Anticoagulant

Résumé

Un anticoagulant est une substance chimique ayant la propriété d'inhiber la coagulabilité naturelle du sang. Le sang ainsi traité ne coagulera pas ou alors moins vite, mais gardera la même viscosité. L'usage principal de l'anticoagulant est à visée médicale. Coagulation et anticoagulation La coagulation est un phénomène physiologique, procédant en cascade et faisant intervenir plusieurs protéines plasmatiques. Ce processus une fois mis en jeu aboutit à la formation d'un caillot (un clou plaquettaire), qui dans le fonctionnement physiologique non pathologique permet de freiner ou de juguler les hémorragies. La coagulation du sang peut être induite par un processus mécanique : en cas de stase, le sang immobile coagule par disparition de l'effet de pompe ; ou encore par mise en jeu de réactions physiologiques. La coagulation sanguine naturelle est régulée par la présence de divers facteurs de coagulation qui de concert se chargent d'un équilibre normal entre les tendances na

Source officielle

https://fr.wikipedia.org/wiki/Anticoagulant

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The associations of tricyclic antidepressants (TCAs) with reduced incidence of gliomas and elevated autophagy in glioma cells motivated investigation in mouse models of gliomagenesis. First, we established that imipramine, a TCA, increased autophagy and conveyed modest therapeutic benefit in tumor-bearing animals. Then we screened clinically approved agents suggested to affect autophagy for their ability to enhance imipramine-induced autophagy-associated cell death. The anticoagulant ticlopidine, which inhibits the purinergic receptor P2Y(12), potentiated imipramine, elevating cAMP, a modulator of autophagy, reducing cell viability in culture, and increasing survival in glioma-bearing mice. Efficacy of the combination was obviated by knockdown of the autophagic regulatory gene ATG7, implicating cell-lethal autophagy. This seemingly innocuous combination of TCAs and P2Y(12) inhibitors may have applicability for treating glioma.

Elsevier2015

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Development and validation of a multiplex UHPLC-MS/MS method for the determination of the investigational antibiotic against multi-resistant tuberculosis macozinone (PBTZ169) and five active metabolites in human plasma

Thierry Buclin, Stewart Cole, Jeff Pitteloud, Anthony Vocat

The emergence of Mycobacterium tuberculosis strains resistant to current first-line antibiotic regimens constitutes a major global health threat. New treatments against multidrug-resistant tuberculosis (MDR-TB) are thus eagerly needed in particular in countries with a high MDR-TB prevalence. In this context, macozinone (PBTZ169), a promising drug candidate with an unique mode of action and highly potent in vitro tuberculocidal properties against MDR Mycobacterium strains, has now reached the clinical phase and has been notably tested in healthy male volunteers in Switzerland. To that endeavor, a multiplex UHPLC-MS/MS method has been developed for the sensitive and accurate human plasma levels determination of PBTZ169 along with five metabolites retaining in vitro anti-TB activity. Plasma protein precipitation with methanol was carried out as a simplified sample clean-up procedure followed by direct injection of the undiluted supernatant for the bioanalysis of the six analytes within 5 min, using 1.8 mu m reversed-phase chromatography coupled to triple quadrupole mass spectrometry employing electrospray ionization in the positive mode. Stable isotopically-labelled PBTZ169 was used as internal standard (ISTD), while metabolites could be reliably quantified using two unlabeled chemical analogues selected as ISTD from a large in-house analogous compounds library. The overall methodology was fully validated according to current recommendations (FDA, EMEA) for bioanalytical methods, which include selectivity, carryover, qualitative and quantitative matrix effect, extraction recovery, process efficiency, trueness, precision, accuracy profiles, method and instrument detection limits, integrity to dilution, anticoagulant comparison and short-and long-term stabilities. Stability studies on the reduced metabolite H-2-PBTZ169 have shown no significant impact on the actual PBTZ169 concentrations determined with the proposed assay. This simplified, rapid, sensitive and robust methodology has been applied to the bioanalysis of human plasma samples collected within the frame of a phase I clinical study in healthy volunteers receiving PBTZ169.

PUBLIC LIBRARY SCIENCE2019

Chargement

The role of the local synthesis of thrombin in platelet recruitment and thrombus stabilization in heparinized blood was examined in vitro. Mural thrombosis was visualized and measured in a thin, rectangular, collagen-coated capillary under controlled rheological conditions by using fluorescence digital videomicroscopy and fluorescence microphotometry. Thrombin activity was inhibited in heparinized blood by the synthetic competitive inhibitor, D-phenylalanyl-L-prolyl-L-arginyl chloromethylketone (FPRCH2Cl), resulting in a marked reduction in the rate of platelet accumulation on collagen surfaces, indicating a role for thrombin in platelet recruitment. Similar although lesser effects were observed by reducing thrombin synthesis with antibodies to factors II and X. To decouple the role of thrombin in platelet recruitment by direct stimulation of platelet activity from its role in thrombus stabilization via fibrin formation, thrombosis was measured in heparinized blood treated with the tetrapeptide glycyl-prolyl-arginyl-proline, which inhibits fibrin monomer assembly into fibrin. The ultimate level but not the initial rate of platelet accumulation was reduced markedly, indicating a role for fibrin in thrombus stabilization against hemodynamic forces. Scanning electron micrographs demonstrated fibrin stands in the heparinized control samples but not in the heparinized samples with glycyl-prolyl-arginyl-proline. These results demonstrate a role for the local action of thrombin synthesized on the surfaces of thrombi even under conditions when the thrombin exerts no bulk effect, such as under heparin anticoagulation. Furthermore, this role appears to be a result of both platelet recruitment and thrombus stabilization. [on SciFinder (R)]

1990

Chargement

Development and validation of a multiplex UHPLC-MS/MS method for the determination of the investigational antibiotic against multi-resistant tuberculosis macozinone (PBTZ169) and five active metabolites in human plasma

Thierry Buclin, Stewart Cole, Jeff Pitteloud, Anthony Vocat

PUBLIC LIBRARY SCIENCE2019