Treatments in respiratory medicine最新文献

Environmental tobacco smoke and constituents are global risks for human health. Considerable evidence shows that environmental tobacco smoke exposure contributes to, and exacerbates, respiratory disorders. This review assesses the causal role of environmental tobacco smoke exposure for childhood respiratory disorders, and in particular asthma. Tobacco smoke and environmental tobacco smoke exposure during pregnancy have an effect upon lung function in newborn infants; exposure after birth also has an effect upon lung function. An effect upon bronchial responsiveness has been suggested but the evidence is not as strong as for lung function. From 1997 to 1999 a comprehensive set of systematic reviews concerning the relationship between exposure to environmental tobacco smoke and respiratory health in children summarized the results from hundreds of published papers. The evidence for a causal relationship between environmental tobacco smoke exposure and asthmatic symptoms on the one hand, and between environmental tobacco smoke exposure and reduction in lung function on the other hand, was quite strong, whereas the evidence between environmental tobacco smoke exposure and development of allergy was much weaker. Here we present an overview of the effects of environmental tobacco smoke exposure on lung health in children. A hypothesis has been put forward regarding upregulation of pulmonary neuroendocrine cells in relationship to mechanisms of tobacco smoke products (TSP)-induced pulmonary disease. It has also been reported that genetic variation makes part of the population especially vulnerable to environmental tobacco smoke exposure during pregnancy. Furthermore, there is a need for intervention to reduce environmental tobacco smoke exposure in young children, by educating parents and adolescents about the health effects of environmental tobacco smoke exposure. Studies are needed to identify possible critical periods when environmental tobacco smoke exposure is more likely to induce harmful effects on lung health in young children in order to implement effective preventive strategies.

Amoxicillin/clavulanic acid 2000 mg/125 mg extended release (Augmentin XR), referred to herein as amoxicillin/clavulanic acid XR, is a pharmacokinetically enhanced formulation designed to provide more effective therapy in adults and adolescents than conventional formulations against community-acquired respiratory tract pathogens, particularly Streptococcus pneumoniae, with reduced susceptibility to amoxicillin.Amoxicillin/clavulanic acid XR maintains plasma amoxicillin concentrations >4 microg/mL for a mean of 49% of the dosing interval indicating that it would be highly effective against S. pneumoniae strains with minimum inhibitory concentrations (MICs) above the National Committee for Clinical Laboratory Standard's amoxicillin +/- clavulanic acid susceptibility breakpoint of < or = 2 microg/mL. Amoxicillin/clavulanic acid XR is at least as effective as conventional amoxicillin/clavulanic acid formulations, levofloxacin, and clarithromycin in treating community-acquired pneumonia, acute bacterial sinusitis, or acute exacerbations of chronic bronchitis, and has a tolerability profile comparable to that of conventional amoxicillin/clavulanic acid formulations. While the incidence of amoxicillin- or multidrug-resistant S. pneumoniae is not currently sufficient in most regions to warrant the routine empiric use of amoxicillin/clavulanic acid XR, the drug would be extremely useful in those regions with a high incidence of resistant pathogens or in selected patients (i.e. those with S. pneumoniae isolates having amoxicillin MICs > or = 2 microg/mL but < or = 4 microg/mL).

Despite improvements in general supportive care and ventilatory strategies designed to limit lung injury, no specific pharmacological therapy has yet proven to be efficacious in the management of acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS). Based on experimental studies, as well as studies of the ex-vivo human lung, pulmonary edema fluid clearance from the alveolar space can be augmented by both inhaled and systemic beta2-adrenoceptor agonists (beta2-agonists). Additionally, in the presence of lung injury, beta2-agonists may reduce lung vascular permeability. Treatment with beta2-agonists may also increase the secretion of surfactant and have anti-inflammatory effects. In view of these potentially beneficial effects, beta2-agonist therapy should be evaluated for the treatment of lung injury in humans, particularly because they are already in wide clinical use and do not seem to have serious adverse effects in critically ill patients.

Introduction: The Patient Satisfaction and Preference Questionnaire (PASAPQ) is a multi-item measure of respiratory inhalation device satisfaction and preference designed to be easily understood and administered to patients with asthma and COPD. This study assessed its validity, reliability and responsiveness and explored the between-group difference in PASAPQ scores that is meaningful.

Methods: The field test version was developed using literature, focus groups and expert opinion. Item reduction followed. The assessment of the validity, reliability and responsiveness of the PASAPQ utilized data from two clinical studies comparing devices delivering the same medication, and was performed with pre-specified criteria. A minimally important difference (MID) was estimated using both anchor- and distribution-based approaches.

Results: Two factors of the PASAPQ, 'performance' and 'convenience', were consistent across studies. Missing and out-of-range data were minimal (<1%) and respondents used a full range of response options. All items correlated most highly with their hypothesized scale and all exceeded the minimum correlation criteria of 0.40. Cronbach's alfa was high (0.87-0.94), providing support for internal reliability for the PASAPQ. Correlations of the overall satisfaction item with the performance domain ranged from 0.78 to 0.91, the convenience domain ranged from 0.54 to 0.71, and the total score ranged from 0.78 to 0.90. These moderate-to-strong correlations provide substantial support for the validity of the PASAPQ domains and total score. Discriminate validity was assessed by calculating PASAPQ scores for patients' ratings of the device that they preferred compared with the other, non-preferred device. The preferred device was rated higher on all satisfaction measures, supporting the ability of the PASAPQ to discriminate between preferred and non-preferred devices. Although a difference of 3 or 4 points may be sufficient to observe a small effect difference between groups, most of the MID estimates were in the 8-10 point range.

Discussion and conclusion: Our analyses across asthma, COPD and patients with mixed respiratory disease (with features of both COPD and asthma), study designs and data sets lead us to conclude that the PASAPQ is a practical, valid, reliable and responsive instrument for measuring respiratory device satisfaction. Furthermore, a difference in satisfaction scores between treatment groups of 10 points is, conservatively, a difference that is meaningful to patients.

The Novolizer is a multidose, refillable, breath-actuated dry powder inhaler that delivers up to 200 metered doses of drug from a single cartridge. It has a multiple-feedback control mechanism to ensure that the inhalation was performed correctly. In randomized studies, almost all patients with asthma or COPD using the Novolizer, including those using the device for the first time and children, were able to generate sufficient peak inspiratory flow rates (PIFRs) to overcome the trigger threshold of the device. Comparative studies have shown that patients generate significantly higher PIFR through the Novolizer than through the Turbuhaler. At PIFR of 54-99 L/min through the Novolizer, the median deposition of budesonide in the lungs of healthy volunteers was 19.9-32.1%. Two randomized, double-blind trials in patients with asthma showed that the clinical efficacy of drugs delivered through the Novolizer in terms of improvement in FEV(1) was at least as good as that of an identical treatment regimen delivered through the Aerolizer (for formoterol) or the Sultanol (for albuterol [salbutamol]). Similarly, therapeutic equivalence was also shown between budesonide delivered through the Novolizer and that through the Turbuhaler in patients with COPD or asthma in a randomized, nonblind study. Device-related adverse events were not reported in patients using the Novolizer in therapeutic trials and in a large (n > 3000) post-marketing surveillance study. Overall, the Novolizer was well accepted, with an improved compliance in 80% of patients that was attributable to the control mechanisms of the device.

Asthma and COPD are chronic inflammatory conditions that affect hundreds of millions of patients worldwide. New therapeutics are desperately needed, especially those that target the underlying causes and prevent disease progression. Although asthma and COPD have distinct etiologies, both are associated with reduced airflow caused by excess infiltration of inflammatory cells into healthy lung tissues. As selectin-mediated adhesion of leukocytes to the vascular endothelium is a key early event in the initiation of the inflammatory response, selectin inhibition is thought to be a good target for therapeutic intervention. Three known selectins are expressed in distinct subsets of cells: P-selectin is presented on the surface of activated platelets and endothelial cells, L-selectin is constitutively expressed on leukocytes, and E-selectin synthesis is upregulated in activated endothelial cells. They mediate cell-cell adhesion in the shear flow of the bloodstream via specialized interactions with clusters of oligosaccharides presented on cell surface glycopeptide ligands. The role of selectin-ligand interactions in the inflammatory response has been demonstrated in various animal models, prompting considerable attention from the pharmaceutical industry.Drug discovery efforts have yielded many different classes of selectin inhibitors, including soluble protein ligands, antibodies, oligosaccharides and small molecules. Although many selectin inhibitors have shown activity in preclinical models, clinical progress of selectin-directed therapies has been slow. Early approaches employed carbohydrate-based inhibitors to mimic the natural ligand sialyl Lewis X; however, these compounds proved challenging to develop. Cytel's CY 1503, a complex oligosaccharide, progressed to phase II/III trials for reperfusion injury, but further development was halted when it failed to demonstrate clinical efficacy. Two protein-based selectin inhibitors have reached phase II development. These included Wyeth's recombinant soluble P-selectin ligand, TSI (PSGL-1), which was discontinued after disappointing results in myocardial infarction trials and Protein Design Labs' humanized anti-L-selectin monoclonal antibody, which is currently in development for trauma. Bimosiamose, discovered by Encysive Pharmaceutical and presently being developed by Revotar Biopharmaceuticals, is an 863 g/mol molecular weight dimer with minimal carbohydrate content and is, to date, the leading selectin inhibitor in clinical development. This compound has shown promise in a phase IIa 'proof of concept' trial in patients with asthma, reducing airway recruitment of eosinophils after intravenous administration. Further clinical development of an inhaled formulation is underway. Despite a significant need for new therapeutics, selectin inhibitors have not yet been explored for the treatment of COPD. Bimosiamose represents an important proof of principle, and hopefully continued success will spark rene

Although influenza vaccination remains the primary method for the prevention of influenza, efficacy may be limited by a poor match between the vaccine and circulating strains and the poor response of elderly patients. Hence, there is an important role for antiviral therapy in the management of influenza. While amantadine and rimantadine have been available for the treatment of influenza in some countries for several years, they are only effective against influenza A viruses, they can have neurological and gastrointestinal adverse effects, and resistant virus is rapidly generated. Neuraminidase inhibitors, a new class of drug, are potent and specific inhibitors of all strains of influenza virus, and they have minimal adverse effects. The greatest benefit is seen in those patients presenting <30 hours after development of influenza symptoms, those with severe symptoms or those in high-risk groups. In addition to treatment of the infection, both drugs are effective prophylactically and have been shown to limit spread of infection in close communities, such as families and in nursing homes. No resistant virus strains have been isolated from normal individuals treated with zanamivir. Resistant virus can be isolated from approximately 1% of adults and 5% of paediatric patients with influenza treated with oseltamivir. However, infectivity of mutant viruses is generally compromised. Governments spend millions of dollars on influenza vaccination campaigns; however, once influenza virus is circulating in the community, vaccination cannot limit the spread of disease. A greater promotion of the use of neuraminidase inhibitors for the treatment and prevention of influenza could have a significant impact on limiting its spread. This could result in saving millions of dollars, not only in direct costs associated with medical and hospital care, but also significant savings in indirect costs associated with the loss of productivity at work, school and home environments. For the benefit of all communities, there needs to be a greater awareness of the symptoms of influenza and the efficacy of neuraminidase inhibitors in disease treatment.

Chronic inflammation and oxidative stress are important features in the pathogenesis of COPD. The increased oxidative stress in patients with COPD is the result of an increased burden of inhaled oxidants, as well as increased amounts of reactive oxygen species (ROS) generated by various inflammatory, immune and epithelial cells of the airways. Oxidative stress has important implications on several events of lung physiology and for the pathogenesis of COPD. These include oxidative inactivation of antiproteases and surfactants, mucus hypersecretion, membrane lipid peroxidation, mitochondrial respiration, alveolar epithelial injury, remodeling of extracellular matrix, and apoptosis. An increased level of ROS produced in the airways is reflected by increased markers of oxidative stress in the airspaces, sputum, breath, lungs, and blood in patients with COPD. The biomarkers of oxidative stress such as H2O2, F2-isoprostanes, malondialdehyde and 4-hydroxy-2-nonenal have been successfully measured in breath condensate. ROS and aldehydes play a key role in enhancing the inflammation through the activation of mitogen-activated protein kinases and redox-sensitive transcription factors such as nuclear factor kappa B and activator protein-1. Oxidative stress also alters nuclear histone acetylation and deacetylation leading to increased gene expression of pro-inflammatory mediators in the lung. Oxidative stress may play a role in the poor clinical efficacy of corticosteroids in the treatment of COPD. Since a variety of oxidants, free radicals, and aldehydes are implicated in the pathogenesis of COPD it is likely that a combination of antioxidants may be effective in the treatment of COPD. Antioxidant compounds may also be of therapeutic value in monitoring oxidative biomarkers indicating disease progression. Various approaches to enhance the lung antioxidant screen and the clinical effectiveness of antioxidant compounds in the treatment of COPD are discussed.

Introduction: The aim of this study was to compare the decongestant properties and tolerability of oral cetirizine and pseudoephedrine in a prolonged release form with those of nasal (aqueous spray) budesonide.

Methods: Thirty-six individuals experiencing allergic rhinitis to house dustmites (HDM) participated in a study according to a randomized, crossover, two-period, two-treatment design with at least a 2-week washout period between treatments. In each period of 4 consecutive days, medications were taken twice daily. On day 1, immediately after the first intake of medication, individuals were exposed to HDM extract in the Vienna Challenge Chamber (VCC) for 5 hours. The primary efficacy parameter was nasal congestion, assessed by active anterior rhinomanometry and rating of nasal cavity photos.

Results: Rhinomanometry and nasal cavity photos both indicated that cetirizine/pseudoephedrine efficacy was statistically superior to budesonide in the management of nasal congestion during VCC sessions. The efficacy of cetirizine/pseudoephedrine was similar to that of budesonide from the end of day 1 up to day 4 when individuals were exposed to their natural environment post exposure to the aeroallergens. This study confirms the efficacy of cetirizine/pseudoephedrine and budesonide in the management of nasal congestion associated with allergic rhinitis. Both medications were well-tolerated. Cetirizine/pseudoephedrine was more effective than budesonide during HDM exposure, whereas budesonide became as effective as cetirizine/pseudoephedrine several hours post exposure to the allergens.