RESUMO
The purpose of this study was to determine the optimal bolus/infusion ratio of urokinase (UK) in a dog model of experimental thrombosis. Radiolabelled clots from dog whole blood were inserted into an extracorporeal jugular loop in anesthetized dogs. Clot size (counts/min) was continuously recorded. UK was administered i.v. as a 1 min bolus (100%/0%), 30 min infusion (0%/100%), or as a bolus/infusion combination at ratios of 75%/25%, 50%/50%, or 25%/75%. The total dose of UK in all groups was 20,000 U/kg. A bolus/infusion ratio of 25%/75% produced twice as much lysis as either bolus or infusion alone. There were no statistical differences between the UK-treated groups in reduction of plasma alpha 2-antiplasmin concentration. We conclude that thrombolytic efficacy was increased by the bolus/infusion administration of UK without a concomitant increase in systemic plasminogen to plasmin conversion.
Assuntos
Tromboflebite/tratamento farmacológico , Ativador de Plasminogênio Tipo Uroquinase/administração & dosagem , Animais , Cães , Esquema de Medicação , Infusões Intravenosas , Injeções Intravenosas , Masculino , Peso Molecular , Ativador de Plasminogênio Tipo Uroquinase/farmacologia , alfa 2-Antiplasmina/análiseRESUMO
Tissue plasminogen activator (tPA) has become available for pharmacologic use, and it appears to produce relatively fewer hemorrhagic complications than the previously available, less specific thrombolytic agents. We tested the effects of tPA in several models of embolic stroke and found that neurologic damage was reduced when the drug was administered as late as 45 minutes after cerebral embolic occlusion. The mechanism of therapeutic efficacy of tPA was probably thrombolysis. Drug-induced hemorrhages did not occur when therapy was started within four hours after the onset of vascular occlusion. These results suggest that tPA may be useful for thrombolytic therapy of embolic stroke if the drug is administered rapidly after the onset of vascular occlusion.
Assuntos
Transtornos Cerebrovasculares/tratamento farmacológico , Embolia e Trombose Intracraniana/tratamento farmacológico , Ativador de Plasminogênio Tecidual/uso terapêutico , Animais , Encéfalo/patologia , Circulação Cerebrovascular/efeitos dos fármacos , Transtornos Cerebrovasculares/patologia , Relação Dose-Resposta a Droga , Avaliação de Medicamentos , Embolia e Trombose Intracraniana/patologia , Coelhos , Fatores de Tempo , Ativador de Plasminogênio Tecidual/administração & dosagemRESUMO
We developed a small animal embolic stroke model for pharmacological screening trials. Microspheres are injected into the carotid circulations and group embolus dose-response relationships are calculated. Emboli quantity is related to neurologic injury, and small changes in neurologic function are detectable. Rabbits tolerated twice as many microspheres when cyproheptadine-treated after embolization. This demonstrated both the sensitivity of the model and the value of serotonin antagonists in reducing neurological injury.
Assuntos
Ciproeptadina/uso terapêutico , Embolia e Trombose Intracraniana/tratamento farmacológico , Animais , Arteríolas/patologia , Córtex Cerebral/irrigação sanguínea , Córtex Cerebral/patologia , Modelos Animais de Doenças , Masculino , Microesferas , Coelhos , Ratos , Ratos EndogâmicosRESUMO
Intravenous administration of tissue plasminogen activator immediately after the injection of numerous small blood clots into the carotid circulation in rabbit embolic stroke model animals caused a significant reduction in neurological damage. In vitro studies indicate that tissue plasminogen activator produced substantial lysis of clots at concentrations comparable to those expected in vivo, suggesting that this may be the mechanism of action of this drug. Drug-induced hemorrhages were not demonstrable. Tissue plasminogen activator may be of value for the immediate treatment of embolic stroke.
