24-hour bronchodilation following a single dose of the novel ß(2)-agonist olodaterol in COPD.

BACKGROUND: Current guidelines recommend long-acting bronchodilators as maintenance therapy in COPD when symptoms are not adequately controlled with short-acting agents. Olodaterol is a novel long-acting ß(2)-adrenoceptor agonist with a pre-clinical profile that suggests 24-h bronchodilation may be achieved with once-daily administration. OBJECTIVE: To assess dose- and time-response in terms of bronchodilator efficacy, and to evaluate pharmacokinetics, safety and tolerability of single doses of olodaterol administered via Respimat(®) Soft Mist™ Inhaler in COPD patients. METHODS: A single-center, double-blind, placebo-controlled, 5-way crossover study including 24-h spirometry (FEV(1), FVC), safety, tolerability and pharmacokinetics (in a subset of patients) following dosing of olodaterol 2 µg, 5 µg, 10 µg and 20 µg; the washout period between test-days was at least 14 days. Primary endpoint of the study was the 24-h post-dosing FEV(1). Patients participating in the pharmacokinetic assessments continued in an open-label extension phase to establish pharmacokinetics of olodaterol 40 µg. RESULTS: 36 patients were assigned to treatment; mean baseline prebronchodilator FEV(1) was 1.01 L (37% predicted normal). All doses of olodaterol provided significantly greater bronchodilation compared to placebo in 24-h FEV(1) post-dose (p < 0.001); a clear dose-response relationship was observed, with values ranging from 0.070 L for olodaterol 2 µg to 0.119 L for olodaterol 20 µg. Similarly, olodaterol was superior to placebo (p < 0.001) in peak FEV(1) (0.121 L to 0.213 L) and average FEV(1) both during the daytime (0-12 h; ranging from 0.099 L to 0.184 L) and night-time (12-24 h; ranging from 0.074 L to 0.141 L). FVC results were consistent with those observed for FEV(1). Pharmacokinetic evaluation of the peak plasma concentrations and renal excretion suggested no obvious deviation from dose-proportionality over the investigated dose range of 2 µg-40 µg; in most patients, no plasma levels could be detected following the 2 µg dose. All treatments were well tolerated with no apparent dose relation in terms of adverse events. CONCLUSIONS: Olodaterol appears to be a promising long-acting ß(2)-adrenoceptor agonist,with bronchodilation maintained over 24 h that offers an opportunity for once-daily dosing in patients who require maintenance bronchodilator therapy for the management of COPD symptoms.

Combining tiotropium and salmeterol in COPD: Effects on airflow obstruction and symptoms.

BACKGROUND: Clinical information on 24-h spirometric efficacy of combining tiotropium and salmeterol compared to single-agent therapy is lacking in patients with COPD. METHODS: A randomized, double-blind, four-way crossover study of 6-week treatment periods comparing combination therapy of tiotropium 18 microg plus qd or bid salmeterol 50 microg versus single-agent therapy. Serial 24-h spirometry (FEV(1), FVC), effects on dyspnea (TDI focal score) and rescue salbutamol use were evaluated in 95 patients. RESULTS: Tiotropium plus qd salmeterol was superior to tiotropium or salmeterol alone in average FEV(1) (0-24h) by 72 mL and 97 mL (p<0.0001), respectively. Compared to this qd regimen, combination therapy including bid salmeterol provided comparable daytime (0-12h: 12 mL, p=0.38) bronchodilator effects, but significantly more bronchodilation during the night-time (12-24h: 73 mL, p<0.0001). Clinically relevant improvements in TDI focal score were achieved with bronchodilator combinations including salmeterol qd or bid (2.56 and 2.71; p<0.005 versus components). Symptom benefit of combination therapies was also reflected in less need for reliever medication. All treatments were well tolerated. CONCLUSION: Compared to single-agent therapy, combination therapy of tiotropium plus salmeterol in COPD provided clinically meaningful improvements in airflow obstruction and dyspnea as well as a reduction in reliever medication.

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.

Pharmacodynamic steady state of tiotropium in patients with chronic obstructive pulmonary disease.

Tiotropium (Spiriva) is a new once-daily inhaled anticholinergic that has its effect through prolonged muscarinic (M)3 receptor antagonism. It has a clinically documented, long duration of action with once-daily dosing in chronic obstructive pulmonary disease (COPD). A single-centre, double-blind, ipratropium-controlled study was conducted in order to characterize the onset of pharmacodynamic steady state of tiotropium in patients with COPD. Thirty-one patients (25 male, six female) with a mean age of 62 yrs and a mean forced expiratory volume in one second (FEV1) of 1.13 L (38% of predicted) were randomly assigned to receive either tiotropium 18 microg once-daily from a dry-powder inhaler (HandiHaler, 20 patients), or ipratropium 40 microg four-times daily from a pressurized metered-dose inhaler (11 patients) for a period of 1 week. FEV1 and forced vital capacity (FVC) were measured 1 h prior to, and just before inhalation (mean value of the two measurements on test-day 1 was the baseline value, while on all other test days it was the trough value), and 0.5, 1, 2, 3, 4, 5, and 6 h after inhalation of the morning dose of the study drug (one capsule and two puffs) on days 1, 2, 3, and 8. Trough FEV1 following 8 days of tiotropium was 0.19 L (18%) above baseline. Approximately 90% of this increase was achieved within 24 h of the first dose (0.17 L, 16%). Trough FVC increased 0.67 L (27%) on test-day 8. Approximately 70% of the improvement was observed after two tiotropium doses (0.47 L, 19%). Achievement of FVC steady state was delayed compared to FEV1. Ipratropium performed typically with an onset of action within 30 min, a peak response between 1-2 h postdosing and a duration of action of approximately 4 h. It was concluded that forced expiratory volume in one second steady state with tiotropium is reached within 48 h, while continued improvements in forced vital capacity can be expected over or beyond the first week of therapy. The continued increases in forced vital capacity beyond 48 h suggests that maintenance bronchodilator therapy is required to achieve maximal changes in hyperinflation.

Delivery of fenoterol via Respimat, a novel 'soft mist' inhaler. a randomised, double-blind (within device), placebo-controlled, cross-over, dose-ranging study in asthmatic patients.

BACKGROUND: The phase-out of chlorofluorocarbons (CFCs) for metered dose inhalers (MDIs) has prompted the development of alternative propellants and the design of propellant-free devices for inhalation therapy. OBJECTIVE: This study was carried out to determine the dose of fenoterol inhaled from Respimat (RMT), a new propellant-free soft mist inhaler, which is equivalent in terms of efficacy and safety to 1 puff of either 100 or 200 microg fenoterol inhaled from a conventional CFC-MDI (Berotec). METHODS: Sixty-two asthmatic patients (35 male, 27 female) with a mean baseline FEV(1) of 1.7 liters, corresponding to 55% of the predicted normal value, were randomized at two study centers to 4 of a total of 8 possible treatments: placebo; 12.5, 25, 50, 100, or 200 microg fenoterol via RMT, and 100 or 200 microg fenoterol delivered via the MDI. RESULTS: Fifty-nine patients completed the study as planned. Results of the therapeutic equivalence test for the primary endpoint, average FEV(1) (AUC(0-6))/6 and for the secondary endpoint, peak FEV(1), showed that the 12.5- and 25-microg fenoterol doses administered via RMT were equivalent to the 100 microg fenoterol dose from the MDI. The 50-, 100- and 200-microg fenoterol doses delivered by RMT did not meet the criterion for therapeutic equivalence with the 100-microg dose from the MDI, and if tested for a difference would have been significantly different in favor of RMT. All 5 RMT fenoterol doses were therapeutically equivalent to the MDI 200-microg fenoterol dose. Headache, reported by 4 patients on test days and 2 patients between test days in those randomized to RMT, was the most common adverse event, but the active treatments were generally well tolerated with no dose-dependent increases in incidence or severity of adverse events observed. CONCLUSIONS: The results from the study suggest that safe and efficacious bronchodilation can be obtained from single-dose fenoterol administered via RMT. Use of lower absolute doses to obtain a clinically significant improvement in pulmonary function may be possible because of the increased lung deposition achievable with the novel soft mist inhaler.

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.

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)

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)

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.

Formoterol in the treatment of nocturnal asthma.

Formoterol fumarate is a new beta 2-adrenergic agonist with a long lasting effect. The bronchospasmolytic effect of 12 micrograms of formoterol was compared with that of 200 micrograms of albuterol (salbutamol) in a single-center, double-blind, randomized within-patient study. The drugs were given as aerosols by MDI to 16 patients with nocturnal asthma in a stable phase. The inhalations were given at 10 PM and the FEV1 values as parameter were measured before and at 1, 2, 6, 8, 10, and 12 hours afterwards. The FEV1 6 hours after administration of formoterol was significantly higher than that after albuterol (ANCOVA: p = 0.008), and this was still the case 12 hours after the test dose at 10 AM the following morning (ANCOVA: p = 0.009). At 4 AM, the FEV1 fell below the basic starting value after albuterol, whereas it remained at least 10 percent above the formoterol inhalation. Five patients required rescue therapy after albuterol and two after formoterol. We conclude that formoterol in a dose of 12 micrograms via MDI confers good protection against nocturnal asthma; this was only insufficient for some patients with severe asthma, and further studies with higher dosages in these patients are clearly indicated.

Bronchodilator effect of inhaled formoterol vs salbutamol over 12 hours.

The bronchodilator effects were compared in 16 stable asthma patients for 12 hours after either 12 micrograms formoterol or 200 micrograms salbutamol from a metered-dose aerosol in a randomized, double-blind, crossover study. The FEV1 measured before 1, 2, 4, 6, 8, 10 and 12 hours after administration was used as the parameter. From 2 hours onwards after dosage, the bronchodilator effect of formoterol was statistically significantly greater than that of salbutamol. The effect of formoterol lasted longer, and even after 12 hours, the FEV1 was still 20 percent above the baseline value. This is clinically significant and offers new possibilities for treatment of the so-called "morning dip." Both agents were well tolerated.

Comparison of a controlled-release tablet of salbutamol given twice daily with a standard tablet given four times daily in the management of chronic obstructive lung disease.

In a double-blind cross-over study 20 patients with reversible airways obstruction were treated either with conventional 4 mg tablets of salbutamol a.i.d., or 8 mg controlled release (CR) tablets of salbutamol b.d. Each treatment was given for 2 weeks. The morning PEFR was significantly higher with the CR tablets (p less than 0.05) but although the evening PEFR was also better the difference was not significant. Wheeze was significantly lower (p less than 0.05) and extra "rescue" inhalation of bronchodilators was required less often and on fewer occasions during treatment with the CR tablets. Comparison of the 12-h mean plasma salbutamol profile showed a peak and trough every 6 h with the standard tablets, and a flatter profile with a single, lower and delayed peak during the 12 h between CR tablets. Although the minimum and average plasma salbutamol levels were similar in the groups on the two preparations, the maximum plasma level was significantly lower and there was significantly less fluctuation on CR tablets (p less than 0.02). The CR and standard tablets had equivalent bio-availability.

Ipratropium bromide (Atrovent) as inhalation powder. A double-blind study of comparison with ipratropium as a pressure aerosol in patients with reversible airways obstruction.

The bronchospasmolytic effects of 40 micrograms ipratropium bromide (Atrovent) given either as an aerosol (2 puffs of 20 micrograms) or as a powder inhalation were compared in a double-blind cross-over study. Following a randomisation list the drug was given on 2 successive days to 20 patients with stable bronchospasm in whom it had previously been shown that the bronchial obstruction was reversible after administration of 40 micrograms ipratropium bromide as an aerosol (with an increase over the baseline value of the FEV1 of at least 15% 1 h after drug administration). The effects of the two presentations of ipratropium bromide were followed by respiratory function tests from 15 min to 6 h after administration of the drug. With both formulations excellent bronchospasmolytic effects were noted in each of the parameters measured. The peak of the effects was noted approximately 1 h after the inhalations. Six hours later there was still a significant improvement in comparison with the baseline values. There was no significant difference between the results with the two different formulations. Inhalation powder of ipratropium bromide was well tolerated and there were no complaints of irritation or coughing. It would appear, therefore, to be a valuable alternative to the pressure aerosol.

Protective effect by UCB JO28 against histamine and methacholine induced bronchial hyperreactivity.

UCB JO28 [( 2-[2-[4-(diphenylmethylene)-1-piperidinyl] ethoxy] ethoxy] acetic acid, hydrochloride) is derived from diphenylmethylene piperidine. Animal experiments have shown that it has spasmolytic properties for smooth muscle, particularly in the bronchi, as well as anti-Hl, anticholinergic and anti-serotonin activities. The degree of protection by JO28 against histamine and methacholine-induced bronchospasm has been investigated in 20 asthmatic patients with serious airways hyper-reactivity. Protection against histamine-induced bronchospasm was almost complete in 11 out of 12 patients, whereas protection against methacholine-induced bronchospasm, although clearly present in seven of eight patients, was less marked.

Measurement of the non-specific threshold stimulus for the bronchial tree by continuous monitoring of respiratory resistance using the oscillation method.

Bronchial hyperreactivity to various stimuli has been used as one of the diagnostic criteria of chronic obstructive lung diseases. We studied bronchial responsiveness to histamine in 30 patients with acute or chronic bronchitis, 28 patients with bronchial asthma and in 42 more patients with other lung diseases, using a new device--the Astograph--which yielded graphically a continuous dose-response curve of the respiratory resistance by the oscillation method during the inhalation of histamine diphosphate. The results of this method were compared with the results of FEV1 and FEF25-75 before and after the challenge procedure. An increase of the respiratory resistance (Ros) during the challenge test gave an indication of a decrease of FEV1. The increase of Ros and the decrease of FEV1 and FEF25-75 were most pronounced in the asthmatics. Not in all cases was there a correlation between the increase of Ros and the decrease of FEV1, possibly due to imperfections in the design of the equipment. We believe that the Ros measurement cannot be totally exchanged for the conventional method. The use of the Astograph alone cannot be recommended because of the false-negative reactions. A combination Astograph/Floop equipment is rather expensive, but it is the most rational and ideal. The test itself does not induce bronchoconstriction and is simple and time-saving. However, this procedure is not yet advised as a diagnostic tool for a challenge test with allergens in the diagnosis of bronchial asthma. A further investigation on the validity and security of such a provocation is still needed.