Kinetic analysis of drug-receptor interactions of long-acting beta2 sympathomimetics in isolated receptor membranes: evidence against prolonged effects of salmeterol and formoterol on receptor-coupled adenylyl cyclase.
(1/2342)
The long-acting beta2 sympathomimetics salmeterol and formoterol have been presumed to exert their prolonged action either by binding to an accessory binding site ("exo-site") near the beta2 adrenoceptor or by their high affinity for beta2 adrenoceptors and correspondingly slow dissociation. Whereas most studies with salmeterol had been done in intact tissues, which have slow diffusion and compartmentation of drugs in lipophilic phases, that restrict drug access to the receptor biophase, we used purified receptor membranes from rat lung and disaggregated calf tracheal myocytes as model systems. Binding experiments were designed to measure the slow dissociation of agonists by means of delayed association of (-)-[125I]iodopindolol. Rat lung membranes were pretreated with high concentrations of agonists (salmeterol, formoterol, isoprenaline) before dissociation was induced by 50-fold dilution. Half-times of association of (-)-[125I]iodopindolol remained unchanged compared with untreated controls, indicating that dissociation of agonists occurred in less than 2 min. Adenylyl cyclase experiments were designed to determine the on and off kinetics of agonists to beta2 adrenoceptors by measuring the rate of receptor-induced cyclic AMP (cAMP) formation. Experiments were performed in tracheal membranes characterized by high Vmax values of cAMP formation. Adenylyl cyclase activation occurred simultaneously with the addition of the agonist, continued linearly with time for 60 min, and ceased immediately after the antagonist was added. Similarly, when receptor membranes were preincubated in a small volume with high salmeterol concentrations, there was a linear increase in cAMP formation, which was immediately interrupted by a 100-fold dilution of the reaction mixture. This militates against the exo-site hypothesis. On the other hand, dissociation by dilution was much less when membranes were preincubated with a large volume of salmeterol at the same concentration, indicating that physicochemical effects, and not exo-site binding, underlie its prolonged mode of action. (+info)
Beta2-adrenoceptor polymorphism and bronchoprotective sensitivity with regular short- and long-acting beta2-agonist therapy.
(2/2342)
The aim of the present study was to investigate bronchoprotective sensitivity in patients receiving regular treatment with short- and long-acting beta2-agonists and to evaluate any possible association with genetic polymorphism. Thirty-eight patients with stable mild to moderate asthma and receiving inhaled corticosteroids were randomized in a parallel group, double-blind, double-dummy fashion to receive 2 weeks of treatment with either formoterol (12 microg once daily, 6 microg twice daily or 24 microg twice daily) or terbutaline (500 microg four times daily). Bronchoprotection against methacholine challenge (as a provocative dose to produce a 20% fall in forced expiratory volume in 1.0 s: PD20) was measured at baseline (unprotected) after an initial 1 week run-in without beta2-agonist, and at 1 h after the first and last doses of each treatment. The PD20 values were log-transformed and calculated as change from baseline. Percentage desensitization of log PD20 for first- versus last-dose bronchoprotection was calculated and analysed according to effects of treatment and beta2-adrenoceptor polymorphism at codon 16 or 27. The mean degree of desensitization for bronchoprotection was comparable with all four treatments and there were no significant differences in absolute PD20 values after 2 weeks of chronic dosing. The PD20 values were (as microg of methacholine, geometric means+/-S. E.M.): formoterol, 12 microg once daily, 99+/-42 microg; formoterol, 6 microg twice daily, 107+/-44 microg; formoterol, 24 microg twice daily, 108+/-45 microg; terbutaline, 500 microg four times daily, 88+/-37 microg. All patients receiving formoterol, 24 microg twice daily, exhibited a loss of protection greater than 30% which was unrelated to polymorphism at codon 16 or 27. For codon 16, the use of lower doses of formoterol (12 microg once daily or 6 microg twice daily) showed wider variability in the propensity for protection loss in patients who were heterozygous, in contrast to a more uniform protection loss seen with homozygous glycine patients. The amount of protection loss was not significantly related to polymorphism at codon 16 or 27, expressed as values (mean+/-S.E.M.) for percentage desensitization according to each genotype (pooled treatments): Gly-16, 66+/-11%; Het-16, 53+/-8%; Arg-16, 69+/-18%; Glu-27, 68+/-12%; Het-27, 58+/-8%; Gln-27, 52+/-12%. The results of this preliminary study showed that bronchoprotective desensitization occurred readily in response to short- or long-acting beta2-agonist exposure irrespective of beta2-adrenoceptor polymorphism at codon 16 or 27. Further studies with larger patient numbers are required to further evaluate the effects of polymorphisms with lower doses of regular formoterol. (+info)
Anaphylactic bronchoconstriction in BP2 mice: interactions between serotonin and acetylcholine.
(3/2342)
1. Immunized BP2 mice developed an acute bronchoconstriction in vivo and airway muscle contraction in vitro in response to ovalbumin (OA) and these contractions were dose dependent. 2. Methysergide or atropine inhibited OA-induced bronchoconstriction in vivo and airway muscle contraction in vitro. 3. Neostigmine potentiated the OA-induced bronchoconstriction in vivo and airway muscle contraction in vitro of BP2 mice. This potentiation was markedly reduced by the administration of methysergide or atropine and when the two antagonists were administered together, the responses were completely inhibited. 4. Neostigmine also potentiated the serotonin (5-HT)- and acetylcholine (ACh)-induced bronchoconstriction and this potentiation was significantly reversed by atropine. 5. These results indicate that OA provokes a bronchoconstriction in immunized BP2 mice by stimulating the release of 5-HT, which in turn acts via the cholinergic mediator, ACh. (+info)
Nitrogen dioxide formation during inhaled nitric oxide therapy.
(4/2342)
BACKGROUND: Nitrogen dioxide (NO2) is a toxic by-product of inhalation therapy with nitric oxide (NO). The rate of NO2 formation during NO therapy is controversial. METHODS: The formation of NO2 was studied under dynamic flows emulating a base case NO ventilator mixture containing 80 ppm NO in a 90% oxygen matrix. The difficulty in measuring NO2 concentrations below 2 ppm accurately was overcome by the use of tunable diode laser absorption spectroscopy. RESULTS: Using a second-order model, the rate constant, k, for NO2 formation was determined to be (1.19 +/- 0.11) x 10(-11) ppm-2s-1, which is in basic agreement with evaluated data from atmospheric literature. CONCLUSIONS: Inhaled NO can be delivered safely in a well-designed, continuous flow neonatal ventilatory circuit, and NO2 formation can be calculated reliably using the rate constant and circuit dwell time. (+info)
The contribution of the swallowed fraction of an inhaled dose of salmeterol to it systemic effects.
(5/2342)
Salmeterol is approximately eight times as potent as salbutamol for systemic effects. This may be because the drug is eight times more potent on receptors or there may be differences in systemic bioavailability. The systemic effects of salbutamol are limited by its fairly high first-pass metabolism, but the oral bioavailability of salmeterol is unknown. The contribution of the swallowed fraction of an inhaled dose of salmeterol to its systemic effects were analysed in a randomized, double-blind, crossover study. Twelve healthy subjects were given inhaled salmeterol 400 microg, inhaled salmeterol 400 microg plus oral activated charcoal or inhaled placebo plus oral activated charcoal on three separate days. Cardiac frequency (fC), Q-T interval corrected for heart rate (QTc), plasma potassium and glucose concentrations were measured for 4 h following the inhaled drug. Salmeterol with and without oral charcoal produced significant changes for all measures compared to placebo. The magnitude of effect following salmeterol alone was significantly greater than that following salmeterol plus charcoal for fC and glucose (mean (95% confidence interval) differences 8 (2-13) beats x min(-1), 0.59 (0.04, 1.13) mmol x L(-1), respectively) and nonsignificantly greater for QTc interval and potassium concentration. The differences between salmeterol given with and without charcoal suggest that 28-36% of the systemic response to salmeterol administered from a metered-dose inhaler are due to drug absorbed from the gastrointestinal tract. Thus, most of the systemic effects are due to the inhaled fraction of the drug. (+info)
Time course of respiratory decompensation in chronic obstructive pulmonary disease: a prospective, double-blind study of peak flow changes prior to emergency department visits.
(6/2342)
The aim of this study was to look at changes in peak expiratory flow rates (PEFR) prior to emergency department visits for decompensated chronic obstructive pulmonary disease (COPD). It was designed as a prospective, double-blind study at the Albuquerque Veterans Affairs Medical Center. Twelve patients with an irreversible component of airflow obstruction on pulmonary function tests were assessed. At entry, all subjects were instructed in the use of a mini-Wright peak flow meter with electronic data storage. They then entered a 6-month monitoring phase in which they recorded PEFR twice daily, before and after bronchodilators. The meter displays were disabled so that the patients and their physicians were blinded to all values. Medical care was provided in the customary manner. Patients were considered to have respiratory decompensation if they required treatment for airflow obstruction in the Emergency Department (ED) and no other causes of dyspnea could be identified. Simple linear regression was used to model changes in PEFR over time. The 12 subjects had 22 episodes of respiratory decompensation during 1741 patient-days of observation. Two episodes could not be analysed because of missing values. Ten episodes in seven subjects were characterized by a significant linear decline in at least one peak flow parameter prior to presentation. The mean rates of change for the four daily parameters varied from 0.22% to 0.27% predicted per day (or 1.19 to 1.44 1 min-1 day-1). The average decrement in these parameters ranged from 30.0 to 33.8 1 min-1 (or 18.6%-25.9% of their baseline values). No temporal trends were found for the 10 episodes occurring in the other five subjects. We concluded that respiratory decompensation is characterized by a gradual decline in PEFR in about half of cases. Future studies should be done to elucidate the mechanisms of respiratory distress in the other cases. (+info)
Randomised controlled trial of budesonide for the prevention of post-bronchiolitis wheezing.
(7/2342)
BACKGROUND: Previous studies suggest that recurrent episodes of coughing and wheezing occur in up to 75% of infants after acute viral bronchiolitis. AIM: To assess the efficacy of budesonide given by means of a metered dose inhaler, spacer, and face mask in reducing the incidence of coughing and wheezing episodes up to 12 months after acute viral bronchiolitis. METHODS: Children under the age of 12 months admitted to hospital with acute viral bronchiolitis were randomised to receive either budesonide or placebo (200 microg or one puff twice daily) for the next eight weeks. Parents kept a diary card record of all episodes of coughing and wheezing over the next 12 months. RESULTS: Full follow up data were collected for 49 infants. There were no significant differences between the two study groups for the number of infants with symptom episodes up to six months after hospital discharge. At 12 months, 21 infants in the budesonide group had symptom episodes compared with 12 of 24 in the placebo group. The median number of symptom episodes was 2 (range, 0-13) in those who received budesonide and 1 (range, 0-11) in those who received placebo. Because there is no pharmacological explanation for these results, they are likely to be caused by a type 1 error, possibly exacerbated by there being more boys in the treatment group. CONCLUSION: Routine administration of budesonide by means of a metered dose inhaler, spacer, and face mask system immediately after acute viral bronchiolitis cannot be recommended. (+info)
Risk factors for death from asthma, chronic obstructive pulmonary disease, and cardiovascular disease after a hospital admission for asthma.
(8/2342)
BACKGROUND: Patients with asthma have an increased risk of death from causes other than asthma. A study was undertaken to identify whether severity of asthma, its treatment, or associated co-morbidity were associated with increased risk of death from other causes. METHODS: Eighty five deaths from all causes occurring within three years of discharge from hospital in a cohort of 2242 subjects aged 16-64 years admitted for asthma were compared with a random sample of 61 controls aged <45 years and 61 aged >/=45 years from the same cohort. RESULTS: Deaths from asthma were associated with a history of clinically severe asthma (OR 6.29 (95% CI 1.84 to 21.52)), chest pain (OR 3.78 (95% CI 1.06 to 13.5)), biochemical or haematological abnormalities at admission (OR 4.12 (95% CI 1.36 to 12.49)), prescription of ipratropium bromide (OR 4.04 (95% CI 1.47 to 11.13)), and failure to prescribe inhaled steroids on discharge (OR 3.45 (95% CI 1.35 to 9.10)). Deaths from chronic obstructive pulmonary disease (COPD) were associated with lower peak expiratory flow rates (OR 2.56 (95% CI 1.52 to 4.35) for each 50 l/min change), a history of smoking (OR 5.03 (95% CI 1.17 to 21.58)), prescription of ipratropium bromide (OR 7.75 (95% CI 2.21 to 27.14)), and failure to prescribe inhaled steroids on discharge (OR 3.33 (95% CI 0.95 to 11.10)). Cardiovascular deaths were more common among those prescribed ipratropium bromide on discharge (OR 3.55 (95% CI 1.05 to 11.94)) and less likely in those admitted after an upper respiratory tract infection (OR 0.21 (95% CI 0.05 to 0.95)). Treatment with ipratropium bromide at discharge was associated with an increased risk of death from asthma even after adjusting for peak flow, COPD and cardiovascular co-morbidity, ever having smoked, and age at onset of asthma. CONCLUSIONS: Prescription of inhaled steroids on discharge is important even for those patients with co-existent COPD and asthma. Treatment with ipratropium at discharge is associated with increased risk of death from asthma even after adjustment for a range of markers of COPD. These results need to be tested in larger studies. (+info)