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)

Isometric contraction to direct supramaximal tetanic stimulation of the anterior tibialis (AT) muscle was measured in 50 New Zealand White rabbits after ischemia and reperfusion. Ischemia was produced unilaterally by collateral ligation and temporary inflow control until AT muscle function decreased to < 5% of contralateral (control) AT muscle and the ischemic interval was recorded. Reperfusion was carried out in one of the following ways: group I (n = 20), release of vascular clamps (blood reperfusion [BR]); group II (n = 10), release of vascular clamps and simultaneous intraarterial administration of 50,000 units of urokinase (urokinase reperfusion [UR]); group III (n = 10), release of vascular clamps and simultaneous administration of 50,000 units of urokinase and 28 mg (5 units) of purified rabbit plasminogen (urokinase plasminogen reperfusion [UPR]); and group IV (n = 10), animals defibrinated to < 50 mg/dl with ancrod prior to ischemia and received BR (ancrod blood reperfusion [ABR]). During reperfusion, function was recorded every 60 min for 2 hr. Recovery of experimental muscle function is expressed as the percentage of contralateral control limb function. The mean ischemic interval (mean +/- SEM), to achieve < 5% of contralateral control limb function, was 206.7 +/- 9.9, 209.5 +/- 16.6, 221.7 +/- 12.5, and 272.0 +/- 14.2 min for animals in groups I-IV, respectively. The mean experimental muscle function (mean +/- SEM) following the ischemic interval was 3.2 +/- 0.8, 4.5 +/- 1.4, 4.4 +/- 1.2, and 3.3 +/- 1.0 for groups I-IV, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effect of hypofibrinogenemia and fibrinolysis on skeletal muscle function after ischemia and reperfusion. 827 73

Stroke is one of the leading causes of death in the industrial nations of the world. Up to now, there has been no therapeutic strategy available which has been proven by controlled clinical trials. In the majority of acute stroke patients acute thrombosis contributes to carotid and vertebrobasilar arterial occlusions. Therefore, significant interest has focused on the possible value of fibrinolytic therapy in acute stroke. The principal goal is the rapid lysis of occluding thrombus with a minimum risk of intracranial or systemic hemorrhage. Clinical investigations on thrombolysis in cerebrovascular ischemia included different plasminogen-activators such as urokinase, streptokinase, and tissue plasminogen activator, either given systemically or locally via an intraarterial catheter. The pivotal trials conducted so far have revealed a wide range of recanalization rates, an acceptable safety and, also, encouraging effects on neurologic outcome. Thrombolysis itself carries the risk of intracranial bleeding, a practical limitation of this approach in acute stroke. On the other hand, hemorrhagic infarction and parenchymatous hematoma are natural consequences of thromboembolic stroke, possibly as a result of persistent occlusion of an artery. Hemorrhage following thrombolysis seems to show the same features seen in untreated patients and with an incidence similar to that in untreated patients. Future developments in thrombolysis in acute stroke should include improved early recruitment of patients, evaluation of noninvasive techniques in the pretreatment assessment of patients, the evaluation of advanced invasive techniques for delivery of the thrombolytic agent and assessment of combined treatment strategies. Clinical studies evaluating these strategies are currently under way.
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PMID:Thrombolytic intervention in acute thrombotic and embolic stroke. 832 15

Eight tests of hemostasis were measured in 233 horses with colic. Blood samples were obtained at admission and for 4 consecutive days of hospitalization. Data were analyzed retrospectively by outcome, by broad-category diagnosis group, by small intestinal disorder, and by smaller categories for comparing specific diseases. Nonsurviving horses and horses with the most severe forms of intestinal ischemia had changes interpreted as hypercoagulative, the intensity of which was increased on the first and second mornings (sample times 2 and 3) after admission, when most significant differences for results of specific tests were detected. Nonsurvivors had decreased antithrombin III activity and prolonged prothrombin and activated partial thromboplastin times; those with strangulating obstructions also had decreased protein C and plasminogen activities. During hospitalization and with survival, these changes tended to reverse. In most horses, regardless of diagnosis or outcome, concentration of fibrin degradation products and fibrinogen, and alpha 2-antiplasmin activity increased over time. Whether these changes reflected specific effects of colic or of the acute-phase response was not determined. In comparisons of small intestinal disorders (proximal enteritis, strangulations, and impactions), diagnostically distinguishing features were not found. Likewise, in comparisons of specific diseases (small vs large intestinal impaction, proximal enteritis vs colitis, small vs large intestinal obstruction), diagnostically distinguishing features were not found.
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PMID:Analysis of hemostasis in horses with colic. 840 38

Intravenous heparin is routinely given after thrombolytic therapy for patients with acute myocardial infarction in the United States and in some, but by no means all, other countries. Several trials have documented improved infarct-artery patency in patients treated with heparin; however, none was large enough individually to assess the effect of heparin on clinical outcomes. We performed a systematic overview of the 6 randomized controlled trials (1,735 patients) to summarize the available data concerning the risks and benefits of intravenous heparin versus no heparin after thrombolytic therapy. Mortality before hospital discharge was 5.1% for patients allocated to intravenous heparin compared with 5.6% for controls (relative risk reduction of 9%, odds ratio 0.91, 95% confidence interval 0.59 to 1.39). Similar rates of recurrent ischemia and reinfarction were observed among those allocated to heparin therapy or control. The rates of total stroke, intracranial hemorrhage, and severe bleeding were similar in patients allocated to heparin; however, the risk of any severity of bleeding was significantly higher (22.7% vs 16.2%; odds ratio 1.55, 95% confidence interval 1.21 to 1.98). There was no significant difference in the observed effects of heparin between patients receiving tissue-type plasminogen activator and those receiving streptokinase or anisoylated plasminogen streptokinase activator complex, or between patients who did and did not receive aspirin. The findings of this overview demonstrate that insufficient clinical outcome data are available to support or to refute the routine use of intravenous heparin therapy after thrombolysis. It is not known if these findings are due to lack of statistical power, inappropriate levels of anticoagulation, or lack of benefit of intravenous heparin. Large randomized studies of heparin (and of new antithrombotic regimens) are needed to establish the role of such therapy.
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PMID:Overview of randomized trials of intravenous heparin in patients with acute myocardial infarction treated with thrombolytic therapy. 861 Jun 1

The focus of new research efforts to improve the morbidity and mortality associated with acute myocardial infarction (AMI) has turned to adjuvant agents that show promise of improving outcomes following coronary thrombolysis. We enrolled 162 patients with AMI in a randomized trial comparing front-loaded tissue-plasminogen activator (t-PA) plus weight-adjusted heparin with anisoylated plasminogen streptokinase activator complex (APSAC) without heparin as well as standard-dose (325 mg) and low-dose (81 mg) aspirin. The primary end point was an in-hospital morbidity profile; secondary end points were clinical and angiographic potency and hemorrhagic events. Selected sites performed an electrocardiographic substudy to determine the time to 50% ST-segment recovery and the time to steady state. Although the trial was terminated when the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries-I trial showed that t-PA had a significant mortality advantage over streptokinase, important trends were evident. Patients given t-PA and heparin were better anticoagulated (p = 0.001), yet AP-SAC-treated patients had more bleeding complications. The primary end point favored t-PA (25.4% vs 31.3%), and the secondary end points were similar in both groups. In the electrocardiographic substudy, the t-PA group achieved both 50% ST-segment recovery and steady-state recovery sooner than the APSAC group. Patients taking low-dose aspirin had lower in-hospital mortality and less recurrent ischemia but more strokes than the standard-dose aspirin group. Thus, this trial demonstrated trends favoring front-loaded t-PA with weight-adjusted heparin over APSAC without heparin in the treatment of AMI. The use of low-dose aspirin did not appear to impose a loss of protection from adverse events, nor did standard-dose aspirin increase serious bleeding.
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PMID:A randomized factorial trial of reperfusion strategies and aspirin dosing in acute myocardial infarction. The DUCCS-II Investigators. 862 29

The use of fibrinolytic agents in acute ischemic stroke has received increasing attention due to the completion of several prospective studies examining the efficacy and safety of these drugs in this clinical setting. Experience with plasminogen activators indicates that recanalization of carotid and vertebrobasilar territory occlusion is feasible within 4-6 hours of symptom onset. The optimal plasminogen activator, its dose-rate and delivery system, however, is not known. The phase III trial of the European Cooperative Acute Stroke Study (ECASS) suggests potential modest benefit in outcome, although recombinant tissue plasminogen activator (rt-PA) had an increased risk of hemorrhage attributable to those patients with early CT-scan signs of ischemia. Complete cervical internal carotid artery occlusions by in situ thrombosis appear more resistant to thrombolysis than occlusions of the stem and major branches of the middle cerebral artery. The issue of hemorrhagic transformation is unsettled. It seams to be increased by delayed intervention on the one hand, but it is not different from that observed in placebo patients in phase I/II series.
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PMID:Thrombolysis in acute stroke. 871 49

Therapy for stroke is undergoing major changes. Many of the changes parallel the advances made in the therapy for myocardial infarction. Acute intervention with cytoprotective and thrombolytic agents is undergoing active investigation. Cytoprotective therapy includes drugs that act to prevent cell death during ischemia and reperfusion. These agents include calpain inhibitors, voltage-sensitive calcium- and sodium-channel antagonists, receptor-mediated calcium-channel antagonists [including N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) antagonists], glutamate-synthesis inhibitors, glutamate-release antagonists, gamma-aminobenzoic acid (GABA) antagonists, 5-HT (serotonin) receptor agonists, gangliosides, antioxidants, growth factors, antiapoptotic agents, and antiadhesion molecules. Thrombolysis is effective in myocardial infarction. Thrombolysis is undergoing evaluation in stroke with streptokinase, anisoylated plasminogen streptokinase activator complex (APSAC), tissue plasminogen activator (t-PA; including recombinant t-PA), urokinase, and single-chain urokinase (scu-PA). Both systemic and selective administration are being evaluated. Preventive therapy with both antiplatelet and anticoagulant drugs sheds new light on how best to stratify patients in terms of a risk-benefit ratio. Continuing public education will be essential as stroke therapy advances.
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PMID:Medical therapy for ischemic stroke. 877 66

Although heart attack is caused by occlusion of a major coronary artery, some patients have occlusion without heart attack because these patients have sufficient collateral circulation to provide an alternate pathway for blood supply to the myocardium at ischemic risk. The growth of new capillary vessels (angiogenesis) and enlargement of preexisting vessels play an important role in the collateral development. We evaluated the hypothesis that extracellular matrix metalloproteinase (MMP) expression is altered in coronary collateral arteries (0.5-1 mm o.d.) isolated from canine hearts 2-4 months after surgical placement of an ameroid occluder around the proximal left circumflex artery (n = 4), during the development of collateral vessels and restructuring new vessels. Histologic studies (hematoxylin and eosin, trichrome, and van Gieson stains) indicated cellular proliferation and increased collagen and elastin content in collateral vessels compared with comparable-sized unoccluded arterial segments of the left anterior descending (LAD) artery. In situ MMP activity of collateral vessels, measured using denatured collagen in the gel matrix, indicated an increase in total MMP activity in the intima of collateral vessels compared with normal LAD vessels. To further identify the type of MMP, tissue homogenates were prepared from collateral and LAD vessels and analyzed by SDS-PAGE zymography. The results suggest induction of gelatinase A and gelatinase B expression in collateral vessels compared with normal LAD tissue, when identical amounts of total protein were loaded onto each lane in the gel. Based on plasminogen-casein zymography, we observed the tissue plasminogen activator level to be increased in collateral vessels. On the basis of immunoblot and mRNA (Northern blot) analyses, we determined that the MMP-1 level was induced in collateral vessels 2 and 4 months after ameroid occlusion. In contrast with MMP-1, the level of TIMP-1 (tissue inhibitor of metelloproteinases) was decreased significantly (p < 0.001) in collateral compared with LAD vessels, suggesting a role for arterial TIMP in anti-angiogenic activity. Collectively, these results suggest that chronic occlusion of a major coronary artery induces upregulation of vascular remodeling mechanisms subserving collateral development. Increased MMP-2 activity in collaterals may be associated with decreased levels of tissue inhibitor of metalloproteinases and fibrous tissue remodeling following angiogenic and (or) adaptive responses of the myocardium to chronic ischemia.
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PMID:Temporal expression of extracellular matrix metalloproteinases and tissue plasminogen activator in the development of collateral vessels in the canine model of coronary occlusion. 896 Mar 89

Current protocols for use of tissue-type plasminogen activator in acute myocardial infarction include heparin estimated by the activated partial thromboplastin time (aPTT). Recent reports indicate a risk of recurrent ischemic events with long aPTT values. Longer aPTT values in the Thrombolysis in Myocardial Infarction-II (TIMI II) Trial, obtained within the first 48 hours, were associated with patency at 18 to 48 hours and better left ventricular function at discharge (average 9.6 days), but also with emergency catheterizations within the first 48 hours and, weakly, with recurrent ischemia during the first 18 hours. A moderate decrease in fibrinogen, compared with a "small" decrease, was also associated with patency, but a "large" decrease was associated with hemorrhagic events. Patency was associated with higher fibrinogen values and higher plasminogen values at baseline. The aPTT results support frequent monitoring during the first 24 to 48 hours to ensure optimal clinical outcome. The coagulation factor results suggest that there may be an optimum window for fibrinogenolysis in this setting.
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PMID:Relation of coagulation parameters to patency and recurrent ischemia in the Thrombolysis in Myocardial Infarction (TIMI) Phase II Trial. 945 18

The middle domain of plasma histidine-proline-rich glycoprotein (HPRG) contains unusual tandem pentapeptide repeats (consensus G(H/P)(H/P)PH) and binds heparin and transition metals. Unlike other proteins that interact with heparin via lysine or arginine residues, HPRG relies exclusively on histidine residues for this interaction. To assess the consequences of this unusual requirement, we have studied the interaction between human plasma HPRG and immobilized glycosaminoglycans (GAGs) using resonant mirror biosensor techniques. HPRG binding to immobilized heparin was strikingly pH-sensitive, producing a titration curve with a midpoint at pH 6.8. There was little binding of HPRG to heparin at physiological pH in the absence of metals, but the interaction was promoted by nanomolar concentrations of free zinc and copper, and its pH dependence was shifted toward alkaline pH by zinc. The affinity of HPRG for various GAGs measured in a competition assay decreased in the following order: heparin > dermatan sulfate > heparan sulfate > chondroitin sulfate A. Binding of HPRG to immobilized dermatan sulfate had a midpoint at pH 6.5, was less influenced by zinc, and exhibited cooperativity. Importantly, plasminogen interacted specifically with GAG-bound HPRG. We propose that HPRG is a physiological pH sensor, interacting with negatively charged GAGs on cell surfaces only when it acquires a net positive charge by protonation and/or metal binding. This provides a mechanism to regulate the function of HPRG (the local pH) and rationalizes the role of its unique, conserved histidine-proline-rich domain. Thus, under conditions of local acidosis (e.g. ischemia or hypoxia), HPRG can co-immobilize plasminogen at the cell surface as well as compete for heparin with other proteins such as antithrombin.
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PMID:Histidine-proline-rich glycoprotein as a plasma pH sensor. Modulation of its interaction with glycosaminoglycans by ph and metals. 948 72


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