BF061, a novel antiplatelet and antithrombotic agent targeting P2Y12 receptor and phosphodiesterase

2011 ◽  
Vol 106 (12) ◽  
pp. 1203-1214 ◽  
Author(s):  
Liang Hu ◽  
Zhichao Fan ◽  
Hongguang Du ◽  
Ran Ni ◽  
Si Zhang ◽  
...  
Keyword(s):  
Arterial Thrombosis ◽  
Thrombus Formation ◽  
Antiplatelet Agent ◽  
Atp Release ◽  
Bleeding Risk ◽  
P2y12 Receptor ◽  
Antithrombotic Agent ◽  
Thrombosis Model ◽  
P2y12 Antagonists ◽  
Pde Inhibition

SummaryThe addition of phosphodiesterase (PDE) inhibitors has been reported to potentiate the antithrombotic effects of P2Y12 antagonists without increasing bleeding risk. In this study, we report that a potent antiplatelet agent, 2-ethylthio-6-phenethylaminoadenosine (BF061), inhibits platelet activation and thrombosis via P2Y12 antagonism and PDE inhibition. We explored the antiplatelet mechanism of BF061 by measuring cAMP, cGMP levels, PDE activity, and the interaction between ADP and P2Y12 using atomic force microscopy. The antithrombotic effect of BF061 was evaluated in mice using intravital microscopy in FeCl3-induced mesenteric and laser-induced cremasteric arterial thrombosis models. BF061 robustly inhibited platelet aggregation and ATP release induced by multiple platelet agonists via P2Y12 antagonism and PDE inhibition. Interestingly, despite being structurally similar to BF061, P2Y12 receptor antagonist AR-C69931MX had no effect on human platelet PDE. In FeCl3-induced mesenteric arterial thrombosis model, BF061 effectively prevented thrombus formation similarly to clopidogrel; it also reduced thrombus volume in laser-injured cremaster arteriole model. In contrast, BF061 induced dramatically less bleeding at an antithrombotic dose compared to clopidogrel. In summary, we developed a novel antiplatelet and antithrombotic agent targeting both P2Y12 and PDE. Given the prevalence of combined antiplatelet therapy in clinical practice, an antiplatelet agent bearing dual activities may have therapeutic advantage as a potential antithrombotic drug.

Comparative Studies of an Orally-active Factor Xa Inhibitor, YM-60828, with other Antithrombotic Agents in a Rat Model of Arterial Thrombosis

1998 ◽  
Vol 79 (02) ◽  
pp. 410-416 ◽  
Author(s):  
Kazuo Sato ◽  
Yumiko Sakai ◽  
Fukushi Hirayama ◽  
Hiroyuki Koshio ◽  
Yuta Taniuchi ◽  
...  
Keyword(s):  
Electrical Stimulation ◽  
Arterial Thrombosis ◽  
Thrombus Formation ◽  
Factor Xa ◽  
Test Drug ◽  
Antithrombotic Agent ◽  
Antithrombotic Activity ◽  
Thrombosis Model ◽  
Treatment And Prevention ◽  
Orally Active

SummaryWe examined the antithrombotic activity of a novel synthetic inhibitor of factor Xa, YM-60828, in an electrically-induced carotid artery thrombosis model in rats. In the first experiment, the antithrombotic activity of YM-60828 after i.v. infusion was compared with those of heparin, darteparin and argatroban. Test drug was administered by i.v. infusion from 30 min before electrical stimulation to the end of the experiment. YM-60828 at 1 mg/kg/h significantly improved patency status, prolonged the time to occlusive thrombus formation and duration of patency. Heparin at 300 U/kg/h also improved these parameters, but were accompanied by a marked increase in systemic coagulation time. In the second experiment, the antithrombotic activity of YM-60828 after oral administration was compared with those of ticlopidine, cilostazol, aspirin, beraprost, ethyl icosapentate and warfarin. Test drug was orally administered to fasted rats 60 min before electrical stimulation. YM-60828 at 30 mg/kg p.o., but not ticlopidine, cilostazol, aspirin, beraprost, ethyl icosapentate or warfarin, significantly reduced the incidence of occlusion and improved carotid arterial patency. These results suggest that YM-60828 may be a promising antithrombotic agent for the treatment and prevention of arterial thrombosis which can be given by oral as well as intravenous administration.

THE ANTITHROMBOTIC EFFECT OF PALM OIL IS CORRELATED WITH ITS CONTENTS OF VITAMIN E

1987 ◽  
Author(s):  
E G Hornstra ◽  
A H Hennissen ◽  
R Kalafusz ◽  
D T S Tan
Keyword(s):  
Fatty Acid ◽  
Platelet Aggregation ◽  
Palm Oil ◽  
Whole Blood ◽  
Arterial Thrombosis ◽  
Edible Oils ◽  
Thrombus Formation ◽  
Saturated Fatty Acids ◽  
Atp Release ◽  
Significant Negative Correlation

Dietary saturated fatty acids are known to increase platelet aggregation and arterial thrombogenesis.We recently demonstrated, however, that palm oil, rich in saturated palmitic acid, has a distinct antithrombotic affect, which is associated with a decrease of the thromboxane-prostacyclin ratio in activated whole blood. To identify the antithrombotic component(s) of palm oil, seven palm oil fractions were prepared with comparable fatty acid compositions of the triglycerides but containing Various amounts of non-triglyceride material with different compositions.These fractions were fed to rats in amounts of 50 energy% for a period of 8 weeks, after which arterial thrombosis tendency was measured upon insertion of an aortic prosthesis, the aorta-loop. During loop insertion, 1 ml blood was collected in citrate for measuring platelet aggregation and ATP release in response to collagen, using the Chronolog whole blood lumi-aggregometer. Arterial thrombosis tendency was found to be negatively related to the total amount of non-triglyceride material in the various fractions (r = 0.78; p <0.05).No significant relationship was observed between arterial thrombus formation and the various sterols present in the non-triglyceride material.A significant negative correlation was found, however, with a-tocopherol (r = 0.86; p <.02). Collagen-induced platelet aggregation and ATP release in whole blood were not correlated to total amounts or α-tocopherol content of the non-triglyceride material.However, significant positive relationships were found between these platelet functions and the amountsof the various sterols (Campesterol: r = 0.70; P < 0.10 β-sitostero1 : r = 0.69; P <0.10. Cholesterol : r = 0.81; P < 0.05).These findings demonstrate that effects of edible oils on platelet function and arterial thrombogenesisare not only mediated by the fatty acid compostion of the triglycerides, but can also be determined by 'minor components', present in the non-triglyceride part of the oils.

scholarly journals A Short Half-Life αIIbβ3 Antagonist ANTP266 Reduces Thrombus Formation

2018 ◽  
Vol 19 (8) ◽  
pp. 2306 ◽  
Author(s):  
Tong-Dan Liu ◽  
Shen-Hong Ren ◽  
Xue Ding ◽  
Zhou-Ling Xie ◽  
Yi Kong
Keyword(s):  
Half Life ◽  
Bleeding Time ◽  
Thrombus Formation ◽  
Bleeding Risk ◽  
Effective Dosage ◽  
Enzyme Linked Immunosorbent Assay ◽  
Severe Bleeding ◽  
Antithrombotic Agent ◽  
Integrin Αiibβ3 ◽  
Plasma Half Life

Integrin αIIbβ3 plays a pivotal role in platelet aggregation. Three αIIbβ3 antagonists have been approved by the Food and Drug Administration (FDA) for the treatment of cardiovascular diseases. Unfortunately, all of these three drugs can cause the side effect of severe bleeding. Therefore, developing a new αIIbβ3 antagonist with low bleeding was needed. In the present study, we screened compounds by using a fibrinogen/integrin αIIbβ3 enzyme-linked immunosorbent assay (ELISA), and a novel αIIbβ3 antagonist ANTP266 was attained. The antithrombotic effects of ANTP266 were estimated by using two animal models, the bleeding risk was estimated by using a mice tail cutting assay, and the plasma half-life time was tested by LC-MS/MS. The results showed that ANTP266 potently decreased thrombosis formation, while not prolonging bleeding time at its effective dosage. The bleeding of ANTP266 reduced rapidly as time went on from 5 to 60 min, but tirofiban produced high bleeding continuously. The plasma half-life of ANTP266 in rats was 10.8 min. Taken together, ANTP266 is an effective antithrombotic agent with a low bleeding risk. The shorter bleeding time benefits from its short plasma half-life. ANTP266 could be a candidate for developing the αIIbβ3 antagonist of rapid elimination for a patient undergoing percutaneous coronary intervention.

“M-AAA-Thrombin”, a New Thrombin Mutant with Potent Anticoagulant and Antiplatelet Properties.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4154-4154
Author(s):  
Kazuya Hosokawa ◽  
Tomoko Ohnishi ◽  
Hiroyuki Matsuda ◽  
Kousuke Kashima ◽  
Takehiko Koide
Keyword(s):  
Platelet Aggregation ◽  
Thrombus Formation ◽  
Antiplatelet Agent ◽  
Dependent Manner ◽  
In Vivo Experiments ◽  
Thrombosis Model ◽  
Venous Shunt ◽  
Prolonged Aptt ◽  
Antithrombotic Efficacy

Abstract Thrombosis is a major cause of morbidity and mortality, and thrombin is a major inducer of thrombus formation. Thus several antithrombotic agents targeting thrombin have been developed. We previously reported an anticoagulant and antiplatelet thrombin derivative, ‘M-anhydrothrombin’ prepared by chemical modifications. In this study, we prepared a new thrombin mutant, specificity of which was highly modulated with substantially improved antithrombotic efficacy. The thrombin mutant designated “AAA-Thrombin” in which Lys65, His43 and Ser205 in B-chain have been replaced by Ala revealed higher affinity and specificity for factor VIII with no enzymatic activity. AAA-Thrombin prolonged APTT much more than anhydrothrombin in a dose dependent manner without affecting PT and TT. Platelet aggregation induced by activation of PAR-1 was also effectively suppressed by AAA-Thrombin. “M-AAA-Thrombin” prepared by further chemical modification of carboxyl groups in AAA-Thrombin enhanced its antithrombotic efficacy. M-AAA-Thrombin (250nM) prolonged APTT approx. two times, and suppressed platelet aggregation by PAR-1 activation, while AAA-Thrombin did not at the same concentration. M-AAA-Thrombin also suppressed ristocetin-induced platelet aggregation. In vivo experiments, M-AAA-Thrombin demonstrated significant antithrombotic property in the arterio-venous shunt thrombosis model and the FeCl3-induced carotid artery thrombosis model in guinea pigs. These results indicate that M-AAA-Thrombin would be a candidate for quite an innovative anticoagulant and antiplatelet agent for both arterial and venous thromboses. Further optimization of mutagenesis and modification, in terms of efficacy and safety is in progress in our laboratory.

Platelet P2Y12 receptor antagonist pharmacokinetics and pharmaco -dynamics: A foundation for distinguishing mechanisms of bleeding and anticipated risk for platelet-directed therapies

2010 ◽  
Vol 103 (03) ◽  
pp. 535-544 ◽  
Author(s):  
Richard Becker ◽  
Paul Gurbel
Keyword(s):  
Arterial Thrombosis ◽  
Bleeding Risk ◽  
Percutaneous Intervention ◽  
P2y12 Receptor ◽  
Clinical Events ◽  
Coagulation Proteins ◽  
Concomitant Reduction ◽  
P2y12 Receptor Antagonist ◽  
Coronary Syndromes ◽  
Stable Aggregate

SummaryThe platelet P2Y12 receptor is involved in all aspects of arterial thrombosis, including adhesion, activation, aggregation, secretion and development of a stable aggregate on which coagulation proteins can assemble and fibrin strands can mesh. Inhibition of the P2Y12 receptor has been shown convincingly to reduce cardiovascular events among patients with acute coronary syndromes (ACS) and in patients undergoing percutaneous intervention (PCI). Current studies are exploring whether there is a threshold of platelet aggregation below which only more bleeding occurs, without a concomitant reduction in clinical events. The following review considers the potential relevance of reversible and irreversible mechanisms of P2Y12 inhibition to bleeding risk, posing the question, “Is it not only how much but how a platelet P2Y12 receptor is inhibited that determines the attributable safety profile?”

scholarly journals A Naphthalenic Derivative ND-1 Inhibits Thrombus Formation by Interfering the Binding of Fibrinogen to Integrin αIIbβ3

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Xue Ding ◽  
Tong-dan Liu ◽  
Zhou-ling Xie ◽  
Qi Zhao ◽  
Yuan Cao ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Thrombus Formation ◽  
Antiplatelet Agents ◽  
Bleeding Risk ◽  
Dependent Manner ◽  
Antithrombotic Effect ◽  
Thrombosis Model ◽  
Prolonged Bleeding Time ◽  
Cutting Model

Integrin αIIbβ3 plays a crucial role in the process of platelet aggregation. Three integrin αIIbβ3 antagonists (abciximab, eptifibatide, and tirofiban) have been approved by FDA for clinical use. Unfortunately, they all showed severe side effects such as thrombocytopenia and bleeding risk. Thus, researches on the development of more effective and safer antiplatelet agents are needed. In this manuscript we reported a novel naphthalenic derivative compound ND-1 with potent antithrombotic effect and lower bleeding risk. ND-1 inhibited ADP-, collagen-, thrombin-, and U46619-induced platelet aggregation with IC50 values of 1.29, 14.46, 12.84, and 40.24 μM, respectively. Mechanism studies indicated that ND-1 inhibited the binding of fibrinogen to integrin αIIbβ3 in a dose-dependent manner with an IC50 value of 3.12 μM. ND-1 inhibited P-selectin expression induced by ADP, collagen, thrombin, and U46619 on the surface of platelets. Additionally, this compound reduced platelets spreading to the immobilized fibrinogen. In vivo, ND-1 potently decreased thrombus formation in an arteriovenous shunt thrombosis model in rats and slightly prolonged bleeding time in a tail cutting model in mice. Taken together, our results reveal that ND-1 is a novel antagonist of αIIbβ3 with strong antithrombotic effect and lower bleeding risk.

scholarly journals The P2Y12 Receptor Antagonist Selatogrel Dissolves Preformed Platelet Thrombi In Vivo

2021 ◽  
Vol 10 (22) ◽  
pp. 5349
Author(s):  
Lydie Crescence ◽  
Markus Kramberg ◽  
Martine Baumann ◽  
Markus Rey ◽  
Sebastien Roux ◽  
...  
Keyword(s):  
Blood Flow ◽  
Guinea Pigs ◽  
Thrombus Formation ◽  
P2y12 Receptor ◽  
Early Application ◽  
Acute Thrombosis ◽  
Thrombosis Model ◽  
Platelet Thrombus ◽  
Platelet Thrombi

Selatogrel, a potent and reversible antagonist of the P2Y12 receptor, inhibited FeCl3-induced thrombosis in rats. Here, we report the anti-thrombotic effect of selatogrel after subcutaneous applications in guinea pigs and mice. Selatogrel inhibited platelet function only 10 min after subcutaneous application in mice. In addition, in a modified Folts thrombosis model in guinea pigs, selatogrel prevented a decrease in blood-flow, indicative of the inhibition of ongoing thrombosis, approximately 10 min after subcutaneous injection. Selatogrel fully normalised blood flow; therefore, we speculate that it may not only prevent, but also dissolve, platelet thrombi. Thrombus dissolution was investigated using real-time intravital microscopy in mice. The infusion of selatogrel during ongoing platelet thrombus formation stopped growth and induced the dissolution of the preformed platelet thrombus. In addition, platelet-rich thrombi were given 30 min to consolidate in vivo. The infusion of selatogrel dissolved the preformed and consolidated platelet thrombi. Dissolution was limited to the disintegration of the occluding part of the platelet thrombi, leaving small mural platelet aggregates to seal the blood vessel. Therefore, our experiments uncovered a novel advantage of selatogrel: the dissolution of pre-formed thrombi without the disintegration of haemostatic seals, suggesting a bipartite benefit of the early application of selatogrel in patients with acute thrombosis.

A novel P2Y12 adenosine diphosphate receptor antagonist that inhibits platelet aggregation and thrombus formation in rat and dog models

2007 ◽  
Vol 97 (05) ◽  
pp. 847-855 ◽  
Author(s):  
Jon Vincelette ◽  
Valdeci Cunha ◽  
Baby Martin-McNulty ◽  
Cornell Mallari ◽  
Richard Fitch ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Receptor Antagonist ◽  
Thrombus Formation ◽  
Therapeutic Index ◽  
Bleeding Risk ◽  
Adenosine Diphosphate ◽  
Similar Efficacy ◽  
Experimental Models ◽  
P2y12 Receptor ◽  
P2y12 Receptor Antagonist

SummaryIrreversible platelet inhibitors, such as aspirin and clopidogrel, have limited anti-thrombotic efficacy in the clinic due to their bleeding risk. We have developed an orally active reversible P2Y12 receptor antagonist, BX 667.The aim of this study was to determine if the reversible antagonist BX 667 had a greater therapeutic index than the irreversible P2Y12 receptor antagonist clopidogrel. Since BX 667 is rapidly converted to its active metabolite BX 048 in rats,we first injected BX 048 intravenously (iv) in a rat arterial venous (A-V) shunt model of thrombosis.BX 048 dose- and concentration-dependently attenuated thrombosis. When administered orally, BX 667 and clopidogrel had similar efficacy, but BX 667 caused less bleeding than clopidogrel. In a rat model of a platelet-rich thrombus induced by vessel injury with FeCl2, both BX 667 and clopidogrel exhibited higher levels of thrombus inhibition after oral administration compared to their potency in the A-V shunt model.Again, BX 667 caused less bleeding than clopidogrel. In a dog cyclic flow model, iv injection of either BX 667 or clopidogrel dose-dependently reduced thrombus formation with lower bleeding for BX 667 than clopidogrel. Inhibition of thrombosis was highly correlated with inhibition of ADP-induced platelet aggregation in these animal models. In dogs pre-treated with aspirin, BX 667 maintained its wider therapeutic index, measured by inhibition of platelet aggregation over bleeding, compared to the aspirin-clopidogrel combination.These data demonstrate that the reversible P2Y12 receptor antagonist, BX 667, has a wider therapeutic index than clopidogrel in experimental models of thrombosis.

Differentiating haemostasis from thrombosis for therapeutic benefit

2013 ◽  
Vol 110 (11) ◽  
pp. 859-867 ◽  
Author(s):  
James D. McFadyen ◽  
Shaun P. Jackson
Keyword(s):  
Arterial Thrombosis ◽  
Platelet Reactivity ◽  
Thrombus Formation ◽  
Bleeding Risk ◽  
Therapeutic Benefit ◽  
Therapeutic Approaches ◽  
Molecular Events ◽  
Heterogeneous Nature ◽  
Flow Changes

SummaryThe central role of platelets in the formation of the primary haemostatic plug as well as in the development of arterial thrombosis is well defined. In general, the molecular events underpinning these processes are broadly similar. Whilst it has long been known that disturbances in blood flow, changes in platelet reactivity and enhanced coagulation reactions facilitate pathological thrombus formation, the precise details underlying these events remain incompletely understood. Intravital microscopy studies have highlighted the dynamic and heterogeneous nature of thrombus development and demonstrated that there are considerable spatiotemporal differences in the activation states of platelets within a forming thrombus. In this review we will consider the factors regulating the activation state of platelets in a developing thrombus and discuss how specific prothrombotic factors may influence this process, leading to excessive thrombus propagation. We will also discuss some potentially novel therapeutic approaches that may reduce excess thrombus development whilst minimising bleeding risk.

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