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Background: Vilanterol (GW642444M) (VI) is a novel, inhaled, long-acting β(2) agonist with inherent 24-h activity under development as a once-daily combination therapy with an inhaled corticosteroid for COPD and asthma. This study assessed the dose response, efficacy, and safety of VI at doses of 3 to 50 μg in patients with moderate to severe COPD.Methods: Six hundred two patients (intent-to-treat) were randomized (double-blind) to VI 3, 6.25, 12.5, 25, or 50 μg or placebo once daily for 28 days. The primary end point was change from baseline in trough FEV1 at the end of the 28-day treatment period. Secondary end points included 0- to 24-h weighted mean FEV(1) on days 1 and 28 and time to increases of ≥ 100 mL or ≥ 12% from baseline FEV(1) on day 1. Safety assessments included adverse events, vital signs, ECG assessment, and clinical laboratory tests.Results: VI once daily for 28 days significantly improved trough FEV(1) in a dose-dependent manner vs placebo. Clinically relevant treatment differences of ≥ 130 mL in trough and 0- to 24-h weighted mean FEV(1) were observed with VI 25- and 50-μg doses vs placebo. All doses of VI were associated with a low incidence of treatment-related adverse events/serious adverse events, with no suggestion of effects on BP, pulse rate, QT intervals corrected for heart rate calculated by Fridericia formula, or blood glucose and potassium levels.Conclusions: VI 25 and 50 μg once daily provided both statistically and clinically relevant 24-h improvements in lung function in patients with COPD compared with placebo. All doses of VI had a safety and tolerability profile similar to placebo. [ABSTRACT FROM AUTHOR]

Presents study findings on the marital satisfaction in the lives of physicians and their spouses. Use of Marital Relationship Inventory; Representativeness of physicians and their spouses; Insider-outsider dilemma in studying interpersonal relationships; Contradiction of the notion that the modal marriage of physicians is dysfunctional.

Background: The benefits of triple therapy for chronic obstructive pulmonary disease (COPD) with an inhaled glucocorticoid, a long-acting muscarinic antagonist (LAMA), and a long-acting β 2 -agonist (LABA), as compared with dual therapy (either inhaled glucocorticoid-LABA or LAMA-LABA), are uncertain., Methods: In this randomized trial involving 10,355 patients with COPD, we compared 52 weeks of a once-daily combination of fluticasone furoate (an inhaled glucocorticoid) at a dose of 100 μg, umeclidinium (a LAMA) at a dose of 62.5 μg, and vilanterol (a LABA) at a dose of 25 μg (triple therapy) with fluticasone furoate-vilanterol (at doses of 100 μg and 25 μg, respectively) and umeclidinium-vilanterol (at doses of 62.5 μg and 25 μg, respectively). Each regimen was administered in a single Ellipta inhaler. The primary outcome was the annual rate of moderate or severe COPD exacerbations during treatment., Results: The rate of moderate or severe exacerbations in the triple-therapy group was 0.91 per year, as compared with 1.07 per year in the fluticasone furoate-vilanterol group (rate ratio with triple therapy, 0.85; 95% confidence interval [CI], 0.80 to 0.90; 15% difference; P<0.001) and 1.21 per year in the umeclidinium-vilanterol group (rate ratio with triple therapy, 0.75; 95% CI, 0.70 to 0.81; 25% difference; P<0.001). The annual rate of severe exacerbations resulting in hospitalization in the triple-therapy group was 0.13, as compared with 0.19 in the umeclidinium-vilanterol group (rate ratio, 0.66; 95% CI, 0.56 to 0.78; 34% difference; P<0.001). There was a higher incidence of pneumonia in the inhaled-glucocorticoid groups than in the umeclidinium-vilanterol group, and the risk of clinician-diagnosed pneumonia was significantly higher with triple therapy than with umeclidinium-vilanterol, as assessed in a time-to-first-event analysis (hazard ratio, 1.53; 95% CI, 1.22 to 1.92; P<0.001)., Conclusions: Triple therapy with fluticasone furoate, umeclidinium, and vilanterol resulted in a lower rate of moderate or severe COPD exacerbations than fluticasone furoate-vilanterol or umeclidinium-vilanterol in this population. Triple therapy also resulted in a lower rate of hospitalization due to COPD than umeclidinium-vilanterol. (Funded by GlaxoSmithKline; IMPACT ClinicalTrials.gov number, NCT02164513 .).

Rationale: Radiographically confirmed pneumonia risk with inhaled corticosteroid use in chronic obstructive pulmonary disease (COPD) has not been assessed to date., Objectives: To determine the incidence of pneumonia, risk factors, and clinical attributes with inhaled fluticasone furoate (FF) in patients with COPD with an exacerbation history., Methods: Two replicate, 1-year, double-blind clinical trials enrolled subjects with COPD with moderate to very severe airflow limitation and at least one exacerbation within the prior year. Subjects were randomized 1:1:1:1 to receive inhaled once-daily vilanterol (VI) 25 μg or VI 25 μg combined with 50, 100, or 200 μg FF. Subjects were required to have a chest radiograph at screening and within 48 hours of any suspected pneumonia or exacerbation., Measurements and Main Results: Among 3,255 randomized subjects, 205 pneumonia events occurred in 181 subjects. Chest imaging was available for 195 (95%) of these events. Chest radiographs were also obtained for 1,793 (70%) of the 2,545 moderate and severe exacerbations. For VI alone and the combination with 50, 100, or 200 μg FF, reported pneumonia incidence was 3, 6, 6, and 7%, respectively. However, for events with compatible parenchymal infiltrates, the respective incidences were 2, 4, 4, and 5%. Factors associated with at least a twofold increase in the risk of pneumonia with FF/VI treatment were being a current smoker, having prior pneumonia, body mass index <25 kg/m(2), and severe airflow limitation., Conclusions: Radiographically confirmed pneumonia risk is increased with inhaled FF/VI, although at less than investigator-defined rates. Modifiable pneumonia risk factors should be considered when attempting to optimize COPD management. Clinical trial registered with www.clinicaltrials.gov (NCT01009463 [HZC102871]; NCT01017952 [HZC102970]).

Background: Whether the combination of a once-daily inhaled corticosteroid with a once-daily longacting β(2) agonist is more protective than a once-daily longacting β(2) agonist alone against exacerbations of chronic obstructive pulmonary disease (COPD) is unknown. We hypothesised that fluticasone furoate and vilanterol would prevent more exacerbations than would vilanterol alone., Methods: We did two replicate double-blind parallel-group 1 year trials. Both studies began on Sept 25, 2009. Study 1 ended on Oct 31, 2011, and study 2 on Oct 17, 2011. Eligible patients were aged 40 years or older, had a history of COPD, a smoking history of 10 or more pack-years, a ratio of forced expiratory volume in 1 s (FEV(1)) to forced vital capacity of 0·70 or less after bronchodilators (and an FEV(1) of 70% or less of predicted), and a documented history of one or more moderate or severe disease exacerbations in the year before screening. Patients were randomly assigned (1:1:1:1) on the basis of the Registration and Medication Ordering System to 25 μg vilanterol alone or 25 μg vilanterol combined with either 50 μg, 100 μg, or 200 μg fluticasone furoate once daily. Our primary endpoint was the yearly rate of moderate and severe exacerbations. The trials were analysed separately and a pooled analysis was also done. These trials are registered with ClinicalTrials.gov (NCT01009463 and NCT01017952)., Findings: 1622 patients in study 1 and 1633 patients in study 2 were randomly assigned. In study 1, no significant difference in exacerbation rate was noted between the 200/25 μg fluticasone furoate/vilanterol group and the vilanterol only group (mean 0·90 events vs 1·05 events per year; ratio 0·9 [95% CI 0·7-1·0]). Because of the statistical hierarchy used, we could not infer significance for the 50 μg and 100 μg groups. In study 2, significantly fewer moderate and severe exacerbations were noted in all fluticasone furoate/vilanterol groups than in the vilanterol only group (p=0·0398 for the 50 μg group, 0·0244 for the 100 μg group, and 0·0004 for the 200 μg group). In the pooled analysis, significantly fewer moderate and severe exacerbations were noted in all fluticasone furoate/vilanterol groups than in the vilanterol only group (0·0141 for the 50 μg group, <0·0001 for the 100 μg group, and 0·0003 for the 200 μg group). Nasopharyngitis was the most frequently reported adverse event in both studies. Pneumonia and fractures were reported more frequently with fluticasone furoate and vilanterol than with vilanterol alone. Eight deaths from pneumonia were noted in the fluticasone furoate/vilanterol groups compared with none in the vilanterol only group., Interpretation: Addition of fluticasone furoate to vilanterol was associated with a decreased rate of moderate and severe exacerbations of COPD in patients with a history of exacerbation, but was also associated with an increased pneumonia risk., Funding: GlaxoSmithKline., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The aim of this review is to present the clinical data on the efficacy and safety of cilomilast in patients with chronic obstructive pulmonary disease (COPD). Over 6000 COPD patients received cilomilast during an extensive clinical development programme performed by GlaxoSmithKline (GSK).Five phase III randomized, double-blind, placebo-controlled, parallel-group pivotal studies were conducted in poorly reversible patients (<15% or <200 mL improvement over baseline in forced expiratory volume in 1 second (FEV(1)) after salbutamol). Patients were randomized to receive oral cilomilast 15 mg (n = 2088) or placebo (n = 1408) twice daily for 24 weeks. The co-primary efficacy variables were changes from baseline in trough (predose) FEV(1) and in total score of the St George's Respiratory Questionnaire (SGRQ).Additional studies were performed to investigate the anti-inflammatory actions of cilomilast by measuring inflammatory cells and mediators in biopsies and induced sputum; to assess the long-term effects of cilomilast; to assess the cardiac safety of cilomilast; and to assess the efficacy of cilomilast on hyperinflation. Results from one of the phase III and from one supportive study have been previously published.In the phase III pivotal studies, when averaged over 24 weeks, the mean change from baseline in FEV(1) in the cilomilast group showed improvement compared with placebo in all studies (range 24-44 mL treatment difference). When averaged over 24 weeks, there was a similar improvement in the mean total SGRQ score in both treatment groups with a decrease ranging from -1.8 to -4.2 units in the cilomilast group and 0.4 to -4.9 units in the placebo group. Only one study, however, showed both a statistically and clinically meaningful difference between the two treatment groups (treatment difference -4.1 units; p < 0.001). Although cilomilast was shown to reduce COPD exacerbations in some of these studies, there was no effect on the incidence of COPD exacerbations in a study specifically powered to detect a difference compared with placebo.No significant change was found in the primary endpoints of the anti-inflammatory studies, although some anti-inflammatory activity was detected, including a reduction in tissue CD8+ T lymphocytes and CD68+ macrophages in airway biopsies. In addition, studies did not demonstrate a consistent significant effect of cilomilast on hyperinflation.In all studies, adverse events associated with the gastrointestinal body system were reported more frequently in the cilomilast group than the placebo group and predominantly occurred within the first 2 weeks of initiating cilomilast therapy.During the cilomilast development programme a number of different endpoints were investigated to characterize the efficacy and safety of this second-generation phosphodiesterase 4 inhibitor. Safety assessments throughout the late-phase programme did not reveal any evidence of serious safety concerns with the use of cilomilast. Previous studies in phase II and early phase III had shown improvements in efficacy endpoints and some evidence of an anti-inflammatory mechanism of action. However, subsequent phase III studies failed to definitively confirm the earlier programme results, which led to termination of the development of cilomilast.

One of the most difficult responsibilities of the forensic toxicologist is the interpretation of postmortem drug levels and their possible significance as to behavior and/or cause of death. During the past 15 years, much work has been performed using human case information and animal studies to illustrate and validate the phenomena of postmortem drug redistribution. These studies provide certain clarification to drug level interpretation. They also cast uncertainty on the interpretation of drugs where analogous studies are incomplete or totally absent. Literature data of more than 30 drugs, as reported by numerous authors, are reviewed to illustrate two phenomena: (a) postmortem redistribution occurs primarily as a function of the diffusion of drugs along a concentration gradient, from sites of high concentration in solid organs into the blood with artificial elevation of the drug levels; and (b) while many drugs seem to subject to postmortem redistribution, there are also others that undergo no change whatsoever. While additional work still needs to be performed, there has been enough achieved to both illustrate and validate that postmortem redistribution does exist. This information is helpful to forensic pathologists in determining sample sets taken during autopsy., (Copyright © 2001 Central Police University.)

Background: Aerosolized asthma medications with chlorofluorocarbon (CFC) propellants are being phased out because of environmental concerns about the ozone layer. Medications are being reformulated with non-ozone-depleting propellants., Objective: To evaluate the clinical comparability of albuterol sulfate formulated in a new hydrofluoroalkane-134a (HFA) propellant (Ventolin HFA Inhalation Aerosol), and conventional CFC-containing albuterol (Ventolin Inhalation Aerosol) in children with asthma., Design: Randomized, double-blind, placebo-controlled 2-week clinical trial with a 1- to 2-week run-in period. During the run-in, patients took Ventolin CFC as needed. Patients (n = 135) aged 4 to 11 years with asthma then were assigned randomly to treatment with Ventolin HFA, Ventolin CFC, or placebo administered 4 times daily via metered-dose inhaler for 2 weeks. All patients were allowed rescue albuterol use in matching propellant as needed for relief of breakthrough symptoms. The main outcome measure was the mean percentage of predicted peak expiratory flow (PEF) after the morning dose of study drug on day 1 and after 2 weeks as assessed by results of 6-hour serial tests., Results: At day 1, the mean (+/- SE) percentage of predicted PEF increased postdose by 14% (+/- 1%) in the Ventolin HFA group and 13% (+/- 1%) in the Ventolin CFC group compared with 6% (+/- 2%) in the placebo group (P

Survey data from 113 female physicians, 634 male physicians, and 41 female dentists were compared. Instruments designed to assess work satisfaction, work stress, marital satisfaction, family competence, and psychiatric symptoms and treatment were used, thereby exploring important life domains concurrently. The results suggest that female physicians are much more like both male physicians and female dentists than anticipated. Generally, female physicians describe high levels of work satisfaction, moderate levels of work stress, average-to-high levels of marital satisfaction, and relatively low levels of psychiatric distress. Their lower levels of practice income remain something of an enigma as gender remains the most powerful predictor of income and is not replaced in statistical analyses by specialty, hours worked, or other significant variables. Finally, female physicians who find higher levels of satisfaction in work also report higher levels of marital satisfaction and fewer psychiatric symptoms. For these women, a highly satisfying medical career does not apparently need to be experienced at the cost of marital or personal distress.

The work stress of physicians is considered high, and many are contemplating leaving the profession. Documenting the specific aspects of practice found to be most stressful is important, and useful insights may be obtained by contrasting physicians who report high and low levels of work stress. Contrasting the work stress of physicians and dentists can be useful for both professions. Accordingly, we surveyed 3156 members of the Dallas County Medical Society and 1273 members of the Dallas County Dental Society plus a large group of their spouses. Although the level of work satisfaction is the most powerful predictor of work stress, other significant predictors are younger age, long working hours, and solo practice. Physicians who report high levels of work stress also report lower levels of marital satisfaction and a higher prevalence of psychiatric symptoms. Dentists are much like physicians in their reports of overall work stress, and the similarities and differences regarding specific stressors suggest the two professions are more alike than different in reporting the stresses of professional practice.

Although the development of psychiatric residents has been studied extensively, continuing changes in psychiatrists after graduation from training have not. The authors present results of a survey research study of 263 psychiatrists recently graduated from a wide variety of training programs. The psychiatrists reported alarming symptoms of stress during this period, yet they used effective coping mechanisms and perceived themselves as increasing in growth, mastery, and confidence. Their overall contenment with their personal and professional lives effective coping mechanisms were those involving the establishment of support systems with loved ones.

Clinical, pathologic, and epidemiologic observations of malignant tumors of children in sub-Sahara Africa suggest alternative theories of causation, and give insight into environmental influences that may play a large role in the etiology and form of malignant lymphatic tumors and cerebral neoplasms of infants.