GP Ilb/IIIa receptor

Ticlopidine inhibits the P2Yj2 platelet ADP receptor, thus inhibiting ADP-dependent activation of the GP Ilb/IIIa receptor. It has a slow onset of action and takes 3-7 days to reach its maximal antiplatelet effect. It is inactive in vitro and must undergo activation by the hepatic cytochrome p450 enzyme system. Secondary prevention trials have found that ticlopidine-treated patients have an estimated RRR of 33% for the composite endpoint of stroke, myocardial infarction, or vascular death after ischemic stroke. Significant adverse effects include bone marrow depression, rash, diarrhea, and thrombotic thrombocytopenic purpura. No clinical trials have studied ticlopidine for the treatment of stroke in the acute phase. 

Junghans and Siebler reported a series of 24 patients with recent stroke or TIA due to LAA and detected ES on TCD who were treated acutely with intravenous tirofiban, a GP Ilb/IIIa receptor antagonist. Median ES rate at baseline was 38 signals per hour. ES were abolished by tirofiban in all patients, and returned following cessation of infusion. Although preliminary, these data support the rationale for trials of acute GP Ilb/IIIa receptor blockade in patients with recently symptomatic LAA awaiting CEA. 

Early pharmacotherapy for NSTE ACS is similar to that for STE ACS except that (1) fibrinolytic therapy is not administered (2) GP Ilb/IIIa receptor blockers are administered to high-risk patients and (3) there are no standard quality performance measures for patients with NSTE ACS with UA. 

Mechanism of Action A glycoprotein Ilb/IIIa receptor inhibitor that rapidly inhibits platelet aggregation by preventing the binding of fibrinogen to GP Ilb/IIIa receptor sites on platelets. Therapeutic Effect Prevents closure of treated coronary arteries. Prevents acute cardiac ischemic complications. 

A. General description Abciximab is the Fab fragment of the chimeric human-murine monoclonal antibody 7E3. It binds to the glycoprotein (gp) Ilb/IIIa receptor of human platelets and inhibits platelet aggregation. The chimeric antibody is produced by continuous perfusion in mammahan cell-culture. The 48kDa F b fragment is purified from cell-culture supernatant. 

Pharmacokinetics Abciximab has an initial half-life of about 10 minutes and a second phase half-hfe of about 30 minutes, probably related to rapid binding to the platelet gp Ilb/IIIa receptors. Although abciximab remains in the circulation for up to 10 days in a platelet-bound state, platelet function generally recovers over the course of 48 hours. 

Coller BS, Smith SR, Scudder LE et al. (1989) Abolition of in vivo platelet thrombus formation in primates with monoclonal antibodies to the platelet GP Ilb/IIIa receptor correlation with bleeding time, platelet aggregation and blockade of GP Ilb/IIIa receptors. Circulation 80 1766-1774... 

Shebuski RJ, Storer BL, Fujita T (1988) Effect of thromboxane synthetase inhibition on the thrombolytic action of tissue-type plasminogen activator in a rabbit model of peripheral arterial thrombosis. Thromb Res 52 381-392 Yasuda T, Gold HK, Fallon JT et al. (1988) Monoclonal antibody against the platelet glycoprotein (GP) Ilb/IIIa receptor prevents coronary artery reocclusion after reperfusion with recombinant tissue type plasminogen activator. J Clin Invest 81 1284-1291... 

Frojmovic MM, Wong T, Searcy GP. Platelets from bleeding Simmental cattle have a long dday in both ADP-activated expression of Gp Ilb-IIIa receptors and fibrinogat-dq>endent platdet aggregation. Thrombos Haanost 1996 76 1047-1052. 

Abciximab is a first-line GP llb/Illa receptor inhibitor for patients undergoing primary PCF " who have not received fibrinolytics. It should not be administered for medical management of the ST-segment-elevation ACS patient who will not be undergoing PCI. Abciximab is preferred over eptifibatide and tirofiban in this setting because abciximab is the most common GP Ilb/IIIa receptor inhibitor studied in primary PCI trials.Abciximab, in combination with aspirin, a thienopyridine, and UFH (administered as an infusion for the duration of the procedure), has been shown to reduce the risk of reinfarction" " " and need for repeat PCI in ST-segment-elevation ACS clinical trials. 

GP Ilb/IIIa receptor blockers are administered to high-risk patients for medical therapy as well as for PCI patients. 

The role of GP Ilb/IIIa receptor antagonists in patients with non-ST-segment-elevation ACS undergoing PCI also was evaluated in two large clinical trials that used GP Ilb/IIIa receptor blockers initiated at... 

As emphasized in the ACC/AHA guidelines, the benefits of GP Ilb/ina receptor blockers are greater in patients undergoing PCI. A recent meta-analysis estimates that 30 adverse outcomes (either death or MI) are prevented for every 1000 patients treated with a GP Ilb/IIIa receptor blocker before PCI, whereas only 4 events are prevented for medical management of non-ST-segment-elevation ACS patients using GP nb/nia receptor blockers without PCI. This translates into a number needed to treat 32 patients to prevent 1 event if a GP Ilb/inareceptor blocker is administered before PCI and 250 patients to prevent 1 event if it is administered as medical therapy without PCI. ... 

Once bound to the platelet, the fibrinogen polymers may induce platelet activation via rearrangement of the GP Ilb/IIIa receptors. According to the mobile receptor hypothesis of Jacobs and Cuatrecasas... 

Refino, C. J. et al.. Pharmacokinetics, pharmacodynamics, and tolerability of a potent, non-peptidic, GP Ilb/IIIa receptor antagonist following multiple oral administration of a prodrug form, Thromb. Haemost, 79 169-176, 1998. 

Lindmark, S. G. Panzer-Knodle, N. S. Nicholson, B. B. Taite, A. K. Salyers, L. W. King, J. G. Campion, and L. P. Feigen, /. Med. Chem., 36, 1811 (1993). Potent In Vitro and In Vivo Inhibitors of Platelet Aggregation Based Upon the Arg-Gly-Asp-Phe Sequence of Fibrinogen. A Proposal on the Nature of the Binding Interactions Between the Arg-Guanidine of the RGDX Mimetics and the Platelet GP Ilb-IIIa Receptor. 

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