A genome-wide analysis of the response to inhaled ß2-agonists in chronic obstructive pulmonary disease.

Short-acting ß2-agonist bronchodilators are the most common medications used in treating chronic obstructive pulmonary disease (COPD). Genetic variants determining bronchodilator responsiveness (BDR) in COPD have not been identified. We performed a genome-wide association study (GWAS) of BDR in 5789 current or former smokers with COPD in one African-American and four white populations. BDR was defined as the quantitative spirometric response to inhaled ß2-agonists. We combined results in a meta-analysis. In the meta-analysis, single-nucleotide polymorphisms (SNPs) in the genes KCNK1 (P=2.02 × 10(-7)) and KCNJ2 (P=1.79 × 10(-7)) were the top associations with BDR. Among African Americans, SNPs in CDH13 were significantly associated with BDR (P=5.1 × 10(-9)). A nominal association with CDH13 was identified in a gene-based analysis in all subjects. We identified suggestive association with BDR among COPD subjects for variants near two potassium channel genes (KCNK1 and KCNJ2). SNPs in CDH13 were significantly associated with BDR in African Americans.The Pharmacogenomics Journal advance online publication, 27 October 2015; doi:10.1038/tpj.2015.65.

Efficacy and safety of 4 weeks' treatment with combined fluticasone furoate/vilanterol in a single inhaler given once daily in COPD: a placebo-controlled randomised trial.

Background Fluticasone furoate/vilanterol (FF/VI) is a novel once-daily (OD) inhaled corticosteroid/long-acting ß(2) agonist combination in development for chronic obstructive pulmonary disease (COPD) and asthma. Trial design A multicentre, randomised, double-blind, parallel-group, placebo-controlled study. Methods Participants were patients with moderate-to-severe COPD treated with placebo or FF/VI 400/25 µg OD for 4 weeks. Study objectives were to assess the safety and efficacy of FF/VI 400/25 µg OD administered for 4 weeks via a novel dry powder inhaler. Co-primary end points were change from baseline in weighted mean (wm) heart rate 0-4 h postdose at day 28 and the incidence of adverse events (AEs). Secondary end points included change from baseline in trough forced expiratory volume in one second (FEV(1)) (23-24 h postdose; day 29) and wm FEV(1) (0-4 h postdose; day 28). Patients were randomised to receive FF/VI 400/25 µg or placebo in a 2:1 ratio; all patients and investigators were blinded to active or placebo treatment. Results 60 patients (mean age 64 years) were randomised (FF/VI: n=40; placebo: n=20), and all contributed data to the analysis. Mean screening post-bronchodilator FEV(1) per cent predicted was comparable between groups (FF/VI: 58.5%; placebo: 60.1%). The wm heart rate 0-4 h postdose was similar between groups (difference: 0.6 beats per minute; 95% CI -3.9 to 5.1). More on-treatment AEs were reported in the FF/VI group (68%) compared with the placebo group (50%). The most common drug-related AEs in the FF/VI group were oral candidiasis (8%) and dysphonia (5%). There were no clinically relevant effects on laboratory values, including glucose and potassium, or on vital signs or ECGs/Holters. The FF/VI group had statistically greater improvements compared with placebo in trough FEV(1) (mean difference 183 ml) and 0-4 h postdose wm FEV(1) (mean difference 236 ml). Conclusion FF/VI has a good safety and tolerability profile and improves lung function compared with placebo in patients with COPD. Trial registration number clinical trials.gov-NCT00731822.

Pneumonia risk in COPD patients receiving inhaled corticosteroids alone or in combination: TORCH study results.

Inhaled corticosteroids (ICS) are important in reducing exacerbation frequency associated with chronic obstructive pulmonary disease (COPD). However, little is known about the risk of associated infections. In a post hoc analysis of the TOwards a Revolution in COPD Health (TORCH) study, we analysed and identified potential risk factors for adverse event reports of pneumonia in this randomised, double-blind trial comparing twice-daily inhaled salmeterol (SAL) 50 microg, fluticasone propionate (FP) 500 microg, and the combination (SFC) with placebo in 6,184 patients with moderate-to-severe COPD over 3 yrs. Despite a higher withdrawal rate in the placebo arm, after adjusting for time on treatment, a greater rate of pneumonia was reported in the FP and SFC treatment arms (84 and 88 per 1,000 treatment-yrs, respectively) compared with SAL and placebo (52 and 52 per 1,000 treatment-yrs, respectively). Risk factors for pneumonia were age > or =55 yrs, forced expiratory volume in 1 s <50% predicted, COPD exacerbations in the year prior to the study, worse Medical Research Council dyspnoea scores and body mass index <25 kg.m(-2). No increase in pneumonia deaths with SFC was observed; this could not be concluded for FP. Despite the benefits of ICS-containing regimens in COPD management, healthcare providers should remain vigilant regarding the possible development of pneumonia as a complication in COPD patients receiving such therapies.

Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE).

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease and not well understood. The forced expiratory volume in one second is used for the diagnosis and staging of COPD, but there is wide acceptance that it is a crude measure and insensitive to change over shorter periods of time. Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) is a 3-yr longitudinal study with four specific aims: 1) definition of clinically relevant COPD subtypes; 2) identification of parameters that predict disease progression in these subtypes; 3) examination of biomarkers that correlate with COPD subtypes and may predict disease progression; and 4) identification of novel genetic factors and/or biomarkers that both correlate with clinically relevant COPD subtypes and predict disease progression. ECLIPSE plans to recruit 2,180 COPD subjects in Global Initiative for Chronic Obstructive Lung Disease categories II-IV and 343 smoking and 223 nonsmoking control subjects. Study procedures are to be performed at baseline, 3 months, 6 months and every 6 months thereafter. Assessments include pulmonary function measurements (spirometry, impulse oscillometry and plethysmography), chest computed tomography, biomarker measurement (in blood, sputum, urine and exhaled breath condensate), health outcomes, body impedance, resting oxygen saturation and 6-min walking distance. Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points is the largest study attempting to better describe the subtypes of chronic obstructive pulmonary disease, as well as defining predictive markers of its progression.

Fluticasone propionate/salmeterol hydrofluoroalkane via metered-dose inhaler with integrated dose counter: Performance and patient satisfaction.

Currently, patients have to keep track of doses to determine when to replace their metered-dose inhalers (MDIs). This study evaluated the performance and patient satisfaction of a novel MDI with an integrated dose counter. In an open-label study at 38 outpatient centres, patients > or =12 years old with asthma or chronic obstructive pulmonary disease (COPD) received two actuations of fluticasone propionate/salmeterol 125/25 microg (115/21 microg ex-actuator) hydrofluoroalkane (ADVAIR) HFA) via MDI with counter twice a day until all 120 actuations were completed. Concordance between counter and diary recordings in patients who reported use of > or =90% of labelled actuations (completer population, n = 228) was high (discrepancy rate of 0.94%) and the incidence of device firing without changes in counter readings was low (0.13%). Mean expected actuations based on canister weights (114) were slightly lower than mean counter (121) and diary reported actuations (120). Upon study completion, 95% of patients were satisfied with the dose counter and 92% agreed it would help prevent them from running out of medication. Safety assessments (intent-to-treat population, n = 237) indicated that the drug was well tolerated. This integrated MDI counter may help patients maintain better disease control by enabling them to accurately track their medication supply.

A review of the pharmacology and pharmacokinetics of inhaled fluticasone propionate and mometasone furoate.

BACKGROUND: Fluticasone propionate is an established corticosteroid administered intranasally for the treatment of rhinitis or by oral inhalation for the treatment of asthma. Mometasone furoate, a closely related corticosteroid currently available in an intranasal formulation, is being investigated in an oral inhalation formulation for the treatment of asthma. OBJECTIVE: This article reviews available data on the comparative structure-activity relationships, chemistry, pharmacology, pharmacokinetics, and systemic bioavailability of fluticasone propionate and mometasone furoate to assess whether claims of differences in the absolute systemic bioavailability of the 2 compounds are supported by the published literature. METHODS: Information for this review was identified through a MEDLINE search of the literature from 1966 to the present that contained the term mometasone or fluticasone. The resulting list was narrowed by excluding articles dealing with dermatologic applications. A systematic review was conducted of the identified literature pertaining to the molecular structure, topical potency, lipophilicity, pharmacokinetics, and bioavailability of the 2 agents. Additionally, the pharmacology of the 2 moieties was assessed by a review of the available literature on receptor binding affinity, transactivation and transrepression potency, and inhibition of inflammatory-cell cytokine expression. RESULTS: Based on the available data, fluticasone propionate and mometasone furoate have similar physicochemical properties and structure-activity relationships. When administered intranasally, mometasone furoate is reported to have comparable relative systemic bioavailability to that of fluticasone propionate (mean plasma area under the curve, 123 pmol x h/L vs 112 pmol x h/L, respectively). When administered as a single dose by dry powder inhaler, orally inhaled fluticasone propionate is reported to have a total systemic bioavailability of approximately 17%, whereas that of mometasone furoate is reported to be < 1%. However, the mometasone furoate bioavailability study that reported the latter value used lower drug doses and a less sensitive assay than the fluticasone propionate bioavailability study. When multiple-dose data were used, mometasone furoate had an estimated 11% systemic bioavailability, similar to that of fluticasone propionate. CONCLUSIONS: Inhaled fluticasone propionate and mometasone furoate appear to have comparable potential systemic absorption and, based on the total systemic bioavailabilities of the parent compounds, have a low potential for systemic side effects at the recommended clinical doses. However, in the case of mometasone furoate, the contribution of the active metabolites to systemic effects has not been adequately assessed.

Clinical practice guidelines vs actual clinical practice : the asthma paradigm.

In recent years, a multitude of practice guidelines, statements, position papers, and "best practices" have been promulgated for a number of disease entities by a variety of medical societies and managed care organizations. In the case of asthma, for example, the National Heart, Lung, and Blood Institute of the National Institutes of Health (NIH) initially published guidelines for the diagnosis and management of asthma in 1991; these recommendations were updated in 1997. However, health-care providers have not widely and consistently adhered to these guidelines. Several recent publications suggest that this underutilization of the NIH asthma guidelines may in part be related to a lack of understanding. This lack of understanding appears to span the spectrum of physicians in private practice, physicians working in health maintenance organizations, as well as university-affiliated physicians. Moreover, both primary-care physicians and "asthma specialists" share deficits in their knowledge base. To compound the problem, patients with asthma also demonstrate poor adherence to the guidelines. This poor adherence is evident irrespective of the patient's socioeconomic status. These types of data clearly indicate a need for further educational programs directed to both physicians and patients. However, as with the development and promulgation of any practice guideline, physicians need to be convinced that there exists compelling evidence from well-controlled clinical trials, for example, or from evidence-based medicine, to substantiate implementation of these guidelines.

Increased gelatinolytic activity in bronchoalveolar lavage fluid in stable lung transplant recipients.

Proteolytic enzymes have been proposed to play a role in the pathogenesis of various inflammatory pulmonary diseases accompanied by parenchymal remodeling. To assess the role of inflammatory cells and proteolytic enzymes in the development of chronic allograft rejection after lung transplantation, bronchoalveolar lavage fluid (BALF) samples from clinically stable lung transplant (LT) recipients (i.e., without evidence of active infection or rejection), heart transplant (HT) recipients, and healthy volunteers (NL) were analyzed for total white blood cell (WBC) count and differential cell count, along with gelatinolytic/type IV collagenolytic activity. The LT group displayed a significantly increased total WBC count, neutrophil count, and percent neutrophils compared with the NL group, confirming the presence of inflammation. Furthermore, gelatin zymography revealed a significant increase in activity of the 72 and 92 kD gelatinases in the LT group compared with the NL group. A positive correlation existed between neutrophil counts and the increase in proteolytic activity. Immunosuppressive therapy did not account for the findings, since no significant difference in cell counts or proteolytic activity existed between the NL and HT control groups. These findings, together with those of others that relate chronic lung allograft dysfunction to an increase in BALF neutrophils and collagen matrix remodeling, collectively indicate that up-regulated proteolytic activity may have a role in chronic rejection after lung transplantation.

Bovine surfactant therapy for patients with acute respiratory distress syndrome.

Lung surfactant is deficient in patients with acute respiratory distress syndrome (ARDS). We performed a randomized, prospective, controlled, open-label clinical study of administration of a bovine surfactant to patients with ARDS to obtain preliminary information about its safety and efficacy. Patients received either surfactant by endotracheal instillation in addition to standard therapy or standard therapy only. Three different groups of patients receiving surfactant were studied: patients receiving up to eight doses of 50 mg phospholipids/kg, those receiving up to eight doses of 100 mg phospholipids/kg, and those receiving up to four doses of 100 mg phospholipids/kg. Outcome measures included ventilatory support parameters, arterial blood gases, organ system failures, bronchoalveolar lavage (BAL) analyses, immunologic analyses, survival, and adverse events during the 28-d study period. Fifty-nine study patients were evaluable; 43 in the surfactant group and 16 in the control group. The FI(O2) at 120 h after treatment began was significantly decreased only for patients who received up to four doses of 100 mg phospholipids/kg surfactant as compared with control patients (p = 0.011). Mortality in the same group of patients was 18.8%, as compared with 43.8% in the control group (p = 0.075). The surfactant instillation was generally well tolerated, and no safety concerns were identified. This pilot study presents preliminary evidence that surfactant might have therapeutic benefit for patients with ARDS, and provides rationale for further clinical study of this agent.

Flow cytometric analysis of lung lymphocytes in lung transplant recipients.

Lung transplantation is an accepted therapeutic modality in end-stage lung disease. Presently, histologic examination of tissue by transbronchial biopsy remains as the definitive diagnostic procedure for determining rejection. To begin addressing the usefulness of flow cytometric analysis of bronchoalveolar lavage fluid (BALF) in acute lung rejection, we prospectively studied the expression of markers on lymphocytes from BALF samples removed from 10 lung and heart-lung transplant recipients and compared their pattern with that of BALF lymphs obtained from normal volunteers (Norm) and nonrejecting heart transplant recipients (HT) who were receiving similar immunosuppressive regimens. Compared with both Norm and HT subjects, CD4+ lymphocytes in the BALF of lung transplant recipients was significantly reduced. A greater percentage of the CD4+ lymphocytes in nonrejecting lung transplant subjects also expressed the interleukin-2 receptor, but only during the early post-transplant period, suggesting possible reactivity to persistent donor cells. However, the CD8+ lymphocytes were increased only in lung transplant recipients undergoing acute lung rejection. We conclude that the immunologic milieu is indeed altered in the transplanted lung. Further studies in lung transplant recipients are required to evaluate the role of flow cytometry in the early detection of acute lung rejection.

Sublethal hydrogen peroxide inhibits alveolar type II cell surfactant phospholipid biosynthetic enzymes.

Alveolar type II cell injury by phagocytic cell-derived reactive oxygen metabolites represents a potential mechanism for the altered surfactant metabolism found in patients with the adult respiratory distress syndrome (ARDS). Previous studies demonstrated altered surfactant phospholipid metabolism after sublethal oxidant exposure. In this study, we measured intracellular ATP levels and the activities of several enzymes involved in surfactant phospholipid biosynthesis after sublethal H2O2 exposure of cultured rat alveolar type II cells. Intracellular ATP levels were reduced by 46.6% after exposure to 75 microM H2O2. The activity of CTP:phosphorylcholine cytidyltransferase was unchanged after H2O2 exposure when measured in whole cell homogenates. However, when measured in the microsomal fraction, cytidyltransferase activity significantly fell after exposure of type II cells to 75 microM H2O2. Activity in the cytosolic fractions remained unchanged. Similarly, microsomal cholinephosphotransferase was reduced after H2O2 exposure. We conclude that H2O2 decreases surfactant phosphatidylcholine biosynthesis independently of its ability to deplete intracellular ATP content. These deleterious effects may partially explain the diminished alveolar surfactant observed in patients with ARDS.

IR-192, low dose rate endobronchial brachytherapy in the treatment of malignant airway obstruction.

PURPOSE: To assess the value of low-dose-rate endobronchial brachytherapy in the treatment of malignant airway obstruction. METHODS AND MATERIALS: Between September 1986 and April 1989, 39 patients with malignant airway obstruction had 49 catheter placements for an afterloading, low-dose-rate Ir-192 endobronchial brachytherapy. A flexible fiberoptic bronchoscope with fluoroscopic guidance was used for positioning. Thirty-eight of 39 (97%) patients completed the prescribed treatments. Ninety-seven percent had received previous external radiation in doses ranging from 36-60 Gy. One patient had metastatic renal cell carcinoma; the remainder had recurrent lung cancer. Endobronchial laser treatments were given to three patients 2-3 weeks prior to endobronchial brachytherapy. All patients were followed until death. The median dose delivered in 48 of the 49 placements was 20 Gy at 1 cm. RESULTS: Follow-up bronchoscopy was performed in 28 (72%) of 39 patients. Of these, 13 (46%) had a complete response, 12 (43%) had a partial response, and 3 (17%) had a minor response. Dyspnea improved in 30 of 37 patients (82%); hemoptysis in 17 of 19 patients (89%); cough in 31 of 39 patients (79%); and postobstructive pneumonia in 21 of 23 patients (92%). The median survival for the entire group was 5 months (range 1-31 months). CONCLUSION: This technique is simple, well-tolerated and offered significant palliation.

Clinical controversies in asbestos-induced lung diseases.

Asbestos is a heterogeneous mineral fiber with considerable heat resistance and sound-abatement properties. It is relatively easily mined and processed and has been applied in a number of forms to ships and buildings. Unfortunately, respirable asbestos fibers have significant pathologic effects on the human lung and other organs. These effects can result in characteristic pleuropulmonary diseases, which become manifest after a latency period of 10 to 40 years from first exposure. This brief review will outline some major current controversies in the clinical approach to evaluation of asbestos-induced lung diseases.

Surfactant chemical composition and biophysical activity in acute respiratory distress syndrome.

Acute Respiratory Distress Syndrome (ARDS) is characterized by lung injury and damage to the alveolar type II cells. This study sought to determine if endogenous surfactant is altered in ARDS. Bronchoalveolar lavage was performed in patients at-risk to develop ARDS (AR, n = 20), with ARDS (A, n = 66) and in normal subjects (N, n = 29). The crude surfactant pellet was analyzed for total phospholipids (PL), individual phospholipids, SP-A, SP-B, and minimum surface tension (STmin). PL was decreased in both AR and A (3.48 +/- 0.61 and 2.47 +/- 0.40 mumol/ml, respectively) compared to N (7.99 +/- 0.60 mumol/ml). Phosphatidylcholine was decreased in A (62.64 +/- 2.20% PL) compared to N (76.27 +/- 2.05% PL). Phosphatidylglycerol was 11.58 +/- 1.21% PL in N and was decreased to 6.48 +/- 1.43% PL in A. SP-A was 123.64 +/- 20.66 micrograms/ml in N and was decreased to 49.28 +/- 21.68 micrograms/ml in AR and to 29.88 +/- 8.49 micrograms/ml in A. SP-B was 1.28 +/- 0.33 micrograms/ml in N and was decreased to 0.57 +/- 0.24 micrograms/ml in A. STmin was increased in AR (15.1 +/- 2.53 dyn/cm) and A (29.04 +/- 2.05 dyn/cm) compared to N (7.44 +/- 1.61 dyn/cm). These data demonstrate that the chemical composition and functional activity of surfactant is altered in ARDS. Several of these alterations also occur in AR, suggesting that these abnormalities occur early in the disease process.

Effects of oxygen metabolites on rat alveolar type II cell viability and surfactant metabolism.

Neutrophil-derived reactive oxygen metabolites have been implicated as one mechanism for the cellular injury in the adult respiratory distress syndrome. Previous studies have demonstrated that alveolar lung fluid of patients with adult respiratory distress syndrome has abnormal composition and surface active properties. To examine the effects of oxygen metabolites on the viability and metabolism of type II alveolar pneumocytes, the cellular source of surfactant, isolated rat type II pneumocytes were exposed to reactive oxygen metabolites generated by the enzymatic action of xanthine oxidase upon hypoxanthine. Utilizing a 51Cr release assay to detect cellular death, we found that oxygen metabolites were lethal to type II cells in a dose-dependent manner. To demonstrate that oxygen metabolites were responsible for the toxicity, we assessed the protective effects of catalase and superoxide dismutase, scavengers of hydrogen peroxide and the superoxide anion, respectively. At a xanthine oxidase concentration of 50 mU/ml, catalase reduced the percentage of 51Cr release from 58.9 +/- 3.1% (SEM) to 7.2 +/- 2.3% (p less than 0.0001), whereas superoxide dismutase was without protection (58.9 +/- 3.1% versus 54.2 +/- 1.8% (p greater than 0.05). To determine whether oxygen metabolites also impair surfactant metabolism, we measured the incorporation of [3H]palmitate into the surfactant component disaturated phosphatidylcholine by type II pneumocytes. We found that sublethal amounts of generated oxygen metabolites caused a progressive decrease in the amount of [3H]palmitate incorporated into disaturated phosphatidylcholine. For example, using a xanthine oxidase concentration of 5 mU/ml (which causes no increased 51Cr release), we found that [3H]palmitate incorporation into disaturated phosphatidylcholine fell from a control level of 3.53 +/- 0.22 X 10(5) to 0.66 +/- 0.10 X 10(5) dpm/10(6) cells/4 hours (p less than 0.0001). Both catalase and superoxide dismutase protected the [3H]palmitate incorporation of oxygen metabolite-exposed type II cells. We conclude that reactive oxygen metabolites are injurious to type II pneumocytes and may result in impaired surfactant synthesis even at sublethal doses. Thus, oxygen metabolites generated by stimulated phagocytic cells may be responsible in part for the decreased surfactant that has been observed in adult respiratory distress syndrome.