Matti Silvasti

Antitussives in the treatment of acute transient cough in children.

Although cough may be caused by several factors, the most common causes are acute viral respiratory infections (1). Cough related to viral infection is usually transient and needs no treatment. However, antitussive drugs are widely used in such situations despite of criticism (2, 3). In this double-blind parallel group study we compared the efficacy of two preparations, an antitussive or an antitussive-& sympathomimetic combination, with that of placebo in the treatment of cough related to acute respiratory infection in children.

Long term treatment of severe hypercholesterolaemia with guar gum

The long term efficacy of granulated guar gum, 15-30 g per day, was studied in 23 patients with severe hypercholesterolaemia (serum cholesterol concentration between 8.0 and 14.3 mmol/l). Originally, 29 patients participated in the study. Two patients dropped out because of gastrointestinal side effects, two others were not willing to complete the study without any given reason, and two discontinued the study because of hospitalization. A 1-month placebo period preceded the guar gum treatment, and another 1-month placebo period followed after 50 weeks of active treatment. The serum total cholesterol concentration (mean +/- SEM) was reduced from 10.0 +/- 0.4 mmol/l to 8.2 +/- 0.3 mmol/l (P less than 0.001) after 8 weeks and to 9.0 +/- 0.4 mmol/l (P less than 0.001) after 50 weeks on guar gum. During the second placebo period serum cholesterol returned to the pretreatment level. After 34 weeks of active treatment the serum LDL-cholesterol concentration had fallen by 15% and that of apoprotein B by 14% from the baseline. The changes in lipid and lipoprotein levels were independent of the initial values and the type of hypercholesterolaemia. Serum triglycerides, HDL-cholesterol, body weight and blood pressure showed no significant changes during the trial. Of the study subjects, 20 reached the maximum intended dose of 30 g per day guar gum between 8 and 14 weeks and thereafter 11 subjects continued the dose of 30 g/day while 12 subjects reduced the dose to 15-25 g/day.(ABSTRACT TRUNCATED AT 250 WORDS)

Easyhaler® a Novel Multiple Dose Powder Inhaler: Clinically Equivalent to Salbutamol Metered Dose Inhaler and Easier to Use

Twenty-one adult asthmatic patients participated in a trial to compare the clinical equivalence of a single dose of salbutamol inhaled either from a novel multiple dose powder inhaler (MDPI), Easyhaler, or from a conventional metered dose inhaler (MDI). The trial was carried out as a randomized, double-blind, crossover study. The study involved 2 study days with a 6-hour follow-up period of spirometric indices. In addition, blood pressure and heart rate were measured immediately before each lung function test. Our data indicate that salbutamol treatment with the MDPI achieves values which are equivalent to those achieved with the conventional pressurized MDI as regards improving pulmonary function and tolerability. The mean maximum forced expiratory volume in 1 s (FEV1) after the powder dose was 2.44 +/- 0.96 liters and after the aerosol dose 2.45 +/- 0.93 liters. The mean area under the curve of absolute FEV1 values was 822 +/- 340 and 829 +/- 335, respectively. The mean percent change from the baseline in FEV1, forced vital capacity and peak expiratory flow following administration of the preparations was of equal magnitude in both cases. The treatments tested had no effect on blood pressure or heart rate and were well tolerated. A further important finding was that most patients found the MDPI easier or no more difficult to use than the conventional MDI and this probably facilitates the transition from pressurized MDIs to the novel MDPI.

Pulmonary Deposition and Clinical Response of99mTc-Labelled Salbutamol Delivered from a Novel Multiple Dose Powder Inhaler

Pulmonary deposition of 99mTc-labelled sulbutamol was determined after delivery from a novel multiple dose powder inhaler (Easyhaler®). The clinical efficacy of the inhalation powder, evaluated simultaneously with gamma camera detection, was compared with that obtained after drug delivery from a metered dose inhaler-spacer combination. The study was performed as an open, non-randomized cross-over trial. A single dose of radiolabelled inhalation powder was inhaled on the first and the inhalation aerosol, as control, on the second study day. Sulbutamol sulphate was labelled with 99mtechnetium, and the inhalation powder was formulated by mixing radioactive drug particles with carrier material. Aerodynamic properties of the radiolabelled inhalation powder were similar to those of the unlabelled salbutamol powder. Delivered dose from the breath-actuated powder inhaler was adjusted to be equal to two puffs from a conventional aerosol actuator with a short plastic mouthpiece. Twelve non-smoking asthmatic patients participated in the trial. The mean pulmonary deposition of 24% was obtained after drug delivery from Easyhaler® powder inhaler. Clinical efficacy of the medications was similar in terms of area under the FEV1 curve, maximum FEV1 and the improvement ratio. Thus it can be suggested that powder delivery from Easyhaler® powder inhaler and the aerosol delivery through the spacer are equally effective.

Equivalence of Two Steroid-Containing Inhalers: Easyhaler Multidose Powder Inhaler Compared with Conventional Aerosol with Large-Volume Spacer

Background and Objectives: An equivalence study was conducted in which the efficacy and safety of a daily dose of 800 μg of beclomethasone diproprionate administered via a multidose powder inhaler, Easyhaler, and via a metered-dose inhaler (MDI) with a large-volume spacer were compared in adult, newly diagnosed, steroid-naive asthmatic patients. Acceptability of the medications was also compared. Methods: One hundred and forty-four patients were recruited into the double-blind, double-dummy, randomised, parallel-group multicentre study. The study treatment period was 8 weeks. It was preceded by a 2-week run-in period. Morning and evening peak expiratory flow (PEF), numbers of inhalations of a sympathomimetic and asthma symptoms were recorded daily. Spirometry and histamine challenge were performed, and health-related quality of life and morning serum cortisol levels measured during control visits. Results: Criteria indicating treatment equivalence were met. The mean of the primary outcome variable, morning PEF, increased significantly, from 426 to 461 litres/min in the Easyhaler group and from 436 to 467 litres/min in the MDI+spacer group. Similar improvements between groups were also seen in relation to all secondary variables. Changes in serum cortisol levels were minor. In 6 out of 10 questions about device acceptability, the majority of patients rated Easyhaler as better than the MDI+spacer combination. Conclusion: It was concluded that the devices tested were equivalent in terms of efficacy and safety.

Effects of Some Preservative Agents on Rat and Guinea Pig Tracheal and Human Nasal Ciliary Beat Frequency

Many preservatives commonly included in nasal drops and sprays are known to impair mucociliary clearance. We studied the effects of four frequently used preservatives on ciliary beat frequency (CBF) in respiratory tissue. Sodium metabisulfite and chlorbutol did not change the CBF at concentrations up to 50 mg/L in rat tracheal mucosa. Chlorocresol 25 mg/L and 50 mg/mL reversibly decreased CBF (by 33% and 68%, respectively) in 60 minutes. Benzalkonium chloride impaired CBF irreversibly already at a relatively low concentration (12.5 mg/L). To further clarify these results, we studied the effects of the most ciliotoxic (benzalkonium chloride) and nonciliotoxic (chlorbutol) preservative on guinea pig tracheal epithelium and human nasal mucosa. Although chlorbutol had no effect on the CBF, a dose-dependent decrease on CBF was seen in guinea pig and human ciliated epithelium during their immersion in benzalkonium chloride. At a concentration of 50 mg/L it stopped the ciliary activity in 40 minutes in guinea pig trachea, and in human nasal mucosa, benzalkonium chloride concentrations of 25 and 50 mg/L, decreased the CBF irreversibly (by 28% and 60%, respectively) in 60 minutes. These results suggest that chlorbutol is a safe and well tolerated preservative. Banzalkonium chloride is ciliostatic in vitro to rat, guinea pig, and human respiratory mucosa. Therefore, prolonged clinical use of benzalkonium chloride may impair mucociliary clearance, a major defense respiratory mechanism.

Guar gum and gemfibrozil - an effective combination in the treatment of hypercholesterolaemia

Twenty-nine hypercholesterolaemic patients, treated for one year with gemfibrozil but being still hypercholesterolaemic (serum total cholesterol greater than or equal to 6.25 mmol/l) were included in a double-blind trial to evaluate the hypocholesterolaemic effects of gemfibrozil-guar gum combination (GE + GU) vs. gemfibrozil-placebo combination (GE + PL) using a cross-over study design. The patients were treated with gemfibrozil on a constant dosage (range 900-1200 mg/day) during the entire trial. After a 4-week run-in period on GE + PL treatment the patients were randomly allocated to 2 groups: one received GE + GU 15 g/day, and the other GE + PL for 3 months and after that groups were crossed over. Guar gum and placebo were administered as granules taken 3 times a day during meals. Serum total cholesterol was 8.61 +/- 0.17 mmol/l before gemfibrozil therapy, and 7.29 +/- 0.15 mmol/l at the end of the run-in period on GE + PL (P less than 0.01). During the double-blind phase serum total cholesterol values were 6.28 +/- 0.19 mmol/l at the end of the GE + GU treatment period and 7.21 +/- 0.16 mmol/l at the end of the GE + PL treatment period (P less than 0.01). At the end of the GE + GU treatment period serum total cholesterol was 27% lower and LDL-cholesterol 39% lower than before gemfibrozil treatment. A marked improvement (23%) was found in HDL/LDL ratio during GE + GU treatment compared with GE + PL treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Antitussive Effect of Dextromethorphan and Dextromethorphan-Salbutamol Combination in Healthy Volunteers with Artificially Induced Cough

The antitussive effects of dextromethorphan (30 mg) + salbutamol (2 mg), dextromethorphan (30 mg) alone and placebo on artificial cough induced by citric acid were compared in 19 healthy non-smoking volunteers in a double-blind crossover study. The method using inhaled citric acid with increasing concentrations to establish the cough threshold level showed an acceptable reproducibility and proved to be suitable for comparison of antitussive drugs. The cough threshold level was assessed before as well as 90 and 180 min after each medication. After placebo the cough threshold level showed no statistically significant rise. However, significant rises were shown following dextromethorphan (p less than 0.001) and the dextromethorphan-salbutamol combination (p less than 0.001). Between the treatments significant differences were shown in favour of the dextromethorphan-salbutamol combination. The results indicate that salbutamol has antitussive action enhancing the effect of plain dextromethorphan.

Therapeutic Equivalence and Acceptability of Two Multidose Powder Inhalers in the Treatment of Asthma

Background: Problems in using conventional inhalation aerosols, in addition to environmental reasons, have driven development of the dry powder inhalers. Objective: To compare therapeutic equivalence and acceptability of two dry powder inhalers, Easyhaler (EH) and Diskhaler (DH), in the delivery of beclomethasone dipropionate (BDP) in the treatment of asthma. Methods: Adult asthmatics (n = 185), previously treated with inhaled steroids, were recruited in this open parallel-group study. After a run-in period of 2 weeks during which the patients inhaled 800 μg/day of BDP via DH, the patients were randomly allocated into three groups: EH 200 group (62 patients) using EH 200 μg/dose inhaler (1 inhalation q.i.d.), EH 400 group (62 patients) using EH 400 μg/dose inhaler (1 inhalation b.i.d.), and DH group (61 patients) using DH 200 μg/dose inhaler (1 inhalation q.i.d.) for 12 weeks. The primary outcome variables were PEF and FEV1. Results: The 95% CI for treatment difference in morning PEF between the EH 200 and DH groups was –16 to 23 litres/min and between the EH 400 and DH groups –18 to 21 litres/min. There was an increase in the morning PEF of 13 litres/min (p < 0.05) in the EH 200 group, and 9 and 11 litres/min in the DH and EH 400 groups. No differences between the groups were seen in the lung function parameters, in the symptom scores, in the use of rescue medication or in the incidence of adverse events. The treatments had no effects on morning cortisol levels. The patients in the EH groups compared the inhalers by using an 11-item questionnaire. In 8 questions the majority of the patients rated EH superior to DH. Conclusion: The tested inhalers were therapeutically equal. However, based on the acceptability data, the EH was better accepted by the patients than DH.

Salbutamol via Easyhaler® Produces Equivalent Bronchodilation to Terbutaline via Turbuhaler® following Inhalation of a Single Dose of Equipotent β2-Sympathomimetic

AbstractObjective: The aim of this study was to compare the bronchodilating effect, tolerability and acceptability of a single 100μg dose of salbutamol inhaled via Easyhaler® multidose dry powder inhaler with a single 250μg dose of terbutaline inhaled via Turbuhaler®, also a multidose dry powder inhaler. Design, Setting and Patients: The study was conducted according to a single-dose, crossover, randomised, double-blind with double-dummy design in four centres in Finland. A total of 29 adult patients with stable asthma without previous experience with the tested devices completed the study, which comprised 2 study days with 4-hour follow-up periods including spirometric measurements. The acceptability of the devices to the patients in the study was also evaluated. Results: The mean (SD) maximum value of forced expiratory volume in 1 second (FEV1max) after salbutamol Easyhaler® was 3.14L (1.26L), and after terbutaline Turbuhaler® was 3.07L(1.11L). The mean (SD) percentage change from baseline of forced expiratory volume in 1 second (FEV1) to FEV1max was 12.7% (12.4%) after Easyhaler® and 13.1% (10.8%) after Turbuhaler®. The observed differences in the increase in FEV1 and in the area under the curve (AUC) of FEV1 between the treatments were not statistically significant. Four patients reported mild adverse events after inhaling salbutamol via Easyhaler®, compared with five patients who reported adverse events after inhaling terbutaline via Turbuhaler®. Based on the VAS assessment of the acceptability, Easyhaler® was found to be better accepted than Turbuhaler® in terms of ease of administration, ease of inhaling, and the strength of sensation on receiving a dose. Overall, 62% of the patients would have chosen Easyhaler®. Conclusions: Easyhaler® containing salbutamol (100μg/dose) is comparable in efficacy and as well tolerated as Turbuhaler® containing terbutaline (250μg/dose), and Easyhaler® was well accepted by patients.