Objectif Comparer la pharmacodynamie après un repas test et la tolérance du lixisénatide (LIXI) 20 µg vs liraglutide (LIRA) 1,2 et 1,8 mg par une étude mécanistique de 8 semaines, randomisée, ...ouverte, en trois bras parallèles chez des patients DT2 après titration optimale de l’insuline glargine ± metformine. Patients et méthodes Le critère principal était la variation par rapport à l’inclusion de l’aire sous la courbe de la glycémie dans les 4 heures (ASC glycémie postprandiale (GPP) (00 h 30-4 h 30) suivant un petit déjeuner standard solide). Résultats LIXI a diminué significativement l’ASC-GPP (00 h 30-4 h 30) (moyenne des moindres carrés ± ESM) de – 240,2 ± 20,0 mg/dl.h, comparativement au liraglutide 1,2 et 1,8 mg (– 131,8 ± 20,2 et – 157,1 ± 21,0 mg/dl.h respectivement, p < 0,0001). LIXI a davantage ralenti la vidange gastrique (mesure de l’acide octanoïque-13C expiré) que LIRA 1,2 et 1,8 mg ( p < 0,0001). L’HbA1c a significativement diminué dans chaque groupe par rapport à l’inclusion avec des baisses comparables sous LIXI et LIRA 1,2 mg et une valeur légèrement mais significativement plus basse (de – 0,16 %) sous LIRA 1,8 mg. L’augmentation de la fréquence cardiaque moyenne sur 24 heures en ambulatoire était plus importante sous LIRA 1,2 et 1,8 mg vs LIXI (différence de 6 bpm, p < 0,0001). Les hypoglycémies symptomatiques ont été légèrement plus fréquentes sous LIXI et plus d’effets digestifs ont été rapportés sous LIRA. Les augmentations des lipases ( p < 0,05 vs inclusion et LIXI) et amylases ( p < 0,05 vs inclusion) ont été plus importantes sous LIRA que sous LIXI et un patient sous LIRA 1,8 mg a présenté une pancréatite œdémateuse asymptomatique mais avec élévation des lipases et anomalies sur l’IRM. Conclusion LIXI et LIRA en association à l’insuline glargine ± metformine améliorent l’équilibre glycémique global chez des patients DT2 tout en notant des différences dans les mécanismes d’action sur la vidange gastrique et dans les profils de sécurité/tolérance. Déclaration d’intérêt Les auteurs déclarent avoir un intérêt avec un organisme privé, industriel ou commercial en relation avec le sujet présenté. Consultant of pharmaceutical companies. Participation in clinical trials phase II, III and I V. Speakers at symposia. Co-funding or grants for clinical research. For the following pharmaceutical and industrial firms: Bristol-Myers Squibb, Sanofi Aventis, GlaxoSmithKline, Novartis, Novo Nordisk, Eli lilly, Boehringer Ingelheim, Janssen, Intarcia, Metacure, Pfizer, MSD, Roche Diagnostic, Medtronic, Menarini Diagnostic, Abbott, Vitalaire, Dinno Santé, Orkyn.
Objectif Cette étude randomisée, ouverte, avec administration répétée pendant 4 semaines, a comparé la pharmacodynamie du lixisénatide (20 µg par jour) vs le liraglutide (1,8 mg par jour) chez des ...patients ayant un DT2 non équilibré sous metformine 1,5 g/jour NCT01175473. Matériels et méthodes Les patients ont reçu en sous-cutané, 30 min avant le petit-déjeuner, soit du lixisénatide (n = 77), soit du liraglutide (n = 71). La dose de lixisénatide était augmentée de 10 à 20 µg après 2 semaines; la dose de liraglutide était augmentée de façon hebdomadaire de 0,6 mg à 1,8 mg. Le critère principal était la différence, entre l’inclusion et la semaine 4, de l’aire sous la courbe (ASC) de GPP (ASC0h30-4h30) après un petit-déjeuner standardisé. Les critères secondaires étaient constitués par le pic maximal de GPP, le profil glycémique sur 24 h, l’HbA1c, le profil en 7 points et l’ASC pour l’insuline, le peptide C, le glucagon et la pro-insuline, ainsi que les effets secondaires/la tolérance. Résultats Le lixisenatide a diminué la GPP de façon significativement plus importante que le liraglutide, avec un ASC 0 h 30-4 h 30 moyen respectivement de-227,3 vs-72,8 h·mg/dl (différence :-154,4 h·mg/dl; p < 0,0001). La différence de pic maximal de GPP était de - 70,4 mg/dl avec le lixisénatide vs - 24,9 mg/dl avec le liraglutide (p < 0,0001). À 4 semaines, plus de patients sous lixisénatide (69%) que sous liraglutide (29%) avaient une GPP à 2 h < 140 mg/dl. Les profils glycémiques de 24 h ont montré une diminution globale de la glycémie dans les deux groupes. Le lixisenatide a induit une diminution significativement plus importante de la glucagonémie postprandiale après 4 semaines de traitement (p = 0,032 vs liraglutide). L’insulinémie et le peptide-C postprandiaux ont également été significativement diminués sous lixisénatide vs liraglutide (p < 0,0001 pour les deux paramètres) alors que la baisse de pro-insuline était comparable (p = 0,10). L’HbA1c moyenne a diminué dans deux groupes de traitement (de 7,2 à 6,9% sous lixisénatide vs 7,4 à 6,9% sous liraglutide), tout comme le poids (respectivement - 1,6 kg vs – 2,4 kg). La fréquence cardiaque en position couchée a diminué de - 3,6 battements/min (bpm) sous lixisénatide vs une augmentation de 5,3 bpm sous liraglutide. Il n’y a pas eu d’événements indésirables (EI) graves ni aucun cas d’hypoglycémie ou de pancréatite. Quatre patients ont arrêté le traitement en raison d’EI : 2 sous lixisénatide (2,6%) en raison de réactions allergiques et 2 sous liraglutide (2,8%) pour des problèmes gastro-intestinaux. L’incidence globale des EI était plus faible avec le lixisénatide (58%) qu’avec le liraglutide (73%) et c’étaient essentiellement des pertes d’appétit (18% vs 37%), des problèmes gastro-intestinaux (36% vs 46%) et des troubles d’ordre neurologique (principalement céphalées/vertiges; 16% vs 24%). Conclusion Chez des patients DT2, le lixisenatide en prise quotidienne a diminué de façon significative par rapport au liraglutide la GPP (-129% vs – 41%), l’insulinémie, le peptide-C et la glucagonémie, et ceci avec un meilleur profil de tolérance gastro-intestinale.
The aim of this study was to assess the performance of the Continuous Research Tool (CRT) in a multicentre clinical-experimental study.
Three patient groups totalling 28 subjects with diabetes group ...A 10 Type 1 (Ulm), group B 10 Type 1 (Neuss), group C eight Type 2 (Aarhus) participated in this trial. Two CRT microdialysis probes were inserted in parallel in the abdominal subcutaneous tissue for 120 h in each subject. In subjects in group A, glucose excursions were induced on one study day and those in group B underwent a glucose clamp (eu-, hypo- or hyperglycaemic) on one study day. CRT data were calibrated once with a retrospective calibration model based on a run-in time of 24 h and three blood glucose measurements per day.
All analysable experiments, covering a broad range of blood glucose values, yielded highly accurate data for the complete experimental time with a mean relative absolute difference of 12.8 +/- 6.0% and a predictive residual error sum of squares of 15.6 +/- 6.3 (mean +/- SD). Of all measurement results, 98.2% were in zones A and B of the error grid analysis. The average absolute differences were 1.14 mmol/l for Type 1 and 0.88 mmol/l for Type 2 diabetic patients. Relative absolute differences were 16.0% for Type 1 and 12.6% for Type 2 diabetic patients.
These results demonstrate that this microdialysis system allows reliable continuous glucose monitoring in patients with diabetes of either type.
Aims We assessed safety and efficacy of two selective 11beta-HSD1 inhibitors (RO5093151/RO-151 and RO5027383/RO-838) in this randomized, controlled study in metformin-treated patients with type 2 ...diabetes. Methods Patients either received placebo (N=21), RO-151 BID 5 mg (N=24) or 200 mg (N=20) or RO-838 QD 50 mg (N=21) or 200 mg (N=24) for 28 days. Metabolic assessments comprising of nine-point plasma glucose profiles, oral glucose tolerance tests and determination of metabolic biomarkers including insulin, C-peptide, glucagon, HbA1c and lipids were done at baseline and end of treatment. Results Despite the short treatment duration, both RO-151 and RO-838 showed trends for improved HbA1c and consistent reductions in body weight (-0.86 to -1.67 kg) exceeding those observed with placebo (-0.28 kg, p=0.019 for 200 mg RO-151 vs. placebo). Insulin sensitivity parameters (e.g. HOMA-IR and Matsuda-Index) improved non-significantly with 200 mg RO-151. Lipid parameters did not consistently improve with either compound, but RO-838 led to non-significant increases in triglycerides and VLDL-cholesterol versus placebo. Both compounds were well tolerated and showed inhibitory effects on 11beta-HSD1 activity based on urinary corticosteroid excretion. As reported for other 11beta-HSD1-inhibitors increased concentrations of ACTH and adrenal androgen precursors were found with RO-151, but not with RO-838. Conclusions Slight metabolic improvements were seen, in particular with RO-151 high dose, however, the observed changes often did not reach statistical significance and were not clearly dose dependent. Studies of longer duration are needed to further investigate potential benefits and risks of these compounds. PUBLICATION ABSTRACT
We used protein extracts from proliferating human HeLa cells to support plasmid DNA replication in vitro. An extract with soluble nuclear proteins contains the major replicative chain elongation ...functions, whereas a high salt extract from isolated nuclei contains the proteins for initiation. Among the initiator proteins active in vitro are the origin recognition complex (ORC) and Mcm proteins. Recombinant Orc1 protein stimulates in vitro replication presumably in place of endogenous Orc1 that is known to be present in suboptimal amounts in HeLa cell nuclei. Partially purified endogenous ORC, but not recombinant ORC, is able to rescue immunodepleted nuclear extracts. Plasmid replication in the in vitro replication system is slow and of limited efficiency but robust enough to serve as a basis to investigate the formation of functional pre-replication complexes under biochemically defined conditions.
A reduced availability of tetrahydrobiopterin (BH4), an essential cofactor for NO-synthesis, is causally involved in the development of endothelial dysfunction associated with ischemia/reperfusion. ...We, therefore, investigated the effect of sepiapterin, a substrate for BH4 synthesis, on postischemic injury in myocardial infarction and myocardial stunning. In rats, myocardial stunning was induced by repetitive ischemia (5 x 10-min ligature of the left coronary artery, 5 x 20-min reperfusion) and myocardial infarction by 50-min ligature and 60-min reperfusion. Myocardial blood flow was determined by H2-clearance, regional myocardial function by pulsed Doppler and infarct size by tetrazolium staining. Myeloperoxidase (MPO) activity was measured as a marker of neutrophil extravasation. cGMP was determined in rat serum as an indicator of increased NO synthesis. In animals treated with sepiapterin, regional myocardial function was significantly improved in both myocardial stunning and infarction and infarct size was significantly reduced. MPO activity decreased with sepiapterin treatment in both models. The systemic level of cGMP was reduced both following myocardial stunning and myocardial infarction in the control group. Pretreatment with sepiapterin induced a significant increase of cGMP level at the end of the protocol in both models. Substitution of sepiapterin reduces postischemic injury both in myocardial stunning and infarction apparently by ameliorating the availability of NO, thereby attenuating the activation of neutrophils in ischemia/reperfusion.
Currently, cellular networks are overloaded with mobile data traffic due to the rapid growth of mobile broadband subscriptions and the increasing popularity of applications for smartphones. One ...possible solution to alleviate this problem is the offloading of mobile data traffic from the primary access technology to the WiFi infrastructure to gain extra capacity and improve the overall network performance. As the strategy what and when to offload data is non-trivial, it is of vital importance to develop novel algorithms to guide this process. This paper addresses solutions for WiFi offloading in Long Term Evolution (LTE) cellular networks when performance needs exceed the capability of the LTE access. It then compares the performance of each access technology using different network performance metrics. In detail, an optimized Signal-to-noise ratio (SNR)-threshold based handover solution and extension to the 3 rd Generation Partnership Project (3GPP) standard for Access Network Discovery and Selection Function (ANDSF) framework for WiFi offloading is proposed. Our simulation results have shown that ANDSF discovery can be used to control the amount of offloading.
Distributed object-oriented applications are commonly implemented atop middleware platforms such as CORBA, .NET Remoting, and Java remote method invocation (RMI). These platforms provide a simple ...mechanism to invoke methods of remote objects. Increasingly more applications are demanding nonfunctional properties such as fault tolerance, high availability, and adaptivity, which require extensions to distributed objects' basic interaction model. A fragmented-object model, such as the one Marc Shapiro proposed, can provide the required flexibility. It's far more generic and flexible than the traditional client-server approach. A fragmented object is a truly distributed object; it consists of multiple fragments located on multiple nodes. Such a model allows arbitrary partitioning of state and functionality on these fragments, and arbitrary internal interaction between fragments of a single object. We have investigated integrating a fragmented-object model into CORBA (AspectIX), which requires internal modifications to the CORBA object request broker. Our approach for transparently integrating fault-tolerant objects into .NET Remoting is also useful for seamlessly integrating fragmented objects. Our FORMI architecture integrates fragmented objects into Java RMI without requiring internal modifications to the RMI runtime
The aim of this study was the development of a reliable and fast method to estimate total abdominal fat volumes (TAF) in diabetic subjects on the basis of T1-weighted MR images. Thirty-seven patients ...with diabetes were examined (age 48 ± 13 y mean ± SD). A semiautomated computer assisted software program was developed to quantify intraabdominal (IAF), subcutaneous (SCF), and total abdominal fat volumes (TAF). The variability of image analysis for fat measurements between two observers and within observers was assessed. Mean volumes (± SD) for IAF, SCF and TAF were 10.5 1 (± 5.0 1), 15.1 1 (±7.3 1) and 25.7 1 (±11.5 1), respectively. Inter- and intraobserver reliability was excellent (r = 0.999 to r = 1.0). Per patient, the analysis required nine minutes in addition to a scan duration of seven minutes. As this analytic method using T1-weighted MR images allows a fast and reliable quantification of TAF, IAF and SCF, it may serve as a valuable tool for respective studies in diabetic subjects.
Development of a feasible and reliable method for determining abdominal fat using breath-hold T1-weighted magnetic resonance imaging.
The high image contrast of T1-weighted gradient echo MR sequences ...makes it possible to differentiate between abdominal fat and non-fat tissue. To obtain a high signal-to-noise ratio, the measurements are usually performed using phased array surface coils. Inhomogeneity of the coil sensitivity leads to inhomogeneity of the image intensities. Therefore, to examine the volume of abdominal fat, an automatic algorithm for intensity correction must be implemented. The analysis of the image histogram results in a threshold to separate fat from other tissue. Automatic segmentation using this threshold results directly in the fat volumes. The separation of intraabdominal and subcutaneous fat is performed by interactive selection in a last step.
The described correction of inhomogeneity allows for the segmentation of the images using a global threshold. The use of semiautomatic interactive volumetry makes the analysis more subjective. The variance of volumetry between observers was 4.6 %. The mean time for image analysis of a T1-weighted investigation lasted less than 6 minutes.
The described method facilitates reliable determination of abdominal fat within a reasonable period of time. Using breath-hold MR sequences, the time of examination is less than 5 minutes per patient.
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