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

Currently, intravenous recombinant tissue plasminogen activator is the only US Food and Drug Administration-approved therapy for acute ischemic stroke. Although efficacious, its usefulness is limited, mainly because of the very limited time window for its administration. Neuroprotective treatments are therapies that block the cellular, biochemical, and metabolic elaboration of injury during or after exposure to ischemia, and have a potential role in ameliorating brain injury in patients with acute ischemic stroke. More than 50 neuroprotective agents have reached randomized human clinical trials in focal ischemic stroke, but none has been unequivocally proven efficacious, despite successful preceding animal studies. The failed neuroprotective trials of the past have greatly increased understanding of the fundamental biology of ischemic brain injury and have laid a strong foundation for future advance. Moreover, the recent favorable results of human clinical trials of hypothermia in human cardiac arrest and global brain ischemia have validated the general concept of neuroprotection for ischemic brain injury. Recent innovations in strategies of preclinical drug development and clinical trial design that rectify past defects hold great promise for neuroprotective investigation, including novel approaches to accelerating time to initiation of experimental treatment, use of outcome measures sensitive to treatment effects, and trial testing of combination therapies rather than single agents alone. Although no neuroprotective agent is of proven benefit for focal ischemic stroke, several currently available interventions have shown promising results in preliminary trials and may be considered for cautious, off-label use in acute stroke, including hypothermia, magnesium sulfate, citicoline, albumin, and erythropoietin. Overall, the prospects for safe and effective neuroprotective therapies to improve stroke outcome remain promising.
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PMID:Potential Role of Neuroprotective Agents in the Treatment of Patients with Acute Ischemic Stroke. 1289 99

Thrombolytic stroke therapy with tissue plasminogen activator (tPA) is limited by serious risks of intracerebral hemorrhage. In this study, the authors show that a novel antiactin-targeted immunoliposome significantly reduced tPA-induced hemorrhage in an established rat model of embolic focal stroke. Spontaneously hypertensive rats were subjected to focal ischemia using homologous blood clot emboli. Delayed administration of tPA (10 mg/kg, 6 hours after ischemia) induced intracerebral hemorrhage at 24 hours. In control rats treated with tPA plus vehicle, hemorrhage volumes were 9.0 +/- 2.4 uL (n = 7). In rats treated with tPA plus antiactin immunoliposomes, hemorrhage volumes were significantly reduced to 4.8 +/- 2.7 uL (n = 8, P < 0.05). No significant effects were seen when rats were treated with tPA plus a nontargeted liposome (7.8 +/- 2.1 uL, n = 9). Fluorescent immunohistochemistry showed that rhodamine-labeled targeted liposomes colocalized with vascular structures in ischemic brain that stained positive for endothelial barrier antigen, a marker of cerebral endothelial cells. These data suggest that immunoliposomes may ameliorate vascular membrane damage and reduce hemorrhagic transformation after thrombolytic therapy in cerebral ischemia.
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PMID:Antiactin-targeted immunoliposomes ameliorate tissue plasminogen activator-induced hemorrhage after focal embolic stroke. 1290 33

The only current FDA-approved treatment for acute ischemic stroke is thrombolysis with tissue plasminogen activator (tPA). However, there are numerous shortcomings to tPA treatment including an increased incidence of intracerebral hemorrhage (ICH) and a short therapeutic window (3-6 h). In recent years, studies have attempted to identify new therapeutics that might be neuroprotective following ischemic strokes. Free radical scavenging spin trap agents have been proposed as potential candidates for stroke therapy because of the hypothesized role of free radicals in the progression of stroke and ischemia-induced neurodegeneration. Novel spin trap agents like (disodium-[(tert-butylimino) methyl] benzene-1,3-disulfonate N-oxide (NXY-059) are of particular interest, not only because they are broad-spectrum nitrone-based free radical scavengers, but also because of their safety profile in humans. Moreover, the rationale for developing NXY-059 for the treatment of acute ischemic stroke is further supported by the drug's reported neuroprotective effects. In addition, NXY-059 may represent a useful adjunct stroke therapy to tPA, since preclinical studies have demonstrated that NXY-059 increases the therapeutic window for tPA and lowers the occurrence of tPA-induced ICH.
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PMID:Development of the nitrone-based spin trap agent NXY-059 to treat acute ischemic stroke. 1453 Jul 97

The serine proteases tissue plasminogen activator, plasmin, and thrombin and their receptors have previously been suggested to contribute to neuronal damage in certain pathological situations. Here we demonstrate that mice lacking protease-activated receptor 1 (PAR1) have a 3.1-fold reduction in infarct volume after transient focal cerebral ischemia. Intracerebroventricular injection of PAR1 antagonist BMS-200261 reduced infarct volume 2.7-fold. There are no detectable differences between PAR1-/- and WT mice in cerebrovascular anatomy, capillary density, or capillary diameter, demonstrating that the neuroprotective phenotype is not likely related to congenital abnormalities in vascular development. We also show that the exogenously applied serine proteases thrombin, plasmin, and tissue plasminogen activator can activate PAR1 signaling in brain tissue. These data together suggest that if blood-derived serine proteases that enter brain tissue in ischemic situations can activate PAR1, this sequence of events may contribute to the harmful effects observed. Furthermore, PAR1 immunoreactivity is present in human brain, suggesting that inhibition of PAR1 may provide a novel potential therapeutic strategy for decreasing neuronal damage associated with ischemia and blood-brain barrier breakdown.
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PMID:The contribution of protease-activated receptor 1 to neuronal damage caused by transient focal cerebral ischemia. 1455 73

Currently, intravenous recombinant tissue plasminogen activator is the only US Food and Drug Administration-approved therapy for acute ischemic stroke. Although efficacious, its usefulness is limited, mainly because of the very limited time window for its administration. Neuroprotective treatments are therapies that block the cellular, biochemical, and metabolic elaboration of injury during or after exposure to ischemia, and have a potential role in ameliorating brain injury in patients with acute ischemic stroke. More than 50 neuroprotective agents have reached randomized human clinical trials in focal ischemic stroke, but none have been unequivocally proven efficacious, despite successful preceding animal studies. The failed neuroprotective trials of the past have greatly increased understanding of the fundamental biology of ischemic brain injury and have laid a strong foundation for future advance. Moreover, the recent favorable results of human clinical trials of hypothermia in human cardiac arrest and global brain ischemia have validated the general concept of neuroprotection for ischemic brain injury. Recent innovations in strategies of preclinical drug development and clinical trial design that rectify past defects hold great promise for neuroprotective investigation, including novel approaches to accelerating time to initiation of experimental treatment, use of outcome measures sensitive to treatment effects, and trial testing of combination therapies rather than single agents alone. Although no neuroprotective agent is of proven benefit for focal ischemic stroke, several currently available interventions have shown promising results in preliminary trials and may be considered for cautious, off-label use in acute stroke, including hypothermia, magnesium sulfate, citicoline, albumin, and erythropoietin. Overall, the prospects for safe and effective neuroprotective therapies to improve stroke outcome remain promising.
 ...
PMID:Potential Role of Neuroprotective Agents in the Treatment of Patients with Acute Ischemic Stroke. 1457 21

To investigate whether marked and sustained lipid-lowering in subjects with stable angina pectoris and dyslipidemia reduces exercise-induced myocardial ischemia, 17 subjects were treated with dose-adjusted atorvastatin over 1 year and underwent serial evaluation of exercise electrocardiographic ischemic parameters, serum biomarkers, and brachial artery endothelial function. Endothelial function improved progressively and C-reactive protein, P-selectin, and tissue plasminogen activator inhibitor levels decreased, but there was no decrease in exercise electrocardiographic ischemia.
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PMID:Effect of atorvastatin on exercise-induced myocardial ischemia in patients with stable angina pectoris. 1460 94

Acute limb ischemia is associated with a high risk of death and loss of the extremity. To restore the blood flow, several percutaneous thrombolytic techniques were developed. To achieve a targeted thrombus infiltration, the continuous application of low-dose urokinase or recombinant tissue plasminogen activator using a specific lysis catheter with sideholes is preferable. Concerning the amputation-free survival, thrombolysis is superior to surgery for occlusions of native vessels or bypass grafts that are not older than 2 weeks. Furthermore, the percutaneous approach permits the simultaneous treatment of the underlying lesion by angioplasty or stent implantation after dissolution of the occluding thrombus. The higher risk of complications must be balanced against risks of surgery in each patient.
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PMID:[Intra-arterial lysis therapy in acute limb ischemia. Technical possibilities and limits of indication]. 1467 32

Although recombinant tissue plasminogen activator (rt-PA) was rapidly implemented as part of the emergency care of acute stroke, its use in daily clinical practice still remains controversial in many countries. The most important question is criteria for careful selection of subgroup of patients for this treatment. It has been hypothesized that early computed tomography (CT) changes of ischemia are risk factors for symptomatic intracerebral hemorrhage and poor outcome. We conducted a prospective outcome study of patients with acute ischemic stroke (IS) admitted to the hospital within 6 h of symptom onset. Experienced neuroradiologists blind to the clinical outcome of the patients read all CT scans carried out in the emergency room. Early CT changes were defined as in European Cooperative Acute Stroke Study (ECASS) 2. There were 150 patients (75 males, mean age 72.5 +/- 9.0) with acute IS (54.7% with mild stroke and 45.3% with severe stroke). Early CT changes were presented with tissue hypodensity - 55.7%, effacement of sulci - 41.3%, hyperdensity of middle cerebral artery (MCA) - 13.3%, hypodensity of lentiform - 20.7%, loss of insular ribbon sign - 28.7%. Follow-up after 30 days showed that 44% of the patients were discharged home, 20% were discharged to rehabilitation facilities, 22% were discharged to chronic care institutions and 14% died. Data were statistically analyzed. Our data suggest that early signs on CT scan could not predict outcome of patients with acute IS.
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PMID:Early CT changes and outcome of ischemic stroke. 1469 91

This study investigated the contribution of endogenous suppression of fibrinolysis and increased fibrin deposition to intestinal dysfunction and injury in a rat model of intestinal ischemia/reperfusion (I/R), as fibrinolytic inhibition may lead to thrombotic obstructions that compromise microcirculation and promote intestinal injury. Circulatory fibrinolysis was enhanced by intravenous administration of recombinant tissue plasminogen activator (rt-PA) or by inhibition of PAI-I by administration of MA-33H1F7. Coagulation and fibrinolysis parameters obtained from portal blood were correlated to fibrin deposition (determined by anti-rat fibrin antibody staining), intestinal function (glucose/water clearance) and intestinal injury (histological evaluation by Park/Chiu score). Enhanced circulatory fibrinolytic activity, as evidenced by increased portal plasma plasminogen activator activity, elevated fibrin degradation products and decreased levels of PAI-I, did not reduce mucosal fibrin deposition and microthrombosis in postischemic intestinal tissue. Furthermore, rt-PA or anti-PAI-I antibody administration did not attenuate I/R-induced intestinal injury or dysfunction, as demonstrated by intestinal histopathology scores of 4.8+/-0.2 and 4.7+/-0.3 (control I/R group 4.7+/-0.2) and glucose clearances of 47+/-6 and 46+/-9 micro L/min g (control I/R group 30+/-8 micro L/min. g) after 40 minutes of intestinal ischemia and 3 hours of reperfusion, respectively. However, both interventions resulted in decreased levels of interleukin-6, which may indicate fibrin-induced modulation of inflammation. Attempts to enhance the fibrinolytic activity (either by rt-PA or by anti-PAI-I administration), indicated by increased portal plasma levels of released FDP, failed to decrease mucosal fibrin deposition and to attenuate intestinal I/R injury. Based on our observations and previous reports, the contribution of suppressed endogenous fibrinolysis to microcirculatory fibrin deposition and I/R-injury may be of limited importance.
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PMID:Enhancement of endogenous fibrinolysis does not reduce local fibrin deposition, but modulates inflammation upon intestinal ischemia and reperfusion. 1498 25

Acute ischemic stroke now is being treated as a medical emergency. The success of the use of tissue plasminogen activator (t-PA) within 3 hours of onset of stroke serves as an impetus for an approach that emphasizes prompt recognition, rapid transportation to a medical center, speedy evaluation and urgent treatment. However, the safe and effective administration of t-PA requires the involvement of physicians who have expertise in the diagnosis and management of stroke, the timely availability of modern brain imaging studies and the facilities to handle complications of treatment. While t-PA improves outcomes, it is just a component of management that also includes measures to limit or prevent medical or neurologic complications, rehabilitation and institution of therapies to forestall recurrent stroke. In the future, additional therapies likely will be shown as effective in lessening the neurologic consequences of brain ischemia.
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PMID:Treatment of acute ischemic stroke. 1498 65


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