Effect of thromboxane A2 receptor antagonists SQ 30,741 and SQ 29,548 on ultimate myocardial infarct size, reperfusion injury and post-ischemic recovery of function

Grover, G J

doi:10.1016/0022-2828(89)92083-x

Cited by 3 publications

(5 citation statements)

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“…Blood flow during reperfusion is improved, but this is most likely related to the increased density of viable tissue (13). Interestingly, TP receptor antagonists do not protect ischemic myocardium by reducing neutrophil accumulation (71), which was surprising given the finding that TxA 2 can augment neutrophil adhesiveness (61).…”

Section: Myocardial Ischemiamentioning

confidence: 95%

“…A deleterious effect of TxA 2 on ischemic myocardium was hypothesized either to be due to vascular effects, platelet effects or direct effects on the myocardium. In diverse animal models and species, inhibition of TxA 2 synthase was shown to exert cardioprotective effects, as was antagonism of TP receptors (2,13,22,31,53). The beneficial effect of TP receptor antagonism (SQ29,548 and BMS-30741) was clearly shown in infarcting myocardium in several species (13,23).…”

Section: Myocardial Ischemiamentioning

confidence: 99%

Section: Myocardial Ischemiamentioning

confidence: 99%

“…The mechanism by which TRA exert their cardioprotective effect is presently unclear, but does not appear to be the consequence of increases in coronary blood flow into the ischemic region (13,16). Blood flow during reperfusion is improved, but this is most likely related to the increased density of viable tissue (13). Interestingly, TP receptor antagonists do not protect ischemic myocardium by reducing neutrophil accumulation (71), which was surprising given the finding that TxA 2 can augment neutrophil adhesiveness (61).…”

Section: Myocardial Ischemiamentioning

confidence: 99%

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Ifetroban Sodium: An Effective TxA₂/PGH₂ Receptor Antagonist

Rosenfeld

Grover

Stier

2001

Cardiovascular Drug Reviews

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This review presents a comprehensive discussion on the chemistry, pharmacokinetics, and pharmacodynamics of ifetroban sodium, a new thomboxane A 2 /prostaglandin H 2 receptor antagonist. Thromboxane A 2 is an arachidonic acid product, formed by the enzyme cyclooxygenase. In contrast to other cyclooxygenase products, thromboxane A 2 has been shown to be involved in vascular contraction and has been implicated in platelet activation. In general, results of clinical studies and animal experiments indicate that hypertension is associated with hyperaggregability of platelets and increased thomboxane A 2 levels in blood, urine, and tissues. The precursors to thromboxane A 2 , prostaglandin G 2 , and prostaglandin H 2 , also bind and activate the same receptors. Thus, a receptor antagonist was thought to be an improved strategy for reversing the actions of thromboxane A 2 /prostaglandin H 2 , rather than a thromboxane synthesis inhibitor. This review describes new methods for the synthesis and analysis of ifetroban, its tissue distribution, and its actions in a variety of animal models and disease states. We describe studies on the mechanisms of how ifetroban relaxes experimentally contracted isolated vascular tissue, and on the effects of ifetroban on myocardial ischemia, hypertension, stroke, thrombosis, and its effects on platelets. These experiments were conducted on several animal models, including dog, ferret, and rat, as well as on humans. Clinical studies are also described. These investigations show that ifetroban sodium is effective at reversing the effects of thromboxane A 2 -and prostaglandin H 2 -mediated processes.

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Section: Myocardial Ischemiamentioning

confidence: 95%

Section: Myocardial Ischemiamentioning

confidence: 99%

Section: Myocardial Ischemiamentioning

confidence: 99%

Section: Myocardial Ischemiamentioning

confidence: 99%

See 2 more Smart Citations

Ifetroban Sodium: An Effective TxA₂/PGH₂ Receptor Antagonist

Rosenfeld

Grover

Stier

2001

Cardiovascular Drug Reviews

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“…Preliminary clinical trials seem to indicate that thromboxane receptor antagonism may be more effective antiplatelet therapy than thromboxane synthase inhibitors [106]; some are very long acting and, moreover, are endowed with an anti-ischemic effect [107,108]. These drugs give a more reproducible and pronounced inhibition of platelet function and prolong the bleeding time more than thromboxane synthase inhibitors.…”

Section: Platelet Inhibitionmentioning

confidence: 99%

Advances in thrombolytic therapy

Verstraete

1992

Cardiovasc Drug Ther

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Alteplase and saruplase are more fibrin-specific thrombolytic drugs than anistreplase. These and the thrombolytic drugs of the first generation (streptokinase and urokinase) have shortcomings and limitations. The prolonged intravenous maintenance infusions have been replaced by a bolus injection, accelerated infusions, or the combined intravenous administration of thrombolytic agents. Numerous truncated alteplase or saruplase molecules have been constructed by deletion and domain substitution or hybrids made of the two molecules without gaining in thrombolytic potency. Recombinant staphylokinase and plasminogen activator from bat saliva have some interesting properties and are being investigated. Thrombus-targeted thrombolytic drugs were constructed using monoclonal antibodies against fibrin fragments or against epitopes of activated platelets. Fibrin-specific thrombolytic drugs require the concomitant use of a potent antithrombotic drug to prevent reocclusion. Whether hirudin or synthetic thrombin inhibitors are superior to heparin and whether novel antiplatelet agents, including monoclonal antibodies to platelet receptors and disintegrins, are more effective than aspirin is under clinical investigation. The place of stable analogues of prostacyclin during thrombolytic treatment is still unsettled.

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Differential effects of thromboxane A2 synthase inhibition, singly or combined with thromboxane A2/prostaglandin endoperoxide receptor antagonism, on occlusive thrombosis elicited by endothelial cell injury or by deep vascular damage in canine coronary arteries.

Vandeplassche

Hemans

Water

et al. 1991

Circulation Research

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In open-chest dogs, cyclic flow reductions (CFRs, 5.1-6.6/hr in controls; n = 24) caused by platelet deposition/dislodgment at sites of endothelial cell injury in critically stenosed left anterior descending coronary arteries (59% flow reduction) were attenuated to the same extent either by single thromboxane A2 (TXA2) synthase inhibition (0.31 mg/kg i.v. ridogrel; CFR, 0.16 +/- 0.16/hr; n = 6; p less than 0.05) or by a comparatively modest degree of TXA2/prostaglandin endoperoxide receptor antagonism on top of TXA2 synthase inhibition (5 mg/kg i.v. ridogrel; CFR, 0.22 +/- 0.1/hr; n = 10; p less than 0.05). By contrast, occlusive thrombosis on deep vascular damage elicited by intraluminal stimulation (150-microA anodal constant current) in nonpreconstricted canine coronary arteries (time to occlusion, 237.1 +/- 13.9 minutes; n = 7; incidence of occlusion within 300 minutes, six of seven experiments) was not affected by platelet cyclooxygenase inhibition (5 mg/kg i.v. acetylsalicylic acid; n = 7), single TXA2 synthase inhibition (1.25 mg/kg i.v. ridogrel; n = 7), or single TXA2/prostaglandin endoperoxide receptor antagonism (10 mg/kg + 10 mg/kg/hr i.v. sulotroban for 300 minutes; n = 5). However, such an occlusive thrombus formation was significantly reduced by combined TXA2 synthase/prostaglandin endoperoxide receptor inhibition (5 mg/kg i.v. ridogrel; time to occlusion greater than 300 minutes, n = 7; incidence of occlusion within 300 minutes, one of seven experiments; p less than 0.05). This study reveals 1) a differential efficacy of TXA2 synthase inhibition, singly or combined with TXA2/prostaglandin endoperoxide receptor antagonism, depending on the extent of the vessel wall lesion triggering thrombosis and the size of the thrombus required to obstruct the vascular lumen and 2) a significant synergism in preventing occlusive thrombosis of extensively damaged coronary arteries between strong TXA2 synthase inhibition and comparatively modest TXA2/prostaglandin endoperoxide receptor antagonism with ridogrel.

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Effect of thromboxane A2 receptor antagonists SQ 30,741 and SQ 29,548 on ultimate myocardial infarct size, reperfusion injury and post-ischemic recovery of function

Cited by 3 publications

References 0 publications

Ifetroban Sodium: An Effective TxA₂/PGH₂ Receptor Antagonist

Ifetroban Sodium: An Effective TxA₂/PGH₂ Receptor Antagonist

Advances in thrombolytic therapy

Differential effects of thromboxane A2 synthase inhibition, singly or combined with thromboxane A2/prostaglandin endoperoxide receptor antagonism, on occlusive thrombosis elicited by endothelial cell injury or by deep vascular damage in canine coronary arteries.

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Effect of thromboxane A2 receptor antagonists SQ 30,741 and SQ 29,548 on ultimate myocardial infarct size, reperfusion injury and post-ischemic recovery of function

Cited by 3 publications

References 0 publications

Ifetroban Sodium: An Effective TxA2/PGH2 Receptor Antagonist

Ifetroban Sodium: An Effective TxA2/PGH2 Receptor Antagonist

Advances in thrombolytic therapy

Differential effects of thromboxane A2 synthase inhibition, singly or combined with thromboxane A2/prostaglandin endoperoxide receptor antagonism, on occlusive thrombosis elicited by endothelial cell injury or by deep vascular damage in canine coronary arteries.

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Ifetroban Sodium: An Effective TxA₂/PGH₂ Receptor Antagonist

Ifetroban Sodium: An Effective TxA₂/PGH₂ Receptor Antagonist