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)

Presented are the clinical data of 18 consecutive patients who were treated by IV recombinant tissue plasminogen activator (r-TPA) for suspected vertebrobasilar (VB) acute ischemia within 7 hours. The mean delay for treatment was 5 +/- 3.6 hours. Mean baseline NIH Stroke Scale score was 17 +/- 4. At 3 months, 10 patients were independent (modified Rankin Scale [mRS] score = 0 to 2), whereas 8 patients showed a poor outcome (mRs = 3 to 6). IV r-TPA in VB ischemia in a 7-hour window may be safe and efficient.
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PMID:Intravenous r-TPA in vertebrobasilar acute infarcts. 1515 94

In France, the incidence of meningococcal infections is increasing and the most severe presentation, called purpura fulminans, has still a death rate of 20-25%. Diagnosis of invasive meningococcal infection must be evoked in any child presenting with febrile purpura (vasculitic rash not disappearing with "tumbler test"); a fulminating form must be suspected in the presence of only one ecchymosis and signs of infection, remembering that recognition of shock is difficult in children. The Health Authority recommend to administer a third generation cephalosporin promptly for any child with signs of infection and an ecchymotic purpura (>3 mm of diameter), and then to refer the patient to the hospital. Children with purpura fulminans should be referred to a paediatric intensive care unit. Management includes antibiotics, steroids, fluid resuscitation and catecholamines (be aware of hypoglycaemia, particularly in infants, and hypocalcaemia). Treatment of cutaneous necrosis and distal ischemia is difficult and still controversial: antithrombin, protein C, tissue plasminogen activator and vasodilator infusion have no proved efficacy. Cases must be rapidly notified to the Public Health Service who will institute chemoprophylaxis for close contacts. Given the predominance of serogroup B in France, we hope that an efficient vaccine will soon become available.
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PMID:[Meningococcal purpura fulminans in children]. 1529 72

Ischemic stroke is a major cause of mortality and morbidity in industrialized countries and is almost always caused by occlusion of a cerebral artery by a clot. As the reversibly injured brain tissue evolves into irreversible infarction within a short period of time after onset of ischemia, it is extremely important and urgent to reverse the serious consequences of brain ischemia in the hyperacute phase when the ischemic brain tissue is still salvageable. Numerous thrombolytic and potentially neuroprotective agents have been studied in stroke patients with little success as the only approved therapy is thrombolysis with recombinant tissue plasminogen activator (r-tPA) within 3 h of stroke onset in highly selected patients (approximately 5 to 10 % of all acute stroke patients). One major obstacle in the development of effective therapies for ischemic stroke has been the lack of versatile imaging techniques. New magnetic resonance imaging (MRI) modalities, specially diffusion- and perfusion-weighted MRI (DWI and PWI, respectively) have been used in experimental studies with great success for over a decade and now are gradually entering clinical use. DWI and PWI can detect brain ischemia in the early phase in its full extent thus ensuring a definite diagnosis, allowing for follow-up of the ischemic lesion size over time with good spatial and temporal resolution, demonstrating perfusion deficit and reperfusion and the existence and the extent of penumbra while only requiring a few minutes of imaging time. DWI and PWI do not just give us the correct diagnosis of ischemic stroke, but allow us to acquire in vivo lesion size before therapeutic regimen is started and monitor the therapeutic efficacy thereafter, thus overcoming the potential pretreatment bias. We used DWI and PWI to evaluate novel therapeutic approaches for ischemic stroke in numerous experimental studies and lately in humans. With DWI and PWI, we are able to determine the in vivo efficacy (or lack of efficacy) of new therapeutic regiments (both neuroprotective and thrombolytic agents, or combination therapies) in a rapid, safe, and reliable way and in a relatively small number of well-selected, well-defined, and homogeneous patients. This approach may, therefore, significantly accelerate the development of new remedies for stroke patients.
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PMID:The role of diffusion- and perfusion-weighted magnetic resonance imaging in drug development for ischemic stroke: from laboratory to clinics. 1532 Aug 14

To increase the sensitivity of MRI parameters to detect tissue damage of ischemic stroke, an unsupervised analysis method, Iterative Self-Organizing Data Analysis Technique Algorithm (ISODATA), was applied to analyze the temporal evolution of ischemic damage in a focal embolic cerebral ischemia model in rat with and without recombinant tissue plasminogen activator (rt-PA) treatment. Male Wistar rats subjected to embolic stroke were investigated using a 7-T MRI system. Rats were randomized into control (n=9) and treated (n=9) groups. The treated rats received rt-PA via a femoral vein at 4 h after onset of embolic ischemia. ISODATA analysis employed parametric maps or weighted images (T1, T2, and diffusion). ISODATA results with parametric maps are superior to ISODATA with weighted images, and both of them were highly correlated with the infarction size measured from the corresponding histological section. At 24 h after embolic stroke, the average map ISODATA lesion sizes were 37.7+/-7.0 and 39.2+/-5.6 mm2 for the treated and the control group, respectively. Average histological infarction areas were 37.9+/-7.4 mm2 for treated rats and 39.4+/-6.1 mm2 for controls. The R2 values of the linear correlation between map ISODATA and histological data were 0.98 and 0.96 for treated and control rats, respectively. Both histological and map ISODATA data suggest that there is no significant difference in infarction area between non-treated and rt-PA-treated rats when treatment was administered 4 h after the onset of embolic stroke. The ISODATA lesion size analysis was also sensitive to changes of lesion size during acute and subacute stages of stroke. Our data demonstrate that the multiparameter map ISODATA approach provides a more sensitive quantitation of the ischemic lesion at all time points than image ISODATA and single MRI parametric analysis using T1, T2 or ADCw.
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PMID:Multiparametric ISODATA analysis of embolic stroke and rt-PA intervention in rat. 1533 14

Three cases of local thrombolysis in the treatment of acute lower limb ischemia complicating the utilization of the Duett sealing device are presented. Routine usage of several vascular closure devices after cardiac catheterization and percutaneous coronary intervention (PCI) has been adopted in our institution during the last 3 years (September 1999 to April 2003). The Duett closure device has been used in 420 patients (post-coronary angiography, 359; post-PCI, 61). Three patients (0.7%) demonstrated acute leg ischemia used by inadvertent intravascular administration of the sealing material related to this device. All three were treated successfully by catheter-directed local thromolysis (tissue plasminogen activator 5 mg bolus followed initially by 1 mg/hr and consequently by 0.5-1.0 mg/hr depending upon the development of significant hematoma and lasting for 24 hr). In conclusion, interventional treatment using local thrombolysis should be the first-line treatment in acute lower limb ischemia complicating the utilization of the Duett sealing device.
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PMID:Treatment of acute lower limb ischemia following the use of the Duett sealing device: report of three cases and review of the literature. 1535 70

Poor recovery after systemic tissue plasminogen activator (tPA) therapy could result from the initial severity of ischemic insult and slow and incomplete thrombolysis. Persisting arterial occlusions can be identified at bedside using portable diagnostic ultrasound by detecting residual flow signals around the thrombus (thrombolysis in brain ischemia [TIBI] flow grades). A narrow pulsed ultrasound beam can be steadily aimed at the thrombus/residual flow interface, exposing more thrombus surface and structures to tPA, and tPA activity can be enhanced with 2 MHz transcranial Doppler (TCD). A randomized, multicenter, clinical trial called CLOTBUST (Combined Lysis of Thrombus in Brain ischemia using transcranial Ultrasound and Systemic tPA) trial showed a 49% rate of complete recanalization or dramatic clinical recovery from stroke within 2 hours after tPA bolus when tPA infusion was continuously monitored with TCD, compared with 30% among patients who received tPA without ultrasound monitoring (P=0.03, number needed to treat, 5). Early complete recanalization was sustained at 2 hours by 38% of monitored patients compared with 12.7% controls. The CLOTBUST Trial showed a trend toward sustaining complete recovery at 3 months (41.5% versus 28%, modified Rankin Scale scores 0 to 1), subject for a pivotal phase III trial. Ultrasound is an inexpensive, noninvasive, real-time monitoring tool to identify nonresponders to systemic tPA and select patients with persisting occlusions for intraarterial interventions. Early brain perfusion augmentation, complete recanalization, and dramatic clinical recovery are feasible goals for ultrasound-enhanced thrombolysis.
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PMID:Ultrasound identification and lysis of clots. 1537 1

In addition to its thrombolytic effect, human recombinant tissue plasminogen activator (tPA) may have parenchymal effects such as protease-dependent neurotoxic and protease-independent neuroprotective effects. The purpose of this study was to examine parenchymal effects of tPA and its non-protease mutant S478A-tPA in permanent focal cerebral ischemia in rats. However, before doing in vivo experiments, effects of tPA and S478A-tPA on zinc or NMDA toxicity were first studied in cortical cultures. Like tPA, which has protease-independent cytoprotective effects, the non-protease mutant S478A-tPA blocked zinc toxicity in cortical cell cultures, but did not affect calcium-mediated NMDA toxicity. Then, effects of tPA and S478A-tPA on infarcts induced by permanent occlusion of middle cerebral artery (MCA) were investigated. tPA and S478A-tPA were administered into the cerebral ventricle 15 min or 1 h after MCA occlusion. Both tPA and its non-protease mutant S478A-tPA, when given 15 min after ischemia, substantially reduced infarcts and ameliorated motor deficits in the MCA occlusion model of focal cerebral ischemia. However, when administered 1 h after MCA occlusion, neither showed protective effects. The protective effects of tPA or S478A-tPA remained unchanged at 7 days after MCA occlusion. Indicating that the native protein conformation is necessary for the protective effect of tPA and S478A-tPA, heat-denatured tPA did not exhibit any protective effect. Since S478A-tPA lacks protease activity, which has been implicated in causing cerebral hemorrhage or aggravating excitotoxicity, its parenchymal neuroprotective effect may be useful in treatment of ischemic stroke.
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PMID:Infarct reduction in rats following intraventricular administration of either tissue plasminogen activator (tPA) or its non-protease mutant S478A-tPA. 1538 Apr 85

To investigate the role of tissue plasminogen activator (tPA) in retinal damage, tPA-deficient and wild-type mice were employed. Two different retinal neuron insult models were used in the present study. One is an excitotoxin-treated retinal model, created by direct intravitreal injection of glutamate analogs, NMDA or kainic acid (KA), and the other is an ischemia-reperfusion model induced by transient elevation of intraocular pressure. TdT-dUTP terminal nick-end labeling (TUNEL) method was used to examine the retinal cell nuclear damage. The number of TUNEL-positive cells in ganglion cell layer (GCL) and inner nuclear layer (INL) in tPA-deficient mice after low-, but not high-dose NMDA was significantly less compared to wild type. In contrast, neither intravitreal KA or transient ischemia produced significant difference in retinal damage in tPA vs. wild-type mice. These data show that tPA-deficient mice are resistant to retinal damage by intravitreal injection of NMDA, and indicate that tPA plays a role in the retinal cell damage induced by excitotoxins, especially NMDA.
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PMID:Endogenous tissue type plasminogen activator facilitates NMDA-induced retinal damage. 1545 7

Although thrombolytic effects of tissue plasminogen activator (tPA) are beneficial, its neurotoxicity is problematic. Here, we report that tPA potentiates apoptosis in ischemic human brain endothelium and in mouse cortical neurons treated with N-methyl-D-aspartate (NMDA) by shifting the apoptotic pathways from caspase-9 to caspase-8, which directly activates caspase-3 without amplification through the Bid-mediated mitochondrial pathway. In vivo, tPA-induced cerebral ischemic injury in mice was reduced by intracerebroventricular administration of caspase-8 inhibitor, but not by caspase-9 inhibitor, in contrast to controls in which caspase-9 inhibitor, but not caspase-8 inhibitor, was protective. Activated protein C (APC), a serine protease with anticoagulant, anti-inflammatory and antiapoptotic activities, which is neuroprotective during transient ischemia and promotes activation of antiapoptotic mechanisms in brain cells by acting directly on endothelium and neurons, blocked tPA vascular and neuronal toxicities in vitro and in vivo. APC inhibited tPA-induced caspase-8 activation of caspase-3 in endothelium and caspase-3-dependent nuclear translocation of apoptosis-inducing factor in NMDA-treated neurons and reduced tPA-mediated cerebral ischemic injury in mice. Data suggest that tPA shifts the apoptotic signal in stressed brain cells from the intrinsic to the extrinsic pathway which requires caspase-8. APC blocks tPA's neurovascular toxicity and may add substantially to the effectiveness of tPA therapy for stroke.
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PMID:Tissue plasminogen activator neurovascular toxicity is controlled by activated protein C. 1558 Feb 49

The aim of this study was to investigate the effects of different doses of exogenous recombinant human tissue plasminogen activator (rt-PA) on the endogenous cerebral plasminogen-plasmin system in focal ischemia in rats. Ischemia was induced using the suture model. Each group of rats (n = 6) received either treatment (0.9, 9 or 18 mg rt-PA/kg body weight) or saline (control group) at the end of ischemia; a sham-operated group was added. The activity of the plasminogen activators was measured by casein-dependent plasminogen zymography. In the cortex urokinase (u-PA) rose from sham (no ischemia), 91 +/- 7% to ischemia, 176 +/- 10% (P < 0.005). Increasing rt-PA doses led to further significant (P < 0.001) cortical u-PA activation which was maximal at 18 mg: 249 +/- 13%. An extreme increase in the u-PA activity was observed in the basal ganglia to 1019 +/- 22% (P < 0.001). This increase was further aggravated by higher rt-PA doses (18 mg, 1236 +/- 15%; P < 0.001). The t-PA level did not change I3R24 during (3 h ischemia followed by reperfusion for 24 h); however, during low and moderate doses of rt-PA, endogenous t-PA was reduced. In conclusion, while ischemia leads to a significant increase in u-PA, mainly in the basal ganglia, t-PA is not altered. Increasing doses of rt-PA lead to a further elevation of u-PA. Thus, u-PA seems to play a major role in the endogenous plasminogen activator system following focal cerebral ischemia.
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PMID:Rt-PA causes a significant increase in endogenous u-PA during experimental focal cerebral ischemia. 1557 44


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