Reduction in days of illness after long-term treatment with N-acetylcysteine controlled-release tablets in patients with chronic bronchitis

The clinical effect of N-acetylcysteine (NAC) controlled-release tablets, 300 mg b.i.d., and placebo, in chronic bronchitis was investigated. The study was performed as a double-blind six month comparison between active drug and placebo in two parallel groups, with statistical evaluation after four and six months. The patients were chosen from nine centres. One hundred and sixteen out-patients were included and ninety one of them completed the six month study. The acetylcysteine-treated group had a significantly reduced number of sick-leave days caused by exacerbations of chronic bronchitis after the four winter months December-March compared with the control group (NAC 173, placebo 456). The number of exacerbation days was also very much reduced, however, not significantly (NAC 204, placebo 399). At the end of the six month trial, including also two spring months, the absolute numbers of sick-leave days and exacerbation days were still fewer in the acetylcysteine-treated group, (NAC 260, placebo 739) and (NAC 378, placebo 557) respectively. This study demonstrates a significant reduction in sick-leave days after four months of NAC-treatment. A constant tendency to reduction in the number of exacerbations and exacerbation days was also registered after four and six months. The differences in these parameters were, however, not statistically significant. This was probably due to the small number of patients participating.     

Inhibitory effect of N-acetylcysteine on adherence of Streptococcus pneumoniae and Haemophilus influenzae to human oropharyngeal epithelial cells in vitro

BACKGROUND: Bacterial adherence to mucosal and epithelial cell structures is of importance for the persistence of bacteria in the airways. Cigarette smoking and chronic bronchitis are associated with increased bacterial adherence. N-Acetylcysteine (NAC) medication reduces the number of infectious exacerbations in patients with chronic bronchitis, and NAC medication has been associated with low intrabronchial bacterial numbers. OBJECTIVE: We investigated whether NAC influences bacterial adherence as a possible mechanism behind its clinical effects. METHODS: Highly adhering test strains of Streptococcus pneumoniae and Haemophilus influenzae were used to investigate the influence of four pharmacological compounds on adherence to oropharyngeal epithelial cells in vitro. Adhesion assays were performed both during short-term exposure to, as well as after long-time incubation with, NAC, lidocaine, hydrocortisone and terbutaline at concentrations not inhibiting bacterial growth. RESULTS: Only NAC showed a significant inhibitory effect on adhesion of H. influenzae during short-term incubation. After long-term incubation, both NAC and hydrocortisone inhibited bacterial adhesion for both strains in a dose-dependent manner. When NAC's effect on three different strains of S. pneumoniae and four strains of H. influenzae was studied, inhibition of bacterial adhesion was found for three strains of each species. CONCLUSIONS: NAC lowers bacterial adhesion in vitro to oropharyngeal epithelial cells in doses equivalent to that is being used clinically. This effect might be a contributory mechanism behind the reduction of infectious exacerbations in chronic bronchitis patients.     

N-acetylcysteine reduces the exacerbation rate in patients with moderate to severe COPD

OBJECTIVE: This study was performed to confirm the efficacy of a 6-month therapy with a formulation of N-acetylcysteine (NAC; 600 mg/day p.o.) on frequency and severity of exacerbations in patients suffering from chronic obstructive pulmonary disease (COPD). METHODS: One hundred sixty-nine patients attending five Italian centres were recruited in an open, randomized, controlled study. The patients were randomly allocated to standard therapy plus NAC 600 mg once a day or standard therapy alone over a 6-month period. At baseline, medical history was evaluated, and physical examination was performed; occurrence and severity of exacerbations and side effects of NAC were analyzed after 3 and 6 months. RESULTS: The results showed a decreased number of exacerbations (by 41%) in the group of patients treated with NAC and standard treatment: 46 patients had at least one exacerbation as compared with 63 patients of the group treated with standard therapy alone. Also the number of the patients with two or more exacerbations was lower in the NAC group (26%) than in the standard-therapy group (49%). The number of sick days was less (82) in the NAC group as compared with the standard-therapy group (155). There was a small but significant improvement in FEV(1) and MEF(50) in the NAC group. NAC once a day was well tolerated. There were no differences in the number of side effects reported in both groups. CONCLUSIONS: These data confirm results of previous studies which reported a reduction in the number of exacerbations in patients having moderate to severe COPD treated with the antioxidant NAC. Further, the once-daily formulation is well tolerated and is likely to improve patient compliance with the prescribed regimen. Copyright Copyright 1999 S. Karger AG, Basel     

N-isobutyrylcysteine, a donor of systemic thiols, does not reduce the exacerbation rate in chronic bronchitis.

N-isobutyrylcysteine (NIC), a new thiol compound that is not rapidly hydrolysed to give higher levels of free thiols in the body than N-acetylcysteine (NAC), was used to test if the effect of NAC on exacerbations in chronic bronchitis was an effect of the unhydrolysed thiol compound. Smokers or exsmokers with chronic bronchitis forced expiratory volume in one second (FEV1) >40% and reversibility < or = 10% predicted were treated with oral NIC 300 mg b.i.d. or placebo for 24 weeks. Steroids, NAC, antibiotics, and nonsteroid anti-inflammatory drugs use were restricted. Exacerbations were recorded by a respiratory symptom diary card and the time to onset of the first exacerbation after the start of treatment was measured using life-table analysis. Spirometry was performed at each visit. Six hundred and thirty-seven patients were randomized to treatment with NIC (n=316) or placebo (n=321). NIC did not prolong the time to first exacerbation (life-table analysis, p=0.59) and no increase in FEV1 or forced vital capacity was observed. Altered taste perception, taste loss and anosmia occurred more often in the NIC group (p<0.001). In conclusion, N-isobutyrylcysteine, a N-acetylcysteine-like drug with a greater bioavailability has, contrary to N-acetylcysteine, no effect on exacerbations in chronic bronchitis. This suggests that the effect of N-acetylcysteine on exacerbations in chronic bronchitis is not due to the relatively low free thiol levels (other than glutathione) produced by N-acetylcysteine therapy.     

The effect of oral N-acetylcysteine in chronic bronchitis: a quantitative systematic review.

The role of N-acetylcysteine (NAC) in the treatment of chronic bronchitis is unclear. Since a number of studies have been published on this topic, a systematic review of published studies seems justified. A systematic search (Medline, Embase, Cochrane Library, bibliographies, no language restriction) for published randomized trials comparing oral NAC with placebo in patients with chronic bronchitis was performed. Dichotomous data on prevention of exacerbation, improvement of symptoms and adverse effects were extracted from original reports. The relative benefit and number-needed-to-treat were calculated for both individual trials and combined data. Thirty-nine trials were retrieved; eleven (2,011 analysed patients), published 1976-1994, were regarded as relevant and valid according to preset criteria. In nine studies, 351 of 723 (48.5%) patients receiving NAC had no exacerbation compared with 229 of 733 (31.2%) patients receiving placebo (relative benefit 1.56 (95% confidence interval (CI) 1.37-1.77), number-needed-to-treat 5.8 (95% CI 4.5-8.1). There was no evidence of any effect of study period (12-24 weeks) or cumulative dose of NAC on efficacy. In five trials, 286 of 466 (61.4%) patients receiving NAC reported improvement of their symptoms compared with 160 of 462 (34.6%) patients receiving placebo (relative benefit 1.78 (95% CI 1.54-2.05), number-needed-to-treat 3.7 (95% CI 3.0-4.9)). With NAC, 68 of 666 (10.2%) patients reported gastrointestinal adverse effects compared with 73 of 671 (10.9%) taking placebo. With NAC, 79 of 1,207 (6.5%) patients withdrew from the study due to adverse effects, compared with 87 of 1,234 (7.1%) receiving placebo. In conclusion, with treatment periods of approximately 12-24 weeks, oral N-acetylcysteine reduces the risk of exacerbations and improves symptoms in patients with chronic bronchitis compared with placebo, without increasing the risk of adverse effects. Whether this benefit is sufficient to justify the routine and long-term use of N-acetylcysteine in all patients with chronic bronchitis should be addressed in further studies and cost-effectiveness analyses.     

No effect of oral N-acetylcysteine on the bioavailability of erythromycin and bacampicillin

In vitro studies with N-acetylcysteine (NAC) solutions used for inhalation treatment have demonstrated inactivation of some antibiotics by NAC. Oral NAC treatment is increasingly common for long-term prophylaxis in chronic bronchitis. During exacerbations, treatment with oral antibiotics will often be given simultaneously. We assessed the effect of simultaneous oral administration of NAC on the bioavailability of two antibiotics in ten healthy volunteers. No effect of NAC was found on the bioavailability of ampicillin, after administration of the prodrug bacampicillin. A slight, but not significant statistical increase in erythromycin serum levels was seen with NAC. Acetylator phenotype did not influence the absorption of NAC, which seemed slightly reduced by bacampicillin, but significantly increased by erythromycin. No decrease of antibacterial activity of sera was found in vitro after the addition of NAC or the related thiol glutathione, employing micrococcus luteus and staphylococcus aureus as indicator organisms.     

N-acetylcysteine by metered dose inhaler in the treatment of chronic bronchitis: a multi-centre study.

Sixty-five patients with chronic bronchitis were studied at five different centres in a double-blind, randomized trial. Two parallel groups were treated with either N-acetylcysteine or placebo by metered dose inhalers for 16 weeks. Following a 1-week run-in period, each patient recorded subjective impressions of the drug action on their bronchitic symptoms in a diary once a week. In addition, exacerbations were registered. Lung function testing and adverse effects were evaluated by four visits to the chest clinics during the 16 weeks. We could not demonstrate that N-acetylcysteine by metered dose inhalers had any significant effect on patients' feeling of well-being, sensation of dyspnoea, intensity of coughing, mucus production, or expectoration or lung function. Its effect in reducing exacerbations could not be estimated because of a very low number of exacerbations reported. N-acetylcysteine inhalation was safe when used over a 16-week period.     

Changes in bronchial inflammation during acute exacerbations of chronic bronchitis.

There are little data describing noncellular changes in bronchial inflammation during exacerbations of chronic bronchitis. The relationship between sputum colour and airway inflammation at presentation has been assessed during an exacerbation in patients with chronic bronchitis and a primary care diagnosis of chronic obstructive pulmonary disease. Sputum myeloperoxidase, neutrophil elastase, leukotriene B4 (LTB4), interleukin-8 (IL-8), sol:serum albumin ratio and serum C-reactive protein were measured in patients presenting with an exacerbation and mucoid (n = 27) or purulent sputum (n = 42). Mucoid exacerbations were associated with little bronchial or systemic inflammation at presentation, and sputum bacteriology was similar to that obtained in the stable state. Purulent exacerbations were associated with marked bronchial and systemic inflammation (p < 0.025 for all features) and positive sputum cultures (90%). Resolution was related to a significant reduction in LTB4 (p < 0.01), but no change in IL-8, suggesting that LTB4 may be more important in neutrophil recruitment in these mild, purulent exacerbations. In the stable state, IL-8 remained higher in patients who had experienced a purulent exacerbation (2p < 0.02). The presented results indicate that exacerbations of chronic bronchitis, defined by sputum colour, differ in the degree of bronchial and systemic inflammation. Purulent exacerbations are related to bacterial infection, and are associated with increased neutrophilic inflammation and increased leukotriene B4 concentrations.     

Acute exacerbation of chronic obstructive pulmonary disease and antibiotics: what studies are still needed?

The use of antibiotics in acute exacerbations of chronic bronchitis (AECBs) remains the subject of controversy despite considerable medical and socioeconomic implications. First, the contribution of bacterial infection to AECBs is difficult to assess in patients with chronic obstructive pulmonary disease (COPD) who are chronically colonized with respiratory pathogens. In addition, several studies suggest a major role of viral infections in AECBs. Secondly, it is unlikely that all COPD patients will benefit from antibiotics during AECBs. In particular, the benefit in mild COPD remains uncertain. Unfortunately, the number of studies complying with evidence-based medicine requirements is too small for definite recommendations in AECBs to be drawn up. Considering the impact of acute exacerbations of chronic bronchitis on chronic obstructive pulmonary disease patients, as well as the community, and the impact of antibiotic therapy on the development of bacterial resistance, there is an urgent need for the design of appropriate multicentric studies to define the usefulness of this type of treatment in acute exacerbations of chronic bronchitis.     

Reduction in the incidence of acute bronchitis by an oral Haemophilus influenzae vaccine in patients with chronic bronchitis in the highlands of Papua New Guinea

Following the administration of a standardized questionnaire, 62 adult patients with chronic bronchitis were enrolled into a double-blind controlled trial of an oral killed Haemophilus influenzae vaccine in the highlands of Papua New Guinea. A 3-day course of vaccine or placebo was given monthly for 3 consecutive months. Participants were monitored weekly over 12 months for acute exacerbations; early morning sputum specimens were collected monthly and during acute exacerbations. Density of colonization by H. influenzae and H. parainfluenzae was determined by standard quantitative and semiquantitative techniques, and the latter method (quadrant score) was used to determine the density of growth of pneumococci. A total of 30 patients received vaccine and 32 placebo. The incidence rate of acute bronchitis in the vaccine group (0.011 episodes/person-weeks) was significantly lower than that in the placebo group (0.021 episodes/person-weeks), but there was no difference between the two groups in the incidence rates of more severe disease. Vaccine efficacy was maximal at times of peak incidence of disease. There was no evidence of a decline in vaccine efficacy for acute bronchitis over the 12-month follow-up period. The number of viable H. influenzae in the sputum declined in both vaccine and placebo groups over the 12-month follow-up period. The average concentration of H. influenzae in the vaccine group fell below that in the placebo group within 1 to 2 months after first immunization and remained so for 12 months, although the difference between the two groups narrowed during the follow-up period.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prulifloxacin versus levofloxacin in the treatment of severe COPD patients with acute exacerbations of chronic bronchitis

RationaleAntimicrobial therapy of chronic bronchitis exacerbations in patients with severe chronic obstructive pulmonary disease (COPD) is based on empiric antibiotic treatment.ObjectivesTo evaluate the efficacy of prulifloxacin versus levofloxacin therapy in severe COPD patients with exacerbations of chronic bronchitis.MethodsThis study involved a multicenter, parallel, double-blind, randomized clinical trial. Patients aged 40 years or older, smokers, or ex-smokers (>10 pack-years) with spirometrically confirmed severe COPD (FEV₁ ≤ 50% predicted and FEV₁/FVC ratio < 0.7) and diagnosed with an acute exacerbation of chronic bronchitis were enrolled in the study. Patients were randomized to receive prulifloxacin 600 mg once a day or levofloxacin 500 mg once a day for 7 days.Measurements and main resultsThe primary outcome measure was clinical assessment at the TOC visit (7–10 days after the end of treatment) of signs and symptoms of exacerbation, namely sputum purulence, sputum volume, dyspnoea, cough and body temperature assessed through semi-quantitative scales. The ITT population included 346 (174 prulifloxacin, 172 levofloxacin) out of 351 treated subjects. A total of 161 patients with prulifloxacin (92.5%) and 166 with levofloxacin (96.5%) were considered cured at TOC (the difference in the percentage of cured patients was ?3.98 with 95%CI of ?8.76; 0.79). At the 6-month follow-up, the rates of patients with no relapse of AECB were higher than 95% in both the prulifloxacin and levofloxacin groups.ConclusionsBoth prulifloxacin and levofloxacin showed efficacy rates higher than 90% in the treatment of severe COPD patients with exacerbations of chronic bronchitis, with no statistically significant differences between the two antibiotics. The long-term follow-up confirmed a very low incidence of relapse, endorsing the appropriateness of this therapeutic approach.EUDRACT no. 2006-004167-56.     

Infections with viruses and Mycoplasma pneumoniae during exacerbations of chronic bronchitis.

The association of viral and Mycoplasma pneumoniae infections with acute exacerbations of chronic bronchitis was studied by serologic or isolation techniques in 46 adult men during the five years from 1964 through 1968. Serologic evidence of viral or M. pneumoniae infection was detected in 25% of 166 episodes of exacerbation and 14% of 138 remission periods (P = 0.02). Influenza A virus, parainfluenza virus type 3, and coronavirus OC43 predominated; infections with other viruses were infrequent. Infection with M. pneumoniae was detected serologically in four patients, but this organism was never isolated from sputum specimens. Rhinoviruses were isolated from frozen-stored sputum specimens in in 2.7% of the episodes of exacerbation and from 0.55% of the remission intervals (P not significant). These data suggest that although exacerbations of chronic bronchitis may be accompanied by viral and M. pneumoniae infections, patients with chronic bronchitis also acquire such infections without a worsening of their respiratory status.     

Double-blind study of OM-85 in patients with chronic bronchitis or mild chronic obstructive pulmonary disease

BACKGROUND: Interventions against acute exacerbations (AEs) of chronic obstructive pulmonary disease (COPD) are increasingly called for to reduce morbidity, mortality and costs. OM-85, a detoxified immunoactive bacterial extract, has been shown to prevent recurrent exacerbations of bronchitis and COPD. OBJECTIVES: It was the aim of this study to demonstrate the protective effect of OM-85 against recurrent bronchitic exacerbations in patients with chronic bronchitis or mild COPD. The primary end point was the mean rate of AEs occurring within the study period. METHODS: This double-blind multi-centre study enrolled adult outpatients>40 years old of both sexes with a history of chronic bronchitis or mild COPD at the time of an AE. The treatment consisted of one capsule of OM-85 or placebo per day for 30 days, followed by three 10-day courses for months 3, 4 and 5, with a 6-month study duration and monthly control visits. RESULTS: One hundred and forty-two patients were treated with OM-85 and 131 received placebo. By the end of the treatment period, the mean number of AEs in the OM-85 group was 0.61 per patient versus 0.86 per patient in the placebo group (-29%; p=0.03). The difference between treatments was most notable in patients with a history of current or past smoking (-40%; p<0.01). No serious adverse events were attributed to the medication and no significant laboratory changes were reported. CONCLUSIONS: OM-85 significantly reduced the frequency of AEs in patients with a history of chronic bronchitis and mild COPD and was well tolerated. This study confirms the findings of previous trials conducted in elderly patients with chronic bronchitis or COPD.     

Die Langzeitbehandlung der chronischen Bronchitis mit dem Breitband-Chemotherapeuticum „Bactrim“

In a double blind trial 22 patients, suffering from chronic obstructive bronchitis, were administered “Bactrim” and 15 patients received placebo for a period of 9 months. All patients received two tablets daily. No side effects of the chemo-therapy were noticed. Airway resistance, interthoracic gas-volume and the volume of the sputum did not change in comparison with the placebo group. The frequency of exacerbations was lower in the Bactrim group than in the placebo group. Bactrim was found to be a valuable complement in the therapy of patients suffering from chronic obstructive bronchitis with a high frequency of exacerbations.     

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.     

Inhalation therapy and laser therapy in chronic bronchitis]

Sixty five patients aged 24 to 68 years who had chronic bronchitis (with the rate of exacerbations of at least twice a year) in the phase of exacerbation were examined. They were 46 males and 19 females. As being examined and diagnosed, all the patients were divided into 3 groups and treated by different regimens. Sixty five took drug therapy, in 44 patients it was supplemented by endobronchial laser radiation, 22 of them also received halo therapy. Following 6-week therapy, signs of endobronchitis disappeared in a significantly larger number of patients undergone laser therapy. Moreover, there was an increase in the interval between exacerbations in patients who additionally received halo therapy.     

Epidemiology of chronic bronchitis and acute infective exacerbations of chronic bronchitis

Acute exacerbations of chronic bronchitis (AECBs) are one of the major causes of morbidity and mortality in the United States, resulting in significant cost to the health care system. Epidemiological information on chronic bronchitis is abundant and has been collected in most industrialized countries. The epidemiology of AECB, however, is less forthcoming. The causes of AECB are multifactorial and include environmental pollutants, allergic responses, and viral and bacterial infections. The role of bacterial infection in AECB is controversial but is believed to account for half of AECB. Because the medical and economic implications of treatment failure in these patients are substantial, an aggressive approach to stratify and treat these patients is necessary. Epidemiological data on chronic bronchitis and acute infective exacerbations of chronic bronchitis will allow us to more precisely define the role of bacterial infection in AECB, and this information may help guide antimicrobial therapy.     

The workplace impact of acute exacerbations of chronic bronchitis (AECB); A literature review

Acute exacerbations of chronic bronchitis (AECB) are known to have a substantial economic burden in terms of medical care costs. The objective of this study was to assess workplace-based costs associated with AECB, including absenteeism and decreased productivity, based on a review of published literature. A secondary goal was to identify factors related to workplace-based costs in AECB. A literature search was conducted to identify relevant articles assessing one or more aspects of work loss or workplace costs among patients with chronic bronchitis. A review of the identified literature indicates that patients with chronic bronchitis had more days off work; patients whose exacerbations were treated were less likely to have additional exacerbations and had comparatively less work loss. Findings suggest that clinical outcomes and workplace costs are related. While this relationship is clearer in terms of work loss, further exploration is needed to assess decreased productivity and to evaluate this relationship using objective indicators of absenteeism and productivity rather than recall.     

The Workplace Impact of Acute Exacerbations of Chronic Bronchitis (AECB); A Literature Review

Acute exacerbations of chronic bronchitis (AECB) are known to have a substantial economic burden in terms of medical care costs. The objective of this study was to assess workplace‐based costs associated with AECB, including absenteeism and decreased productivity, based on a review of published literature. A secondary goal was to identify factors related to workplace‐based costs in AECB. A literature search was conducted to identify relevant articles assessing one or more aspects of work loss or workplace costs among patients with chronic bronchitis. A review of the identified literature indicates that patients with chronic bronchitis had more days off work; patients whose exacerbations were treated were less likely to have additional exacerbations and had comparatively less work loss. Findings suggest that clinical outcomes and workplace costs are related. While this relationship is clearer in terms of work loss, further exploration is needed to assess decreased productivity and to evaluate this relationship using objective indicators of absenteeism and productivity rather than recall.