Treatments in respiratory medicine最新文献

Inhaled corticosteroids are effective in controlling airway inflammation. Their anti-inflammatory effect is primarily topical, at the site of deposition in the airways. Consequently, traditional pharmacodynamic and pharmacokinetic concepts, which rely on measuring blood concentrations of drug, have limited applicability for evaluating the efficacy of topically acting inhaled corticosteroids. Important factors affecting efficacy of inhaled corticosteroids are: (i) intrinsic properties of the drugs, particularly their affinity for the corticosteroid receptor; and (ii) the newer pharmacodynamic concept of deposition characteristics of the drug formulation. Small particle formulations, especially those developed in the metered-dose inhaler with the new hydrofluoroalkane propellant, deposit to a much greater extent in the lung and may consequently have improved clinical efficacy. Lipid conjugation of inhaled corticosteroids within the lung may allow prolonged duration of effect, enabling once-daily administration. Pharmacodynamic and pharmacokinetic principles probably do not play a role in describing upper airway adverse effects occurring with inhaled corticosteroids. These are probably also determined by intrinsic properties of the drug and deposition characteristics. However, pharmacodynamic and pharmacokinetic principles seem to be important in addressing systemic safety concerns with inhaled corticosteroids. Those inhaled corticosteroids with a longer serum half-life, especially if they have higher affinity for the corticosteroid receptor, may be associated with greater systemic effects. A new pharmacokinetic concept suggests that increased protein binding within the systemic circulation and high systemic clearance of an inhaled corticosteroid may reduce the risk for systemic effects. These new pharmacodynamic and pharmacokinetic concepts provide a useful framework for identifying the characteristics of an inhaled corticosteroid with an improved benefit-to-risk profile. Increased lung deposition and reduced deposition in the upper airway should result in an inhaled corticosteroid with favorable clinical efficacy and a decreased risk for topical upper airway adverse effects. An inhaled corticosteroid with high plasma protein binding and rapid clearance might pose much less risk for systemic adverse effects than currently available drugs in this class.

The purpose of this article is to review the economics of systemic therapies for the treatment of lung cancer. Lung cancer treatment is moderately expensive. The overall cost to society is significant given its high incidence. Most analyses in patients with small cell lung cancer focus on supportive care measures. The economics of chemotherapy in patients with advanced small cell lung cancer, as assessed in one study, shows alternating chemotherapy to be cost effective. Numerous economic analyses of chemotherapy in patients with non-small cell lung cancer (NSCLC) have been completed using varying methodologies in a number of countries. In patients with advanced NSCLC, third generation chemotherapy in the first-line setting can be administered within reasonable incremental cost effectiveness. Single-agent docetaxel chemotherapy in the second-line setting has also been shown to fall within a reasonable cost-effective range. Based on this review, systemic therapies for lung cancer are, for the most part, cost effective. Information on the cost-utility of systemic therapies is more limited. In a population of cancer patients with poor prognosis, the inclusion of quality indicators in the calculation of costs (i.e. cost-utility analyses) will be of great importance to refine our understanding of costs and benefits using a more global approach. Future economic analyses of adjuvant chemotherapy and novel targeted therapies will be of great interest.

Pulmonary oxidant stress plays an important pathogenetic role in disease conditions including acute lung injury/adult respiratory distress syndrome (ALI/ARDS), hyperoxia, ischemia-reperfusion, sepsis, radiation injury, lung transplantation, COPD, and inflammation. Reactive oxygen species (ROS), released from activated macrophages and leukocytes or formed in the pulmonary epithelial and endothelial cells, damage the lungs and initiate cascades of pro-inflammatory reactions propagating pulmonary and systemic stress. Diverse molecules including small organic compounds (e.g. gluthatione, tocopherol (vitamin E), flavonoids) serve as natural antioxidants that reduce oxidized cellular components, decompose ROS and detoxify toxic oxidation products. Antioxidant enzymes can either facilitate these antioxidant reactions (e.g. peroxidases using glutathione as a reducing agent) or directly decompose ROS (e.g. superoxide dismutases [SOD] and catalase). Many antioxidant agents are being tested for treatment of pulmonary oxidant stress. The administration of small antioxidants via the oral, intratracheal and vascular routes for the treatment of short- and long-term oxidant stress showed rather modest protective effects in animal and human studies. Intratracheal and intravascular administration of antioxidant enzymes are being currently tested for the treatment of acute oxidant stress. For example, intratracheal administration of recombinant human SOD is protective in premature infants exposed to hyperoxia. However, animal and human studies show that more effective delivery of drugs to cells experiencing oxidant stress is needed to improve protection. Diverse delivery systems for antioxidants including liposomes, chemical modifications (e.g. attachment of masking pegylated [PEG]-groups) and coupling to affinity carriers (e.g. antibodies against cellular adhesion molecules) are being employed and currently tested, mostly in animal and, to a limited extent, in humans, for the treatment of oxidant stress. Further studies are needed, however, in order to develop and establish effective applications of pulmonary antioxidant interventions useful in clinical practice. Although beyond the scope of this review, antioxidant gene therapies may eventually provide a strategy for the management of subacute and chronic pulmonary oxidant stress.

Idiopathic pulmonary arterial hypertension (IPAH) is a rare progressive disorder historically associated with mortality in <3 years post-diagnosis. The etiology of PAH is complex, multifactorial, and likely involves the interplay between genetic and environmental factors. These are reviewed with emphasis on the nitric oxide pathway. Use of treatment modalities including vasodilator therapy have resulted in improved symptoms, hemodynamics, and survival in these patients. Vasodilators, including the calcium channel antagonists, prostanoids, and endothelin receptor antagonists, have been used to counteract potential imbalances in vasoactive mediators in PAH patients; all have produced improved long-term symptomatology and hemodynamics. Only the prostanoid epoprostenol has improved survival in IPAH patients. Although these medications have worked well in many patients with PAH, each of them has limitations. The phosphodiesterase-5 (PDE-5) inhibitors are a relatively new form of treatment for PAH. They are designed to potentiate the effects of cyclic guanosine monophosphate, thereby mimicking endogenous nitric oxide within the vasculature. PDE-5 inhibitors are selective pulmonary vasodilators effective in animal models of pulmonary hypertension. The published clinical studies evaluating their use have been small in size to date but appear to demonstrate benefit. The recently completed 12-week randomized placebo-controlled Sildenafil Use in Pulmonary Hypertension (SUPER-1) trial demonstrated improvement in 6-minute walk distance and hemodynamics in patients receiving sildenafil. These data suggest that the PDE-5 inhibitors are effective in treating PAH and that it is likely that their usage will increase over time. The purpose of this review is to present a current view of the pathogenesis and treatment of PAH, with an emphasis on the use of PDE-5 inhibitors in these patients.

Pleural infection remains a common illness, with a high morbidity and mortality. The development of frank empyema from a simple exudative pleural effusion is a result of biochemical changes within the pleural space in response to bacterial invasion. These changes can be used in the diagnosis of pleural infection and used to predict which patients will require intercostal drainage for resolution of infection. Recent large trials in empyema have further advanced our knowledge of microbiologic patterns, informing important decisions about empiric antibacterial therapy. Diagnosis of pleural infection relies on high clinical suspicion in association with clinical features, radiology, and pleural fluid characteristics. Treatment of pleural infection is based upon accurate and often empiric choice of antibacterial agents, intercostal drainage in certain contexts, and appropriate surgical referral. Intrapleural thrombolytic therapy is not currently recommended for the treatment of pleural infection, on the basis of evidence from the largest randomized trial in empyema to date.

Objective: The purpose of this study was to measure costs associated with care for adults with cystic fibrosis, from a societal perspective.

Methods: Over a 4-week period, 110 participants completed the Ambulatory and Home Care Record, a self-administered data collection instrument that measures costs to the health system, costs to employers, care recipients' direct out-of-pocket expenditures, and time costs borne by care recipients and their family caregivers. Health system costs were based on the costs incurred through expenditures on physicians, hospital clinics, pharmaceuticals, and home care agencies. Out-of-pocket costs were obtained using self-reports by care recipients, and time losses were valued using the human capital approach.

Results: The annual mean societal costs of ambulatory care for cystic fibrosis was $Can29 885 per care recipient (year 2002 value). Time losses incurred by care recipients and their family caregivers accounted for the majority (72%) of these costs, and system costs accounted for the second highest percentage of costs (21%). Although almost all participants (109) recorded out-of-pocket expenditures, these costs accounted for only a small proportion (3%) of total costs.

Conclusion: Measuring societal costs is necessary for practitioners, managers, and policy decision-makers, to ensure that care recipients and their families receive the necessary resources to provide care.

Respiratory syncytial virus (RSV) is the most important cause of viral lower respiratory tract illness in infants and children worldwide and is responsible for over 120 000 annual hospitalizations in infants in the US alone. RSV is also recognized as a major respiratory viral pathogen in the elderly and other high-risk populations. Bronchiolitis, pneumonia, apnea, respiratory failure, and death are well known manifestations of severe acute RSV disease. RSV infection has also been associated with recurrent wheezing in children, but the mechanisms involved in this association are not completely understood. The host immune response plays a significant role in controlling the infection but is likely also involved in augmenting the disease through pathways that have not been completely identified. The treatment options for RSV infection are very limited. Ribavirin, corticosteroids, and bronchodilators are not used routinely because they have not proven to be sufficiently effective. Education of caregivers, strict handwashing, and avoidance of exposure to environmental factors associated with severe forms of RSV infection are among the most effective preventive means. Passive immunization with monoclonal antibodies provides protection against severe RSV disease in high-risk children. Clinical trials to evaluate the safety and efficacy of a second-generation monoclonal antibody are underway. Efforts to develop a safe and effective RSV vaccine have continued despite the poor outcomes observed following the administration of formalin-inactivated formulations in the 1960s. In the last decade, live attenuated vaccines (including those developed by recombinant techniques) and purified subunit vaccines have all been evaluated in humans. Results of clinical trials have been encouraging, but the availability of a safe and effective RSV vaccine is not a reality yet. Better prevention strategies will have an impact, not only on acute morbidity caused by RSV, but will also likely have an effect on ameliorating the chronic consequences of this disease.

Introduction: The aim of this study was to compare the efficacy and tolerability of pholcodine with that of dextromethorphan, one of the most used cough sedative products, in patients with acute, non-productive cough.

Methods: 129 adults with a diagnosis of acute, frequent, non-productive cough participated in a randomized, double-blind, parallel-group, multicenter trial. Medications were in a syrup formulation and were taken orally three times daily for 3 days. The efficacy endpoints were the change from baseline in the daytime and night-time cough frequency on 5-point scales at day 3, and cough intensity.

Results: A reduction of 1.4 and 1.3 points in the mean daytime cough frequency at day 3 was seen in the pholcodine and dextromethorphan groups, respectively, in the per-protocol population. The reduction in mean night-time cough was 1.3 for both groups. Cough intensity reduction was 0.7 for pholcodine and 0.8 for dextromethorphan.

Conclusions: These findings indicate that the efficacy of a 3-day course of pholcodine is similar to that of dextromethorphan in the treatment of adult patients with acute, non-productive cough. Both medications were well tolerated.

Histamine is an important mediator in airway inflammation. It is elevated in the airways of asthmatic patients and is responsible for many of the pathophysiological features in asthma. Antihistamines block the actions of histamine and also have effects on inflammation which is independent of histamine-H(1)-receptor antagonism. Antihistamines have been shown to have bronchodilatory effects, effects on allergen-, exercise-, and adenosine-monophosphate-challenge testing, and also to prevent allergen-induced nonspecific airways hyperresponsiveness. Clinical studies have shown mixed results, and some studies have reported beneficial effects of azelastine, cetirizine, desloratadine, and fexofenadine on asthma symptoms or physiological measures in patients with asthma. The combination of an antihistamine and a leukotriene receptor antagonist has been shown to have additive effects in certain studies. Antihistamines have also been shown to delay or prevent the development of asthma in a subgroup of atopic children. These data suggest that antihistamines may have beneficial effects in the management of asthma.