Rapid and sustained coronary artery recanalization with combined bolus injection of recombinant tissue-type plasminogen activator and monoclonal antiplatelet GPIIb/IIIa antibody in a canine preparation.

Gold, Herman K.; Coller, Barry S.; Yasuda, Tsunehiro; Saito, Tomiyoshi; Fallon, John T.; Guerrero, J. Luis; Leinbach, Robert C.; Ziskind, Andrew A.; Collen, D.

doi:10.1161/01.cir.77.3.670

Cited by 402 publications

(116 citation statements)

References 24 publications

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“…As shown in Table 4, a decreasing order of binding affinity of 7E3 for human (5), dog (22), and rat (23) platelets is observed, whereas 7E3 does not bind at all to platelets from pig (B.S.C., unpublished observation) and mouse. Dog ␤3 shares the same 177-184 sequence as human, but has the W129S substitution found in ␤3M.…”

Section: Discussionmentioning

confidence: 84%

Integrin β3 regions controlling binding of murine mAb 7E3: Implications for the mechanism of integrin αIIbβ3 activation

Artoni

Mitchell

et al. 2004

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

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Abciximab, a derivative of the murine mAb 7E3, protects against ischemic complications of percutaneous coronary interventions by inhibiting ligand binding to the ␣IIb␤3 receptor. In this study we identified regions on integrin ␤3 that control 7E3 binding. Murine͞ human amino acid substitutions were created in two regions of the ␤A domain that previous studies found to influence 7E3 binding: the C177-C184 loop and K125-N133. The T182N substitution and a K125Q mutation reduced 7E3 binding to human ␤3 in complex with ␣IIb. The introduction of both the human C177-C184 region and human W129 into murine ␤3 was necessary and sufficient to permit 7E3 binding to the human ␣IIb͞murine ␤3 complex. Although we cannot exclude allosteric effects, we propose that 7E3 binds between C177-C184 and W129, which are within 15 Å of each other in the crystal structure and close to the ␤3 metal ion-dependent adhesion site. We previously demonstrated that 7E3 binds more rapidly to activated than unactivated platelets. Because it has been proposed that ␣IIb␤3 changes from a bent to an extended conformation upon activation, we hypothesized that 7E3 binds less well to the bent than the extended conformation. In support of this hypothesis we found that 7E3 bound less well to an ␣IIb␤3 construct locked in a bent conformation, and unlocking the conformation restored 7E3 binding. Thus, our data are consistent with ␣IIb␤3 existing in variably bent conformations in equilibrium with each other on unactivated platelets, and activation resulting in ␣IIb␤3 adopting a more extended conformation.T he integrin ␣IIb␤3 and ␣V␤3 receptors are important in a number of physiologic and pathologic phenomena, including hemostasis, thrombosis, tumor angiogenesis, and bone resorption (1, 2). The murine mAb 7E3 (3) blocks ligand binding to both ␣IIb␤3 and ␣V␤3 receptors (4, 5). Abciximab is a mouse͞ human chimeric Fab fragment of the mAb 7E3 that inhibits ␣IIb␤3-mediated platelet aggregation and is approved for human use to prevent the ischemic complications associated with percutaneous coronary interventions (6).Previous studies of 7E3 binding to cells expressing recombinant ␣IIb␤3 receptors demonstrated that: (i) swapping select murine for human ␣IIb sequences does not decrease 7E3 binding (7), (ii) removing the specificity determining loop (SDL) (K156-G189 sequence) from ␤3 results in loss of 7E3 binding (8), (iii) swapping the murine for human C177-C184 sequence within the SDL region in ␤3 results in loss of 7E3 binding (7), and (iv) swapping the murine S129-T133 sequence for the human W129-N133 sequence results in partial loss of 7E3 binding (7).The above human͞mouse swapping studies identified regions within ␤3 that affect 7E3 binding, but the biochemical and functional properties of these chimeric receptors were not characterized. In addition, the W129-N133 region contains two amino acid differences between human ␤3 (␤3Hu) and mouse ␤3 (␤3M) and the C177-C184 region contains three amino acid differences (Table 1). To define further the regions on ␣IIb␤3 th...

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Section: Discussionmentioning

confidence: 84%

Integrin β3 regions controlling binding of murine mAb 7E3: Implications for the mechanism of integrin αIIbβ3 activation

Artoni

Mitchell

et al. 2004

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

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“…9,10 Second, work with other GP IIb/IIIa inhibitors (particularly abciximab) in animals suggested that Ͼ80% platelet inhibition prevented platelet-induced thrombosis in stenotic coronary arteries and similar models. 11,12 Whereas Ͼ80% platelet inhibition nearly eliminated platelet aggregation, the bleeding times only became prolonged to Ͼ15 to 30 minutes when receptor blockade was Ͼ90%. 13,14 The first dose-finding studies of eptifibatide were designed to identify doses that also achieved Ͼ80% inhibition of platelet aggregation.…”

Section: Discussionmentioning

confidence: 99%

Pharmacodynamics and Pharmacokinetics of Higher-Dose, Double-Bolus Eptifibatide in Percutaneous Coronary Intervention

et al. 2001

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Background-Pharmacodynamics of eptifibatide, a cyclic heptapeptide antagonist of platelet glycoprotein IIb/IIIa, are substantially altered by anticoagulants that chelate calcium, resulting in overestimation ex vivo of the in vivo effects of this agent. We conducted a dose-ranging study to characterize the pharmacodynamics and pharmacokinetics of eptifibatide under physiological conditions. Methods and Results-Patients (nϭ39) undergoing elective percutaneous coronary intervention were randomly assigned to an eptifibatide bolus followed by an infusion (180-g/kg bolus followed by 2 g/kg per minute or 250-g/kg bolus followed by 3 g/kg per minute) for 18 to 24 hours. In a 2:1 ratio, these patients received either a second bolus of eptifibatide (90 g/kg or 125 g/kg for the initial 180-g/kg or 250-g/kg groups, respectively) or placebo 30 minutes after the initial bolus. Bleeding times, ex vivo platelet aggregation, receptor occupancy, and plasma eptifibatide levels at baseline and at 1, 2, 3, 4, 6, and 8 hours were evaluated. Platelet inhibition was dose dependent and Ͼ80% in all groups by steady state. The single-bolus regimens had a transient loss of inhibition at 1 hour, consistent with rapid distribution and drug elimination. Pharmacokinetic modeling suggested that optimal dosing of eptifibatide would be obtained with a 180-g/kg bolus and a 2-g/kg per minute infusion followed by a second 180-g/kg bolus 10 minutes later. Conclusions-

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“…Pathological examination of the material responsible for reocclusion in this model revealed that it consisted of a platelet-rich thrombus, possibly of similar composition to the thrombolysis-insensitive material responsible for reocclusion in humans. 33 Using the present experimental model, we have investigated the effect of an aspirin and prostacyclin analogue on protection against reocclusion after coronary thrombolysis. Simultaneous or individual use of heparin as an anticoagulant and aspirin as an antiplatelet drug did not overcome this situation.…”

Section: Discussionmentioning

confidence: 99%

Cilostazol, a novel cyclic AMP phosphodiesterase inhibitor, prevents reocclusion after coronary arterial thrombolysis with recombinant tissue-type plasminogen activator.

Saitoh

Saito

Otake

et al. 1993

Arterioscler Thromb

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Inhibitors of cyclic nucleotide phosphodiesterase hydrolysis of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate are known to inhibit platelet aggregation, which plays an important role in acute reocclusion after thrombolysis in acute myocardial infarction. In the present study of a canine preparation of coronary artery thrombosis superimposed on high-grade stenosis, we tested whether the antithrombotic agent cilostazol, an inhibitor of cAMP phosphodiesterase, could prevent acute reocclusion or sustain coronary blood flow after thrombolysis when used with recombinant tissue-type plasminogen activator (rt-PAJ and heparin. Intravenous infusion of rt-PA (0.5 mg/kg body wt for 30 minutes) and heparin (a 150 11)/kg body wt i.v. bolus and then 25 IU/kg body wt per hour i.v.) was combined with cilostazol (0.6 or 1.8 mg/kg body wt for 60 minutes). Without cilostazol, reperfusion was observed in seven of eight dogs, but reocclusion occurred in six of these seven dogs after 9±2 minutes. After administration of 1.8 mg/kg body wt cilostazol (group B-2; a 120-minute observation after the start of rt-PA infusion), reperfusion occurred in all seven dogs (p<0.05 versus control group), and brief cyclic reocclusion was observed in only one dog 63 minutes after reperfusion. At the same dose of cilostazol (group B-2L; a 240-minute observation after the start of rt-PA infusion), reperfusion occurred in all five dogs (p<0.05 versus control group), and coronary blood flow was well maintained except for one short reocclusion in one dog. Cilostazol inhibited cyclic flow reduction in a dose-dependent fashion. We conclude that cilostazol is a new potent antiplatelet agent for preventing reocclusion after coronary thrombolysis, when used in combination with rt-PA and heparin. (

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Rapid and sustained coronary artery recanalization with combined bolus injection of recombinant tissue-type plasminogen activator and monoclonal antiplatelet GPIIb/IIIa antibody in a canine preparation.

Cited by 402 publications

References 24 publications

Integrin β3 regions controlling binding of murine mAb 7E3: Implications for the mechanism of integrin αIIbβ3 activation

Integrin β3 regions controlling binding of murine mAb 7E3: Implications for the mechanism of integrin αIIbβ3 activation

Pharmacodynamics and Pharmacokinetics of Higher-Dose, Double-Bolus Eptifibatide in Percutaneous Coronary Intervention

Cilostazol, a novel cyclic AMP phosphodiesterase inhibitor, prevents reocclusion after coronary arterial thrombolysis with recombinant tissue-type plasminogen activator.

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