Randomised double-blind comparison of oral gatifloxacin and co-amoxiclav for acute exacerbation of chronic Bronchitis.

Antimicrobial therapy can have a significant impact in the treatment of acute infectious exacerbations in patients with chronic bronchitis, in whom repeated episodes are common. The aim of this randomised, double-blind, double-dummy, parallel group study was to compare the efficacy and safety of oral gatifloxacin (200 and 400 mg once daily) administered for 5 days with co-amoxiclav (500 mg amoxicillin/125 mg clavulanic acid t.i.d.) administered for 10 days in 414 adult patients with acute exacerbation of chronic bronchitis. Overall clinical response rates (cure plus improvement) were 86.2%, 79.4% and 81.7% in the gatifloxacin 200 mg, gatifloxacin 400 mg and co-amoxiclav groups, respectively, and the equivalence hypothesis used for statistical analysis showed equivalent efficacy for both gatifloxacin 200 and 400 mg compared to co-amoxiclav. The same was true for rates of bacterial response, with eradication or presumed eradication of causative pathogens achieved in 87.5%, 87.3% and 79.1% of cases in the gatifloxacin 200 mg, gatifloxacin 400 mg and co-amoxiclav groups, respectively. All treatments were well tolerated, with the nature and frequency of treatment-related adverse events similar in all groups. The results of the study show that gatifloxacin is a safe and effective agent for the treatment of patients with chronic bronchitis experiencing an acute infectious exacerbation.

Clinical effectiveness of levofloxacin in patients with acute purulent exacerbations of chronic bronchitis: the relationship with in-vitro activity.

The objective of this randomized, double-blind study was to compare the clinical efficacy of levofloxacin at two different dosages with that of cefuroxime axetil in patients with acute purulent exacerbations of chronic bronchitis and, in particular, to assess the impact of the susceptibility to levofloxacin on the clinical findings. In total, 124 evaluable patients were treated for 7 days with oral levofloxacin 250 mg or 500 mg od, or cefuroxime axetil 250 mg bd. Sputum cultures were monitored pre-treatment, and at 1 and 7 days after the end of treatment. The susceptibility of Streptococcus pneumoniae isolates was tested by agar dilution in Columbia blood agar and by disc diffusion, but all other isolates were tested solely by the disc diffusion method. A greater number of infections were eradicated by levofloxacin than by cefuroxime axetil: infections were eradicated in 68% of patients receiving the 500 mg dosage and in 63% of those taking 250 mg levofloxacin, whereas the eradication rate with the comparator drug was much lower (48%). Against all pre-treatment S. pneumoniae isolates (n = 39), the MICs of levofloxacin were between 0.25 and 2 mg/L (geometric mean 0.95 mg/L), similar to those of the post-treatment strains (n = 32; mean 1.11 mg/L). All except one of the S. pneumoniae isolates were susceptible to penicillin G (MIC < or = 0.06 mg/L), and the remaining isolate was inhibited by 0.5 mg/L of penicillin G, but was fully susceptible to levofloxacin. Some pretreatment strains of Pseudomonas aeruginosa were resistant to levofloxacin, but many more resistant strains were encountered afterwards. All strains of Moraxella catarrhalis and Haemophilus influenzae were highly susceptible to levofloxacin in the disc diffusion tests. All the antimicrobial agents used in the study were well tolerated: only two patients discontinued treatment because of adverse drug effects. The results of this study indicated that, although there were some failures in patients with S. pneumoniae and P. aeruginosa infections, resistance to levofloxacin did not emerge rapidly among strains of S. pneumoniae during therapy with levofloxacin, and that natural resistance among pneumococci, H. influenzae and M. catarrhalis was rare.

Levofloxacin versus cefuroxime axetil in the treatment of acute exacerbation of chronic bronchitis: results of a randomized, double-blind study.

A randomized, double-blind, double-dummy, three-arm parallel design, multicentre study was conducted among adult patients with acute exacerbation of chronic bronchitis (AECB) in order to compare the efficacy and safety of two different doses of levofloxacin with cefuroxime axetil. A total of 832 patients were randomized to receive oral levofloxacin (250 mg od or 500 mg od) or oral cefuroxime axetil (250 mg bd) for 7-10 days. The primary efficacy analysis was based on the clinical response in patients with bacteriologically confirmed AECB, determined 5-14 days after the end of therapy (per-protocol population). Of 839 patients enrolled (at 71 centres in 14 countries), seven were not treated, giving an intention-to-treat (ITT) population of 832. In total, 281 patients received levofloxacin 250 mg, 280 received levofloxacin 500 mg and 271 received cefuroxime axetil. The cure rates in the ITT population were: levofloxacin 250 mg, 70% (196/281); levofloxacin 500 mg, 70% (195/280); cefuroxime axetil, 61% (166/271); those in the per-protocol population were: 78% (121/156), 79% (108/137) and 66% (88/134), respectively. Both doses of levofloxacin were at least as effective as cefuroxime axetil and were active against the main pathogens of clinical relevance (Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis). All three treatment regimens were equally well tolerated. In conclusion, the results show that levofloxacin (250 mg and 500 mg) od is effective and well tolerated in the treatment of AECB in adult patients.

A comparison of the onset of action of salbutamol and formoterol in reversing methacholine-induced bronchoconstriction.

This single-centre, randomized, double-blind, double-dummy four-way cross-over study in 24 moderately severe asthmatic patients compared the speed of onset of recommended doses of salbutamol (200 micrograms) and formoterol (12 micrograms) delivered by metered-dose inhaler in reversing the bronchoconstriction induced by a cumulative dose of methacholine to produce a 20% decrease (PD20) in forced expiratory volume in 1 s (FEV1). Specific airway conductance (SGAW) and airway resistance (RAW) were measured in baseline condition, immediately after challenge and 0.5, 1.5, 3, 5, 10, 15, 30, 60 min and every hour up to 4 h after inhalation of the trial drug. FEV1 was measured in baseline condition, after challenge and 15, 30 and 60 min and then every 30 min up to 4 h after inhalation of the study drug. The primary efficacy parameter was the change in SGAW. Salbutamol produced a two-fold increase in SGAW within 4 min and a maximum increase after 79.3 min. Formoterol produced a two-fold increase in SGAW after 5 min and a maximum increase after 119.6 min. Changes in SGAW were slightly, but consistently, higher during the first 2 h after inhalation of salbutamol, both in absolute values and as a percentage of the maximum response. Differences were significant at 10, 15 and 30 min time points. There was no significant difference between the maximum values of SGAW after the two drugs. Changes in RAW and FEV1 reflected the differences in SGAW. It was concluded that in methacholine-induced bronchoconstriction both formoterol and salbutamol have a very fast onset of action, achieving prechallenge values of SGAW within 3 min, salbutamol being slightly faster than formoterol.

Therapeutic equivalence of a novel HFA134a-containing metered-dose inhaler and the conventional CFC inhaler (Berodual) for the delivery of a fixed combination of fenoterol/ipratropium bromide. A randomized double-blind placebo-controlled crossover study in patients with asthma.

The efficacy and safety of a novel fenoterol/ipratropium bromide metered-dose inhaler (MDI) formulated with a non-chlorinated propellant, HFA134a, has been compared with placebo and the conventional chlorofluorocarbon (CFC)-containing fenoterol/ipratropium bromide inhaler (Berodual) in asthmatic patients. Fifty-two patients were enrolled in two centres. The fenoterol/ ipratropium bromide treatment produced significantly (P < 0.0001) greater bronchodilatation than placebo. There were no significant differences between the mean peak and average forced expiratory volume in the first second (FEV1) for patients receiving 2 puffs of the fenoterol/ipratropium bromide HFA134a inhaler and the conventional CFC inhaler. In addition, time to onset and duration of efficacy were comparable for these two treatments. None of the patients showed a fall of > or = 15% in baseline FEV1 or needed rescue medication within 30 min after inhalation of the test drug. No paradoxical bronchoconstriction was observed as measured by sGaw. The two inhaler formulations were well tolerated. A taste-related complaint, lasting for a few minutes after inhalation, was reported by a higher proportion of patients who inhaled the HFA134a formulation, mainly by patients selected in one of the two centres. In conclusion, a dose of 100 micrograms fenoterol/40 micrograms ipratropium bromide inhaled from a MDI containing HFA134a propellant is safe and provides effective bronchodilatation of equivalent degree, onset and duration of action to the same dose from the conventional CFC formulation.

Salmeterol versus formoterol in patients with moderately severe asthma: onset and duration of action.

We evaluated the profile of the bronchodilatory effect of three inhaled beta2-agonists, 24 microg formoterol, 50 microg salmeterol and 200 microg salbutamol, in patients with stable, moderately severe asthma. Thirty asthmatics (mean+/-SD age 54+/-8 yrs; forced expiratory volume in one second (FEV1) 58+/-12% predicted; reversibility of FEV1 21+/-8% from baseline) participated in a single-centre, double-blind, randomized, single-dose, cross-over study. FEV1 was obtained in baseline condition and 10, 20, 30, 60 min, and every hour up to 12 h after inhalation of the trial drug. Specific airway conductance (sGaw) was measured at baseline condition and 1, 3, 5, 7, 10, 20, 30, 60 min, and every hour up to 12 h after inhalation. Formoterol produced a mean increase in sGaw (as % of baseline) of 44% after 1 min, maximal (135%) after 2 h, and 56% after 12 h. The mean increase in FEV1 was maximal (27%) after 2h, and 10% after 12 h. After salmeterol, mean increase in sGaw amounted to 16% after 3 min, maximal (111%) after 2-4 h, and 58% after 12 h. The mean increase in FEV1 was maximally 25% after 3h, being 11% after 12 h. After salbutamol, mean increase in sGaw was 44% after 1 min and maximal (100%) after 30 min. The peak increase in FEV1 was 25%. We conclude that formoterol (24 microg) and salmeterol (50 microg) had an equal bronchodilatory capacity, which was similar to that of 200 microg salbutamol and lasted for at least 12 h in patients with asthma. However, formoterol had a more rapid onset of action than salmeterol, equal to that of salbutamol.

Onset of action of eformoterol by dry powder inhaler: objective and subjective measures.

This double-blind, randomised, placebo-controlled crossover trial in 18 adults with asthma evaluated the onset of efficacy of doses of 12 and 24 micrograms eformoterol delivered as a dry powder, and compared patients' subjective assessments of efficacy with objective measures. Bronchodilatory efficacy was measured in terms of specific conductance (sGaw) and forced expiratory volume in one minute (FEV1). With both doses of eformoterol, a bronchodilatory effect was observed one minute after inhalation. The difference in bronchodilator effect (sGaw and FEV1) between both eformoterol doses and placebo was statistically significant (p < 0.01) from one minute onwards. No significant difference in onset of action or peak effect was seen between the two doses of eformoterol. Patients' subjective reports were closely related to the observed onset of efficacy and indicated no difference between the two eformoterol doses.

Tiotropium bromide, a new long-acting antimuscarinic bronchodilator: a pharmacodynamic study in patients with chronic obstructive pulmonary disease (COPD). Dutch Study Group.

The objective of the present study was to investigate the dose-dependent bronchodilator efficacy and duration of action of the newly developed antimuscarinic agent tiotropium bromide in patients with chronic obstructive pulmonary disease (COPD). In a randomized, double-blind, placebo-controlled, crossover design, patients inhaled single doses of 10-80 micrograms tiotropium bromide and placebo, formulated in lactose powder capsules. The washout period between test doses was 72 h. Thirty five patients were enrolled in the trial (32 males and 3 females; mean age 64 yrs). Baseline forced expiratory volume in one second (FEV1) (mean 1.34 L) was less than 65% of predicted and was < 70% of forced vital capacity (FVC). All subjects had a smoking history of more than 10 pack-years. The mean reversibility of FEV1 after inhalation of 40 micrograms ipratropium bromide was 28%. Pulmonary function testing was performed before and at regular time intervals for up to 32 h after test drug administration. Compared to placebo, tiotropium bromide produced significant improvements in FEV1, FVC, peak expiratory flow rate (PEFR) and forced mid-expiratory flow (FEF25-75%). The bronchodilator response was almost immediate; peak improvement in FEV1 was reached 1-4 h after test drug inhalation, and the duration of action extended to 32 h after the 20, 40 and 80 micrograms doses. A clear dose-response relationship was seen for peak FEV1 and for the average FEV1 over differing time periods during the 32 h observation period, 80 micrograms of test drug being superior to the 10 micrograms dose. Peak improvement in FEV1 ranged 19-26% of test-day baseline for tiotropium bromide doses compared to 16% for placebo. The large improvement for placebo is probably due to carry-over effect which was significant. After excluding carry-over effect, the peak response to placebo decreased to 11%, whilst for tiotropium bromide doses it ranged 20-25%; standard error for mean difference was about 4%. There was no evidence of systemic anticholinergic effects. In this population of patients with COPD, tiotropium bromide was found to be a safe and long-acting bronchodilator, demonstrating a clear dose-response relationship following single dose administration.

Comparison of performance of four instruments in evaluating the effects of salmeterol on asthma quality of life.

Quality of life measures are increasingly used as important efficacy endpoints in studies of drugs for asthma. The purpose of this study was to assess both the sensitivity to change and the construct validity of four different quality of life instruments in patients with asthma. In a double-blind, parallel group study, 120 moderate asthma patients, aged between 18-70 yrs, received either inhaled salmeterol 50 micrograms b.i.d. or inhaled salbutamol 400 micrograms b.i.d. In addition to respiratory outcomes, quality of life was measured at a 6 weeks follow-up using: 1) Asthma Quality of Life Questionnaire (AQLQ); 2) Living With Asthma Questionnaire (LWAQ); 3) Sickness Impact Profile (SIP); 4) Rating Scale (RS); and Standard Gamble (SG) utilities. Salmeterol led to significant improvements over salbutamol on virtually all clinical outcomes. Although all the quality of life instruments showed the same trend in favour of salmeterol, only the AQLQ and RS utilities showed significantly greater improvement on salmeterol than on salbutamol. Except for the AQLQ, the correlation between change in lung function and change in quality of life was generally low. Whereas, the AQLQ correlated well with the patient's overall assessment of efficacy (r = 0.64), the LWAQ, SIP and utilities failed to show such a correlation. The AQLQ showed the best correlation with symptom scores. The cross-sectional correlation between the AQLQ and the LWAQ was 0.73, whereas the longitudinal correlation was only 0.29. The SG generally showed poor correlation with other measures, including the RS. In conclusion, patients given salmeterol showed a greater improvement in quality of life compared to patients given salbutamol. Of the disease-specific questionnaires the Asthma Quality of Life Questionnaire was found to be more responsive to change than the Living With Asthma Questionnaire and showed greater validity. Of the generic instruments, the rating scale utilities were most responsive. The Standard Gamble showed poor correlation with other measures.

Evaluation of different doses of formoterol from a newly developed powder inhalation device in asthmatic patients.

Administration of different doses of formoterol from a recently developed multiple dose dry powder device was tested in a placebo-controlled, single-centre, double-blind, within-patient trial. Eighteen patients of both sexes, aged 18-65 years, with a FEV1 of 50-80% and a reversibility of at least 15% were randomized. During four treatment periods of 8 days each, divided by approximately 6 days, patients received placebo or 6, 12 or 24 micrograms (PL, F6, F12 and F24, respectively) of formoterol from the powder device. Efficacy parameters (FEV1) and safety parameters (primarily pulse rate, electrocardiogram [ECG] and subjective experiences) were evaluated during 24 hours on the last day of each treatment period. Peak flow and the number of puffs of used rescue medication (100 micrograms of salbutamol) were registered during treatment periods. For efficacy analysis, 17 patients remained. For FEV1 0.5 hour before the last dose and 12 and 24 hours after the last dose all formoterol doses were statistically significant superior to placebo. Clinically relevant differences from placebo were found up to 8 hours (F6) and 12 hours (F12 and F24). The difference between doses was clinically relevant for the area under the FEV1 curve between F6 and F24. PEF on the treatment days corresponded to these findings. In three cases of 13 reported adverse effects, the relation to trial medication was probable (tremor) or possible (insomnia and hyperaesthesia). All other safety measurements showed no significant differences. We conclude that formoterol dry powder in the newly developed multiple dose inhalation device is an effective and safe beta 2-stimulant with a long duration of action in doses of 6, 12 and 24 micrograms. The 24 micrograms dose is superior to the 6 micrograms dose. Efficacy decreased considerably between the 12th and 24th hour after dosing.

Effect of zatebradine, a novel 'sinus node inhibitor', on pulmonary function compared to placebo.

Zatebradine, a member of a novel class of drugs called 'sinus node inhibitors', is a specific heart rate lowering drug suitable for the treatment of stable angina pectoris. Animal studies showed that relatively high intravenous doses of zatebradine contracted guinea-pig airways by a histamine-like mechanism. Therefore, the objective of the present study was to assess the bronchopulmonary effects in asthmatic patients who showed a moderate to severe bronchial hyperreactivity towards histamine (PC20 FEV1 < or = 1 mg/ml). Moreover, it had to be established to what extent the bronchial responsiveness to inhaled salbutamol was retained and whether pulmonary effects were related to the severity of bronchial hyperreactivity. By means of a double-blind cross-over design, single oral doses of zatebradine (10 mg) or placebo were administered on two occasions with a washout phase of at least 3 days. Sixteen patients, four female and 12 male, with stable mild to moderate bronchial asthma (FEV1 less than 80% predicted) were selected. Their mean age was 54 years and the mean FEV1 was 1.831 (59% predicted). They showed a mean improvement in FEV1 of 27% 15 min after inhaling 200 micrograms salbutamol; the mean PC20 was 0.35 mg/ml. Following test drug intake, the respiratory and cardiac effects were assessed at regular time intervals up to 6 h after administration. In comparison to placebo, zatebradine induced small, but significant (P < 0.05), mean falls of 128 ml and 168 ml in FEV1 at 3 h and 6 h after drug intake. A large inter-individual variation in response was noted.(ABSTRACT TRUNCATED AT 250 WORDS)

Lipoma of the external thoracic wall.

We report the case history of an external thoracic wall lipoma, which was noticed incidentally on a chest roentgenogram because of its calcification. A probable diagnosis was made by computer tomography. Because of the increase in size of the tumour it was removed surgically, but no evidence of malignant degeneration was found.

Ba 679 Br, a new long-acting antimuscarinic bronchodilator: a pilot dose-escalation study in COPD.

Preclinical studies with Ba 679 Br have demonstrated a significantly longer duration of action than ipratropium bromide. Following inhalation of single doses, no systemic antimuscarinic effects were noted at doses likely to be bronchodilating in man. The objective of the present pilot-study of Ba 679 Br was to establish the dose-range for its bronchodilatory activity in a small number of chronic obstructive pulmonary disease (COPD) patients, before initiating a formal dose- and time-response study. Employing an open cross-over design, the efficacy of Ba 679 Br was tested, following single inhalational administration of five doses of increasing magnitude on separate days in six patients with COPD. A piezoelectric crystal was used, in order to nebulize an aqueous solution into a mist suitable for inhalation. There was a mean increase in forced expiratory volume in one second (FEV1) of 36% 30 min after inhaling ipratropium bromide 40 micrograms. Pulmonary function tests (FEV1, and specific airways conductance (sGaw)) were performed, at regular time intervals up to 24 h after test drug inhalation. The bronchodilatory activity of Ba 679 Br appeared to be dose-related in the dose-range tested (10-160 micrograms). A peak response was reached in 1.5-2 h, and persisted for 10-15 h in the majority of patients with return to baseline FEV1 approximately 19 h after dosing. No changes in physical examination, electrocardiogram (ECG) and laboratory safety tests from predose values were noted, and no serious adverse events were reported by the patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Agenesis of the right upper lobe.

Bronchoscopy and bronchography revealed a very rare abnormality in the embryonal anatomy of the right bronchial tree in a 54-year-old woman with cough. There was a proximal migration of the apical branch of the right upper bronchus toward the trachea and a distal migration of the two other branches toward the middle lobe bronchus. The proximal migration was accompanied by a narrowing of the trachea. This case is considered an extremely rare embryonal variation in the development of the right bronchial tree.

Formoterol suspension aerosol. Comparison with formoterol solution aerosol for 12 weeks in asthmatic patients.

UNLABELLED: Formoterol solution aerosol has proved to be a fast and long-acting beta 2-sympathicomimetic drug in many clinical trials. The physical stability, however, was such that storage needed to be at 4 degrees C to 8 degrees C before first use; afterwards, the aerosol could be used for another three months at room temperature. To improve the stability, new ways have been investigated to formulate ann aerosol with improved shelf life and thus more convenient storage conditions, which was reached with a formoterol suspension aerosol. Equivalent single doses between the two formulations revealed no differences in onset or duration of action. In a double-blind, randomized parallel group multicenter study, organized in the Netherlands, 186 patients with stable asthma and reversible airway obstruction were treated either with one puff of 12 micrograms twice daily of formoterol metered dose inhaler (MDI) supension (SP) or a same dose of solution (SL) aerosol for 12 weeks to study the efficacy and tolerability of both presentations after a longer period of use. The following criteria of effectiveness were used: the FEV1 values on the mornings of the control days at 0, +4, +8, and + 12 weeks, the peak flow values (PEF) in the mornings and in the evenings before, and 1/2 to 1 h after treatment, the number of asthma attacks at night and during the day, the number of extra puffs at night and during day, and the subjective impression of patients and investigator. RESULT: No statistically significant differences between the two formoterol preparations were found. There was no indication of tachyphylaxis. CONCLUSION: The results are consistent with the hypothesis that the biologic effects of formoterol when delivered from MDI containing the two different formulations of the drug are equivalent.

Formoterol as dry powder inhalation. A dose finding study in comparison with formoterol metered dose inhaler and placebo.

We compared the bronchodilator effects and systemic tolerability of 12, 24 and 48 micrograms formoterol DP capsules with 12 micrograms formoterol MDI and placebo in 30 patients with reversible obstructive airway disease. Pulmonary function tests were done and pulse rate and blood pressure were recorded. We observed significant differences between all active substances vs placebo regarding peak effect, duration of effect and AUC value. No significant difference was observed between either 12 or 24 micrograms formoterol DP and 12 micrograms from MDI in all mentioned parameters. With 48 micrograms DP, increased peak effect, AUC and duration of effect were noted. Heart rate Holter monitoring showed a slightly more pronounced effect with 48 micrograms. We conclude that 12 to 24 micrograms formoterol DP capsules are equivalent to 12 micrograms of formoterol MDI regarding efficacy and tolerability, while 48 micrograms formoterol DP capsules cause more profound effects in bronchodilation and on the heart rate.

Clinical and bacteriological experience with cefodizime in acute purulent exacerbations of chronic bronchitis.

1 or 2 g doses of cefodizime i.m. were studied in 287 patients admitted to hospital with acute purulent exacerbations of chronic bronchitis, mostly associated with Haemophilus influenzae, Streptococcus pneumoniae or Moraxella catarrhalis. Pharmacokinetic studies in serum and sputum on the first treatment day yielded mean peak serum concentrations of 50 to 100 mg/l, with corresponding sputum concentrations of 1.4 and 2.7 mg/l, after the two respective doses. No great differences were found between the clinical and microbiological results in the various dosage groups, and no corresponding improvement was noted with the highest dosages studied. In general, infection was eliminated in 90 to 95% of patients at the end of treatment, and in approximately 70 to 80% after a follow-up week. Some infections associated with beta-lactamase producing M. catarrhalis persisted or relapsed after treatment. Unwanted drug effects were recorded in five patients, leading to discontinuation in two. It is concluded that a single daily intramuscular dose of 1 g cefodizime for seven days produces satisfactory results in most patients.

The effect of maximal doses of formoterol and salbutamol from a metered dose inhaler on pulse rates, ECG, and serum potassium concentrations.

In a randomized, double-blind, crossover cumulative study, the individual maximal bronchodilator dosages for formoterol (F) and salbutamol (S) were assessed for their respective influence on ECG, pulse rate, and serum potassium levels in 13 patients with stable and reversible asthma. The following dosages were administered with an interval of 1 h: 12-24-48-(48)-(48) micrograms for F and 100-200-400-400-(400)-(400) micrograms for S. The study day was discontinued if pulse rate was above 140 beats min-1, a flattening of T wave on the ECG was recorded, or a maximal bronchodilation in FEV1 was observed (above 110 percent of the predicted value or an increase in FEV1 in the last two measurements below 5 percent). The maximal individual dose of F administered was 84 micrograms in six patients, 132 micrograms in three patients, 180 micrograms in three patients, and 228 micrograms in one patient. For S, the maximal individual dose was 400 micrograms in three patients, 2,200 micrograms in eight patients, 3,000 micrograms in one patient, and 3,800 micrograms in one patient. The mean maximal increase in FEV1 was 36.0 percent after F and 35.1 percent after S. Pulse rate increased from 73 to S3 beats.min-1 after F and from 75 to 84 beats.min-1 after S (both statistically significant). No pulse rate above 140 beats.min-1 was observed. In the high-therapeutic range (up to 36 micrograms of F and 6,090 micrograms of S), no changes in potassium level were observed. In still higher dosages, mean potassium level decreased from 4.16 to 3.78 mmol.L-1 after F and from 4.02 to 3.88 mmol.L-1 after S (not clinically relevant). The lowest individual potassium level recorded was 3.1 mmol.L-1. No clinically important changes in ECG were observed. In conclusion, very high doses of F and S administered from a metered dose inhaler proved to be safe for patients.