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Objective: In previous experiments we showed that monodisperse bronchodilator aerosols with a median mass aerodynamic diameter of 2.8 microm induced stronger bronchodilatations than larger aerosols and that the dilatations were clinically relevant at low doses. To discover whether the bronchodilator effects of these low-dose monodisperse aerosols differed from those of standard dosages delivered by metered-dose inhalers, we carried out a comparative trial., Methods: Ten stable outpatients with a mean forced expiratory volume in 1 s (FEV1) of 58.1% of the predicted value inhaled a placebo aerosol, 8 microg of a 2.8-microm monodisperse ipratropium bromide aerosol and 40 microg from a metered-dose inhaler plus spacer; lung-function measurements followed. Data were analysed with repeated measurements analysis of variance (ANOVA)., Results: Greater improvements than with placebo were evident for the forced vital capacity (FVC), the FEV1, the specific airway conductance (sGaw), the peak flow (PEF) and the maximum expiratory flow at 75% of the forced vital capacity (MEF75). In these cases, the low-dose 2.8-microm aerosol proved to be equivalent to the higher-dose metered-dose inhaler., Conclusion: By changing the polydisperse characteristic of inhaled aerosols to a monodisperse pattern, the dose of the drug administered can be reduced without loss of efficacy.

Objective: Otilonium is a smooth muscle spasmolytic with greater affinity for receptors in the smooth muscle of distal than proximal gut in rats. This study was the first to compare distal and proximal GI transit effects in human subjects., Methods: Using an increasing dose design for the safe exploration of clinical and supraclinical single dose levels, two groups of eight volunteers received either 40, 120 and 200 mg or 80, 160 and 240 mg otilonium. Gastric emptying of 400 ml 10% glucose solution was assessed by epigastric impedance (EI), orocaecal transit time (OCTT) by the lactulose breath-hydrogen method and whole gut transit time (WGTT) by the method of Hinton et al. [1]. Potential anticholinergic effects were assessed via visual accommodation using the RAF rule and saliva flow in response to sucking a sweet., Results: Median WGTT after 120 mg significantly increased by 4.1 h relative to placebo, but at higher doses median changes relative to placebo were not significant due to wide increases in group variance. The EI t50% was delayed by 1.4 min when results from the two highest doses were combined and compared with placebo; this small difference was statistically significant but seems unlikely to achieve physiological or clinical significance. OCTT, visual accommodation and saliva flow were unaltered. Otilonium bromide was well tolerated at all doses, due mainly to low systemic absorption.

Twelve patients suffering from partially reversible chronic obstructive pulmonary disease (COPD) took past in a single blind, randomised, 4-way cross-over trial to determine the optimal dose and duration of action of the anticholinergic agent oxitropium bromide (OTB) inhaled as a nebulised solution. Single doses of 500, 1000, 1500 and 2000 micrograms nebulised OTB were compared during a 6 hour-observation period. Lung function test results indicated that 500 and 1000 micrograms OTB only induced slight bronchodilatation, whereas 1500 and 2000 micrograms OTB produced a significantly greater increase in mean FEV1 compared to 500 micrograms. There was a trend for 2000 micrograms to be superior to 1000 micrograms, but 2000 micrograms and 1500 micrograms were not significantly different. Significant bronchodilatation (> 15% rise in FEV1 from baseline) persisted for 6 h after 1500 micrograms. A significant decrease in airway resistance (Raw) was observed following inhalation of 2000 micrograms. The mean decrease in Raw was 33% after 30 min, 20% after 4 h and 12% after 6 h. In this trial, 2000 micrograms OTB administered by an ultrasonic nebuliser was the optimal dose, but a satisfactory result was also obtained with 1500 micrograms.

The pharmacokinetics of diphemanil methylsulphate was evaluated after oral administration of a single 3 mg.kg-1 dose to 5 infants being treated for symptomatic bradycardia. The mean pharmacokinetic parameters of oral diphemanil methylsulphate in infants were similar to those in adults. The mean half-life was 8.6 h. This would allow administration three times a day in infants instead of four to six times a day, as currently prescribed. The mean residence time decreases significantly with age (Spearman's r' = -1), and there is a trend for the half-life to decrease with age (r' = -0.9; NS), suggesting an influence of maturation on its elimination.

Oxitropium bromide (OXBR) is a new anticholinergic drug, which is expected to be useful in the treatment of nocturnal asthma. The only pharmacokinetic data were obtained with the 14C-labelled compound. A sensitive radioreceptor assay for the determination of unlabelled OXBR in plasma was developed, based on competition between OXBR and 3H-N-methylscopolamine for binding to muscarinic receptors. OXBR was isolated from plasma by ion-pair extraction and re-extraction. Active metabolites present in significant amounts might interfere in the assay, but this was not the case for OXBR metabolites. Detection limits were 300 pg.ml-1 and 3 ng.ml-1 for plasma and urine, respectively. For the latter no extraction step was required. The single dose pharmacokinetics of OXBR was studied following inhalation (3 mg), oral (2 mg) and i.v. (1 mg) administration to 12 men, following an open, cross-over design. After i.v. administration the kinetic parameters were: Vc 38.41; t1/2 alpha 5.3 min; t1/2 beta 142 min; AUC 8.9 h.ng.ml-1; renal excretion 50.2%, k10 3.5 l.h-1 and total clearance 1874 ml/min. The apparent bioavailabilities were 0.48% and 12.4% by the oral and inhalation routes, respectively, based on the cumulative renal excretion. There were moderate adverse reactions due to the anticholinergic properties of the drug.

Cetiedil, a new vasodilating drug with anticholinergic properties, was shown to be metabolised very rapidly in man after intravenous and oral administration of the 14C-compound. Higher concentrations of labelled compound after oral than after intravenous administration at the same sampling time, and proportional differences in urinary excretion, suggest that metabolic handling of the drug differs depending on the route of administration. Experiments in which inhibition of saliva secretion was measured indicated that (an) active metabolite(s) probably was (were) responsible for the action of the drug. As an anticholinergic drug, cetiedil is at least 400 times weaker than atropine.

Sixteen young adult sufferers from extrinsic paroxysmal asthma with pollen hypersensitivity took part in a therapeutic trial of the synthetic anticholinergic agent oxitropium bromide administered by a metered dose inhaler. The study comprised three 3-week periods. The first, run-in period was carried out to confirm the ability of the patients to maintain a daily record of symptoms. During the second and third periods, the patient received 3 X 2 inhalations of drug or placebo in a cross-over design. The medical staff was blind to the nature of the aerosol (drug or placebo), which was given in random order. The run-in clinical score was high. Asymptomatic days were relatively infrequent and daily drug consumption was high. Functional studies between the cross-over periods showed flow-rate values close to normal, with an increase in residual volume and functional residual capacity. During treatment either with placebo or oxitropium, there was a statistically significant decrease in clinical scores. Results for oxitropium bromide treatment were significantly better than the run-in values (p less than 0.005) and the placebo period (p less than 0.02). There was no significant change in non-trial drug consumption. Functional values showed no difference in terms of flow rate, although oxitropium did cause a significant improvement in the RV/TLC ratio (p less than 0.05). No adverse reactions were reported.

The effect of cimetropium bromide, a new potent antimuscarinic compound, on caerulein-induced gall bladder emptying in 8 male volunteers was studied by real time ultrasonography. During saline infusion, caerulein (10-40 ng.kg-1.h-1) induced dose-dependent emptying of the gall bladder. There was a significant linear correlation between the dose of the peptide and the reduction in gall bladder size. A continuous infusion of cimetropium bromide (5 mg.h-1) significantly inhibited the contracting effect of caerulein on the human gall bladder, by 74% in response to the lowest dose and by 45% and 22%, respectively, to the two higher doses. The data confirm that the contracting effect of CCK-like peptides on the human gall bladder is at least partly cholinergically mediated, and they demonstrate the relaxing activity of cimetropium previously shown in animals. Provided its antispasmodic activity is also evident in disease, cimetropium should be regarded as a potentially useful agent for the treatment of biliary colic and spasm of the biliary tree.

We have studied the pharmacokinetics of oxybutynin (Ditropan) after single oral (5 mg) and intravenous administration (1 and 5 mg), and after repeated oral administration in healthy volunteers. Oxybutynin was rapidly absorbed, maximum plasma concentrations (8 ng.ml-1) being reached in less than 1 h. The absolute systemic availability averaged 6% and the tablet and solution forms displayed similar relative systemic availability. Plasma concentrations of oxybutynin fell biexponentially, the elimination half-life being about 2 h. There was a large interindividual variation in oxybutynin plasma concentrations. Almost no intact drug could be recovered in the urine. During repeated oral administration steady-state was reached after eight days of treatment. The low absolute systemic availability of oxybutynin, the large interindividual variability in its plasma concentrations, and the apparent absence of intact oxybutynin in the urine suggest that its major pathway of elimination is hepatic metabolism.