Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0022116 (ischemia)
91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute peripheral arterial occlusion occurs as a result of thrombosis or embolism. A reduction in the prevalence of rheumatic heart disease accounts for a shift in the frequency of embolic to thrombotic occlusions. Also, a dramatic increase in the number of lower extremity arterial bypass graft procedures explains the predominance of graft occlusions in most recent series of patients with acute limb ischemia. While open surgical procedures remain the gold standard in the treatment of peripheral arterial occlusion, thrombolytic agents have been employed as an alternative to primary surgical revascularization in patients with acute limb ischemia. Systemic administration of thrombolytic agents, while effective for small coronary artery clots, fails to achieve dissolution of the large peripheral arterial thrombi. Catheter-directed administration of the agents directly into the occlusive thrombus is the only means of effecting early recanalization. Prior to 1999, urokinase was the sole agent used in North America for peripheral arterial indications, but the loss of the agent from the marketplace forced clinicians to turn to alternate agents, specifically alteplase and reteplase. Interest in the use of platelet glycoprotein inhibitors and mechanical thrombectomy devices also rose, coincident with the loss of urokinase from the marketplace. Most clinicians welcome the predicted return of urokinase to the marketplace. New investigative trials should be organized and executed to answer some of the remaining questions related to thrombolytic treatment of peripheral arterial disease. Foremost in this regard remains the question of which patients are best treated with percutaneous thrombolytic techniques and which are best treated with primary operative intervention. Ultimately, however, the thrombolytic agents are but one tool in the armamentarium of the vascular practitioner. This review is directed at providing the practicing clinician with the basic fund of knowledge necessary when determining the most appropriate intervention in a particular patient with peripheral arterial occlusion, be it thrombolytic therapy, percutaneous mechanical thrombectomy, primary surgical revascularization, or a combination of the three.
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PMID:Current status of thrombolysis for peripheral arterial occlusive disease. 1239 7

Duchenne muscular dystrophy is caused by mutations in the gene encoding dystrophin, a 427 kd protein normally found at the cytoplasmic face of the sarcolemma. In normal muscle, dystrophin is associated with a multimolecular glycoprotein complex. Primary mutations in the genes encoding members of this glycoprotein complex are also associated with muscular dystrophy. The dystrophin-glycoprotein complex provides a physical linkage between the internal cytoskeleton of myofibers and the extracellular matrix, but the precise functions of the dystrophin-glycoprotein complex remain uncertain. In this review, five potential pathogenetic mechanisms implicated in the initiation of myofiber injury in dystrophin-glycoprotein complex deficiencies are discussed: (1) mechanical weakening of the sarcolemma, (2) inappropriate calcium influx, (3) aberrant cell signaling, (4) increased oxidative stress, and (5) recurrent muscle ischemia. Particular emphasis is placed on the multifunctional nature of the dystrophin-glycoprotein complex and the fact that the above mechanisms are in no way mutually exclusive and may interact with one another to a significant degree.
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PMID:Molecular pathophysiology of myofiber injury in deficiencies of the dystrophin-glycoprotein complex. 1240 21

The early use of glycoprotein (GP) IIb/IIIa-receptor inhibitors in patients with non-ST-segment-elevation (NSTE) acute coronary syndromes (ACSs) is discussed. Unstable angina and NSTE myocardial infarction, collectively known as NSTE ACSs, are among the leading causes of morbidity and mortality in the United States. Updated guidelines from the American College of Cardiology and the American Heart Association for the management of NSTE ACSs strongly recommend that patients with intermediate- to high-risk features (e.g., ST-segment depression, elevated cardiac markers, and recurrent ischemia) be managed with an early invasive or other aggressive strategy (diagnostic angiography within 48 hours and, if warranted, percutaneous or surgical revascularization) and immediate treatment with a GP IIb/IIIa-receptor inhibitor. In low-risk patients, either an early invasive or an early conservative strategy (diagnostic angiography only for recurrent or refractory ischemia or a positive stress test result) is appropriate. For patients managed with an early conservative approach, the guidelines recommend GP IIb/IIIa-receptor inhibitor therapy with eptifibatide or tirofiban hydrochloride, especially in high-risk patients. Abciximab should not be used in patients in whom percutaneous coronary intervention is not planned. Greater implementation of the recommendations concerning the early use of GP IIb/IIIa-receptor inhibitors may result in reduced mortality rates. A large body of clinical evidence supports the updated ACC and AHA recommendations for managing patients with NSTE ACSs.
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PMID:Early use of glycoprotein IIb/IIIa-receptor inhibitors in non-ST-segment-elevation acute coronary syndromes. 1243 11

Changes in transcription factors (TFs) accompany many types of cell stresses. By using electrophoretic mobility assays we show that the DNA binding of signal transducer and activator of transcription 3 (STAT3) is activated in rat liver by heat shock and ischemia-reperfusion. Northern blot and Western blot analysis reveal an increase of the mRNA and protein level of this transcription factor. Under both conditions the phosphorylation of pre-existing STAT3 is prompt and precedes the increase in the STAT3 protein. The activation: (1) is functional, i.e. is followed by the transcription of the target gene alpha(1)-acid glycoprotein (2) is strongly inhibited by pretreatment with the interleukin-1 receptor antagonist before heat shock but only slightly by pretreatment before ischemia-reperfusion (3) might, at least in part, be mediated by a cytokine cascade involving also interleukin-6. These results are consistent with the hypothesis that different kinds of stress can activate a number of common TFs.
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PMID:Activation of signal transducer and activator of transcription 3 in rat liver after heat shock and reperfusion stress. 1253 Dec 44

The low-molecular-weight heparins (LMWHs) enoxaparin and dalteparin have shown superior and equivalent efficacy, respectively, over unfractionated heparin (UFH) in patients with unstable angina pectoris (UAP) or non-ST-segment elevation myocardial infarction (NSTEMI). This study aimed to identify markers of blood cell activation that are independent predictors of outcomes at 1 month and to compare the effects of enoxaparin, dalteparin, and UFH on any such markers. In this multicenter, prospective, open-label study, 141 patients with UAP or NSTEMI were randomized to treatment for 48 to 120 hours with enoxaparin (n = 46), dalteparin (n = 48), or UFH (n = 47). Blood samples were taken at the time of randomization and after > or =48 hours of treatment but before catheterization. Multivariate analysis identified increased plasma levels of von Willebrand factor (vWF) and decreased platelet levels of glycoprotein Ib/IX complexes as independent predictors of 1-month adverse outcome (a composite of death, myocardial infarction, and recurrent ischemia). vWF release was strongly related to and may have been released by inflammation as measured by C-reactive protein. Both LMWHs reduced the release of vWF in plasma (as well as C-reactive protein) compared with UFH. Enoxaparin had a more favorable effect on glycoprotein Ib/IX complexes than either dalteparin or UFH. The incidence of the composite clinical efficacy end point was: 13% (enoxaparin), 19% (dalteparin), and 28% (UFH). vWF and its receptor glycoprotein Ib/IX play a key role in acute coronary syndromes. vWF is linked to inflammation and, like glycoprotein Ib/IX, is affected more favorably by the LWMHs than by UFH.
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PMID:Comparison of effects on markers of blood cell activation of enoxaparin, dalteparin, and unfractionated heparin in patients with unstable angina pectoris or non-ST-segment elevation acute myocardial infarction (the ARMADA study). 1268 29

Vascular inflammation is central to the pathogenesis of acute coronary syndromes (ACS) and the response to vascular injury after percutaneous coronary intervention (PCI). For both ACS and PCI, the magnitude of vascular inflammation is linked to adverse late clinical outcomes (e.g., death, recurrent myocardial infarction [MI] or ischemia, and restenosis). Many pharmacologic therapies with demonstrated efficacy for the treatment of ACS have anti-inflammatory properties, which are distinct from their perceived primary mechanism of action. The anti-inflammatory effects of aspirin, clopidogrel, low-molecular-weight heparin (LMWH), platelet glycoprotein (GP) IIb/IIIa receptor inhibitors, statins, and angiotensin converting enzyme (ACE) inhibitors are reviewed, and the hypothesis is generated that modulation of vascular inflammation at least in part contributes a common basis for the long-term clinical benefit ascribed to these medications. A therapeutic algorithm based on clinical risk stratification and coronary revascularization strategy is proposed for incorporating the current American College of Cardiology (ACC)/American Heart Association (AHA) guideline recommendations for treatment of patients who present with non-ST-elevation ACS.
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PMID:Adjunctive pharmacotherapy before percutaneous coronary intervention in non-ST-elevation acute coronary syndromes: the role of modulating inflammation. 1460 16

Platelet activation and subsequent aggregation play a key role in the pathogenesis of ischemic brain damage. Recent studies revealed that enhanced platelet activation is also observed after ischemia, suggesting that secondary thrombus formation might participate in the development of cerebral infarction. The binding of platelet glycoprotein GPIIb/IIIa (integrin alpha(IIb)beta3) to fibrinogen is the final common pathway in platelet aggregation. Therefore, GPIIb/IIIa antagonists might be useful in acute ischemic stroke as well as in the secondary prevention of ischemic stroke. In the present study, we evaluated the effect of three compounds, FK419 ((S)-2-acetylamino-3-[(R)-[1-[3-(piperidin-4-yl) propionyl] piperidin-3-ylcarbonyl] amino] propionic acid trihydrate), a novel nonpeptide GPIIb/IIIa antagonist, ozagrel, a selective thromboxane A(2) synthase inhibitor, and argatroban, a thrombin inhibitor, on middle cerebral artery (MCA) patency and ischemic brain damage using photochemically induced MCA thrombosis model in guinea pigs. FK419, ozagrel, or argatroban was administered 5 min after the termination of photoirradiation. FK419 dose-dependently improved MCA patency by decreasing the total occlusion time, time to continuous reperfusion, and the number of cyclic flow reductions, at doses that inhibited ADP-induced platelet aggregation ex vivo. In contrast, ozagrel only improved total occlusion time, and argatroban showed no improvement in MCA patency. FK419 also reduced ischemic brain damage in a dose-dependent fashion, whereas ozagrel and argatroban did not. Finally, FK419 ameliorated neurological deficits, whereas ozagrel and argatroban did not. These results indicate that FK419, a GPIIb/IIIa antagonist, ameliorates ischemic brain damage by improving MCA patency after occlusion and that FK419 is a promising candidate for the treatment of acute ischemic stroke.
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PMID:Antithrombotic effects of FK419, a novel nonpeptide platelet GPIIb/IIIa antagonist, in a guinea pig photochemically induced middle cerebral artery thrombosis model: comparison with ozagrel and argatroban. 1463 48

The study sought to determine whether cerebral ischemia is associated with inflammatory reactions indicated by an increase in levels of selected acute phase proteins (APP), C-reactive protein (CRP), fibrinogen, alpha-1 antitrypsin (AAT) and acidic alpha-1 glycoprotein (AGP). These proteins are thought to be markers of inflammatory reactions. We investigated 30 patients with acute cerebrovascular ischemia, 20 patients with transient ischemic attack, and 20 patients from a control group. Levels of CRP, AAT, AGP, and fibrinogen in blood sera were determined in all patients by kinetic turbidimetry. In the patients with cerebral infarct an increase was found in the levels of APP, which suggests that ischemic necrosis is associated with inflammatory reactions. All patients require active treatment of an inflammatory process that is associated with stroke.
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PMID:Markers of inflammation in cerebral ischemia. 1465 49

Recombinant soluble human complement receptor type 1 (sCR1) is a highly glycosylated glycoprotein intended for use as a drug to treat ischemia-reperfusion injury and other complement-mediated diseases and injuries. sCR1-sLe(x) produced in the FT-VI-expressing mutant CHO cell line LEC11 exists as a heterogeneous mixture of glycoforms, a fraction of which include structures with one or more antennae terminated by the sialyl Lewis X (sLe(x)) [Neu5Acalpha2-3Galbeta1-4(Fucalpha1-3)GlcNAc]) epitope. Such multivalent presentation of sLe(x) was shown previously to effectively target sCR1 to activated endothelial cells expressing E-selectin. Here, we describe the use of the soluble, recombinant alpha2-3 sialyltransferase ST3Gal-III and the alpha1-3 fucosyltransferase FT-VI in vitro to introduce sLe(x) moieties onto the N-glycan chains of sCR1 overexpressed in standard CHO cell lines. The product (sCR1-S/F) of these in vitro enzymatic glycan remodeling reactions performed at the 10-g scale has approximately 14 N-glycan chains per sCR1 molecule, comprised of biantennary (90%), triantennary (8.5%), and tetraantennary (1.5%) structures, nearly all of whose antennae terminate with sLe(x) moieties. sCR1-S/F retained complement inhibitory activity and, in comparison with sCR1-sLe(x) produced in the LEC11 cell line, contained twice the number of sLe(x) moieties per mole glycoprotein, exhibited a twofold increase in area under the intravenous clearance curve in a rat pharmacokinetic model, and exhibited a 10-fold increase in affinity for E-selectin in an in vitro binding assay. These results demonstrate that in vitro glycosylation of the sCR1 drug product reduces heterogeneity of the glycan profile, improves pharmacokinetics, and enhances carbohydrate-mediated binding to E-selectin.
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PMID:Production of a complement inhibitor possessing sialyl Lewis X moieties by in vitro glycosylation technology. 1519 8

The combined use of a fibrinolytic and a platelet glycoprotein (GP) IIb/IIIa receptor inhibitor to target the fibrin and platelet components of occlusive thrombi offers the potential for more rapid and complete reperfusion in patients with acute myocardial infarction (MI), although there have been concerns about the safety of this combination therapy. Data from the recent GUSTO-V and the ASSENT-3 trials support the use of this regimen in that the 30-day death or nonfatal reinfarction rate (7 days) in GUSTO-V and death or in-hospital reinfarction or in-hospital refractory ischemia rate in ASSENT-3 were reduced (p = 0.001 and p = 0.0001, respectively). The need for revascularization in both these trials was also reduced significantly. There was no increased risk of intracranial hemorrhage or stroke with the combination therapy, but an increased rate of nonintracranial severe or major bleeding was observed. At present, patients aged > 75 years should not receive combination therapy. Further studies in subgroup patient populations are warranted.
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PMID:Considerations in combination therapy: fibrinolytics plus glycoprotein IIb/IIIa receptor inhibitors in acute myocardial infarction. 1529 36


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