Treatments in respiratory medicine最新文献

Severe alpha(1)-antitrypsin (AAT) deficiency is an inherited disorder that leads to the development of emphysema in smokers at a relatively young age; most are disabled in their forties. Emphysema is caused by the protease-antiprotease imbalance when smoking-induced release of neutrophil elastase in the lung is inadequately inhibited by the deficient levels of AAT, the major inhibitor of neutrophil elastase. This protease-antiprotease imbalance leads to proteolytic damage to lung connective tissue (primarily elastic fibers), and the development of panacinar emphysema. AAT replacement therapy, most often applied by weekly intravenous infusions of AAT purified from human plasma, has been used to partially correct the biochemical defect and raise the serum AAT level above a theoretically protective threshold level of 0.8 g/L. A randomized controlled clinical trial was not considered feasible when purified antitrypsin was released for clinical use. However, AAT replacement therapy has not yet been proven to be clinically effective in reducing the progression of disease in AAT-deficient patients. There was a suggestion of a slower progression of emphysema by computed tomography (CT) scan in a small randomized trial. Two nonrandomized studies comparing AAT-deficient patients already receiving replacement therapy with those not receiving it, and a retrospective study evaluating a decline in FEV(1) before and after replacement therapy, suggested a possible benefit for selected patients. Because of the lack of definitive proof of the clinical effectiveness of AAT replacement therapy and its cost, we recommend reserving AAT replacement therapy for deficient patients with impaired FEV(1) (35-65% of predicted value), who have quit smoking and are on optimal medical therapy but continue to show a rapid decline in FEV(1) after a period of observation of at least 18 months. A randomized placebo-controlled trial using CT scan as the primary outcome measure is required. Screening for AAT deficiency is recommended in patients with chronic irreversible airflow obstruction with atypical features such as early onset of disease or disability in their forties or fifties, or positive family history, and in immediate family members of patients with AAT deficiency.

Aspiration is a leading cause of nosocomial infection in the intensive care unit. Techniques to avoid or reduce aspiration are important in preventing pneumonia and pneumonitis. The most important preventive measures include the semi-recumbent position, the surveillance of enteral feeding, the use of promotility agents, and avoiding excessive sedation. The analysis of the pathogens involved in these syndromes usually shows a minor role for the anerobes. With regard to treatment, aspiration pneumonitis does not require any antimicrobials; on the contrary, aspiration pneumonia has to be treated. Empiric antimicrobials treatment should be started on clinical suspicion. The choice of the drug has to be guided by local pathogen epidemiology and clinical features; in fact, community type pneumonia requires a first-line antimicrobial such as amoxicillin/clavulanic acid. On the contrary, a nosocomial type of infection needs to be treated as a ventilator-associated pneumonia in agreement with published guidelines. Nevertheless, quantitative culture should be obtained in order to de-escalate antimicrobials. In conclusion, aspiration pneumonia is a frequently encountered disease that can be prevented by relatively simple measures.

Objective: To compare the onset of bronchodilation with a new formoterol hydrofluoroalkane (HFA) pressurized metered-dose inhaler (pMDI) with albuterol (salbutamol) HFA pMDI.

Patients and methods: Thirty patients with stable mild or moderate asthma (23 using inhaled corticosteroids, mean FEV(1) 82% of predicted, >or=15% reversibility to terbutaline 1mg after 30 minutes) received formoterol HFA (Oxis) 2 x 4.5microg, albuterol HFA (Ventoline) Evohaler) 2 x 100microg, or placebo at three separate visits in this randomized, double-blind, double-dummy, three-way crossover study. FEV(1) was measured before and 3, 10, 20, 30 and 60 minutes after inhalation. Change in FEV(1) at 3 minutes after inhalation was the primary variable.

Results: Mean baseline FEV(1) was stable on all study days (range 2.92-2.94L). FEV(1) values at 3 minutes were: formoterol 3.22L (8% increase), albuterol 3.23L (9% increase) and placebo 2.99L (both p < 0.001 vs placebo). Maximum FEV(1) increased similarly with formoterol and albuterol, with no differences observed between the active treatments at any time point. Patients rated treatment effective at 3 minutes in 15 of 30, 19 of 30 and 7 of 30 cases with formoterol, albuterol and placebo, respectively. All treatments were well tolerated.

Conclusion: In stable, mild, or moderate asthma, formoterol 9microg and albuterol 200microg, both by HFA pMDI, provided equally rapid and effective bronchodilation.

Ipratropium bromide is a nonselective antagonist of the muscarinic receptors located on airway smooth muscle, and is delivered via a metered-dose inhaler (MDI). Because of the requirement to phase out chlorofluorocarbon (CFC)-propelled MDIs, the ipratropium bromide inhalation aerosol MDI has been redesigned with a hydrofluoroalkane as the propellant (ipratropium bromide HFA). Ipratropium bromide HFA has recently been approved in the US for the maintenance treatment of bronchospasm associated with COPD. Ipratropium bromide HFA 42 microg four times daily (one dose [42 microg] is delivered via two puffs of the inhaler) demonstrated comparable efficacy to that of ipratropium bromide CFC 42 microg four times daily, as measured by spirometric testing, in a large, randomized, double-blind, placebo-controlled, 12-week trial in patients with stable COPD. Similarly, four-times-daily ipratropium bromide HFA 42 microg and ipratropium bromide CFC 42 microg provided a comparable degree of bronchodilation in patients with stable COPD during a 1-year, open-label study primarily designed to assess safety. In both studies, the tolerability profiles of ipratropium bromide HFA and ipratropium bromide CFC were comparable. The most common adverse events were related to respiratory system disorders. During the 1-year study, dry mouth was reported by 1.3% and 0.7% of patients in the ipratropium bromide HFA or ipratropium bromide CFC groups.

Since the early 1960s, considerable advancements have been made to standardize and provide quality assurance for clinical susceptibility testing procedures of antimicrobial agents. Controversy, however, remains as to the interpretation of clinical laboratory susceptibility test results. While some feel susceptibility breakpoints should only detect resistance mechanisms, others believe they should predict a high probability of clinical response. This has resulted in confusion among clinicians, as it has been apparent for some time that there can be discordance between interpretive test results and clinical response to therapy (generally cures of infections caused by resistant pathogens). Nearly simultaneous with the beginning of the standardization process for clinical susceptibility testing procedures, the first penicillin-resistant Streptococcus pneumoniae isolates were detected. During the ensuing decades, penicillin-resistant pneumococci became a greater clinical concern, resulting in macrolides emerging as safe therapeutic alternatives to beta-lactam agents for the treatment of community-acquired respiratory tract infections. During the last 10 years, the incidence of pneumococcal isolates with elevated macrolide minimum inhibitory concentration (MIC) values has also increased, yet the debate over the clinical meaning of these statistics persists. The youthful science of pharmacokinetics-pharmacodynamics provides a useful platform to determine which pneumococcal strains with elevated MIC values can be treated with contemporary dosing regimens and also facilitates the proper selection of antimicrobial breakpoints for all antimicrobial classes, including the newer macrolides.

Severe refractory asthma is a heterogeneous condition with different patterns of severity and different reasons for loss of asthma control. The three main patterns include asthma with frequent exacerbations, asthma with irreversible airway obstruction, and asthma with reduced sensitivity or resistance to corticosteroids. Each of these patterns has distinct risk factors. The assessment of patients with severe asthma requires a systematic, diagnostic and management protocol. The majority of patients will benefit from thorough analysis and treatment of aggravating factors. In some patients with severe refractory asthma, in particular those with concomitant chronic rhinosinusitis, long-term administration of systemic corticosteroids may be necessary. In these patients all efforts should be directed towards reducing the dose of corticosteroids as much as possible. Although several corticosteroid-sparing agents and immunosuppressants have been proposed in the literature, none of these has gained complete acceptance in clinical practice, either because of limited efficacy or unacceptable adverse effects. Novel potent anti-inflammatory therapies aimed at reducing the need for systemic corticosteroids in patients with severe, refractory asthma are urgently needed.

The lung disease of cystic fibrosis (CF) is characterized by a self-sustaining cycle of airway obstruction, infection, and inflammation. Therapies aimed at decreasing the inflammatory response represent a relatively new strategy for treatment. Attention has focused primarily upon the therapeutic potential of corticosteroids and NSAIDs. Although beneficial, the use of systemic corticosteroids is limited by their unacceptable adverse effects. It is unclear if inhaled corticosteroids are a viable alternative, although their use in CF has dramatically increased in recent years. High-dose ibuprofen has been shown to slow progression of CF lung disease, but its use has not been widely adopted despite a favorable risk-benefit profile. Thus, other anti-inflammatory approaches are under investigation. Since the inflammatory response can be triggered by many stimuli and since the pathways activated by these stimuli produce many mediators, there are a plethora of targets for anti-inflammatory therapeutics. Specific antibodies, receptor antagonists, and counter-regulatory cytokines, such as interleukin (IL)-10 and interferon-gamma, inhibit the pro-inflammatory mediators responsible for the damaging inflammation in the CF airway, including tumor necrosis factor-alpha, IL-1beta and IL-8. Studies of molecules that modulate intracellular signaling cascades that lead to the production of inflammatory mediators, are underway in CF. For patients with established disease, recent and projected advances in therapies that are directed at neutrophil products, such as DNase, antioxidants, and protease inhibitors, hold great promise for limiting the consequences of the inflammatory response. To optimize anti-inflammatory therapy, it is necessary to understand the mechanism of action of these agents in the CF lung to determine which agents will be most beneficial, and to determine which therapies should be initiated at what age and stage of lung disease. Hope remains that correction of the abnormal CF transmembrane conductance regulator protein or gene replacement therapy will be curative. However, correction of the basic defect must also correct the dysregulated inflammatory response in order to be effective. Until those therapies aimed at repairing the basic defect are realized, limiting the effects of the inflammatory process will be important in slowing the decline in lung function and thus prolonging survival in patients with CF.

Bronchodilator therapy forms the mainstay of treatment for symptomatic patients with COPD. Long-acting bronchodilators, which maintain sustained airway patency over a 24-hour period, represent an advance in therapy. Tiotropium bromide is a new long-acting inhaled anticholinergic agent with superior pharmacodynamic properties compared with the short-acting anticholinergic, ipratropium bromide. Tiotropium bromide has been consistently shown to have a greater impact than ipratropium bromide on clinically important outcome measures such as health status. The mechanisms of clinical benefit with tiotropium bromide are multifactorial, but improved airway function, which enhances lung emptying and allows sustained deflation of over-inflated lungs, appears to explain improvements in dyspnea and exercise endurance in COPD. Inhaled tiotropium bromide therapy has also been associated with reduction in acute exacerbations of COPD as well as reduced hospitalizations. The safety profile of tiotropium bromide is impressive: dry mouth is the most common adverse event and rarely necessitates termination of the drug. No tachyphylaxis to tiotropium bromide has been demonstrated in clinical trials lasting up to 1 year. There is preliminary information that the combination of long-acting anticholinergics and long-acting beta2-adrenoceptor agonists provides additive physiological and clinical benefits. According to recent international guidelines, long-acting bronchodilators should be considered early in the management of symptomatic patients with COPD in order to achieve effective symptom alleviation and reduction in activity limitation. Tiotropium bromide, because of its once-daily administration and its established efficacy and tolerability profile, has emerged as an attractive therapeutic option for this condition.