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Morphologic correlation of physiologic changes caused by SO2-induced bronchitis in dogs. The role of inflammation.

Chronic bronchitis was induced in 6 mongrel dogs by exposure to SO2 gas for 6 to 18 months. All of the dogs developed cough and mucus hypersecretion. Chronic airway obstruction and decreased airway responsiveness to inhaled histamine developed in 5 of the dogs. Histologic changes in dogs evaluated after SO2 exposure included significant mucous gland hypertrophy and hyperplasia, epithelial thickening, and a decrease in the number of luminal cells containing undischarged secretory granules. Acute and chronic inflammation were found in the dogs with airway obstruction and decreased responsiveness to histamine, but such inflammation was absent in the one dog that failed to develop physiologic changes. After a period of recovery from SO2 exposure of 9 to 21 months, inflammation regressed dramatically and the other histologic changes returned toward normal. Physiologic changes regressed somewhat in those dogs that had had changes. These findings suggest that inflammation may be an important factor influencing the development of airway obstruction and altered airway responsiveness in the setting of chronic bronchitis.

Airway Resistance↗

The efficacy of orally administered theophylline, inhaled salbutamol, and a combination of the two as chronic therapy in the management of chronic bronchitis with reversible air-flow obstruction.

The efficacy of bronchodilator therapy was assessed in the long-term management of patients with chronic bronchitis and varying degrees of reversible air-flow obstruction. Twenty-five patients with a mean forced expiratory volume in one second (FEV1) 38.7% predicted received: optimized doses of orally administered, sustained-release theophylline, inhaled salbutamol (200 micrograms 4 times a day), a combination of the 2 drugs, and identical placebo therapy for periods of 3 wk in a randomized, double-blind, crossover trial. Patients who deteriorated during treatment were assessed immediately and designated "treatment failures" if additional therapy proved necessary. Such "failures" occurred in 9 patients with placebo, in 8 with salbutamol, in 6 with theophylline, and in only 1 with combined therapy. Using a ranking system based on "treatment failures" and mean daily peak flow rates, first preference was given to combined therapy in 13 patients, theophylline in 6, salbutamol in 4, and placebo in 2. Thus, both combined therapy (p less than 0.001) and theophylline (p less than 0.05) were better than placebo, but this was not so for inhaled salbutamol. Objective improvements in FEV1 and forced vital capacity were a consistent finding with combined therapy compared with placebo, although not with single agents, and additive effects were clearly demonstrated. In the subgroup of patients able to tolerate placebo therapy, no subjective benefit could be discerned during any of the 3 periods of active treatment. Thus, the combination of orally administered, sustained-release theophylline and inhaled salbutamol offered significant advantages in the clinical control of patients with chronic bronchitis with air-flow obstruction.

Administration, Oral↗

A comparison of the effects of almitrine or oxygen breathing on pulmonary arterial pressure and right ventricular ejection fraction in hypoxic chronic bronchitis and emphysema.

Almitrine bismesylate is a new, orally administered, respiratory stimulant that improves arterial blood gas tensions in patients with chronic bronchitis and emphysema, and it may have an effect on the pulmonary circulation and on right ventricular performance. We have, therefore, compared the effects of Almitrine with those of oxygen (given as 3 L/min by nasal prongs) on arterial blood gas tensions, mean pulmonary arterial pressure (Ppa), and right ventricular ejection fraction (RVEF) measured both at rest and during exercise in patients with chronic hypoxemia caused by chronic bronchitis and emphysema. Arterial oxygen tension improved significantly both at rest and during exercise after either 100 mg Almitrine by mouth or when breathing oxygen, both at rest and during exercise. Almitrine increased the mean Ppa at rest from 22 +/- 4 to 35 +/- 5 mmHg (p less than 0.001), and mean Ppa rose further during exercise from 38 +/- 5 mmHg before Almitrine to 49 +/- 7 mmHg (p less than 0.001) after Almitrine. In contrast, oxygen breathing did not change Ppa when at rest but reduced the amount of rise in Ppa during exercise. The change in Ppa after Almitrine correlated with the plasma Almitrine concentration (r = 0.69, p less than 0.05) and was associated with a fall in RVEF at rest from 0.38 +/- 0.03 to 0.32 +/- 0.02 (p less than 0.001). In 5 of the patients who received 50 mg of Almitrine by mouth twice daily for 3 months, the Ppa both at rest and during exercise remained significantly higher than in the control study before receiving Almitrine, but RVEF was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Lung function decline, chronic bronchitis, and occupational exposures in young adults.

RATIONALE: Occupational exposures to vapors, gas, dust, or fumes have been shown to be a risk factor of airway obstruction in cross-sectional studies in the general population. OBJECTIVES: Our aim was to study the relationships between specific occupations and occupational exposures during a 9-yr follow-up period and changes in lung function and symptoms of chronic bronchitis. METHODS: Subjects from the general population aged 20 to 45 yr were randomly selected in 1991-1993 within the European Community Respiratory Health Survey. Follow-up took place from 1998 to 2002 among 4,079 males and 4,461 females in 27 study centers. A total of 3,202 men and 3,279 women twice completed lung function measurements. Job history during follow-up was linked to a job exposure matrix and consequently translated into cumulative exposure estimates. MAIN RESULTS: Individuals exposed to dusts, gases, and fumes during the period of follow-up did not have a steeper decline of FEV1 than did individuals with consistently white-collar occupations without occupational exposures (relative change among men and women, + 1.4 and -3.1 ml/yr, respectively; p > 0.2), nor an increase of prevalence or incidence of airway obstruction defined as an FEV1/FVC ratio of less than 0.7. The incidence of chronic phlegm increased in men exposed to mineral dust (relative risk, 1.94 [1.29-2.91]) and gases and fumes (relative risk, 1.53 [0.99-2.36]), which was not modified by smoking. CONCLUSION: Occupational exposures to dusts, gases, and fumes occurring during the 1990s are associated with incidence of chronic bronchitis, although these did not impair lung function in a population of relatively young age.

Adult↗

Substance P content and preprotachykinin gene-I mRNA expression in a rat model of chronic bronchitis.

Chronic exposure of rats to high concentrations of SO2 gas induces a syndrome similar to human chronic bronchitis. The aim of these studies was to determine if substance P (SP) content in the trachea or lungs was elevated in this animal model of chronic bronchitis, and whether an increase in SP content was associated with an increase in preprotachykinin gene-I (PPT) mRNA expression. Rats were exposed to air (controls) or 250 ppm SO2 gas, 5 h per day, 5 days per week, for a period of 4 wk. Animals were killed and the lungs and trachea were frozen in liquid nitrogen for measurement of SP content by enzyme-linked immunosorbent assay. The SP content of the tracheas from SO2-exposed rats was 3-fold greater than controls (8.9 +/- 1.2 and 3.0 +/- 0.7 pmol/g tissue, respectively; P=0.0005), whereas the SP content of the lungs was not different (SO2 = 4.8 +/- 0.8 and air = 3.0 +/- 0.7 pmol/g tissue, respectively; P = 0.06). In order to determine whether SP synthesis in the cell bodies of the C-fibers innervating the trachea and lungs accompanied a change in SP levels, thoracic dorsal root ganglia and nodose ganglia were removed and PPT mRNA quantitated by Northern analysis. There was no difference in PPT mRNA between control and SO2-exposed rats in nodose or dorsal root ganglia. These results suggest a post-transcriptional mechanism of PPT regulation. Elevated SP levels could play a protective role in the responses of the airways to chronic exposure of inhaled irritants.

Animals↗

Chondroitin sulfate in sputum from patients with cystic fibrosis and chronic bronchitis.

In order to ascertain whether or not the presence of glycosaminoglycans in sputa of patients suffering from chronic bronchial disorders was related to tracheobronchial infection, an electrophoretic procedure was set up. The different acidic macromolecular components of sputum, namely nucleic acids, glycosaminoglycans, and bronchial glycopeptides could be identified in proteolyzed sputum using agarose electrophoresis before and after the action of different enzymes: nucleases, chondroitinases, hyaluronidase and heparinase. This procedure was used to analyze 13 sputum samples from patients suffering from cystic fibrosis (CF) and 12 sputum samples from patients suffering from chronic bronchitis. Chondroitin sulfate was identified in 11 infected sputum samples from patients with CF and also in the noninfected sputum from a patient with chronic bronchitis. These data suggest a relationship between the presence of chondroitin sulfate proteoglycans in sputum and severe tracheobronchial infection in CF.

Adolescent↗

Gene expression and immunolocalization of 15-lipoxygenase isozymes in the airway mucosa of smokers with chronic bronchitis.

15-lipoxygenase (15-LO) has been implicated in the inflammation of chronic bronchitis (CB), but it is unclear which of its isoforms, 15-LOa or 15-LOb, is primarily involved. To detect 15-LO gene (mRNA) and protein expression, we have applied in situ hybridization (ISH) and immunohistochemistry (IHC), respectively, to bronchial biopsies obtained from 7 healthy nonsmokers (HNS), 5 healthy smokers (HS), and 8 smokers with CB, and additionally include the airways of lungs resected from 11 asymptomatic smokers (AS) and 11 smokers with CB. Compared with HNS, biopsies in CB demonstrated increased numbers of 15-LOa mRNA+ cells (median: HNS = 31.3/mm(2) versus CB = 84.9/mm(2), P < 0.01) and protein+ cells (HNS = 2.9/mm(2) versus CB = 32.1/mm(2), P < 0.01). The HS group also showed a significant increase in protein+ cells (HNS = 2.9/mm(2) versus HS = 14/mm(2), P < 0.05). In the resected airways, 15-LOa protein+ cells in the submucosal glands of the CB group were more numerous than in the AS group (AS = 33/mm(2) versus CB = 208/mm(2); P < 0.001). 15-LOa mRNA+ and protein+ cells consistently outnumbered 15-LOb by approximately 7- and 5-fold, respectively (P < 0.01). Quantitative reverse transcriptase polymerase chain reaction of complementary biopsies confirmed the increased levels of 15-LOa in CB compared with that in either HNS or HS (P < 0.05). There was no difference between the subject groups with respect to 15-LOb expression. The numbers of cells expressing mRNA for 15-LOa in CB showed a positive association with those expressing interleukin (IL)-4 mRNA (r = 0.80; P < 0.01). We conclude that the upregulation of 15-LO activity in the airways of HS and of smokers with CB primarily involves the 15-LOa isoform: the functional consequences of its association the upregulation of IL-4 in chronic bronchitis requires further study.

Adult↗

Effect of Vaporub on the restlessness of children with acute bronchitis.

In this study pneumographs of children with acute bronchitis treated with Vicks Vaporub or Petrolatum were used. Movement artifacts were used as a measure of the so-called "restlessness" of the children. The experimental schedule consisted of a 10-minute phase of recording before a 3-minute treatment with Vaporub or Petrolatum, followed by a 70-minute observation period, during which time pneumograms were also recorded. Thirty-four Vaporub-treated children showed an increase in periods without movement artifacts of up to 213.8%, the Petrolatum controls, twenty-six children, up to 62.4% as compared to the corresponding pre-treatment values. It is concluded that Vaporub is effective in decreasing restlessness in children suffering from acute bronchitis. This effect is quite marked and cannot be due solely to psychological effects of the rub therapy, or to effects of petrolatum without aromatics.

Acute Disease↗

Efficacy and tolerance of enteric-coated erythromycin base (Ery-Max) administered twice or four times daily in patients with acute bronchitis.

We performed a double-blind trial of a new formulation of erythromycin base as enteric-coated pellets (Ery-Max) in the treatment of acute bronchitis in 220 patients. Subjects were randomized to receive either 500 mg twice or 250 mg four times a day for 10 days. The response to treatment as assessed clinically and by changes in sputum purulence was the same in the two groups. Thus 97% and 98% of the patients had a good or improved clinical effect. Treatment was well tolerated, but side-effects were encountered more often in the q.i.d. group (p greater than 0.05). In conclusion, the study showed that the enteric-coated erythromycin as pellets, given twice or four times daily for 10 days, was well tolerated and equally effective in acute bronchitis. Hence, the more convenient b.i.d. regimen can be recommended.

Acute Disease↗

A comparison of pivmecillinam/pivampicillin and amoxycillin in acute exacerbations of chronic bronchitis.

Courses of 7 days on either 200 mg pivmecillinam/250 mg pivampicillin given twice daily or 250 mg amoxycillin given three times daily were compared in 3783 general practice patients with acute exacerbations of chronic bronchitis in a single-blind parallel group study. Patients on pivmecillinam/pivampicillin had significantly more 'excellent' responses, although there was no difference in overall response between treatments. Post-treatment sputum colour and consistency and peak expiratory flow rates were significantly better with pivmecillinam/pivampicillin. The incidence of side-effects was the same for both groups (approximately 10%), although significantly more patients reported lower gastro-intestinal problems with amoxycillin. Treatment was withdrawn due to side-effects in 47 (2.5%) patients on pivmecillinam/pivampicillin and 51 (2.7%) patients on amoxycillin. Amoxycillin is a standard therapy in the treatment of patients with acute exacerbations of chronic bronchitis. In this study, however, it was shown that pivmecillinam/pivampicillin offers benefits over amoxycillin in these patients.

Acute Disease↗

A novel protein polymorphism differentiates the California serotype of infectious bronchitis from other serotypes common to California.

The California (Cal) serotype of infectious bronchitis virus (IBV) was isolated from layer flocks in southern California in the early 1980s. Since then, it has spread to the broiler-producing regions of central California, where it has been implicated in respiratory disease outbreaks in vaccinated flocks. Lack of a procedure for quickly identifying IBV serotypes in commercial chicken flocks has prevented the causal association of the IBV Cal serotype with respiratory disease outbreaks. A protein polymorphism has been identified in the matrix protein of the Cal serotype; it appears to be unique among other common serotypes of infectious bronchitis virus found in California. This polymorphism can be identified on western blots using raw or concentrated infectious allantoic fluid as the source material. Identification of the Cal serotype and of serotypes in the Mass and Conn groups can be performed rapidly using field samples from suspect flocks. The identification of this polymorphism provides an alternative method for the rapid identification of the Cal serotype of IBV.

Animals↗

Azithromycin versus pivampicillin in the treatment of acute exacerbations of chronic bronchitis: a single-blind, double-dummy, multicentre study.

This single-blind, double-dummy, multicentre study compared oral azithromycin, administered as tablets, 500 mg once daily for 3 days, versus oral pivampicillin, 700 mg twice daily for 10 days, in adults with acute exacerbations of chronic bronchitis (not needing parenteral antibiotic therapy, hospitalization or oxygen support). Clinical success (cure + improvement) rates were similar for both groups at the end of treatment (day 10; azithromycin, 124 of 133 [93%]; pivampicillin, 79 of 92 [86%]) and at follow-up (day 52; 98 of 126 [78%] versus 66 of 81 [81%]). The treatments produced similar levels of pathogen eradication at the end of treatment (49 of 54 [91%] versus 32 of 37 [86%]). Azithromycin-treated patients had significantly reduced chest discomfort at the end of treatment, and a trend towards improved lung function. The two groups were similar with respect to improvements in other clinical symptoms and patient well-being, and to the incidences of adverse events and treatment discontinuations. This oral azithromycin regime is an effective treatment for acute exacerbations of chronic bronchitis, similar in efficacy to the longer pivampicillin regime and may offer superior patient compliance.

Adult↗

Comparative evaluation of the clinical and microbiological efficacy of co-amoxiclav vs cefixime or ciprofloxacin in bacterial exacerbation of chronic bronchitis.

In an open randomized study 218 outpatients (159 males and 59 females) ranging between 18 and 85 years of age (mean 61.9) suffering from bacterial exacerbation of chronic bronchitis have been randomly treated: 79 with co-amoxiclav (amoxicillin 875 mg+clavulanic acid 125 mg) twice daily, 69 with cefixime (400 mg) once daily, and 70 with ciprofloxacin (500 mg) twice daily for an average period of 10 days. Before treatment start, 234 bacterial strains (105 Gram-positive and 129 Gram-negative) were isolated as the cause of exacerbation; the leading pathogens were Streptococcus pneumoniae and Haemophilus spp. Eradication rates at the end of treatment were 82.2% for the co-amoxiclav group, 77.6% for the cefixime group, and 81.2% for ciprofloxacin group. Clinical success (cure+improvement) was obtained in 90.8% of the cases treated with co-amoxiclav, in 80.9% for the cefixime group and in 85.7% of patients treated with ciprofloxacin. Seven adverse events (8.9%) of which 4 cases of diarrhea and 3 of itching, were recorded in the co-amoxiclav group. Eleven adverse events (14.7%) were recorded in the cefixime group including gastrointestinal disturbances in 6 patients and mild to moderate increase of liver function in 2. Nine adverse events (12.9%) occurred in the ciprofloxacin group, including insomnia in 3 patients, gastrointestinal disturbances in 2, and serious increase of liver function tests in one patient. It can be concluded that there were no statistically significant differences among the three treatment groups. However, co-amoxiclav demonstrated a higher efficacy rate than cefixime and ciprofloxacin and was better tolerated. Therefore, it can be used as a first-choice drug in the treatment of exacerbation of chronic bronchitis.

Adolescent↗

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.

Aged↗

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 Disease↗

Efficacy of gemifloxacin in acute exacerbations of chronic bronchitis: a randomised, double-blind comparison with trovafloxacin.

This randomised, double-blind, double-dummy, multinational study compared the efficacy and safety of gemifloxacin with trovafloxacin in the treatment of acute exacerbations of chronic bronchitis. There were 617 patients randomised: 303 to gemifloxacin and 314 to trovafloxacin. Clinical success rates at follow-up (clinical per-protocol population) were 91.5% for gemifloxacin and 87.6% for trovafloxacin. For the intent-to-treat population, the clinical efficacy of gemifloxacin was statistically significantly superior to that of trovafloxacin. In general, the in vitro activity of gemifloxacin against the major respiratory bacterial pathogens was superior to that of other antibiotics tested. Per-patient bacteriological success rates at follow-up (bacteriology per-protocol population) were 86.8% for gemifloxacin and 82.4% for trovafloxacin. Both agents were well tolerated. The clinical and bacteriological efficacy of a once-daily 5-day course of gemifloxacin is at least as good as that of a similar regimen of trovafloxacin in the treatment of acute exacerbations of chronic bronchitis.

Adult↗

Interleukin-13 and -4 expression in the central airways of smokers with chronic bronchitis.

The aim of this study was to determine whether the T-helper 2-type cytokines interleukin (IL)-13 and -4 are involved in mucus hypersecretion, the hallmark of chronic bronchitis (CB). Surgical specimens were examined from 33 subjects undergoing lung resection for localised peripheral malignant pulmonary lesions: 21 smokers with symptoms of CB, 10 asymptomatic smokers (AS) and two nonsmokers with normal lung function. The number of IL-4 and -13 positive (+) cells in the central airways was quantified. To better assess the cytokine profile, a count was also made of IL-5+ and interferon (IFN)-gamma+ cells. Compared to AS, the CB group had an increased number of IL-13+ and -4+ cells in the bronchial submucosa, while the number of IL-5+ and IFN-gamma+ cells were similar in all the groups. No significant associations were found between the number of cells expressing IL-13 or -4 and the number of inflammatory cells. Double labelling showed that 13.2 and 12.9% of IL-13+ cells were also CD8+ and CD4+, whereas 7.5 and 5% of IL-4+ cells were CD8+ and CD4+, respectively. In conclusion, T-helper-2 and -1 protein expression is present in the central airways of smokers and interleukin-4 and -13 could contribute to mucus hypersecretion in chronic bronchitis.

Adult↗

Variation of CD8+ T-lymphocytes around the bronchial internal perimeter in chronic bronchitis.

The variation of CD8+ cells has been determined around the internal perimeter of intrapulmonary bronchi in smokers with chronic bronchitis (CB), and the amount of tissue required to confidently estimate the true mean has been calculated. Lung specimens were obtained from 10 smokers with CB. Paraffin sections of intrapulmonary bronchi were immunostained and CD8+ cells counted in the epithelium and subepithelium in up to 10 sequential 1-mm segments around the internal perimeter of each airway. The percentage of counts falling between +/-20% of the final mean was 43.0% for epithelium and 40.9% for subepithelium. In 90% of subjects, the cumulative mean was stable after examination of subepithelial tissue associated with 5 mm of reticular basement membrane. There is considerable variation in the counts of CD8+ cells between adjacent 1-mm airway mucosal segments in chronic bronchitis. In order to achieve a representative count and to maximise statistical power to detect differences between study populations, subepithelial tissue including a minimum of 5 mm of reticular basement membrane length should be examined.

Aged↗