimuli is influenced by the resting tone of the bronchial smooth muscle, the airway responses to inhaled histamine solution and inhaled isoprenaline were measured in 19 patients with airway obstruction. There was a significant positive correlation between the size of the constrictor response to histamine and the dilator response to isoprenaline (r = +0.83; p less than 0.01) as measured by changes in specific airway conductance. Patients with asthma showed greater bronchial reactivity to both histamine and isoprenaline than those with chronic bronchitis, although some patients had changes intermediate between the two extremes.     

Airway response to salbutamol: effect of regular salbutamol inhalations in normal, atopic, and asthmatic subjects.

This study was designed to determine whether resistance to the airway effects of the beta-agonist, salbutamol, would develop in three groups of subjects while taking large doses of inhaled salbutamol. Six normal non-atopic, six atopic non-asthmatic, and eight atopic asthmatic subjects were studied by an identical technique. The development of resistance was assessed from salbutamol dose-response studies in which the airway response was measured as specific airway conductance (sGaw). Further evidence was sought in the atopic and asthmatic subjects by measuring the airway response to a standard histamine inhalation challenge and the protective effect of 100 micrograms salbutamol on this challenge, and by six-hourly peak flow recordings. Subjects were assessed before and during four weeks in which they took inhaled salbutamol regularly in doses increasing to 500 microgram quid in week 4. Normal subjects showed a progressive reduction in the bronchodilator (sGaw) response to salbutamol during the four weeks, indicating the progressive development of resistance. The atopic subjects, both asthmatic and non-asthmatic, showed no reduction in the response to salbutamol during the four weeks, nor any change in the response to histamine challenge or in regular peak flow readings. These results demonstrate that asthmatic patients do not develop bronchial beta-adrenoceptor resistance easily and suggests that they and atopic non-asthmatic subjects are less susceptible to its development than normal subjects.     

Effect of differing doses of inhaled budesonide on markers of airway inflammation in patients with mild asthma

BACKGROUND: It is desirable to prescribe the minimal effective dose of inhaled steroids to control asthma. To ensure that inflammation is suppressed whilst using the lowest possible dose, a sensitive and specific method for assessing airway inflammation is needed. METHODS: The usefulness of exhaled nitric oxide (NO), sputum eosinophils, and methacholine airway responsiveness (PC20) for monitoring airway inflammatory changes following four weeks of treatment with an inhaled corticosteroid (budesonide via Turbohaler) were compared. Mild stable steroid naive asthmatic subjects were randomised into two double blind, placebo controlled studies. The first was a parallel group study involving three groups receiving either 100 micrograms/day budesonide (n = 8), 400 micrograms/day budesonide (n = 7), or a matched placebo (n = 6). The second was a crossover study involving 10 subjects randomised to receive 1600 micrograms budesonide or placebo. The groups were matched with respect to age, PC20, baseline FEV1 (% predicted), exhaled NO, and sputum eosinophilia. RESULTS: There were significant improvements in FEV1 following 400 micrograms and 1600 micrograms budesonide (11.3% and 6.5%, respectively, p < 0.05). This was accompanied by significant reductions in eosinophil numbers in induced sputum (0.7 and 0.9 fold, p < 0.05). However, levels of exhaled NO were reduced following each budesonide dose while PC20 was improved only with 1600 micrograms budesonide. These results suggest that exhaled NO and PC20 may not reflect the control of airway inflammation as accurately as the number of eosinophils in sputum. There were dose dependent changes in exhaled NO, sputum eosinophils, and PC20 to inhaled budesonide but a plateau response of exhaled NO was found at a dose of 400 micrograms daily. CONCLUSION: Monitoring the number of eosinophils in induced sputum may be the most accurate guide to establish the minimum dose of inhaled steroids needed to control inflammation. This, however, requires further studies involving a larger number of patients.     

Effect of inhaled frusemide and oral indomethacin on the airway response to hypertonic saline challenge in asthmatic subjects

BACKGROUND: Inhaled frusemide inhibits airway narrowing and causes a transient increase in forced expiratory volume in one second (FEV1) during hypertonic saline challenge. This inhibitory effect could be secondary to prostaglandin release during challenge. The involvement of prostaglandins in the inhibitory action of frusemide during challenge with 4.5% NaCl was investigated by premedicating with indomethacin, a prostaglandin synthetase inhibitor. METHODS: Fourteen asthmatic subjects (eight women) aged 26.6 (range 18-56) years participated in a double blind, placebo controlled, crossover study. The subjects attended five times and inhaled 4.5% NaCl for 0.5, 0.75, 1, 1.5, 2, 4, 8, 8, and 8 minutes, or part thereof, or until a provocative dose causing a 20% fall in FEV1 (PD20 FEV1) was recorded. Indomethacin (100 mg/day) or placebo were taken three days before all visits, except control day. The FEV1 was measured and frusemide (38.0 (6.4) mg, pH = 9) or vehicle (0.9% NaCl, pH = 9) were inhaled 10 minutes before the challenge. Bronchodilation was calculated as the percentage rise in FEV1 from the prechallenge FEV1 to the highest FEV1 recorded during the challenge. RESULTS: Frusemide caused a fold increase in PD20 FEV1 compared with the vehicle which was similar in the presence of both indomethacin and placebo (3.7 (95% CI 2.0 to 7.3) versus 3.3 (2.0 to 5.4)). Frusemide, but not vehicle, also caused a transient percentage rise in FEV1 during challenge with 4.5% NaCl which was not blocked by indomethacin (3.6% (1.2 to 6.0)) or placebo (3.1% (1.0 to 5.2)). CONCLUSIONS: Inhaled frusemide inhibited airway narrowing and caused a transient increase in FEV1 during challenge with 4.5% NaCl. These effects were not blocked by indomethacin, which suggests that the inhibitory action of frusemide is not secondary to prostaglandin release.


     

Effect of inhaled formyl-methionyl-leucyl-phenylalanine on airway function.

Formyl-methionyl-leucyl-phenylalanine (FMLP), a synthetic, acylated tripeptide analogous to bacterial chemotactic factors, has been shown to cause bronchoconstriction in guinea pig, rabbit, and human airways in vitro. To determine whether FMLP causes bronchoconstriction in man in vivo, a preliminary study was undertaken in which five non-smokers (mean age 35 years, FEV1 94% (SEM 5%) predicted) and five smokers (mean age 34 years, FEV1 93% (6%) predicted) inhaled aerosols of FMLP. None of the subjects showed airway hyperresponsiveness to histamine (the provocative concentrations of histamine causing a fall of greater than or equal to 20% in FEV1 (PC20) were over 8 mg/ml). FMLP dissolved in 50% dimethylsulphoxide and 50% saline in concentrations of 0, 0.06, 0.12, 0.25, 0.5, 1.0, 2.0, and 4.0 mg/ml was administered to the subjects by means of a French-Rosenthal dosimeter, FEV1 being recorded after inhalation of each concentration. Dose dependent falls in FEV1 occurred in five non-smokers (geometric mean 1.76, 95% confidence limits 0.87-3.53 mg/ml) and three smokers (0.23, 0.07-0.78 mg/ml), with two smokers not responding by 20% to the highest concentration of FMLP. On a separate day the FMLP dose-response curves were repeated after nebulisation of 500 micrograms of ipratropium bromide. The PC20 FMLP in the responders more than doubled. In six additional normal subjects a histamine inhalation test was performed before and four and 24 hours after inhalation of FMLP. All subjects remained unresponsive to histamine. These results show that FMLP is a potent bronchoconstrictor in some non-asthmatic individuals in vivo and this may be important in bronchoconstriction related to infection in patients with chronic obstructive lung disease.     

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.     

Effects of hypothyroidism on bronchial reactivity in non-asthmatic subjects.

The effect of hypothyroidism on non-specific bronchial reactivity was studied in 11 patients without pulmonary disease (mean age 40 (SD 13) years) who had had a total thyroidectomy and radioiodine treatment for thyroid cancer 41 (36) months before the study. All patients when mildly hyperthyroid while having long term thyroxine replacement treatment and once when hypothyroid two weeks after stopping triiodothyronine for the purpose of screening for metastases. Bronchial reactivity was assessed by measuring specific airways conductance (sGaw) after increasing doses of inhaled carbachol (45-1260 micrograms). The dose producing a 35% decrease in sGaw (PD35) was determined from the cumulative log dose-response curve by linear regression analysis. Mean baseline sGaw values were similar when the patients were hypothyroid and when they were hyperthyroid (1.35 (0.36) and 1.41 (0.56) s-1 kPa-1). The interstudy coefficients of variation of baseline sGaw were higher in the thyroid patients than in a euthyroid control group (14% versus 8%). Geometric mean PD35 was lower when the patients were hypothyroid (97 micrograms) than when they were mildly hyperthyroid (192 micrograms). It is concluded that acute hypothyroidism increases non-specific bronchial reactivity in nonasthmatic subjects.     

The effect of inhaled frusemide on airway sensitivity to inhaled 4.5% sodium chloride aerosol in asthmatic subjects.

BACKGROUND: Frusemide inhaled by asthmatic subjects before a variety of indirect bronchial challenges inhibits the airway response to these challenges. Since inhalation of hyperosmolar saline is an indirect bronchial challenge, the effect of inhaled frusemide and its vehicle on airway sensitivity to a 4.5% sodium chloride (NaCl) aerosol challenge was investigated. METHODS: Eleven asthmatic subjects (five females, six males) who had a 20% fall in forced expiratory volume in one second after 4.5% NaCl challenge were enrolled in this double blind controlled crossover trial. Sensitivity was measured as the dose of aerosol required to provoke a 20% fall in FEV1. Frusemide (33.2 mg) or its vehicle was delivered through a Fisoneb ultrasonic nebuliser and inhaled 10 minutes before challenge with 4.5% NaCl. A Mistogen ultrasonic nebuliser was used to generate the 4.5% NaCl aerosol and FEV1 was measured before and one minute after each challenge period of 0.5, one, two, four, eight, eight and eight minutes. The doubling dose difference for PD20 was calculated. RESULTS: Frusemide or vehicle had no effect on baseline lung function. The geometric mean PD20 after vehicle was 1.3 ml with a 95% confidence interval of 0.7-2.3 and after frusemide was 8.2 ml with a 95% confidence interval of 4.7-14.1. This represented a 2.6 doubling dose increase in PD20 after frusemide inhalation. In five of the 11 subjects an increase from baseline FEV1 occurred after exposure to 4.5% NaCl challenge in the presence of frusemide. This transient bronchodilatation may be caused by the release of prostaglandin E2. CONCLUSION: Inhalation of frusemide is very effective in delaying airway narrowing induced by an aerosol of 4.5% NaCl in asthmatic subjects.     

Effect of an inhaled neutral endopeptidase inhibitor, phosphoramidon, on baseline airway calibre and bronchial responsiveness to bradykinin in asthma.

BACKGROUND--Bradykinin is a potent vasoactive peptide which has been proposed as an important inflammatory mediator in asthma since it provokes potent bronchoconstriction in asthmatic subjects. Little is known at present about the potential role of lung peptidases in modulating bradykinin-induced airway dysfunction in vivo in man. The change in bronchial reactivity to bradykinin was therefore investigated after treatment with inhaled phosphoramidon, a potent neutral endopeptidase (NEP) inhibitor, in a double blind, placebo controlled, randomised study of 10 asthmatic subjects. METHODS--Subjects attended on six separate occasions at the same time of day during which concentration-response studies with inhaled bradykinin and histamine were carried out, without treatment and after each test drug. Subjects received nebulised phosphoramidon sodium salt (10(-5) M, 3 ml) or matched placebo for 5-7 minutes using an Inspiron Mini-neb nebuliser 5 minutes before the bronchoprovocation test with bradykinin or histamine. Agonists were administered in increasing concentrations as an aerosol generated from a starting volume of 3 ml in a nebuliser driven by compressed air at 8 1/min. Changes in airway calibre were measured as forced expiratory volume in one second (FEV1) and responsiveness as the provocative concentration causing a 20% fall in FEV1 (PC20). RESULTS--Phosphoramidon administration caused a transient fall in FEV1 from baseline, FEV1 values decreasing 6.3% and 5.3% on the bradykinin and histamine study days, respectively. When compared with placebo, phosphoramidon elicited a small enhancement of the airways response to bradykinin, the geometric mean PC20 value (range) decreasing from 0.281 (0.015-5.575) to 0.136 (0.006-2.061) mg/ml. In contrast, NEP blockade failed to alter the airways response to a subsequent inhalation with histamine, the geometric mean (range) PC20 histamine value of 1.65 (0.17-10.52) mg/ml after placebo being no different from that of 1.58 (0.09-15.21) mg/ml obtained after phosphoramidon. CONCLUSIONS--The small increase in bronchial reactivity to bradykinin after phosphoramidon exposure suggests that endogenous airway NEP may play a modulatory role in the airways response to inflammatory peptides in human asthma.     

Effects of platelet activating factor on airway calibre, airway responsiveness, and circulating cells in asthmatic subjects.

The effects of inhaled platelet activating factor were compared with those of inhaled methacholine (control) on airway calibre, airway responsiveness to methacholine and isoprenaline, and circulating cells in eight subjects with mild, stable asthma. Platelet activating factor was given in six doses at 15 minute intervals and airway response measured as change in partial expiratory flow at 30% of vital capacity (Vp30). Platelet activating factor caused a fall in Vp30, the mean (SEM) maximum percentage fall being 28.9 (4.2) five minutes after the first dose (12 micrograms) and 50.9 (8.0) after the second dose (24 micrograms). Tachyphylaxis occurred, however, with the four subsequent doses of inhaled platelet activating factor. There was transient neutropenia after the first dose, from a mean of 3.6 (0.2) x 10(9) to 2.2 (0.5) x 10(9) neutrophils/l; this response also showed tachyphylaxis with subsequent doses. The mean PC40 (the concentration of methacholine needed to cause a 40% fall in Vp30) was unchanged one, three, and seven days after administration of platelet activating factor. There was no significant correlation between baseline PC40 methacholine and the maximal fall in Vp30 after either the first (12 micrograms) or the second dose (24 micrograms) of platelet activating factor. The control challenge with methacholine produced a degree of bronchoconstriction similar to that of platelet activating factor but was not associated with any significant change in bronchial responsiveness or in circulating cells. The bronchodilator response to inhaled isoprenaline measured three days after inhalation of platelet activating factor and of methacholine was similar after the two challenges. Thus asthmatic subjects who are hyperresponsive to methacholine show a similar bronchoconstrictor response to platelet activating factor, as has been observed in normal subjects; overall this did not cause airway hyperresponsiveness to methacholine.     

Modification of the thermogenic effect of acutely inhaled salbutamol by chronic inhalation in normal subjects.

BACKGROUND--Acute inhalation of clinical doses of salbutamol in normal volunteers increases resting metabolic rate by up to 20% above control values. This study was designed to see if chronic treatment with salbutamol causes a sustained increase in metabolic rate and whether it modifies the acute thermogenic response to the drug. METHODS--The effects of chronic inhaled salbutamol on resting oxygen consumption (VO2) and carbon dioxide output (VCO2) were studied in seven normal subjects (age 20-47 years, weight 52-105 kg, five men). An open canopy method of indirect calorimetry was used to measure VO2, VCO2, and respiratory quotient (RQ). Subjects inhaled two puffs of salbutamol or placebo four times a day in a double blind manner. Measurements of resting VO2 and VCO2 after 10 days of salbutamol were compared with the values after 10 days of placebo and with those taken at the start of the study. At the end of each treatment period subjects inhaled eight puffs (800 micrograms) of salbutamol and the acute effects on VO2, VCO2 and RQ were monitored for one hour. RESULTS--Resting VO2, VCO2, and RQ were not significantly different at the end of the salbutamol and placebo periods but the acute response to eight puffs of salbutamol was abolished by regular inhalation. The mean VO2 integrated over one hour after 800 micrograms salbutamol given acutely was different (241.3 and 210.7 ml/kg/h in the placebo and salbutamol groups respectively). Differences were not significant between placebo and salbutamol groups for changes in VCO2, heart rate, blood pressure, and RQ after acute inhalation. CONCLUSION--Regular treatment with inhaled salbutamol (800 micrograms/day) does not cause a sustained increase in resting metabolic rate but prevents the increase in VO2 that occurs after acute inhalations in normal subjects.     

Changes in neurokinin A (NKA) airway responsiveness with inhaled frusemide in asthma

BACKGROUND: Inhaled frusemide exerts a protective effect against bronchoconstriction induced by several indirect stimuli in asthma which could be due to interference of airway nerves. A randomised, double blind, placebo controlled study was performed to investigate the effect of the potent loop diuretic, frusemide, administered by inhalation on the bronchoconstrictor response to neurokinin A (NKA) and histamine in 11 asthmatic subjects. METHODS: Subjects attended the laboratory on four separate occasions to receive nebulised frusemide (40 mg) or matched placebo 10 minutes prior to bronchial challenge with NKA and histamine in a randomised, double blind order. Changes in airway calibre were followed as forced expiratory volume in one second (FEV1) and responsiveness to the agonists was expressed as the provocative concentration causing a 20% fall in FEV1 from baseline (PC20). RESULTS: Compared with placebo, inhaled frusemide reduced the airway responsiveness to NKA in all the subjects studied, the geometric mean (range) values for PC20NKA increasing significantly (p < 0.001) from 130.3 (35.8-378.8) to 419.9 (126.5-1000) micrograms/ml after placebo and frusemide, respectively. Moreover, a small but significant change in airway responsiveness to histamine was recorded after frusemide, their geometric mean (range) PC20 values being 0.58 (0.12-3.80) and 1.04 (0.28-4.33) mg/ml after placebo and frusemide, respectively. CONCLUSIONS: The decrease in airway responsiveness to NKA after administration of frusemide by inhalation suggests that this drug may interfere with the activation of neurotransmission in human asthma.




     

Dose related effects of salbutamol and ipratropium bromide on airway calibre and reactivity in subjects with asthma.

The relationship between change in airway calibre and change in airway reactivity after administration of bronchodilator drugs has been investigated by comparing the effect of increasing doses of inhaled salbutamol and ipratropium bromide on the forced expiratory volume in one second (FEV1), specific airways conductance (sGaw), and the dose of histamine causing a 20% fall in FEV1 (PD20) in six subjects with mild asthma. On each of 10 occasions measurements were made of baseline FEV1, sGaw, and PD20 after 15 minutes' rest, and followed one hour later, when the FEV1 had returned to baseline, by a single nebulised dose of salbutamol (placebo, 5, 30, 200 and 1000 micrograms) or ipratropium (placebo, 5, 30, 200 and 1000 micrograms) given in random order. Measurements of FEV1, sGaw, and PD20 were repeated 15 minutes after salbutamol and 40 minutes after ipratropium. Salbutamol and ipratropium caused a similar dose related increase in FEV1 and sGaw, with a mean increase after the highest doses of 0.76 and 0.69 litres for FEV1 and 1.15 and 0.96 s-1 kPa-1 for sGaw. Salbutamol also caused a dose related increase in PD20 to a maximum of 2.87 (95% confidence interval 2.18-3.55) doubling doses of histamine after the 1000 micrograms dose, but ipratropium bromide caused no significant change in PD20 (maximum increase 0.24 doubling doses, 95% confidence interval -0.73 to 1.22). Thus bronchodilatation after salbutamol was associated with a significantly greater change in airway reactivity than a similar amount of bronchodilatation after ipratropium bromide. This study shows that the relation between change in airway reactivity and bronchodilatation is different for two drugs with different mechanisms of action, suggesting that change in airway calibre is not a major determinant of change in airway reactivity with bronchodilator drugs.     

Effect of inhaled leukotriene B4 alone and in combination with prostaglandin D2 on bronchial responsiveness to histamine in normal subjects.

The effect of intradermal injection of leukotriene B4 alone and in combination with prostaglandin D2 and E2 and the effect of inhaled leukotriene B4 in combination with prostaglandin D2 were studied in six non-asthmatic men. The intradermal injection of leukotriene B4 (1 microgram) alone caused no immediate or late response in five of the six subjects but greatly potentiated the flare response to intradermal prostaglandin D2 (0.5 microgram) and E2 (0.5 microgram) in all subjects. In contrast, inhaled prostaglandin D2 (6 micrograms) alone and in combination with inhaled leukotriene B4 (12 micrograms) caused no change in the response to inhaled histamine, measured 30 minutes and three and six hours after the inhalation. These findings provide no support for the suggestion that leukotriene B4 has an important role in causing bronchial hyperresponsiveness. The possibility that higher doses of inhaled leukotriene B4 may alter bronchial responsiveness cannot, however, be ruled out.