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1.
Thromb Haemost ; 95(3): 469-75, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16525575

RESUMO

Under high shear arterial blood flow von Willebrand Factor (vWF) binds the platelet receptor glycoprotein (GP) Ibalpha, leading to platelet adhesion, activation and thrombosis. Blockade of vWF-GPIb alpha interactions by GPG-290 was investigated in a canine model of coronary artery thrombosis alone and in combination with clopidogrel. GPG-290 (100 microg/kg, n=6; 500 microg/kg, n=6) prolonged time to thrombotic occlusion (TTO) to 105+/-34 and 156+/-23 (p<0.05) min, respectively compared to the saline treated control group (32+/-6 min, n=6). Patency of the injured vessel was sustained in 1/6 (100 microg/kg) and 3/6 vessels (500 microg/kg) 4 hours after injury, in contrast to 0/6 in the control group. There was an increase in bleeding after the 500 microg/kg dose, but only at the 1 hr time point. Clopidogrel was studied in two dosing regimens representing either a clinical pretreatment regimen (PTR) of 4.3 mg/kg on day -2 followed by 1.1 mg/kg daily for 2 days prior to the procedure or pre-procedural loading dose regimen (LDR) of 4.3 mg/kg 3 hr pre-procedure. The PTR and LDR clopidogrel treatments prolonged TTO to 98.2+/-30.0 min and 136.1+/-39.5 min (p<0.05), and sustained patency in 1/6 and 4/8 vessels, respectively. However, template bleeding time in the LDR clopidogrel group was sustained higher than the control group. The combination of PTR clopidogrel and GPG-290 (100 microg/kg) prolonged TTO equivalent to LDR clopidogrel alone (141.4 +/- 35.1 min) and sustained patency in 3/7 dogs, without increased bleeding while LDR clopidogrel combined with 100 microg/kg GPG-290 prevented occlusion in 5/8 dogs and further prolonged TTO (173.5+/-32.6 min) but was associated with increased bleeding compared to control. GPG-290 is an antithrombotic agent that may be combined with lower doses of clopidogrel to yield similar antithrombotic efficacy as higher loading doses.


Assuntos
Trombose Coronária/prevenção & controle , Fibrinolíticos/farmacologia , Complexo Glicoproteico GPIb-IX de Plaquetas/farmacologia , Animais , Tempo de Sangramento , Clopidogrel , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Eptifibatida , Fibrinolíticos/uso terapêutico , Peptídeos/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologia , Inibidores da Agregação Plaquetária/uso terapêutico , Complexo Glicoproteico GPIb-IX de Plaquetas/genética , Complexo Glicoproteico GPIb-IX de Plaquetas/uso terapêutico , Proteínas Recombinantes de Fusão/farmacologia , Proteínas Recombinantes de Fusão/uso terapêutico , Ticlopidina/análogos & derivados , Ticlopidina/farmacologia , Ticlopidina/uso terapêutico , Fatores de Tempo , Grau de Desobstrução Vascular/efeitos dos fármacos , Fator de von Willebrand/antagonistas & inibidores
2.
Xenotransplantation ; 11(2): 203-9, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-14962282

RESUMO

In xenotransplantation, donor endothelium is the first target of immunological attack. Activation of the endothelial cell by preformed natural antibodies leads to platelet binding via the interaction of the glycoprotein (GP) Ib and von Willebrand factor (vWF). TMVA is a novel GPIb-binding protein purified from the venom of Trimeresurus mucrosquamatus. In this study, the inhibitory effect of TMVA on platelet aggregation in rats and the effect on discordant guinea pig-to-rat cardiac xenograft survival were investigated. Three doses (8, 20 or 40 microg/kg) of TMVA were infused intravenously to 30 rats respectively. Platelet aggregation rate was assayed 0.5, 12, and 24 h after TMVA administration. Wister rats underwent guinea pig cardiac cervical heterotopic transplantation using single dosing of TMVA (20 microg/kg, i.v., 0.5 h before reperfusion). Additionally, levels of TXB(2) and 6-keto-PGF(1alpha) within rejected graft tissues were determined by radioimmunoassay. Treatment with TMVA at a dose of 20 or 40 microg/kg resulted in complete inhibition of platelet aggregation 0.5 h after TMVA administration. Rats receiving guinea pig cardiac xenografts after TMVA therapy had significantly prolonged xenograft survival. Histologic and immunopathologic analysis of cardiac xenografts in TMVA treatment group showed no intragraft platelet microthrombi formation and fibrin deposition. Additionally, the ratio of 6-keto-PGF(1alpha) to TXB(2) in TMVA treatment group was significantly higher than those in control group. We conclude that the use of this novel GPIb-binding protein was very effective in preventing platelet microthrombi formation and fibrin deposition in a guinea pig-to-rat model and resulted in prolongation of xenograft survival. The increased ratio of PGI(2)/TXA(2) in TMVA treatment group may protect xenografts from the endothelial cell activation and contribute to the prolongation of xenograft survival.


Assuntos
Sobrevivência de Enxerto/fisiologia , Transplante de Coração/fisiologia , Lectinas Tipo C/uso terapêutico , Complexo Glicoproteico GPIb-IX de Plaquetas/uso terapêutico , Trombose/prevenção & controle , Transplante Heterólogo/fisiologia , Venenos de Víboras/uso terapêutico , Fator de von Willebrand/uso terapêutico , Difosfato de Adenosina/farmacologia , Animais , Plaquetas/efeitos dos fármacos , Plaquetas/fisiologia , Cobaias , Masculino , Agregação Plaquetária/efeitos dos fármacos , Ratos , Ratos Wistar
3.
Eur Heart J ; 23(3): 239-46, 2002 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11792139

RESUMO

BACKGROUND: Many patients with acute coronary syndromes are offered percutaneous coronary intervention. However, the appropriate indications for, and optimal timing of, such procedures are uncertain. We analysed timing of intervention and associated events (death and myocardial infarction) in the PURSUIT trial in which 9461 patients received a platelet glycoprotein IIb/IIIa inhibitor, eptifibatide, or placebo for 72 h. Other treatment was left to the investigators. 2430 patients underwent percutaneous coronary intervention within 30 days. Four groups were distinguished, who underwent percutaneous coronary intervention on day 1; on days 2 or 3; at 4 to 7 days; or between 8 until 30 days, for eptifibatide- and placebo-treated patients. RESULTS: The four groups treated with placebo demonstrated total 30-day events of 15.9% for day 1 percutaneous coronary intervention, 17.7%, 15.0% and 18.2%, respectively, for successive intervals of later intervention. Later intervention was associated with more pre-procedural events (2.2% to 13.7%, P=0.001) which was balanced by a decrease in procedure-related events (12.1 to 3.1%, P=0.001), while the overall 30-day event rates were similar. Eptifibatide-treated patients with percutaneous coronary intervention on day 1 had the lowest rate of 30-day events (9.2%, P<0.05 vs other groups). In this group, pre-procedural risk was only 0.3%, while percutaneous coronary intervention on eptifibatide treatment was associated with low procedural risk (7.2%). The total 30-day event rate for later percutaneous coronary intervention in patients receiving eptifibatide was 14.0 on days 2 and 3, 15.0% for days 4 to 7 and 17.4% for days 7 to 30, respectively. CONCLUSION: Patients treated with a platelet glycoprotein IIb/IIIa receptor blocker, and early percutaneous coronary intervention (within 24 h) had the lowest event rate in this post hoc analysis. Thus 'watchful waiting' may not be the optimal strategy. Rather an early invasive strategy with percutaneous coronary intervention under protection of a platelet glycoprotein IIb/IIIa receptor blocker should be considered in selected patients. Randomized trials are warranted to verify this issue.


Assuntos
Angioplastia Coronária com Balão , Doença das Coronárias/terapia , Eletrocardiografia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/uso terapêutico , Complexo Glicoproteico GPIb-IX de Plaquetas/antagonistas & inibidores , Complexo Glicoproteico GPIb-IX de Plaquetas/uso terapêutico , Glicoproteínas da Membrana de Plaquetas , Doença Aguda , Terapia Combinada , Doença das Coronárias/complicações , Doença das Coronárias/mortalidade , Determinação de Ponto Final , Eptifibatida , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeos/antagonistas & inibidores , Peptídeos/uso terapêutico , Placebos , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/mortalidade , Análise de Sobrevida , Síndrome , Fatores de Tempo , Resultado do Tratamento
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