The platelet P2T receptor plays a major role in platelet aggregation, and its antagonists are predicted to have significant therapeutic potential as antithrombotic agents. We have explored analogues of adenosine triphosphate (ATP), which is a weak, nonselective but competitive P2T receptor antagonist. Modification of the polyphosphate side chain to prevent breakdown to the agonist adenosine diphosphate (ADP) and substitution of the adenine moiety to enhance affinity and selectivity for the P2T receptor led to the identification of 10e (AR-C67085MX), having an IC50 of 2.5 nM against ADP-induced aggregation of human platelets. Compound 10e was the first very potent antagonist of the P2T receptor, with a selectivity for that subtype of the P2 receptor family of >1000-fold. Further modification of the structure produced compound 10l (AR-C69931MX) having an IC50 of 0.4 nM. In vivo, at maximally effective antithrombotic doses, there is little prolongation of bleeding time (1.4-fold), which is in marked contrast to the 5-6-fold found with GPIIb/IIIa antagonists.

12Functionally graded materials (FGMs), with varying spatial, chemical and mechanical gradients 13 (continuous or stepwise), have the potential to mimic heterogenous properties found across biological 14 tissues. They can prevent stress concentrations and retain healthy cellular functions. Here, we show for 15 the first time the fabrication of polydimethylsiloxane and poly(ether) ether ketone (PDMS-PEEK) 16composites. These were successfully manufactured as a bulk material and functionally graded 17 (stepwise) without the use of hazardous solvents or the need of additives. Chemical, irreversible 18 adhesion between layers (for the FGMs) was achieved without the formation of hard, boundary 19interfaces. The mechanical properties of PDMS-PEEK FGMs are proven to be further tailorable across 20 the entirety of the build volume, mimicking the transition from soft to harder tissues. The introduction 21 of 20 wt.% PEEK particles into the PDMS matrix resulted in significant rises in the elastic modulus 22

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Fifty-six patients with acute or chronic arterial or venous thromboembolic occlusions received treatment with low dose (5,000 U per hour) streptokinase via an indwelling intravascular catheter. Successful clot lysis was achieved in 13 of 14 (92%) postprocedural occlusions that were less than one week in age, in 8 of 11 (73%) atherosclerotic occlusions that were less than six weeks in age, in 2 of 3 (67%) emboli from cardiac thrombi, and in all of the pulmonary emboli and superior vena cava occlusions. In the chronic occlusions, successful thrombus lysis occurred less frequently (8 of 21, 38%). Although the initial objective of fibrinolytic therapy is clot lysis, the long term clinical success depends on the diagnosis and treatment of the underlying cause of the thromboembolism.

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