The Antiaggregating and Antithrombotic Activity of Clopidogrel Is Potentiated by Aspirin in Several Experimental Models in the Rabbit

1998 ◽  
Vol 80 (09) ◽  
pp. 512-518 ◽  
Author(s):  
Frédérique Dol ◽  
André Bernat ◽  
Robert Falotico ◽  
Alain Lalé ◽  
Pierre Savi ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Carotid Artery ◽  
Ex Vivo ◽  
Thrombus Formation ◽  
Experimental Models ◽  
Arteriovenous Shunt ◽  
Thrombotic Occlusion ◽  
Antithrombotic Activity ◽  
Rabbit Carotid Artery ◽  
Antithrombotic Efficacy

SummaryIt is unknown whether the addition of aspirin might increase both the efficacy and the potency of clopidogrel, a potent and selective ADP blocker. For that purpose, the efficacy of clopidogrel (1–20 mg/kg, p.o.) administered orally to rabbits alone or in combination with aspirin (0.1–10 mg/kg, p.o.) was determined in several experimental models. A potent synergistic effect of the clopidogrel/aspirin association was demonstrated with regard to collagen-induced platelet aggregation measured ex vivo. Similarly, aspirin potentiated the antithrombotic activity of clopidogrel measured with regard to experimental thrombosis induced by a silk thread or on stents placed in an arteriovenous shunt, thrombus formation following electrical stimulation of the rabbit carotid artery and with regard to 111In-labeled platelet deposition on a stent implanted in an arteriovenous shunt or on the subendothelium following air drying injury of the rabbit carotid artery. A similar potentiating effect of aspirin was obtained with regard to myointimal proliferation (restenosis) in the femoral arteries of atherosclerotic rabbits which occurred as a consequence of stent placement. The clopidogrel/aspirin combination showed only additive-type effects on bleeding time prolongation induced by ear transection in the rabbit, therefore showing that combined inhibition of cyclooxygenase and ADP‘s effects provide a marked enhanced antithrombotic efficacy. Such a combination may provide substantial protection against platelet aggregation leading to thrombotic occlusion at sites of endothelial injuries and coronary artery stenosis in humans.

The Antiaggregating and Antithrombotic Activity of Ticlopidine Is Potentiated by Aspirin in the Rat

1996 ◽  
Vol 76 (01) ◽  
pp. 094-098 ◽  
Author(s):  
J M Herbert ◽  
A Bernat ◽  
M Samama ◽  
J P Maffrand
Keyword(s):  
Platelet Aggregation ◽  
Carotid Artery ◽  
Bleeding Time ◽  
Ex Vivo ◽  
Experimental Models ◽  
Silk Thread ◽  
Antithrombotic Activity ◽  
Additive Type ◽  
Wire Coil ◽  
Antithrombotic Efficacy

SummarySince ticlopidine specifically inhibits ADP-induced platelet aggregation without affecting prostaglandin metabolism, it seemed interesting to evaluate the effect of aspirin with regard to the antithrombotic efficacy of ticlopidine. Ticlopidine was administered orally to rats alone or in combination with aspirin and the efficacy of the association was determined in several experimental models. A synergistic effect of the ticlopidine/aspirin association was demonstrated with regard to ADP- and collagen-induced platelet aggregation measured ex vivo but also in several experimental thrombosis models including silk thread-induced thrombosis in an arteriovenous shunt, wire coil-induced thrombosis and 111In-labelled platelet deposition on the subendothelium following air drying injury of the rat carotid artery. Similar results were obtained with regard to myointimal proliferation following air-induced injury of the rat carotid artery which occurred as a consequence of vascular injury. The ticlopidine/aspirin combination showed only additive-type effects on bleeding time prolongation induced by tail transection in the rat.

Antithrombotic Effects and Bleeding Time Prolongation with Synthetic Platelet GPIIb/llla Inhibitors in Animal Models of Platelet-Mediated Thrombosis

1994 ◽  
Vol 71 (01) ◽  
pp. 095-102 ◽  
Author(s):  
Désiré Collen ◽  
Hua Rong Lu ◽  
Jean-Marie Stassen ◽  
Ingrid Vreys ◽  
Tsunehiro Yasuda ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Bleeding Time ◽  
Bolus Injection ◽  
Cell Injury ◽  
Ex Vivo ◽  
Thrombus Formation ◽  
Femoral Vein ◽  
Thrombotic Occlusion ◽  
Antithrombotic Effects

SummaryCyclic Arg-Gly-Asp (RGD) containing synthetic peptides such as L-cysteine, N-(mercaptoacetyl)-D-tyrosyl-L-arginylglycyl-L-a-aspartyl-cyclic (1→5)-sulfide, 5-oxide (G4120) and acetyl-L-cysteinyl-L-asparaginyl-L-prolyl-L-arginyl-glycyl-L-α-aspartyl-[0-methyltyrosyl]-L-arginyl-L-cysteinamide, cyclic 1→9-sulfide (TP9201) bind with high affinity to the platelet GPIIb/IIIa receptor.The relationship between antithrombotic effect, ex vivo platelet aggregation and bleeding time prolongation with both agents was studied in hamsters with a standardized femoral vein endothelial cell injury predisposing to platelet-rich mural thrombosis, and in dogs with a carotid arterial eversion graft inserted in the femoral artery. Intravenous administration of G4120 in hamsters inhibited in vivo thrombus formation with a 50% inhibitory bolus dose (ID50) of approximately 20 μg/kg, ex vivo ADP-induccd platelet aggregation with ID50 of 10 μg/kg, and bolus injection of 1 mg/kg prolonged the bleeding time from 38 ± 9 to 1,100 ± 330 s. Administration of TP9201 in hamsters inhibited in vivo thrombus formation with ID50 of 30 μg/kg, ex vivo platelet aggregation with an ID50 of 50 μg/kg and bolus injection of 1 mg/kg did not prolong the template bleeding time. In the dog eversion graft model, infusion of 100 μg/kg of G4120 over 60 min did not fully inhibit platelet-mediated thrombotic occlusion but was associated with inhibition of ADP-induccd ex vivo platelet aggregation and with prolongation of the template bleeding time from 1.3 ± 0.4 to 12 ± 2 min. Infusion of 300 μg/kg of TP9201 over 60 min completely prevented thrombotic occlusion, inhibited ex vivo platelet aggregation, but was not associated with prolongation of the template bleeding time.TP9201, unlike G4120, inhibits in vivo platelet-mediated thrombus formation without associated prolongation of the template bleeding time.

Enhanced Platelet Aggregation and Thrombogenic Tendency in Adiponectin-Deficient Mice.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 800-800 ◽  
Author(s):  
Hisashi Kato ◽  
Hirokazu Kashiwagi ◽  
Masamichi Shiraga ◽  
Shigenori Honda ◽  
Shigeki Miyata ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Carotid Artery ◽  
Ex Vivo ◽  
Platelet Rich Plasma ◽  
Thrombus Formation ◽  
Atherosclerotic Lesion ◽  
Blue Dye ◽  
Globular Domain ◽  
Wild Type ◽  
Obesity And Diabetes

Abstract Adiponectin is a 30 kDa protein secreted specifically from adipocytes and structurally composed of two distinct domains, C-terminal collagen-like domain and N-terminal complement C1q-like globular domain. Adiponectin is abundantly present in plasma at high concentration ranging from 2 to 30 μg/ml. The plasma levels of adiponectin decreased in patients with obesity and diabetes. Recently it has been demonstrated that adiponectin has an anti-atherogenic activity. Hypoadiponectinemia is an independent risk factor for coronary artery disease in men. However, the role of adiponectin in hemostasis and thrombosis still remains obscure. In this study, we examined its role in hemostasis and thrombosis using adiponectin-deficient (APN-KO) mice (Nat. Med. 2002 Maeda et al.). APN-KO mice were fed by normal chaw and studied at 8–12 weeks old. There were no differences in platelet counts, PT, APTT and plasma fibrinogen levels between APN-KO and Wild-Type mice. Neither Wild-Type nor APN-KO mice showed detectable atherosclerotic lesion in carotid artery as well as whole aorta. We examined tail-bleeding times as a measure of primary hemostasis. The tail bleeding time was 96.9 ± 34.9 seconds in APN-KO mice, which was shorter than that in wild type mice (130.9 ± 52.1 seconds, n=30, p<0.05). We next studied thrombus formation in mice carotid artery using He-Ne laser induced in vivo thrombus formation model. Thrombus formation was induced by the interaction of irradiated He-Ne laser with evans blue dye injected into blood flow. The thrombus volumes formed during 10 minutes were significantly larger in APN-KO mice (6.74 ± 2.87 x 107 arbitrary units for wild-type v.s. 13.4 ± 4.25 x 107 arbitrary units for APN-KO mice, n=10, p<0.01). Adenovirus-mediated supplement of adiponectin compensated for the thrombotic tendency in APN-KO mice. In order to clarify the effects of adiponectin on platelet functon, we performed ex vivo experiments. In platelet aggregation studies under stirring conditions using platelet-rich plasma, platelet aggregation induced by low concentrations of agonists (ADP 2.5μM, collagen 2.5μg/ml, PAR4 peptide 75μM) was enhanced in APN-KO mice. Again the adenovirus-mediated supplement of adiponectin compensated for the enhancement of platelet aggregation. We next studied the thrombus formation on collagen coated surface under flow conditions. The thrombus formation was enhanced in APN-KO mice under shear rate at 250s−1. Our data provide a first evidence that adiponectin plays a role in hemostasis and thrombosis as a negative modulator of platelet function.

Antithrombotic Activity of Polydeoxyribonucleotides of Maml1Alian Origin (Laboratory Code: Fraction P) in Experimental Animals

1979 ◽  
Author(s):  
R. Niacia ◽  
H. Hantovani ◽  
G. Prino ◽  
R. Pescador ◽  
G.F. Nardi
Keyword(s):  
Ex Vivo ◽  
Thrombus Formation ◽  
Local Level ◽  
Femoral Vein ◽  
Dry Weight ◽  
Experimental Models ◽  
Cheek Pouch ◽  
Hamster Cheek Pouch ◽  
Antithrombotic Activity

Fraction P(FP)is a polydeoxyribonucleotidic substance of mammalian 9rigin which was found able to ac tivat e the fibrinolytic system of some experimental animals.We have investigat ed the possible antithrombotic activity of FP in three different experimental models. In the col lagen-induced thrombosis of the rabbit femoral vein,pretreatment with FP i.v.(50, 100 or 200 mg/kg) reduced the thrombus dry weight by 427, (P < 0.005). 50% (P < 0.001) and 72% (P < 0.001), respectively; pretreatment with FP peros02.5, 25 or 50 mg/kg) decreased the thrombus dry weight by 22% (n.s.), 46% (P < 0.001) and 69% (P < 0.001), respectively. In the electrical l y induced thrombosis of rat carotid artery, pretreatment with FP i.v. (37.5, 75 or 150 mg/kg)reduced the fall in arterial surface temperature by 20%(P < 0.005), 62% (P < 0.025) and 86% (P < 0.001), respectively. In the hamster cheek pouch model, venular thrombosis induced by iontophoresis of ADP was inhibited by 85 %(P < 0.025) when the animals were pretreated with FP i.v. (2 mg/kg) or by 957, (P < 0.025) when FP was given per os (1 mg/kg). These antithrombotic effects lasted longer than the activation of fibrinolysis measured in ex vivo studies in the same animal species. This would suggest that a more complex mechanism(possibly including vascul ar factors at local level)could be responsible for the in vivo effect of FP as an inhibitor of thrombus formation.

Antiplatelet Effect of FK633, a Platelet Glycoprotein Ilb/IIIa Antagonist, on Thrombus Formation and Vascular Patency after Thrombolysis in the Injured Hamster Carotid Artery

1997 ◽  
Vol 77 (03) ◽  
pp. 562-567 ◽  
Author(s):  
Takehiro Kaida ◽  
Hiroyuki Matsuno ◽  
Masayuki Niwa ◽  
Osamu Kozawa ◽  
Hideo Miyata ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Carotid Artery ◽  
Vascular Injury ◽  
Bleeding Time ◽  
Thrombus Formation ◽  
Separate Experiment ◽  
Platelet Glycoprotein ◽  
Neointima Formation ◽  
Vascular Patency ◽  
Injured Artery

SummaryThe antithrombotic and restenosis-preventing effects of FK633, an inhibitor of platelet aggregation via binding to the glycoprotein (GP) Ilb/IIIa receptor, were studied. IC50 value of FK633 against platelet aggregation ex vivo induced by 2.5 |iM adenosine diphosphate (ADP) was 5.4 X 10"7 M as determined using hamster platelet rich plasma. The inhibitory effect was also investigated in vivo on thrombus formation at the carotid arterial wall injured by a modified catheter. As a control, the left carotid artery was injured and the time required to develop a thrombotic occlusion (3.9 ±1.1 min, mean ± S.E.M., n = 18) was determined. Then, the right carotid artery of the same animal was injured while a continuous intravenous (i.v.) infusion of FK633 was administered at doses of 0 (saline), 0.1,0.3 or 1.0 mg/kg/h. The time to occlusion was dose-dependently prolonged. In a separate experiment, 10% of the total tPA dose (0.52 mg/kg) was injected into the injured artery as a bolus and the remaining was infused i.v. at a constant rate for 30 min. When FK633 (0.3 or 1.0 mg/kg/h) was infused together with tPA, late patency of the reperfused artery was much improved as compared with that of treatment with tPA alone. Bleeding time, measured at the end of the tPA infusion, was markedly prolonged when the higher dose of FK633 (1.0 mg/kg/h) was coadministered, however coadministration of the lower dose of FK633 (0.3 mg/kg/h) was almost without prolongation on the bleeding time, despite a significant effect on the vascular patency after thrombolysis. Next, neointima formation was evaluated 2 weeks after the vascular injury. When FK633 (0.3 mg/kg/h) was continuously infused i. v. by an implanted osmotic pump for 3,7 or 14 days after the vascular injury, the neointimal area formation was significantly suppressed in the treatment groups for 7 or 14 days. These findings suggest that FK633 inhibits platelet activation in the injured artery and improves vascular patency after thrombolysis with tPA with a concomitant suppression of neointima formation.

Biochemical and Pharmacological Properties of SANORG 34006, a Potent and Long-Acting Synthetic Pentasaccharide

Blood ◽  
1998 ◽  
Vol 91 (11) ◽  
pp. 4197-4205 ◽  
Author(s):  
J.M. Herbert ◽  
J.P. Hérault ◽  
A. Bernat ◽  
R.G.M. van Amsterdam ◽  
J.C. Lormeau ◽  
...  
Keyword(s):  
Thrombin Generation ◽  
Ex Vivo ◽  
Thrombus Formation ◽  
Factor Xa ◽  
Therapeutic Index ◽  
Inhibitory Effect ◽  
Experimental Models ◽  
Treatment And Prevention ◽  
Long Acting

Abstract SANORG 34006 is a new sulfated pentasaccharide obtained by chemical synthesis. It is an analog of the “synthetic pentasaccharide” (SR 90107/ ORG 31540) which represents the antithrombin (AT) binding site of heparin. SANORG 34006 showed a higher affinity to human AT than SR 90107/ORG 31540 (kd = 1.4 ± 0.3 v 48 ± 11 nmol/L), and it is a potent and selective catalyst of the inhibitory effect of AT on factor Xa (1,240 ± 15 anti–factor Xa U/mg v850 ± 27 anti-factor Xa U/mg for SR 90107/ORG 31540). In vitro, SANORG 34006 inhibited thrombin generation occurring via both the extrinsic and intrinsic pathway. After intravenous (IV) or subcutaneous (SC) administration to rabbits, SANORG 34006 displayed a long-lasting anti–factor Xa activity and inhibition of thrombin generation (TG) ex vivo. SANORG 34006 was slowly eliminated after IV or SC administration to rats, rabbits, and baboons, showed exceptionally long half-lives (between 9.2 hours in rats and 61.9 hours in baboons), and revealed an SC bioavailability near 100%. SANORG 34006 displayed antithrombotic activity by virtue of its potentiation of the anti–factor Xa activity of AT. It strongly inhibited thrombus formation in experimental models of thromboplastin/stasis-induced venous thrombosis in rats (IV) and rabbits (SC) (ED50values = 40.0 ± 3.4 and 105.0 ± 9.4 nmol/kg, respectively). The duration of its antithrombotic effects closely paralleled the ex vivo anti–factor Xa activity. SANORG 34006 enhanced rt-PA–induced thrombolysis and inhibited accretion of125I-fibrinogen onto a preformed thrombus in the rabbit jugular vein suggesting that concomitant use of SANORG 34006 during rt-PA therapy might be helpful in facilitating thrombolysis and preventing fibrin accretion onto the thrombus under lysis. Contrary to standard heparin, SANORG 34006 did not enhance bleeding in a rabbit ear incision model at a dose that equals 10 times the antithrombotic ED50 in this species and, therefore, exhibited a favorable therapeutic index. We suggest that SANORG 34006 is a promising compound in the treatment and prevention of various thrombotic diseases.

RPR120844, a Novel, Specific Inhibitor of Coagulation Factor Xa Inhibits Venous Thrombosis in the Rabbit

1999 ◽  
Vol 81 (01) ◽  
pp. 157-160 ◽  
Author(s):  
Ross Bentley ◽  
Suzanne Morgan ◽  
Karen Brown ◽  
Valeria Chu ◽  
Richard Ewing ◽  
...  
Keyword(s):  
Jugular Vein ◽  
Drug Effect ◽  
Ex Vivo ◽  
Thrombus Formation ◽  
Specific Inhibitor ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Antithrombotic Activity ◽  
Fxa Inhibitor

SummaryThe in vivo antithrombotic activity of RPR120844, a novel synthetic coagulation factor Xa (fXa) inhibitor (Ki = 7 nM), was assessed by its ability to inhibit thrombus formation in a damaged segment of the rabbit jugular vein. Intravenous dose-response studies were performed and thrombus mass (TM), activated partial thromboplastin time (APTT), prothrombin time (PT), inhibition of ex vivo fXa activity and plasma drug levels (PDL) were determined. TM, measured at the end of a 50 min infusion, was significantly reduced (p <0.05 vs saline-treated animals) by RPR120844 at 30 and 100 μg/kg/min. At doses of 10, 30 and 100 μg/kg/min, APTT was prolonged by 2.1, 4.2 and 6.1-fold, and PT was prolonged by 1.4, 2.2 and 3.5-fold, respectively. PDL were determined by measuring anti-fXa activity using an amidolytic assay. Peak PDL were 0.8 ± 0.3, 1.5 ± 0.9 and 2.4 ± 0.6 μM, respectively. The drug effect was reversible with APTT, PT and PDL returning toward pretreatment values 30 min after termination of treatment. The results suggest that RPR120844, or similar compounds, may provide an efficacious, yet easily reversible, means of inhibiting thrombus formation.

scholarly journals Antithrombotic effect of a monoclonal antibody to the platelet glycoprotein IIb/IIIa receptor in an experimental animal model

Blood ◽  
1986 ◽  
Vol 68 (3) ◽  
pp. 783-786 ◽  
Author(s):  
BS Coller ◽  
JD Folts ◽  
LE Scudder ◽  
SR Smith
Keyword(s):  
Monoclonal Antibody ◽  
Animal Model ◽  
Platelet Aggregation ◽  
Ex Vivo ◽  
Thrombus Formation ◽  
Platelet Glycoprotein ◽  
Antithrombotic Effect ◽  
Antithrombotic Agent ◽  
Antithrombotic Effects ◽  
Platelet Thrombus

A murine monoclonal antibody directed at the platelet glycoprotein IIb/IIIa complex, which blocks platelet aggregation ex vivo, was tested for its antithrombotic effects in an established animal model of acute platelet thrombus formation in partially stenosed arteries. Infusion of 0.7 to 0.8 mg/kg of the F(ab')2 fragment of the antibody completely blocked new thrombus formation despite multiple provocations, making it the most potent antithrombotic agent tested in this model.

scholarly journals Comparative Study on the Effect of Carbenicillin, Inhibitors of Platelet Function and Heparin on Experimental Thrombus Formation

1977 ◽  
Author(s):  
R. Zimmermann ◽  
K. Andrassy ◽  
C. Zeltsch ◽  
D. Lange ◽  
F. Hof
Keyword(s):  
Platelet Aggregation ◽  
Bleeding Time ◽  
Thrombus Formation ◽  
Platelet Aggregation Inhibitors ◽  
Venous System ◽  
Arterial System ◽  
Antithrombotic Activity ◽  
Lower Extent ◽  
Aggregation Inhibitors ◽  
Blood Elements

Previous studies documented an impairment of haemostasis by synthetic penicillins (Thromb. Haem. 34: 115, 1976) and penicillin (Lancet II : 1039, 1976). Therefore the antithrombotic activity of synthetic penicillin. (carbenicillin)(C) was compared with that of aspirin (ASA), dipyridamole (DIPY) and heparin in 150 rabbits. Thrombus formation was induced by standardized endothelial lesions. The dose of C was adjusted to a 4.2 fold prolongation of bleeding time, similar to that seen in clinical patients. Analysis and composition of thrombi was done by measurement of incorporation of labeled blood elements (51cr labeled platelets, 125J-fibrinogen and 59Fe labeled red cells). The ‘specific thrombus/blood ratio’ with values of 19.1 and 50.9 (51cr) in venous and arterial thrombi evidenced the significance of platelets in this model. In the venous system C reduced formation of thrombi by 43%, ASA by 34%, ASA and DIPY by 55% and heparin by 90%. In the arterial system C inhibited thrombus formation by 89%, ASA by 15%, ASA and DIPY by 46% and heparin by 60%. It is concluded, that C effectively prevents thrombus formation in the arterial system and to lower extent in the venous system. The results prove the importance of platelets in arterial thrombogenesis and the efficacy of platelet aggregation inhibitors in preventing thrombi in the arterial system. In comparison with other known antiplatelet drugs it seems, that C is the most effective platelet aggregation inhibitor to date.

Ex vivo evaluation of anti-GPVI antibody in Cynomolgus monkeys: Dissociation between anti-platelet aggregatory effect and bleeding time

2006 ◽  
Vol 96 (08) ◽  
pp. 167-175 ◽  
Author(s):  
Yutaka Matsumoto ◽  
Hisao Takizawa ◽  
Kazuhiro Nakama ◽  
Xiaoqi Gong ◽  
Yoshihisa Yamada ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Bleeding Time ◽  
Ex Vivo ◽  
Thrombus Formation ◽  
Inhibitory Effect ◽  
Bleeding Tendency ◽  
Fab Fragment ◽  
Dose Escalation Study ◽  
Cynomolgus Monkeys ◽  
Induced Aggregation

SummaryRecent progress in the understanding of thrombus formation has suggested an important role of glycoprotein (GP)VI. In contrast to its pivotal role in collagen-induced platelet activation, it has been suggested that its blockade does not induce massive bleeding tendency. To demonstrate the dissociation between inhibitory effect on platelet aggregation and bleeding by GPVI blockade, we examined the effects of Fab fragment of OM2, an anti-human GPVI monoclonal antibody on ex vivo collagen-induced platelet aggregation and skin bleeding time after intravenous injection in cynomolgus monkeys. In a dose-escalation study, OM2 potently (>80%) inhibited collagen-induced platelet aggregation at the cumulative dose of 0. 2 mg/kg with a slight prolongation of bleeding time (1. 3 times baseline value). Furthermore, at 18. 8 mg/kg, the highest dose tested, prolongation of bleeding time was still mild (1. 9 times). In contrast, abciximab, Fab fragment of anti-GPIIb/IIIa antibody prolonged bleeding time by 5. 0 times at 0. 35 mg/kg, the lowest effective dose on platelet aggregation. Ina pharmacodynamic study,a bolus injection of OM2 at 0. 4 mg/kg produced potent inhibition of collagen-induced aggregation up to six hours after injection, showing longer half-life than that of abciximab. The injection of OM2 Fab did not induce thrombocytopenia and GPVI depletion in monkeys. These results suggest that blockade of GPVI by antibody can exerta potent inhibitory effect on collagen-induced platelet aggregation with a milder prolongation of bleeding time than blockade of GPIIb/IIIa. This study indicates that OM2 has the potential to be developed as a new class of therapeutic tool.

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