American journal of respiratory medicine : drugs, devices, and other interventions最新文献

Descriptive studies have shown an association between eosinophils, interleukin (IL)-5 and pathophysiological processes in patients with atopic asthma. These observations have led to an interest in the eosinophil as the pathogenic cell responsible for many of the clinical features of asthma including symptoms of wheeze, shortness of breath and cough, along with the physiological events such as airway hyperresponsiveness (AHR) and changes in lung function. IL-5 is one of the key cytokines responsible for eosinopoiesis in the bone marrow, along with recruitment and survival of eosinophils in the tissues. In view of this, IL-5 has been an attractive target for the development of anti-IL-5 monoclonal antibodies, inhibiting its action. The results of preclinical studies are viewed as encouraging. Preclinical development involved studies in mice, guinea-pigs and cynomolgus monkeys, with conflicting results in terms of changes in blood and bronchoalveolar lavage eosinophils, AHR and pulmonary resistance. These may be attributed to interspecies differences and to the different models used. Monoclonal antibodies directed against IL-5 have been used in at least four studies involving patients with asthma. Those preliminary studies have shown clear reductions in both blood and sputum eosinophils but no significant changes in physiological parameters of AHR, the late asthmatic reaction or in lung function or symptoms. As in the animal studies, these results suggest a dissociation between eosinophils, AHR, lung function and symptoms of asthma, which may be explained by the multitude of cells involved in the pathogenesis of asthma.

Cystic fibrosis (CF) is a lethal genetic disease caused by a mutation in a membrane protein, the cystic fibrosis transmembrane conductance regulator (CFTR), which mainly (but not exclusively) functions as a chloride channel. The main clinical symptoms are chronic obstructive lung disease, which is responsible for most of the morbidity and mortality associated with CF, and pancreatic insufficiency. About 1000 mutations of the gene coding for CFTR are currently known; the most common of these, present in the great majority of the patients (Delta508) results in the deletion of a phenylalanine at position 508. In this mutation, the aberrant CFTR is not transported to the membrane but degraded in the ubiquitin-proteasome pathway. The aim of this review is to give an overview of the pharmacologic strategies currently used in attempts to overcome the ion transport defect in CF. One strategy to develop pharmacologic treatment for CF is to inhibit the breakdown of DeltaF508-CFTR by interfering with the chaperones involved in the folding of CFTR. At least in in vitro systems, this can be accomplished by sodium phenylbutyrate, or S-nitrosoglutathione (GSNO), and also by genistein or benzo[c]quinolizinium compounds. It is also possible to stimulate CFTR or its mutated forms, when present in the plasma membrane, using xanthines, genistein, and various other compounds, such as benzamidizoles and benzoxazoles, benzo[c]quinolizinium compounds or phenantrolines. Experimental results are not always unambiguous, and adverse effects have been incompletely tested. Some clinical tests have been done on sodium phenyl butyrate, GSNO and genistein, mostly in respect to other diseases, and the results demonstrate that these drugs are reasonably well tolerated. Their efficiency in the treatment of CF has not yet been demonstrated, however. An alternative strategy is to compensate for the defective chloride transport by CFTR by stimulation of other chloride channels. This can be done via purinergic receptors. A phase I study using a stable uridine triphosphate analog has recently been completed. A second alternative strategy is to attempt to maintain hydration of the airway mucus by inhibiting Na(+) uptake by the epithelial Na(+) channel using amiloride or stable analogs of amiloride. Clinical tests so far have been inconclusive. A number of other suggestions are currently being explored. The minority of patients with CF who have a stop mutation may benefit from treatment with gentamicin. The difficulties in finding a pharmacologic treatment for CF may be due to the fact that CFTR has additional functions besides chloride transport, and interfering with CFTR biosynthesis or activation implies interference with central cellular processes, which may have undesirable adverse effects.

Eosinophilic bronchitis is a common and treatable cause of chronic cough. The major pathological feature is eosinophilic airway inflammation, similar to that seen in asthma. However, the associated airway dysfunction is quite different, with evidence of heightened cough reflex sensitivity, but no variable airflow obstruction or airway hyperresponsiveness. Recent evidence suggests that the differences in functional association are related to differences in localization of mast cells in airway wall, with airway smooth muscle infiltration occurring in asthma and epithelial infiltration in eosinophilic bronchitis. Diagnosis is usually made with induced sputum analysis after exclusion of other causes for chronic cough on clinical, radiological and lung function assessment. The cough responds well to inhaled corticosteroids but dose and duration of treatment remain unclear. Little is known about the natural history of this condition. However, some patients with COPD without a history of previous asthma have sputum eosinophilia, so one possibility is that some cases of eosinophilic bronchitis may develop fixed airflow obstruction. Further study of this interesting condition will increase our understanding of airway inflammation and airway responsiveness, leading to novel targets for therapeutics for both eosinophilic bronchitis and asthma.

Background: The efficacy and safety of Symbicort (budesonide and formoterol in a single inhaler) were compared with those of a high dose of the commonly used corticosteroid fluticasone propionate in patients with moderate persistent asthma.

Methods: This randomized, double-blind, double-dummy, parallel-group study involved 373 patients with asthma (mean age 42 years; FEV(1) 78% of predicted; reversibility 21%). After a 2-week run-in period, during which patients received budesonide 200 microg twice daily, they were randomly assigned to treatment with either Symbicort Turbuhaler (budesonide/formoterol 160/4.5 microg, one inhalation twice daily) or Flovent/Flixotide Diskus (fluticasone propionate 250 microg twice daily) for 12 weeks.

Results: Significantly greater increases in morning PEF, the primary efficacy variable, were observed in patients treated with budesonide/formoterol compared with fluticasone propionate (27.4 L/min vs 7.7 L/min; p < 0.001). Evening PEF and clinic FEV(1) also favored budesonide/formoterol compared with fluticasone propionate (p < 0.001), as did use of reliever medication (p = 0.04) and the proportion of reliever-free days (p < 0.001). There were also numerical improvements in symptom-free days (60.4% vs 55.5%), night-time awakenings (7.9% vs 9.6%) and asthma-control days (57.8% vs 52.4%) in favor of budesonide/formoterol. The risk of an exacerbation was reduced by 32% in the budesonide/formoterol group compared with the fluticasone propionate group (p < 0.05). Both treatments were well tolerated.

Conclusion: Symbicort (budesonide/formoterol in a single inhaler) was more effective than a high dose of fluticasone propionate in improving lung function, reducing use of reliever medication and improving control of moderate persistent asthma.

Leukotriene modifiers have been shown to be efficacious in the treatment of asthma. Because of this success, and the fact that leukotrienes can be recovered not only from bronchoalveolar lavage fluid but also nasal lavage fluid, some researchers have suggested that these medications may also be useful for treating allergic rhinitis. Because the upper and lower airways are linked physically, there has been an assumption that therapy for upper and lower airway disease should be similar. This critical appraisal examines available data both supporting and refuting the emerging role of leukotriene modifiers in the treatment of allergic rhinitis. Although many studies have shown an improvement in nasal symptoms when comparing a leukotriene modifier with placebo, few studies have conclusively shown that a leukotriene modifier is any more effective in treating allergic rhinitis than an antihistamine. Results from several reported studies suggest that the addition of a leukotriene antagonist to an antihistamine is no more efficacious than antihistamine alone. However, many of these studies were small and/or primarily designed to examine the asthmatic response, with nasal symptoms being a lesser endpoint. To better understand how, where, and when leukotriene modifiers should be used in the armamentarium of therapies for allergic rhinitis, larger clinical investigations designed specifically to study allergic rhinitis need to be undertaken. We conclude that currently, the data do not support widespread use of a leukotriene modifier with or without an antihistamine in place of an intranasal corticosteroid with or without an antihistamine in the treatment of allergic rhinitis.

COPD is a common disease with increasing prevalence. The chronic course of the disease is characterized by acute exacerbations that cause significant worsening of symptoms. Bacterial infections play a dominant role in approximately half of the episodes of acute exacerbations of COPD. The importance of pseudomonal infection in patients with acute exacerbations of COPD stems from its relatively high prevalence in specific subgroups of these patients, and particularly its unique therapeutic ramifications. The colonization rate of Pseudomonas aeruginosa in patients with COPD in a stable condition is low.A review of a large number of clinical series of unselected outpatients with acute exacerbations of COPD revealed that P. aeruginosa was isolated from the patients' sputum at an average rate of 4%. This rate increased significantly in COPD patients with advanced airflow obstruction, in whom the rate of sputum isolates of P. aeruginosa reached 8-13% of all episodes of acute exacerbations of COPD. However, the great majority of bacteria isolated in these patients were not P. aeruginosa, but the three classic bacteria Streptococcus pneumoniae, Hemophilus influenzae, and Moraxella catarrhalis. The subgroup of patients, with acute exacerbations of COPD, with the highest rate of P. aeruginosa infection, which approaches 18% of the episodes, is mechanically ventilated patients. However, even in this subgroup the great majority of bacteria isolated are the above-mentioned three classic pathogens. In light of these epidemiologic data and other important considerations, and in order to achieve optimal antibacterial coverage for the common infectious etiologies, empiric antibacterial therapy should be instituted as follows. Patients with acute exacerbations of COPD with advanced airflow obstruction (FEV(1) <50% of predicted under stable conditions) should receive once daily oral therapy with one of the newer fluoroquinolones, i.e. levofloxacin, moxifloxacin, gatifloxacin, or gemifloxacin for 5-10 days. Patients with severe acute exacerbations of COPD who are receiving mechanical ventilation should receive amikacin in addition to one of the intravenous preparations of the newer fluoroquinolones or monotherapy with cefepime, a carbapenem or piperacillin/tazobactam. In both subgroups it is recommended that sputum cultures be performed before initiation of therapy so that the results can guide further therapy.

Background: Noninvasive ventilatory support (NIVS) is intended to provide ventilatory assistance for a wide range of respiratory disturbances. The use of NIVS for treatment of respiratory distress may be applicable in the emergency department (ED). It may prevent endotracheal intubation and, likewise, may favorably influence the course of the patient's hospitalization, depending on the primary disease or ventilatory disturbance.

Objective: To evaluate the efficacy of bilevel positive airway pressure (BiPAP) ventilation in patients with acute respiratory distress presenting in the ED.

Methods: A prospective, uncontrolled, nonrandomized, nonblind study enrolled 30 patients. They were cooperative and hemodynamically stable, aged over 18 years, and presented with acute respiratory distress as defined by predetermined criteria. They were connected to a BiPAP machine through a face mask, using an initial pressure of 8/3 cm H(2)O, which was gradually raised to 12/7 cm H(2)O inspiratory positive airway pressure/expiratory positive airway pressure. Standard drugs, inhalation and oxygen therapies were administered as needed. The BiPAP was disconnected either upon relief of respiratory distress or on deterioration of the patient's condition.

Results: Of the 30 patients in the study, 19 had cardiogenic pulmonary edema, four had acute asthma, three had exacerbation of COPD, three had pneumonia and one had malignant pleural effusion. BiPAP was instituted subsequent to failure of standard therapies. Twenty-six patients were classified as responders to the BiPAP ventilation and four as nonresponders (three patients were intubated after 1 hour and one patient 24 hours, post BiPAP). The total length of stay (LOS) in the ED was 3-5 hours and the mean LOS in hospital was 4.1 +/- 1.5 days, versus 6.5 +/- 1.2 days in LOS reports of similar patients in the same hospital during 1999, who did not undergo BiPAP ventilation. No other complications were observed.

Conclusions: We found BiPAP ventilation simple, safe, effective and well tolerated by patients in respiratory distress. The rate of endotracheal intubation after successful BiPAP ventilation was low. In carefully selected patients with respiratory distress, BiPAP ventilation may successfully replace endotracheal intubation.

Background: A number of different inhaler devices are available to deliver beta(2)-adrenoceptor agonist (beta(2)-agonist) bronchodilators in asthma. These include hydrofluoroalkane or chlorofluorocarbon (CFC)-free propelled pressurized metered-dose inhalers (pMDIs), many dry powder inhalers and breath-actuated inhalers.

Objective: To determine the clinical efficacy of all available hand-held inhaler devices compared with the standard CFC-containing pMDI for the delivery of short-acting beta(2)-agonist bronchodilators in nonacute asthma in both children and adults.

Methodology: A systematic review and meta-analysis was carried out of all available randomized, controlled trials (RCTs) using the standard pMDI compared with any other hand-held inhaler device, delivering short-acting beta(2)-agonist bronchodilators in patients with stable asthma.

Results: One hundred and eighteen RCTs were included in this review. No clinical differences were found between the standard CFC-containing pMDI and 12 other hand-held inhaler devices for most outcome measures. We found no evidence of clinical differences between studies using either a 1 : 1 (pMDI: another inhaler) or a 2 : 1 dosing ratio.

Conclusions: In patients with stable asthma, short-acting beta(2)-agonist bronchodilators in standard CFC-pMDIs are as effective as any other hand-held inhaler device; therefore the cheapest available device that the patient is able to use should always be considered. Pharmaceutical companies should in future submit to regulatory authorities clinical outcome data (as opposed to in vitro data) in support of any dosing schedules greater than 1 : 1 when compared with the standard pMDI. Clinical effectiveness studies that use an intention-to-treat analysis and report more patient-centered outcomes are required.

Infection with Legionella spp. is an important cause of serious community- and hospital-acquired pneumonia, occurring sporadically and in outbreaks. Outbreaks of Legionnaires' disease have recently received considerable media attention, and some factors indicate that the problem will increase in future. Infection with Legionella spp. ranks among the three most common causes of severe pneumonia in the community setting, and is isolated in 1-40% of cases of hospital-acquired pneumonia. Underdiagnosis and underreporting are high. Only 2-10% of estimated cases are reported. Detection of a single case should not be considered an isolated sporadic event, but rather indicative of unrecognized cases. There are no clinical features unique to Legionnaires' disease; however, suspicion should be raised by epidemiologic information commensurate with the diagnosis and the presence of headache, confusion, hyponatremia, elevated creatine kinase and/or severe pneumonia. An arterial oxygen partial pressure <60mm Hg on presentation and progression of pulmonary infiltrates despite appropriate antibacterial therapy should always alert clinicians to this cause.Macrolides, fluoroquinolones and rifampin (rifampicin) are the most widely used drugs in treatment. Fluoroquinolones or azithromycin are the treatment of choice in immunosuppressed patients and those with severe pneumonia. Incorporation of the legionella urinary antigen test in emergency departments in hospitals and progressive improvement in this test will, in the near future, permit appropriate diagnosis and treatment of this frequent, sometimes severe, illness.

Among all nonmetastatic non-small-cell lung cancer (NSCLC) patients, the best survival rates are observed in patients who undergo surgery. Nevertheless, 5-year survival rates vary between 20% and 60% depending on the stage of the disease. Several combined modality treatments have been investigated to improve outcome in localized NSCLC. These include local treatment, systemic before local treatment, concomitant systemic and local treatments, and systemic after local treatment. Preoperative irradiation was shown to be of no benefit on local recurrence rates or overall survival. Even doses of radiation >/=40 grays (Gy) were associated with lower survival rates. Postoperative irradiation did not influence survival in stage III disease and seemed to be deleterious in stages I and II disease. Modern radiotherapy techniques might be of interest in this setting but have been insufficiently tested. The early phase III studies of preoperative chemotherapy versus primary surgery in stage III NSCLC showed a tremendous difference in favor of chemotherapy. A larger study did not confirm these results but suggested that preoperative chemotherapy might have a greater effect in stages I and II of the disease. In locally advanced disease, chemotherapy followed by radiotherapy was shown to increase survival when compared with radiotherapy alone. Studies comparing concurrent chemoradiation with radiotherapy only were in favor of the concomitant schedule, which improved local control. Promising results have been reported with chemoradiation followed by surgery in stage IIIa and even stage IIIb disease. Randomized studies of postoperative chemotherapy demonstrated a 5% improvement in 5-year survival over adjuvant-free treatment. Postoperative chemoradiation showed no advantage over postoperative radiotherapy. Several trials that are ongoing or whose accrual was recently completed should further define the role of perioperative chemotherapy in resectable NSCLC and of trimodality treatments in advanced disease. Targeted agents are being developed in the postoperative setting. New schedules of chemoradiation with higher therapeutic indexes are also being investigated in nonresectable stage III NSCLC.