INITIAL STUDIES IN MAN WITH A NOVEL THROMBOXANE RECEPTOR BLOCKING DRUG GR32191

1987 ◽  
Author(s):  
M Thomas ◽  
P Lumley ◽  
P Ballard ◽  
J R O'Brien
Keyword(s):  
Platelet Aggregation ◽  
Bleeding Time ◽  
Ex Vivo ◽  
Plasma Concentrations ◽  
Blocking Drug ◽  
Double Blind ◽  
Receptor Blocking ◽  
Thromboxane Receptor ◽  
Pre Treatment ◽  
Induced Aggregation

In-vitro GR32191 is a potent and specific thromboxane receptor blocking drug on platelets, and vascular and airways smooth muscle (Lumley et al this meeting). We have undertaken studies in healthy male subjects (n) to examine the effects of oral GR32191 upon platelet aggregation ex-vivo and template bleeding time. Platelet aggregation was monitored in whole blood by counting platelets electronically. Concentration-effect curves to U-46619 and ADP were constructed prior to and following drug or placebo. The degree of rightward displacement of a curve due to treatment was expressed as a concentration-ratio (CR) which was calculated at the 50% aggregation level (ECso post-treatment ECso pre-treatment). Plasma concentrations of GR32191 were determined by h.p.l.c. After single doses of GR32191 mean peak CR's of 8 and 80 were achieved with 0.125 and 0.25mg/kg (n=4) and values of 74 and 234 with 0.5 and lmg/kg (n=4). Peak effects were seen within 2 hours of dosing while activity was still present between 8 and 24 hours. ADP-induced aggregation was unaffected by drug (CR<2) and placebo was without significant effect upon the sensitivity to either aggregating agent (CR<2). GR32191 was rapidly absorbed and the plasma elimination half-life was about 2 hours. GR32191 17.5mg 12-hourly for 10 days (n=6) produced a progressive antagonism of U-46619 induced aggregation which resulted in a large continuous blockade in all subjects (range of 12htrough CR's 85 to 287). However, plasma concentrations of GR32191 did not accumulate on repeated administration. In a double-blind, placebo-controlled, cross-over study (n=16), a statistically significant (p= 0.002) increase in bleeding time was seen following treatment with GR32191 40mg twice daily for 7 days (pre-treatment mean 3.79 min, post-placebo mean 3.47 min, post-GR32191 mean 5.42 min). Rectal bleeding (n=l) has occurred with GR32191 but otherwise tolerability has been good. No drug related changes have been seen in routine laboratory safety screens. Clinical studies are in progress.

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.

The d-Enantiomer Form of Indobufen Totally Accounts for the Anti-Cyclooxygenase and Antiplatelet Activity Ex Vivo and for the Increase in Bleeding Time by Indobufen in Man

1992 ◽  
Vol 67 (02) ◽  
pp. 258-263 ◽  
Author(s):  
Raffaele De Caterina ◽  
Rosa Sicari ◽  
An Yan ◽  
Walter Bernini ◽  
Daniela Giannessi ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Plasma Levels ◽  
Bleeding Time ◽  
Ex Vivo ◽  
Random Sequence ◽  
Antiplatelet Agent ◽  
Antiplatelet Drug ◽  
Double Blind

SummaryIndobufen is an antiplatelet drug able to inhibit thromboxane production and cyclooxygenase-dependent platelet aggregation by a reversible inhibition of cyclooxygenase. Indobufen exists in two enantiomeric forms, of which only d-indobufen is active in vitro in inhibiting cyclooxygenase. In order to verify that also inhibition of platelet function is totally accounted for by d-indobufen, ten patients with proven coronary artery disease (8 male, 2 female, age, mean ± S.D., 58.7 ± 7.5 years) were given, in random sequence, both 100 mg d-indobufen and 200 mg dl-indobufen as single administrations in a double-blind crossover design study with a washout period between treatments of 72 h. In all patients thromboxane (TX) B2 generation after spontaneous clotting (at 0, 1, 2, 4, 6, 8, 12, 24 h), drug plasma levels (at the same times), platelet aggregation in response to ADP, adrenaline, arachidonic acid, collagen, PAF, and bleeding time (at 0, 2, 12 h) were evaluated after each treatment. Both treatments determined peak inhibition of TXB2 production at 2 h from administration, with no statistical difference between the two treatments (97 ±3% for both treatments). At 12 h inhibition was 87 ± 6% for d-indobufen and 88 ± 6% for dl-indobufen (p = NS). Inhibition of TXB2 production correlated significantly with plasma levels of the drugs. Maximum inhibitory effect on aggregation was seen in response to collagen 1.5 pg/ml (63 ± 44% for d-indobufen and 81 ± 22% for dl-indobufen) and arachidonic acid 0.5-2 mM (78 ± 34% for d-indobufen and 88 ± 24% for dl-indobufen) at 2 h after each administration. An effect of both treatments on platelet aggregation after 12 h was present only for adrenaline 2 μM (55 ± 41% for d-indobufen and 37 ± 54% for dl-indobufen), collagen 1.5 pg/ml (69 ± 30% for d-indobufen and 51 ± 61% for dl-indobufen), arachidonic acid 0.5-2 mM (56 ± 48% for d-indobufen and 35 ± 49% for dl-indobufen). The extent of inhibition of TX production and the extent of residual platelet aggregation were never significantly different between treatments. Bleeding time prolongation was similar in the two treatment groups without showing a pronounced and long lasting effect (from 7.0 ± 2.0 min to 10.0 ± 3.0 min at 2 h and 8.0 ± 2.0 min at 12 h for d-indobufen; from 6.0 ±1.0 min to 8.5 ± 2.0 min at 2 h and 8.0 ± 1.0 min at 12 h for dl-indobufen). These results demonstrate that the biological activity of dl-indobufen as an antiplatelet agent in vivo is totally accounted for by d-indobufen.

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.

THE EFFECTS OF GR32191, A NEW THROMBOXANE RECEPTOR BLOCKING DRUG,ON PLATELETS AND VASCULAR SMOOTH MUSCLE IN VITRO

1987 ◽  
Author(s):  
P Lumley ◽  
E W Collington ◽  
P Hallett ◽  
E J Hornby ◽  
p PA Humphrey ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Guinea Pig ◽  
Vascular Smooth Muscle ◽  
Inhibitory Activity ◽  
Whole Blood ◽  
Blocking Drug ◽  
Receptor Blocking ◽  
Thromboxane Receptor ◽  
Induced Aggregation

The effect of a new thromboxane receptor blocking drug GR32191 ([1R-[1α(Z),2β,3β,5α]]-(+)-7-[5-[[(1,1"-biphenyl)-4-yl]methoxy] -3-hydroxy-2-(l-piperidinyl)cyclopentyl]-4-heptenoic acid,hydrochloride) has been examined upon platelets and vascular smooth muscle. In human platelet-rich plasma (PRP), aggregation to thromboxane(Tx) A2, PGH2, arachidonic acid, collagen andU-46619 was antagonised by GR32191 (IC50 range 2-36 nM).Primary aggregation (PRP treated with aspirin 10 pM) to ADP, 5-HT and adrenaline were unaffected by concentrations of GR32191 up to 10 pM. In human PRP, U-46619-induced aggregation and 5-HT release were antagonised by GR32191(10-100 nM). In contrast, in theabsence of aspirin, ADP-induced 5-HT release,but not aggregation, was antagonised by the compound implicating a role for TXA2 in the release process. In human PRP GR32191 (up to 30μM) did not itself induce aggregation or, in the presence of EGTA (4 mM), induce detectable shape change. Up to 10 μM GR32191 was without effect upon the inhibitory activity of PGI2 or PGD2 and at 1μMhad no significant inhibitory activity upon fatty acid cyclooxygenase, thromboxane synthase, prostacyclin synthase, 12-lipoxygenase orphosphodiesterase. The effect of GR32191was quantified further in human platelets suspended in whole blood or physiological salt solution. Aggregation to U-46619 was antagonised byGR32191 with a pA2 (slope of the Schild regression) of 8.2 (1.3) in whole blood and 8.8 (1.3) in resuspended platelets. The compound competitively and specifically antagonised the contractions of strips of human isolatedpulmonary blood vessels and rat and guinea-pig aortic strips produced by U-46619 with pA2 (slope) values of 8.2 (1.1), 7.9 (0.9) and 8.7(0.9) respectively. In contrast contractions induced by KC1 and 5-HT (rat) orKC1and histamine (guinea-pig) were unaffectedbyconcentrations of GR32191 up to 30 μM.Thus GR32191 is a potent and specific thromboxane receptor blocking drug on platelets and vascular smooth muscle in vitro. It is orally active and long lasting in man (Thomas, M et al.,this meeting).

The Effects Of Ticlopidine Hydrochloride On Bleeding Time And Platelet Function In Man

1981 ◽  
Author(s):  
D J Ellis ◽  
R L Roe ◽  
J J Bruno ◽  
B J Cranston ◽  
M M McSpadden
Keyword(s):  
Platelet Aggregation ◽  
Platelet Function ◽  
Bleeding Time ◽  
Ex Vivo ◽  
Atp Release ◽  
Phosphodiesterase Inhibitor ◽  
Optimal Dosage ◽  
Post Dose ◽  
Induced Aggregation ◽  
Dose Dependent

Ticlopidine hydrochloride (T) was given to healthy male and female subjects in doses ranging from 125-500 mg/day for up to 8 days to study the rate of onset and offset of action and to define the optimal dosage for inhibition of platelet function tests.Template bleeding time (BT) using the Simplate® device and ex vivo platelet aggregation were done every day from the start of dosing through the post-dosing period until platelet function had returned to baseline.Achievement of maximal bleeding time prolongation and maximal inhibition of platelet aggregation induced by ADP, collagen, and epinephrine required 3-5 days of dosing. Rate of onset was higher at higher drug doses. Post-dose return to baseline took 4-8 days.BT prolongation was dose-dependent with 2.0 × prolongation at 125 mg/d, 2.5 × at 250 mg/d, 3.4 × at 375 mg/d and 4.7 × at 500 mg/d.At steady state, ADP aggregation (1st and 2nd phase) was inhibited by 50-60%, epinephrine aggregation was inhibited by 40-80%, and collagen aggregation was inhibited by 5580%. Inhibition was dose-dependent. Arachidonic acid (1 × 10-3M) induced aggregation was not inhibited. ATP release during collagen aggregation was inhibited by 20-50% and malondialdehyde production induced by thrombin was inhibited 20-55%, both in a dose-related fashion.Ticlopidine hydrochloride is a potent inhibitor of platelet function with a broad spectrum of activity and a delayed onset and offset of action. The drug is neither a prostaglandin synthetase nor a phosphodiesterase inhibitor and appears to act by a novel mechanism.

Antiplatelet Effects of the Addition of Acetylsalicylic Acid 40 Mg Daily to Ticlopidine in Human Healthy Volunteers

1997 ◽  
Vol 3 (4) ◽  
pp. 245-250 ◽  
Author(s):  
Thomas P. Lecompte ◽  
Chantal Lecrubier ◽  
Cyril Bouloux ◽  
Marie-Hélène Horellou ◽  
Jacques Galleyrand ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Acetylsalicylic Acid ◽  
Healthy Volunteers ◽  
Drug Combination ◽  
Bleeding Time ◽  
Dependent Manner ◽  
High Concentration ◽  
Double Blind ◽  
Coronary Stent Implantation ◽  
Induced Aggregation

Clinical studies have shown that acetylsalicylic acid (ASA) or ticlopidine (T) bring a partial clinical benefit in a subset of patients threatened by thrombosis on atherosclerotic plaques. Acetylsalicylic acid and T have different impacts on platelet function and the combination of the drugs seems logical to achieve a greater antiplatelet effect. Healthy volunteers were randomly allocated to any of the three treatment groups: T 250-placebo; T 250-T 250; placebo-placebo (treatment was administered in a double blind manner). Acetylsalicylic acid 40 mg was openly administered once a day to the subjects of the three groups after the first week of treatment. Simplate I bleeding time and platelet aggregation testing were performed before treatment and at the end of the two treatment periods. We confirmed that T alone prolongs bleeding time and impairs, in a dose-dependent manner, ADP-induced aggregation; platelet responses that depend on released ADP were also affected. Inhibition of thromboxane-dependent aggregation, associated with a doubling of the bleeding time, was observed after one week of low-dose ASA inhibition of thromboxane synthesis. An additive effect of ASA 40 mg to T 250 mg on the bleeding time was evidenced. There was also a wider alteration of platelet aggregation, with a trend towards an inhibition of the response to a high concentration of collagen as compared to ASA or T used alone. Such a powerful, logical drug combination is in good agreement with preliminary encouraging results obtained after coronary stent implantation and deserves further studies in patients at high risk for arterial thrombosis to define its benefit-risk profile. Key Words: Aspirin—Ticlopidine— Drug combination—Bleeding time—Platelet aggregation.

scholarly journals Pimpinellin Inhibits Collagen-induced Platelet Aggregation and Activation Through Inhibiting Granule Secretion and PI3K/Akt Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Gang Liu ◽  
Zhaowei Yuan ◽  
Xiaoyun Tian ◽  
Xiuqin Xiong ◽  
Fang Guo ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Bleeding Time ◽  
Ex Vivo ◽  
Atp Release ◽  
Human Platelets ◽  
Dense Granule ◽  
Coated Surface ◽  
Granule Secretion ◽  
Toddalia Asiatica ◽  
Induced Aggregation

Pimpinellin is a coumarin-like compound extracted from the root of Toddalia asiatica. Its effects on platelet function has not been investigated. This study found that pimpinellin pretreatment effectively inhibited collagen-induced platelet aggregation, but did not alter ADP- and thrombin-induced aggregation. Platelets pretreated with pimpinellin showed reduced α granule (CD62) level and secretion of dense granule (ATP release). Pimpinellin-treated platelets also exhibited decreased clot reaction and TxB2 production. Pimpinellin pretreatment suppressed adhesion and spreading of human platelets on the fibrinogen coated surface. Analysis of tail bleeding time of mice administered with pimpinellin (40 mg/kg) revealed that pimpinellin did not change tail bleeding time significantly, number of blood cells, and APTT and PT levels. Pimpinellin inhibited collagen-induced ex vivo aggregation of mice platelets. Immunoblotting results showed that pimpinellin suppressed collagen-induced phosphorylation of PI3K-Akt-Gsk3β and PKC/MAPK in platelets.

THE BLEEDING TENDENCY OF PROGRESSIVE RENAL FAILURE IS NOT ASSOCIATED WITH DEFECTIVE PLATELET AGGREGATION

1987 ◽  
Author(s):  
M P Gordge ◽  
R W Faint ◽  
P B Rylance ◽  
G H Neild
Keyword(s):  
Renal Failure ◽  
Platelet Aggregation ◽  
Bleeding Time ◽  
Ex Vivo ◽  
Plasma Creatinine ◽  
Bleeding Tendency ◽  
Platelet Response ◽  
Normal Platelet ◽  
Von Willebrand ◽  
Induced Aggregation

The bleeding tendency of uraemia may be related to reduction by anaemia of erythrocyte/platelet interaction, toxic inhibition of platelet aggregation and abnormal von Willebrand Factor (vWF) mediated platelet adhesion. Our aim in this study was to determine at what stage of renal failure bleeding time becomes prolonged and to investigate the mechanisms involved.We have measured bleeding time (Simplate II), plasma levels of fibrinogen and vWF, and ex-vivo platelet responsiveness in 31 patients with chronic renal failure (CRF) of various degrees of severity and compared them with values obtained in 22 healthy controls. No patient was dialysed, nephrotic or suffering from immunological renal disease. Patients were divided into mild (plasma creatinine <300 umol/1), n=10, moderate (300-600 umol/1), n=14, or severe (>600 umol/1), n=7, CRF.Bleeding time became significantly prolonged only in severe CRF (p<0.005). Haematocrit fell as renal failure advanced, and correlated with bleeding time (r=0.40, p<0.05). Platelet counts were normal. Platelet aggregation in response to ristocetin (mediated by vWF) and ADP increased progressively (p<0.005 in severe CRF), as did spontaneous aggregation (p<0.005 in severe CRF). This was associated with an increase in plasma vWF and fibrinogen (p<0.005 in severe CRF). Collagen induced aggregation was slightly, but not significantly increased. Thromboxane (TxB2) generation in clotting blood was the only measurement that showed a reduced platelet response (p<0.025 in severe CRF).In summary, a bleeding tendency develops late in the course of progressive CRF when plasma creatinine has risen to at least 600 umol/1. Platelet aggregation is enhanced rather than reduced and platelet interaction with vWF is not defective. Anaemia appears more important than abnormal platelet aggregation in mediating uraemic bleeding, although reduced serum TxB2 generation suggests a defect in platelet response to endogenous thrombin which may also contribute. Increased platelet aggregation and fibrinogen concentrations might promote glomerular thrombosis and contribute to the progression of CRF.

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.

Ex Vivo Inhibition of Platelet Aggregation in Patients with Severe Limb Arteriopathy Treated with BAY U3405, a Specific IX A2 Receptor Antagonist

1994 ◽  
Vol 72 (05) ◽  
pp. 659-662 ◽  
Author(s):  
S Bellucci ◽  
W Kedra ◽  
H Groussin ◽  
N Jaillet ◽  
P Molho-Sabatier ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Ex Vivo ◽  
Randomized Study ◽  
In Vivo Studies ◽  
Walking Distance ◽  
Peripheral Blood Flow ◽  
Walking Ability ◽  
Double Blind ◽  
Platelet Factor

SummaryA double-blind, placebo-controlled randomized study with BAY U3405, a specific thromboxane A2 (TX A2) receptor blocker, was performed in patients suffering from severe stade II limb arteriopathy. BAY U3405 or placebo was administered in 16 patients at 20 mg four times a day (from day 1 to day 3). Hemostatic studies were done before therapy, and on day 2 and day 3 under therapy. On day 3, BAY U3405 was shown to induce a highly statistically significant decrease of the velocity and the intensity of the aggregations mediated by arachidonic acid (56 ± 37% for the velocity, 58 ± 26% for the intensity) or by U46619 endoperoxide analogue (36 ± 35% for the velocity, 37 ± 27% for the intensity). Similar results were already observed on day 2. By contrast, such a decrease was not noticed with ADP mediated platelet aggregation. Furthermore, plasma levels of betathrombo-globulin and platelet factor 4 remained unchanged. Peripheral hemodynamic parameters were also studied. The peripheral blood flow was measured using a Doppler ultrasound; the pain free walking distance and the total walking ability distance were determined under standardized conditions on a treadmill. These last two parameters show a trend to improvement which nevertheless was not statistically significant. All together these results encourage further in vivo studies using BAY U3405 or related compounds on a long-term administration.

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