American journal of respiratory medicine: drugs, devices, and other interventions (Am J Respir Med)
The American Journal of Respiratory Medicine is a peer reviewed journal providing comprehensive coverage of the therapy and management of a wide range of respiratory disorders. The journal publishes up to date, critical reviews and high quality original clinical research relating to the use of drugs, devices, diagnostics and other interventions for the treatment of patients with respiratory disorders. The American Journal of Respiratory Medicine publishes a regular program of independent review articles covering all aspects of the management of respiratory disorders, particularly the place in therapy of newer and established drugs and devices, with the aim of promoting rational therapy and effective patient management within the discipline of respiratory medicine.
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|Other titles||American journal of respiratory medicine (Online)|
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Publications in this journal
- [Show abstract] [Hide abstract] ABSTRACT: 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 (FEV1 <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.
Article: Adult Respiratory Distress Syndrome[Show abstract] [Hide abstract] ABSTRACT: The adult respiratory distress syndrome (ARDS) is a form of acute lung injury that is characterized by florid extravascular fibrin deposition. Thrombosis in the pulmonary vasculature and disseminated intravascular coagulation have also been observed in association with ARDS. Fibrin deposition does not occur in the normal lung but is virtually universal in acute lung injury induced by disparate insults. A large body of basic and preclinical evidence further implicates abnormalities of pathways of fibrin turnover in the pathogenesis of acute inflammation and fibrotic repair. Coagulation is locally upregulated in the injured lung, while fibrinolytic activity is depressed. These abnormalities occur concurrently and favor alveolar fibrin deposition. The systemic derangements of fibrin turnover in sepsis are similar to those that occur in the injured lung. Recent clinical trials demonstrate that interventions using selective anticoagulation can provide a mortality advantage and that selective anticoagulants differ in their ability to provide clinical benefit. Preclinical trials in primates with sepsis-induced ARDS now indicate that anticoagulant interventions that block the extrinsic coagulation pathway can protect against the development of pulmonary fibrin deposition as well as lung dysfunction and acute inflammation. These observations provide proof of principle that key steps in the coagulation cascade are appropriate therapeutic targets to prevent the development of acute lung injury in ARDS. Ongoing studies and prior publications also support the hypothesis that reversal of the fibrinolytic defect in ARDS could protect against the development of acute lung injury. In all, these studies suggest that fibrin deposition in the injured lung as well as abnormalities of coagulation and fibrinolysis are integral to the pathogenesis of ARDS. The ability of selective anticoagulants to effectively and safely alter clinical outcome in ARDS remains to be determined.
- [Show abstract] [Hide abstract] ABSTRACT: Introduction Despite attempts to limit their use, systemic antibiotics are extensively prescribed for respiratory infections in France. This survey analyzed data from the Thales database, which contains information from 1010 representative French general practitioners (GPs). The objective was to assess French GP prescribing patterns in upper respiratory tract infections (URTIs) including the rate of prescription of systemic antibiotics and anti-inflammatory drugs in the presence or absence of prescribing fusafungine (Locabiotal®), an antibiotic with anti-inflammatory activity indicated for local use in URTIs. Drug costs to the French National Sickness Fund were also assessed. Methods This was a retrospective, longitudinal, case-control analysis. Prescribing patterns and costs were compared between patients who did and patients who did not receive fusafungine for a URTI (rhinopharyngitis, tonsillitis, or an influenza-like condition). The fusafungine group consisted of all patients in the database who were prescribed fusafungine at least once between 1 December 1999 and 30 November 2000. The control group was made up of randomly selected patients, matched for age and sex with the study group, who received at least one drug prescription (but not fusafungine) for a URTI during the same period. Patients were selected at the time of their first prescription, and their records for 1 year were analyzed. Results Each group contained 22 164 patients. For URTIs overall, systemic antibiotics were widely prescribed (at a rate of 54.6% and 67.8% in the fusafungine and control groups, respectively; p NSAIDs and corticosteroids per prescription and per episode was significantly lower in the fusafungine group than in the control group. The mean cost per prescription for the French National Sickness Fund was significantly lower for the three URTIs overall when fusafungine was prescribed (9.21 euros [€] vs €9.67; p NSAIDs, and corticosteroids was also significantly lower in the fusafungine group compared with the control group. The cost of nasal preparations was higher in the fusafungine group because Locabiotal® is classified as a nasal preparation. The cost per prescription to the National Sickness Fund was increased by the presence of systemic antibiotics, NSAIDs, or corticosteroids among the prescribed drugs and decreased with the prescription of fusafungine. Conclusion When fusafungine was prescribed for URTIs, fewer systemic antibiotics were prescribed, an important result in the current context of concern about emerging antibiotic resistance. The use of fusafungine was associated with a lower mean cost per prescription to the French National Sickness Fund.
Article: Lung Cancer Screening[Show abstract] [Hide abstract] ABSTRACT: Lung cancer is the second most common cancer and the leading cause of cancer-related deaths in the US. It as been shown that when treated in its early stages, survival rates improve. Despite this, controversy remains regarding screening for the early detection of lung cancer, primarily because mortality reductions were not observed in the trials that studied chest x-ray and sputum cytology. Nevertheless, renewed interest in screening, due in part to better screening options, has prompted further research exploring the potential cost-effectiveness of implementing lung cancer screening programs. This article provides a critical review of the literature of economic evaluations of lung cancer screening programs. The focus of this review is the methodology implemented in these studies. Based on an electronic search of the literature (Pubmed, Medline and CancerLit) from Sep 1988–Sep 2001, seven articles that quantified the cost-effectiveness of lung cancer screening programs were identified. For most of the studies, the cost-effectiveness aspect was a minor component with little or no description of the methods. Although some studies focused more on estimating the economic efficiency of screening, their methodology was weak and still not well documented. Only two studies implemented fully a cost-effectiveness analysis and provided the necessary level of detail. If consensus can be reached regarding the clinical benefit of lung cancer screening, future studies related to cost-effectiveness would have to be implemented on much sounder methodology. The publications reviewed do provide preliminary support for the economic efficiency of screening for lung cancer.
Article: β2-Agonist Eutomers[Show abstract] [Hide abstract] ABSTRACT: β2-adrenoceptor agonists (β2-agonists) such as albuterol (salbutamol) and terbutaline and their long-acting analogs salmeterol and formoterol are widely used as bronchodilators in the treatment of asthma. They are chiral drugs historically marketed as racemic mixtures of an active (eutomer) and essentially inactive (distomer) stereoisomer. Despite their obvious therapeutic value and widespread use, β2-agonists have been implicated, somewhat controversially, in causing an increase in asthma mortality and a deterioration of asthma control by a mechanism that remains elusive. Inherent toxicity of the distomers has been widely touted as an explanation and has given rise to pressure for the replacement of the racemates with pure eutomer formulations (the so-called chiral or racemic switch). This has culminated in the recent introduction into clinical practice of the single active stereoisomer of albuterol (levalbuterol) and the promise of other pure β2-agonist eutomer formulations to follow. This article examines the evidence on which these chiral switches are based. Clinical studies designed to reveal negative effects of β2-agonists have searched for reductions in lung function, increases in airway responsiveness to bronchoconstrictor mediators and worsening of asthma control. Crossover studies administering the pure stereoisomers and racemate of albuterol have not shown a clear superiority of the pure eutomer formulation over the racemate in terms of either bronchial hyperresponsiveness, tachyphylaxis to bronchoprotective effects or improvements in lung function. Clinical toxicity of β2-agonist distomers on any aspect of asthmatic lung function has also not been demonstrated in the relatively short-term inhalational studies (single dose or repeated dose studies <1 week) that have been carried out. In animal studies, the administration of β2-agonist racemates and distomers has been shown to enhance bronchial hyperresponsiveness but only in ovalbumin-sensitized animals where the relevance to humans is questionable. The pharmacokinetics and metabolism of β2-agonist stereoisomers appear to be essentially similar whether administered as single stereoisomers or as racemates. Levalbuterol may be slightly more potent than an equivalent dose given as racemate, but there is some evidence that it forms a small amount of the distomer in vivo which detracts somewhat from its purported benefits over use of the racemate. Whilst there remains a clear need for studies of longer duration with sensitive clinical endpoints to evaluate the benefits of β2-agonist eutomers and to investigate distomer toxicity, the chiral switch for β2-agonists in general, and for albuterol in particular, does not appear to be justified on the basis of the evidence available to date.
- [Show abstract] [Hide abstract] ABSTRACT: Evidence suggests that allergy is a significant triggering factor in asthma in children and adults alike. In immunoglobulin (Ig) E-mediated allergic reactions, sensitization occurs when allergen-specific B cells are stimulated and switched to IgE antibody production by interleukin (IL)-4 and IL-13 provided by helper T cells type 2 (Th2). The IgE antibodies act by arming cells bearing either the high-affinity (FcεRI) or low-affinity (FcεRII or CD23) receptor. The subsequent interaction of allergen with IgE-FcεRI complexes on mast cells and basophils causes cross-linking of receptors that triggers the release of a variety of inflammatory mediators, cytokines and chemokines. Therefore, the ability to lower circulating free IgE levels is desirable because most individuals are exposed to multiple allergens to which they are sensitive at any given time. Omalizumab (formerly known as rhuMAb-E25) is a recently developed humanized monoclonal anti-IgE antibody directed at the FcεRI binding domain of human IgE. It inhibits binding of IgE to mast cells without provoking mast cell activation. Preliminary clinical data from randomized controlled trials have shown that the addition of omalizumab to standard asthma therapy reduces asthma exacerbations and decreases inhaled corticosteroid and rescue medication use. The compound is also well tolerated. Omalizumab represents a novel therapeutic approach in the management of asthma.
- [Show abstract] [Hide abstract] ABSTRACT: Non-small cell lung cancer (NSCLC) is cured with surgery in a minority of affected persons. Chemotherapy and radiation can palliate and extend survival of patients with disease not amenable to surgery. Consequently, new treatment options are urgently needed. In the era of molecularly targeted therapeutics, the recent direction in cancer research has been to identify and modulate specific events in tumorigenesis. Angiogenesis, or new vessel formation, is one such event elucidated to be fundamental to the development, growth, and metastasis of cancers and is one of the characteristics that differentiates tumor from host. Thus, targeting of tumor neovasculature continues to generate tremendous enthusiasm and effort in drug development. Extensive research into the role of angiogenesis in NSCLC has produced a host of novel targets; their potential inhibitors, now numbering over 40, are in various phases of clinical testing around the world. The current lead compounds include inhibitors of matrix metalloproteinases, angiogenic growth factors and their receptor tyrosine kinases. Despite their impressive activity in animal models, definitive evidence of their antitumor activity in humans is yet to be established. We face several challenges as we look to advance the field of antiangiogenesis for the treatment of cancer, namely, the need for a better understanding of the optimal timing and dosing of antiangiogenic agents, the validation of imaging and quantification methods of tumor angiogenesis, and a new clinical trials design for a more expedient evaluation of novel cytostatic target modulators.
- [Show abstract] [Hide abstract] ABSTRACT: Patients with community-acquired pneumonia (CAP) are treated in hospital or in the ambulatory care setting depending on the severity of illness. Despite numerous guidelines proposed, there is no agreement on specific criteria for hospitalization other than the clinicians’ experience. The purpose of this review is to discuss the importance of the appropriate choice and timely administration of antibacterial agents, either in the hospital or in the outpatient setting. Since a high proportion of CAP patients will not have an etiologic agent identified at the time of initiation of treatment, the choice of antibacterial therapy is usually empiric. Antibacterial agents with activity against pneumococci and atypical pathogens causing pneumonia are the preferred choices. Macrolides, doxycycline, or respiratory fluoroquinolones have been recommended by various guidelines committees in North America for the treatment of pneumonia in patients with or without underlying comorbidities. Because of the increasing resistance to β-lactams as well other antibacterial agents such as macrolides, doxycycline, and sulfamethoxazole/trimethoprim (cotrimoxazole), it is important that clinicians are aware of local statistics on resistance to Streptococcus pneumoniae, as infection with this bacterium is associated with high rates of morbidity and mortality. More recently, fluoroquinolone resistance has been reported, but the percentage of pneumococcal strains resistant to this agent is relatively low compared with the other antibacterial agents. Switch (intravenous to oral) therapy is recommended for hospitalized patients with CAP to facilitate early discharge, which has been shown to improve patient satisfaction and reduce hospital costs. Early conversion to oral therapy has not been shown to be associated with increased complications or higher mortality. Following prompt intravenous therapy and stabilization, patients with CAP should be treated with oral therapy in the ambulatory setting.
- [Show abstract] [Hide abstract] ABSTRACT: It is important to find interventions that will reduce the frequency and severity of exacerbations of COPD, because of their effect on morbidity and healthcare expenditure. A Cochrane systematic review included 23 studies that had evaluated the effects of treatment with mucolytic agents in patients with chronic bronchitis or COPD. Mucolytic treatment was associated with a significant reduction of 0.79 exacerbations per patient per year compared with placebo, a 29% decrease. Patients who received treatment with mucolytic agents were twice as likely to remain exacerbation-free in the study period than if they had received placebo, with six patients needing regular treatment with mucolytic agents for 3–6 months to achieve one less exacerbation over that time. Treatment with mucolytic agents resulted in nearly 7 days less illness per patient per year. How mucolytic agents work is unknown, although they may reduce exacerbations by altering mucus production, antioxidation, or antibacterial or immunostimulatory effects. They do not appear to affect the decline in lung function that occurs in COPD. The treatment appears to be without any adverse effects, apart from the need to take oral medication daily. Cost-effectiveness analysis suggests that the point at which the costs of treatment and non-treatment were equal was 1.2 less exacerbations per year. This is higher than the effect observed in the Cochrane review, suggesting that treating everyone with COPD with mucolytic agents would not be cost effective. Those with more frequent and severe exacerbations appear to have the most to gain.
Article: New and Emerging Antifungal Agents[Show abstract] [Hide abstract] ABSTRACT: Fungal pathogens are increasingly important causes of respiratory disease, yet the number of antifungal agents available for clinical use is limited. Use of amphotericin B deoxycholate is hampered by severe toxicity. Triazole agents currently available have significant drug interactions; fluconazole has a limited spectrum of activity and itraconazole was, until recently, available only in oral formulations with limited bioavailability. The development of resistance to all three agents is increasingly being recognized and some filamentous fungi are resistant to the action of all of these agents. In the past few years, new antifungal agents and new formulations of existing agents have become available. The use of liposomal amphotericin B preparations is associated with reduced, but still substantial, rates of nephrotoxicity and infusion-related reactions. An intravenous formulation of itraconazole has been introduced, and several new triazole agents have been developed, with the view of identifying agents that have enhanced potency, broader spectra of action and improved pharmacodynamic properties. One of these, voriconazole, has completed large-scale clinical trials. In addition, caspofungin, the first of a new class of agents, the echinocandins, which inhibit cell wall glucan synthesis, was approved for use in the US in 2001 as salvage therapy for invasive aspergillosis. It is hoped that the availability of these agents will have a significant impact on the morbidity and mortality of fungal respiratory infections. However, at the present time, our ability to assess their impact is limited by the problematic nature of conducting trials for antifungal therapy.
Article: Formoterol[Show abstract] [Hide abstract] ABSTRACT: Abstract Inhaled formoterol is a long-acting selective β2-adrenoceptor agonist, with an onset of action of 5 minutes postdose and a bronchodilator effect that lasts for at least 12 hours. Statistically significant and clinically relevant (> 120ml) improvements in lung function [assessed using standardized/normalized area under the forced expiratory volume in 1 second (FEV1) versus time curve (AUC FEV1)] were observed with inhaled formoterol 12μg twice daily (the approved dosage in the US) compared with placebo in 12-week and 12-month, randomized, double-blind trials in patients with chronic obstructive pulmonary disease (COPD). The bronchodilator efficacy of formoterol 12μg twice daily was greater than that of oral slow-release theophylline (individualized dosages) in a 12-month trial or inhaled ipratropium bromide 40μg four times daily in a 12-week trial. Improvement in AUC FEV1 with formoterol, but not theophylline, compared with placebo was observed in patients with irreversible or poorly-reversible airflow obstruction. Formoterol also significantly improved health-related quality of life compared with ipratropium bromide or placebo and significantly reduced symptoms compared with placebo. Combination therapy with formoterol 12μg twice daily plus ipratropium bromide 40μg four times daily was significantly more effective than albuterol (salbutamol) 200μg four times daily plus the same dosage of ipratropium bromide in a 3-week, randomized, double-blind, double-dummy, crossover trial. Inhaled formoterol was well tolerated in clinical trials. The incidence of investigator-determined drug-related adverse events with inhaled formoterol 12μg twice daily was similar to that with placebo and inhaled ipratropium bromide 40μg four times daily but lower than that with oral slow-release theophylline (individualized dosages). Importantly, there were no significant differences between formoterol and placebo or comparator drugs in cardiovascular adverse events in patients with COPD and corrected QT interval values within the normal range. In conclusion, inhaled formoterol improved lung function and health-related quality of life and reduced symptoms relative to placebo in clinical trials in patients with COPD. The drug had greater bronchodilator efficacy than oral slow-release theophylline or inhaled ipratropium bromide and showed efficacy in combination with ipratropium bromide. The adverse events profile (including cardiovascular adverse events) with formoterol was similar to that with placebo. Thus, inhaled formoterol may be considered as a first-line option for the management of bronchoconstriction in patients with COPD who require regular bronchodilator therapy for the management of symptoms. Pharmacodynamic Properties Inhaled formoterol is a long-acting selective β2-adrenoceptor agonist (β2-agonist); it has a rapid onset of action (5 minutes in single- and multiple-dose studies) and, like salmeterol, maintains a bronchodilator effect for at least 12 hours. The onset of postdose bronchodilator action was faster with formoterol 12μg than with salmeterol 100μg in a double-blind, randomized, placebo-controlled trial. Formoterol 6 to 24μg improved forced expiratory volume in 1 second (FEV1) compared with baseline and placebo in single-dose crossover trials in patients with chronic obstructive pulmonary disease (COPD), and was at least as effective as salmeterol 50 or 100μg or albuterol (salbutamol) 400μg at improving FEV1. Mean peak FEV1 was reached 1 hour after inhalation of formoterol 12μg; values for this parameter were 1 hour after albuterol 200μg, and 2 to 5 hours after salmeterol 50μg. Formoterol 4.5 to 18μg twice daily for 1 week prolonged the time to exhaustion on a bicycle ergometer test compared with placebo; results were similar to those for ipratropium bromide 80μg three times daily. All β2-agonists have the potential to increase heart rate and plasma glucose concentrations, and to decrease plasma potassium concentrations, through effects on extrapulmonary β2 receptors. Dose-dependent increases in heart rate, corrected QT (QTc) interval and plasma glucose concentrations, and dose-dependent decreases in plasma potassium concentrations, were observed with inhaled formoterol 24 to 96μg or salmeterol 100 to 400μg in a double-blind, placebo-controlled, crossover trial in 16 healthy volunteers. In patients with COPD, pre-existing mild to moderate cardiac arrhythmias and hypoxemia [PaO2 (arterial oxygen pressure) <60mm Hg], formoterol 12μg had similar systemic effects to salmeterol 50μg. Complex ventricular arrhythmias were observed in formoterol 12 and 24μg recipients, but not in salmeterol 50μg or placebo recipients. Pharmacokinetic Properties The maximum plasma concentration (92 ng/L) of formoterol was reached within 5 minutes of inhalation of a single supraoptimal dose (120μg) in 12 healthy volunteers. Urinary excretion data suggest that absorption was linear with inhaled formoterol 12 to 96μg in ten healthy volunteers. In vitro plasma protein binding of formoterol was 61 to 64% at concentrations 0.1 to 100 μg/L. Mean plasma concentrations of the drug at 10 minutes to 6 hours postinhalation were 4.0 to 8.8 ng/L and 8.0 to 17.3 ng/L, respectively, after multiple doses of formoterol 12 or 24μg administered twice daily for 12 weeks in patients with COPD, with some evidence of accumulation of formoterol in the plasma (accumulation index 1.19 to 1.38). Formoterol is metabolized primarily in the liver by four cytochrome P450 (CYP) isoenzymes (CYP2D6, CYP2C19, CYP2C9 and CYP2A6). These enzymes were not inhibited by the drug at therapeutic concentrations. Following inhalation of formoterol 12 or 24μg by 18 patients with COPD, 7% of the total dose was excreted in the urine as unchanged drug and 6 to 9% of the total dose was eliminated as direct conjugates of formoterol. The mean terminal elimination half-life was determined to be 10 hours (based on plasma concentrations) following inhalation of single-dose formoterol 120μg by 12 healthy volunteers. Currently, there are no pharmacokinetic data for the use of formoterol in patients with hepatic or renal impairment or in elderly individuals. Therapeutic Efficacy Inhaled formoterol has been evaluated as monotherapy or combination therapy for the management of patients with COPD. In clinical trials, COPD was diagnosed using the American Thoracic Society guidelines. The bronchodilator effect [measured as normalized area under the FEV1 versus time curve (AUC FEV1)] with formoterol 12μg twice daily (n = 194) was significantly greater than that with ipratropium bromide 40μg four times daily (n = 194; p = 0.001) or placebo (n = 200; p < 0.001) in a randomized, double-blind, 12-week trial in patients with COPD. Significant improvements were also observed in mean morning premedication peak expiratory flow (PEF; p 20%; p < 0.001) in formoterol compared with ipratropium bromide recipients. The differences in health-related quality of life between the two treatments were clinically relevant (exceeding 4 points) for the Activity and the Impacts domains of the SGRQ. Compared with oral slow-release theophylline (individualized dosages targeted at plasma concentrations of 8 to 20 mg/L), formoterol 12μg twice daily significantly increased standardized AUC12h FEV1 (primary end-point; p = 0.026) and mean morning premedication PEF (p ≤ 0.020) and reduced the percentage of ‘bad days’ (p ≤ 0.035) in a randomized, double-blind (with the exception of the theophylline arm), 12-month trial. A subgroup analysis in this trial indicated that at 3 (p = 0.007) and 12 months (p = 0.002), formoterol (n = 118), but not oral slow-release theophylline (n = 105), produced significant bronchodilation compared with placebo (n = 117) in patients with irreversible or poorly-reversible airflow obstruction (i.e. patients whose FEV1 values increased <15% after receiving albuterol). Both formoterol (p ≤ 0.026) and oral slow-release theophylline (p ≤ 0.013) were significantly more effective than placebo at managing COPD during the night (measured as morning premedication FEV1). In these two monotherapy trials, inhaled formoterol 24μg twice daily did not provide any additional benefit over the 12μg twice daily dosage in patients with COPD. The combined efficacy of inhaled formoterol 12μg twice daily plus inhaled ipratropium bromide 40μg four times daily for 3 weeks has been compared with that of albuterol 200μg four times daily for 3 weeks via a pressurized metered-dose inhaler plus inhaled ipratropium bromide 40μg four times daily in a randomized, double-blind, double-dummy, crossover trial in 172 patients with COPD. Formoterol combination therapy was significantly more effective than albuterol combination therapy at increasing mean morning premedication PEF (primary endpoint; p = 0.0003). Combination therapy with formoterol was also more effective according to secondary endpoints, significantly increasing postmedication FEV1 to 6 hours (p< 0.0001), peak postmedication FEV1 (p < 0.0001) and AUC FEV1 (p < 0.0001) and improving symptoms of COPD (measured as mean total symptoms score, p = 0.0042) and the SGRQ symptoms score (p = 0.0408) relative to albuterol combination therapy. Tolerability Inhaled formoterol was well tolerated in clinical trials in patients with COPD. The percentage of patients experiencing at least one adverse event with inhaled formoterol 12μg twice daily was similar to that with placebo, inhaled ipratropium bromide 40μg four times daily or oral slow-release theophylline (individualized dosages targeted at plasma concentrations of the drug of 8 to 20 mg/L) in randomized, double-blind, comparative trials of 12 weeks’ and 12 months’ duration. Viral infection, exacerbation of COPD, bronchitis, upper respiratory tract infection, dyspnea and headache were the most commonly reported adverse events (i.e. occurring in >5% of formoterol 12μg twice daily recipients); however, the incidence of these events was not significantly different compared with oral slow-release theophylline or placebo. Drug-related adverse events, serious adverse events and events leading to withdrawal from the study occurred with a similar incidence with inhaled formoterol, placebo or ipratropium bromide. In contrast, drug-related adverse events and withdrawal because of adverse events occurred with a higher incidence in patients receiving oral slow-release theophylline in the 12-month trial. There were no significant differences in the incidence of cardiovascular adverse events with inhaled formoterol (0.5% of patients) compared with inhaled placebo (2.5%) or ipratropium bromide (2.6%) after 12 weeks’ treatment or in the incidence of serious cardiovascular adverse events with inhaled formoterol (2.4% of patients) compared with placebo (0.9%) or oral slow-release theophylline (2.4%) after 12 months’ treatment in patients with COPD and QTc interval values within the normal range; heart rate and rhythm disorders were infrequent. The incidences of QTc interval prolongation (>0.46s), ECG abnormalities or clinically relevant changes in serum potassium or fasting plasma glucose concentrations were similar with inhaled formoterol 12μg twice daily compared with placebo, inhaled ipratropium bromide or oral slow-release theophylline in clinical trials. Dosage and Administration Formoterol, inhaled orally using an Aerolizer™1 inhaler, is indicated in the US for the long-term maintenance treatment of bronchoconstriction associated with COPD (including chronic bronchitis and emphysema). The recommended dosage of formoterol in this patient group is 12μg twice daily approximately 12 hours apart; the total daily dose should not exceed 24μg. Formoterol should be used with caution in patients with cardiovascular disorders (especially coronary insufficiency, cardiac arrhythmias or hypertension), convulsive disorders or thyrotoxicosis, or hypersensitivity to sympathomimetic amines. Extreme caution is advised if formoterol is used concomitantly with monoamine oxidase inhibitors, tricyclic antidepressants or drugs that are known to prolong the QTc interval, and caution is recommended with the concomitant use of formoterol and non-potassium-sparing diuretics.
Article: The Dilemma of Occupational Rhinitis[Show abstract] [Hide abstract] ABSTRACT: Occupational rhinitis is a common heterogeneous group of inflammatory conditions in the nose, caused by exposure to airborne irritants and sensitizers in the occupational environment. The mechanism can be allergic, neurogenic or toxic. Data from several epidemiologic studies indicate that animal dander, organic dusts, latex and chemicals can cause occupational rhinitis, but because of methodological problems as well as weaknesses in the definition of occupational rhinitis, occupational exposure is probably an underestimated cause of rhinitis. The effect of rhinitis on the mental aspects of quality of life and substantial costs due to loss of productivity make it important to diagnose and treat occupational rhinitis. Diagnosis relies on a history of exposure, skin prick testing and, if possible, nasal provoacation. Avoidance of exposure, protective measures at the workplace and medical treatment, with agents such as second generation antihistamines and nasal corticosteroids, can make it possible to avoid progress of the disease from rhinitis to asthma. The efficacies of montelukast, a leukotrienne receptor antagonist, and omalizumab, an anti-immunoglobulin E monoclonal antibody in the treatment of occupational rhinitis are yet to be evaluated
Article: Adverse Effects of β-Agonists[Show abstract] [Hide abstract] ABSTRACT: Inhaled β2-adrenoceptor agonists (β2-agonists) are the most commonly used asthma medications in many Western countries. Minor adverse effects such as palpitations, tremor, headache and metabolic effects are predictable and dose related. Time series studies suggested an association between the relatively nonselective β-agonist fenoterol and asthma deaths. Three case-control studies confirmed that among patients prescribed fenoterol, the risk of death was significantly elevated even after controlling for the severity of asthma. The Saskatchewan study not only found an increased risk of death among patients dispensed fenoterol, but also suggested this might be a class effect of β2-agonists. However, in subsequent studies, the long-acting β2-agonist salmeterol was not associated with increased asthma mortality. In a case-control study blood albuterol (salbutamol) concentrations were found to be 2.5 times higher among patients who died of asthma compared with controls. It is speculated that such toxic concentrations could cause tachyarrhythmias under conditions of hypoxia and hypokalemia. The risk of asthma exacerbations and near-fatal attacks may also be increased among patients dispensed fenoterol, but this association may be largely due to confounding by severity. Although salmeterol does not appear to increase the risk of near-fatal attacks, there is a consistent association with the use of nebulized β2-agonists. Nebulized and oral β2-agonists are also associated with an increased risk of cardiovascular death, ischemic heart disease and cardiac failure. Caution should be exercised when first prescribing a β-agonist for patients with cardiovascular disease. A potential mechanism for adverse effects with regular use of β2-agonists is tachyphylaxis. Tachyphylaxis to the bronchodilator effects of long-acting β2-agonists can occur, but has been consistently demonstrated only for formoterol (eformoterol) a full agonist, rather than salmeterol, a partial agonist. Tachyphylaxis to protection against induced bronchospasm occurs with both full and partial β2-agonists, and probably within a matter of days at most. Underlying airway responsiveness to directly acting bronchoconstricting agents is not increased when the bronchodilator effect of the regular β2-agonist has been allowed to wear off, although there may be an increase in responsiveness to indirectly acting agents. While there has been speculation that underlying airway inflammation in asthma may be made worse by regular use of short-acting β2-agonists, in contradistinction, a number of studies have shown that long-acting β2-agonists have positive anti-inflammatory effects. An Australian Cochrane Airways Group systematic review of the randomized, controlled trials of short-acting β-agonists found only minimal and clinically unimportant differences between regular use and use as needed. Regular short-acting treatment was better than placebo. However, a subsequent systematic review has found that regular use of long-acting β-agonists had significant advantages over regular use of short-acting β-agonists. More studies and data are needed on the regular use of β2-agonists in patients not taking inhaled corticosteroids, and in potentially vulnerable groups, such as the elderly and those with particular genotypes for the β-receptor, who might be more prone to adverse effects.
- [Show abstract] [Hide abstract] ABSTRACT: Cystic fibrosis (CF), is an autosomal recessive disease frequently seen in the Caucasian population. It is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CF is characterized by enhanced airway Na+ absorption, mediated by epithelial Na+ channels (ENaC), and deficient Cl− transport. In addition, other mechanisms may contribute to the pathophysiological changes in the CF lung, such as defective regulation of HCO3− secretion. In other epithelial tissues, epithelial Na+ conductance is either increased (intestine) or decreased (sweat duct) in CF. CFTR is a cyclic AMP-regulated epithelial Cl− channel, and appears to control the activity of several other transport proteins. Accordingly, defective epithelial ion transport in CF is likely to be a combination of defective Cl− channel function and impaired regulator function of CFTR, which in turn is linked to impaired mucociliary clearance and development of chronic lung disease. As the clinical course of CF is determined primarily by progressive lung disease, novel pharmacological strategies for the treatment of CF focus on correction of the ion transport defect in the airways. In recent years, it has been demonstrated that activation of purinergic receptors in airway epithelia by extracellular nucleotides (adenosine triphosphate/uridine triphosphate) has beneficial effects on mucus clearance in CF. Activation of the dominant class of metabotropic purinergic receptors, P2Y2 receptors, appears to have a 2-fold benefit on ion transport in CF airways; excessive Na+ absorption is attenuated, most likely by inhibition of the ENaC and, simultaneously, an alternative Ca2+-dependent Cl− channel is activated that may compensate for the CFTR Cl− channel defect. Thus activation of P2Y2 receptors is expected to lead to improved hydration of the airway surface liquid in CF. Furthermore, purinergic activation has been shown to promote other components of mucociliary clearance such as ciliary beat frequency and mucus secretion. Clinical trials are under way to test the effect of synthetic purinergic compounds, such as the P2Y2 receptor agonist INS37217, on the progression of lung disease in patients with CF. Administration of these compounds alone, or in combination with other drugs that inhibit accelerated Na+ transport and help recover or increase residual activity of mutant CFTR, is most promising as successful therapy to counteract the ion transport defect in the airways of CF patients.
- [Show abstract] [Hide abstract] ABSTRACT: Background: A number of different inhaler devices are available to deliver β2-adrenoceptor agonist (β2-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 β2-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 β2-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 β2-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.
Article: Macrolides in Cystic Fibrosis[Show abstract] [Hide abstract] ABSTRACT: A spectrum of anti-inflammatory properties, evidence of anti-infective action against Pseudomonas aeruginosa at sub-inhibitory concentrations and positive clinical experience in patients with diffuse panbronchiolitis, a disease with features in common with cystic fibrosis (CF), has prompted research to evaluate the role of macrolide therapy in patients with CF. Newer macrolides such as azithromycin have the advantage of improved tolerability and a prolonged intracellular half-life requiring an infrequent dosing regimen. Results from initial studies suggest a benefit from several months of macrolide therapy in patients with CF. An improvement in lung function was initially shown in a small open study in children, while maintenance of lung function compared with placebo, reduced acute respiratory exacerbations, and reduced systemic markers of inflammation were demonstrated in a randomized, placebo-controlled study of macrolide therapy in adult patients with CF. Additional controlled studies are required to determine optimal drug, dosage, and duration of therapy, and long-term adverse effects of prolonged therapy with macrolides in patients with CF. The potential, with long-term use, to induce resistance against other bacteria colonizing the upper respiratory tract e.g. pneumococci has not been explored. Measurement of cytokines and inflammatory mediators from the sputum of patients with CF is technically difficult and does not correlate with disease activity. There is a need for easily measurable, reproducible and clinically meaningful end-points for evaluation of new therapies in CF. The choice of appropriate outcome measures, apart from lung function, to monitor disease activity needs careful consideration in clinical trials determining the efficacy of macrolides in patients with CF. Evidence-based recommendations for the use of macrolides in the treatment of CF are not expected for some years although macrolides are already being prescribed for long-term use in some centers. There is a need for further research into mechanisms of anti-inflammatory action of macrolides in the lungs of patients with CF and whether or not such therapy may be beneficial in the long term.
Article: Peptide Receptor Imaging[Show abstract] [Hide abstract] ABSTRACT: Radiolabeled cell-surface peptide receptor-binding molecules are emerging as an important class of radiopharmaceuticals. Their binding to specific cell membrane receptors allows for noninvasive assessment of regional receptor proteomics in vivo. Information thus obtained can be used for diagnostic purposes and for predicting and monitoring response to treatment. This paradigm also applies to pulmonary diseases. In this review, available radiopharmaceuticals of great potential or already in clinical use for imaging of lung cancer, lung inflammation and infection and pulmonary embolism are discussed. In lung cancer, somatostatin receptor imaging by means of technetium-99m (99mTc)-octreotide scintigraphy has proven useful for characterizing malignancy in solitary pulmonary nodules. Additionally, several radiopharmaceuticals targeting tyrosine-kinase, e.g. 99mTc labeled epidermal growth factor and indium-111 (111In)-diethylene triamine penta-acetic acid-trastuzumab, or G-protein coupled receptors, e.g. 99mTc-bombesin, iodine-123-vasoactive intestinal peptide and 111In-tetraazacyclododecane tetra-acetic acid (DOTA)-cholecystokinine-B, are being explored for their diagnostic as well as treatment monitoring potential. With the purpose of better evaluating the source of pulmonary embolism, as well as to differentiate acute from chronic deep venous thrombosis, several radiolabeled peptides targeting the glycoprotein IIb/IIIa fibrinogen receptor found on activated platelets have been developed. Out of these, 99mTc-P280 is now approved by the US Food and Drug Administration for scintigraphic imaging of suspected acute venous thrombosis in the lower extremities of patients. In the field of lung inflammation and infection, non-specific 111In and 99mTc-human polyclonal immunoglobulins have been successfully used to identify the presence and extent of Pneumocystis carinii, cytomegalovirus, Mycobaterium avium and fungal infections in patients with HIV infection. The clinical role of other radiopharmaceuticals such as 99mTc-J001X, a nonpyrogenic acylated polygalactoside isolated from Klebsiella pneumoniae and binding with high affinity to CD11b and CD14 lipopolysaccharide receptors expressed on monocytes/macrophages, and 111In-octreotide, binding to up-regulated somatostatin receptors on activated lymphocytes needs to be further defined.
Article: Legionnaires’ Disease[Show abstract] [Hide abstract] ABSTRACT: 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.
Article: Obstructive Sleep Apnea in Children[Show abstract] [Hide abstract] ABSTRACT: Obstructive sleep apnea (OSA) is a common condition of childhood, and is associated with significant morbidity. Prevalence of the condition peaks during early childhood, due in part to adenoidal and tonsillar enlargement within a small pharyngeal space. The lymphoid tissues regress after 10 years of age, in the context of ongoing bony growth, and there is an associated fall in the prevalence of OSA. Obstruction of the nasopharynx by adenoidal enlargement promotes pharyngeal airway collapse during sleep, and the presence of large tonsils contributes to airway obstruction. Administration of systemic corticosteroids leads to a reduction in the size of lymphoid tissues due to anti-inflammatory and lympholytic effects. However, a short course of systemic prednisone has been demonstrated not to have a significant effect on adenoidal size or the severity of OSA, and adverse effects preclude the long-term use of this therapy. Intranasal corticosteroids are effective in relieving nasal obstruction in allergic rhinitis, and allergic sensitization is more prevalent among children who snore than among those who do not snore. Intranasal corticosteroids have also been demonstrated to reduce adenoidal size, independent of the individual’s atopic status. There is preliminary evidence of an improvement in the severity of OSA in children treated with intranasal corticosteroids, but further studies are needed before such therapy can be routinely recommended. Prescribing clinicians should take into account the potential benefits to the patient, the age of the child, the presence of comorbidities such as allergic rhinitis, the agent used, and the dose and duration of treatment when considering such therapy.
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