Development of a DHA-Losartan hybrid as a potent inhibitor of multiple pathway-induced platelet aggregation

2021 ◽  
pp. 1-12
Author(s):  
Antonis D. Tsiailanis ◽  
Eirinaios I. Vrettos ◽  
Maria Choleva ◽  
Sofia Kiriakidi ◽  
Ab Majeed Ganai ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Potent Inhibitor ◽  
Multiple Pathway

A Thiazole Compound with Potential Antithrombotic Activity

1982 ◽  
Vol 47 (02) ◽  
pp. 173-176 ◽  
Author(s):  
E E Nishizawa ◽  
A R Mendoza ◽  
T Honohan ◽  
K A Annis
Keyword(s):  
Platelet Aggregation ◽  
Potent Inhibitor ◽  
Platelet Rich Plasma ◽  
Development Program ◽  
Antithrombotic Agent ◽  
Antithrombotic Activity ◽  
Thiazole Derivative ◽  
Cyclooxygenase Activity ◽  
Drug Development Program

SummaryA thiazole derivative, 4,5-bis(p-methoxyphenyl)-2-(trifluoromethyl)-thiazole was found to be a potent inhibitor of collagen-induced platelet aggregation, in vitro, using platelets from at least six species, including man. It was active in human platelet-rich plasma at a concentration of 1 ng/ml. While its antiplatelet activity was greater than that of flurbiprofen, its cyclooxygenase activity was equivalent to that of flurbiprofen. Also, compared to flurbiprofen, the thiazole had less anti-inflammatory activity in the hind-paw edema test. The thiazole derivative inhibited platelet aggregation following oral administration in five laboratory species. In the guinea pig it was active at 0.5 mg/kg. The LD50 in mice was greater than 1000 mg/kg (i.p.). This compound, which was designed through a systematic drug development program, may have high potential as an antithrombotic agent.

Interactions Between Blood Platelets and Vascular Endothelium in vitro Studies

1979 ◽  
Author(s):  
M.A. Gimbrone ◽  
K.D. Curwen ◽  
R. I. Handin
Keyword(s):  
Platelet Aggregation ◽  
Vascular Endothelium ◽  
Potent Inhibitor ◽  
Platelet Reactivity ◽  
Blood Platelets ◽  
Primary Cultures ◽  
Adenosine Diphosphate ◽  
Human Platelets ◽  
Platelet Adherence

Endothelial cells (EC) can actively influence the hemostatic response at sites of vascular injury through multiple mechanisms. For example, EC can degrade adenosine diphosphate, release plasminogen activator, and synthesize prostacyclin (PGI2), a potent inhibitor of platelet aggregation. We have examined whether PGI2 also might account for the normal lack of platelet adherence to the uninjured EC surface. In a monolayer adherence assay, radiolabeled human platelets in citrated plasma showed minimal interaction with primary cultures of human EC (<1 platelet adhering per cell). Platelets from aspirin-treated and untreated donors behaved similarly. However, aspirin pretreatment of EC consistently resulted in ~2-fold increases in platelet adherence which could be completely abolished by exogenous PGI2 (0.5–1.0 μg/ml). SV40-transformed human EC (SVHEC), which are deficient in PGI2 production compared to primary EC, showed 10-30 times more platelet adherence. Exogenous PGI2 produced a dose - related (.001-1.0 μg/ml) decrease in platelet adherence to SVHEC but did not result in the basal levels observed with normal EC monolayers. These data suggest that : 1) In addition to its effects on platelet aggregation, PGI2 can influence platelet endothelial cell interactions; 2) The increased platelet reactivity of transformed EC is associated with, but not completely attributable, to decreased PGI2 production; and 3) Factors other than PGI2 may play a role in the thromboresistance of normal vascular endothelium.

Extracellular fibrinogen binding protein, Efb, from Staphylococcus aureus binds to platelets and inhibits platelet aggregation

2004 ◽  
Vol 91 (04) ◽  
pp. 779-789 ◽  
Author(s):  
Oonagh Shannon ◽  
Jan-Ingmar Flock
Keyword(s):  
Platelet Aggregation ◽  
Potent Inhibitor ◽  
Specific Binding ◽  
Binding Protein ◽  
Dependent Manner ◽  
Platelet Surface ◽  
Putative Receptor ◽  
Activated Platelets ◽  
Fibrinogen Binding ◽  
Dose Dependent

Summary S. aureus produces and secretes a protein, extracellular fibrinogen binding protein (Efb), which contributes to virulence in wound infection. We have shown here that Efb is a potent inhibitor of platelet aggregation. Efb can bind specifically to platelets by two mechanisms; 1) to fibrinogen naturally bound to the surface of activated platelets and 2) also directly to a surface localized component on the platelets. This latter binding of Efb is independent of fibrinogen. The specific binding of Efb to the putative receptor on the platelet surface results in a stimulated, non-functional binding of fibrinogen in a dose dependent manner, distinct from natural binding of fibrinogen to platelets. The natural binding of fibrinogen to GPIIb/IIIa on activated platelets could be blocked by a monoclonal antibody against this integrin, whereas the Efb-mediated fibrinogen binding could not be blocked. The enhanced Efb-dependent fibrinogen binding to platelets is of a nature that does not promote aggregation of the platelets; instead it inhibits aggregation. The anti-thrombotic action of Efb may explain the effect of Efb on wound healing, which is delayed in the presence of Efb.

Thromboxane-Synthetase Inhibitors Could Be “Large Spectrum” Anti-Aggregating Agents

1981 ◽  
Author(s):  
C Bonne ◽  
B Martin
Keyword(s):  
Platelet Aggregation ◽  
Potent Inhibitor ◽  
Platelet Rich Plasma ◽  
Rat Aorta ◽  
The Other ◽  
Vascular Tissues ◽  
Synthetase Inhibitor ◽  
Compound C ◽  
Thromboxane Synthetase ◽  
Dependent Pathway

“Large spectrum”anti-aggregating activity could be only achieved by agents which increased the c AMP content of platelets. Cyclo-oxygenase inhibitors could only block the Thromboxane (Tx)- dependent pathway of platelet aggregation. Conversely, Tx-synthetase inhibitors could deviate the endoperoxides metabolism to anti-aggregating prostaglandins in particular in the presence of vascular tissues. In this study we have investigated the effect of CBS634 (1-(3-hydroxy- 1 - octenyl)-imidazole nicotinic ester, dichlorhydra- teD, a potent inhibitor of T×A2 synthesis, both on the production of anti-aggregating prosta- glandins and on the simultaneous c AMP synthesis in platelets.Rat aorta fragments pretreated with aspirin were incubated with rat platelet rich plasma in the presence or absence of tested compound, c AMP, T×B2, PGE2 and 6-keto-PGFF1α were determined by radioimmunoassays.In the presence of CBS63U (50μM), T×B2 formation was reduced from 17 ± 2 to 0.2 ng/ml/min. In parallel, PGE production in controls was 1.4 ± 0.6 and 8 ± 1 ng/ml/min in the presence of the drug. On the other hand, 6-keto-PGF1α formation, very low in controls, rose to 4 ±1.2 ng/mV min in the presence of CBS63U. Radiochemical assays performed with c14C)-arachidonate confirmed that metabolic deviation. The increased level of c AMP formed in the presence of T×A2-synthetase inhibitor supports the hypothesis that such a drug could present a “large spectrum”antiaggregating activity.

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