8 research outputs found
Effects of PCSK9 Inhibition With Alirocumab on Lipoprotein Metabolism in Healthy Humans
BACKGROUND: Alirocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), lowers plasma low-density lipoprotein (LDL) cholesterol and apolipoprotein B100 (apoB). Although studies in mice and cells have identified increased hepatic LDL receptors as the basis for LDL lowering by PCSK9 inhibitors, there have been no human studies characterizing the effects of PCSK9 inhibitors on lipoprotein metabolism. In particular, it is not known whether inhibition of PCSK9 has any effects on very low-density lipoprotein or intermediate-density lipoprotein (IDL) metabolism. Inhibition of PCSK9 also results in reductions of plasma lipoprotein (a) levels. The regulation of plasma Lp(a) levels, including the role of LDL receptors in the clearance of Lp(a), is poorly defined, and no mechanistic studies of the Lp(a) lowering by alirocumab in humans have been published to date.
METHODS: Eighteen (10 F, 8 mol/L) participants completed a placebo-controlled, 2-period study. They received 2 doses of placebo, 2 weeks apart, followed by 5 doses of 150 mg of alirocumab, 2 weeks apart. At the end of each period, fractional clearance rates (FCRs) and production rates (PRs) of apoB and apo(a) were determined. In 10 participants, postprandial triglycerides and apoB48 levels were measured.
RESULTS: Alirocumab reduced ultracentrifugally isolated LDL-C by 55.1%, LDL-apoB by 56.3%, and plasma Lp(a) by 18.7%. The fall in LDL-apoB was caused by an 80.4% increase in LDL-apoB FCR and a 23.9% reduction in LDL-apoB PR. The latter was due to a 46.1% increase in IDL-apoB FCR coupled with a 27.2% decrease in conversion of IDL to LDL. The FCR of apo(a) tended to increase (24.6%) without any change in apo(a) PR. Alirocumab had no effects on FCRs or PRs of very low-density lipoproteins-apoB and very low-density lipoproteins triglycerides or on postprandial plasma triglycerides or apoB48 concentrations.
CONCLUSIONS: Alirocumab decreased LDL-C and LDL-apoB by increasing IDL- and LDL-apoB FCRs and decreasing LDL-apoB PR. These results are consistent with increases in LDL receptors available to clear IDL and LDL from blood during PCSK9 inhibition. The increase in apo(a) FCR during alirocumab treatment suggests that increased LDL receptors may also play a role in the reduction of plasma Lp(a).
CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01959971
Caractérisation du comportement thermique d'une interface solide-fluide (application à la surveillance des décharges d'ordures ménagères par thermographie infrarouge aérienne)
Cette étude trouve son application dans les possibilités de surveillance de décharges d'ordures ménagères (OM) par thermographie infrarouge (TIR) aérienne : il s'agit d'identifier d'éventuelles anomalies de fonctionnement de décharges à partir des évolutions de la température d'interface couverture de décharge-atmosphère (seule donnée accessible par TIR). Cette température est conditionnée par les échanges thermiques avec l'atmosphère et avec le réacteur naturel que constitue un stock de déchets en fermentation. Une modélisation thermique des échanges de chaleur en régime instationnaire au niveau de cette interface a été entreprise. A partir du concept des Fonctions de Transfert, bien adapté aux techniques inverses et généralisable à d'autres types d'applications (par exemple le contrôle-commande en temps réel), nous avons notamment mis en oeuvre une procédure de détermination du rapport coefficient d'échange/effusivité, préalable nécessaire à toutes simulations en mode direct ou inverse. Une modélisation, par méthode nodale, avec condition limite radiative a également permis de mettre en évidence le rôle prépondérant du rayonnement solaire sur l'évolution des températures d'interface. De même, une modélisation 2D a permis de vérifier la faisabilité de la méthode en vue de la détection d'anomalies thermiques de fonctionnement "typiques" d'une décharge d'OM (fermentation trop élevée, affaissement de la couverture). Ces résultats, après validations expérimentales en laboratoire et en extérieur ont permis de mettre en évidence les paramètres les plus représentatifs influant sur l'évolution des températures d'interface, de définir à la fois un protocole d'obtention des thermogrammes IR (instants de mesures, conditions climatiques optimales) et une méthodologie d'exploitation de ces derniers à partir de traitements d'images adaptés. Enfin, des expérimentations aériennes sur plusieurs sites de décharges illustrent les possibilités (détections de fuites de biogaz, de zones humides...) et les limites (notamment la nécessité d'une étude complémentaire au sol) d'application de l'outil IR à la surveillance des centres de stockage de déchets.POITIERS-BU Sciences (861942102) / SudocSudocFranceF
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Relationship Between Low‐Density Lipoprotein Cholesterol, Free Proprotein Convertase Subtilisin/Kexin Type 9, and Alirocumab Levels After Different Lipid‐Lowering Strategies
Background: Alirocumab undergoes target‐mediated clearance via binding of proprotein convertase subtilisin/kexin type 9 (PCSK9). Statins increase PCSK9 levels; the effects of nonstatin lipid‐lowering therapies are unclear. Every‐4‐weeks dosing of alirocumab may be appropriate for some patients in absence of background statin but is not yet approved. Methods and Results: Low‐density lipoprotein cholesterol (LDL‐C), PCSK9, and alirocumab levels were assessed in subjects (LDL‐C >130 mg/dL, n=24/group) after a 4‐week run‐in taking oral ezetimibe, fenofibrate, or ezetimibe placebo, when alirocumab 150 mg every 4 weeks (days 1, 29, and 57) was added. Maximal mean LDL‐C reductions from day −1 baseline (prealirocumab) occurred on day 71 in all groups: alirocumab plus placebo, 47.4%; alirocumab plus ezetimibe, 56.6%; and alirocumab plus fenofibrate, 54.3%. LDL‐C reductions were sustained through day 85 with alirocumab plus placebo (47.0%); the duration of effect was slightly diminished at day 85 versus day 71 with ezetimibe (49.6%) or fenofibrate combinations (43.2%). Free PCSK9 concentrations were lowest at day 71 in all groups, then increased over time; by day 85, free PCSK9 concentrations were higher, and alirocumab levels lower, with alirocumab plus fenofibrate, and to a lesser extent alirocumab plus ezetimibe, versus alirocumab plus placebo. Conclusions: Alirocumab 150 mg every 4 weeks produced maximal LDL‐C reductions of 47% in combination with placebo and 54% to 57% in combination with ezetimibe or fenofibrate. The oral lipid‐lowering therapies appear to increase PCSK9 levels, leading to increased alirocumab clearance. Although the duration of effect was modestly diminished with alirocumab plus ezetimibe/fenofibrate versus placebo, the effect was less than observed in trials with background statins, and it would not preclude the use of alirocumab every 4 weeks in patients taking these nonstatin lipid‐lowering therapies concomitantly. Clinical Trial Registration URL: http://www.Clinicaltrials.gov. Unique identifier: NCT01723735