Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thrombolysis with tissue plasminogen activator (tPA) and hypothermia are two potential treatment modalities for acute ischemic stroke. Many investigators are studying these modalities both in the laboratory and in clinical trials. Because these modalities each appear to show benefit in animal models, there is considerable interest in studying combined therapy with both thrombolysis and hypothermia. However, it is known that alterations in the coagulation system can occur with decreased body temperature. Clinicians have frequently observed bleeding problems when patients are subjected to hypothermia for a variety of reasons. Hypothermia induced coagulopathy has been attributed to a variety of factors. Hypothermia can cause platelet dysfunction, inhibition of clotting factors, increased fibrinolysis and endogenous production of a heparin-like factor. Groups who studied fibrinolysis and temperature, however, found the opposite to be the case. Clot lysis studies with streptokinase showed increased fibrinolysis at higher temperatures. Data by Mumme suggested that the peak fibrinolytic activity of streptokinase was at 40 degrees C, but at 43 degrees C fibrinolytic activity was decreased. Rijken et al studied plasminogen activation with tissue plasminogen activator (tPA), urokinase and streptokinase at extremely low temperatures. They found less plasminogen activation and fibrinogen degradation at 25 degrees C compared to 37 degrees C, but negligible differences at 10 degrees C, 0 degrees C and -8 degrees C. To our knowledge, there is no data studying the fibrinolytic activity of tissue plasminogen activator (tPA) at temperature ranges between 25-37 degrees C which is the range of temperatures used clinically for therapeutic purposes.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Thrombolysis with tissue plasminogen activator (tPA) is temperature dependent. 777 62

The importance of fibrinogen has been identified in two prospective observational studies. Reactive elevations in fibrinogen levels that occur within hours of a major stroke invalidate most cross-sectional case-control studies evaluating fibrinogen as a risk factor. However, as no elevation is seen following fresh episodes of transient ischaemic attacks, reliable conclusions drawn from a case-control study using such patients support the findings of the prospective studies. The association is related to occlusive stroke, but the relationship with intracerebral haemorrhage is unclear. The relationship has been found to be independent of other haemostatic and haemorheological factors (e.g. von Willebrand factor, tissue plasminogen activator and packed cell volume). Adjustment for regression dilution bias would further strengthen the observed relationship. Therefore, after blood pressure, fibrinogen is the most important potentially treatable risk factor for ischaemic stroke. There are several mechanisms whereby fibrinogen could promote athero-thromboembolism: thrombosis through a hypercoagulable state; the acceleration of atherosclerosis; or the reduction of blood flow due to high blood or plasma viscosity. The mechanism, however, is unlikely to be mediated through high blood viscosity per se as secondary erythrocytosis (another major determinant of blood viscosity) has not consistently been found to be a risk factor for stroke. Studies relating fibrinogen levels to the degree of carotid artery stenosis support the accelerating influence of fibrinogen on atherosclerosis. Fibrinogen should be considered a risk factor for ischaemic stroke and included in the assessment of individual risk factors.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Fibrinogen and cerebrovascular disease. 779 30

In 87 patients (studied on average 1 year after their strokes) and 26 of their first-degree relatives, our specific aim was to assess the prevalence of the following stroke risk factors: hypofibrinolysis, familial hypofibrinolysis, high lipoprotein (a) level, and dyslipidemia. At least 2 months after their strokes (primarily ischemic), 87 patients had measures of lipids and lipoprotein (a); 69 and 67 patients had measures of basal and stimulated fibrinolytic activity, respectively, four new findings were as follows. (1) Hypofibrinolysis was common, with bottom decile-stimulated tissue plasminogen activator activity (the major stimulator of fibrinolysis) in 21% of stroke probands and in 30% of their first-degree relatives, versus 7% of 29 nomolipidemic control subjects (p = 0.09 and 0.026, respectively). (2) The hypofibrinolysis was mediated by top-decile levels of basal plasminogen activator inhibitor activity (the major inhibitor of fibrinolysis), which were observed in 20% of stroke probands and in 21% of their first-degree relatives, versus 8% of 175 nomolipidemic control subjects (p = 0.007 and 0.04, respectively). Mean (SD) basal plasminogen activator inhibitor activity and antigen level were higher in stroke probands (18 +/- 18 U/ml and 35 +/- 31 ng/ml, respectively) than in the 175 normolipemic control subjects (14 +/- 10 [p = 0.002], 28 +/- 34 [p = 0.016]). (3) Levels of basal tissue plasminogen activator antigen, a probable marker for atherosclerosis, were much higher in stroke probands than in the 175 normolipemic control subjects (15 +/- 7.3 ng/ml vs 7 +/- 3.8, p = 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Hypofibrinolytic and atherogenic risk factors for stroke. 789 94

The efficacy of delayed thrombolysis with recombinant tissue plasminogen activator was tested in combination with the ischaemic protecting drug NBQX in an embolic stroke model. In 113 rats the carotid territory was embolized with a fibrin-rich clot formed in polyethylene tube. Hemispheric cerebral blood flow (CBF) was measured by intra-arterial 133Xenon injection method before and after embolization. Two hours after embolization 67 animals were treated with tissue plasminogen activator 20 mg kg-1, 46 control animals with saline. NBQX was given to 53 animals, of which 41 animals also received thrombolytic therapy and 12 were saline controls. Carotid angiography displayed the rate of occlusion of the cerebral arterial supply before and after treatment. Brains were fixed after two days, evaluated neuropathologically, and infarct volume was measured. Embolization caused a 60-78% reduction of median CBF. The comparison of post-treatment angiography of thrombolytic treated animals to controls showed significant (p < 0.01) reperfusion in thrombolytic treated animals, while NBQX alone did not enhance reperfusion. Thrombolytic therapy significantly reduced the total infarct volume from 19.5% to 4.5% of embolized hemisphere volume (p = 0.006). NBQX alone reduced total infarct volume from 19.5% to 6.5% and cortical infarct volume from 7.9% to 0.3% (p = 0.03). In thrombolytic treated animals NBQX reduced total infarct volume from 4.5% to 2.1%. The more than 50% reduction of total infarction volume caused by NBQX was not statistically significant due to the variation of infarct size in this model. Small haemorrhagic lesions in infarcts were observed in thrombolytic treated animals. The clinical outcome correlated well with infarct volume.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Neuroprotection with NBQX and thrombolysis with rt-PA in rat embolic stroke. 790 10

The thrombolytic activity of tissue plasminogen activator was evaluated in a rabbit model of thromboembolic stroke using both various concentrations (3, 5, and 10 mg/kg; 20% bolus with the remaining 80% given over 30 min.) and routes of administration (intravenous versus regional intra-arterial). An autologous tin-tagged clot was embolized to the brain via the carotid artery. Tissue plasminogen activator was then given at the doses and routes noted (n = 3 in all groups). Thrombolytic activity was followed by serial x-rays of the tin-laden clot over a four-hour period. The brains were then removed and subjected to gross inspection. Only the intravenous dose of 5 mg/kg tissue plasminogen activator produced greater than 50% clot lysis in all animals. Doses of t-PA higher (10 mg/kg) or lower (3 mg/kg) than this were less effective in producing thrombolysis, demonstrating greater than 50% clot lysis in only one animal of each group. We conclude that in this model of thromboembolic stroke the intravenous administration of tissue plasminogen activator is more effective than intra-arterial, and that the optimal dose is in the range of 5 mg/kg.
 ...
PMID:Tissue plasminogen activator: comparison of dose and route of administration in a rabbit model of thromboembolic stroke. 790 9

Few haematological or lipid risk factors have been identified for stroke, by contrast with coronary heart disease. To find out whether a marker of endogenous fibrinolytic function might be associated with stroke risk, we measured tissue plasminogen activator (tPA) antigen concentrations in baseline plasma samples from 88 healthy participants in the Physicians' Health Study who subsequently had first-ever strokes (71 thromboembolic, 12 haemorrhagic, 5 indeterminate) and from 471 participants who remained free of cardiovascular disease during 5 years of follow-up (controls). Mean baseline tPA concentrations were significantly higher among men who later had strokes than in the controls (11.14 [SE 0.80] vs 9.59 [0.27] ng/mL, p = 0.03). The difference was largely due to an excess of abnormally high values among stroke cases. The age-adjusted relative risk for stroke among men with baseline tPA concentrations above the 95th percentile of the control distribution was 3.51 (95% CI 1.72-7.17, p = 0.0006) for total stroke and 3.89 (1.83-8.26, p = 0.0004) for thromboembolic stroke. These findings did not change substantially in analyses that also controlled for stroke risk factors (high blood pressure, body-mass index, smoking, presence of diabetes, and parental history of myocardial infarction) or the plasma lipid profile. This prospective study shows that high concentrations of tPA antigen among apparently healthy men are independently associated with high risks of future stroke, especially thromboembolic stroke. This finding is consistent with the hypothesis that activation of the endogenous fibrinolytic system occurs years in advance of arterial vascular occlusion.
 ...
PMID:Prospective study of endogenous tissue plasminogen activator and risk of stroke. 791 Sep 26

The effects of hyperthermia on potentially prothrombotic endothelial function were investigated by measuring levels of von Willebrand factor, thrombospondin, tissue plasminogen activator and plasminogen activator inhibitor-1 secreted by unstimulated human umbilical vein endothelial cells cultured at 37 degrees C, 39 degrees C, 41 degrees C and 43 degrees C for 24 h. Endothelial barrier function at 43 degrees C was compared with that at 37 degrees C by measuring permeability to radiolabelled human serum albumin and low density lipoprotein. Thrombospondin levels were unaffected by a temperature of 39 degrees C; they increased after 3 h at 41 degrees C and subsequently declined to values significantly below the 37 degrees C control. At 43 degrees C, secretion exhibited a time-dependent decrease. Secretion of von Willebrand factor was not discernibly affected by exposure to 39 degrees C or 41 degrees C. Its response to 43 degrees C resembled that of thrombospondin to 41 degrees C. In contrast, elevated temperatures markedly increased plasminogen activator inhibitor-1 while decreasing t-PA secretion, though after prolonged exposure to 43 degrees C the levels of both returned to control values. After 12-24 h at 43 degrees C, endothelial permeability to both albumin and low density lipoprotein increased markedly. Vascular endothelium may contribute to the thrombotic tendency associated with heat stroke by increasing access to the prothrombotic subendothelium and reducing fibrinolysis.
 ...
PMID:The effects of hyperthermia on human endothelial monolayers: modulation of thrombotic potential and permeability. 805 50

We evaluated the effect of antibodies directed against a leukocyte adhesion molecule (ICAM-1) in an embolic model of stroke followed by thrombolysis with tissue plasminogen activator (tPA). To test whether reperfusion injury after ischemia was related to white cell adhesion, microclots were injected into carotid circulation. The conditions examined were control, alpha-ICAM 5 min following ischemia, tPA 30 min after ischemia, and the combination of alpha-ICAM and tPA. alpha-ICAM and tPA both increased the amount of clot necessary to produce permanent neurological damage. Combined therapy was no more effective than either substance alone. A similar outcome was obtained when tPA was delayed until 90 min postischemia. When thrombolysis was delayed 3 h following embolism, neither tPA nor the tPA/alpha-ICAM combination reduced neurological damage. Thus, the alpha-ICAM antibody and tPA each effectively reduced neurological damage but the interaction was not significant.
 ...
PMID:Monoclonal antibody to the ICAM-1 adhesion site reduces neurological damage in a rabbit cerebral embolism stroke model. 809 42

Streptokinase has been administered to many thousands of elderly patients with acute myocardial infarction. Results of large, randomised trials provide convincing evidence that intravenous streptokinase confers a distinct survival benefit in this population subgroup following myocardial infarction. The placebo-controlled ISIS-2 study demonstrated a 5-week absolute mortality reduction of 38 per 1000 patients aged 60 to 69 years administered streptokinase, compared with only 16 per 1000 for patients aged less than 60 years. Combining streptokinase with aspirin further reduces mortality, as shown by a 5-week absolute mortality reduction of 70 per 1000 patients aged 60 to 69 years administered this regimen in the ISIS-2 trial. While ideally patients should receive streptokinase as soon as possible after symptom onset, late benefit has been observed in patients presenting up to 12 hours after pain onset, as is often the case with the elderly. Indeed, in patients treated > 6 hours after infarct in the GUSTO trial, streptokinase produced lower mortality results than accelerated recombinant tissue plasminogen activator (rt-PA). However, in contrast to the similar effects of streptokinase and conventionally administered rt-PA on overall survival demonstrated in previous large trials, the GUSTO study showed a lower mortality rate for accelerated rt-PA than for streptokinase in the elderly and in the total patient population. The most frequent adverse effects associated with streptokinase therapy are haemorrhagic complications, with an incidence of 0.4% for major bleeding (requiring transfusion) and 3.6% for minor bleeding among the total population in the GISSI-1 and ISIS-2 trials. An excess of stroke, particularly haemorrhagic stroke, occurring with rt-PA in GUSTO and other major mortality trials affirms the use of streptokinase as a suitable option in the elderly who are at increased risk of this complication. Significantly reduced values of end-systolic volume and regional wall motion index have been observed in elderly patients following streptokinase therapy. Overall, streptokinase and rt-PA seem to cause similar improvements in left ventricular function in this age group. Patency of occluded coronary arteries appears to be achieved in a high percentage of elderly patients following streptokinase therapy, based on a small sample. Thus, in view of the extensive clinical experience that now exists, intravenous streptokinase represents an appropriate alternative in elderly patients with acute myocardial infarction, and may be considered a first-line therapy in selected individuals, such as those with multiple risk factors for stroke or who present later than 6 hours after infarct.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Streptokinase. A review of its pharmacology and therapeutic efficacy in acute myocardial infarction in older patients. 813 Mar 84

The need for careful assessment of stroke incidence in a trial comparing highly effective thrombolytic regimens was recognised in the design of the GUSTO trial. There was a gradation of stroke incidence from 1.22% in the streptokinase (SK) and subcutaneous heparin group, to 1.4% in the SK and intravenous heparin group, 1.55% in the tissue plasminogen activator (t-PA) and intravenous heparin group and 1.64% in the combination t-PA and SK group. The concept of net clinical benefit was developed to balance the adverse effect of stroke with the benefit of mortality reduction. On this analysis, the net clinical benefit favoured the accelerated t-PA regimen over the SK regimens.
 ...
PMID:Strokes and net clinical benefit. 814 14


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>