Theophylline is the most widely used anti-asthma drug worldwide and is classified as a bronchodilator, although there is increasing evidence that it may have immunomodulatory effects. We have investigated the effects of theophylline withdrawal under placebo control in 27 asthmatic patients (25 to 70 yr) treated with long-term theophylline who were also treated with high dose inhaled corticosteroids. We measured asthma symptoms (diary card), lung function (spirometry and home records of peak expiratory flow), and peripheral leukocyte populations using dual color flow cytometry. In eight of these patients, we examined fiberoptic bronchial biopsies by immunocytochemistry. We also studied peripheral blood lymphocytes in eight asthmatic patients who have never received theophylline. Mean steady state plasma theophylline concentrations during theophylline therapy were 8.6 +/- 0.9 mg/L. Theophylline withdrawal was associated with a significant increase in asthma symptoms, particularly at night, and a fall in spirometry and morning peak flow. This was accompanied by a significant fall in peripheral blood monocytes (CD14+, activated CD4+ T-lymphocytes (CD4+/CD25+) and activated CD8+ T-cells (CD8+/HLA-DR+) in patients with a plasma theophylline > 5 mg/L. The lymphocyte populations in theophylline-naive patients were similar to those found after theophylline withdrawal. Bronchial biopsies showed a mirror image of the peripheral blood with an increase in CD4+ and CD8+ lymphocytes in the airway. Chronic treatment with theophylline, even at low plasma concentrations, controls asthma symptoms and has effects on T-lymphocyte populations in the peripheral blood which are the inverse of those observed in the airways.(ABSTRACT TRUNCATED AT 250 WORDS)
The evaluation for European Union market approval of coronary stents falls under the Medical Device Directive that was adopted in 1993. Specific requirements for the assessment of coronary stents are laid out in supplementary advisory documents. In response to a call by the European Commission to make recommendations for a revision of the advisory document on the evaluation of coronary stents (Appendix 1 of MEDDEV 2.7.1), the European Society of Cardiology (ESC) and the European Association of Percutaneous Cardiovascular Interventions (EAPCI) established a Task Force to develop an expert advisory report. As basis for its report, the ESC-EAPCI Task Force reviewed existing processes, established a comprehensive list of all coronary drug-eluting stents that have received a CE mark to date, and undertook a systematic review of the literature of all published randomized clinical trials evaluating clinical and angiographic outcomes of coronary artery stents between 2002 and 2013. Based on these data, the TF provided recommendations to inform a new regulatory process for coronary stents. The main recommendations of the task force include implementation of a standardized non-clinical assessment of stents and a novel clinical evaluation pathway for market approval. The two-stage clinical evaluation plan includes recommendation for an initial pre-market trial with objective performance criteria (OPC) benchmarking using invasive imaging follow-up leading to conditional CE-mark approval and a subsequent mandatory, large-scale randomized trial with clinical endpoint evaluation leading to unconditional CE-mark. The data analysis from the systematic review of the Task Force may provide a basis for determination of OPC for use in future studies. This paper represents an executive summary of the Task Force's report.
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No abstract is provided for this article.
Asthma and COPD are multidimensional diseases, with several systemic manifestations and associations with a number of comorbid diseases. The most likely link between asthma and COPD and these extrapulmonary conditions is the spillover of inflammatory mediators from the lung, as systemic inflammation is associated with skeletal muscle wasting and cachexia as well as with cardiovascular, metabolic, and bone diseases. Asthma is characterized by chronic airway inflammation, and infiltration of T-lymphocytes, mast cells, eosinophils and monocytes/macrophages. This is associated with the increased expression of several inflammatory proteins, including cytokines, enzymes, receptors and adhesion molecules. Chronic obstructive pulmonary disease (COPD) is currently a leading cause of morbidity and mortality worldwide, with the main cause being long-term cigarette smoking in the Western world. Accumulation of inflammatory mucous exudates in the lumen and infiltration of the wall by innate and adaptive inflammatory immune cells, such as CD4+ cells, CD8+ cells, B cells, macrophages, and neutrophils, and the formation of lymphoid follicles are all features of the observed inflammation that correlate with the severity of COPD. Previous studies have suggested that autoimmune mechanisms may contribute to the pathogenesis of COPD. Serum autoantibodies against elastin and bronchial epithelial cells along with corresponding IgG and complement (C3) deposition have been observed in COPD. In this regard, we have shown the presence of antibodies against carbonyl-modified protein neoepitopes in both COPD and a murine model of chronic exposure to oxidative stress. Thus, it seems that asthma and COPD are not only respiratory system dysfunctions but are also involved in multi-organ disorders. More research is needed to understand the links between these diseases and to search for common treatable components. It seems likely that treatments, such as statins, that are already used to manage cardiovascular and metabolic diseases might also provide benefit in COPD patients, although it is important that randomized placebo-controlled trials be conducted to confirm this possibility. It is important to consider how the existence of a comorbid disease may affect the management of a patient who also has COPD. Guidelines are needed that recognize the association of these various diseases and provide advice on management, as well as defining questions for future clinical research. In turn, it is important for specialists in nonpulmonary areas to recognize that COPD may commonly occur in association with certain diseases in their specialty and to make the diagnosis using spirometry so that appropriate treatment may be instituted. Treatments already used for COPD might also be beneficial in some comorbid diseases. New therapies should also be considered as potentially beneficial to systemic manifestations and comorbidities. For example, an effective inhaled anti-inflammatory therapy may improve comorbidities by reducing the overspill of inflammatory mediators from the lungs that contribute to systemic inflammation. Alternatively, an oral anti-inflammatory treatment, as well as suppressing inflammation on the respiratory tract, may directly reduce systemic inflammation. It is clear that much more clinical and basic research is needed to understand the complexity of COPD so that more effective management of COPD and its various comorbidities will be possible in the future.
