Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q9UID3 (FFR)
 233 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A decision to perform coronary angioplasty on a constricted coronary artery should always be preceded by objective evidence of myocardial ischaemia in the flow region concerned. However, for patients with multi-vessel coronary disease it can be difficult to determine which of the several coronary stenoses present is responsible for the anginal complaints. Recently, special miniaturized sensor-equipped guide wires are introduced in the cardiac catheterisation laboratory. Therefore it is now possible to selectively evaluate coronary stenoses by means of haemodynamic parameters: fractional flow reserve (FFR, based on intracoronary derived pressure measurements) and coronary flow velocity reserve (CFVR, based on intracoronary derived Doppler flow velocity measurements). The diagnosis of coronary artery disease in the cardiac catheterisation laboratory has improved considerably due to the use of these intracoronary derived haemodynamic parameters. Several clinical studies have shown that it is safe to defer a coronary angioplasty based on an FFR > or = 0.75 or a CFVR > or = 2.0. In the case of an abnormal FFR or CFVR result, the appropriate treatment strategy can be implemented. Furthermore, these parameters can be used to evaluate the result of the therapy.
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PMID:[Fractional and coronary flow reserve: intracoronary diagnosis of coronary artery disease]]. 1158 40

Tissue factor (TF) is the essential cofactor for the coagulation protease factor VIIa (FVIIa), initiating the coagulation cascade. The role of TF in thrombotic diseases is becoming increasingly evident. Recent findings suggest that inhibition of TF/FVIIa activity could be important in the prevention of clinical sequelae associated with plaque rupture or vessel damage that exposes TF to blood. Furthermore, selective inhibitors of TF/FVIIa may be associated with less bleeding risk than other antithrombotic agents. Several TF/FVIIa inhibitors are in development, including the protein-based inhibitors (such as NAPc2, Corsevin M, FFR-FVIIa, and Tifacogin). Research into the development of small molecule inhibitors is on-going, but is at a less advanced stage.
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PMID:The role of tissue factor/factor VIIa in the pathophysiology of acute thrombotic formation. 1171 90

Factor VIIIa consists of three subunits designated A1, A2, and A3-C1-C2. The isolated A2 subunit possesses limited cofactor activity in stimulating factor IXa-catalyzed activation of factor X. This activity is markedly enhanced by the A1 subunit (inter-subunit K(d) = 1.8 microm). The C-terminal region of A1 subunit (residues 337-372) is thought to represent an A2-interactive site. This region appears critical to factor VIIIa, because proteolysis at Arg(336) by activated protein C or factor IXa is inactivating. A truncated A1 (A1(336)) showed similar affinity for A2 subunit (K(d) = 0.9 microm) and stimulated its cofactor activity to approximately 50% that observed for native A1. However, A1(336) was unable to reconstitute factor VIIIa activity in the presence of A2 and A3-C1-C2 subunits. Fluorescence anisotropy of fluorescein (Fl)-FFR-factor IXa was differentially altered by factor VIIIa trimers containing either A1 or A1(336). Fluorescence energy transfer demonstrated that, although Fl-A1(336)/A3-C1-C2 bound acrylodan-A2 with similar affinity as the native dimer, an increased inter-fluorophore separation was observed. These results indicate that the C-terminal region of A1 appears necessary to properly orient A2 subunit relative to factor IXa in the cofactor rather than directly stimulate A2 and elucidate the mechanism for cofactor inactivation following cleavage at this site.
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PMID:Cofactor activities of factor VIIIa and A2 subunit following cleavage of A1 subunit at Arg336. 1179 30

Initiation of coagulation by tissue factor (TF) is a potentially powerful regulator of local inflammatory responses. We hypothesized that blockade of TF-factor VIIa (FVIIa) complex would decrease lung inflammation and proinflammatory cytokine release after tracheal instillation of Escherichia coli lipopolysaccharide (LPS 0111:B4). At the time of injury, rats received one dose of site-inactivated FVIIa (FFR-FVIIa) or saline intravenously. At 0, 6,12, 24, and 48 h after injury, lungs were examined for histologic changes and bronchoalveolar lavage (BAL) was performed to assess protein, lactate dehydrogenase (LDH) activity, cell counts, and cytokine levels. LPS-injured rats treated with FFR-FVIIa showed decreased intra-alveolar inflammation and fibrin deposition by light microscopy compared with untreated rats. This was accompanied by decreased protein leakage (P < 0.0001), LDH activity (P < 0.0001), and local elaboration of interleukin (IL)-1beta, IL-6, and IL-10 (all P < 0.0001), but not tumor necrosis factor (TNF)-alpha. Protection was associated with reduction of TF mRNA expression in whole lung, but not with changes in nuclear translocation of nuclear factor (NF)-kappaB. FFR-FVIIa given 6 h after LPS afforded equivalent lung protection. Therefore, blockade of TF-FVIIa complex protects the lung from injury by LPS in part by reducing local expression of proinflammatory cytokines and may offer promise for therapy of acute lung injury.
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PMID:Extrinsic coagulation blockade attenuates lung injury and proinflammatory cytokine release after intratracheal lipopolysaccharide. 1203 63

Recombinant human FVIIa (rFVIIa) was inactivated by coupling Phe-Phe-Arg-CK- (FFR) covalently to the active site of the enzyme. To test the chemically-modified human protein for potential antigenicity prior to clinical trial an immune-tolerant rat model was established. Intraperitoneal injection of the parent compound, human rFVIIa, within 30 h after birth, followed by repeated subcutaneous challenge with rFVIIa in Freunds incomplete adjuvant resulted in 79% non-responding rats at day 32. Monthly subcutaneous challenge showed that the induced tolerance was stable over the 3 months study period in 80% of the rats. The clinically relevant route, intravenous administration, was used for evaluating the potential antigenicity of FFR-rFVIIa. Repeated intravenous administration of different dosages of FFR-rFVIIa did not break tolerance, indicating that FFR-rFVIIa might not be antigenic, for a limited number of intravenous administrations in a clinical setting.
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PMID:Evaluation of potential antigenicity of active-site-inhibited recombinant human FVIIa (FFR-rFVIIa) in an immune-tolerant rat model. 1203 86

To investigate the vascular endothelial dysfunction in the insulin resistance syndrome, muscarinic and alpha2-adrenergic mediated relaxations were studied in the fructose-fed rat. Male Sprague-Dawley rats were fed either fructose-rich chow (FFR, n=14) or normal chow (CNT, n=13) for 8 weeks. Systolic blood pressure (SBP) was measured by the tail-cuff method. A 3 mm segment of mesenteric artery was cannulated and pressurized, pretreated with prazosin (10(-6) mol/l) and propranolol (3x10(-6) mol/l), then pre-contracted with serotonin (10(-6) mol/l). Endothelium-dependent relaxation was induced by addition of acetylcholine (ACh, 10(-9)-10(-4) mol/l) or a selective alpha2-agonist, B-HT 920 (10(-9)-10(-5) mol/l), with or without the nitric oxide (NO) synthase inhibitor, L-NAME (10(-4) mol/l). SBP was significantly elevated in FFR but not in CNT. Plasma triglyceride in FFT (241+/-115 mg/dl) was significantly (p<0.01) higher than in CNT (84+/-34 mg/dl). Insulin and insulin/glucose ratio were higher but not significantly. Plasma glucose was not different between the two groups. In the dose-response curves to ACh, maximum relaxation and ED50 were similar between FFR and CNT. Moreover, L-NAME shifted the dose-response curves similarly to the right in both groups. Dose-response curves to B-HT 920, however, showed less relaxation in FFR than in CNT (p<0.05). B-HT 920-induced relaxations were mostly abolished by L-NAME. It is concluded that endothelial alpha2-adrenergic relaxation, predominantly mediated by NO, is likely more sensitive to the development of insulin resistance than muscarinic receptor relaxation in this 8-weeks FFR model. This early impairment of endothelial alpha2-adrenergic relaxation may contribute to the development of hypertension and insulin resistance in the FFR.
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PMID:Impaired endothelial alpha-2 adrenergic receptor-mediated vascular relaxation in the fructose-fed rat. 1204 35

FFR-rFVIIa is an inactivated recombinant factor VIIa (rFVIIa) that inhibits the binding of factor VIIa to tissue factor (TF). It has been shown to prevent TF-induced thrombosis in animals. The present study is a substudy of the Active Site Inhibited Seven (ASIS) trial and examines the antithrombotic effect of 3 doses of FFR-rFVIIa in 24 patients undergoing percutaneous coronary intervention (PCI). Group 1 (n=9) received 400 microg/kg FFR-rFVIIa and 40 to 50 U/kg heparin, group 2 (n=7) received 200 microg/kg FFR-rFVIIa and 100 U/kg heparin, and group 3 (n=8) received 50 microg/kg FFR-rFVIIa and 100 U/kg heparin. Blood thrombogenicity was assessed as total thrombus area and fibrin deposition on the perfusion chamber at shear rate conditions typical of mild-moderate coronary stenosis. Baseline blood thrombogenicity was evaluated a day before PCI, after heparin administration. A second perfusion chamber study was performed just before PCI, 15 minutes after the administration of heparin and FFR-rFVIIa. Thrombus formation at a high shear rate was markedly reduced in groups 1 and 2 after drug administration, by 79% to 84% and 76% to 87%, respectively (P<0.004 [group 1], P<0.04 [group 2]). In group 3, moderate thrombus reduction of 46% to 48% was achieved (P<0.04). Fibrin deposition in all 3 groups was nearly eliminated after drug administration. Our data demonstrate that FFR-rFVIIa has a potent antithrombotic effect at different shear rates and severe arterial injury conditions.
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PMID:Antithrombotic effect of tissue factor inhibition by inactivated factor VIIa: an ex vivo human study. 1206 17

Widely used non-invasive stress modalities, like exercise ECG, MPS and stress-echocardiography, are the tests of first choice for the diagnosis of CAD. It has been shown in numerous studies that non-invasive assessment of perfusion abnormalities is an adequate strategy for risk stratification. Moreover, non-invasive stress testing should be performed before a diagnostic cardiac catheterization to document the presence of myocardial ischemia, as a prerequisite for coronary revascularization. Coronary angiography is the gold standard for identifying CAD; however this technique is limited in assessing functional severity of coronary narrowings ('illusion of luminology'; see also Figure 5). The recently introduced i.c. hemodynamic parameters (CFVR and FFR) can identify functional severity of specific lesions and have shown a good agreement with the results of non-invasive stress test in validation studies. Furthermore, there is accumulating evidence that it is safe to defer a PTCA procedure, based on normal FFR and CFVR values. As these indices are derived during an invasive cardiac catheterization procedure, its use is recommended during a so called 'ad hoc' PTCA setting. Furthermore, they are particularly useful for clinical decision making in patients with documented multivessel CAD, as both indices allow selective evaluation of coronary narrowings in different arteries. Revascularization procedures are costly and always have a potential risk. It is important to be aware that, using above mentioned methods, unnecessary interventions (lacking potential benefit) may be avoided.
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PMID:Adequate patient selection for coronary revascularization: an overview of current methods used in daily clinical practice. 1213 22

Objectives. After conventional balloon angioplasty (PTCA) for acute myocardial infarction in 77 patients (77 lesions), we used myocardial fractional flow reserve (FFR(myo)) to assess the endpoint of percutaneous coronary intervention (PCI) and to determine whether adjunctive stenting was required. Of these, a total of 37 lesions with FFR > or = 0.94 after PTCA received no further treatment (FFR-PTCA group), while the remaining 40 lesions (FFR < 0.94) underwent adjunctive stenting (FFR-stent group). A further 78 patients (78 lesions) comprised the control group; these patients underwent direct stenting without FFR measurement (stent-only group). The restenosis rate at 14-day discharge (mean time to discharge) was 5.1% in the two groups treated with FFR guidance (FFR-PTCA and FFR-stent), but was 0% in the control group (p = ns). There were no significant differences in reocclusion rates between the FFR-guided patients (1.7%) and the controls (0%). There was no incidence of in-hospital mortality or reinfarction in any of the groups. The number of balloons used (mean, 1.3 0.6 balloons for FFR patients versus 1.8 0.5 balloons for control patients) and the total cost of hospitalization and treatment ($16,213 versus $19,730 in U.S. currency; 1,945,571 998,726 yen versus 2,367,656 538,444 yen in Japanese currency) were both higher in the control group. Long-term survival rates were comparable in the two groups. These findings indicate that FFR guidance for PCI of acute myocardial infarction is a useful, low-cost technique that results in similar clinical outcomes as primary stenting.
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PMID:Usefulness of fractional flow reserve guidance for PCI in acute myocardial infarction. 1240 93

Originally isolated from a haematophagous hookworm, recombinant nematode anticoagulant protein c2 (rNAPc2) is an 85-amino acid protein with potent anticoagulant properties. Unlike conventional anticoagulants that attenuate blood coagulation via inhibition of thrombin or activated factor X (FXa) at the downstream portion of the cascade, rNAPc2 is a potent inhibitor of the activated factor VII/tissue factor complex (FVIIa/TF), the key physiological initiator of blood coagulation. Its mechanism of action requires prerequisite binding to circulating FXa or zymogen factor X (FX) to form a binary complex prior to its interaction and inhibition of membrane-bound FVIIa/TF. The binding of rNAPc2 to FX results in an elimination half-life of longer than 50 h following either subcutaneous or intravenous administration. Recombinant NAPc2, like other inhibitors of FVIIa/TF including tissue factor pathway inhibitor (TFPI) and active site-blocked FVIIa (ASIS, FFR-rFVIIa or FVIIai), may have a promising role in the prevention and treatment of venous and arterial thrombosis, as well as potential efficacy in the management of disseminated intravascular coagulopathies because of their potent and selective inhibition of FVIIa/TF.
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PMID:Recombinant nematode anticoagulant protein c2 and other inhibitors targeting blood coagulation factor VIIa/tissue factor. 1297 70


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