Bronchodilator and anti-inflammatory activities of glaucine: In vitro studies in human airway smooth muscle and polymorphonuclear leukocytes.
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1. Selective phosphodiesterase 4 (PDE4) inhibitors are of potential interest in the treatment of asthma. We examined the effects of the alkaloid S-(+)-glaucine, a PDE4 inhibitor, on human isolated bronchus and granulocyte function. 2. Glaucine selectively inhibited PDE4 from human bronchus and polymorphonuclear leukocytes (PMN) in a non-competitive manner (Ki=3.4 microM). Glaucine displaced [3H]-rolipram from its high-affinity binding sites in rat brain cortex membranes (IC50 approximately 100 microM). 3. Glaucine inhibited the spontaneous and histamine-induced tone in human isolated bronchus (pD2 approximately 4.5). Glaucine (10 microM) did not potentiate the isoprenaline-induced relaxation but augmented cyclic AMP accumulation by isoprenaline. The glaucine-induced relaxation was resistant to H-89, a protein kinase A inhibitor. Glaucine depressed the contractile responses to Ca2+ (pD'2 approximately 3.62) and reduced the sustained rise of [Ca2+]i produced by histamine in cultured human airway smooth muscle cells (-log IC50 approximately 4.3). 4. Glaucine augmented cyclic AMP levels in human polymorphonuclear leukocytes challenged with N-formyl-Met-Leu-Phe (FMLP) or isoprenaline, and inhibited FMLP-induced superoxide generation, elastase release, leukotriene B4 production, [Ca2+]i signal and platelet aggregation as well as opsonized zymosan-, phorbol myristate acetate-, and A23187-induced superoxide release. The inhibitory effect of glaucine on superoxide generation by FMLP was reduced by H-89. 5. In conclusion, Ca2+ channel antagonism by glaucine appears mainly responsible for the relaxant effect of glaucine in human isolated bronchus while PDE4 inhibition contributes to the inhibitory effects of glaucine in human granulocytes. The very low PDE4/binding site ratio found for glaucine makes this compound attractive for further structure-activity studies. (+info)
Patient compliance in a clinical trial with inhaled budesonide in children with mild asthma.
(42/2342)
Children's use of inhalation devices can give valuable information about their adherence to asthma therapy. The aim of this study was to examine treatment adherence of low dose inhaled budesonide or placebo administered via Turbuhaler twice daily in children with mild asthma participating in an asthma trial, by comparing diary registration with the number of doses remaining in the inhaler. A total of 163 children (age 7-16 yrs, 56 females, 107 males) with mild asthma (mean baseline forced expiratory volume in one second (FEV1) was 103% of predicted), were included into a double blind, randomized study. After a two-week run-in period, the children received inhaled budesonide, either 100 microg or 200 microg daily, and/or placebo for 12 weeks. All patients used daily diary cards throughout the study. Results from 161 patients were analysed. Mean compliance according to the diary was 93%, whereas estimated mean compliance when counting remaining doses in the Turbuhaler was 77%. Overuse of medication was found in 7% of the children. There was no significant difference in compliance between sex in the study group, whereas children aged < or =9 yrs had significantly better drug adherence than older children. No significant relationship was found between symptom score and compliance. In conclusion, even with optimal patient follow-up in a clinical trial, adherence to prophylactic asthma treatment is considerably lower than the patients own reports from the use of daily diary cards. (+info)
Mass balance and metabolism of [(3)H]Formoterol in healthy men after combined i.v. and oral administration-mimicking inhalation.
(43/2342)
Mass balance and metabolism of formoterol were investigated in six healthy men in an open study. Mean age was 49.7 years (range: 40-63). Simultaneous oral (mean dose 88.6 nmol, 49.3 MBq) and i.v. (mean dose 38.2 nmol, 21.4 MBq) doses of tritium-labeled formoterol were administered. The combination of these two administrations was aimed at simulating the fate of inhaled formoterol. Total radioactivity was monitored for 24 h in blood plasma and for at least 4 days in urine and feces. Formoterol and metabolites were determined using liquid chromatography plus radiodetection, directly after centrifugation in urine and after sample workup in blood plasma and feces. Metabolites were identified in urine, sampled from two subjects, using liquid chromatography-electrospray ionization mass spectrometry. Mean total recovery was 86% of the administered formoterol dose, 62% in urine and 24% in feces. Tritiated water was generated and because its in vivo turnover is slow, the terminal decline of total radioactivity was slow and dose recovery was incomplete during the sampling period. Formoterol was conjugated to inactive glucuronides and a previously unidentified sulfate. The phenol glucuronide of formoterol was the main metabolite in urine. Formoterol was also O-demethylated and deformylated. Plasma exposure to these pharmacologically active metabolites was low. O-demethylated formoterol was seen mainly as inactive glucuronide conjugates and deformylated formoterol only as an inactive sulfate conjugate. Intact formoterol and O-demethylated formoterol dominated recovery in feces. Mean recovery of unidentified metabolites was 7. 0% in urine and 2.0% in feces. (+info)
Pharmacokinetics of bambuterol during oral administration to asthmatic children.
(44/2342)
AIMS: To investigate dose proportionality, dosing frequency, and ethnic aspects of the pharmacokinetics of bambuterol in asthmatic children, and to discuss the relationship with previous observations in adults. METHODS: Forty-eight children in four different studies completed two double-blind bambuterol treatments each (daily doses of bambuterol hydrochloride): 12 preschool (5 mg x 2 vs 10 mg) and 12 school (10 mg vs 20 mg) Caucasians, 12 preschool (2.5 mg vs 5 mg), and 12 school (10 mg vs 20 mg) Orientals. Peak plasma concentrations and dosing interval area under curve (AUC) of bambuterol and the active metabolite terbutaline were assessed at steady state. Treatment differences were analysed statistically within each study. Differences between the studies and the relation to steady-state AUC in adults were described. RESULTS: Dose proportionality was seen for terbutaline but not for bambuterol. Twice-daily dosing (2 x AUC(0,12 h)) could not be shown to differ from once-daily dosing (AUC(0,24 h)) in the preschool Caucasians. Mean AUC of terbutaline was 128 and 242 nmol l-1 h in the preschool Caucasians (5 mg/12 h; 10 mg/24 h), 213 and 406 nmol l-1 h in the Caucasian school children (10 mg; 20 mg), 87.4 and 202 nmol l-1 h in the Oriental preschool children (2.5 mg; 5 mg), and 356 and 640 nmol l-1 h in the Oriental school children (10 mg; 20 mg). Oriental school children had higher plasma concentrations of bambuterol and terbutaline than Caucasian school children. The strict ethnic implication of the difference could not be elucidated, because demographic data were not perfectly matched. Terbutaline AUC was only moderately increased in the Caucasian school children compared with Caucasian adults. The increase was more pronounced in Oriental children and in some preschool Caucasians. The highest concentration of terbutaline, 58 nmol l-1, was seen in an Oriental school child after a 20 mg dose. CONCLUSIONS: Caucasian school children can be given bambuterol hydrochloride very much as Caucasian adults, 10 or 20 mg once daily, but Oriental preschool and school children plus preschool Caucasians should be given lower doses. (+info)
Dose-proportional pharmacokinetics of budesonide inhaled via Turbuhaler.
(45/2342)
AIMS: The present pharmacokinetic study was undertaken to determine the dose proportionality of three different doses of budesonide-400 microg, 800 microg or 1600 microg administered twice daily by a dry-powder inhaler (Turbuhaler ) in adult patients with mild asthma. METHODS: A total of 38 patients received budesonide by inhalation, 13 received 400 microg twice daily, 12 received 800 microg twice daily and 13 received 1600 microg twice daily. Mean FEV1 at inclusion was 3.4, 4.0 and 3.9 l min-1 in the three groups, respectively. Blood samples were taken after a single dose, and after 3 weeks of daily treatment, for pharmacokinetic evaluation. Plasma concentrations of budesonide were determined by liquid chromatography plus mass spectrometry. RESULTS: Eleven evaluable patients remained in each dose group. Mean time to peak budesonide plasma concentration (tmax ) was short (0.28-0.40 h) and did not differ between treatment groups. Budesonide concentrations declined rapidly thereafter, indicating efficient pulmonary absorption and rapid elimination with a half-life of approximately 3 h. Cmax was 1. 4(2.0) nmol l-1 (single (repeated) doses), 2.6(3.6) nmol l-1 and 5. 4(6.4) nmol l-1 after 400, 800 and 1600 microg twice daily, respectively. The corresponding results for the area under the plasma concentration vs time curve (AUC) were 271(325), 490(628) and 915(1096) nmol l-1 min. Ninety percent confidence intervals for pairwise dose-normalized Cmax and AUC comparisons between groups were large but contained unity in all cases, thus indicating dose-proportional pharmacokinetics. Regression on analysis supported these findings. Mean AUC after repeated doses (AUC(0,12 h,RD)) was on average 23% higher than the mean AUC after single doses (AUC(0, infinity,SD)(P=0.04) with no significant differences between doses, indicating slight accumulation following bid dosing. CONCLUSIONS: In this relatively small study, budesonide inhaled via Turbuhaler appeared to have dose-proportional pharmacokinetics, both within and above the clinically recommended dose range for asthmatic patients. (+info)
Lack of drug interaction between omeprazole, lansoprazole, pantoprazole and theophylline.
(46/2342)
AIMS: Theophylline is a model substrate of cytochrome P4501A2. The ability of the proton pump inhibitors (PPI) omeprazole, lansoprazole and pantoprazole to induce cytochrome P4501A2 has not yet been unequivocally resolved. The aim of this comprehensive study was to compare directly the effect of the three PPI on the absorption and disposition of theophylline. METHODS: Twenty healthy, nonsmoking, male and female volunteers (extensive metabolisers of cytochrome P4502C19 and Helicobacter pylori negative) participated in a randomized, double-blind, four-period, placebo-controlled crossover study. In each of the four periods they received either omeprazole (40 mg), lansoprazole (60 mg), pantoprazole (80 mg) or placebo once daily for 10 days. Sustained release theophylline (350 mg twice daily) was coadministered from day 8-10. Pharmacokinetics of theophylline as well as of all three PPI were determined at steady-state (day 10). RESULTS: In all periods, point estimates and 90% confidence intervals of the area under the concentration-time curves (AUC), maximum steady-state concentrations and peak-trough fluctuations of theophylline were not altered by PPI pretreatment and met the required limits for bioequivalence. Point estimates (90% confidence intervals) of the AUC ratios of theophylline plus PPI to theophylline alone were 0.92 (0.87-0.97), 0.90 (0.85-0.95) and 1.00 (0.95-1.06) for omeprazole, lansoprazole and pantoprazole, respectively. CONCLUSIONS: Concomitant intake of omeprazole, lansoprazole or pantoprazole at high therapeutic doses does not affect the absorption and disposition of theophylline. (+info)
The long-acting beta2-agonist salmeterol xinafoate: effects on airway inflammation in asthma.
(47/2342)
Salmeterol xinafoate is an inhaled long-acting beta2-adrenoceptor agonist recently introduced for the treatment of asthma. Both in vitro and animal studies suggest that it may have anti-inflammatory activities of benefit in this disease. To assess this directly, the effects of 6 weeks' treatment with salmeterol on indices of clinical activity, airway dysfunction and inflammation in subjects with stable atopic asthma were investigated. In a double blind study, asthmatic patients were randomized to 6 weeks' treatment with either salmeterol 50 microg twice daily (n=14) or placebo (n=12). They underwent bronchoscopy with bronchoalveolar lavage (BAL) and bronchial biopsy immediately before starting treatment and again after 6 weeks. Treatment with salmeterol improved clinical indices of asthma activity, but there were no changes in BAL differential cell counts or mediator levels, and no change in T-cell numbers or activation status. In the biopsy specimens there were no changes in numbers of inflammatory cells, sub-basement membrane collagen deposition or mast cell degranulation. Regular treatment with salmeterol improves clinical indices of asthma but has no effect on the underlying inflammatory process. These findings strengthen guideline recommendations that long-acting beta2-agonists should not be prescribed as sole antiasthma medication. (+info)
Tolerance to beta-agonists during acute bronchoconstriction.
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Previous reports suggest that regular use of beta-agonists does not lead to tolerance to their bronchodilator effects. However, most studies have been conducted in stable asthma. This study investigates whether bronchodilator tolerance can be demonstrated during acute bronchoconstriction. Thirty-four asthmatic subjects were treated with 6 weeks inhaled terbutaline (1 mg q.i.d.), budesonide (400 microg, b.i.d.), both drugs or placebo in a randomized, double-blind, cross-over study. After each treatment methacholine was administered to induce a 20% fall in the forced expiratory volume in one second (FEV1). The response to inhaled salbutamol 100, 100, 200 microg at 5 min intervals) was then measured. Dose-response curves were compared using an analysis of covariance. Pre-methacholine FEV1, the highest pre-methacholine FEV1, the fall in FEV1 induced by methacholine and the logarithm of the provocative dose of methacholine required to induce the 20% fall in FEV1 (PD20) were used as covariates. There was a significantly reduced response to salbutamol after 6 weeks terbutaline treatment: the mean (95% confidence intervals (CI)) area under the dose-response curve was reduced by 36% (24, 47) compared to placebo (p<0.0001). The reduction in bronchodilator response was not affected by concomitant treatment with budesonide. Significant tolerance to the bronchodilator effect of inhaled beta-agonists may be demonstrated when tested during acute bronchoconstriction. Continuous treatment with inhaled beta-agonists may lead to a reduced response to emergency beta-agonist treatment during asthma exacerbations. (+info)