rhHNS administration via IDDD appeared generally safe and well tolerated. Treatment resulted in consistent declines in CSF heparan sulfate, suggesting in vivo activity in the relevant anatomical compartment. Results of this small study should be interpreted with caution. Future studies are required to assess the potential clinical benefits of rhHNS and to test improved IDDD models.
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 mol/L) completely inhibited ristocetin-induced platelet aggregation in whole blood (PϽ0.001), but also diminished collagen, ADP, arachidonic acid, and thrombin receptor activating peptide-induced platelet aggregation to some extent (PϽ0.05). ARC15105 (40 nmol/L) decreased platelet adhesion by Ͼ90% on denuded porcine aortas (PϽ0.001), 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 Ͼ90% (PϽ0.001). The IV and SC terminal half-lives in cynomolgus monkeys were 67 and 65 hours, respectively, and the SC bioavailability was Ϸ98%. Allometric scaling estimates the human T 1/2 would be Ϸ217 hours. Pharmacodynamic analysis confirms that ARC15105 inhibits von Willeband factor activity Ͼ90% in blood samples taken 300 hours after a 20 mg/kg IV or SC dose in monkeys. VWF is required for normal hemostasis and mediates the adhesion of platelets to sites of vascular damage by binding to specific platelet membrane glycoproteins and constituents of exposed connective tissue. 3 VWF is also a carrier protein for blood clotting factor VIII and therefore stabilizes and prevents factor VIII from early inactivation. 4 It is released from endothelial cells and platelets following activation by a number of agents including thrombin. VWF plays a role in shear-dependent thrombogenesis, which occurs in stenotic coronary arteries or ruptured atherosclerotic plaque lesions.
Conclusion-The
3Its levels are also heightened in patients, who experienced adverse cardiac events that are linked to a poorer prognosis. [5][6][7] Conventional therapy of myocardial infarction reduces platelet activation and aggregation, but mostly addresses receptors and targets other than VWF.8 Nevertheless, the central role of VWF in thrombogenesis made it a promising target in research on new antiplatelet therapies that specifically inhibit VWF, 9 like the anti-VWF aptamers. ARC1779 is an anti-VWF aptamer, which has been shown to potently and specifically inhibit excessive VWF activity in blood from patients with acute myocardial infarction (AMI), 10,11 and clinical proof of mechanism and concept has been demonstrated.12-14 ARC15105 is ...
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