Effective delivery of particles with the HandiHaler dry powder inhalation system over a range of chronic obstructive pulmonary disease severity.

The HandiHaler is a dry powder breath activated inhaler system developed for inhalation therapy for patients with airway disease. Its operation is based on the evacuation of powder from a pierced capsule. We sought to document the inspiratory flow rates attained by patients inspiring through the HandiHaler with various degrees of airflow limitation. Subjects with stable chronic obstructive pulmonary disease (COPD) were the study's population. An in vitro study of fine particle dose was conducted using an Andersen Cascade Impactor to assess medication delivery at low inspiratory flow rates. Subsequently, an in vivo study was conducted to determine inspiratory flow rates in patients with COPD as measured through a pneumotach with a custom coupler device with and without the HandiHaler. Patients were classified into three approximately equal groups of spirometric severity ranging from mild (46-65% predicted normal forced expiratory volume in 1 sec [FEV1]), to moderate (28-45%) to severe (< or = 27%). The in vitro study indicated delivery of medication at flow rates as low as 20 L/min. Twenty-six men completed the in vivo study (age 66.9 +/- 10.9 years, FEV1 = 1.02 +/- 0.45 l.). The median peak inspiratory flow rates attained in the mild (n = 8), moderate (n = 10), and severe (n = 8) categories were 45, 45.6, and 35.4 L/min respectively. The minimum peak inspiratory flow rates in the three groups were 28.2, 21.6 and 20.4 L/min. The HandiHaler device effectively delivers particles to the lung over a wide range of airflow limitation in patients with COPD.

Pharmacokinetic/pharmacodynamic predictors of time to clinical resolution in patients with acute bacterial exacerbations of chronic bronchitis treated with a fluoroquinolone.

Forty nine subjects with acute bacterial exacerbations of chronic bronchitis (ABECB) treated with grepafloxacin were evaluated for parameters predictive of clinical outcome. Signs and symptoms associated with ABECB were serially collected and evaluated for changes. Coughs per day, sputum volume and the percentage of sputum neutrophils were associated with clinical outcome. A by groups analysis, based on clinical success was performed using Cox regression analysis to determine factors associated with time to clinical success and time to reduction in sputum volume, coughs per day and sputum neutrophil percent. Factors evaluated included AUIC (AUC/MIC), isolate species, years and type of underlying lung disease, alcohol use, smoking history and number of ABECB within the previous 12 months. AUIC<276 (mg h/l)/mg/l (P<0.03) and or the presence of mild bronchiectasis (P<0.01) were associated with longer time to clinical success. In addition a relationship was found between AUIC>212 (mg h/l)/mg/l (P<0.01) and AUIC>576 (mg h/l)/mg/l (P<0.02) and decreasing days to sputum volume reduction and coughs per day, respectively. A diagnosis of mild bronchiectasis prolonged the time to reduce coughs per day (P<0.03) and neutrophil percentage (P<0.01). Patients with mild bronchiectasis were found to have an increase in the time to clinical success, coughs per day improvement and sputum neutrophil percent improvement. AUIC is an important PK/PD parameter predictive of successful outcome in ABECB, even in subjects with mild bronchiectasis. Grepafloxicin has been withdrawn from sale since these studies were carried out. This work is published to illustrate the relationship between pharmacodynamics and clinical efficacy and the use of AUIC as a valuable predictive parameter for fluoroquinolones.

Short-course moxifloxacin therapy for treatment of acute bacterial exacerbations of chronic bronchitis. The Bronchitis Study Group.

Chronic bronchitis is common among adults and infectious exacerbations contribute considerably to morbidity and mortality. We aimed to compare the safety and efficacy of moxifloxacin to clarithromycin for the treatment of patients with acute bacterial exacerbations of chronic bronchitis (ABECB) using a prospective, randomized, double-blind, parallel group trial. Between November 21, 1996 and April 7, 1998, 936 patients with acute exacerbations of chronic bronchitis (AECB) were enrolled at 56 centers across the United States of which 491 (52%) had ABECB (i.e. pretherapy pathogen). Patients were randomized to either oral moxifloxacin 400 mg administer once daily, for either 5 or 10 days, or clarithromycin 500 mg bid for 10 days. For the purpose of study blinding, the patients taking moxifloxacin received placebo to maintain uniform dosing. The main outcome measures were bacteriological response at the end of therapy (post-therapy days 0-6) and follow-up (7-17 days post-therapy) visits, as well as overall clinical response, clinical response at the end of therapy and clinical response at follow-up. Two patient populations were analyzed: efficacy-valid (i.e., those with a pretherapy pathogen) and intent-to-treat (i.e., all subjects that took drug). In 420 efficacy valid patients with a pretherapy organism, overall clinical resolution was 89% for 5 days moxifloxacin vs. 91% for 10 day moxifloxacin vs. 91% for 10 day clarithromycin. Bacteriological eradication rates at the end of therapy were 94% and 95% for 5-day moxifloxacin and 10-day moxifloxacin, respectively, and 91% for the clarithromycin group. Eradication rates at follow-up were 89% and 91% for 5-day moxifloxacin and 10-day moxifloxacin respectively, and 85% for the clarithromycin group. Among 926 intent-to-treat patients (312 5-day moxifloxacin, 302 10-day moxifloxacin and 312 clarithromycin), drug-related events were reported for 26%, 30% and 35%, respectively. Moxifloxacin 400 mg once daily, as a 5 or 10 day regimen, was found to be clinically and bacteriologically equivalent to 10 day clarithromycin for the treatment of ABECB. Given its favorable safety and tolerability profile, moxifloxacin administered once daily for 5 days may be as effective and a more convenient treatment than a standard course of clarithromycin for patients with ABECB.

Randomized, double-blind study of ciprofloxacin and cefuroxime axetil for treatment of acute bacterial exacerbations of chronic bronchitis. The Bronchitis Study Group.

In a prospective, multicenter, double-blind study, the interval to clinical relapse in patients with acute bacterial exacerbations of chronic bronchitis from whom a pretherapy pathogen was isolated was compared following treatment with ciprofloxacin or cefuroxime axetil. Clinical and microbiological responses at the end of therapy were secondary efficacy variables. Outpatients randomly received either ciprofloxacin or cefuroxime axetil (500 mg twice a day for 14 days). Three hundred seven patients with acute exacerbations of chronic bronchitis were enrolled, of whom 208 had an exacerbation due to a bacterial pathogen. Clinical resolution at the end of ciprofloxacin and cefuroxime axetil therapy for patients for whom efficacy could be evaluated was 93% and 90%, respectively. Bacteriologic eradication rates were statistically higher for ciprofloxacin recipients (96% [89 of 93]) than for cefuroxime axetil recipients (82% [80 of 97]) (P < .01). The median infection-free interval was 146 days for ciprofloxacin recipients vs. 178 days for cefuroxime axetil recipients (P = .37). In conclusion, ciprofloxacin was associated with an infection-free interval and clinical response that were similar to those associated with cefuroxime axetil, but the bacteriologic eradication rate associated with ciprofloxacin was statistically significantly higher than that associated with cefuroxime axetil.

Efficacy of oral ciprofloxacin vs. clarithromycin for treatment of acute bacterial exacerbations of chronic bronchitis. The Bronchitis Study Group.

In this prospective, multicenter, double-blind study, the efficacy of ciprofloxacin was compared with that of clarithromycin as therapy for patients with acute bacterial exacerbations of chronic bronchitis (ABECB) from whom a pretherapy pathogen was isolated; the efficacy was measured by the infection-free interval. Clinical and microbiological responses at the end of therapy were secondary efficacy variables. Patients randomly received either ciprofloxacin or clarithromycin (500 mg twice a day for 14 days). Three hundred seventy-six patients with acute exacerbations of chronic bronchitis were enrolled in the study of whom 234 had an ABECB. Clinical resolution was observed in 90% (89 of 99) of ciprofloxacin recipients and 82% (75 of 91) of clarithromycin recipients for whom efficacy could be evaluated. The median infection-free interval was 142 days for ciprofloxacin recipients and 51 days for clarithromycin recipients (P = .15). Bacteriologic eradication rates were 91% (86 of 95) for ciprofloxacin recipients and 77% (67 of 87) for clarithromycin recipients (P = .01). In summary, compared with clarithromycin, treatment of ABECB with ciprofloxacin was associated with a trend toward a longer infection-free interval and a statistically significantly higher bacteriologic eradication rate.

Sparfloxacin vs ofloxacin in the treatment of acute bacterial exacerbations of chronic bronchitis: a multicenter, double-blind, randomized, comparative study. Sparfloxacin Multicenter ABECB Study Group.

STUDY OBJECTIVE: Comparison of efficacy and safety of sparfloxacin vs ofloxacin for treatment of acute bacterial exacerbations of chronic bronchitis (ABECB). DESIGN: Multicenter, double-blind, randomized study. SETTING: Sixty-eight private offices and outpatient clinics in the United States and Canada. PATIENTS: Seven hundred ninety-eight adults with ABECB, as confirmed by the acute onset of new (or worsened from the immediate premorbid state) cough and sputum production. INTERVENTIONS: Randomization 1:1 to sparfloxacin, 400 mg on day 1, then 200 mg once daily, or ofloxacin, 400 mg twice daily, with matching comparator placebos, given concurrently for 10 consecutive days. RESULTS: The primary efficacy parameter was overall response in the bacteriologically evaluable population. Overall success rates in this population were 85.3% and 89.3% for sparfloxacin and ofloxacin, respectively. The two-sided 95% confidence interval was -9.9, 1.9, indicating that sparfloxacin was statistically equivalent to ofloxacin. The all-treated population analysis was similar to that in the evaluable population. Bacterial eradication rates were similar in both treatment groups for Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis, Chlamydia pneumoniae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Enterobacter cloacae, and Staphylococcus aureus. The frequency of adverse events overall was comparable in the two treatment groups. The sparfloxacin group had a lower frequency of digestive and nervous system adverse events, but a higher frequency of photosensitivity reactions than the ofloxacin group. CONCLUSIONS: Once-daily oral treatment with 200 mg sparfloxacin (after initial 400 mg dose) is as effective as twice-daily treatment with 400 mg ofloxacin in patients with ABECB.

Efficacy and safety of a 10-day course of 400 or 600 milligrams of grepafloxacin once daily for treatment of acute bacterial exacerbations of chronic bronchitis: comparison with a 10-day course of 500 milligrams of ciprofloxacin twice daily.

A randomized, prospective, double-blind, double-dummy, multicenter study investigated the efficacy and safety of 10 days of oral therapy with grepafloxacin at 400 mg once daily, grepafloxacin at 600 mg once daily, or ciprofloxacin at 500 mg twice daily in 624 patients with acute bacterial exacerbations of chronic bronchitis. At the end of treatment, clinical success (cure or improvement) was achieved for 93% (140 of 151), 88% (137 of 156), and 91% (145 of 160) of patients in the groups receiving grepafloxacin at 400 mg, grepafloxacin at 600 mg, and ciprofloxacin, respectively (clinically evaluable population). At follow-up (14 to 28 days posttreatment), the clinical success rates were 87% (124 of 143), 81% (122 of 151), and 80% (123 of 154) in the groups receiving grepafloxacin at 400 mg and 600 mg and ciprofloxacin, respectively. A total of 379 pathogens were isolated from 290 patients, with the most common isolates being Moraxella catarrhalis (21%), Staphylococcus aureus (20%), Haemophilus influenzae (18%), and Streptococcus pneumoniae (7%). For the evaluable population, successful bacteriologic response was obtained at the end of treatment for 96% (92 of 96), 98% (87 of 89), and 92% (82 of 90) of patients receiving grepafloxacin at 400 mg, grepafloxacin at 600 mg, and ciprofloxacin, respectively, and was maintained in 86% (82 of 95), 88% (78 of 89), and 82% (69 of 84) of patients, respectively, at follow-up. All pretreatment S. pneumoniae isolates were susceptible to grepafloxacin, but two strains were resistant to ciprofloxacin. All treatments were well tolerated, with the most frequently reported drug-related adverse events being nausea, taste perversion, and headache. All drug-related adverse events in the grepafloxacin groups were mild or moderate in severity. This study demonstrates that 10-day courses of grepafloxacin given at 400 or 600 mg once daily were as effective, clinically and bacteriologically, as ciprofloxacin given at 500 mg twice daily for the treatment of acute bacterial exacerbations of chronic bronchitis.

Pharmacokinetics and pharmacodynamics of oral grepafloxacin in patients with acute bacterial exacerbations of chronic bronchitis.

This analysis was designed to characterize the population pharmacokinetics and pharmacodynamics of oral grepafloxacin (OPC-17,116) in patients with acute bacterial exacerbations of chronic bronchitis (ABECB). The study group included 76 patients (43 male, 33 female) between 23 and 81 years of age, who were part of a multicentre, randomized, double-blind, dose-response study. Patients were randomly assigned to receive oral regimens of grepafloxacin, 200, 400 or 600 mg, each administered once daily for 14 days. Plasma samples for drug assay (typically eight per subject; four samples on either day 3, 4 or 5, plus troughs on other clinic visit days), were obtained during treatment. Population pharmacokinetic analysis was accomplished using iterative two-stage analysis. Cultures and quantitative Gram stains from serial 24 h collections of sputum were used to determine the time (in days) taken to eradicate each bacterial strain. Population pharmacodynamic analysis was performed for three measures of antibacterial response: probability of bacteriological cure, probability of clinical cure, and time to eradication. Grepafloxacin plasma concentration profiles were best fitted by a pharmacokinetic model with first-order absorption following a lag time between administration of the dose and onset of systemic absorption. All three measures of response were strongly related to the 24 h AUIC (AUC/MIC). At an AUIC of <75, the percent probability of clinical cure was 71%; at an AUIC of 75-175, it was 80% (P < 0.05) and at an AUIC of >175, it was 98% (P < 0.01). In conclusion, antibacterial response for grepafloxacin in ABECB patients was highly related to AUIC; values of <75 appear inadequate and values of >175 were optimal.

Pharmacokinetics of [18F]fleroxacin in patients with acute exacerbations of chronic bronchitis and complicated urinary tract infection studied by positron emission tomography.

The pharmacokinetics of fleroxacin, a new broad-spectrum fluoroquinolone, were measured by positron emission tomography (PET) with [18F]fleroxacin in five patients with acute bacterial exacerbations of chronic bronchitis and in five patients with symptomatic, complicated urinary tract infection. Two studies were performed with each patient, one within 24 h of the initiation and one within 24 h of the completion of a 7-day course of fleroxacin, 400 mg/day. For each study, the patient received an infusion of that day's therapeutic dose of fleroxacin (400 mg) supplemented with approximately 740 MBq of [18F]fleroxacin, and serial PET images and blood samples were collected for 6 to 8 h starting at the initiation of the infusion. Between studies, the drug was administered orally. In all infected tissues, there was rapid accumulation of radiolabeled drug, with stable levels achieved within 1 h after completion of the infusion. In kidneys, accumulation was greater in the presence of active infection (P < 0.01), while in lungs, accumulation was lower (P < 0.02). Infection of the lung or urinary tract had no effect on drug delivery to uninvolved tissues. Also, there was no difference between the results obtained at the beginning and the end of therapy. Overall, peak concentrations of drug many times the MIC at which 90% of the infecting organisms are inhibited (MIC90) were achieved in the kidneys (> 30 micrograms/g), prostate glands (> 11 micrograms/g), and lungs (> 14 micrograms/g). Plateau concentrations (2 to 8 h; given as mean micrograms per gram +/- standard error of the mean) of drug in kidneys (15.11 +/- 0.55), prostate glands (5.08 +/- 0.19), and lungs (5.75 +/- 0.22) were also well above the MIC90 for most relevant pathogens. All patients had a good therapeutic response to fleroxacin.

Efficacy of fleroxacin versus amoxicillin in acute exacerbations of chronic bronchitis.

In a multicenter study the efficacy and safety of oral fleroxacin at 400 mg once a day and amoxicillin at 500 mg three times daily for 7 days were compared for the treatment of patients with acute bacterial exacerbations of chronic bronchitis due to drug-susceptible bacteria. A total of 194 patients were enrolled, 102 in the fleroxacin group and 92 in the amoxicillin group. Of those enrolled, 22 in the fleroxacin group and 30 (29 for clinical efficacy) in the amoxicillin group were included in the efficacy analysis. All were included in the safety analysis. Clinical success was noted in 21 (95%) of 22 fleroxacin-treated patients and 22 (76%) of 29 amoxicillin-treated patients. Bacteriologic cure was obtained in 21 (95%) of 22 of the fleroxacin group and 18 (60%) of 30 of the amoxicillin group. One Haemophilus parainfluenzae strain persisted with fleroxacin. Persisting organisms with amoxicillin included Haemophilus influenzae (four), Haemophilus parainfluenzae (three), Escherichia coli (two), Streptococcus pneumoniae (one), Neisseria species (one), and Proteus mirabilis (one). Adverse events were reported by 41% of 102 patients receiving fleroxacin and 15% of 92 patients receiving amoxicillin. Insomnia, dizziness, and nausea occurred more frequently with fleroxacin. Fleroxacin may be indicated for the treatment of acute bacterial infection in chronic bronchitis known to be due to Haemophilus species and Moraxella catarrhalis. The 92% incidence of resistance among the S. pneumoniae isolates recovered from all enrolled patients suggests that fleroxacin may not be useful for such infections.

Sputum eosinophilia negates need to perform sputum Gram's stain.

A total of 1878 sputum specimens were evaluated to assess the potential of encountering a sputum Gram's stain with clinically useful positive data in the presence of sputum eosinophilia. Wet preparations were used to assess the adequacy of the specimen and to quantitate eosinophils. Quantitative sputum Gram's stains were performed. When more than 50% of the cells observed on sputum wet preparation were eosinophils, there were no positive Gram's stains. When more than 20% of the cells were eosinophils, there was a 1% prevalence of potentially clinically useful positive Gram's stains. The data strongly suggest that sputum eosinophilia obviates the need to perform a sputum Gram's stain since it is extremely unlikely that it would be useful in diagnosing a bacterial infection of the lower respiratory tract.

Temafloxacin compared with ciprofloxacin in mild to moderate lower respiratory tract infections in ambulatory patients. A multicenter, double-blind, randomized study.

The efficacy and safety of oral temafloxacin (600 mg) and ciprofloxacin (500 mg) twice daily for seven days were compared in patients with mild to moderate lower respiratory tract infections. Fifty-eight of 64 (91 percent) patients who received temafloxacin and 63 of 67 (94 percent) patients who received ciprofloxacin had clinical cure or improvement; bacteriologic cure occurred in 61 (95 percent) and 63 (94 percent), respectively. All 14 patients with pneumonia were clinically cured or improved and bacteriologically cured; 11 had complete resolution of roentgenographic evidence of pneumonia. Both quinolones eradicated most major respiratory pathogens. In the ciprofloxacin group, organisms persisted in three of seven Pseudomonas aeruginosa isolates and in one of eight Hemophilus parainfluenzae isolates; all these pathogens were eliminated with temafloxacin. Theophylline blood levels significantly increased by 25 percent in the ciprofloxacin group and decreased by 5 percent in the temafloxacin group. Adverse events, mostly dizziness, headache, and gastrointestinal effects, occurred in 43 percent of temafloxacin patients and in 31 percent of ciprofloxacin patients.

Use of quinolones for the treatment of acute exacerbations of chronic bronchitis.

The availability of a new generation of quinolones expands the choices of antimicrobials for therapy of acute exacerbations of chronic bronchitis. These agents have broad antimicrobial activity, including good in vitro activity against respiratory pathogens, and advantageous pharmacokinetic characteristics, including bronchial tissue penetration. Ciprofloxacin, enoxacin, ofloxacin, and temafloxacin have been evaluated in a number of clinical trials, compared to the reference agents ampicillin, amoxicillin (with and without clavulanate), cefaclor, doxycycline, and erythromycin. Ciprofloxacin, ofloxacin, and temafloxacin have generally demonstrated greater clinical success than enoxacin. While these agents are effective against many respiratory pathogens, Streptococcus pneumoniae and Pseudomonas aeruginosa infections appear to pose problems. Temafloxacin and ciprofloxacin have been compared; temafloxacin eradicated S. pneumoniae more efficiently and did not interact with theophylline. Fluoroquinolones are an important addition to the agents useful for bacterial exacerbations of chronic bronchitis.

Treatment of acute exacerbations of chronic bronchitis: state of the art.

Effective treatment of acute bacterial exacerbations of chronic bronchitis (ABE) reduces the number of such exacerbations in such patients and may decrease or eliminate background symptoms and improve pulmonary function. The pathologic and physiologic abnormalities of the bronchial system in chronic bronchitis that predispose to bacterial infection probably include impaired mucociliary clearance, obstructed bronchioles, and bacterial infections of the bronchial epithelium. Exacerbations of bronchopulmonary symptoms are usually observed with ABE, although these symptoms are not unique to ABE. While culture and sensitivity testing is not usually required, microscopic examination of sputum is critical to determine the presence of bacterial infection. Bacteria in numbers significantly above the levels present when the patient's condition is stable and at least a doubling of the sputum neutrophil inflammatory level are essential criteria. Bacterial species observed with ABE include Haemophilus influenzae, Haemophilus parainfluenzae, Streptococcus pneumoniae, Moraxella catarrhalis, and Neisseria species, with a lesser incidence of Klebsiella and Pseudomonas species. One or more elements of background therapy for ABE should accompany antimicrobial therapy, for example, physiotherapy, bronchodilators, and so forth. Ampicillin is effective, safe, economical, and thus remains the drug of choice for ABE. Quinolones are an effective alternative when ampicillin cannot be tolerated or if organisms are resistant. Dosing is at the upper range of recommendations, and the chosen drug should be given for a 10-14-day regimen. Patients should be reevaluated if symptoms and physical findings do not return to baseline after 5-7 days.

Comparison of ciprofloxacin with ampicillin in acute infectious exacerbations of chronic bronchitis. A double-blind crossover study.

Two separate acute bacterial exacerbations of chronic bronchitis and/or asthma were treated in 22 patients in a double-blind crossover study. One course of treatment consisted of 750 mg of ciprofloxacin twice daily and the other of 500 mg of ampicillin four times a day; each drug was given for 14 days. Patients were observed initially, every three to four days during therapy, and weekly during the post-therapy period. Observations that were recorded included graded chest symptoms and physical findings, vital signs, hematologic parameters, and objective sputum measurements (daily volume, purulence, differential quantitative cytology, bacterial counts, and physical properties). Both antibiotic regimens were effective in resolving these acute bacterial exacerbations. Paired t test analysis revealed that ciprofloxacin is as clinically effective as ampicillin in the treatment of acute bacterial exacerbations in chronic bronchial disease, and appears to be superior in clearing bacterial pathogens from the sputum.

Prazosin in hypertensive patients with chronic bronchitis and asthma: a brief report.

The effects of prazosin therapy were recently evaluated in ambulatory patients with essential hypertension and chronic obstructive pulmonary disease. Both the ability of prazosin to control high blood pressure and its effects on pulmonary function were observed. Systolic and diastolic blood pressures were significantly reduced at the end of the maintenance period. Of the 17 patients completing the trial, 82.4 percent attained a target diastolic blood pressure of less than 90 mm Hg, and 70.6 percent attained a diastolic reduction of greater than 10 mm Hg. Results of six-hour pulmonary function tests showed no significant differences after dosing with placebo or with prazosin. There was a significant increase in the number of patients who noted increased wheezing, but these patients did not have any increase in cough or sputum symptoms.

Comparative effects of pirbuterol acetate, metaproterenol, and placebo aerosols on pulmonary function and incidence of cardiac ectopy.

This single-center, double-blind, randomized study compared the efficacy and safety of single-dose pirbuterol aerosol (0.2 mg and 0.4 mg) with metaproterenol (1.3 mg) and placebo aerosols. Twenty-four patients with asthma or chronic obstructive pulmonary disease (COPD) completed this crossover design study. Statistically significant improvement over placebo (p less than 0.05 to p less than 0.001) was noted for pirbuterol 0.2 mg and 0.4 mg in FEV1 (forced expiratory volume in 1 second) duration, peak, and area under the curve (AUC) responses, and in maximum midexpiratory flow rate (MMEF) peak and AUC responses. Pirbuterol at both the 0.2 mg and 0.4 mg doses demonstrated statistically significant improvements in pulmonary function tests and clinical assessment over metaproterenol 1.3 mg. Both drugs were well-tolerated and neither drug increased cardiac ectopy, as measured on 5-h Holter monitor tapes.

Comparative trials of doxycycline versus amoxicillin, cephalexin and enoxacin in bacterial infections in chronic bronchitis and asthma.

The comparative efficacy of doxycycline versus amoxicillin, cephalexin, cefaclor and enoxacin was examined in four separate cross-over and blinded studies of acute bacterial bronchitis in chronic bronchitis and asthma. The efficacy of doxycycline over the eleven-year period (1975-1986) covered by these studies also was examined. Patients with acute bacterial exacerbations, defined by increased chest symptoms, increased bacteria and sputum neutrophilia, were randomly entered. When a new acute infection occurred, they were re-entered and received the other antibacterial. Response was recorded as successful or not; early rebound infections and the periods free of infection were noted. A total of 136 exacerbations were evaluated in the comparison of doxycycline with the other 4 antibacterials, and 93 exacerbations in the long-term efficacy of doxycycline. The acute success was similar for doxycycline with the other antibacterials and was superior to cefaclor. Early rebound infections occurred less frequently with doxycycline as compared to the cephalosporins and was similar versus amoxicillin and enoxacin. The infection-free period was longer after doxycycline than with the other four antimicrobials. Doxycycline maintained its efficacy to elicit a prompt response and provide a long infection-free period, but an increase of early rebound infections was noted over the eleven-year period.

The effects of dilevalol, metoprolol, and placebo on ventilatory function in asthmatics.

Dilevalol combines a nonselective blocking action on beta-receptors with selective beta 2-agonist activity. In this double-blind, three-way, crossover study, the effects of relatively high single doses of dilevalol (400 mg), metoprolol (200 mg), a placebo on pulmonary function and their interaction with isoproterenol (160 and 480 micrograms) were evaluated in 16 patients with reversible bronchial asthma [isoproterenol-induced increase in forced expiratory volume in 1 s (FEV1) of greater than or equal to 15%]. When the lowest or minimum values observed during the 2 h postdrug evaluation period were considered, there was no significant difference from baseline in the percentage change in FEV1 after placebo (-4.4%) and dilevalol (-10%), with the difference between these treatments not being statistically significant. However, following metoprolol, FEV1 decreased by 18.3%, a decrease significantly different (p less than 0.01), from baseline and from the effects of placebo (p less than 0.01), although not from dilevalol. Furthermore, following metoprolol, 7 of 16 patients (44%) showed a greater than or equal to 20% decrease in FEV1 as compared to only 3 patients (19%) following dilevalol and 1 patient (6%) following placebo. The effects of the three treatments on forced vital capacity (FVC) and maximal midexpiratory flow (MMEF) were qualitatively similar to those observed in FEV1. Both dilevalol and metoprolol similarly and significantly (p less than or equal to 0.01) inhibited the isoproterenol (160 and 480 micrograms) response in FEV1 as compared to placebo.(ABSTRACT TRUNCATED AT 250 WORDS)