A placebo-controlled dose-response study of enprofylline in the maintenance therapy of asthma.

We assessed the efficacy and side effects of oral enprofylline in the maintenance therapy of 206 asthmatics 19 to 71 yr of age. After a 1-wk placebo run-in, patients were randomized to receive in double-blind fashion one of three doses of slow-release enprofylline tablets (150 mg, 300 mg, or 450 mg twice daily) or matching placebo for 4 wk. At baseline, mean (SD) peak expiratory flow rate (PEFR) was 62 (19)% of predicted normal values. The mean increase in morning PEFR 12 h after dosing was: for 450 mg, 14(17)%; for 300 mg, 8(23)%; for 150 mg, 2(11)%, for placebo 0(10)%. The increases over baseline for 450 mg and 300 mg compared with 150 mg and placebo were statistically significant. The mean asthma symptoms score (scale zero to 3) exhibited a dose-related reduction. Significantly less beta 2-receptor agonist inhalations were used in the 450-mg group than in the placebo group. There was a statistically significant increase in headache and nausea with the doses 450 mg and 300 mg given twice daily during the first treatment week compared with 150 mg and placebo. Subsequent to the first week, there were no differences between the active treatments and placebo with respect to the incidence of these and other side effects. We conclude that oral enprofylline, in a dosage of 300 to 450 mg twice daily is an effective and well-tolerated drug that may be useful in the maintenance therapy of asthma.

Penetration of enoxacin into human bronchial mucosa.

Enoxacin is a new quinolone-azaquinolone antibiotic that possesses in vitro activity against a broad spectrum of bacteria including Pseudomonas aeruginosa. We studied the distribution ratio of enoxacin between plasma and bronchial mucosa under steady-state conditions. Bronchial mucosal biopsies were obtained during fiberoptic bronchoscopy in 18 patients after receiving enoxacin, 400 mg every 12 h for 4 days. Bronchial mucosa and plasma were sampled at 3, 4, or 5 h (6 patients each) after the fifth day morning 400-mg dose and assayed for enoxacin by high pressure liquid chromatography. There was no significant difference in the enoxacin bronchial mucosa to plasma concentration ratios at the 3 sampling times. This suggests that equilibrium between bronchial mucosa and plasma had been achieved within 3 h after dose. The mean (SD) bronchial mucosal concentration for all patients was 117.0 (47.8) micrograms/g, the mean (SD) plasma concentration was 3.1 (1.1) micrograms/ml, and the mean (SD) ratio was 46.8 (45.9). The bronchial mucosal enoxacin concentrations were significantly higher than the minimal inhibitory concentrations for common respiratory pathogens including Ps. aeruginosa (90% inhibited by 2.0 micrograms/ml). These results provide pharmacokinetic support for the use of enoxacin in gram-negative bronchial infections.

Studies of ipratropium bromide and fenoterol administered by metered-dose inhaler and aerosolized solution.

Two double-blind, placebo-controlled studies were performed in patients with chronic, partially reversible airflow limitation to compare ipratropium bromide and fenoterol administered singly with the combination treatment. In the first study, ipratropium bromide, 40 micrograms, or placebo was administered 2 h before fenoterol, 400 micrograms, or placebo, both by metered-dose inhaler. The combined treatment demonstrated significant additive bronchodilatation with an improved forced expiratory volume in 1 s (FEV1) response from 3 to 6 h after fenoterol administration. In the second study, ipratropium bromide, 0.5 mg, fenoterol, 2.0 mg, or placebo was administered by aerosolized solution with a nebulizer. The FEV1 response to the combined treatment, administered at the same time, was significantly greater than for fenoterol (0.5, 0.75, 4 and 6 h) and for ipratropium bromide (0.25-1.5, and 4 h) at various times. There was a disproportionate increase in forced vital capacity (FVC) compared with FEV1 for all treatments, suggesting dilatation and increased stability of small airways. In both studies, no synergistic effect is implied. In summary, additive bronchodilatation may be achieved with combined ipratropium bromide and fenoterol treatment by metered-dose inhaler or aerosolized solution.

The use of fibreoptic bronchoscopy with sterile catheter in the diagnosis of pneumonia.

The use of fibreoptic bronchoscopy with sterile catheter sampling of pulmonary secretions was evaluated in 70 patients with a provisional diagnosis of pneumonia. In 37 patients quantitative analysis of the sterile catheter isolates was performed (colony forming units (CFU) per ml). Potential bacterial pathogens were isolated in 37 patients and in the quantitative analysis, 14 of 22 isolates were grown in counts greater than or equal to 10(3) CFU/ml. Sterile catheter increased the bacterial isolation rate as in only 19 patients blood (2) or sputum (18) cultures yielded the same organisms. Sputum cultures showed a 25% false-positive rate in patients with no growth from sterile catheter. Quantitative analysis did not yield any further information in patients receiving antibiotics. Atypical or fungal pneumonia was diagnosed in 22 patients, while ten patients had other pathology simulating pneumonia. Sterile catheter sampling of pulmonary secretions at fibreoptic bronchoscopy proved to be a valuable tool in the diagnosis of bacterial pneumonia.

Evaluation of domiciliary treatment with terbutaline by wet nebulisation in patients with chronic bronchitis and emphysema.

Domiciliary treatment with terbutaline by wet nebulisation (5 mg, four times daily) was compared with placebo in a double-blind study over four consecutive periods, each of seven days duration, in eight patients with severe airflow limitation due to chronic bronchitis and emphysema. Lung function tests performed at the conclusion of each treatment period showed small but significant improvements in FEV1 before and after 500 micrograms of terbutaline by metered dose inhaler (MDI), with reductions in functional residual capacity and residual volume for terbutaline compared with placebo. Morning and evening peak expiratory flow rate recordings were greater and there was a significant reduction in the use of terbutaline by MDI during the terbutaline treatment. Three patients were unable to complete the placebo treatment because of excessive symptoms. Analysing all individual results, only one patient appeared not to benefit from nebulised terbutaline, while the preference rating for the other seven patients was significantly in favour of terbutaline.

The role of alpha and beta adrenoceptors in airway hyperresponsiveness to histamine.

The effect of a specific alpha 1-adrenoceptor antagonist, prazosin, on histamine-induced bronchoconstriction was compared to a beta 2-adrenoceptor agonist, salbutamol, in 16 subjects with nonspecific bronchial hyperresponsiveness whose PC20H ranged from 0.10 to 5.12 mg/ml. PC20H was calculated from a histamine inhalation test performed before and after 0.5 mg of prazosin by dry powder inhalation and 200 mcg of salbutamol by pressurized aerosol. PC20H was also measured in six subjects before and after placebo (20 mg lactose) by dry powder inhalation in a randomized double-blind study with prazosin. Mean (+/- SE) PC20H before and after placebo was 1.77 (0.32) and 1.57 (0.38) mg/ml, respectively, an 0.89-fold change. Mean (+/- SE) PC20H before and after prazosin for the 16 subjects was 1.92 (0.34) and 3.10 (0.72) mg/ml, a 1.51-fold change (p less than 0.001), and PC20H before and after salbutamol was 2.08 (0.33) and 9.54 (2.51) mg/ml, a 4.08-fold change (p less than 0.001). There was a positive correlation between the prazosin and salbutamol responses (r = 0.55, p less than 0.05). A dose response for salbutamol was performed in eight subjects, and PC20H was determined by use of increasing doses of salbutamol until PC20H was more than 16 mg/ml. The dose of salbutamol required varied widely between subjects and did not relate to baseline PC20H. The results suggest a role for alpha-adrenoceptors in addition to beta-adrenoceptors in histamine-induced bronchoconstriction.

Penetration of cefaclor into bronchial mucosa.

Bronchial mucosal biopsy specimens were obtained during fibreoptic bronchoscopy in 30 patients receiving a new oral cephalosporin antibiotic, cefaclor (10 had 250 mg, 10 had 500 mg, and 10 had 1000 mg every eight hours). In 10 patients (from all dosage groups) cefaclor was undetectable in the bronchial mucosa but in every case the serum concentration was low, suggesting incomplete absorption. The mean (SD) bronchial mucosal concentration after 250 mg was 3.78 (1.77) micrograms/g (range 2.1-5.8 micrograms/g, n = 4), after 500 mg 4.43 (2.04) micrograms/g (range 2.0-7.1 micrograms/g, n = 8), and after 1000 mg 7.73 (2.76) micrograms/g (range 5.0-12.7 micrograms/g, n = 6). A significantly higher concentration in the bronchial mucosa was achieved with 1000 mg than with 250 mg (p less than 0.05) or 500 mg (p less than 0.025). These concentrations should be effective against Streptococcus pneumoniae, most strains being inhibited below 1.0 microgram/ml. The concentrations were within one dilution of the minimal inhibitory concentration for Haemophilus influenzae, most strains being inhibited below 4.0 micrograms/ml. Some strains of H influenzae will not be inhibited by the concentrations of cefaclor found in the bronchial mucosa, particularly those that are ampicillin resistant.

Study of serum levels, venous irritation and gastrointestinal side-effects with intravenous erythromycin lactobionate in patients with bronchopulmonary infection.

Sixteen patients with bronchopulmonary infection received 500 mg erythromycin lactobionate by intravenous infusion every 8 h for 2 days. The duration of infusion was either 30 (8 patients) or 60 min (8 patients). An inline filterset (0.22 micrometer) was included in the intravenous administration set in 4 patients of each infusion group. Serum erythromycin levels were obtained before and at various times for 8 h after the first and fourth doses and before and immediately after the other doses. The incidence and severity of venous irritation and gastrointestinal side-effects were assessed. Mean (S.D.) peak erythromycin levels for the 30 min infusion were 26.31 (6.89) micrograms/ml (first dose) and 26.85 (6.11) micrograms/ml (fourth dose) and for the 60 min infusions, 23.96 (7.91) micrograms/ml (first dose) and 23.65 (6.55) micrograms/ml (fourth dose). Venous irritation was experienced by 12 patients, ranging from localized discomfort to thrombophlebitis, but the severity was significantly reduced by inline filtration (P less than 0.005). Gastrointestinal side-effects were reported by 8 patients and 1 patient withdrew because of severe abdominal pain and nausea. These symptoms were usually relieved by spasmolytic agents and possibly could be explained by high concentrations reaching the gut wall either by biliary excretion or direct transport from blood and stimulating smooth muscle motility.

Pafenolol, a highly selective beta 1-adrenoceptor-antagonist, in asthmatic patients: interaction with terbutaline.

Pafenolol, a new beta 1-adrenoceptor antagonist, has been shown in animals to be more selective for beta 1-adrenoceptors than metoprolol. It was studied in asthmatic patients to evaluate whether it was more selective with respect to circulatory effects and especially whether this selectivity influenced bronchial muscle tone less than metoprolol, which has been shown to have beta 1-adrenoceptor selectivity similar to that of atenolol. Intravenous pafenolol (5 mg and 7.5 mg), metoprolol (15 mg), and saline were given double-blind at random and thereafter four increasing doses of terbutaline were given intravenously to seven asthmatic patients with reproducible reversibility of airways obstruction. After the terbutaline dose-response curve was determined, terbutaline was inhaled three times in increasing doses. A separately reported exercise study in the same patients showed that 5 mg pafenolol and 15 mg metoprolol were equipotent with respect to beta 1-adrenoceptor blockade, whereas 7.5 mg pafenolol tended to increase the blockade. The reflex tachycardia on terbutaline stimulation after pafenolol was greater than after metoprolol due to less blockade of beta 2-adrenoceptors in peripheral blood vessels. The bronchial effect of pafenolol was equal to that of saline, but there was a difference between the terbutaline dose-response curves after pafenolol and metoprolol that caused a rightward shift of the dose-response curve. Thus, pafenolol was shown to be more beta 1-selective than metoprolol.

Ipratropium bromide and fenoterol by aerosolized solution.

Ipratropium bromide (0.5 mg) and fenoterol (2 mg) produced equivalent peak bronchodilatation between 1 and 2 h after administration to eight patients with chronic partially reversible airways obstruction. The duration of action compared with saline was 6 h for ipratropium and 4 h for fenoterol. Both drugs in combination produced greater bronchodilatation than either drug alone. The increase in FVC was disproportionately greater than FEV1 with both drugs and saline, suggesting relief of obstruction of small airways.

Comparison of ipratropium bromide and salbutamol by aerosolized solution.

Ipratropium bromide (0.125 mg, 0.25 mg and 0.5 mg) and salbutamol (5 mg) by aerosolized solution produced equivalent peak bronchodilatation between one and two hours after administration to ten patients with chronic partially reversible airways obstruction. The duration of action of the two higher doses of ipratropium bromide (0.25 mg--6 hours; 0.5 mg--5 hours) was significantly greater than salbutamol (4 hours). FVC increases with both drugs and saline were greater than FEV1 increases which may indicate dilatation of small peripheral airways or removal of bronchial mucus from these sites after coughing. A dose of 0.25 mg ipratropium bromide as an aerosolised solution is recommended for clinical use.

Penetration of piperacillin into bronchial mucosa and sputum.

Bronchial mucosal biopsies were obtained during fibreoptic bronchoscopy in 12 patients receiving a new semisynthetic penicillin, piperacillin. The piperacillin levels estimated in bronchial mucosa exceeded those required to eradicate organisms associated with acute bronchitis, Haemophilus influenzae and Streptococcus pneumoniae, and compared favourably with those required for activity against a wide variety of anaerobic and Gram-negative organisms including Pseudomonas aeruginosa. Sputum and serum piperacillin levels were obtained from eight patients with bronchial disease receiving a five to seven day course (8 to 16 g/day). Sputum/serum level ratios were constant for the two dosages (10.7% for 8 g/day; 14.3% for 16 g/day) suggesting a diffusion transfer process, although the presence of pus in the sputum appeared to facilitate penetration. Seven patients achieved sputum levels exceeding those required for activity against Haemophilus influenzae and Streptococcus influenzae, and four for Pseudomonas aeruginosa. This study provides pharmacolinetic support of the use of piperacillin in bronchopulmonary infection.