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Immunological and clinical effect of long-term oral treatment with RU 41740 in patients with chronic bronchitis: double-blind trial long-term versus standard dose regimen.

The immunological and clinical effects of two oral treatment schedules of RU 41740 (standard for 3 months vs. long-term for 6 months) were assessed in 40 patients with chronic bronchitis by a controlled, double-blind, randomized trial. Both treatments significantly improved phagocytosis index of both neutrophils and monocytes, and the phagocytosis frequency and the candidacidal activity of neutrophils, showing the maximum stimulation at the end of the third course of treatment. Both treatment schedules reduced the number and the duration of infectious exacerbations of chronic bronchitis with respect to those observed in the corresponding period of the previous year. However, no significant difference between standard and long-term treatment with RU 41740 was found with respect to the immunological and clinical effect and tolerability.

Administration, Oral↗

Salivary immunoglobulin A production in chronic bronchitis patients given an orally administered bacterial extract.

The concentration of secretory immunoglobulin A (IgA) has been measured by the immunodiffusion method in 28 chronic bronchitis patients (group A) and in 11 comparable patients receiving corticosteroid therapy (0.5 mg/kg/day prednisone; group B). The measurements have been taken before and after oral administration of Broncho-Vaxom which is an extract of bacteria that usually cause infection of the respiratory tract. The mean concentration of secretory IgA in the saliva was increased by over 130% after the 10-day administration of the preparation to group A patients. This increase was statistically significant between the 12th and 40th day after the beginning of the treatment (p < 0.001). It fell to initial levels after 1 month in 15 patients (group A2) who received a single treatment course. In 13 patients (group A1) who received a second treatment course, beginning 1 month after termination of the first course, the high concentration of IgA in saliva persisted for at least 3 months. The saliva IgA was increased by over 35% in 11 chronic bronchitis patients (group B) who received corticosteroid therapy. In this group of patients the rise of IgA levels began later than in group A. The IgA fell to initial level after 1 month in 5 patients (group B2) who received a single treatment course. In 6 patients (group B1) who received a second treatment course the high concentration persisted longer. The saliva level of IgA in groups A and A1 was higher than in groups B and B1 (p < 0.05 and p < 0.001, respectively). No differences of IgA in the saliva between groups A2 and B2 were found during the study.

Adjuvants, Immunologic↗

Prevention of acute exacerbations of chronic obstructive bronchitis with carbocysteine lysine salt monohydrate: a multicenter, double-blind, placebo-controlled trial.

The efficacy and safety of carbocysteine lysine salt monohydrate (SCMC-Lys) in the prevention of acute exacerbations associated with chronic obstructive bronchitis were evaluated in a multicenter double-blind, placebo-controlled, parallel group trial in 662 outpatients. After a 1-month run-in period, patients were randomized to three groups and assigned to receive one of the following oral treatments: continuous SCMC-Lys 2.7 g once daily, intermittent SCMC-Lys at the same dosage (1-week courses alternating with 1-week intervals on placebo) or placebo. Each treatment lasted for 6 months and spanned the cooler months of the year. Evaluation was based on a daily recording of relevant clinical symptoms and signs and subsequent evaluation of the collected data by three blinded independent physicians. A total of 146 patients (23%) failed to complete the 6-month treatment (mostly due to difficulties in complying with protocol requirements), without clear-cut differences in the dropout rate in the three groups. An intention-to-treat analysis revealed that the incidence of patients without exacerbations in the group assigned to continuous SCMC-Lys treatment was significantly higher than in the placebo-treated group (p < 0.001). The total number of patients with at least one exacerbation was 66 (29.6%) in the group treated with continuous SCMC-Lys compared with 100 (45.9%) with placebo. In the former group the time between initiation of treatment and first exacerbation was significantly prolonged. The average number of days with acute respiratory illness was significantly decreased in the group receiving continuous SCMC-Lys compared with the group receiving placebo, and this was associated with a significant reduction in the antibiotic consumption during the trial period. In patients assigned to intermittent treatment, results of the assessed endpoints did not differ significantly from those observed in the placebo group. No serious adverse effects were reported. It is concluded that continuous administration of SCMC-Lys throughout the winter season is effective in preventing acute exacerbations in patients with chronic obstructive bronchitis and it is well tolerated.

Adult↗

Mucolytic and antibiotic effect of a new compound in chronic bronchitis.

The purpose of the study was the objective evaluation of the mucolytic and antibiotic properties of Fluimucil Antibiotic, a molecular combination of acetylcysteine and thiamphenicol. The preparation was administered to 45 patients in the dose of 3 tablets daily each containing 500 mg of thiamphenical. Statistical analysis of the data obtained showed mucolytic effects on the 4th to 5th day of treatment and marked antibiotic activity. The evaluation is positive particularly if the relatively low dose of antibiotic normally used in chronic bronchitis is considered. The preparation Fluimucil Antibiotic can be recommended for the treatment of chronic bronchitis also in view of its good tolerability.

Acetylcysteine↗

Efficacy and tolerance of erythromycin acistrate in the treatment of acute exacerbations of chronic bronchitis in the elderly.

This randomized, investigator-blind, parallel-group trial compared erythromycin acistrate (EA) and erythromycin base (EB) in the treatment of elderly patients with acute exacerbations of chronic bronchitis. In total, 57 hospitalized patients were included, of whom 28 received EA 400 mg three times daily, and 29 EB 500 mg three times daily for 10-21 days. The mean age of the patients was 70 and 68 years in the EA and EB groups, respectively. The patients underwent medical examination before the onset of the study, at the 7th day during the treatment and 3-5 days after termination of the treatment. The efficacy assessment was based on clinical signs and symptoms of infection as well as on bacteriological culture from sputum samples. 55% of the patients in the EA group and 61% in the EB group were totally cured, 23 and 29%, respectively, had only mild symptoms at the end of the therapy and 14 versus 11% of the patients did not respond at all. The predominant pathogens isolated from sputum were Haemophilus influenzae, Branhamella catarrhalis and Streptococcus pneumoniae. 60% of the patients in the EA group and 46% in the EB group from whom a sample was taken had normal flora in the posttreatment culture. In the EA group, 8 patients and in the EB group 7 patients complained of gastrointestinal side effects and 4 and 1, respectively, discontinued the treatment prematurely. Slight, reversible elevations of one or more liver parenchymal enzyme activities during and after treatment were seen at the same frequency in both treatment groups. The results show that EA is as effective and well tolerated as EB in the treatment of exacerbations of chronic bronchitis in elderly patients.

Aged↗

Chronic bronchitis. A bronchologic evaluation.

214 patients with chronic bronchitis were subjected to bronchial studied at Päivärinne Chest Hospital during the period 1967-1973. Bronchoscopy alone gave a frequency of 30% for bronchiectases while the information from bronchography increased this figure to 44%. In addition, 24% of the patients showed bronchographic changes in the form of naked filling or mucus obstrcution. Sputum specimens were less reliable indicators of infection than bronichial aspirates in patients with chronic bronchitis. Tracheobroncho-malacia was found in 50 patients and greatly increased the gravity of the disease.

Adolescent↗

Airway epithelial damage and inflammation in children with recurrent bronchitis.

Inflammation and epithelial damage of the bronchial mucosa are frequently identified in children with bronchial diseases. Nevertheless, until now the quantitative assessment of the epithelial damage has never been studied in relation to clinical or respiratory function or mucus abnormalities. Bronchial biopsies and brushings were performed in 31 children with recurrent bronchitis and without atopia. The quantitative histologic data were compared with clinical results, the endoscopic appearance of the mucosa, ciliary beating frequency, mucus transport capacity, leukocyte count, and protein concentration in mucus samples. Most of the biopsies (87%) collected in this group of children without recent acute infections showed extensive epithelial damage. A significant correlation was observed between the degree of shedding and edema (p < 0.01). Bronchial epithelial edema was associated with a significantly decreased (p < 0.01) mucus transport rate. Inflammation of the submucosa was significantly correlated with lymphocyte epithelial infiltration (p < 0.01), total mucus protein content (p < 0.01), and local airway inflammation estimated by bronchoscopy. These results demonstrate that children with recurrent bronchitis develop a severe bronchial inflammation associated with an increased mucus protein content and a reduction in the mucociliary function.

Biological Transport↗

Chronic bronchitis alters the pattern of aerosol deposition in the lung.

Knowledge of the local and regional doses of inhaled particulates is crucial for inhalation therapy and for understanding the progression of pulmonary disease. We studied the deposition pattern of radioactively tagged particles in rats with chronic bronchitis. Rats were exposed to sulfur dioxide (SO2; 236 +/- 14 ppm) for 5 h/d, 5 d/wk for 7 wk to produce chronic bronchitis (CB). Control rats were exposed to room air. The control animals gained 85% more weight over the 7-wk period than did the CB rats. Five control and five CB rats were then exposed for 30 min to an insoluble 99mTc-labeled aerosol. The animals were killed within 5 min after the exposure period. The lungs were excised, dried at total lung capacity (TLC), and sliced into 1 mm sections. The distribution of the radiolabeled particles retained in the lungs was determined in two ways. First, autoradiographs were made of the distribution of the radioactivity throughout a lung slice. Autoradiographs were quantified by image analysis to determine the amount of radioactivity (relative density of the film) associated with airway versus parenchyma (ratio of airway to parenchyma density). The lung slices were then dissected into pieces, the weight and radioactivity content of each piece was measured, and its evenness index (EI) was calculated. This type of analysis enables the homogeneity of particle deposition throughout the lungs to be assessed. If deposition were totally uniform, the average EI would be 1.0 with an SD = 0. The total amount of radioactivity retained in the lungs was similar in control and CB rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Aerosols↗

Subcutaneous administration of hyaluronan reduces the number of infectious exacerbations in patients with chronic bronchitis.

Hyaluronan (HA) is a high molecular weight glycosaminoglycan found in large amounts in the skin, joints, and other organs. Previous studies have shown that HA stimulates neutrophil functions both in vitro and in vivo. The object of this study was to test the hypothesis that HA administration subcutaneously might reduce the number of bacterial infections in humans with an increased susceptibility to such infections. For this purpose we have studied 29 patients with chronic bronchitis and recurrent acute exacerbations of their disease. The patients were randomly separated into two groups. One group had HA for 6 mo followed by 6 mo of placebo, and the other group started with placebo treatment followed by HA. The treatment periods occurred during two consecutive winter periods. HA-treated patients had significantly fewer acute exacerbations (p = 0.01) than did placebo-treated patients. Likewise the consumption of antibiotics and other signs of bacterial infections were reduced. In the crossover study the placebo-treated patients again had much higher numbers of acute exacerbations than did the HA-treated patients (p < 0.0001). It is concluded that HA reduces the number of infectious exacerbations in patients with chronic bronchitis, possibly by enhancing cellular host defense mechanisms. HA is a new endogenous substance that can be used to stimulate host defense reactions and reduce the need of antibiotics. Before being recommended for clinical use, however, our results should be confirmed by further studies.

Aged↗

Asthma, wheezy bronchitis, and atopy across two generations.

Although the prevalence of asthma has risen significantly during the last 30 yr, it is not clear whether this has occurred primarily in persons with a strong genetic predisposition to asthma and atopy or in other sections of the population. We have investigated outcomes in children of nuclear families selected through probands previously characterized by studies in 1964 and 1989 as having histories of persistent childhood onset atopic asthma, transient childhood wheezy bronchitis, and no respiratory symptoms or atopy. Children of wheezy bronchitic probands had a significantly better symptomatic outcome in adolescence, irrespective of the atopic status of the parent proband, than do children of either asthmatic or asymptomatic probands, suggesting that this may be a syndrome that shows familial aggregation and is distinct from asthma. Total serum IgE levels were significantly lower in children of nonatopic asymptomatic probands, including those with wheezing symptoms. In contrast children of nonatopic asymptomatic probands had an unexpectedly high prevalence of wheezing (33%), positive skin prick tests (56%), and positive specific serum IgE to common allergens (48%) that was similar to that found in children of atopic asthmatic probands. Our findings support the concept that wheezy bronchitis is a separate syndrome from atopic asthma. High total serum IgE levels within our population appear to be an important marker of genetic predisposition to atopy. Our data also suggest that much of the increase in asthma prevalence is associated with specific IgE sensitization and is occurring in persons previously considered to be at low risk of developing asthma or atopy.

Adolescent↗

Airway inflammation in nonobstructive and obstructive chronic bronchitis with chronic haemophilus influenzae airway infection. Comparison with noninfected patients with chronic obstructive pulmonary disease.

Nonencapsulated Haemophilus influenzae often causes chronic infections of the lower respiratory tract in both nonobstructive and obstructive chronic bronchitis. We assessed airway inflammation in clinically stable, chronically H. influenzae-infected patients with nonobstructive (CB-HI, n = 10) and in patients with obstructive chronic bronchitis (COPD-HI, n = 10) by analyses of the sol phase of spontaneously expectorated sputum (SSP). As compared with the CB-HI group, the COPD-HI group had significantly higher (p < 0.05) levels of myeloperoxidase (MPO) and tumor necrosis factor (TNF)-alpha in their SSP, whereas the degree of plasma protein leakage (SSP-to-serum ratio of plasma proteins) and the levels of interleukin (IL)-8, secretory IgA, and lactoferrin were similar in the two groups. These findings point to differences in pathophysiology in CB-HI and COPD-HI. The high level of TNF-alpha in the SSP of COPD-HI patients is in accord with the proposed role of TNF-alpha in the development of airway obstruction in COPD patients. In apparent contradiction, low levels of TNF-alpha were found in the SSP of noninfected but otherwise similar COPD patients (n = 9). This finding, however, does not exclude an exaggerated TNF-alpha response to infection or another stimulus in the airways of COPD patients. The SSP levels of MPO and IL-8, and the degree of plasma protein leakage in the COPD-HI group, were retrospectively compared with and found significantly higher than those of noninfected COPD patients, suggesting a more marked inflammatory response in COPD-HI. Whether this reflects a direct cause-and-effect relationship should be addressed in a future long-term prospective study involving repeated measurements in the same patients.

Bronchitis↗

Effect of aerosolized uridine 5'-triphosphate on mucociliary clearance in mild chronic bronchitis.

Previous studies show that uridine 5'-triphosphate (UTP), a P2Y(2) receptor agonist, is effective at acutely enhancing mucociliary clearance in healthy, nonsmoking adults. UTP solution for inhalation is being developed by Inspire Pharmaceuticals under the compound number INS316. In a double-blind, randomized, crossover, placebo-controlled study we tested the single-dose effect of UTP in chronic smokers with mild chronic bronchitis (n = 15) by measuring the clearance of (99m)Tc-Fe(2)O(3) particles (4.0 microm mass median aerodynamic diameter [MMAD]) after inhalation of nebulized placebo (0.9% saline) and two doses of UTP (20 and 100 mg in the nebulizer). On each study day, gamma camera scanning was performed over a 2-h period. After an initial deposition scan, subjects inhaled placebo or UTP during the first 20 min of scanning. Analysis of whole lung clearance showed that the retention-time curves for each day were biphasic and that the earliest break point in the average curves occurred at 50 min. Mean particle clearance rate (Clr in %/min) through 50 min for placebo treatment was Clr = 0.65 +/- 0.27 whereas treatment with UTP showed Clr significantly increased to 0.95 +/- 0.48 and 0.93 +/- 0.44 for the 20-mg and 100-mg dose respectively, p < 0.005 for both as compared with placebo. These data show that mucociliary clearance associated with mild chronic bronchitis is acutely improved with minimal doses of aerosolized UTP, presumably because of its stimulation of ciliary beating and hydration of airway secretions.

Administration, Inhalation↗

Airway responsiveness to methacholine does not change during chemotherapy in patients with chronic bronchitis and bronchial carcinoma.

To investigate the role of leukocytes and neutrophils in the peripheral blood on airway responsiveness, we studied nine patients with chronic bronchitis and histologically proved bronchial carcinoma before and after chemotherapy. The concentration of methacholine (in mg/ml) necessary to increase specific airway resistance by 100%, PC100SRaw, and the number of leukocytes and neutrophils (in cells x 10(6)/ml) were measured before, and 8 and 16 days after chemotherapy. Mean (SEM) total number of leukocytes decreased significantly (p less than 0.001) from 9.0 (0.8) to 4.4 (0.6) and 3.4 (0.4), and mean (SEM) number of neutrophils decreased significantly (p less than 0.005) from 5.1 (0.7) to 2.8 (0.5) and 1.0 (0.4), respectively. Mean (SEM) PC100SRaw was 3.3 (0.9) at baseline and 3.5 (1.2) and 3.8 (1.0) mg/ml at Days 8 and 16, respectively, without significant differences. These data suggest that a significant chemotherapy-induced leukocyte depletion in the peripheral blood does not influence airway responsiveness in patients with chronic bronchitis and bronchial carcinoma.

Bronchial Neoplasms↗

Characterization of distal bronchial microflora during acute exacerbation of chronic bronchitis. Use of the protected specimen brush technique in 54 mechanically ventilated patients.

To obtain accurate information on distal bronchial microflora during acute exacerbation in patients with chronic bronchitis, we prospectively studied 54 such patients who had been receiving mechanical ventilation because of hypercapnic respiratory failure. Fiberoptic bronchoscopy using a protected specimen brush (PSB) was performed on each patient within the first 24 h after admission. Cultures of protected brush specimens demonstrated no growth in 27 patients (50%). With the exception of fever (38.2 +/- 0.8 versus 37.7 +/- 0.6 degrees C; p less than 0.05), the initial severity of the episode of exacerbation was similar in patients with and without infection. A total of 44 organisms were isolated in the 27 patients with positive cultures; the predominant pathogens were Hemophilus spp. and Streptococcus spp. (involved in 74% of cases), but other organisms were isolated in 12 of 27 patients. Mortality rates, duration of mechanical ventilation, and duration of hospitalization were not significantly different between patients with bronchial microflora treated with appropriate antimicrobial therapy (n = 27) and patients without bronchial microflora either receiving empirical antibiotic therapy (n = 18) or not (n = 9). These data suggest that distal bronchial infection due to the usual pathogens, as far as shown by protected specimen brush cultures, may not be the sole or even the predominant cause of acute exacerbation of chronic bronchitis in patients requiring mechanical ventilation.

Acute Disease↗

Antimicrobial resistance of Haemophilus species in patients with chronic bronchitis.

Haemophilus influenzae strains resistant to ampicillin have become an important cause of disease in pediatric patients. Because many adults with chronic bronchitis carry Haemophilus organisms in their tracheobronchial tree and because antimicrobial agents are used commonly in these patients, we assessed the prevalence of resistance to ampicillin and other antimicrobial agents in this population. We studied 150 Haemophilus isolates (73 H. influenzae, 69 H. parainfluenzae, 6 H. parahemolyticus, and 2 H. hemolyticus) obtained from 138 patients with chronic bronchitis from January 1978 through March 1979. Ampicillin resistance due to production of beta-lactamase was found in 7 of the 150 isolates (4.7 %)-2 H. influenzae, 4 H. parainfluenzae and 1 H. parahemolyticus. Resistance to tetracycline was found in 9 strains (6 %), but all strains were susceptible to chloramphenicol.

Adult↗

Experimental induction of chronic bronchitis in dogs: effects on airway obstruction and responsiveness.

Chronic bronchitis was induced in 6 mongrel dogs by chronic exposure to SO2 gas; the degree of chronic airway obstruction and the effects on airway responsiveness to inhaled histamine, carbachol, and prostaglandin F2 alpha were examined. Five dogs developed chronic airway obstruction, as indicated by an increase in pulmonary resistance, and clinical mucous hypersecretion. In addition, in each of the animals in which chronic airway obstruction developed there was a decrease in the airway responsiveness to inhaled mediators. Those findings demonstrate that induction of chronic bronchitis in dogs results in hyporesponsiveness to inhaled mediators, a finding distinctly different from that reported in human subjects with naturally occurring disease.

Airway Resistance↗

The effect of erythromycin on theophylline pharmacokinetics in chronic bronchitis.

We examined theophylline pharmacokinetics for changes caused by the addition of erythromycin in patients with chronic bronchitis and obstructive pulmonary disease. Twelve hospitalized patients were randomized in a crossover fashion to receive aminophylline and either erythromycin or placebo. After the eighth dose, plasma was analyzed for theophylline, using the enzyme-mediated immunoassay technique. A 6-h urine collection was analyzed for theophylline metabolites, using high-pressure liquid chromatography. Erythromycin significantly decreased mean theophylline clearance by 22% from 4.9 L/min to 3.87 L/min (p less than 0.05). Mean peak theophylline levels increased 28% from 11.9 micrograms/ml to 15.3 micrograms/ml (p = 0.05). No change in urine theophylline metabolites was found. Patients with chronic bronchitis and obstructive pulmonary disease who begin erythromycin while receiving a preexisting therapeutic theophylline regimen experience a significant elevation of theophylline concentration, which predisposes to theophylline toxicity. For those patients with theophylline levels at the higher end of the therapeutic range (15 to 20 micrograms/ml), we recommend an initial 25% reduction in theophylline dosage when erythromycin is added. Serum theophylline levels should be monitored for further refinement of dosage.

Adult↗

Hemophilus influenzae biotypes and chronic bronchitis.

Hemophilus influenzae can be differentiated into 6 biotypes on the basis of 3 biochemical reactions. This study was undertaken to determine the biotypes of respiratory isolates from an adult population with chronic bronchitis and to compare the biotypes of upper and lower respiratory tract isolates of individual patients. For rapid biotyping of serologically nontypable H. influenzae, we used 2 commercially prepared kits (Minitek and IDS RapID Systems). Twenty-three of 29 isolates (79%) had biochemical characteristics of biotype II with the Minitek system. Eighteen of the same 29 isolates were retested with the IDS RapID System and reacted as biotype II organisms. Seven of 9 and 4 of 4 paired transtracheal/oropharyngeal samples had identical biotypes when tested with the Minitek and IDS RapID System, respectively. These findings suggest that H. influenzae organisms are exchanged between the oropharynx and tracheobronchial tree of elderly male patients with chronic bronchitis.

Bronchitis↗