Acute effects of higher than customary doses of salmeterol and salbutamol in patients with acute exacerbation of COPD.

Worsening of underlying bronchospasm may be associated with acute exacerbations of chronic obstructive pulmonary disease (COPD). As airway obstruction becomes more severe, the therapeutic option is to add salbutamol, but not salmeterol, as needed to cause rapid relief of bronchospasm. Unfortunately the most effective dosage of beta2-agonists may increase above that recommended during acute exacerbations. In this study, we compared the acute effects of higher than customary doses of salmeterol and salbutamol in 20 patients with acute exacerbation of COPD. A dose-response curve to salmeterol pMDI, 25 microg/puff or salbutamol pMDI, 100 microg/puff, was constructed using 1, 1, and 2 puff' i.e., a total cumulative dose of 100 microg salmeterol or 400 microg salbutamol on 2 consecutive days. After baseline measurements, dose increments were given at 30-min intervals with measurements being made 25 min after each dose. Hear rate (HR) and pulse-oximetry (SpO2) measurements were then taken. Both salmeterol and salbutamol induced a larg and significant (P < 0.05) dose-dependent increase in FEV1 [mean differences from baseline (L) = after 100 microg salmeterol 0.174 (95% CI: 0.112 to 0.237); after 400 microg salbutamol: 0.165 (95% CI: 0.080 to 0.249)], in IC [mean differences from baseline (L) = after 100 microg salmeterol: 0.332 (95% CI: 0.165 to 0.499); after 400 microg salbutamol: 0.281 (95% CI: 0.107 to 0.456)] (Fig. 2), and in FVC mean differences from baseline (L) = after 100 microg salmeterol: 0.224 (95% CI: 0.117 to 0.331); after 400 microg salbutamol: 0.242 (95% CI: 0.090 to 0.395)]. There was no significant difference between the FEV1 values (P=0.418), the ICvalues (P=0.585), and the FVCvalue (P=0.610) after 100 microg salmeterol and 400 microg salbutamol. HR [mean differences from baseline (beats/min) = after 100 microg salmeterol: 3.15 (95% CI: -0.65 to 6.96); after 400 microg salbutamol: 2.30 (95% CI: -0.91 to 5.51)] and SpO2 [mean differences from baseline (%) = after 100 microg salmeterol: -0.20 (95% CI: -1.00 to 0.60); after 400 microg salbutamol: -0.11 (95% CI: -1.00 to 0.79)] did not change significantly from baseline (P > 0.05). These data indicate that salmeterol is effective and safe in the treatment of acute exacerbation of COPD and support its use in this clinical condition.

Formoterol as dry powder oral inhalation compared with salbutamol metered-dose inhaler in acute exacerbations of chronic obstructive pulmonary disease.

BACKGROUND: Acute exacerbations of chronic obstructive pulmonary disease (COPD) are managed with increased doses or frequency of the patient's existing bronchodilator therapy. The use of formoterol in the treatment of mild acute exacerbations of COPD has been suggested; however, a comparison of cumulative doses of formoterol with salbutamol, the gold standard bronchodilator agent for this pathologic condition, is still lacking. OBJECTIVE: The aim of the study was to compare the inhaled beta2-agonists salbutamol (rapid onset, short duration of action) and formoterol (rapid onset, long duration of action), both used as needed in patients attending outpatient clinics because of mild acute exacerbations of COPD (Anthonisen exacerbation type I or II). METHODS: A dose-response curve to formoterol via Turbuhaler or salbutamol via pressurized metered-dose inhaler (pMDI) was constructed. On 2 consecutive days, the patients received, in randomized order, both of the following active dose regimens: A = 12 + 12 + 24 microg formoterol via Turbuhaler (48-microg cumulative metered dose); B = 200 + 200 + 400 microg salbutamol via pMDI (800-microg cumulative metered dose). Dose increments were given at 30-minute intervals, with measurements made 25 minutes after each dose. The maximum forced expiratory volume in 1 second (FEV1) value during the dose-response curve to formoterol or salbutamol was chosen as the primary outcome variable to compare the 2 treatments. Oxygen saturation by pulse oximetry (SpO2) and pulse rate were also measured at each assessment period. Every adverse event, either reported spontaneously by the patients or observed by the investigators, was recorded. RESULTS: Sixteen patients (2 women, 14 men) aged 51 to 77 years (most older than 65 years) participated in the study. Both formoterol and salbutamol induced a large, significant, dose-dependent increase in FEV1, inspiratory capacity (IC), and forced vital ca- pacity (FVC). There was no significant difference between FEV1, IC, and FVC values after 48 microg formoterol and 800 microg salbutamol. There was no significant difference in FEV1 after 24 microg formoterol and 800 microg salbutamol; however, the difference in FEV1 after 24 and 48 microg formoterol was significant. Neither heart rate (mean differences from baseline after 48 microg formoterol, 1.9 beats/min [95% CI, -3.4, 7.2] and 800 microg salbutamol, 3.7 beats/min [95% CI, -1.1, 8.5]) nor SpO2 (mean percentage differences from baseline after 48 microg formoterol, -0.37% [95% CI, -1.22, 0.47] and 800 microg salbutamol, -0.75% [95% CI, -1.73, 0.23]) changed significantly. However, SpO2 decreased below 90% in 2 patients after the highest dose of formoterol and in 1 patient after the highest dose of salbutamol. CONCLUSIONS: In this small, selected group of patients with mild acute exacerbations of COPD, formoterol via Turbuhaler induced a fast bronchodilation that was dose dependent and not significantly different from that caused by salbutamol. Furthermore, formoterol appeared to be as well tolerated as salbutamol.

Formoterol Turbuhaler for as-needed therapy in patients with mild acute exacerbations of COPD.

Worsening of underlying bronchospasm may be associated with acute exacerbations of chronic obstructive pulmonary disease (COPD). As airway obstruction becomes more severe, the therapeutic option is to add a short-acting inhaled beta2-agonist as needed to cause rapid relief of bronchospasm. Unfortunately however, the most effective dosage may increase above that recommended during acute exacerbations. Formoterol (Oxis) Turbuhaler has a rapid onset of action (within minutes) and demonstrates a maintained effect on a rway function. In this study, we examined the effects of formoterol used as needed in 20 patients with acute exacerbations of COPD. A dose response curve to inhaled formoterol (9 microg per inhalation) or placebo was constructed using three separate inhalations, i.e. a total cumulative dose of 27 microg. Dose increments were given at 20-min intervals, with measurements being made 15 min after each dose. Formoterol, but not placebo, induced a large and significant (P<0.001) dose-dependent increase in forced expiratory volume in 1 sec (FEV1) [mean differences from baseline = 0.1311 after 9 microg formoterol (95% CI: 0.096-0.167)] 0.1811 after 18 microg formoterol (95% CI: 0.140-0.2221) and 0.2081 after 27 microg formoterol (95% CI: 0.153-0.2631). However, 27 microg formoterol did not induce further benefit [0.0271 (95% CI: -0.008-0.0621); P=0.121] when compared wth 18 microg formoterol. Results of this study suggest the use of higher than customary dose of formoterol for as-needed therapy to provide rapid relief of bronchospasm in patients suffering from acute exacerbations of partially reversible COPD.

Onset of action of single doses of formoterol administered via Turbuhaler in patients with stable COPD.

We studied 16 patients with stable COPD in a double blind, double dummy, placebo-controlled, within patient study to see if formoterol could be used as a rescue drug. We compared the of onset of bronchodilation obtained with formoterol 12 microg (metered dose corresponding to 9 microg delivered dose) and formoterol 24 microg (metered dose corresponding to 18 microg delivered dose), both delivered via Turbuhaler, with that of salbutamol 400 microg and salbutamol 800 microg delivered via pressurized metered-dose inhaler (pMDI). Patients inhaled single doses of placebo, formoterol and salbutamol on five separate days. FEV1 was measured in baseline condition and 3, 6, 9, 12, 15, 18, 21, 24, 30, 40, 50, and 60 min after inhalation of each treatment. We examined two separate criteria for deciding if a response was greater than that expected by a random variation of the measurement: (1) a rise in FEV1 of at least 15% from the baseline value; (2) an absolute increase in FEV1 of at least 200 ml. Formoterol 12 microg (15.2 min; 95% CI 9.5-21.0) and formoterol 24 microg (15.1 min; 95% CI 8.9-21.2) caused a rise in FEV1 of at least 15% from the baseline value almost rapidly as salbutamol 400 microg (13.6 min; 95% CI 7.1-20.1) and salbutamol 800 microg (14.5 min; 95% CI 7.1-21.9). No significant difference (P=0.982) in onset of action was seen between the four active treatments. According to Criterion 2, the mean time to 200 ml increase in FEV1 was 11.1 min (95% CI: 7.0-15.2) after salbutamol 400 microg, 13.0 min (95% CI: 7.9-18.1) after salbutamol 800 microg, 14.7 min (95% CI: 7.1-22.4) after formoterol 12 microg, and 12.7 min (95% CI: 7.4-18.0) after formoterol 24 microg. Again, there was no significant difference (P= 0.817) between the four active treatments. Formoterol Turbuhaler 12 microg and 24 microg caused bronchodilation as rapidly as salbutamol 400 microg and 800 microg given via pMDI.

Additive effects of salmeterol and fluticasone or theophylline in COPD.

BACKGROUND: ss(2)-Agonists and corticosteroids or theophylline can interact to produce beneficial effects on airway function in asthma, but this has not been established in COPD. METHODS: Eighty patients with well-controlled COPD were randomized to receive 3 months of treatment in one of four treatment groups: (1) salmeterol, 50 microg bid; (2) salmeterol, 50 microg, plus fluticasone propionate, 250 microg bid; (3) salmeterol, 50 microg, plus fluticasone propionate, 500 microg bid; and (4) salmeterol, 50 microg, plus titrated theophylline bid. At each visit, a dose-response curve to inhaled salbutamol was constructed using a total cumulative dose of 800 microg. RESULTS: A gradual increase in FEV(1) was observed with each of the four treatments. Maximum significant increases in FEV(1) over baseline values that were observed after 3 months of treatment were as follows: salmeterol, 50 microg bid, 0.163 L (95% confidence interval [CI], 0.080 to 0.245 L); salmeterol, 50 microg, plus fluticasone propionate, 250 microg bid, 0.188 L (95% CI, 0.089 to 0. 287 L); salmeterol, 50 microg, plus fluticasone propionate, 500 microg bid, 0.239 L (95% CI, 0.183 to 0.296 L); and salmeterol, 50 microg, plus titrated theophylline bid, 0.157 L (95% CI, 0.027 to 0. 288 L). Salbutamol always caused a significant dose-dependent increase in FEV(1) (p < 0.001), although the 800-microg dose never induced further significant benefit when compared with the 400-microg dose. The mean differences between the highest salbutamol FEV(1) after salmeterol, 50 microg, plus fluticasone propionate, 500 microg bid, and that after salmeterol, 50 microg, plus titrated theophylline bid or salmeterol, 50 microg bid, were statistically significant (p < 0.05). CONCLUSION: These data show that both long-acting ss(2)-agonists and inhaled corticosteroids have a role in COPD. The data also show that fluticasone propionate and salmeterol given together are more effective than salmeterol alone. Moreover, it suggests that the addition of fluticasone propionate to salmeterol allows a greater improvement in lung function after salbutamol, although regular salmeterol is able to improve lung function in COPD patients without development of a true subsensitivity to its bronchodilator effect. In any case, patients must be treated for at least 3 months before a real improvement in lung function is achieved.

Interrelationship between the pharmacokinetics and pharmacodynamics of cefaclor advanced formulation in patients with acute exacerbation of chronic bronchitis.

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 microg/ml (95% CI: 8.1 microg/ml - 9.1 microg/ml) and 1.5 microg/ml (95% CI: 1.4 microg/ml - 1.7 microg/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 pharmacodynamic parameter that correlated best with therapeutic efficacy for cefaclor. Our data demonstrate that when cefaclor AF is dosed twice-daily, the in vivo pharmacodynamic susceptibility breakpoint is 8 microg/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.

Acute effect of pretreatment with single conventional dose of salmeterol on dose-response curve to oxitropium bromide in chronic obstructive pulmonary disease.

BACKGROUND: An earlier study documented that, in patients with chronic obstructive pulmonary disease (COPD), addition of ipratropium bromide at the clinically recommended dose (40 microg) does not produce any further bronchodilation than that achieved with salmeterol 50 microg alone. However, the dose of ipratropium bromide needed to produce near maximal bronchodilation is several times higher than the customary dosage. The full therapeutic potential of combined salmeterol plus an anticholinergic drug can therefore only be established using doses higher than those currently recommended in the marketing of these agents. A study was undertaken to examine the possible acute effects of higher than conventional doses of an anticholinergic agent on the single dose salmeterol induced bronchodilation in patients with stable and partially reversible COPD. METHODS: Thirty two outpatients received 50 microg salmeterol or placebo. Two hours after inhalation a dose-response curve to inhaled oxitropium bromide (100 microg/puff) or placebo was constructed using one puff, one puff, two puffs, and two puffs-that is, a total cumulative dose of 600 microg oxitropium bromide. Dose increments were given at 20 minute intervals with measurements being made 15 minutes after each dose. On four separate days all patients received one of the following: (1) 50 microg salmeterol + 600 microg oxitropium bromide; (2) 50 microg salmeterol + placebo; (3) placebo + 600 microg oxitropium bromide; (4) placebo + placebo. RESULTS: Salmeterol induced a good bronchodilation (mean increase 0.272 l; 95% CI 0.207 to 0.337) two hours after its inhalation. Oxitropium bromide elicited an evident dose-dependent increase in forced expiratory volume in one second (FEV(1)) and this occurred also after pretreatment with salmeterol with a further mean maximum increase of 0.152 l (95% CI of differences 0.124 to 0.180). CONCLUSIONS: This study shows that acute pretreatment with 50 microg salmeterol does not block the possibility of inducing more bronchodilation with an anticholinergic agent when a higher than normal dosage of the muscarinic antagonist is used.

Incremental benefit of adding oxitropium bromide to formoterol in patients with stable COPD.

The effects of the long-acting beta(2)-agonist formoterol, the anticholinergic drug oxitropium bromide, and their combination were compared in 16 patients with partially reversible stable COPD. On each of 4 study days patients inhaled both drugs separated by 180 min in alternate sequence, with formoterol being administered in two doses (formoterol 12 microg + oxitropium bromide 200 microg; oxitropium bromide 200 microg + formoterol 12 microg; formoterol 24 microg + oxitropium bromide 200 microg; oxitropium bromide 200 microg + formoterol 24 microg). FEV(1)and FVC were measured baseline and after 30, 60, 120, 180, 210, 240, 300 and 360 min. In terms of onset of action, formoterol performed better than oxitropium bromide. Within the first 180 min after inhalation formoterol 24 microg was the most effective drug (maximal change in FEV(1): formoterol 24 microg = 25.6%, formoterol 12 microg = 21.1%, oxitropium bromide = 18.2%). Increased bronchodilation was obtained when the second drug was added, the sequence formoterol 24 microg + oxitropium bromide being the most effective (maximal change in FEV(1)over baseline: formoterol 24 microg + oxitropium bromide 28.8%, oxitropium bromide + formoterol 24 microg 20.9%, formoterol 12 microg + oxitropium bromide 26.6%, oxitropium bromide + formoterol 12 microg 22.5%). Significant improvement in pulmonary function may be achieved by giving two different bronchodilators in stable COPD patients. The sequence formoterol 24 microg + oxitropium bromide 200 microg seems to be the most effective.

Comparative study of dirithromycin and azithromycin in the treatment of acute bacterial exacerbations of chronic bronchitis.

We compared the clinical and microbiological efficacy of dirithromycin with that of azithromycin in outpatients with acute bacterial exacerbations of chronic bronchitis who could be graded into stage III according to Ball's system of stratification. A total of 80 patients was studied. Of these, 40 were treated with dirithromycin as a once-daily dose of 500 mg for 5 days, and 40 with azithromycin as a once-daily dose of 500 mg for 3 days. At post-therapy, treatment success (cure or improvement) was achieved in 36 out of 40 (90%) patients receiving dirithromycin compared with 37 out of 40 (92.5%) in the azithromycin group. At the late post-therapy visit, 34 out of 36 (94.4%) dirithromycin-treated patients were cured as were 33 of 37 (89.2%) azithromycin-treated patients. A small proportion of patients treated with dirithromycin (10%) or with azithromycin (12.5%) suffered mild side effects. Gastrointestinal disorders, including abdominal cramps, nausea, or diarrhea, were common adverse effects. The main pathogens isolated before treatment were Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. Eradication rates at the end of treatment were 90% (36 out of 40) for the dirithromycin group and 92.5% (37 out of 40) for the azithromycin group. Persistence of H. influenzae isolates was found in 3 out of 11 (27.3%) patients treated with dirithromycin and in 2 out of 9 (22.2%) who had received azithromycin. At the late post-therapy visit, eradication occurred in 34 out of 36 (94.4%) strains in the dirithromycin group and in 33 out of 37 (89.2%) in the azithromycin group. We conclude that dirithromycin and azithromycin appear to be equally effective in the treatment of acute bacterial exacerbations of chronic bronchitis.

Cardiac effects of formoterol and salmeterol in patients suffering from COPD with preexisting cardiac arrhythmias and hypoxemia.

OBJECTIVE: There are several reports of documented adverse cardiac effects during treatment with beta-agonists. Since one should be aware that this may be a problem in patients with preexisting cardiac disorders, we have conducted a randomized, single-blind, balanced, crossover, placebo-controlled study to assess the cardiac effects of two single doses of formoterol (12 microg and 24 microg) and one single dose of salmeterol (50 microg) in 12 patients suffering from COPD with preexisting cardiac arrhythmias and hypoxemia (PaO2<60 mm Hg). DESIGN: Each patient was evaluated at a screening visit that included spirometry, blood gas analysis, plasma potassium measurement, and 12-lead ECG. In following nonconsecutive days, all patients underwent Holter monitoring 24 h during each of the four treatments. Holter monitoring was started soon before drug administration in the morning. Plasma potassium level was measured before drug inhalation, at 2-h intervals for 6 h, and at 9, 12, and 24 h following administration. None of our patients took rescue medication during the 24-h period. RESULTS: Holter monitoring showed a heart rate higher after formoterol, 24 microg, than after formoterol, 12 microg, and salmeterol, 50 microg, and supraventricular or ventricular premature beats more often after formoterol, 24 microg. Formoterol, 24 microg, significantly reduced plasma potassium level for 9 h when compared with placebo, whereas formoterol, 12 microg, was different after 2 h and salmeterol, 50 microg, from 4 to 6 h. CONCLUSIONS: The results of this study suggest that if a COPD patient is suffering from preexisting cardiac arrhythmias and hypoxemia, long-acting beta-agonists may have adverse effects on the myocardium, although the recommended single dose of salmeterol and formoterol, 12 microg, allows a higher safety margin than formoterol, 24 microg.

Effects of formoterol, salmeterol or oxitropium bromide on airway responses to salbutamol in COPD.

We examined whether a pretreatment with formoterol, oxitropium bromide, or salmeterol might modify the dose-response curves to inhaled salbutamol in patients with stable and partially reversible chronic obstructive pulmonary disease (COPD). Sixteen outpatients with partially reversible, stable COPD received 24 microg formoterol, 50 microg salmeterol, 200 microg oxitropium bromide, or placebo on four non-consecutive days. Spirometric testing was performed immediately before inhalation of treatment and after 2 h. A dose-response curve to inhaled salbutamol was then constructed using doses of 100, 100, 200 microg and 400 microg--that is, a total cumulative dose of 800 microg. Dose increments were given at 20 min intervals with measurements being made 15 min after each dose. Formoterol, salmeterol, or oxitropium bromide elicited a significant increase in forced expiratory volume in one second (FEV1) compared with placebo (mean differences (L) = placebo 0.05; formoterol 0.34; salmeterol 0.27; oxitropium bromide 0.23). Dose-dependent increases in FEV1 were seen (mean values (L) before salbutamol and after a cumulative dose of 100, 200, 400, and 800 microg = placebo: 1.06, 1.28, 1.35, 1.39, 1.41; formoterol: 1.33, 1.37, 1.41, 1.44, 1.44; salmeterol: 1.30, 1.33, 1.36, 1.39, 1.42; oxitropium bromide: 1.27, 1.34, 1.37, 1.41, 1.40). Statistical analysis revealed no significant differences in FEV1 and forced vital capacity (FVC) responses to salbutamol after therapy with formoterol, salmeterol, or oxitropium bromide compared with placebo. This study clearly shows that a pretreatment with a conventional dose of formoterol, salmeterol, or oxitropium bromide does not preclude the possibility of inducing a further bronchodilation with salbutamol in patients suffering from partially reversible chronic obstructive pulmonary disease.

A comparison of bronchodilating effects of salmeterol and oxitropium bromide in stable chronic obstructive pulmonary disease.

Anti-cholinergic agents are generally regarded as the bronchodilator therapy of first choice in the treatment of stable chronic obstructive pulmonary disease (COPD), considering that they may be more effective than in inhaled beta 2-agonist. However, results of the authors' recent studies conflict to some extent with this suggestion because they demonstrate that this is true only for short acting beta 2-agonists but not for long-acting beta 2-agonists. Oxitropium bromide is an anti-cholinergic drug that has been shown to produce a similar degree of bronchodilation to that obtained with ipratropium bromide, but with a longer-lasting effect. In the present study, the time course of inhaled oxitropium bromide bronchodilation in comparison to that of inhaled salmeterol in a group of patients with partially reversible COPD was evaluated. Twelve male patients with moderate to severe COPD participated in the study. The study had a single-bind, cross-over, randomized design. The bronchodilator activity of 50 micrograms salmeterol hydroxynaphthoate, 200 and 400 micrograms oxitropium bromide and placebo, which were all inhaled from a metered-dose inhaler, was investigated on several non-consecutive days. The highest FVC and FEV1, obtained from one or the other of the reproducible curves, were kept for analysis. Measurements were performed at the following times: immediately before inhalation of treatment, and at 15, 30, 60, 120, 180, 240, 300, 360, 480, 600 and 720 min after inhalation of the individual treatment. Salmeterol tended to have a delayed time to peak effect, but had a longer duration of effect than oxitropium. The response to salmeterol exceeded the response to 200 micrograms oxitropium for 12 h, but its responses were significantly (P < 0.05) greater than those to 200 micrograms oxitropium from 10 to 12 h. From 3 to 12 h, salmeterol also surpassed 400 micrograms oxitropium but differences were not significant (P < 0.05). The mean FEV1 area under the curve was significantly (P < 0.05) larger after salmeterol when compared to 200 micrograms oxitropium bromide, but there was no significant difference (P < 0.05) between salmeterol and 400 micrograms oxitropium bromide. No significant changes in pulse rate, blood pressure or electrocardiograms were found among the four groups as compared with placebo group. These findings confirm and extend what has been demonstrated by the authors' previous studies, and show that salmeterol compares conveniently with anti-cholinergic drugs in terms of effects on lung function at clinically recommended doses.

[Correlation between pulmonary pharmacokinetics and pharmacodynamics support the hypothesis of the usefulness of ceftazidime at a single 1g daily dose in the treatment of bacterial exacerbation of chronic obstructive bronchopneumonia with moderate functional damage]. / Le correlazioni esistenti tra farmacocinetica polmonare e farmacodinamica permettono di ipotizzare l'utilizzo del ceftazidime alla dose di 1 g una sola volta al giorno nel trattamento delle riacutizzazioni batteriche della broncopneumopatia cronica ostruttiva con danno funzionale moderato.

INTRODUCTION AND BACKGROUND: Experimental studies have shown that cephalosporins have an antibacterial effect in vivo even when their levels are above MIC for only 40-50% of dosing intervals, whereas maximum killing is obtained when concentrations are above MIC for 60-70% of the time. Since most patients treated with antibiotics have neutrophils and other natural defence mechanisms, it is likely that a bacteriostatic effect should be sufficient to induce an effective therapeutic response. METHODS: Given that in the potential sites of lung infection ceftazidime reaches significantly higher levels than the MIC of the most commonplace respiratory pathogens, even 8-12 hours after the administration of 1 g i.m., the authors evaluated the efficacy of treatment of renewed acute episodes of COPD using this antibiotic at a dose of 1 g once a day. In order to do this, 20 outpatients were enrolled in the study, half of whom presented moderate bronchial obstruction (FEV1 = 50-70% of theoretical) whereas the remainder presented marked bronchial obstruction (FEV1 = < 50% of theoretical). RESULTS: The 10 patients with moderate obstruction at the time of enrollment, who presented Haemophilus influenzae, Streptococcus pneumoniae or Moraxella catarrhalis as causal agents in the sputum (Escherichia coli was only isolated in one patient), showed a marked improvement following treatment with 1 g ceftazidime one a day. A real or presumed eradication of the causal microorganism was observed in all subjects. Treatment with ceftazidime at the dose of 1 g/die once a day was much less effective in patients with marked bronchial obstruction. Treatment was successful in 7 out of 10 subjects, but 2 of them relapsed within 2 weeks. In this second group, Pseudomonas aeruginosa was found in the sputum of 3 patients; one of the patients showed a persistence of the bacterium after ceftazidime treatment, and another presented reinfection 12 days after the end of treatment. The two patients in whom Staphylococcus aureus was isolated did not benefit from ceftazidime treatment at this dosage. One subject who initially presented Streptococcus pneumoniae in his sputum and was then thought to have recovered, underwent a new acute episode caused by Moraxella catarrhalis 2 weeks after the suspension of ceftazidime treatment. CONCLUSIONS: The therapeutic responses observed during this study suggest the possibility of using ceftazidime in a single daily dose of 1 g i.m. to treat those patients with exacerbations of COPD who only present moderately impaired functional symptoms. On the contrary, this type of therapeutic approach must be used with extreme caution in subjects with marked functional damage, although a satisfactory clinical response may be obtained in some cases. However, the small number of patients included in this study does not allow firm conclusions to be drawn. Only a study involving a larger group of patients could provide the necessary information to confirm the hypothesis for treatment put forward by the authors.

Early reversibility to salbutamol does not always predict bronchodilation after salmeterol in stable chronic obstructive pulmonary disease.

The assessment of reversibility is recognized as being an essential part of the management of airways obstruction, but testing for reversibility of airways obstruction may not be useful for identifying patients with chronic obstructive pulmonary disease (COPD) who are likely to benefit from bronchodilator treatment. We studied 100 patients with stable COPD. Early reversibility of airways obstruction to 200 mg salbutamol and peak bronchodilation to 50 micrograms salmeterol or 200 micrograms salbutamol were evaluated in four different sessions (two for salbutamol and two for salmeterol), using a double-blind, cross-over, randomized study. Fifteen minutes after inhalation of salbutamol, 47 patients presented an increase in FEV1 greater than 15% of baseline, whereas 48 showed an increase of FEV1 of at least 160 ml from basal value and 33 an increase in FEV1 greater than both 15% of baseline and 200 ml. On the contrary, 69 patients presented an increase in FEV1 greater than 15% of baseline, 65 an increase of FEV1 of at least 160 ml from basal value and 60 an increase in FEV1 greater than both 15% of baseline and 200 ml as maximum increase over baseline usually 2-4 h after inhalation of salmeterol. Twenty-seven other subjects defined as irreversible by the lack of acute improvement in FEV1 after salbutamol, showed an increase in FEV1 greater than 15% of baseline, 20 showed an increase of FEV1 of at least 160 ml from basal value, and 18 showed an increase in FEV1 greater than both 15% of baseline and 200 ml; all had the maximum degree of bronchodilation usually 1-2 h after salbutamol administration. These findings clearly demonstrate that many patients suffering from stable COPD show early reversibility to a short-acting beta 2-agonist and patients who do not manifest early reversibility to salbutamol can still benefit from salbutamol or salmeterol. Therefore, treatments with beta 2-agonists must always be tried.

A comparison of the bronchodilating effects of salmeterol, salbutamol and ipratropium bromide in patients with chronic obstructive pulmonary disease.

Bronchodilator efficacy of salbutamol (200 micrograms), salmeterol (50 micrograms) and ipratropium bromide (40 micrograms) aerosols has been compared in 16 patients with stable chronic obstructive pulmonary disease (COPD) using a double-blind placebo controlled cross-over design. When absolute changes in FEV1 were used as the response criterion, efficacy of the three drugs was significantly better than placebo (P < 0.05). The onset of bronchodilatation after ipratropium bromide was slower than after salbutamol, but ipratropium induced more and longer-lasting bronchodilatation than the adrenergic drug. Salmeterol was slower but its duration was longer than salbutamol. The onset of the effect of salmeterol was slower than ipratropium bromide, but salmeterol showed, on average, superior bronchodilator efficacy compared with the anticholinergic agent, sustaining bronchodilation longer than ipratropium bromide (responses to salmeterol were significantly (P < 0.05) greater than those to ipratropium bromide from 4-12 h time period, but from 15 min to 1 h time periods response to ipratropium bromide exceeded salmeterol). The mean FEV1 area under the curve was significantly (P < 0.05) larger after salmeterol when compared to ipratropium bromide and salbutamol. Moreover, the mean FEV1 area under the curve after ipratropium bromide was significantly (P < 0.05) higher than that after salbutamol. In any case, our data showed individual differences in patient response. We conclude that salmeterol compares favourably with ipratropium bromide in terms of effects on lung function at clinically recommended doses because it has a longer duration of action than ipratropium bromide. The longer dosing intervals, which may enhance compliance, encourage its administration in patients with COPD.