Enantiomeric disposition of inhaled, intravenous and oral racemic-salbutamol in man--no evidence of enantioselective lung metabolism. (65/2342)

Aims To establish whether enantioselective metabolism of racemic (rac )-salbutamol occurs in the lungs by determining its enantiomeric disposition following inhalation, in the absence and presence of oral charcoal, compared with that following the oral and intravenous routes. Methods Fifteen healthy subjects (eight male) were randomized into an open design, crossover study. Plasma and urine salbutamol enantiomer concentrations were measured for 24 h following oral (2 mg) with or without oral charcoal (to block oral absorption), inhaled (MDI; 1200 microg) with or without oral charcoal and intravenous (500 microg) rac-salbutamol. Systemic exposure (plasma AUC(0,infinity) and urinary excretion (Au24h ) of both enantiomers were calculated, and relative exposure to (R)-salbutamol both in plasma (AUC(R)-/AUC(S)- ) and urine (Au(R)-/Au(S)- ) was derived for each route. Relative exposure after the inhaled with charcoal and oral routes were compared with the intravenous route. Results AUC(R)-/AUC(S)- [geometric mean (95% CI)] was similar following the intravenous [0.32 (0.28, 0.36)] and inhaled with charcoal rates [0.29 (0.24, 0.36); P=0.046], but was far lower following oral dosing [0.05 (0.03, 0.07); P<0.001]. Similar results were found when relative exposure was analysed using Au24h. Conclusions These results show no evidence of significant enantioselective presystemic metabolism in the lungs, whilst confirming it in the gut and systemic circulation, indicating that the (R)- and (S)-enantiomers are present in similar quantities in the airways following inhaled rac-salbutamol.  (+info)

Relaxant effect of propofol on the airway in dogs. (66/2342)

Propofol has been suggested to produce airway relaxant effects in vivo, although the mechanism is unclear. We have evaluated the bronchodilating effect of propofol using a direct visualization method with a superfine fibreoptic bronchoscope. We studied 21 mongrel dogs anaesthetized with pentobarbital 30 mg kg-1 i.v. and pancuronium 0.2 mg kg-1 h-1. The animals were allocated randomly to one of three groups (n = 7 in each): propofol group, atropine-propofol group and histamine-propofol group. The trachea was intubated using a tracheal tube that had a second lumen for insertion of the bronchoscope to monitor continuously bronchial cross-sectional area (BCA). BCA was measured using the NIH Image program. In the propofol group, dogs were given the following doses of propofol at 10-min intervals: 0 (saline), 0.2, 2.0 and 20 mg kg-1 i.v. In the atropine-propofol group, saline, atropine 0.2 mg kg-1 and propofol 20 mg kg-1 were given at 10-min intervals. In the histamine-propofol group, bronchoconstriction was elicited with histamine 10 micrograms kg-1 and 500 micrograms kg-1 h-1 until the end of the experiment. Thirty minutes after the start of infusion of histamine, propofol (0, 0.2, 2.0 and 20 mg kg-1) was administered. Changes in BCA were expressed as percentage of basal area. Histamine decreased BCA by 39.2 (SEM 5.4%). Propofol increased significantly basal and histamine-decreased BCA in a dose-dependent manner by 18.4 (4.5%) and 15.8 (4.9%), respectively after 20 mg kg-1 i.v. However, propofol following atropine i.v. did not increase BCA (129.9 (8.2)% after atropine vs 125.7 (8.9)% after propofol). Therefore, the relaxant effect of propofol may be a result of reduction in vagal tone.  (+info)

Emergency pre-hospital management of patients admitted with acute asthma. (67/2342)

BACKGROUND: Little is known about the management of acute asthma prior to hospital admission. Pre-hospital treatment of patients referred to hospital with acute asthma was therefore studied in 150 patients divided into three groups: those in the Edinburgh Emergency Asthma Admission Service (EEAAS) who can contact an ambulance and present directly to respiratory services when symptoms arise (n = 38), those under continuing supervision at a hospital respiratory outpatient clinic (n = 54), and those managed solely in primary care (n = 58). METHODS: Standardised admission forms detailing aspects of pre-hospital management, case records, GP referral letters, and ambulance patient transport forms were analysed. RESULTS: In each group airflow obstruction had improved upon arrival at hospital, the effect being most marked in patients transported by ambulance (p<0. 001) and in those receiving nebulised beta(2) agonists prior to admission (p<0.005). However, 25% of patients arrived without having nebulised beta(2) agonists and 37% without having glucocorticoids. EEAAS patients were least likely to receive nebulised beta(2) agonists before arrival at hospital (p<0.05). This observation was attributable to a tendency for these patients to travel to hospital by car rather than by ambulance. CONCLUSIONS: There is an important shortfall in administration of bronchodilators and glucocorticoids for acute asthma before arrival at hospital. Ambulances equipped with nebulised bronchodilators provide the optimal mode of transport to hospital for patients with acute asthma. In Edinburgh ambulances are not being used by a significant proportion of the population with asthma, possibly because of the mistaken belief that personal transport arrangements reduce journey time to hospital.  (+info)

Randomised placebo controlled trial of nebulised corticosteroids in acute respiratory syncytial viral bronchiolitis. (68/2342)

OBJECTIVE: To evaluate short and long term effects of giving nebulised budesonide early in respiratory syncytial viral (RSV) bronchiolitis. DESIGN: A multicentre randomised double blind placebo controlled trial. SUBJECTS: Infants admitted to hospital with their first episode of RSV positive bronchiolitis. INTERVENTION: Randomisation to receive either 1 mg of nebulised budesonide (Bud) or placebo (Pla) twice daily from admission until 2 weeks after discharge. Follow up was for 12 months. MAIN OUTCOME MEASURES: Duration of hospital admission, time taken to become symptom free, re-admission rates, general practitioner consultation rates, and use of anti-wheeze medication during follow up. RESULTS: 161 infants were studied. Both arms were similar with respect to initial clinical severity, age, sex, socioeconomic class, and tobacco exposure. Median time from first nebulisation to discharge: Bud and Pla, 2 days. Median number of days for 50% of infants to be symptom free for 48 hours: Bud, 10 days; Pla, 12 days. Respiratory re-admission rates in the 12 month follow up: Bud, 16%; Pla, 18%; median difference (95% confidence interval (CI)), -2 (-14 to 10). Median respiratory related general practitioner attendances: Bud, 4.0; Pla, 4.5; median difference (95% CI), -1 (-2 to 0). Percentage of infants receiving at least one prescription for anti-wheeze medication during follow up, corticosteroids: Bud, 50%; Pla, 60%; difference (95% CI), -10 (-26 to 6); bronchodilators: Bud, 60%; Pla, 67%; difference (95% CI), -7 (-22 to 8). CONCLUSIONS: There are no short or long term clinical benefits from the administration of nebulised corticosteroids in the acute phase of RSV bronchiolitis.  (+info)

Bronchodilating effects of bambuterol on bronchoconstriction in guinea pigs. (69/2342)

AIM: To study the effects of bambuterol (Bam) on bronchoconstriction in guinea pigs. METHODS: Bronchospasm induced by histamine aerosol, lung resistance (RL) and dynamic lung compliance (Cdyn) changes induced by ovalbumin aerosol in vivo, isolated resting lung parenchyma strips, and carbamylcholine-induced tracheal constriction in vitro in guinea pig were investigated. RESULTS: Bam dose-dependently prolonged the time to histamine-induced collapse, ED50 values (95% confidence limits) of Bam intragastric gavage (i.g.) after 1 h, 4 h, and 24 h were 0.74 (0.60-0.91), 0.75 (0.61-0.91) and 1.00 (0.77-1.30) mg.kg-1, respectively. Bam 2 or 10 mg.kg-1 i.g. 2 h before ovalbumin aerosol partly or almost completely inhibited bronchial challenge of ovalbumin-induced change of RL and Cdyn. Bam 0.1-1.0 mumol.L-1 gave a weak relaxation on isolated tracheal strips induced by carbamylcholine and failed to relax the isolated resting lung parenchyma strips in guinea pig. CONCLUSION: Bam showed a long-acting bronchodilation by its slow metabolism in vivo.  (+info)

Budesonide and formoterol inhibit ICAM-1 and VCAM-1 expression of human lung fibroblasts. (70/2342)

The glucocorticoid budesonide and the long-acting beta2-adrenoceptor agonist formoterol are used in asthma therapy for their anti-inflammatory and bronchodilating effects, respectively. Since expression of adhesion molecules on resident cells in the lung plays an important role in asthmatic inflammatory responses, the effects of these drugs on the cytokine-induced intercellular adhesion molecule-1 (ICAM)-1 and vascular cell adhesion molecule-1 (VCAM)-1 expression of human lung fibroblasts were investigated. Budesonide and formoterol were added in the absence or presence of interleukin (IL)-1beta, tumour necrosis factor-alpha (TNF-alpha), interferon gamma (IFN-gamma) or IL-4 to human lung fibroblasts; ICAM-1 and VCAM-1 expression were measured after 8 h using a cell surface enzyme linked immunosorbent assay (ELISA). It was found that both budesonide and formoterol significantly inhibited (p<0.05) the increased expression of ICAM-1 and VCAM-1 after stimulation with IL-1beta (maximal inhibition (median (25-75% percentiles) 50 (48-52) and 61% (42-69), respectively, with budesonide and 55 (50-73) and 86% (64-94), respectively, with formoterol (10(-7) M)), TNF-alpha (maximal inhibition 49 (46-57) and 57% (44-68), respectively, with budesonide and 44 (40-75) and 62% (52-83) respectively, with formoterol), IFN-gamma (maximal inhibition 64% (41-67) with budesonide and 39% (29-49) with formoterol for ICAM-1) and IL-4 (maximal inhibition 82% (69-92) with budesonide and 43% (33-67) with formoterol for VCAM-1) in a dose-dependent manner. The results show that budesonide, as well as formoterol, in probably clinically relevant concentrations inhibits cytokine-induced adhesion molecule expression on human lung fibroblasts from a concentration of 10(-9) M. This inhibitory effect on resident cells may have implications for the infiltration of inflammatory cells into pulmonary tissue during therapy with these drugs in asthma.  (+info)

Lack of association between ipratropium bromide and mortality in elderly patients with chronic obstructive airway disease. (71/2342)

BACKGROUND: Ipratropium is commonly used for the management of elderly patients with obstructive airway disease. However, a recent report suggested that its use might be associated with a significant increase in mortality. A study was therefore conducted to compare all-cause mortality rates between users and non-users of ipratropium in elderly patients with either asthma or chronic obstructive pulmonary disease (COPD). METHODS: A retrospective cohort study was performed using linked data from the Canadian Institute for Health Information, the Ontario Drug Benefit Program, the Ontario Health Insurance Plan, and the Ontario Registered Persons database. A total of 32 393 patients were identified who were aged 65 years or older and who had been discharged from hospital with asthma or COPD between 1 April 1992 and 31 March 1997. All-cause mortality rates were compared between those treated and those not treated with ipratropium following discharge from hospital. RESULTS: In total, 49% of patients received ipratropium within 90 days of discharge. After adjusting for age, sex, comorbidity, use of health services, and other airway medications there was no significant association in patients with COPD between the use of ipratropium and mortality (relative risk (RR) 1.03; 95% confidence interval (CI) 0.98 to 1.08). In patients with asthma, however, there was a slight increase in the relative risk of mortality associated with the use of ipratropium (RR 1.24; 95% CI 1.11 to 1.39). A dose-response increase in the mortality rate was not observed with increasing use of ipratropium in either COPD or asthma. CONCLUSIONS: The use of ipratropium in patients with COPD was not associated with an increase in mortality. However, in asthma there was a small increase in the mortality rate. Since asthmatic patients who received ipratropium had greater use of other airway medications and health services, the difference in mortality rate between users and non-users may be a reflection of unmeasured differences in asthma severity.  (+info)

Pituitary adenylate cyclase-activating peptide 38 a potent endogenously produced dilator of human airways. (72/2342)

Pituitary adenylate cyclase-activating peptide (PACAP) 38 displays several biological activities relevant to obstructive airway disease. In this study, the occurrence of PACAP 38 in human small bronchi and corresponding pulmonary arteries was analysed immunocytochemically. The dilatory effects of this peptide on the same structures were also studied in vitro. A moderate number of PACAP-like immunoreactive nerve fibres was seen in association with bronchial and vascular smooth muscle and around seromucous glands. PACAP 38 caused a concentration-dependent relaxation of precontracted bronchial and pulmonary arterial segments. The maximal relaxation was more pronounced in the airways than in the arteries, whereas the potency in both was identical. PACAP 38 caused relaxation of all segments tested (nine patients), whereas vasoactive intestinal polypeptide (VIP) failed to cause relaxation of bronchial segments from six of nine patients. Both PACAP and VIP dilated all pulmonary arterial segments tested. In conclusion, pituitary adenylate cyclase-activating peptide 38 is a potent dilator of human bronchi and is present in the human lung. Pituitary adenylate cyclase-activating peptide 38 may, therefore, play a role in the endogenous regulation of airway tone. The inhibitory effects of pituitary adenylate cyclase-activating peptide 38 are more consistent than those of the related neuropeptide vasoactive intestinal polypeptide, perhaps reflecting a difference in susceptibility to degrading enzymes.  (+info)