Pharmacokinetics and pharmacodynamics of tiotropium solution and tiotropium powder in chronic obstructive pulmonary disease.

The aim of the study was to characterize pharmacokinetics of tiotropium solution 5 µg compared to powder 18 µg and assess dose-dependency of tiotropium solution pharmacodynamics in comparison to placebo. In total 154 patients with chronic obstructive pulmonary disease (COPD) were included in this multicenter, randomized, double-blind within-solution (1.25, 2.5, 5 µg, and placebo), and open-label powder 18 µg, crossover study, including 4-week treatment periods. Primary end points were peak plasma concentration (Cmax,ss ), and area under the plasma concentration-time profile (AUC0-6h,ss ), both at steady state. The pharmacodynamic response was assessed by serial spirometry (forced expiratory volume in 1 second/forced vital capacity). Safety was evaluated as adverse events and by electrocardiogram/Holter. Tiotropium was rapidly absorbed with a median tmax,ss of 5-7 minutes postdosing for both devices. The gMean ratio of solution 5 µg over powder 18 µg was 81% (90% confidence interval, 73-89%) for Cmax,ss and 76% (70-82%) for AUC0-6h,ss , indicating that bioequivalence was not established. Dose ordering for bronchodilation was observed. Powder 18 µg and solution 5 µg were most effective, providing comparable bronchodilation. All treatments were well tolerated with no apparent relation to dose or device. Comparable bronchodilator efficacy to powder18 µg at lower systemic exposure supports tiotropium solution 5 µg for maintenance treatment of COPD.

Comparison of tiotropium once daily, formoterol twice daily and both combined once daily in patients with COPD.

This study compared the bronchodilator effects of tiotropium, formoterol and both combined in chronic obstructive pulmonary disease (COPD). A total of 71 COPD patients (mean forced expiratory volume in one second (FEV1) 37% predicted) participated in a randomised, double-blind, three-way, crossover study and received tiotropium 18 microg q.d., formoterol 12 microg b.i.d. or both combined q.d. for three 6-week periods. The end-points were 24-h spirometry (FEV1, forced vital capacity (FVC)) at the end of each treatment, rescue salbutamol and safety. Compared with baseline (FEV1 prior to the first dose in the first period), tiotropium produced a significantly greater improvement in average daytime FEV1 (0-12 h) than formoterol (127 versus 86 mL), while average night-time FEV1 (12-24 h) was not different (tiotropium 43 mL, formoterol 38 mL). The most pronounced effects were provided by combination therapy (daytime 234 mL, night-time 86 mL); both differed significantly from single-agent therapies. Changes in FVC mirrored the FEV1 results. Compared with both single agents, daytime salbutamol use was significantly lower during combination therapy (tiotropium plus formoterol 1.81 puffs.day(-1), tiotropium 2.41 puffs x day(-1), formoterol 2.37 puffs x day(-1)). All treatments were well tolerated. In conclusion, in chronic obstructive pulmonary disease patients, tiotropium q.d. achieved a greater improvement in daytime and comparable improvement in night-time lung function compared with formoterol b.i.d. A combination of both drugs q.d. was most effective and provided an additive effect throughout the 24-h dosing interval.

Antimuscarinic treatment for lung diseases from research to clinical practice.

Inhaled antimuscarinic drugs are the treatment of choice, recommended by guidelines, in chronic obstructive pulmonary disease (COPD). In long-term clinical studies ipratropium shows important effects beyond relaxation of airway smooth muscle, e.g. reduction of exacerbations of COPD. In phase III clinical trials the new generation antimuscarinic tiotropium, inhaled once daily, has provided more than 24 hours of stable bronchodilation, that was sustained over the one year treatment period. In addition, tiotropium in comparison to placebo and even ipratropium, has been shown to provide improvement in dyspnea, reduction of exacerbations of COPD, reduced hospital admissions for exacerbations, reduced duration of hospitalisations as well as improved health-related quality of life. Chronic effects, such as reduction of hospitalisations, are conventionally attributed to an anti-inflammatory action and not to symptomatic bronchodilation. The 24 hour stabilisation of airway patency, avoiding fluctuations of the diameter with occasional closure and consequent need for reopening, may explain the extended therapeutic profile of tiotropium. Inhibition by antimuscarinics of pro-inflammatory cholinergic effects may also occur, e.g. inhibition of 5-HETE release from epithelial cells and inhibition of release of neutrophil and eosinophil chemotactic activity from alveolar macrophages. Antimuscarinics have shown increasing value as a therapeutic approach in COPD. The elucidation of their anti-inflammatory potential constitutes an interesting target for future studies.

Tiotropium (Spiriva): mechanistical considerations and clinical profile in obstructive lung disease.

Inhaled antimuscarinics, often called anticholinergics in clinical medicine, are established as first line bronchodilators in COPD. Tiotropium has been developed as a new generation antimuscarinic following ipratropium. Tiotropium is a specific, highly potent antimuscarinic, demonstrating very slow dissociation from muscarinic receptors. Dissociation from M2-receptors is faster than from M3 or M1, which in functional in vitro studies, appeared as kinetic receptor subtype selectivity of M3 and M1 over M2. The high potency and slow receptor dissociation found its clinical correlate in significant and long lasting bronchodilatation and bronchoprotection in patients with COPD and asthma. In asthma, protection against methacholine challenge exceeded the study period of 48 hours. In COPD, bronchodilatation of about 80% of the plateau was demonstrated after the first dose. Following chronic once daily inhalation for 28 days, the improvement in pulmonary function was sustained and there was a further increase in peak effects, but more importantly a rising baseline, achieving steady state within 2 weeks. Tiotropium achieves very stable long lasting effects with comparatively low variation of bronchodilatation between peak and trough (the level before the next administration). Stable 24 hour effectiveness profiles the compound as the first once daily bronchodilator. Clinical correlates of kinetic receptor subtype selective blockade remain to be shown. Plasma levels of tiotropium at trough are in the low pg/ml range and are unlikely to explain the sustained effectiveness in the airways. Slow dissociation from muscarinic receptors is likely to be responsible for the long duration of action.

Ba 679 BR, a novel long-acting anticholinergic bronchodilator.

The use of anticholinergics in antiobstructive therapy is well established in pulmonary medicine. We sought to improve the duration of action of inhaled antimuscarinics. A newly developed compound, Ba 679 BR (abbreviated Ba 679) proved to be a highly potent muscarinic antagonist in guinea pig tracheal rings. Its binding to human receptors (Hm1, Hm2, Hm3) was characterized by KD-values in the 10(-10) M concentration range. Assessment of the dissociation rate of complexes of labelled Ba 679 and human muscarinic receptors revealed very slow dissociation in comparison to ipratropium. The half-lives in hours were: Ba 679-Hm3: 34.7, -Hm1: 14.6, -Hm2: 3.6; ipratropium-Hm3: 0.26, -Hm1: 0.11, -Hm2: 0.035. The duration of action in vivo was determined by means of acetylcholine-induced bronchospasms in dogs following inhalation of the drugs. Ba 679 demonstrated a significantly longer duration of protection than an equipotent dose of ipratropium. The plasma levels following inhalation in dogs declined rapidly and are unlikely to reflect the duration of the pharmacological activity. In summary, Ba 679 represents a novel type of antimuscarinic bronchodilator with a long duration of action, most likely due to its slow dissociation from Hm3-receptors. In addition, the drug showed "kinetic receptor subtype selectivity" by having a more rapid dissociation from Hm2 than from Hm1 and Hm3 receptors.

[Effect of smoking on pulmonary glycoprotein metabolism and phospholipid content]. / Einfluss des Rauchens auf den pulmonalen Glykoprotein-Stoffwechsel und Phospholipid-Gehalt.

We investigated the influence of smoking on the cell count, proteins and phospholipids in the bronchoalveolar lavage fluid in 371 patients. In the case of smokers, the cell count and the content of N-acetylglucosaminidase-an enzyme involved in glycoprotein metabolism were elevated. In contrast, the concentrations of protein, alpha amylase and phospholipids were lower than in the nonsmokers. The figures for ex-smokers were, for the most part, similar to those of the non-smokers.

Effects of bovine surfactant in premature lambs after intra-tracheal application.

Twenty-two premature lambs (gestational age 124-125 days, term 144-160 days) were intubated and supported by infant ventilators immediately after delivery. Respiratory rate was 60/min, inspiratory time 0.4 s, peak inspiratory pressure (PIP) 35 cm H2O, positive endexpiratory pressure (PEEP) 2 cm H2O, FiO2 1.0. 15 min after delivery 10 lambs (group 1) were treated with 35 mg/kg body weight bovine surfactant (SF-RI 1), whereas 1 ml/kg body weight saline was instilled in 12 lambs as controls (group 2). Sequential measurements of blood gases and acid base status (every 30 min) as well as continuous registration of PIP, PEEP, respiratory rate and tidal volume (TV) were performed in all lambs for 300 min. PIP was varied between 20 and 40 cm H2O in order to attain paCO2 values between 35 and 50 mm Hg. Significantly improved oxygenation was observed in group 1 lambs with maximum differences 30 min after delivery for 2 h. Ventilation was likewise affected: paCO2 and PIP values were significantly lower in the surfactant-treated animals (group 1). Total lung-thorax compliances (calculated from TV and delta P, i.e. PIP-PEEP) per kg body weight also significantly reflected the improvement of pulmonary function in group 1 compared to group 2 lambs. Intratracheal instillation of SF-RI 1 improved gas exchange in premature lambs, whereas control animals exhibited severe respiratory failure characteristic of respiratory distress syndrome (RDS).

[Treatment of respiratory distress syndrome in very small premature infants with bovine surfactant]. / Die Behandlung des Atemnotsyndroms (RDS) sehr kleiner Frühgeborener mit bovinem Surfactant.

In a clinical, uncontrolled study, bovine surfactant was administered intratracheally to 32 very low birth weight infants. In the first 18 patients, the dose was 20-40 mg/kg body weight (group 1, median birth weight 750 g) in the other 14 infants 40-50 mg/kg (group 2, median birth weight 840 g). The bovine surfactant was given, if the peak inspiratory pressures (PIP) were above 22-27 cm H2O depending on the infant's birth weight or whether the fraction of inspired oxygen (FiO2) was greater than 0.5. The FiO2 decreased from the pretreatment value of 0.7 to 0.46 after 1 hour, whereas PIP could not be lowered as rapidly as FiO2 (PIP from 29 to 26 cm H2O after 1 h). Surfactant treatment was more effective in group 2 comparing the reduction in FiO2 (delta FiO2 0.34 versus 0.16 in group 1 after 1 h), survival in group 2 was higher (71%) than in group 1 (56%). Our data are consistent with those of other groups using other natural surfactant preparations.

Pharmacodynamic mechanism and therapeutic activity of ambroxol in animal experiments.

The mucokinetic activity of ambroxol was demonstrated as an increase in mucus or particle transport rate on the frog palate and in guinea pig tracheas. To clarify the mechanism we examined the influence of the drug on the ciliary beat frequency (CBF) of isolated cells from guinea pig tracheas. Ambroxol significantly stimulated the CBF up to 10.8%, salbutamol up to 19.5%. The effect of ambroxol on CBF certainly contributes to, but does not explain the more pronounced increase in transport rate. Thus a stimulation of the mucociliary transport rate by the other major pharmacodynamic mechanisms, secretagogue activity and stimulation of pulmonary surfactant, has to be considered. The therapeutic activity of ambroxol in models of the infant and adult respiratory distress syndrome and of the chronic bronchitic syndrome is reviewed.

The pharmacology of ambroxol--review and new results.

The major pharmacodynamic actions of ambroxol are surfactant stimulation, mucokinetic and secretagogue activity. The therapeutic activities of the drug in animal models of the infant and adult respiratory distress syndrome (IRDS and ARDS) are reviewed. SO2 exposed rats, which exhibited increased airway resistance and work of breathing, were used as an animal model of a bronchitic syndrome. The active group was treated with 25 mg kg-1 oral ambroxol for 10 days. The airway resistance of this group (53.6 +/- 7.0 Pa.ml-1.s) was significantly lower than that of the control (81.2 +/- 11.4). Specific work of breathing was also lower in the treated group (0.26 +/- 0.02 mJ.ml-1, control: 0.35 +/- 0.029). The alleviation of airflow limitation was a consequence of subacute treatment and not of acute bronchodilatation. Treatment with the beta 2-adrenergic drug clenbuterol further improved both active and placebo groups.

Pharmacokinetics of erythromycin in patients with different degrees of renal impairment.

The kinetics of erythromycin (E.) was studied in 16 patients with different degrees of impairment of renal function after a single intravenous dose. Renal clearance of E. was found to be significantly correlated to the creatinine clearance. Total recovery in urine did not exceed 7.5%. As expected from the small fraction excreted via the kidneys, the elimination half-life and the total clearance of E. did not depend on renal function. We conclude that impairment of renal function does not justify a dose adjustment of E. Hearing acuity should, however, be monitored during treatment since transient deafness predominantly in patients with renal failure has been reported by various authors.

Biosynthesis of 16 alpha, 17 alpha-epoxy-4-androsten-3-one in rat liver microsomes.

4,16-Androstadien-3-one was incubated with the microsomal fraction of male rat liver in the presence of a NADPH generating system and oxygen. The metabolites formed were extracted from the incubation medium and purified by thin-layer chromatography (tlc). Final identification was performed by combined gas liquid chromatography-mass spectrometry. Incubation of 4,16-androstadien-3-one resulted in the formation of a non-polar metabolite which proved to be 16 alpha, 17 alpha-epoxy-4-androsten-3-one. This epoxide is a shortlived intermediate which is rapidly hydrolysed by the microsomal epoxide hydratase to 16 beta, 17 alpha-dihydroxy-4-androsten-3-one. In order to increase the amounts of epoxide in the incubation mixtures, styrene oxide which is a potent inhibitor of the epoxide hydratase was added. Under these conditions, up to 8% of the 16-dehydro-steroid incubated was transferred to the 16 alpha, 17 alpha-epoxy-compound.