Platelet Anti-Aggregating Activity and Tolerance of Clopidogrel in Atherosclerotic Patients

1996 ◽  
Vol 76 (06) ◽  
pp. 0939-0943 ◽  
Author(s):  
B Boneu ◽  
G Destelle ◽  
Keyword(s):  
Platelet Aggregation ◽  
Large Scale ◽  
Bleeding Time ◽  
Antithrombotic Activity ◽  
Ambulatory Patients ◽  
Patients At Risk ◽  
Set Up ◽  
Ischemic Events ◽  
Large Scale Clinical Trial ◽  
Selection Of

SummaryThe anti-aggregating activity of five rising doses of clopidogrel has been compared to that of ticlopidine in atherosclerotic patients. The aim of this study was to determine the dose of clopidogrel which should be tested in a large scale clinical trial of secondary prevention of ischemic events in patients suffering from vascular manifestations of atherosclerosis [CAPRIE (Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events) trial]. A multicenter study involving 9 haematological laboratories and 29 clinical centers was set up. One hundred and fifty ambulatory patients were randomized into one of the seven following groups: clopidogrel at doses of 10, 25, 50,75 or 100 mg OD, ticlopidine 250 mg BID or placebo. ADP and collagen-induced platelet aggregation tests were performed before starting treatment and after 7 and 28 days. Bleeding time was performed on days 0 and 28. Patients were seen on days 0, 7 and 28 to check the clinical and biological tolerability of the treatment. Clopidogrel exerted a dose-related inhibition of ADP-induced platelet aggregation and bleeding time prolongation. In the presence of ADP (5 \lM) this inhibition ranged between 29% and 44% in comparison to pretreatment values. The bleeding times were prolonged by 1.5 to 1.7 times. These effects were non significantly different from those produced by ticlopidine. The clinical tolerability was good or fair in 97.5% of the patients. No haematological adverse events were recorded. These results allowed the selection of 75 mg once a day to evaluate and compare the antithrombotic activity of clopidogrel to that of aspirin in the CAPRIE trial.

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.

scholarly journals Breeding Theorem Proving Heuristics with Genetic Algorithms

10.29007/gms9 ◽  
2018 ◽  
Author(s):  
Simon Schäfer ◽  
Stephan Schulz
Keyword(s):  
Genetic Algorithms ◽  
Large Scale ◽  
First Order ◽  
Proof Search ◽  
Theorem Provers ◽  
Search Heuristics ◽  
Practical Performance ◽  
Set Up ◽  
The Given ◽  
Selection Of

First-order theorem provers have to search for proofs in an infinitespace of possible derivations. Proof search heuristics play a vitalrole for the practical performance of these systems. In the currentgeneration of saturation-based theorem provers like SPASS, E,Vampire or Prover~9, one of the most important decisions is theselection of the next clause to process with the given clausealgorithms. Provers offer a wide variety of basic clause evaluationfunctions, which can often be parameterized and combined in manydifferent ways. Finding good strategies is usually left to the usersor developers, often backed by large-scale experimentalevaluations. We describe a way to automatize this process usinggenetic algorithms, evaluating a population of different strategieson a test set, and applying mutation and crossover operators to goodstrategies to create the next generation. We describe the design andexperimental set-up, and report on first promising results.

scholarly journals Synthesis and Thrombin, Factor Xa and U46619 Inhibitory Effects of Non-amidino and Amidino N2-Thiophenecarbonyl- and N2-Tosylanthranilamides

2017 ◽  
Author(s):  
Soo Hyun Lee ◽  
Wonhwa Lee ◽  
Nguyen Thi Ha ◽  
Il Soo Um ◽  
Jong-Sup Bae ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Bleeding Time ◽  
Ex Vivo ◽  
Factor Xa ◽  
Inhibitory Effects ◽  
Human Endothelial Cells ◽  
Antithrombotic Activity ◽  
Pharmacological Targets

Thrombin (factor IIa) and factor Xa (FXa) are key enzymes at the junction of the intrinsic and extrinsic coagulation pathways and are the most attractive pharmacological targets for the development of novel anticoagulants. Twenty non-amidino N2-thiophencarbonyl- and N2-tosyl anthranilamides 1-20 and six amidino N2-thiophencarbonyl- and N2-tosylanthranilamides 21-26 were synthesized and evaluated prothrombin time (PT) and activated partial thromboplastin time (aPTT) using human plasma at concentration 30 μg/mL in vitro. From these results, compounds 5, 9, and 21-23 were selected to study the further antithrombotic activity. The anticoagulant properties of 5, 9, and 21-23 significantly exhibited a concentration-dependent prolongation of in vitro PT and aPTT, in vivo bleeding time, and ex vivo clotting time. These compounds concentration-dependently inhibited the activities of thrombin and FXa and inhibited the generation of thrombin and FXa in human endothelial cells. In addition, data showed that 5, 9, and 21-23 significantly inhibited thrombin catalyzed fibrin polymerization and mouse platelet aggregation and inhibited platelet aggregation induced U46619 in vitro and ex vivo. N-(3'-Amidinophenyl)-2-((thiophen-2''-yl)carbonyl amino)benzamide (21) was most active.

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.

Roman Inscriptions 1995–2000

2003 ◽  
Vol 93 ◽  
pp. 212-294
Author(s):  
Richard Gordon ◽  
Joyce Reynolds
Keyword(s):  
Large Scale ◽  
Recent Progress ◽  
Second Century ◽  
Roman History ◽  
New Work ◽  
Previous Survey ◽  
Set Up ◽  
The City ◽  
Spanish Province ◽  
Selection Of

The intention of this survey, as of its predecessors, is to assess the contribution to Roman studies of recent progress in epigraphy. Its aim is to draw attention to the more important newly-published inscriptions, to known or familiar texts whose significance has been reinterpreted, to the progress of publishing projects, and to a selection of recent work based upon epigraphic sources. It is mainly, but not exclusively, concerned with the implications of new work for Roman history and for that reason does not consider a number of otherwise interesting Hellenistic texts. It hardly needs to be said that there has been no publication remotely as significant as theSC de Cn. Pisone patre, which was reported in the previous survey, and to which we devote some further space here. But there are plenty of new or revised texts of sufficient interest: an honorific decree from Pergamon for a member of the city élite who clearly played a key part in the negotiations with the Romans at the time of the war with Aristonicus; the uncle of Cicero initiated into the Samothracian mysteries in 100B.C.; Octavian honoured at Klaros on account of his ‘quasi-divine exploits’; theTessera Paemeiobrigensisoraes Bergidense, which appears to be an edict by Augustus of 15 B.C. alluding to a hitherto unknown Spanish province of this period — ‘Transduria(na)’; a startling re-interpretation of the significance of the ‘Tiberiéum’ inscription set up by Pontius Pilate at Caesarea Maritima; the splendid replacement for Henzen'sActa Arvalium; the foundation inscription of Sarmizegetusa; one of the very earliest references to waterwheels, calledhydromēchanai(a word unknown to LSJ), in a long-known second-century A.D. text from Macedonia, where they were evidently employed on a large scale to produce income for the city; the transport by ‘barbarians’ of a Roman votive inscription, besides more obviously valuable booty, more than 200 km from the Roman frontier into what is now the Ukraine; and a re-reading suggesting that the well-known ‘milestone’ from Phoenicia honouring Julian astemplorum restauratorwas indeed, as Bowersock argued, erected immediately before the Persian expedition.

ADP Plays a Key Role in Thrombogenesis in Rats

1988 ◽  
Vol 59 (02) ◽  
pp. 225-230 ◽  
Author(s):  
J P Maffrand ◽  
A Bernat ◽  
D Delebassée ◽  
G Defreyn ◽  
J P Cazenave ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Bleeding Time ◽  
Thrombus Formation ◽  
Vascular Wall ◽  
Cyclooxygenase Inhibitors ◽  
High Dose ◽  
Silk Thread ◽  
Dense Granules ◽  
Prolonged Bleeding Time ◽  
Venous Shunt

SummaryThe relative importance of ADP, arachidonic acid metabolites and serotonin as thrombogenic factors was evaluated in rats by comparing, after oral administration, the effects of two inhibitors of ADP-induced platelet aggregation (ticlopidine and PCR 4099), three cyclo-oxygenase inhibitors (aspirin, triflusal and indobufen) and a selective serotonin 5HT2 receptor antagonist (ketanserin) on platelet aggregation, in four platelet-dependent thrombosis models and on bleeding time. Platelet aggregation induced by ADP and collagen was completely inhibited by ticlopidine and PCR 4099 whereas only the collagen aggregation was reduced by the cyclo-oxygenase inhibitors. Ketanserin or a depletion of platelet serotonin by reserpine did not affect platelet aggregation. Ticlopidine and PCR 4099 greatly prolonged rat tail transection bleeding time. This is probably related to their known ability to inhibit ADP-mediated platelet aggregation. In contrast, the cyclooxygenase inhibitors did not affect bleeding time at all. Reserpine and ketanserin prolonged bleeding time by interfering with the action of serotonin on the vascular wall. Ticlopidine and PCR4099 were very potent antithrombotics in all the models. Aspirin, only at a high dose, inhibited poorly thrombus formation on a silk thread in an arterio-venous shunt, suggesting that the inhibition of cyclo-oxygenase was not responsible. Triflusal was inactive in all models while indobufen slightly reduced thrombus formation in the silk thread and metallic coil models. Ketanserin and reserpine reduced thrombus only in the metallic coil model. Thrombus formation was greatly reduced in fawn-hooded rats, which lack ADP in their platelet dense granules because of a genetic storage pool deficiency. Taken together, the results obtained with the drugs and with the fawn-hooded rats support the concept that ADP plays a key role in thrombogenesis in rats.

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.

Comparative Arterial Antithrombotic Activity of Clopidogrel and Acetyl Salicylic Acid in the Pig

1992 ◽  
Vol 68 (05) ◽  
pp. 500-505 ◽  
Author(s):  
Ch M Samama ◽  
Ph Bonnin ◽  
M Bonneau ◽  
G Pignaud ◽  
E Mazoyer ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Femoral Artery ◽  
Bleeding Time ◽  
Ex Vivo ◽  
Flow Reduction ◽  
Cyclic Flow ◽  
Left Femoral Artery ◽  
Before And After ◽  
The Right ◽  
Induced Aggregation

SummaryWe investigated the comparative antithrombotic properties of clopidogrel, an analogue of ticlopidine, and aspirin, using the Folts' model on femoral arteries in 22 pigs. On each animal, clopidogrel or aspirin were used to treat the thrombotic process on the left femoral artery and to prevent this process on the right femoral artery. Sequentially: an injury and stenosis were carried out on the left femoral artery; the thrombotic process was monitored with a Doppler during a 30-min observation period for cyclic flow reductions or permanent cessation of flow; after the first cyclic flow reduction occurred, clopidogrel (5 mg kg-1) or aspirin (2.5, 5, 100 mg kg-1) were injected intravenously; if cyclic flow reductions were abolished, epinephrine (0.4 µg kg-1 min-1) was injected to try to restore cyclic flow reductions and/or permanent cessation of flow; then injury and stenosis were applied on the right femoral artery. Before and after injection of clopidogrel or aspirin, ear immersion bleeding times and ex-vivo platelet aggregation were performed. Clopidogrel (n = 7) abolished cyclic flow reductions in all animals and epinephrine did not restore any cyclic flow reduction. On the right femoral artery, cyclic flow reductions were efficiently prevented, even for two injuries. Basal bleeding time (5 min 28) was lengthened (>15 min, 30 min after clopidogrel and remained prolonged even after 24 h). ADP-induced platelet aggregation was inhibited (more than 78%). Comparatively, aspirin had a moderate and no dose-dependent effect. Aspirin 2.5 mg kg-1 (n = 6) abolished cyclic flow reductions in 2 animals, CFR reoccurred spontaneously in one animal and epinephrine restored it in a second animal. Aspirin 5 mg kg-1 (n = 6) abolished cyclic flow reductions in only 3 animals and epinephrine always restored it. Aspirin 100 mg kg-1 (n = 3) was unable to abolish cyclic flow reductions. On the right femoral artery, aspirin did not significantly prevent cyclic flow reductions which occurred in all animals after one (n = 14) or two injuries (n = 1), except for one animal. Basal bleeding time was lengthened but it shortened rapidly, reaching its basal value after 24 h. ADP-induced aggregation was not significantly inhibited, whereas arachidonic acid induced aggregation was always inhibited. Clopidogrel appears as a more potent antithrombotic drug than aspirin in this model, in treating and preventing spontaneous or epinephrine-induced cyclic flow reductions and lengthening bleeding time.

Platelet Function and the Bleeding Time in Progressive Renal Failure

1988 ◽  
Vol 60 (01) ◽  
pp. 083-087 ◽  
Author(s):  
M P Gordge ◽  
R W Faint ◽  
P B Rylance ◽  
G H Neild
Keyword(s):  
Renal Failure ◽  
Platelet Aggregation ◽  
Platelet Function ◽  
Bleeding Time ◽  
C Reactive Protein ◽  
Severe Renal Failure ◽  
Reactive Protein ◽  
Thromboxane Production ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryBleeding time and platelet function tests were performed on 31 patients with progressive chronic renal failure (CRF) due to non-immunological (urological) causes, and compared with 22 healthy controls. Patients were classified as mild (plasma creatinine <300 μmol/l), moderate (300-600 μmol/l) or severe renal failure (>600 μmol/l). Bleeding time was rarely prolonged in mild and moderate CRF and mean bleeding time significantly elevated only in severe CRF (p <0.005). Haematocrit was the only index which correlated with bleeding time (r = -0.40). Platelet counts, collagen stimulated thromboxane generation, and platelet aggregation responses to ADP, collagen and ristocetin were all either normal or increased in all three CRF groups, but thromboxane production in clotting blood was reduced. Plasma fibrinogen, C reactive protein and von Willebrand factor (vWF) were elevated in proportion to CRF. We found no evidence that defects in platelet aggregation or platelet interaction with vWF prolong the bleeding time in patients with progressive CRF.

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