The affinities of prostaglandin H2 and thromboxane A2 for their receptor are similar in washed human platelets

Mayeux, Philip R.; Morton, Howard E.; Gillard, John W.; Lord, A.; Morinelli, Thomas A.; Boehm, Andreas; Mais, Dale E.; Halushka, Perry V.

doi:10.1016/s0006-291x(88)80311-5

Cited by 54 publications

(28 citation statements)

References 12 publications

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“…Of the four compounds, only 10,10-difluoro-TXA2, which possesses stereochemistry identical with that ofTXA2, was a full agonist in both platelets and saphenous veins. The EC50 value for 10,10-difluoro-TXA2 to aggregate washed human platelets is 4-5 times lower than that seen for synthetic TXA2 (163 nM) and comparable to that of PGH2 (45 nM) (23). The Kd value for 10,10-difluoro-TXA2 10,10-Difluoro-TXA2 has a cis 5,6 double bond, and the 15-hydroxyl group is in the S orientation.…”

Section: Discussionmentioning

confidence: 83%

Difluorothromboxane A2 and stereoisomers: stable derivatives of thromboxane A2 with differential effects on platelets and blood vessels.

Morinelli

Okwu

Mais

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

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Section: Discussionmentioning

confidence: 83%

Difluorothromboxane A2 and stereoisomers: stable derivatives of thromboxane A2 with differential effects on platelets and blood vessels.

Morinelli

Okwu

Mais

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

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“…Therefore, we assumed an insufficient antiplatelet effect of ASA when platelet-derived TX increased above a predefined threshold, which is sufficiently high to allow for platelet activation. Mayeux et al [21] reported that TX concentrations exceeding 25 ng/ml were required to stimulate platelet aggregation. We observed a similar threshold concentration in our laboratory [22].…”

Section: Methodsmentioning

confidence: 99%

Variable Platelet Response to Aspirin in Patients with Ischemic Stroke

Hohlfeld

Weber²,

Junghans³

et al. 2007

Cerebrovasc Dis

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Background: A large number of patients experience ischemic stroke despite treatment with aspirin (acetylsalicylic acid, ASA). It is not clear whether all of these patients with ischemic stroke respond normally to ASA or are hyporesponsive as assessed by inhibition of aggregation and thromboxane (TX) synthesis. Methods: We studied the effect of ASA given orally and ASA in vitro on collagen- and arachidonic-acid-induced TX formation and aggregation in platelet-rich plasma of 90 patients with ischemic stroke and 25 healthy control subjects. Results: Thirty-seven patients were being treated with ASA at the time of stroke. Arachidonic-acid-induced TX formation was not depressed below a predefined threshold of 25 ng/ml in 9 patients. Eight of these however exhibited a normal platelet sensitivity to ASA in vitro, suggesting poor compliance or a pharmacokinetic mechanism of nonresponse. The addition of ASA in vitro did not inhibit arachidonic-acid-induced TX formation below the above threshold in 6 patients (11%) in the group of 53 stroke patients not receiving oral ASA, indicating an impaired response to ASA at the platelet level. Moreover, platelets from stroke patients showed an increased collagen-induced, TX-independent aggregation as compared with those of healthy individuals. Conclusion: Different categories of ASA nonresponders can be distinguished in patients with ischemic stroke. These include patients with poor bioavailability or noncompliance, an impaired platelet response to ASA in vitro and an increased, TX-independent hyperreactivity to collagen.

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“…ozagrel is explained by prostaglandin endoperoxide accumulation, which can directly stimulate TXA 2 receptor on platelets (Mayeux et al, 1988) due to inhibition of TXA 2 synthase. Accumulated prostaglandin endoperoxide, however, is rapidly converted to prostaglandin I 2 (PGI 2 ), a potent antiaggregatory and vasodilatory factor, by PGI 2 synthase in the presence of blood vessels (Kuzuya et al, 1986).…”

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confidence: 99%

Antithrombotic Effects of FK419, a Novel Nonpeptide Platelet GPIIb/IIIa Antagonist, in a Guinea Pig Photochemically Induced Middle Cerebral Artery Thrombosis Model: Comparison with Ozagrel and Argatroban

Moriguchi

Aoki²,

Mihara³

et al. 2003

J Pharmacol Exp Ther

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Platelet activation and subsequent aggregation play a key role in the pathogenesis of ischemic brain damage. Recent studies revealed that enhanced platelet activation is also observed after ischemia, suggesting that secondary thrombus formation might participate in the development of cerebral infarction. The binding of platelet glycoprotein GPIIb/IIIa (integrin ␣ IIb ␤3) to fibrinogen is the final common pathway in platelet aggregation. Therefore, GPIIb/IIIa antagonists might be useful in acute ischemic stroke as well as in the secondary prevention of ischemic stroke. In the present study, we evaluated the effect of three compounds, FK419 ((S)-2-acetylamino-3-[(R)- [1-[3-(piperidin-4-yl) propionyl] piperidin-3-ylcarbonyl] amino] propionic acid trihydrate), a novel nonpeptide GPIIb/IIIa antagonist, ozagrel, a selective thromboxane A 2 synthase inhibitor, and argatroban, a thrombin inhibitor, on middle cerebral artery (MCA) patency and ischemic brain damage using photochemically induced MCA thrombosis model in guinea pigs. FK419, ozagrel, or argatroban was administered 5 min after the termination of photoirradiation. FK419 dose-dependently improved MCA patency by decreasing the total occlusion time, time to continuous reperfusion, and the number of cyclic flow reductions, at doses that inhibited ADP-induced platelet aggregation ex vivo. In contrast, ozagrel only improved total occlusion time, and argatroban showed no improvement in MCA patency. FK419 also reduced ischemic brain damage in a dose-dependent fashion, whereas ozagrel and argatroban did not. Finally, FK419 ameliorated neurological deficits, whereas ozagrel and argatroban did not. These results indicate that FK419, a GPIIb/IIIa antagonist, ameliorates ischemic brain damage by improving MCA patency after occlusion and that FK419 is a promising candidate for the treatment of acute ischemic stroke.

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The affinities of prostaglandin H2 and thromboxane A2 for their receptor are similar in washed human platelets

Cited by 54 publications

References 12 publications

Difluorothromboxane A2 and stereoisomers: stable derivatives of thromboxane A2 with differential effects on platelets and blood vessels.

Difluorothromboxane A2 and stereoisomers: stable derivatives of thromboxane A2 with differential effects on platelets and blood vessels.

Variable Platelet Response to Aspirin in Patients with Ischemic Stroke

Antithrombotic Effects of FK419, a Novel Nonpeptide Platelet GPIIb/IIIa Antagonist, in a Guinea Pig Photochemically Induced Middle Cerebral Artery Thrombosis Model: Comparison with Ozagrel and Argatroban

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