| Therapeutic thrombolysis with plasminogen activators is an effective and potentially life-saving measure in the management of patients with acute myocardial infarction and cerebral ischemia. Liposomal encapsulation of plasminogen activators by multiple laboratories around the world has shown promise. However, liposomes suffer from physical instability that results in a short shelf-life. The use of polymer microcapsules as an encapsulation vehicle has now demonstrated comparable, if not superior, thrombolytic potential compared to liposomes with improved storage capability.; The capacity of liposomal (LESK) and microencapsulated streptokinase (MESK) to digest an occlusive arterial thrombus were compared to an identical dosage of free streptokinase (FREE SK) in a rabbit model of carotid thrombosis (Chapter 3). Compared to FREE SK (74.5 ± 16.9 min; mean ± SEM), LESK demonstrated significantly reduced reperfusion times (19.3 ± 4.6 min) while MESK exhibited even greater improvement (7.3 ± 1.6 min). LESK and MESK also resulted in reduced residual clot mass and greater return of arterial blood flow.; In vitro studies utilizing clots formed of whole blood or plasma in glass capillary tubes were completed to elucidate the mechanism of lysis with MESK (Chapter 4). In both clot types, lysis occurred more rapidly at higher pressures and MESK restored flow faster than FREE SK. Light and confocal microscopies were used to capture images of clot digestion. FREE SK, like other free plasminogen activators, binds to the leading edge of the thrombus and initiates digestion through a series of localized reactions at the front. MESK, however, accelerates digestion by improving the distribution of streptokinase throughout the clot following greater penetration of the leading edge, a finding confirmed by a computer simulation (Chapter 5). Clot digestion occurs within the thrombus and at the front, thereby promoting faster clot digestion and restoration of flow.; The potential benefit of MESK was also explored in a canine model of coronary thrombosis, a clinically relevant model of myocardial infarction. Compared to FREE SK (68 ± 7 min), MESK significantly reduced the time to achieve sustained reperfusion of the occluded artery (29 ± 4 min). In addition, MESK-treatment resulted in substantial reductions in infarct size, residual clot mass, and bleeding complications.; MESK accelerates thrombolysis and the restoration of blood flow compared to identical dosages of FREE SK while also reducing systemic fibrinogenolysis and blood loss. Accelerated clot digestion is achieved by distributed intraclot thrombolysis following greater spatial distribution of the plasminogen activator. Microencapsulation may produce an improved dosage form for restoring arterial blood flow and reducing bleeding complications with thrombolytic therapy. |
