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ARC15105 is a potent antagonist of von Willebrand factor mediated platelet activation and adhesion.
Arterioscler Thromb Vasc Biol ; 32(4): 902-9, 2012 Apr.
Article de En | MEDLINE | ID: mdl-22282355
ABSTRACT

OBJECTIVE:

We investigated the stability, pharmacokinetic, and pharmacodynamic profile of the 2(nd) generation anti-von Willeband factor aptamer ARC15105. METHODS AND

RESULTS:

Platelet plug formation was measured by collagen/adenosine diphosphate-induced closure time with the platelet function analyzer-100 and platelet aggregation by multiple electrode aggregometry. Platelet adhesion was measured on denuded porcine aortas and in a flow chamber. Aptamer stability was assessed by incubation in nuclease rich human, monkey, and rat serum for up to 72 hours. Pharmacokinetic and pharmacodynamic profiles were tested in cynomolgus monkeys after IV and SC administration. The median IC(100) and IC(50) to prolong collagen/adenosine diphosphate-induced closure timewere 27 nmol/L and 12 nmol/L, respectively. ARC15105 (1.3 µmol/L) completely inhibited ristocetin-induced platelet aggregation in whole blood (P<0.001), but also diminished collagen, ADP, arachidonic acid, and thrombin receptor activating peptide-induced platelet aggregation to some extent (P<0.05). ARC15105 (40 nmol/L) decreased platelet adhesion by >90% on denuded porcine aortas (P<0.001), which was comparable to the degree of inhibition obtained with abciximab. ARC15105 (100 nmol/L) also inhibited platelet adhesion to collagen under arterial shear in a flow chamber by >90% (P<0.001). The IV and SC terminal half-lives in cynomolgus monkeys were 67 and 65 hours, respectively, and the SC bioavailability was ≈98%. Allometric scaling estimates the human T(1/2) would be ≈217 hours. Pharmacodynamic analysis confirms that ARC15105 inhibits von Willeband factor activity >90% in blood samples taken 300 hours after a 20 mg/kg IV or SC dose in monkeys.

CONCLUSIONS:

The potency, pharmacokinetic profile, and SC bioavailability of ARC15105 support its clinical investigation for chronic inhibition of von Willeband factor -mediated platelet activation.
Sujet(s)

Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Sujet principal: Plaquettes / Facteur de von Willebrand / Antiagrégants plaquettaires / Activation plaquettaire / Adhésivité plaquettaire / Aptamères peptidiques / Aptamères nucléotidiques / Infarctus du myocarde Type d'étude: Clinical_trials / Observational_studies / Prevalence_studies / Risk_factors_studies Pays/Région comme sujet: America do norte / Europa Langue: En Journal: Arterioscler Thromb Vasc Biol Sujet du journal: ANGIOLOGIA Année: 2012 Type de document: Article Pays d'affiliation: Autriche

Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Sujet principal: Plaquettes / Facteur de von Willebrand / Antiagrégants plaquettaires / Activation plaquettaire / Adhésivité plaquettaire / Aptamères peptidiques / Aptamères nucléotidiques / Infarctus du myocarde Type d'étude: Clinical_trials / Observational_studies / Prevalence_studies / Risk_factors_studies Pays/Région comme sujet: America do norte / Europa Langue: En Journal: Arterioscler Thromb Vasc Biol Sujet du journal: ANGIOLOGIA Année: 2012 Type de document: Article Pays d'affiliation: Autriche
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