The anti-platelet and anti-thrombotic effects of FK633, a peptide-mimetic antagonist

Aoki, Toshiaki; Cox, Dermot; Senzaki, Kayoko; Seki, Jiro; Tanaka, Akihito; Takasugi, Hisashi; Motoyama, Yukio

doi:10.1016/0049-3848(96)00016-3

Cited by 37 publications

(29 citation statements)

References 27 publications

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“…The current report evaluated, for the first time, the effect of GP IIb/IIIa antagonist on the neointimal hyperplasia in the model of coronary stenting, which closely mimicked the clinical interventions, and revealed that the drug was ineffective in reducing neointimal hyperplasia. The discrepancy in the results of the studies reported so far may be explained by the differences in (1) animal species, (2) type of injury, and (3) 10 our result is consistent with those of previous reports. Although the prevention of thrombus formation by anticoagulant drugs 16 -19 reduces the intimal thickening, we have shown that the continuous prevention of platelet aggregation by a GP IIb/IIIa antagonist does not reduce intimal thickening.…”

Section: Gp Iib/iiia Antagonists and Restenosis In Previous Reportssupporting

confidence: 68%

Glycoprotein IIb/IIIa Antagonist FK633 Could Not Prevent Neointimal Thickening in Stent Implantation Model of Canine Coronary Artery

Ueda

Kitakaze

Imakita

et al. 1999

ATVB

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Abstract-The platelet glycoprotein (GP) IIb/IIIa receptor antagonist appears to reduce the need for revascularization after coronary angioplasty. However, since the effect of GP IIb/IIIa receptor antagonist on the in-stent neointimal thickening has not been clarified, we examined it in the canine model. The beagle dogs were assigned to the control (nϭ7) or the GP IIb/IIIa receptor antagonist FK633 group (nϭ7). FK633 was administered by subcutaneous osmotic pumps (0.2 mg ⅐ kg Ϫ1 ⅐ h Ϫ1) and an intravenous bolus injection (1 mg/kg) before stenting. A coil stent was implanted in the left circumflex coronary arteries. The platelet aggregation capability was significantly (Ͻ5%) and consistently reduced by FK633 except for the mild elevation (10% to 30%) on the next day of stenting. Hearts were excised 3 months after stent implantation. The area of intima and media and the area stenosis were obtained from the sections of the stented arteries. The area of intima and media and the area stenosis (1.3Ϯ0.2 mm 2 , 41.8Ϯ7.5% and 1.3Ϯ0.2 mm 2 , 33.9Ϯ6.7% in the FK633 and the control group, respectively) were not different between the groups. We conclude that, although GP IIb/IIIa antagonist FK633 prevented the platelet aggregation significantly and consistently, it could not prevent the neointimal thickening after stent implantation in canine coronary artery. (Arterioscler Thromb Vasc Biol. 1999;19:343-347.) Key Words: restenosis Ⅲ platelet Ⅲ glycoprotein IIb/IIIa Ⅲ stent A lthough restenosis after coronary intervention has been a major issue for a long time, a viable or effective means of prevention has not been found. Several prospective randomized trials 1,2 revealed that coronary stents, which prevent elastic recoil and vascular remodeling, reduce the incidence of restenosis. However, in-stent restenosis is still observed in 20% to 30% of patients and is mainly attributable to neointimal thickening. [3][4][5][6] Although various drugs have proven effective in reducing neointimal thickening in animal experiments, no drug is clinically available at present to prevent restenosis. Although the platelet glycoprotein (GP) IIb/IIIa antagonists have been evaluated recently in clinical trials [7][8] and are reported to reduce the ischemic events after coronary angioplasty and need for revascularization, their effectiveness in preventing restenosis has been refuted by the increasing evidence from clinical trials so far.The current study was designed to evaluate the effect of GP IIb/IIIa antagonist FK633 9 -10 (Fujisawa Pharmaceutical Co) on neointimal thickening after stent implantation in canine coronary arteries. Methods Study ProtocolThe animal study was approved by the Animal Care and Use Committee of the Animal Research Institute of Osaka University. Fourteen specific-pathogen-free, one-year-old beagle dogs weighing 8 to 12 kg (Oriental Yeast Co, Tokyo, Japan) were randomly assigned to the FK633 group (nϭ7) or the control group (nϭ7). A day before the stent implantation, the platelet aggregation induced by 20 mol/L ADP (Sigma)...

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Section: Gp Iib/iiia Antagonists and Restenosis In Previous Reportssupporting

confidence: 68%

Glycoprotein IIb/IIIa Antagonist FK633 Could Not Prevent Neointimal Thickening in Stent Implantation Model of Canine Coronary Artery

Ueda

Kitakaze

Imakita

et al. 1999

ATVB

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“…Our results support the findings of these other workers in showing that IgG alone did not support platelet aggregation and that there is a requirement for fibrinogen. This latter conclusion is based on several pieces of evidence including our previous data showing that platelets from Glanzmann's thrombasthenia patients do not aggregate with NCTC 7863 (Ford et al, 1993), and, from this study, that antibody to GPIIb/IIIa inhibits platelet aggregation and that the specific fibrinogen receptor antagonist, FK633 (Aoki et al, 1996), also inhibited platelet aggregation. We showed that fibrinogen binds to the surface of NCTC 7863 during incubation in plasma but the role of this surface-bound fibrinogen in adhesion to and activation of platelets is unclear.…”

Section: Discussionmentioning

confidence: 98%

The role of immunoglobulin G and fibrinogen in platelet aggregation by Streptococcus sanguis

et al. 1997

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Summary.Previous work has shown that the type strain of Streptococcus sanguis, NCTC 7863, induces aggregation of normal platelets by a complement-dependent mechanism. We investigated the roles of IgG and fibrinogen in the aggregation process. Plasma depleted of IgG by passage through protein A-sepharose failed to support platelet aggregation, as did plasma absorbed at 0ЊC with whole bacteria. However, absorption of plasma with a non-aggregating strain of S. sanguis, SK96, did not remove aggregating activity for NCTC 7863. Supplementing 0ЊC-absorbed plasma with purified IgG restored the aggregation supporting activity. A monoclonal antibody to the FcgRII receptor inhibited platelet aggregation by the bacteria, indicating a requirement for bacteria-IgG complexes interacting with the Fc receptor in platelet aggregation. There was a lag time to the onset of platelet aggregation of 7-19 min depending upon the platelet donor, but the length of this lag did not correlate with either total IgG concentration recognizing NCTC 7863 in subjects' plasma, or the concentration any of the four IgG subclasses or with IgG avidity levels.Fibrinogen was shown to bind rapidly to the bacterial cell surface. Monclonal antibody to GPIIb/IIIa, RGDS peptide, and a specific antagonist for the platelet fibrinogen receptor, GPIIb/IIIa, FK633, inhibited platelet aggregation by NCTC 7863, indicating that platelet aggregation is fibrinogen dependent. These data suggest that platelet aggregation by some strains of S. sanguis requires multiple stimuli/agonists, including IgG-Fc receptor interaction, complement and fibrinogen.

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“…FK633 (N-(N-{4-(4-Amidinophenoxy)butyl}-a-L-aspartyl-L-valine), a peptidomimetic antagonist specific for ␣ IIb ␤ 3 , and Arg-Gly-Asp-Trp (RGDW) peptide were generously provided by Dr. Jiro Seki (Fujisawa Pharmaceutical Co., Osaka, Japan) (37).…”

Section: Methodsmentioning

confidence: 99%

“…We then examined the dose-dependent induction of AP5 epitope by RGDW peptide or a peptidomimetic FK633. FK633 is a high affinity, ␣ IIb ␤ 3 -selective, RGD mimetic, which, like RGDW, binds to nonactivated ␣ IIb ␤ 3 and inhibits platelet aggregation with a 50% inhibitory concentration (IC 50 ) of 110 nM ‫ف(‬ 160-fold more potent than RGDW) (37). As shown in Fig.…”

Section: Ko ␣mentioning

confidence: 99%

A two-amino acid insertion in the Cys146- Cys167 loop of the alphaIIb subunit is associated with a variant of Glanzmann thrombasthenia. Critical role of Asp163 in ligand binding.

Honda¹,

Tomiyama²,

Shiraga³

et al. 1998

J. Clin. Invest.

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The ligand binding site(s) of the ␣ subunit of integrin ␣ IIb ␤ 3 (GPIIb-IIIa), a prototypic non-I domain integrin, remains elusive. In this study, we have characterized a Japanese variant of Glanzmann thrombasthenia, KO, whose platelets express normal amounts of ␣ IIb ␤ 3 . KO platelets failed to bind the activation-independent ligand-mimetic mAb OP-G2 and did not bind fibrinogen or the activation-dependent ligand-mimetic mAb PAC-1 following activation of ␣ IIb ␤ 3 under any condition examined. Sequence analysis of PCR fragments derived from KO platelet mRNA revealed a 6-bp insertion leading to a 2-amino-acid insertion (Arg-Thr) between residues 160

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The anti-platelet and anti-thrombotic effects of FK633, a peptide-mimetic antagonist

Cited by 37 publications

References 27 publications

Glycoprotein IIb/IIIa Antagonist FK633 Could Not Prevent Neointimal Thickening in Stent Implantation Model of Canine Coronary Artery

Glycoprotein IIb/IIIa Antagonist FK633 Could Not Prevent Neointimal Thickening in Stent Implantation Model of Canine Coronary Artery

The role of immunoglobulin G and fibrinogen in platelet aggregation by Streptococcus sanguis

A two-amino acid insertion in the Cys146- Cys167 loop of the alphaIIb subunit is associated with a variant of Glanzmann thrombasthenia. Critical role of Asp163 in ligand binding.

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