Assessment of the cardiac safety and pharmacokinetics of a short course, twice daily dose of orally-administered mifepristone in healthy male subjects

Background: Mifepristone is approved to control hyperglycemia in adults with endogenousCushing’s syndrome and is described as a mildly QTc prolonging drug, based on a TQT study.The aim of the present study was to assess the effect of mifepristone on the QTc interval at plasmamifepristone concentrations exceeding those observed in the TQT study.Methods: Twenty healthy, male volunteers were given three doses of 1200 mg mifepristoneevery 12 h with a high-fat meal in a randomized, placebo-controlled 2-period crossover study.Holter ECG recordings were made on Day 1 and 2.Results: Eighteen subjects completed the study. Mean peak plasma mifepristone concentrationswere 4.01 μg/mL (CV: 31%) on the fi rst dose and 5.77 μg/mL (CV: 29%) on the thirddose. Mifepristone did not have a meaningful QTc effect. The placebo-corrected, change-from--baseline QTcF (ΔΔQTcF) was between –1.6 and 0.7 ms on the fi rst dose (upper bound of 90%CI 3.8 ms) and the largest ΔΔQTcF on the third dose was 4.9 ms (upper bound of 90% CI: 8.4 ms).Concentration effect modeling showed a slightly negative slope of –0.01 ms/ng/mL.Conclusions: Mifepristone did not cause a clinically meaningful QTc prolongation in healthyvolunteers at plasma concent rations of mifepristone and its main metabolites that clearlyexceeded those seen in a previous TQT study

»Pakt für den Euro«: Kann mit dem Maßnahmenpaket die Europäische Union die Euro-Schuldenkrise überwinden?

ein Maßnahmenpaket zur Überwindung der Euro-Schuldenkrise geeinigt. Georg Milbradt, TU Dresden, ist der Ansicht, dass die verabredeten Maßnahmen die Probleme in der Eurozone nicht lösen werden. Zwar knüpfen die Vorschläge an wichtige Probleme an, wie z.B. Schuldenstand, private Verschuldung etc., sie unterliegen aber weiter einem politischen Verfahren mit den bekannten Schwächen. Von einer wirklichen Stabilisierung des Euroraums könne nicht gesprochen werden. Joachim Starbatty, Aktionsgemeinschaft Soziale Marktwirtschaft, sieht den permanenten Rettungsschirm als »eine weitere Etappe auf einer sich weiter drehenden Interventionsspirale« an. Andreas Haufler, Universität München, sieht in einer Festlegung auf das Ziel, kurzfristige Finanzmarktkrisen zu verhindern, das Risiko einer schleichenden Umwandlung des temporären Hilfsmechanismus in akuten Krisensituationen in eine Dauerfinanzierung hoch verschuldeter Mitgliedstaaten. Nach Meinung von Volker Grossmann, Universität Freiburg/Schweiz, gefährdet erst der Rettungsfonds den Euro, aufgrund der enormen Risiken für die Geberländer. Markus Ferber, Europäisches Parlament, erwartet von den Be - schlüssen die Erhöhung des Drucks auf finanzschwache Eurostaaten, ihre Haushalte zu konsolidieren und wieder wettbewerbsfähig zu werden. Insgesamt seien die Beschlüsse ein wichtiges stabilisierendes Signal an die weltweiten Finanzmärkte. Lüder Gerken, Stiftung Ordnungspolitik und Centrum für Europäi - sche Politik, Freiburg, sieht in den Vereinbarungen keine Lösung der Probleme der Eurozone. Im Gegenteil: Mit ihnen sei die letzte Gelegenheit versäumt worden, die Abschaffung des Bail-out-Verbots an rigide realwirtschaftliche Reformprogramme für die maroden Volkswirtschaften vor allem Südeuropas zu koppeln. Damit rücke die Anpassung dieser Volkswirtschaften in weite Ferne.Euro Währungskrise Schulden EU-Stabilitätspakt Konjunkturpolitik Europäische Wirtschafts- und Währungsunion

Single Doses up to 800 mg of E-52862 Do Not Prolong the QTc Interval--A Retrospective Validation by Pharmacokinetic-Pharmacodynamic Modelling of Electrocardiography Data Utilising the Effects of a Meal on QTc to Demonstrate ECG Assay Sensitivity.

BACKGROUND: E-52862 is a Sigma-1 receptor antagonist (S1RA) currently under investigation as a potential analgesic medicine. We successfully applied a concentration-effect model retrospectively to a four-way crossover Phase I single ascending dose study and utilized the QTc shortening effects of a meal to demonstrate assay sensitivity by establishing the time course effects from baseline in all four periods, independently from any potential drug effects. METHODS: Thirty two healthy male and female subjects were included in four treatment periods to receive single ascending doses of 500 mg, 600 mg or 800 mg of E-52862 or placebo. PK was linear over the dose range investigated and doses up to 600 mg were well tolerated. The baseline electrocardiography (ECG) measurements on Day-1 were time-matched with ECG and pharmacokinetic (PK) samples on Day 1 (dosing day). RESULTS: In this conventional mean change to time-matched placebo analysis, the largest time-matched difference to placebo QTcI was 1.44 ms (90% CI: -4.04, 6.93 ms) for 500 mg; -0.39 ms (90% CI: -3.91, 3.13 ms) for 600 mg and 1.32 ms (90% CI: -1.89, 4.53 ms) for 800 mg of E-52862, thereby showing the absence of any QTc prolonging effect at the doses tested. In addition concentration-effect models, one based on the placebo corrected change from baseline and one for the change of QTcI from average baseline with time as fixed effect were fitted to the data confirming the results of the time course analysis. CONCLUSION: The sensitivity of this study to detect small changes in the QTc interval was confirmed by demonstrating a shortening of QTcF of -8.1 (90% CI: -10.4, -5.9) one hour and -7.2 (90% CI: -9.4, -5.0) three hours after a standardised meal. TRIAL REGISTRATION: EU Clinical Trials Register EudraCT 2010 020343 13

How to improve walking, balance and social participation following stroke: a comparison of the long term effects of two walking aids--canes and an orthosis TheraTogs--on the recovery of gait following acute stroke. A study protocol for a multi-centre, single blind, randomised control trial

<p>Abstract</p> <p>Background</p> <p>Annually, some 9000 people in Switzerland suffer a first time stroke. Of these 60% are left with moderate to severe walking disability. Evidence shows that rehabilitation techniques which emphasise activity of the hemiplegic side increase ipsilesional cortical plasticity and improve functional outcomes. Canes are commonly used in gait rehabilitation although they significantly reduce hemiplegic muscle activity. We have shown that an orthosis "TheraTogs" (a corset with elasticated strapping) significantly increases hemiplegic muscle activity during gait. The aim of the present study is to investigate the long term effects on the recovery of gait, balance and social participation of gait rehabilitation with TheraTogs compared to gait rehabilitation with a cane following first time acute stroke.</p> <p>Methods/Design</p> <p>Multi-centre, single blind, randomised trial with 120 patients after first stroke. When subjects have reached Functional Ambulation Category 3 they will be randomly allocated into TheraTogs or cane group. TheraTogs will be applied to support hip extensor and abductor musculature according to a standardised procedure. Cane walking held at the level of the radial styloid of the sound wrist. Subjects will walk throughout the day with only the assigned walking aid. Standard therapy treatments and usual care will remain unchanged and documented. The intervention will continue for five weeks or until patients have reached Functional Ambulation category 5. Outcome measures will be assessed the day before begin of intervention, the day after completion, 3 months, 6 months and 2 years. Primary outcome: Timed "up and go" test, secondary outcomes: peak surface EMG of gluteus maximus and gluteus medius, activation patterns of hemiplegic leg musculature, temporo-spatial gait parameters, hemiplegic hip kinematics in the frontal and sagittal planes, dynamic balance, daily activity measured by accelerometry, Stroke Impact Scale. Significance levels will be 5% with 95% CI's. IntentionToTreat analyses will be performed. Descriptive statistics will be presented.</p> <p>Discussion</p> <p>This study could have significant implications for the clinical practice of gait rehabilitation after stroke, particularly the effect and appropriate use of walking aids.</p> <p>The results could be important for the development of clinical guidelines and for the socio-economic costs of post-stroke care</p> <p>Trial registration number</p> <p>ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT01366729">NCT01366729</a>.</p

Der Beyden so offters vermähleten Chur- und Hoch-Fürstlichen Häusere/ Sachsen und Brandenburgks Je Länger je Lieber/ Bey Des ... Herrn Christian Ernsten/ Marggrafen zu Brandenburgk ... Und Der ... Fräul. Erdmuth Sophien/ Hertzogin zu Sachsen/ Jülich/ Cleve und Berg ... Am 19. Tag des Weinmonats In Dreßden angestellten Hoch-Fürstlichen Beylager

Zu unterthänigster Glückwünschung eingeführet durch Georg Ferbern ... Im Jahr 1662

Kurtzer Gelücks-Wuntzsch/ Alß Der Durchlauchtigste Hochgebohrne Fürst und Herr/ Herr Johann Georg Der Dritte/ Hertzog zu Sachsen/ Jülich/ Cleve und Berg ... Mit Der Durchlauchtigsten Princessin und Frauen/ Frauen Annen Sophien/ Gebohrner Erb-Princessin zu Dennemarck und Norwegen ... Den 31. Decembris, 1666. Dero glücklichen Einzugk in die Chur-Fürstl. Sächß. Residentz und Haupt-Vestung Dreßden gehalten

In Einfalt übergeben/ Und in reden außgeführet Durch Dero unterthänigsten Diener und Churfürstl. Sächß. bestalten Pritzschmeistern/ George Ferber

The Power of Phase I Studies to Detect Clinical Relevant QTc Prolongation: A Resampling Simulation Study

Concentration-effect (CE) models applied to early clinical QT data from healthy subjects are described in the latest E14 Q&amp;A document as promising analysis to characterise QTc prolongation. The challenges faced if one attempts to replace a TQT study by thorough ECG assessments in Phase I based on CE models are the assurance to obtain sufficient power and the establishment of a substitute for the positive control to show assay sensitivity providing protection against false negatives. To demonstrate that CE models in small studies can reliably predict the absence of an effect on QTc, we investigated the role of some key design features in the power of the analysis. Specifically, the form of the CE model, inclusion of subjects on placebo, and sparse sampling on the performance and power of this analysis were investigated. In this study, the simulations conducted by subsampling subjects from 3 different TQT studies showed that CE model with a treatment effect can be used to exclude small QTc effects. The number of placebo subjects was also shown to increase the power to detect an inactive drug preventing false positives while an effect can be underestimated if time points around max are missed

Concentration-effect modeling based on change from baseline to assess the prolonging effect of drugs on QTc together with an estimate of the circadian time course

As ICH E14 was adopted by the US FDA and the EU CPMC in 2005, thorough QT studies have routinely been analyzed by looking at the time-matched difference between (baseline corrected) QTcF or QTcI under the supra-therapeutic dose and placebo. A study is considered negative, if the two-sided 90% confidence interval for this difference is below 10 ms for all investigated time points. ICH E14 suggests including a positive control, such as moxifloxacin, for assay sensitivity. Concentration–response analysis has been considered a more powerful alternative, but its application to parallel group studies was hampered as a double difference of QTcF per subject cannot be calculated. Recently, a new model based on change from baseline with fixed time and concentration effects has been proposed. It allows for a placebo-corrected prediction of the drug effect with an unbiased standard error, and the estimate of a time effect can be used for assay sensitivity. We demonstrate this approach, utilizing 2 studies reported elsewhere with a crossover design. We compare the results from a conventional concentration–response analysis based on the difference to placebo with results from the novel analysis based on the change from average baseline that includes a fixed time effect