Anti-thrombotic Activity of KBT-3022 in Experimental Models of Thrombosis

Yokota, Koichi; Yamashita, Akira; Oda, M.

doi:10.1254/jjp.68.201

Cited by 14 publications

(7 citation statements)

References 25 publications

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“…The metabolite desethyl KBT-3022 was also able to inhibit ASA insensitive thrombosis in a photochemically-induced rat thrombosis model [133] and serotonin secretion more potently than ticlopidine [131]. In experimental models of aortic thrombosis KBT-3022 proved superior to ASA and ticlopidine regarding inhibition of thrombus formation, while in stasis-induced venous thrombosis models KBT-3022 failed to inhibit thrombosis [134].…”

Section: Inhibitors Of Cox/prostaglandin H 2 Synthasementioning

confidence: 94%

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Inhibitors of platelet signal transduction as anti-aggregatory drugs

Geiger

2001

Expert Opinion on Investigational Drugs

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In the treatment and prevention of cardiovascular diseases, inhibition of platelet aggregation is of fundamental importance. Inhibition of platelet aggregation can be achieved by either inhibition of membrane receptors or by interception of signalling pathways. While receptor antagonism provides high specificity, the inhibition of platelet signal transduction is more effective. The effectiveness results from the inhibition of platelets, regardless of the cause of activation. These common pathway inhibitors are either intercepting platelet activating mechanisms or amplifying the action of endogenous platelet inhibitors. The physiological anti-aggregants are the endothelial factors NO and prostacyclin, which elevate intracellular cGMP or cAMP content, respectively. By administration of NO-releasing agents, prostacyclin analogues or other cyclic nucleotide elevating drugs the platelet anti-aggregatory action of endothelial factors can be effectively mimicked. Besides antiplatelet activity these drugs also act on vascular smooth muscle causing relaxation and therefore vasodilation, an additional beneficial effect. Inhibition of phosphodiesterases causes elevation of platelet cyclic nucleotide content and thus inhibits platelet aggregation and causes vasodilation. Another relevant target for anti-aggregatory treatment is the arachidonic acid metabolic pathway. This pathway can be intercepted by blockade of either cyclooxygenase-1 (COX-1) or thromboxane synthase. Inhibition of these enzymes may be further amplified by additional antagonism of the thromboxane receptor thus not only preventing formation of thromboxane but also activation of thromboxane receptor by thromboxane precursors, which were particularly effective in clinical trials. In vivo these precursors may be metabolised to prostacyclin in the endothelium and consequently provide additional platelet anti-aggregatory activity. A rather new target for platelet anti-aggregatory treatment is the ecto-nucleotidase CD-39 which limits the plasma level of nucleotides. While several of the novel anti-aggregatory drugs were disappointing in clinical studies combinations of drugs with different effector enzymes showed potent antithrombotic efficacy.

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Section: Inhibitors Of Cox/prostaglandin H 2 Synthasementioning

confidence: 94%

“…The structural analogue of ASA, triflusal (18) is a potent and irreversible platelet COX inhibitor [134] but also an inhibitor of COX-2 [136] and cAMP-PDE. In a study for the prophylaxis of deep vein thrombosis no statistically significant difference between triflusal and ASA treatment could be established.…”

Section: Inhibitors Of Cox/prostaglandin H 2 Synthasementioning

confidence: 99%

Inhibitors of platelet signal transduction as anti-aggregatory drugs

Geiger

2001

Expert Opinion on Investigational Drugs

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“…The protection offered by the test agents was evaluated against death subsequent to thrombotic challenge. Results are expressed as per cent protection in the compound or standard drug‐treated group (12).…”

Section: Methodsmentioning

confidence: 99%

Antithrombotic Activity of a Newly Synthesized Coumarin Derivative 3‐(5‐Hydroxy‐2,2‐dimethyl‐chroman‐6‐yl)‐N‐{2‐[3‐(5‐hydroxy‐2,2‐dimethyl‐chroman‐6‐yl)‐propionylamino]‐ethyl}‐propionamide

et al. 2013

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Anti-platelet therapy is a useful strategy to prevent acute thromboembolic artery occlusions. This study was designed to assess the efficacy of seselin derivatives against murine pulmonary thromboembolism, bleeding time, platelet activation and thrombosis. Administration of C3 (16 mg/kg) offered 70% protection against collagen- and epinephrine-induced pulmonary thromboembolism and 30% protection against arachidonic acid-induced death in mice, without adversely affecting bleeding time. No significant difference was observed by C3 in ferric chloride-induced arterial thrombosis in rats. Significant reduction in thrombus weight was observed in arteriovenous shunt model. In rat PRP, C3 reduced ADP and collagen-induced platelet aggregation. In chronic hamster model of dyslipidemia, administration of C3 (16 mg/kg p.o. for 90 days) had no effect on plasma lipids, vasoreactivity and platelet adhesion. C3 fed hamsters showed reduced whole-blood aggregation response to ADP and collagen compared to HC-fed hamsters. In addition, C3 augmented thrombin time; however, time to occlusion was not increased. These results convincingly demonstrated that C3 is a novel molecule that reduces the risk of thrombosis and alleviates prothrombotic state associated with hyperlipidemia without any adverse effect on bleeding time. The high benefit/risk ratio of this compound makes it a suitable candidate for future valid studies.

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“…It has been reported 1) that KBT-3022 and its main metabolite, desethyl KBT-3022, inhibit the activity of both cyclooxygenase (COX) and 5-lipoxygenase (5-LO), 2) that oral administration of KBT-3022 inhibits TXA 2 synthesis in platelets more potently than PGI 2 synthesis in the vessel wall [Yamashita et al, 1990], and 3) that this drug, at concentrations sufficient to product its antiplatelet and antithrombotic action, shows few gastrointestinal side effects which are induced by aspirin [Yokota et al, 1995a]. Moreover, KBT-3022 has been reported to inhibit thrombus formation both in an arterial-thrombosis model in rabbits, and in an arteriovenous-shunt model in guinea-pigs [Yokota et al, 1995b], and to improve hemorheological properties, including red blood cell deformability, wholeblood viscosity and whole-blood filterability in guineapigs [Yamamoto et al, 1995]. On this basis, KBT-3022 may be expected to have a greater antithrombotic efficacy than either aspirin or ticlopidine.…”

Section: Introductionmentioning

confidence: 99%