Treatments in respiratory medicine最新文献

The new respiratory fluoroquinolones (gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, and on the horizon, garenoxacin) offer many improved qualities over older agents such as ciprofloxacin. These include retaining excellent activity against Gram-negative bacilli, with improved Gram-positive activity (including Streptococcus pneumoniae and Staphylococcus aureus). In addition, gatifloxacin, moxifloxacin and garenoxacin all demonstrate increased anaerobic activity (including activity against Bacteroides fragilis). The new fluoroquinolones possess greater bioavailability and longer serum half-lives compared with ciprofloxacin. The new fluoroquinolones allow for once-daily administration, which may improve patient adherence. The high bioavailability allows for rapid step down from intravenous administration to oral therapy, minimizing unnecessary hospitalization, which may decrease costs and improve quality of life of patients. Clinical trials involving the treatment of community-acquired respiratory infections (acute exacerbations of chronic bronchitis, acute sinusitis, and community-acquired pneumonia) demonstrate high bacterial eradication rates and clinical cure rates. In the treatment of community-acquired respiratory tract infections, the various new fluoroquinolones appear to be comparable to each other, but may be more effective than macrolide or cephalosporin-based regimens. However, additional data are required before it can be emphatically stated that the new fluoroquinolones as a class are responsible for better outcomes than comparators in community-acquired respiratory infections. Gemifloxacin (except for higher rates of hypersensitivity), levofloxacin, and moxifloxacin have relatively mild adverse effects that are more or less comparable to ciprofloxacin. In our opinion, gatifloxacin should not be used, due to glucose alterations which may be serious. Although all new fluoroquinolones react with metal ion-containing drugs (antacids), other drug interactions are relatively mild compared with ciprofloxacin. The new fluoroquinolones gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin have much to offer in terms of bacterial eradication, including activity against resistant respiratory pathogens such as penicillin-resistant, macrolide-resistant, and multidrug-resistant S. pneumoniae. However, ciprofloxacin-resistant organisms, including ciprofloxacin-resistant S. pneumoniae, are becoming more prevalent, thus prudent use must be exercised when prescribing these valuable agents.

Study objectives: Treatment of chronic obstructive pulmonary disease (COPD) in the emergency department (ED) or hospital accounts for a significant portion of COPD costs. This study estimates the cost of a COPD ED or hospitalization visit in the US.

Design: This observational study utilized administrative data from 218 acute care hospitals. ED/hospital discharges for COPD (International Classification of Diseases - Ninth Revision - Clinical Modification codes 491.xx. 492.xx, 496.xx) during 2001 were identified. Costs were determined for three groups: (i) ED only; (ii) standard admission; and (iii) severe admissions (intensive care unit [ICU] or intubation). Severe admissions were stratified into: (i) ICU/no intubation; (ii) intubation/no ICU; and (iii) ICU + intubation. Mean total costs and length of stay (LOS) were calculated for each group.

Results: A total of 59 735 ED/hospital encounters were identified: 20 431 ED only, 33 210 standard admissions, and 6094 severe admissions (4456 ICU/no intubation, 496 intubation/no ICU, and 1142 ICU/intubation). ED visits had a mean cost of $US571 +/- 507 (year 2001 value). Inpatient costs ranged from $US5997 (+/- 5752) for a standard admission to $US36 743 (+/- 62 886) for ICU plus intubation admissions, while LOS ranged from 5.1 days (+/- 4.5) to 14.8 days (+/- 16.7), respectively. In addition, only 10% of encounters required an intubation/ICU admission, but these accounted for 34% of the cost.

Conclusion: Cost of a COPD hospitalization is substantial in the US, with one-third of those costs being associated with severe admissions, which make up only 10% of all COPD admissions. Treatments aimed at reducing hospitalizations and length of stay could result in substantial cost savings.

In asthma the bronchial epithelium is highly abnormal, with various structural changes. As a consequence, the epithelium becomes an important source of inflammatory mediators that contribute to the ongoing inflammation and remodeling responses occurring in asthma. Compared with normal individuals, the fraction of exhaled nitric oxide (NO) is elevated in patients with asthma, and these levels have been shown to vary with disease activity. Thus, in asthma, epithelial cells may be exposed to large amounts of NO. Increased NO production is associated with the formation of various nitrosating species capable of promoting DNA damage. In this study we investigated the effect of NO on DNA of rat trachea epithelial cells in the presence or absence of flunisolide. Rat airway epithelial cells were prepared and incubated with the NO donor S-nitroso-L-glutathione monoethyl ester (GSNO-MEE). DNA damage was evaluated using single cell gel electrophoresis 'comet assay.' The parameters used as an index of DNA damage were tail length, tail intensity, and tail moment. Results of our study demonstrated that NO induced significant DNA damage in rat airway epithelial cells. Flunisolide in amounts of 11-110 mumol/L significantly reduced all the considered parameters indicating DNA damage. These data indicate that flunisolide may protect epithelial cells from the NO-mediated DNA damage. NO overproduction could contribute to epithelial injury in asthma, and flunisolide seems to attenuate this damage.

Presentation of clinical data can have a profound effect on treatment decisions, and there is a need for measures that are objective, have clinical relevance, and are easily interpreted. Relative risk is often used to summarize treatment comparisons, but does not account for variations in baseline risk profiles and does not convey information on absolute sizes of treatment effects. Absolute risk reduction gives this information, but the data are dimensionless and abstract, and lack a direct connection with the clinical environment.The number needed to treat, or NNT, has been developed to address this issue. NNT is the reciprocal of the absolute risk reduction associated with an intervention, and may also be calculated as 100 divided by the absolute risk reduction expressed as a percentage. The result is the number of patients who would have to receive treatment for one of them to benefit or to avoid an adverse outcome over a given period of time. Since its introduction, the concept of NNT has been expanded to include number needed to harm (NNH), which illustrates adverse events or other undesirable outcomes associated with treatment, and the epidemiologic tool of number needed to screen.NNT has been used to describe treatment effects from many clinical trials. A recent example illustrates benefit of inhaler therapy combining a long-acting beta(2)-agonist (LABA) and corticosteroid for COPD over treatment with LABA alone. NNT has also been extended to systematic reviews and meta-analyses, where it has been used to rank different treatments where baseline profiles, treatment outcomes and time periods under examination are similar.NNT is therefore a concise and easily understood tool for quantifying treatment efficacy, particularly when applying trial results to the clinic setting.

Nasal polyposis, occurring in about 2% of the general population, is the ultimate form of inflammation of the upper airways. For unknown reasons, polyps develop preferentially in subtypes of inflammatory diseases and are associated with perennial non-allergic rhinitis, asthma, intolerance of aspirin (acetylsalicylic acid)/NSAIDs, allergic fungal rhinosinusitis, cystic fibrosis, and primary ciliary dyskinesia. In contrast to common beliefs, IgE-mediated allergy does not seem to play an etiological role in nasal polyposis.The polyps originate from the mucosa around the clefts of the lateral nasal wall, especially in the region of the ostiomeatal complex. The factors that determine the localization of the disease to a few square centimeters of the airways are not known.Polyps are edematous bags covered by respiratory epithelium and contain very few nerves, blood vessels, and glands that have undergone cystic degeneration. They contain degranulated mast cells, have a very high concentration of histamine, and are characteristically infiltrated by eosinophils. These cells accumulate due to the release of proinflammatory cytokines (in particular, interleukin-5).Nasal polyposis is preceded by a prolonged history of rhinitis accompanied by severe and persistent nasal blockage; typically, the sense of smell is seriously impaired when polyps develop. The diagnosis is based on anterior rhinoscopy or, preferably, endoscopy.Nasal polyposis is medically treatable. Surgical treatment is carried out when medication fails. Intranasal corticosteroids reduce rhinitis symptoms, improve nasal breathing, reduce the size of polyps, and prevent, in part, their recurrence, but this treatment has little effect on the sense of smell. Intranasal corticosteroids can, as basic long-term therapy, be used alone in mild cases or together with systemic corticosteroids and/or surgery in severe cases. Systemic corticosteroids administered for 2-3 weeks have a beneficial effect on all observed symptoms and pathology, including the sense of smell. When nasal blockage is a problem in spite of medical treatment, surgery is recommended. Simple polypectomy can be performed, but endoscopic surgery is recommended in more severe and persistent cases.

In this comprehensive review, two very closely related interstitial pneumonias are discussed: the cryptogenic form of organizing pneumonia (COP); and secondary forms of organizing pneumonia (OP), which occur in association with identifiable medical conditions. Some newer and lesser known of these associated conditions are described, most importantly post-radiation OP.Rapidly progressive, corticosteroid-resistant and poor prognostic forms of OP have been described. These types purportedly occur more frequently in secondary OP. However, OPs frequently coexist with other interstitial pneumonias, especially when associated with connective tissue diseases. Therefore, tissue sampling error or an incorrect morphologic diagnosis can be the basis for the occurrence of clinically aggressive OPs. By using the 2002 American Thoracic Society/European Respiratory Society diagnostic criteria, some pre-2002 cases reported as OP would be re-classified today.Although COP is considered to have a good prognosis and to be corticosteroid responsive, approximately 70% of patients, treated with corticosteroids, relapse even during initial treatment. Multiple and late relapses occur in about one-third of the patients. We performed a meta-analysis of second-line treatment options for corticosteroid-refractory forms of OP. Three alternative nonsteroid agents - cyclophosphamide, azathioprine, and cyclosporin - have been used in combination with corticosteroids. On careful review, in a number of cases reported as secondary OP, other histologic interstitial patterns besides OP were described. The need for second-line therapy in these patients might have been dictated by the non-organizing pneumonic component. Most of the scant number of reports come from outside the US. World experience with these is limited, but good clinical outcomes have been noted, even in patients with interstitial patterns in addition to OP.The initiation of the OP tissue response in the bronchiolar and sub-bronchiolar location may be due to the presence of bronchiolar-associated lymphoid tissue found at the bifurcations of the bronchioles. Inhaled antigens stimulate granulocyte colony stimulating factor-mediated airway inflammation, followed later by CD44-mediated clearance. Repair requires intrabronchiolar formation of granulation tissue and a favorable ratio of matrix metalloproteinase to tissue inhibitors of metalloproteinase (MMP : TIMP) within the stroma. This reparative milieu allows extracellular matrix degradation and re-synthesis to occur. MMP-expressing fibroblasts then phagocytose the collagen fibrils and microfibrils produced earlier in repair, reversing the initial fibrosis.

Despite aggressive fixed-dose (FD) combination therapy with inhaled glucocorticosteroids (ICS) and long acting beta(2)-adrenoceptor agonists (LABA), many patients with asthma remain suboptimally controlled, based on the need for rescue therapy and rates of severe exacerbations. The strategy of adjustable maintenance dosing (AMD) involves adjustment of the maintenance dose, (using a single combination [budesonide/formoterol] inhaler, Symbicort((R))) in response to variability of asthma control over time. The AMD strategy, like the FD approach, involves the use of a short-acting beta(2)-adrenoceptor agonist (SABA) for rapid relief of bronchospasm. The dose-response characteristics of budesonide/formoterol make the AMD strategy a feasible option that cannot be exploited with the combination of salmeterol/fluticasone propionate (Advair((R))). Several studies suggest that the AMD strategy is superior to a FD approach in terms of overall asthma control.Budesonide/formoterol in a single inhaler is as effective as albuterol (salbutamol) for relief of acute asthma episodes, a feature that makes it possible to use this combination for both maintenance and reliever therapy without the need for the use of a SABA. The single-inhaler strategy has been shown to be safe and more efficacious than FD therapy. In particular, the COSMOS study has demonstrated that exacerbation burden is reduced more effectively when the combination (budesonide/formoterol) single inhaler is used for both maintenance and relief compared with FD therapy with salmeterol/fluticasone and albuterol for rescue in patients with moderate-to-severe asthma. These findings suggest that we will have to reconsider our definition of reliever therapy for patients that require long-term therapy with combination ICS and LABA.The concept of single-inhaler therapy represents a paradigm shift in asthma management that has been validated in several large studies involving thousands of patients. The single-inhaler strategy represents one of the most significant advances in asthma management in many years, and one that appears ideal for adoption in primary care.

Hypersensitivity pneumonitis (HP) represents a group of lung disorders caused by the inhalation of a wide variety of organic particles by susceptible individuals. HP occurs mainly in nonsmokers, but smoking may promote an insidious and chronic disease. The prevalence of HP is difficult to estimate accurately since several antigens can produce the disease, but the range spans infancy to old age. Regardless of the causative antigen or its environmental setting, the clinical manifestations are essentially the same. Three different clinical presentations have been recognized: acute, subacute, and chronic. In the acute form, patients show flu-like symptomatology, followed by dyspnea and dry cough. Symptoms subside a few hours or days later. The subacute and chronic forms result from recurrent low-level antigen exposure and are characterized by progressive dyspnea and dry cough. Other constitutional symptoms such as fatigue, anorexia, and weight loss can be apparent. Fever may occur in the subacute form. Importantly, chronic HP may evolve insidiously or may result from repeated acute/subacute episodes. Recurrent acute, subacute, and chronic HP may progress to irreversible lung fibrosis or provoke emphysematous changes.HP can be difficult to identify, and precise diagnosis requires a history of exposure and a constellation of clinical, imaging, laboratory, bronchoalveolar lavage and pathologic findings. General laboratory tests show an increase of acute phase reactants. Specific precipitating antibodies, when present, are evidence of antigen exposure, and are a hallmark for diagnosis. Chest radiograph usually reveals widespread ground-glass attenuation, and nodular or reticulonodular shadowing. High-resolution CT features include diffuse or patchy ground-glass opacities with small poorly defined nodules and air trapping. Pulmonary function tests are characterized by a predominantly restrictive ventilatory defect with loss of lung volume and hypoxemia at rest that worsens with exercise. Bronchoalveolar lavage reveals a significant increase in lymphocytes, mostly over 40%. In the acute form there is also an increase in neutrophils. Antigen-induced lymphocyte proliferation, and environmental or laboratory-controlled inhalation challenge, may be used for diagnostic purposes and can help to establish a diagnosis of insidious forms of HP. In subacute or chronic cases, lung biopsy may be necessary. Typical findings include bronchiolitis, lymphocytic alveolitis, and loosely formed granulomas, although occasionally other morphologic patterns such as nonspecific interstitial pneumonia may exist. Treatment focuses on avoiding further exposure to the offending antigen(s). Corticosteroids are recommended in subacute and chronic forms. The usual regimen consists of initial high doses of systemic corticosteroid (e.g. prednisone 0.5-1.0 mg/kg/day), followed by gradual tapering.

Paclitaxel and docetaxel, drugs that bind tightly to beta-tubulin and disrupt microtubule dynamics, are widely used in the treatment of non-small cell lung cancer (NSCLC), the most common cause of cancer death in men and women living in the US. These well tolerated drugs, alone or in combination with another cytotoxic agent, have been shown to increase the survival of patients with metastatic disease or malignant effusions. Both paclitaxel and docetaxel can be combined with concurrent chest irradiation for patients with locally advanced NSCLC. The combination of carboplatin and paclitaxel, when given postoperatively to patients with stage IB NSCLC, improved survival compared with surgery alone, with little toxicity. Taxane combinations are undergoing study as adjuvant therapy for patients with other stages of operable disease. Except for a recent trial with bevacizumab, efforts to improve the efficacy of taxane/platinum combinations in patients with advanced disease by adding a third 'targeted' drug have thus far been unsuccessful.