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Beeh K.-M.,Insaf Respiratory Research Institute | Wagner F.,Charite Research Organisation | Khindri S.,Novartis | Drollmann A.F.,Novartis
COPD: Journal of Chronic Obstructive Pulmonary Disease | Year: 2011

Indacaterol is a novel, inhaled once-daily ultra long-acting β2-agonist for the treatment of COPD. This randomised, double-blind, placebo-controlled, two-period crossover study evaluated the effect of two-week treatment with indacaterol 300 μg on peak and isotime exercise inspiratory capacity (IC) in patients with COPD. Patients (4080 years) with post-bronchodilator forced expiratory volume in 1 s (FEV 1)/forced vital capacity (FVC) <70%, percent predicted FEV 1 ≥40% and ≤80%, smoking history ≥20 pack-years and functional residual capacity >120% of predicted normal were randomised to receive indacaterol 300 μg or placebo once-daily via a single-dose dry powder inhaler. Following 14 days of treatment, IC at peak and isotime during constant-load (80% of maximum workload) cycle ergometry was analysed using linear mixed-effects models. Safety and tolerability were also monitored. Twenty-seven patients (67% male; mean age, 61.3 years) were randomised; 24 completed the study. On Day 14, indacaterol showed statistically significant improvements over placebo in peak (317 mL [95% CI: 118517]; p < 0.01) and isotime IC (268 mL [95% CI: 104432]; p < 0.01). Statistically significant improvements were observed with indacaterol versus placebo on Day 14 for the following secondary endpoints: resting IC, trough FEV 1, dyspnoea (BDI/TDI and Borg CR10 scale at isotime) and exercise endurance time. Indacaterol was well tolerated, with no serious adverse events or deaths. In conclusion, indacaterol 300 μg administered once-daily showed a clinically relevant increase in IC after 14 days of treatment, reflecting a reduction in dynamic hyperinflation. © 2011 Informa Healthcare USA, Inc.


Beeh K.-M.,Insaf Respiratory Research Institute | Kanniess F.,KLB Healthresearch Lubeck | Wagner F.,Charite Research Organisation | Schilder C.,Health Center Schilder | And 7 more authors.
Journal of Allergy and Clinical Immunology | Year: 2013

Background: Allergen-specific TH2 responses contribute to the development of allergic asthma. Their increase may be due to a reduced early exposure to environmental pathogens, which induces a TH1 response, and thereby suppresses the allergic TH2 response. QbG10 (bacteriophage Qbeta-derived virus-like particle with CpG-motif G10 inside), a novel Toll-like receptor 9 agonist packaged into virus-like particles, was designed to stimulate the immune system toward a TH1-mediated protective response. Objective: We examined clinical efficacy, safety, and tolerability of QbG10 with patient-reported and objective clinical outcome parameters in patients with mild-to-moderate persistent allergic asthma. Methods: In this proof-of-concept parallel-group, double-blind, randomized trial, 63 asthmatic patients followed conversion to a standardized inhaled steroid and were treated with 7 injections of either QbG10 or placebo. Incorporating a controlled steroid withdrawal, the effects on patient-reported (day- and nighttime asthma symptoms, salbutamol usage, and 7-item-Asthma Control Questionnaire scores) and objective clinical outcome measures (FEV1, fraction of exhaled nitric oxide, and blood eosinophils) were assessed over 12 weeks (ClinicalTrials.gov number, NCT00890734). Results: All patient-reported parameters improved overall between week 0 and 12 in QbG10-treated patients (n = 33) despite steroid withdrawal, compared with deteriorations observed under placebo (n = 30, P <.05). At week 12, two thirds of the QbG10-treated patients had their asthma "well controlled" (Asthma Control Questionnaire score ≤0.75) compared with one third under placebo. FEV 1 had worsened to a clinically significant extent in patients on placebo, while it remained stable in QbG10 patients. Adverse events were mostly injection site reactions occurring after QbG10 administration. Conclusion: Treatment with QbG10 may contribute to continued asthma control during steroid reduction in patients on moderate or high-dose inhaled steroids. © 2013 American Academy of Allergy, Asthma & Immunology.


Sponholz C.,Jena University Hospital | Matthes K.,Jena University Hospital | Rupp D.,Jena University Hospital | Backaus W.,Jena University Hospital | And 12 more authors.
Critical Care | Year: 2016

Background: The aim of extracorporeal albumin dialysis (ECAD) is to reduce endogenous toxins accumulating in liver failure. To date, ECAD is conducted mainly with the Molecular Adsorbents Recirculating System (MARS). However, single-pass albumin dialysis (SPAD) has been proposed as an alternative. The aim of this study was to compare the two devices with a prospective, single-centre, non-inferiority crossover study design with particular focus on reduction of bilirubin levels (primary endpoint) and influence on paraclinical and clinical parameters (secondary endpoints) associated with liver failure. Methods: Patients presenting with liver failure were screened for eligibility and after inclusion were randomly assigned to be started on either conventional MARS or SPAD (with 4 % albumin and a dialysis flow rate of 700 ml/h). Statistical analyses were based on a linear mixed-effects model. Results: Sixty-nine crossover cycles of ECAD in 32 patients were completed. Both systems significantly reduced plasma bilirubin levels to a similar extent (MARS: median -68 μmol/L, interquartile range [IQR] -107.5 to -33.5, p = 0.001; SPAD: -59 μmol/L, -84.5 to +36.5, p = 0.001). However, bile acids (MARS: -39 μmol/L, -105.6 to -8.3, p < 0.001; SPAD: -9 μmol/L, -36.9 to +11.4, p = 0.131), creatinine (MARS: -24 μmol/L, -46.5 to -8.0, p < 0.001; SPAD: -2 μmol/L, -9.0 to +7.0/L, p = 0.314) and urea (MARS: -0.9 mmol/L, -1.93 to -0.10, p = 0.024; SPAD: -0.1 mmol/L, -1.0 to +0.68, p = 0.523) were reduced and albumin-binding capacity was increased (MARS: +10 %, -0.8 to +20.9 %, p < 0.001; SPAD: +7 %, -7.5 to +15.5 %, p = 0.137) only by MARS. Cytokine levels of interleukin (IL)-6 and IL-8 and hepatic encephalopathy were altered by neither MARS nor SPAD. Conclusions: Both procedures were safe for temporary extracorporeal liver support. While in clinical practice routinely assessed plasma bilirubin levels were reduced by both systems, only MARS affected other paraclinical parameters (i.e., serum bile acids, albumin-binding capacity, and creatinine and urea levels). Caution should be taken with regard to metabolic derangements and electrolyte disturbances, particularly in SPAD using regional citrate anti-coagulation. Trial registration: German Clinical Trials Register ( www.drks.de ) DRKS00000371. Registered 8 April 2010. © 2016 Sponholz et al.


Ras R.T.,Unilever | Koppenol W.P.,Unilever | Garczarek U.,Unilever | Otten-Hofman A.,Unilever | And 3 more authors.
Nutrition, Metabolism and Cardiovascular Diseases | Year: 2016

Background and aims: Plant sterols (PS) lower plasma LDL-cholesterol through partial inhibition of intestinal cholesterol absorption. Although PS themselves are poorly absorbed, increased intakes of PS result in elevated plasma concentrations. In this paper, we report time curves of changes in plasma PS during 12 weeks of PS intake. Furthermore, the impact of cholesterol synthesis and absorption on changes in plasma PS is explored. Methods and results: The study was a double-blind, randomized, placebo-controlled, parallel-group study with the main aim to investigate the effects of PS on vascular function (clinicaltrials.gov: NCT01803178). Hypercholesterolemic but otherwise healthy men and women (n = 240) consumed low-fat spreads without or with added PS (3 g/d) for 12 weeks after a 4-week run-in period. Blood sampling was performed at week 0, 4, 8 and 12. Basal cholesterol-standardized concentrations of lathosterol and sitosterol + campesterol were used as markers of cholesterol synthesis and absorption, respectively. In the PS group, plasma sitosterol and campesterol concentrations increased within the first 4 weeks of intervention by 69% (95%CI: 58; 82) starting at 7.2 μmol/L and by 28% (95%CI: 19; 39) starting at 11.4 μmol/L, respectively, and remained stable during the following 8 weeks. Placebo-corrected increases in plasma PS were not significantly different between high and low cholesterol synthesizers (P-values >0.05). Between high and low cholesterol absorbers, no significant differences were observed, except for the cholesterol-standardized sum of four major plasma PS (sitosterol, campesterol, brassicasterol and stigmasterol) showing larger increases in low absorbers (78.3% (95%CI: 51.7; 109.5)) compared to high absorbers (40.8% (95%CI: 19.9; 65.5)). Conclusions: Increases in plasma PS stabilize within 4 weeks of PS intake and do not seem impacted by basal cholesterol synthesis or absorption efficiency. © 2015 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University.


Schurmann D.,Charite - Medical University of Berlin | Schurmann D.,Charite Research Organisation | Sobotha C.,Charite Research Organisation | Gilmartin J.,Merck And Co. | And 10 more authors.
AIDS | Year: 2016

Objective: To assess the antiviral activity, pharmacokinetics, and safety of doravirine in nonnucleoside reverse transcriptase inhibitor-naïve, HIV-infected men. Design: Double-blind, randomized, two-panel, dose-escalation study. Methods: In two sequential panels, 18 individuals received doravirine [25 mg (Panel A) or 200 mg (Panel B)] or matching placebo once daily for 7 days. Plasma samples were collected daily for measurement of HIV-1 RNA levels and doravirine pharmacokinetics. Results: For the mean change from baseline in HIV RNA (log10 copies/ml) at 24 h after the day 7 dose, the mean difference (90% confidence interval) between doravirine and placebo was -1.37 (-1.60, -1.14) in the 25-mg group and -1.26 (-1.51, -1.02) in the 200-mg group. None of the participants had viral breakthrough. Increases in mean AUC 0-24 h, C max, and C 24 h were slightly less than dose-proportional, with median T max of 1.0-2.0 h. Steady state was achieved after 3-5 days of once-daily dosing. At steady state, accumulation ratios (day 7/day 1) for AUC 0-24 h, C max, and C 24 h were 1.2-1.6. The calculated effective t 1/2 (10-16 h) was similar to that in HIV-uninfected individuals. Adverse events were limited in number, transient, and generally mild to moderate in intensity. One participant had a serious adverse event of elevated liver enzymes (judged probably not drug related) in concurrence with a newly acquired hepatitis C infection. Conclusion: Doravirine monotherapy demonstrated robust antiviral activity at both dose levels, without evidence of viral resistance, and was generally well tolerated. Doravirine pharmacokinetics in HIV-infected individuals were similar to those in uninfected individuals receiving similar doses in prior studies. © Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved.

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