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

Asthma is a chronic inflammatory disease of the airways that affects approximately 100 million people worldwide. In order to reduce symptoms, improve pulmonary function, and decrease morbidity, current treatment guidelines emphasize the importance of controlling the underlying inflammation in patients with asthma. Leukotrienes are leukocyte-generated lipid mediators that promote airway inflammation. Recognition of the importance of leukotrienes in the pathogenesis of asthma has led to the development of leukotriene modifiers, the first new class of drugs for the treatment of asthma to become available in 25 years. Controlled clinical trials with the four currently used leukotriene modifiers (montelukast, zafirlukast, and zileuton in the US and pranlukast in Japan) have established their efficacy in improving pulmonary function, reducing symptoms, decreasing night-time awakenings, and decreasing the need for rescue medications. They exert anti-inflammatory effects that attenuate cellular infiltration and bronchial hyperresponsiveness and complement the anti-inflammatory properties of inhaled corticosteroids. In patients with moderate and severe asthma, they permit tapering of the corticosteroid dose. In patients with exercise-induced asthma, leukotriene modifiers limit the decline in and quicken the recovery of pulmonary functions without the tolerance issues seen with chronic long-acting beta(2)-adrenoceptor agonist use. In patients with aspirin (acetylsalicylic acid)-induced asthma, they improve pulmonary function and shift the dose response curve to the right, reducing the patient's response to aspirin. In patients with seasonal allergic rhinitis, with or without concomitant asthma, they improve nasal, eye, and throat symptoms as well as quality of life. Leukotriene modifiers are generally safe and well tolerated with adverse effect profiles similar to that of placebo. The one safety issue raised with leukotriene modifiers, Churg-Strauss Syndrome, appears to be the unmasking of an already present syndrome that is manifested when the leukotriene modifiers permit corticosteroid doses to be reduced. Although current treatment guidelines recommend their use in patients with mild persistent asthma, these guidelines were developed just as leukotriene modifiers were coming to the market, before much of the clinical efficacy data were published. Because asthma is a heterogeneous disease, the different asthma phenotypes respond differently to therapies; consequently asthma therapy needs to be individualized. Leukotriene modifiers increase the therapeutic options for patients with asthma and, based on recent data, it is expected that future guidelines will describe expanded uses for these agents in clinical circumstances where these drugs are effective.

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 < 0.01). The rate of prescription of systemic antibiotics, 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 [euro] vs euro9.67; p < 0.01). The mean cost to the National Sickness Fund per prescription of systemic antibiotics, 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.

Inhaled beta(2)-adrenoceptor agonists (beta(2)-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 beta-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 beta(2)-agonists. However, in subsequent studies, the long-acting beta(2)-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 beta(2)-agonists. Nebulized and oral beta(2)-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 beta-agonist for patients with cardiovascular disease. A potential mechanism for adverse effects with regular use of beta(2)-agonists is tachyphylaxis. Tachyphylaxis to the bronchodilator effects of long-acting beta(2)-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 beta(2)-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 beta(2)-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 beta(2)-agonists, in contradistinction, a number of studies have shown that long-acting beta(2)-agonists have positive anti-inflammatory effects. An Australian Cochrane Airways Group systematic review of the randomized, controlled trials of short-acting beta-agonists found only minimal and clinically unimportant differences between regular use and use as needed. Regular short-acting treatment was better

Modern sleep medicine has been in existence for only 20 years and therefore has to be regarded as a comparatively recent field of specialization. For this reason it is not surprising that there are numerous new trends and developments concerning the treatment of sleep-related breathing disorders. This review focuses on developments in the treatment of obstructive sleep apnea (OSA) over the last 5 years.The review is based on a Medline bibliographic search using the key words 'treatment', 'obstructive sleep apnea' and 'sleep-related breathing disorders' and covers papers published since 1997, including references in these articles. In respect to conservative treatments the following important developments were found. Oral devices were shown to be effective in about 50-70% of patients with OSA, but at this stage it is not possible to predict in which patients successful treatment can be expected. As subjective compliance averages only about 50%, thermoplastic devices used as trial devices provide a reasonable alternative to reduce costs. Automatic continuous positive airway pressure (CPAP) units have been shown to cut costs when used for pressure titration in severe sleep apneics during the day or when used in so-called split-night procedures in appropriate cases. Nasal CPAP has proven to be effective in children, showing higher compliance rates than in adults. The development of mouth-pieces provides the possibility of using CPAP orally, e.g. after nasal surgery. Electrical stimulation of the tongue muscles shows promising preliminary results. Nevertheless, further research in this field is necessary. In the field of surgery, the most valuable development has been tissue reduction using radiofrequency energy, which has been shown to be effective and minimally invasive. Other fundamentally new surgical techniques have not been attempted within the last 5 years; instead, development in this area appears to be defined by a combination of previously known methods (so-called multilevel surgery) and optimized methods of patient selection. Such combined surgical procedures has achieved success rates of about 70%. Taking all these developments into account, CPAP therapy remains the gold standard for treatment of patients with OSA; yet the low long-term compliance rates of 60-70% have to be regarded as a major challenge warranting further effort.

Children and adolescents experiencing acute exacerbations of asthma benefit from the use of beta(2)-adrenoceptor agonists (beta(2)-agonists) and systemic corticosteroids. However, there have been conflicting reports regarding the efficacy of inhaled anticholinergic agents. This article summarizes the evidence provided by randomized controlled trials studying the efficacy of adding inhaled anticholinergic agents to beta(2)-agonists in nonhospitalized children and adolescents with acute exacerbations of asthma. This systematic review of randomized controlled trials suggests that the addition of inhaled anticholinergic agents to beta(2)-agonists is beneficial in children and adolescents, particularly those with severe exacerbations of asthma. When given in repeated doses, the addition of inhaled anticholinergic agents to beta(2)-agonists improves lung function and reduces the risk of hospital admission by 25%. Several treatment regimens, namely ipratropium bromide (250 or 500 microg per dose) every 20-60 minutes for two to three doses have been tested with similar beneficial effects. The addition of a single dose of an inhaled anticholinergic agent to beta(2)-agonists improves lung function but does not prevent hospital admission. The review did not identify any beneficial effects of anticholinergic agents in children with nonsevere asthma. Use of anticholinergic agents was not associated with increase in the incidence of nausea, vomiting or tremor. In conclusion, the addition of repeated doses of an inhaled anticholinergic agent to inhaled beta(2)-agonist is indicated in the emergency room management of children and adolescents with acute asthma, particularly those with severe exacerbations.

Unlabelled: Cefepime (Maxipime), Maxcef, Cepimax, Cepimex, Axepim, a parenteral fourth-generation cephalosporin, is active against many organisms causative in pneumonia. Cefepime has in vitro activity against Gram-positive organisms including Staphylococcus aureus and penicillin-sensitive, -intermediate and -resistant Streptococcus pneumoniae similar to that of cefotaxime and ceftriaxone. Cefepime also has good activity against Gram-negative organisms, including Pseudomonas aeruginosa, similar to that of ceftazidime. Importantly, cefepime is stable against many of the common plasmid- and chromosome-mediated beta-lactamases and is a poor inducer of AmpC beta-lactamases. As a result, it retains activity against Enterobacteriaceae that are resistant to third-generation cephalosporins, such as derepressed mutants of Enterobacter spp. Cefepime may be hydrolyzed by the extended-spectrum beta-lactamases produced by some members of the Enterobacteriaceae, but to a lesser extent than the third-generation cephalosporins. Monotherapy with cefepime 1 or 2g, usually administered intravenously twice daily, was as effective for clinical and bacteriological response as ceftazidime, ceftriaxone or cefotaxime monotherapy (1 or 2g two or three times daily) in a number of randomized, clinical trials in hospitalized adult, or less commonly, pediatric, patients with generally moderate to severe community-acquired or nosocomial pneumonia. More limited data indicated that monotherapy with cefepime 2g three times daily was also as effective in treating patients with nosocomial pneumonia as imipenem/cilostatin 0.5g four times daily, and when combined with amikacin, cefepime was as effective as ceftazidime plus amikacin. Patients with pneumonia who failed to respond to previous antibacterial therapy with penicillins or other cephalosporins responded to treatment with cefepime. Cefepime is generally well tolerated, with a tolerability profile similar to those of other parenteral cephalosporins. In clinical trials, the majority of adverse events experienced by cefepime recipients were mild to moderate and reversible. The most common adverse events with a causal relationship to cefepime reported in clinical trials included rash and diarrhea. Other, less common, adverse events included pruritus, urticaria, nausea, vomiting oral candidiasis, colitis, headache, fever, erythema and vaginitis.

Conclusion: Cefepime is an established and generally well tolerated parenteral drug with a broad spectrum of antibacterial activity which, when administered twice daily, provides coverage of most of the pathogens that may be causative in pneumonia. In randomized clinical trials in hospitalized patients with generally moderate to severe community-acquired or nosocomial pneumonia, cefepime monotherapy exhibited good clinical and bacteriological efficacy. Cefepime may become a preferred antibacterial agent for infections caused by Enterobacter spp. Wit

Pulmonary arterial hypertension (PAH) is a severe condition that markedly reduces exercise capacity and survival in the affected patient population. PAH includes primary pulmonary hypertension (PPH) and pulmonary hypertension associated with collagen vascular diseases, congenital systemic-to-pulmonary shunts, portal hypertension and HIV infection. All these conditions share virtually identical obstructive pathologic changes of the pulmonary microcirculation and probably similar pathobiologic processes. The pathophysiology is characterized by a progressive increase in pulmonary vascular resistance, leading to right ventricular failure and death. Prostacyclin is an endogenous substance that is produced by vascular endothelial cells and induces vasodilatation, inhibition of platelet activity, and antiproliferative effects. A dysregulation of prostacyclin metabolic pathways has been shown in patients with PAH and this represents the rationale for the exogenous therapeutic administration of this substance. The clinical use of prostacyclin in patients with PAH has been made possible by the synthesis of stable analogs that possess different pharmacokinetic properties but share similar pharmacodynamic effects. Experience in humans has been initially collected with epoprostenol, which is a synthetic salt of prostacyclin. Epoprostenol has a short half-life in the circulation and requires continuous administration by the intravenous route by means of infusion pumps and permanent tunnelized catheters. In addition, epoprostenol is unstable at room temperature, and the complex delivery system required is associated with several adverse effects and potentially serious complications. For these reasons, alternatives to intravenous epoprostenol have been sought and this has led to the development of analogs that can be administered subcutaneously (treprostinil), orally (beraprost sodium) or by inhalation (iloprost). Three unblinded clinical trials and several uncontrolled trials have shown that treatment with epoprostenol improved symptoms and exercise capacity in New York Heart Association (NYHA) class III and IV PAH patients and also survival in patients with PPH. Subcutaneous treprostinil improved symptoms, exercise, hemodynamics and clinical events in the largest clinical trial ever performed in PAH, but local infusion site reactions limited efficacy in a proportion of patients. Oral beraprost sodium improved exercise capacity only in patients with PPH and is the only prostacyclin analog that has also been tested in NYHA class II patients. Inhaled iloprost has improved symptoms, exercise capacity and clinical events in patients with PAH and inoperable chronic thromboembolic pulmonary hypertension. The favorable effects of prostanoids observed in all studies coupled with different profiles of adverse events and tolerability for each prostacyclin analog allow the unique opportunity to select the most appropriate compound for the individual patient with PAH

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.

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 beta-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.