Humans ; Platelet Aggregation Inhibitors ; therapeutic use ; Platelet Glycoprotein GPIIb-IIIa Complex ; antagonists & inhibitors

Integrin alphaIIbbeta3 of the platelet surfaces regulates the thrombosis formation. alphaIIbbeta3 binds to the RGD sequence (Arg-Gly-Asp) of fibrinogen, promotes the platelet aggregation and finally leads to the thrombus. We obtained the three-dimensional molecular structure of alphaIIbbeta3 using homology-modeling (modeller8v2 software), with integrin alphavbeta3 (pdb code 1JV2) as the template. Accordingly, a cyclic RGD(RGD-c) peptide was designed to bind alphaIIbbeta3 as an antagonist and to block the formation of thrombus. We added two amino acids X, Y to both sides of RGD-c. X and Y could bind to each other by disulfide bond that finally made RGD-c a cyclic peptide. The optimum structure of RGD-c was obtained from the energetic optimization processes. All amino acids were placed at the X and Y to conduct Molecular Docking to the integrin alphaIIbbeta3 We got the optimum structure of RGD-c by energetic optimization and the antagonistic combination analysis. The results might provide an insight into designing and screening integrin alphaIIbbeta3 antagonists.
Amino Acid Sequence ; Drug Design ; Humans ; Models, Molecular ; Oligopeptides ; chemistry ; Platelet Aggregation Inhibitors ; chemical synthesis ; chemistry ; Platelet Glycoprotein GPIIb-IIIa Complex ; antagonists & inhibitors ; chemistry

OBJECTIVETo observe the safety and efficiency of ultra-early glycoprotein IIb/IIIa receptor blockade tirofiban use in patients with acute ST-elevation myocardial infarction (STEMI) treated by primary percutaneous coronary intervention (PCI).

METHODSFrom April 2005 to April 2006, 158 consecutive AMI patients (117 males, mean age of 58.8 +/- 25.2 years) were randomly received tirofiban (10 microg/kg bolus i.v. followed by 0.15 microgxkg(-1)xmin(-1) for 36 hours) before PCI in emergency room (early, n = 78) or immediately before PCI in catheterization lab (late, n = 80). Clinical and angiographic features between 2 groups before and after PCI were analyzed.

RESULTSBaseline clinical characteristics before PCI were similar between the two groups. Tirofiban was administered 39.8 minutes earlier in early group than that in the late group. The TIMI 3 flow rate (23.1% vs. 10.0%, P = 0.032) and the combined TIMI 2 or 3 flow rate (39.7% vs. 23.8%, P = 0.040) at initial angiography before PCI were significantly higher in early group than that in late group. However, TIMI 3 flow rate, myocardial Blush grade or corrected TIMI frames immediately after PCI were similar between the groups. The combined incidence of death or recurrent MI as well as bleeding complications or thrombocytopenia rate during early follow-up were similar between the groups (P > 0.05).

CONCLUSIONSEarly initiation of tirofiban in patients with acute STEMI treated by primary PCI was safe. A better patency (TIMI 3 and TIMI 2-3 flow) in infarct related artery was obtained in patients with early tirofiban administration.

Adult ; Aged ; Angioplasty, Balloon, Coronary ; methods ; Electrocardiography ; Female ; Humans ; Male ; Middle Aged ; Myocardial Infarction ; physiopathology ; therapy ; Platelet Glycoprotein GPIIb-IIIa Complex ; antagonists & inhibitors ; Tyrosine ; administration & dosage ; analogs & derivatives

OBJECTIVETo evaluate the early clinical result of percutaneous transluminal coronary intervention (PCI) and stenting on saphenous vein grafts.

METHODSPercutaneous intervention was performed in 91 saphenous vein grafts in 64 patients. The data of clinical results during operation and hospitalization and that of other interventional assisting device were recorded in database and were analyzed.

RESULTSThe success rate of operation was 95.3%, non-Q wave myocardial infarction occurred in 1 patient (1.6%) and temporary no-reflow phenomenon occurred in 4 patients (6.3%) during operation. Reduced antegrade flow and ventricular fibrillation happened in 1 patient after stenting and normal antegrade flow obtained after cardiac compression and tracheal intubation and insertion of IABP. The distal protection devices were used in 7 patients (10.9%), X-sizer extraction system in 4 patients. Platelet glycoprotein IIb/IIIa receptor blockers were administered in 25 patients (35.9%). Non-Q wave myocardial infarction occurred in two cases, the incidence of major adverse clinical event was 3.1% during the period of hospitalization.

CONCLUSIONSThe instant success rate of PTCA and stenting of saphenous vein bypass grafts is high and recent clinical result is promising, but the middle and long term results remain to be further followed. The use of distal embolic protection device and GPIIb/IIIa receptor blockers may improve its prognosis.

Aged ; Angioplasty, Balloon, Coronary ; Coronary Artery Bypass ; Graft Occlusion, Vascular ; surgery ; Humans ; Male ; Middle Aged ; Platelet Glycoprotein GPIIb-IIIa Complex ; antagonists & inhibitors ; Saphenous Vein ; surgery ; Treatment Outcome

Batifiban, a synthetic cyclic peptide, is a potent platelet glycoprotein GPIIb/IIIa antagonist which may be useful in the treatment and prevention of acute coronary syndromes. The pharmacokinetics and pharmacodymanic (inhibition of platelet aggregation) effects, and tolerability of batifiban were investigated in healthy subjects following single bolus injection with doses of 55, 110, or 220 microg/kg, or multiple doses of an bolus followed intravenous infusion for 24 h (180 microg/kg plus 2.0 microg/min.kg, and 220 microg/kg plus 2.5 microg/min.kg) in this phase I clinical trial. Plasma levels of batifiban and areas under the curve were found to be proportional to doses. Batifiban was rapidly eliminated with a half-life of approximately 2.5 h. Significant differences were noted for plasma levels of batifiban and areas under the curve between males and females. No significant differences in the terminal half-life were found between males and females. Batifiban reversibly inhibited ex vivo platelet aggregation in a dose- and concentration-dependent manner, consistent with its mechanism as a GPIIb/IIIa antagonist. Single and multiple intravenous doses of batifiban were found to be safe and well tolerated in healthy subjects. These results support a bolus injection plus intravenous infusion regimen of batifiban for the treatment and prevention of acute coronary syndromes.
Injections, Intravenous ; Peptides, Cyclic/*pharmacokinetics ; Peptides, Cyclic/*pharmacology ; Platelet Aggregation Inhibitors/adverse effects ; Platelet Aggregation Inhibitors/*pharmacokinetics ; Platelet Aggregation Inhibitors/*pharmacology ; Platelet Glycoprotein GPIIb-IIIa Complex/*antagonists & inhibitors ; Young Adult

OBJECTIVETo analyze the risk factors related to in-hospital bleeding for patients with acute coronary syndrome (ACS).

METHODSClinical and therapeutic data of 3807 patients who were registered with acute coronary syndrome in SINO-GRACE in China from March 2001 to December 2007 were reviewed. A total of 57 patients were grouped to bleeding group and 234 out of the remaining 3750 patients without bleeding were randomly chosen and served as non-bleeding group. Hemorrhage-related factors were screened and compared between the two groups. Unitary logistic regression analysis was performed to detect the possible factors related to hemorrhage. Factors with P < 0.1 were further analyzed by stepwise regression method and multivariate conditional logistic regression analyses.

RESULTS(1) Age, history of coronary artery bypass graft (CABG), previous hemorrhage, renal failure and heart failure as well incidence of acute coronary syndrome were significantly higher in bleeding group than in non-bleeding group (all P ≤ 0.05). Patients were more often treated with clopidogrel and glycoprotein (GP) IIb/IIIa receptor antagonist in bleeding group than in non-bleeding group. (2) Single factor logistic regression analysis showed that age > 70 years, history of previous bleeding, renal failure, heart failure, clopidogrel and GP IIb/IIIa receptor antagonists use, non-ST-segment elevation myocardial infarction, inferior wall, lateral myocardial infarction, CABG were risk factors for bleeding (all P < 0.05). (3) Multivariate logistic regression analysis showed that history of renal failure (OR = 19.77, 95%CI 4.38 - 89.18, P < 0.01) and clopidogrel (OR = 19.77, 95%CI 4.38 - 89.18, P < 0.01) and GPIIb/IIIa receptor antagonist (OR = 343.57, 95%CI 40.39 - 999.99, P < 0.01) use were the independent risk factors for bleeding.

CONCLUSIONOur results show that renal failure history and clopidogrel and GPIIb/IIIa receptor antagonist use are independent risk factors for in-hospital bleeding in patients with acute coronary syndrome.

Acute Coronary Syndrome ; complications ; pathology ; Age of Onset ; Aged ; Female ; Hemorrhage ; etiology ; Hospitalization ; Humans ; Incidence ; Logistic Models ; Male ; Middle Aged ; Platelet Glycoprotein GPIIb-IIIa Complex ; antagonists & inhibitors ; Renal Insufficiency ; Risk Factors ; Ticlopidine ; analogs & derivatives ; therapeutic use

BACKGROUNDPrimary percutaneous coronary intervention (PCI) has been identified as the first therapeutic option for patients with acute ST-segment elevation myocardial infarction (STEMI). The strategy of transferring patient to a PCI center was recently recommended for those with acute STEMI who were present to PCI incapable hospitals, which include lack of facilities or experienced operators. In China, some local hospitals have been equipped with PCI facilities, but they have no interventional physicians qualified for performing primary PCI. This study was conducted to assess the feasibility, safety and efficacy of the strategy of transferring physician to a PCI-equipped hospital to perform primary PCI for patients with acute STEMI.

METHODSThree hundred and thirty-four consecutive STEMI patients with symptom presentation = 12 hours in five local hospitals from November 2005 to November 2007 were randomized to receive primary PCI by either physician transfer (physician transfer group, n=165) or patient transfer (patient transfer group, n=169) strategy. Door-to-balloon time, in-hospital and 30-day major adverse cardiac events (MACE, including death, non-fatal re-infarction, and target vessel revascularization) were compared between the two groups.

RESULTSBaseline characteristics between the two groups were comparable. Thrombolysis in myocardial infarction (TIMI) 3 flow was revealed in more patients in the physician transfer group at initial angiography (17.6% vs 10.1%, P<0.05). The success rate of primary PCI (96.3% vs 95.4%, P>0.05) and length of hospital stay were similar between the two groups ((15+/-4) days vs (14+/-3) days, P>0.05). In the physician transfer group, door-to-balloon time was significantly shortened ((95+/-20) minutes vs (147+/-29) minutes, P<0.0001) and more patients received primary PCI with door-to-balloon time less than 90 minutes (21.2% vs 7.7%, P<0.001). During hospitalization, MACE occurred in 6.7% and 11.2% of patients in the physician and patient transfer groups, respectively (P=0.14). At 30-day clinical follow-up, the occurrence rates of death, non-fatal re-infarction, and target vessel revascularization (TVR) were 3.6% vs 5.9%, 4.2% vs 8.9%, and 1.2% vs 2.4% in the physician and patient transfer groups, respectively (all P>0.05). The cumulative composite of MACE was significantly reduced (8.9% vs 17.2%, P=0.03) and MACE free survival (91.0% vs 82.9%, P<0.05) was significantly improved in the physician transfer group at 30 days.

CONCLUSIONThe strategy of transferring physician to local hospital to perform primary PCI for patients with acute STEMI is feasible, safe and efficient in reducing the door-to-balloon time and 30-day MACE rate.

Adult ; Aged ; Angioplasty, Balloon, Coronary ; Female ; Hospital Communication Systems ; organization & administration ; Humans ; Interdisciplinary Communication ; Male ; Middle Aged ; Myocardial Infarction ; therapy ; Patient Care Team ; Patient Transfer ; Platelet Glycoprotein GPIIb-IIIa Complex ; antagonists & inhibitors ; Time Factors

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid ; pharmacology ; Adolescent ; Adult ; Blood Platelets ; metabolism ; Calcium ; metabolism ; Chloride Channels ; antagonists & inhibitors ; Cytosol ; metabolism ; Dose-Response Relationship, Drug ; Female ; Humans ; Male ; Niflumic Acid ; pharmacology ; Oligopeptides ; pharmacology ; Platelet Aggregation ; drug effects ; Platelet Glycoprotein GPIIb-IIIa Complex ; antagonists & inhibitors

To investigate the effect of GST-KGDX (glutathione S-transferase-Lys-Gly-Asp-X) fusion protein, GP IIb/IIIa receptor antagonist, on platelet function in vitro. The KGDX (Lys-Gly-Asp-X) gene was assembled from 2 synthetic oligonucleotides, 36 bp in length, using BamH I and Xho I restriction enzyme sites at the end of the gene for cloning into the expression vector pGEX4T-1. Expression of fusion protein was directed by the tac promoter. The Escherichia coli DH5a contained the plasmid pGEX-4T-1-KGDX was expressed by 37 degrees C heat induction. The fusion protein of KGDX with glutathione S-transferase (GST-KGDX) was purified in one step from the bacterial lysate by glutathione-agarose beads for affinity chromatography. GST-KGDX was found to be soluble and abundant, the yield of 35 mg/L of cultures was obtained. The GST-KGDX was expressed in E. coli to a level of 48.02% of total cellular protein. GST-KGDX inhibited ADP-induced human platelet aggregation stronger than GST (P < 0.05 or < 0.01). In flow cytometry assay for fibrinogen binding, both GST and GST-KGDX inhibited platelet aggregation by binding with high affinity to GPIIb/IIIa. Mean fluorescence intensity of GST-KGDX fusion protein was significantly higher than that of GST. It is concluded that the GST-KGDX fusion protein can be produced by E. coli and used as an antiplatelet agent.
Adult ; Escherichia coli ; genetics ; Female ; Fibrinogen ; metabolism ; Flow Cytometry ; Glutathione Transferase ; pharmacology ; Humans ; Male ; Oligopeptides ; pharmacology ; Platelet Aggregation ; drug effects ; Platelet Aggregation Inhibitors ; isolation & purification ; pharmacology ; Platelet Glycoprotein GPIIb-IIIa Complex ; antagonists & inhibitors ; metabolism ; Recombinant Fusion Proteins ; biosynthesis ; isolation & purification ; pharmacology

BACKGROUND: Previously, the inhibition of coronary restenosis with Abciximab (ReoPro (R) ) -coated stent in a porcine model was reported. ReoPro (R) inhibits platelet aggregation, the proliferation of vascular smooth muscle cells and the inflammatory reaction. METHODS: A prospective randomized trial was performed to compare two types of stent for revascularization in the native coronary artery. The primary effective end points were major adverse coronary events (MACE) : cardiac death, acute myocardial infarction, target vessel revascularization (TVR) and restenosis at the 6-month clinical and angiographic follow-ups. RESULTS: One hundred and fifty-five patients were enrolled between August 2001 and June 2003. The mean ages (56.0 +/- 10.0 vs. 56.9 +/- 10.8 years), baseline diameter of stenosis and minimal luminal diameter were no different between the two groups. There was one myocardial infarction and revascularization during the hospital stay in control stent group. During the clinical follow-up there were two myocardial infarctions in control group. Follow-up coronary angiograms were performed in 62.3% (48/77) and 65.4% (51/78) of the coated and control groups, respectively. The diameter of stenosis and late loss were significantly less in the ReoPro (R) -coated stent group compared with the controls (16.4 +/- 5.8% vs. 34.3 +/- 6.1%, p=0.009; and 0.33 +/- 0.28 mm vs. 0.88 +/- 0.41 mm; p=0.002). The restenosis and TVR rates of the ReoPro (R) -coated stent were relatively lower compared with the control stent [14.6% (7/48) vs. 29.4% (15/51), p=0.062; and 9.2% (7/76) vs. 14.7% (11/75) ; p=0.327]. CONCLUSION: A ReoPro (R) -coated stent is safe, and may be effective in the prevention of coronary restenosis.
Antibodies, Monoclonal/pharmacokinetics/*therapeutic use ; Coated Materials, Biocompatible/pharmacokinetics/*therapeutic use ; Coronary Arteriosclerosis/*surgery ; Coronary Restenosis/epidemiology/prevention & control ; Female ; Humans ; Immunoglobulins, Fab/*therapeutic use ; Korea/epidemiology ; Male ; Middle Aged ; Platelet Aggregation Inhibitors/pharmacokinetics/*therapeutic use ; Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors ; Prospective Studies ; Research Support, Non-U.S. Gov't ; *Stents