B. Boveri

Effect of inhaled bronchodilators on inspiratory capacity and dyspnoea at rest in COPD

It has been shown that patients with chronic obstructive pulmonary disease (COPD) develop dynamic hyperinflation (DH), which contributes to dyspnoea and exercise intolerance. Formoterol, salmeterol and oxitropium have been recommended for maintenance therapy in COPD patients, but their effect on DH has only been assessed for salmeterol. The aim of the present study was to compare the acute effect of four inhaled bronchodilators (salbutamol, formoterol, salmeterol and oxitropium) and placebo on forced expiratory volume in one second, inspiratory capacity, forced vital capacity and dyspnoea in COPD patients. A cross-over, randomised, double-blind, placebo-controlled study was carried out on 20 COPD patients. Patients underwent pulmonary function testing and dyspnoea evaluation, in basal condition and 5, 15, 30, 60 and 120 min after bronchodilator or placebo administration. The results indicate that in chronic obstructive pulmonary disease patients with decreased baseline inspiratory capacity, there was a much greater increase of inspiratory capacity after bronchodilator administration, which correlated closely with the improvement of dyspnoea sensation at rest. For all bronchodilators used, inspiratory capacity reversibility should be tested at 30 min following the bronchodilator. On average, formoterol elicited the greatest increase in inspiratory capacity than the other bronchodilators used, though the difference was significant only with salmeterol and oxitropium. The potential advantage of formoterol needs to be tested in a larger patient population.

Comparison of the Bronchodilating Effect of Salmeterol and Zafirlukast in Combination with That of Their Use as Single Treatments in Asthma and Chronic Obstructive Pulmonary Disease

Background: It has been suggested that the effect of a β2-agonist is additive with that of a cysteinyl leukotriene 1 receptor antagonist. Objectives: The present study was designed to answer the question of whether combined administration of inhaled salmeterol and oral zafirlukast at the standard doses would result in greater bronchodilation in patients with chronic airway obstruction than the use of either drug alone. Methods: The study was performed using a double-blind, double-dummy, crossover, randomised design, and was conducted on 4 non-consecutive days. Sixteen patients with moderate to severe chronic obstructive pulmonary disease (COPD) and 10 non-smoker asthmatic patients received 40 mg of oral zafirlukast, 50 µg of inhaled salmeterol, 50 µg of inhaled salmeterol plus 40 mg of oral zafirlukast of placebo. Lung function was assessed before drug administration and 30, 60, 120, 180 and 240 min thereafter. At the end of the 4-hour period, each patient received 400 µg of inhaled salbutamol and spirometric testing was performed 30 min later. Results: In both asthmatic and COPD patients, the overall effect of salmeterol and zafirlukast on the forced expiratory volume in 1 s (FEV1) was considered extremely significant (p < 0.0001), with a maximum bronchodilation above baseline after 180 min (20.7 and 11.0%, respectively) in asthmatics and after 2 h (21.7 and 11.2%, respectively) in COPD subjects. Zafirlukast did not produce any further significant acute bronchodilation in addition to that achieved with salmeterol alone in either asthmatic or COPD patients. Nevertheless, 7 out of 16 COPD patients and 7 out of 10 asthmatic patients had a further improvement after the combination of salmeterol and zafirlukast. The mean difference in pre- and post-salbutamol FEV1 values in both asthmatic and COPD patients after zafirlukast was significant (p < 0.05), but that after salmeterol and the combination of the two drugs was not significant (p > 0.05). The difference between placebo and zafirlukast was not significant following inhaled salbutamol given 4 h after each treatment. Conclusions: Both salmeterol and zafirlukast induced a significant increase in FEV1, although salmeterol elicited a greater improvement in both asthmatic and COPD patients. Apparently, zafirlukast at the clinically recommended dose did not produce any further significant acute bronchodilation in addition to that achieved with salmeterol alone, either in asthma or COPD. In any case, evaluation of the effect of the combination over a 12-hour period is mandatory.

Bronchodilation test in COPD: effect of inspiratory manoeuvre preceding forced expiration

The effects of an inspiratory manoeuvre preceding forced expiration on functional tests performed under routine conditions before and after inhalation of a bronchodilator drug (salbutamol) were assessed on 150 consecutive chronic obstructive pulmonary disease outpatients. The patients performed forced vital capacity manoeuvres either immediately after a rapid inspiration (manoeuvre no. 1) or after a slow inspiration with a 4–6 s pause (manoeuvre no. 2). Under baseline conditions, forced expiratory volume in one second (FEV1) values were 8% (% control) larger with manoeuvre no. 1 than no. 2. FEV1 values increased with salbutamol administration by ∼8% and were, on average, still 7% larger with manoeuvre no. 1 than no. 2. The incidence of reversibility, assessed according to American Thoracic Society criteria, was 76% when manoeuvre no. 2 was selected to represent baseline conditions and manoeuvre no. 1 was chosen to represent the effects of bronchodilator administration, whereas the lowest incidence (2%) was found when manoeuvre no. 1 was selected to represent baseline conditions and manoeuvre no. 2 was chosen to represent the effects of bronchodilator administration. These results indicate that the time dependence of the forced vital capacity manoeuvre has an important impact on the assessment of routine lung function in a clinical setting and supports the notion that the time course of the inspiration preceding the forced vital capacity manoeuvre should be standardised.

Non-pulmonary effects induced by the addition of formoterol to budesonide therapy in patients with mild or moderate persistent asthma

Objective: The present study was designed to assess the non-pulmonary effects of a 2-week treatment with the addition of formoterol to budesonide therapy in 10 patients with mild or moderate asthma. Methods: Each patient was invited to perform a screening visit which included spirometry before and after inhalation of 12 μg formoterol with a metered dose inhaler (MDI), measurement of arterial blood pressure, baseline electrocardiography and 24-hour Holter monitoring, and a test for evaluating upper limb tremor. Patients then began bronchodilating therapy with 12 μg formoterol MDI and 400 μg budesonide Turbuhaler b.i.d. Each patient was also given a peak flowmeter and a diary in which he had to record the morning and evening values measured before taking inhaled drugs. Two weeks later, the patients repeated the same examinations; the diary card was returned 2 months after the beginning of the study. Results: Adding formoterol to budesonide therapy caused a significant improvement in lung function, but neither induced any statistically significant effect on mean heart rate, nor altered the circadian rhythm of autonomic regulation nor elicited significant alterations in cardiac morphology. However, the evaluation of upper limb tremor revealed a statistically significant increase (p = 0.02). Conclusions: This study shows that adding the recommended dose of formoterol to an inhaled corticosteroid therapy does not induce significant cardiac undesirable effects, although tremor, surely due to stimulation of β2 receptors of the skeletal muscles, may sometimes be a limiting effect.

Interrelationship Between the Pharmacokinetics and Pharmacodynamics of Cefaclor Advanced Formulation in Patients with Acute Exacerbations of Chronic Bronchitis

Abstract Cefaclor advanced formulation (cefaclor AF) is an extended-release form of the oral cephalosporin cefaclor. When cefaclor AF 750 mg twice-daily and cefaclor immediate release 500 mg three-times-a-day are compared there is a skew to the right of the pharmacokinetic profile and higher levels are achieved. Based on this pharmacokinetic finding, we examined the relationship between the bacterial susceptibility to cefaclor (MIC), the achieved cefaclor AF serum and sputum concentrations, and in vivo eradication of the bacteria in 36 patients with acute exacerbations of chronic bronchitis. The mean peak concentrations in serum and sputum 5 h after administration were 8.6 μg/ml (95% CI: 8.1 μg/ml − 9.1 μg/ml) and 1.5 μg/ml (95% CI: 1.4 μg/ml − 1.7 μg/ml), respectively. Cefaclor was always detectable 8 h after administration. At post therapy, treatment was successful in 31 (86.1%) patients. Cefaclor concentrations in serum persisted above the MIC for more than 40% of dosing interval in 31 subjects, and those in sputum in 24 patients. Treatment was successful in all subjects with percent of time above the MIC in serum of >40%, whereas the time that levels in sputum stayed above the MIC was not the pharmacody-namic parameter that correlated best with therapeutic efficacy for cefaclor. Our data demonstrate that when cefaclor AF is dosed twice-daily, the in vivo phar-macodynamic susceptibility breakpoint is 8 μg/ml. The good activity and pharmacokinetics of cefaclor AF provide serum concentrations higher than the MIC of Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis for more than 40% of the validated dosing interval. Therefore, it might be considered for first choice treatment of acute exacerbations of chronic bronchitis.