scholarly journals A new oral antiplatelet agent with potent antithrombotic properties: Comparison of DZ-697b with clopidogrel in a randomised phase I study

2010 ◽  
Vol 103 (01) ◽  
pp. 205-212 ◽  
Author(s):  
Urooj Zafar ◽  
Borja Ibáñez ◽  
Brian Choi ◽  
David Vorchheimer ◽  
Antonio Piñero ◽  
...  
Keyword(s):  
Platelet Adhesion ◽  
Bleeding Time ◽  
Antiplatelet Agent ◽  
Post Dose ◽  
Shear Rates ◽  
Antithrombotic Effects ◽  
Oral Doses ◽  
Orally Active ◽  
Dose Dependent ◽  
Low Shear

SummaryDZ-697b is a new orally active antiplatelet agent that inhibits collagen and ristocetin-mediated platelet activation. It does not require meta-bolisation to generate its active compound and has a safer profile than clopidogrel in pre-clinical studies. We compared the antithrombotic effects and bleeding time prolongations of three DZ-697b doses with clopidogrel 300 mg. In a four-treatment, three-period, crossover-design, 20 healthy subjects (31 ± 7 years, 85% males) were randomised to single oral doses of DZ-697b (60, 120 and 360 mg), and clopidogrel (300 mg) (n=15 in each treatment with crossing-over). Antithrombotic effects were assessed by measuring six-hour post-dose changes from baseline in thrombus size in the Badimon chamber and platelet adhesion using Diamed Impact-R platelet function assay. Bleeding times were also measured pre-dose and at six hours post-dose. DZ-697b caused dose-dependent reductions in thrombus size at both high- and low-shear rates (mean reductions at 60, 120 and 360 mg doses of: 13.0%, 18.7%, 26.4% and 11.4%, 12.7%, 22.1% respectively, p<0.05 for all). Effect of clopidogrel (reductions of 18.7% and 11.0% respectively, p<0.05 for both) was closest to DZ-697b 120 mg. Reductions in platelet adhesion were also dose-dependent. Bleeding time ratio from baseline were shorter with DZ-697b versus clopidogrel (1.3, 1.4 and 1.5 versus 1.9, p<0.05 for all). The oral agent DZ-697b shows potent, dose-dependent, antithrombotic effects that are comparable to 300 mg clopidogrel at the 120 mg dose. Despite having equal or greater anti-platelet potency than 300 mg clopidogrel, bleeding time prolongations are significantly shorter with DZ-697b.

scholarly journals Hirudin interruption of heparin-resistant arterial thrombus formation in baboons

Blood ◽  
1991 ◽  
Vol 77 (5) ◽  
pp. 1006-1012 ◽  
Author(s):  
AB Kelly ◽  
UM Marzec ◽  
W Krupski ◽  
A Bass ◽  
Y Cadroy ◽  
...  
Keyword(s):  
Bleeding Time ◽  
Thrombus Formation ◽  
Dependent Manner ◽  
Fibrin Deposition ◽  
Recombinant Hirudin ◽  
Arterial Thrombus ◽  
Dependent Inhibition ◽  
Antithrombotic Effects ◽  
Dose Dependent

Abstract To determine the role of thrombin in high blood flow, platelet- dependent thrombotic and hemostatic processes we measured the relative antithrombotic and antihemostatic effects in baboons of hirudin, a highly potent and specific antithrombin, and compared the effects of heparin, an antithrombin III-dependent inhibitor of thrombin. Thrombus formation was determined in vivo using three relevant models (homologous endarterectomized aorta, collagen-coated tubing, and Dacron vascular graft) by measuring: (1) platelet deposition, using gamma camera imaging of 111In-platelets; (2) fibrin deposition, as assessed by the incorporation of circulating 125I-fibrinogen; and (3) occlusion. The continuous intravenous infusion of 1, 5, and 20 nmol/kg per minute of recombinant hirudin (desulfatohirudin) maintained constant plasma levels of 0.16 +/- 0.03, 0.79 +/- 0.44, and 3.3 +/- 0.77 mumol/mL, respectively. Hirudin interrupted platelet and fibrin deposition in a dose-dependent manner that was profound at the highest dose for all three thrombogenic surfaces and significant at the lowest dose for thrombus formation on endarterectomized aorta. Thrombotic occlusion was prevented by all doses studied. In contrast, heparin did not inhibit either platelet or fibrin deposition when administered at a dose that maximally prolonged clotting times (100 U/kg) (P greater than .1), and only intermediate effects were produced at 10-fold that dose (1,000 U/kg). Moreover, heparin did not prevent occlusion of the test segments. Hirudin inhibited platelet hemostatic function in concert with its antithrombotic effects (bleeding times were prolonged by the intermediate and higher doses). By comparison, intravenous heparin failed to affect the bleeding time at the 100 U/kg dose (P greater than .5), and only minimally prolonged the bleeding time at the 1,000 U/kg dose (P less than .05). We conclude that platelet-dependent thrombotic and hemostatic processes are thrombin-mediated and that the biologic antithrombin hirudin produces a potent, dose-dependent inhibition of arterial thrombus formation that greatly exceeds the minimal antithrombotic effects produced by heparin.

Vascular PG‐M/versican variants promote platelet adhesion at low shear rates and cooperate with collagens to induce aggregation

2002 ◽  
Vol 16 (14) ◽  
pp. 1903-1916 ◽  
Author(s):  
Mario Mazzucato ◽  
Maria Rita Cozzi ◽  
Paola Pradella ◽  
Daniela Perissinotto ◽  
Anders Malmström ◽  
...  
Keyword(s):  
Platelet Adhesion ◽  
Shear Rates ◽  
Low Shear

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.

scholarly journals Calin from Hirudo medicinalis, an inhibitor of von Willebrand factor binding to collagen under static and flow conditions

Blood ◽  
1995 ◽  
Vol 85 (3) ◽  
pp. 705-711 ◽  
Author(s):  
J Harsfalvi ◽  
JM Stassen ◽  
MF Hoylaerts ◽  
E Van Houtte ◽  
RT Sawyer ◽  
...  
Keyword(s):  
Shear Stress ◽  
Platelet Adhesion ◽  
Thrombus Formation ◽  
High Shear ◽  
High Shear Stress ◽  
Flow Conditions ◽  
Shear Rates ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Low Shear

Calin from the saliva of the medicinal leech, Hirudo medicinalis, is a potent inhibitor of collagen mediated platelet adhesion and activation. In addition to inhibition of the direct platelet-collagen interaction, we presently demonstrate that binding of von Willebrand to coated collagen can be prevented by Calin, both under static and flow conditions in agreement with the occurrence of binding of Calin to collagen, confirmed by Biospecific Interaction Analysis. To define whether Calin acted by inhibiting the platelet-collagen or the platelet- von Willebrand factor (vWF)-collagen-mediated thrombus formation, platelet adhesion to different types of collagens was studied in a parallel-plate flow chamber perfused with whole blood at different shear rates. Calin dose-dependently prevented platelet adhesion to the different collagens tested both at high- and low-shear stress. The concentration of Calin needed to cause 50% inhibition of platelet adhesion at high-shear stress was some fivefold lower than that needed for inhibition of vWF-binding under similar conditions, implying that at high-shear stress, the effect of Calin on the direct platelet- collagen interactions, suffices to prevent thrombus formation. Platelet adhesion to extracellular matrix (ECM) of cultured human umbilical vein endothelial cells was only partially prevented by Calin, and even less so at a high-shear rather than a low-shear rate, whereas the platelet binding to coated vWF and fibrinogen were minimally affected at both shear rates. Thus, Calin interferes with both the direct platelet- collagen interaction and the vWF-collagen binding. Both effects may contribute to the inhibition of platelet adhesion in flowing conditions, although the former seems to predominate.

scholarly journals Favorable therapeutic index of an orally-active small-molecule antagonist of the platelet protease-activated receptor-4, BMS-986141, compared with the P2Y12 antagonist ticagrelor in cynomolgus monkeys

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
P Wong ◽  
J Banville ◽  
R Wexler ◽  
E Priestley ◽  
A Marinier ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Small Molecule ◽  
Ex Vivo ◽  
Antiplatelet Agent ◽  
Thrombin Receptor ◽  
Funding Source ◽  
Private Company ◽  
Post Dose ◽  
Orally Active ◽  
P2y12 Antagonist

Abstract Introduction BMS-986141 is an orally-active small-molecule platelet thrombin receptor antagonist selective for the protease-activated receptor-4 (PAR4), a human platelet thrombin receptor. Purpose This study assessed effects of BMS-986141 vs. the P2Y12 antagonist ticagrelor, a standard of care antiplatelet agent, on arterial thrombosis (AT), mesenteric bleeding time (MBT) and platelet aggregation in monkeys. Methods Studies were conducted in models of electrically-mediated carotid artery thrombosis and MBT in anesthetized monkeys. Monkeys were given a single oral dose of BMS-986141 (0.05, 0.1, 0.5 mg/kg) or vehicle (n=8/group). At 2 hr post-dose, in vivo AT, MBT as well as ex vivo platelet aggregation were monitored in the same animal. Ticagrelor was studied as a comparator and given as IV bolus plus infusion at 0.0023+0.017 to 0.075+0.6 (mg/kg+mg/kg/h) (n=5–6/group). Thrombus weight reduction, MBT increase over vehicle, and platelet aggregation inhibition were determined. Peak platelet aggregation responses to activation peptides selective for PAR4 (PAR4-AP, 12.5 μM) and PAR1 (PAR1-AP, 18 μM), to collagen (5 μg/ml) and to ADP (20 μM) were determined by whole blood aggregometry. Results BMS-986141 inhibited platelet aggregation induced by PAR4-AP in human and monkey blood in vitro with comparable IC50 of 1.8±0.3 and 1.2±0.3 nM, respectively. BMS-986141 at 0.5 mg/kg completely inhibited platelet aggregation induced by PAR4-AP but not PAR1-AP, ADP and collagen, suggesting PAR4 receptor selectivity. In the AT model, BMS-986141 at 0.05, 0.1 and 0.5 mg/kg reduced thrombus weight by 36±7*, 63±8*, and 88±3%*, respectively (*P&lt;0.05 vs. vehicle). BMS-986141 increased MBT by up to 1.2-fold. In a separate study, ticagrelor at 0.0023+0.017, 0.0068+0.055, 0.0255+0.18 and 0.075+0.6 (mg/kg+mg/kg/h IV) reduced thrombus weight by 19±8, 36±5*, 76±6* and 89±1%*, and increased MBT by respectively by 1.7-, 6.4-*, &gt;10-*, and &gt;10-fold*, respectively (*P&lt;0.05 vs. vehicle). Conclusion Comparable antithrombotic efficacy was observed between BMS-986141 and ticagrelor in monkeys. BMS-986141 exhibited lower MBT compared with ticagrelor at equivalent antithrombotic doses. This study suggests that PAR4 antagonism provides a potentially safer antiplatelet therapy. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Research was supported by Bristol-Myers Squibb

In vitro platelet adhesion to endothelial cells at low shear rates during copper deficiency in rats

1999 ◽  
Vol 12 (1) ◽  
pp. 25-36 ◽  
Author(s):  
David Lominadze ◽  
Jack T. Saari ◽  
Frederick N. Miller ◽  
James L. Catalfamo ◽  
Susan S. Percival ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Platelet Adhesion ◽  
Copper Deficiency ◽  
Shear Rates ◽  
Low Shear

scholarly journals Hirudin interruption of heparin-resistant arterial thrombus formation in baboons

Blood ◽  
1991 ◽  
Vol 77 (5) ◽  
pp. 1006-1012 ◽  
Author(s):  
AB Kelly ◽  
UM Marzec ◽  
W Krupski ◽  
A Bass ◽  
Y Cadroy ◽  
...  
Keyword(s):  
Bleeding Time ◽  
Thrombus Formation ◽  
Dependent Manner ◽  
Fibrin Deposition ◽  
Recombinant Hirudin ◽  
Arterial Thrombus ◽  
Dependent Inhibition ◽  
Antithrombotic Effects ◽  
Dose Dependent

To determine the role of thrombin in high blood flow, platelet- dependent thrombotic and hemostatic processes we measured the relative antithrombotic and antihemostatic effects in baboons of hirudin, a highly potent and specific antithrombin, and compared the effects of heparin, an antithrombin III-dependent inhibitor of thrombin. Thrombus formation was determined in vivo using three relevant models (homologous endarterectomized aorta, collagen-coated tubing, and Dacron vascular graft) by measuring: (1) platelet deposition, using gamma camera imaging of 111In-platelets; (2) fibrin deposition, as assessed by the incorporation of circulating 125I-fibrinogen; and (3) occlusion. The continuous intravenous infusion of 1, 5, and 20 nmol/kg per minute of recombinant hirudin (desulfatohirudin) maintained constant plasma levels of 0.16 +/- 0.03, 0.79 +/- 0.44, and 3.3 +/- 0.77 mumol/mL, respectively. Hirudin interrupted platelet and fibrin deposition in a dose-dependent manner that was profound at the highest dose for all three thrombogenic surfaces and significant at the lowest dose for thrombus formation on endarterectomized aorta. Thrombotic occlusion was prevented by all doses studied. In contrast, heparin did not inhibit either platelet or fibrin deposition when administered at a dose that maximally prolonged clotting times (100 U/kg) (P greater than .1), and only intermediate effects were produced at 10-fold that dose (1,000 U/kg). Moreover, heparin did not prevent occlusion of the test segments. Hirudin inhibited platelet hemostatic function in concert with its antithrombotic effects (bleeding times were prolonged by the intermediate and higher doses). By comparison, intravenous heparin failed to affect the bleeding time at the 100 U/kg dose (P greater than .5), and only minimally prolonged the bleeding time at the 1,000 U/kg dose (P less than .05). We conclude that platelet-dependent thrombotic and hemostatic processes are thrombin-mediated and that the biologic antithrombin hirudin produces a potent, dose-dependent inhibition of arterial thrombus formation that greatly exceeds the minimal antithrombotic effects produced by heparin.

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.

Inhibition of Platelet Adhesion to Fibrin(ogen) in Flowing Whole Blood by Arg-Gly-Asp and Fibrinogen γ-Chain Carboxy Terminal Peptides

1992 ◽  
Vol 68 (06) ◽  
pp. 694-700 ◽  
Author(s):  
Roy R Hantgan ◽  
Silvia C Endenburg ◽  
I Cavero ◽  
Gérard Marguerie ◽  
André Uzan ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Whole Blood ◽  
Platelet Adhesion ◽  
Integrin Receptor ◽  
Shear Rates ◽  
Perfusion Chamber ◽  
Receptor Recognition ◽  
Adhesive Interactions ◽  
Coated Surfaces ◽  
Carboxy Terminal

SummaryWe have employed synthetic peptides with sequences corresponding to the integrin receptor-recognition regions of fibrinogen as inhibitors of platelet aggregation and adhesion to fibrinogen-and fibrin-coated surfaces in flowing whole blood, using a rectangular perfusion chamber at wall shear rates of 300 s–1 and 1,300 s–1. D-RGDW caused substantial inhibition of platelet aggregation and adhesion to fibrinogen and fibrin at both shear rates, although it was least effective at blocking platelet adhesion to fibrin at 300 s–1. RGDS was a weaker inhibitor, and produced a biphasic dose-response curve; SDRG was inactive. HHLGGAK-QAGDV partially inhibited platelet aggregation and adhesion to fibrin(ogen) at both shear rates. These results support the identification of an RGD-specific receptor, most likely the platelet integrin glycoprotein IIb: III a, as the primary receptor responsible for platelet: fibrin(ogen) adhesive interactions under flow conditions, and indicate that platelet adhesion to surface bound fibrin(ogen) is stabilized by multivalent receptor-ligand contacts.

Involvement of 5-Hydroxytryptamine in Platelet Aggregation In Vivo in Rats and Guinea Pigs

1989 ◽  
Vol 61 (03) ◽  
pp. 463-467 ◽  
Author(s):  
G M Smith
Keyword(s):  
Platelet Count ◽  
Guinea Pigs ◽  
Platelet Adhesion ◽  
Adenosine Diphosphate ◽  
Rate Of Return ◽  
Low Doses ◽  
Dose Dependent ◽  
Higher Doses ◽  
Rat Platelets

SummaryIn this study, 5-hydroxytryptamine (5-HT) caused a dose- dependent fall in the circulating platelet count suggesting that 5-HT receptors are activated in rat platelets to cause platelet adhesion and aggregation. When low doses of adenosine diphosphate (ADP) were simultaneously injected with 5-HT, there was a significant potentiation of the responses to ADR Ketanserin significantly reduced the potentiated responses. When higher doses of ADP were infused with bolus injections of 5-HT there was no potentiation and ketanserin did not reduce these responses. Ketanserin did not inhibit the collagen-induced fall in circulating platelet count, but did significantly increase the rate of return to the basal platelet count compared with control. 5-HT did not cause a fall in platelet count in guinea-pigs

Sign in / Sign up

Export Citation Format

Share Document