Effects of terbogrel on platelet function and prostaglandin endoperoxide transfer

Muck, Stephanie; Weber, Artur‐Aron; Schrör, Karsten

doi:10.1016/s0014-2999(97)01612-9

Cited by 17 publications

(6 citation statements)

References 14 publications

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“…Platelet-rich plasma (PRP) was generated from healthy volunteers as described recently. 22 Platelets were stimulated with U46619 (10 Ϫ7 mol/L), a TXA2 analog. Aggregation was determined turbimetrically.…”

Section: Discussionmentioning

confidence: 99%

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Angiotensin II Receptor–Independent Antiinflammatory and Antiaggregatory Properties of Losartan

Kramer

Sunkomat

Witte

et al. 2002

Circulation Research

146

109

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Abstract-Angiotensin II (Ang II) type 1 receptor (AT 1 ) antagonists such as losartan (LOS) are widely used for the treatment of hypertension and elicit antiinflammatory and antiaggregatory in vitro and in patients, although the underlying mechanism are unclear. Following computer-based molecule similarity, we proposed that on cytochrome-P450 degradation, the LOS metabolite EXP3179 is generated, which shows molecule homology to indomethacin, a cyclooxygenase inhibitor with antiinflammatory and antiaggregatory properties. Subsequently, serum-levels of EXP3179 were determined for 8 hours in patients receiving a single oral dose of 100 mg LOS. High-performance liquid chromatography followed by liquid chromatography-mass spectrometry (LC-MS) from serum samples revealed a maximum of 10 Ϫ7 mol/L for EXP3179 peaking between 3 to 4 hours. The increase in serum-EXP3179 levels was associated with a significant reduction in platelet aggregation in vivo (Ϫ35Ϯ4%, PϽ0.001 versus control). EXP3179 generation was investigated in a chemical reaction mimicking the liver cytochrome-P450 -dependent LOS-degradation and human endothelial cells were exposed to Ang II or lipopolysaccharides (LPS) in the presence of EXP3179 (10

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Section: Discussionmentioning

confidence: 99%

“…22 Platelets were stimulated with U46619 (10 Ϫ7 mol/L), a TXA2 analog, and with increasing doses of arachidonic acid (AA). Aggregation was determined turbimetrically (aggregometer APACT Inc).…”

Section: Effect Of Exp3179 On Platelet Aggregationmentioning

confidence: 99%

Angiotensin II Receptor–Independent Antiinflammatory and Antiaggregatory Properties of Losartan

Kramer

Sunkomat

Witte

et al. 2002

Circulation Research

146

109

View full text Add to dashboard Cite

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“…The guanidino derivative terbogrel inhibits both with an IC 50 of about 10 nmol/L. 15 Indeed, terbogrel prevented thromboxane formation, P-selectin expression, and effectively inhibited aggregation, which further supports an abnormal interaction of aspirin with platelet COX-1.…”

Section: Zimmermann Et Al Aspirin Resistance After Coronary Bypass Sumentioning

confidence: 79%

“…The PRP of 8 additional nonresponders served to evaluate the effect of terbogrel, an equipotent inhibitor of thromboxane synthase and thromboxane receptors. 15 Indomethacin, celecoxib, and terbogrel (each 1 mol/L) were added 5 minutes before PRP was stimulated by 1 mmol/L arachidonic acid and aggregation and thromboxane formation were determined as described. Previous measurements have shown that 1 mol/L celecoxib and terbogrel inhibit COX-2 and thromboxane synthase by Ͼ90%.…”

Section: Platelet Aggregation and Thromboxane Formationmentioning

confidence: 99%

Functional and Biochemical Evaluation of Platelet Aspirin Resistance After Coronary Artery Bypass Surgery

et al. 2003

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Background-Aspirin inhibits platelet activation and reduces atherothrombotic complications in patients at risk of myocardial infarction and stroke. However, a sufficient inhibition of platelet function by aspirin is not always achieved. The causes of this aspirin resistance are unknown. Methods and Results-Patients undergoing coronary artery bypass grafting (CABG) have a high incidence of aspirin resistance. To evaluate functional and biochemical responses to aspirin, platelet-rich plasma was obtained before and at days 1, 5, and 10 after CABG. Thromboxane formation, aggregation, and ␣-granule secretion were effectively inhibited by 30 or 100 mol/L aspirin in vitro before CABG, but this inhibition was prevented or attenuated after CABG. Whereas the inhibition of thromboxane formation and aggregation by aspirin in vitro partly recovered at day 10 after CABG, oral aspirin (100 mg/d) remained ineffective. The inducible isoform of cyclooxygenase in platelets, COX-2, has been suggested to confer aspirin resistance. In fact, immunoreactive COX-2 was increased 16-fold in platelets at day 5 after CABG, but the COX-2 selective inhibitor celecoxib did not alter aspirin-resistant thromboxane formation. By contrast, the combined inhibitor of thromboxane synthase and thromboxane receptor antagonist terbogrel equally prevented thromboxane formation of platelets obtained before (control) and after CABG. Conclusions-Platelet aspirin resistance involves an impairment of both in vivo and in vitro inhibition of platelet functions and is probably due to a disturbed inhibition of platelet COX-1 by aspirin. (Circulation. 2003;108:542-547.)

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“…These compounds were noted to have good clinical efficacy in patients with thrombotic disorders (Keith et al, 1994;Neirotti et al, 1994). Terbogrel exhibits an equipotent (IC 50 of about 10 nM) activity as TXA 2 synthase inhibitor and TP receptor antagonist (Muck et al, 1998). In our study, we demonstrated that PBT-3, a novel combined TXA 2 synthase inhibitor/TP receptor antagonist (Pace-Asciak et al, 2002), selectively inhibits TXA 2 -dependent platelet activation but exhibits a more potent activity as TP receptor antagonist (IC 50 for inhibition of 125 I-BOP binding, intracellular calcium release, platelet aggregation are 8, 7, and 56 nM, respectively) compared with its activity as TXA 2 synthase inhibitor (IC 50 for inhibition of TXA 2 formation and platelet aggregation evoked by collagen are 0.4 and 0.64 M).…”

Section: Pbt-3 Antagonizes the Tp␣ Isoform Of The Thromboxane Receptomentioning

confidence: 99%

The Thromboxane Receptor Antagonist PBT-3, a Hepoxilin Stable Analog, Selectively Antagonizes the TPα Isoform in Transfected COS-7 Cells

Qiao¹,

Reynaud²,

Demin³

et al. 2003

J Pharmacol Exp Ther

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The hepoxilin analog PBT-3 [10(S)-hydroxy-11,12-cyclopropyleicosa-5Z,8Z,14Z-trienoic acid methyl ester] was previously shown to inhibit the aggregation of human platelets and to antagonize the binding of the thromboxane receptor agonist I-BOPin human platelets (Pace-Asciak et al., 2002). We show herein that PBT-3 inhibits, to different degrees, binding of the TP receptor antagonist, to the TP receptor isoforms in TP␣-and TP␤-transfected COS-7 cells. These isoforms possess a different tail length, the ␣ being shorter than the ␤ isoform. In contrast, SQ 29,548 shows no selection for the two TP isoforms. The IC 50 value for PBT-3 ϭ 2.0 Ϯ 0.3 ϫ 10 Ϫ7 M was observed for TP␣, whereas this was one-sixth less active on the TP␤ isoform (IC 50 ϭ 1.2 Ϯ 0.2 ϫ 10 Ϫ6 M), suggesting selectivity for the TP␣ isoform. To investigate whether the tail contributes to the difference in competition binding by PBT-3, we investigated the tailless TP isoform expressed in transfected COS-7 cells. Its IC 50 was similar to that of the TP␣ isoform. In additional studies, we investigated the effect of PBT-3 on the collagen and I-BOP evoked intracellular calcium release and on the collagen and I-BOP evoked phosphorylation of pleckstrin. PBT-3 blocked both pathways further demonstrating its TP receptor antagonist activity. These results demonstrate that the action of PBT-3 in inhibiting platelet aggregation is mediated via inhibition of the TP␣ isoform of the thromboxane receptor and that the tail may play an important role in recognition of this TP receptor antagonist.

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Effects of terbogrel on platelet function and prostaglandin endoperoxide transfer

Cited by 17 publications

References 14 publications

Angiotensin II Receptor–Independent Antiinflammatory and Antiaggregatory Properties of Losartan

Angiotensin II Receptor–Independent Antiinflammatory and Antiaggregatory Properties of Losartan

Functional and Biochemical Evaluation of Platelet Aspirin Resistance After Coronary Artery Bypass Surgery

The Thromboxane Receptor Antagonist PBT-3, a Hepoxilin Stable Analog, Selectively Antagonizes the TPα Isoform in Transfected COS-7 Cells

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