RESUMO
Defibrotide (DEF), a compound previously found to stimulate vascular prostacyclin (PGI2) formation, has been investigated in an experimental model of septic shock. Anesthetized pigs were subjected to i.v. infusion of lipid A (1.5 mg/kg per hr for 4 hr). DEF (50 mg/kg per hr) or vehicle were infused i.v. throughout the experiments, starting 1 hr prior to lipid A. Two out of 7 pigs receiving vehicle survived lipid A infusion for 4 hr, whereas 6 out of 7 DEF treated animals survived this period (P less than 0.05). DEF delayed the shock-induced depression of platelet count and preserved platelet secretory function (collagen-induced ATP-secretion). DEF increased plasma PGI2 by 45% (P less than 0.05) during lipid A infusion and tended to reduce thromboxane levels. DEF did not change eicosanoid formation in sham-shock pigs (n = 4 per group). In vivo treatment with DEF significantly increased the stimulatory effect of bradykinin (1 microM) and arachidonic acid (100 microM) on PGI2 formation ex vivo of mesenteric and iliac artery segments. The improvement of survival in lipid A-induced shock by DEF may be related to an enhancement of vascular PGI2 generation, potentially due to a reduction of shock-induced platelet activation and microcirculatory dysfunction.
Assuntos
Plaquetas/efeitos dos fármacos , Epoprostenol/biossíntese , Polidesoxirribonucleotídeos/farmacologia , Choque/metabolismo , Tromboxano A2/biossíntese , Animais , Ácido Araquidônico , Bradicinina , Modelos Animais de Doenças , Sinergismo Farmacológico , Lipídeo A , Contagem de Plaquetas/efeitos dos fármacos , Choque/induzido quimicamente , Taxa de Sobrevida , SuínosRESUMO
The effect of hirudin and heparin on thrombin-induced consumption of antithrombin III, fibrinogen and platelets was studied in a rat model. Antithrombin III is consumed by tolerated thrombin doses by about 20 per cent. Hirudin and heparin ameliorate the consumption of fibrinogen and platelets at the low thrombin dose used. At high thrombin doses, tolerated only during simultaneous administration of exogenous inhibitors, heparin leads to markedly increased consumption of anti-thrombin III, whereas hirudin does not. With either kind of treatment, the thrombin effect on fibrinogen and platelets is inhibited, however, hirudin acts independently of a cofactor in contrast to heparin.
Assuntos
Antitrombina III/metabolismo , Coagulação Intravascular Disseminada/sangue , Hirudinas/administração & dosagem , Animais , Plaquetas/efeitos dos fármacos , Coagulação Intravascular Disseminada/induzido quimicamente , Feminino , Fibrinogênio/metabolismo , Heparina/administração & dosagem , Infusões Intravenosas , Masculino , Ratos , Ratos Endogâmicos , TrombinaRESUMO
The effect of heparin, hirudin, and a synthetic thrombin inhibitor on antithrombin III, fibrinogen and platelets was studied in a rat model of disseminated intravascular coagulation (DIC) induced by thrombin infusion. Antithrombin III is consumed during thrombin infusion to a limited degree. Simultaneous administration of exogenous thrombin inhibitors ameliorates the consumption of fibrinogen and platelets. At high thrombin doses, tolerated only during additional administration of thrombin inhibitors, heparin leads to increased consumption of antithrombin III, whereas hirudin and the synthetic inhibitor do not. In every case, the thrombin effect on fibrinogen and platelets is inhibited.
Assuntos
Antitrombina III/metabolismo , Dipeptídeos , Heparina/farmacologia , Hirudinas/farmacologia , Piperidinas/farmacologia , Animais , Coagulação Intravascular Disseminada , Feminino , Fibrinogênio/análise , Masculino , Contagem de Plaquetas/efeitos dos fármacos , Ratos , Ratos Endogâmicos , TrombinaRESUMO
Synthetic, low-molecular weight thrombin inhibitors may substitute for antithrombin III in inactivating thrombin in vitro and in vivo. They are superior to heparin as antithrombotic agents in antithrombin deficiency or consumption. Studies in experimental animals show the effectiveness of synthetic thrombin inhibitors in immunologic antithrombin depletion, thrombin-induced consumption and CCl4-induced liver failure.