Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies of interventional therapy by way of the coronary venous system have demonstrated that it can protect acutely ischemic myocardium. To evaluate the efficacy of coronary venous retroinfusion compared with systemic intravenous administration of recombinant tissue-type plasminogen activator (rt-PA), 14 dogs were studied with a copper coil-induced thrombus in the left anterior descending coronary artery. The rt-PA (24,000 fluorescence units/kg) was administered continuously, either intravenously (n = 8) or retrogradely (n = 6), for 30 min beginning 60 min after coronary occlusion. Thrombolysis was determined by repetitive coronary angiography. All dogs were killed 3 h after termination of rt-PA infusion and infarct size was measured by the triphenyltetrazolium chloride staining technique. Complete thrombolysis occurred in five of the six dogs in the retroinfusion group and four of the eight dogs in the systemic intravenous infusion group. Partial lysis was achieved in two dogs treated by intravenous infusion. Lysis did not occur in one dog treated with retroinfusion and in two dogs treated with intravenous infusion. Time to thrombolysis was 13.4 +/- 2.3 min in the retroinfusion group versus 27.8 +/- 4.8 min in the intravenous group (p less than 0.001). Myocardial functional recovery in the ischemic zone measured by two-dimensional echocardiography 60 min after reperfusion was significant only in the retroinfusion group (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Retrograde coronary venous administration of recombinant tissue-type plasminogen activator: a unique and effective approach to coronary artery thrombolysis. 190 6

To determine the clinical consequences of reocclusion of an infarct-related artery after reperfusion therapy, we evaluated 810 patients with acute myocardial infarction. Patients were admitted into four sequential studies with similar entry criteria in which patency of the infarct-related artery was assessed by coronary arteriography 90 minutes after onset of thrombolytic therapy. Successful reperfusion was established acutely in 733 patients. Thrombolytic therapy included tissue-type plasminogen activator (t-PA) in 517, urokinase in 87, and a combination of t-PA and urokinase in 129 patients. All patients received aspirin, intravenous heparin and nitroglycerin, and diltiazem during the recovery phase. A repeat coronary arteriogram was performed in 88% of patients at a median of 7 days after the onset of symptoms. Reocclusion of the infarct-related artery occurred in 91 patients (12.4%), and 58% of these were symptomatic. Angiographic characteristics at 90 minutes after thrombolytic therapy that were associated with reocclusion compared with sustained coronary artery patency were right coronary infarct-related artery (65% versus 44%, respectively) and Thrombolysis in Myocardial Infarction (TIMI) flow 0 or 1 (21% versus 10%, respectively) before further intervention. Median (interquartile value) degree of stenosis in the infarct-related artery at 90 minutes was similar between groups: 99% for reoccluded (value, 90/100%) compared with 95% for patent (value, 80/99%). Patients with reocclusion had similar left ventricular ejection fractions compared with patients with sustained patency at follow-up. However, patients with reocclusion at follow-up had worse infarct-zone function at -2.7 (value, -3.2/-1.8) versus -2.4 (SD/chord) (value, -3.1/-1.3) (p = 0.016). The recovery of both global and infarct-zone function was impaired by reocclusion of the infarct-related artery compared with maintained patency; median delta ejection fraction was -2 compared with 1 (p = 0.006) and median delta infarct-zone wall motion was -0.10 compared with 0.34 SD/chord (p = 0.011), respectively. In addition, patients with reocclusion had more complicated hospital courses and higher in-hospital mortality rates (11.0% versus 4.5%, respectively; p = 0.01). We conclude that reocclusion of the infarct-related artery after successful reperfusion is associated with substantial morbidity and mortality rates. Reocclusion is also detrimental to the functional recovery of both global and infarct-zone regional left ventricular function. Thus, new strategies in the postinfarction period need to be developed to prevent reocclusion of the infarct-related artery.
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PMID:Consequences of reocclusion after successful reperfusion therapy in acute myocardial infarction. TAMI Study Group. 188 72

Current limitations of recombinant tissue-type plasminogen activator (rt-PA) therapy for acute myocardial infarction include failure to achieve recanalization in 25% of patients, reocclusion and reperfusion injury. Iloprost, a stable analogue of prostacyclin (PGI2), has been demonstrated to facilitate thrombolysis and reduce myocardial stunning in experimental models. To evaluate combined therapy, rt-PA (100 mg 3 h) and Iloprost (2 ng/kg per min for 48 h) were administered to 25 patients and then rt-PA alone (same dose) was given to an additional 25 patients with evolving myocardial infarction. At 90 min after drug administration, infarct-related vessel patency was observed in 11 (44%) of 25 who received rt-PA plus Iloprost compared with 15 (60%) of 25 who received rt-PA alone (p = 0.26). At 1 week, reocclusion had occurred in 3 (14%) of 21 patients who received combined therapy compared with 6 (26%) of 23 patients treated with rt-PA alone (p = 0.46). Ejection fraction increased significantly from baseline to 7 days for rt-PA alone whereas it decreased with combined therapy (rt-PA alone whereas it decreased with combined therapy (rt-PA alone: 47.3 +/- 11.5% at baseline to 50.4 +/- 9.8% at 7 days; rt-PA plus Iloprost: 51.3 +/- 10.1% at baseline to 49.0 +/- 9.4% at 7 days; difference between groups p = 0.05). At 4 h after therapy, fibrinogen decreased 33% for rt-PA plus Iloprost compared with a 52% for rt-PA alone (p = 0.001). Fibrinogen degradation products increased 60% more for rt-PA alone than for rt-PA plus Ilprost. Thus, the combination of rt-PA plus Iloprost at the doses employed did not improve immediate or follow-up coronary artery patency or left ventricular functional recovery compared with that achieved with rt-PA alone.
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PMID:Combined tissue-type plasminogen activator and prostacyclin therapy for acute myocardial infarction. Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) 4 Study Group. 247 26

The effect of beta-adrenergic blockade on the salvage and functional recovery of reperfused myocardium was investigated in anesthetized dogs. Immediately after thrombotic occlusion of the left anterior descending coronary artery, the cardioselective beta-blocking agent metoprolol was given intravenously at a dose of 0.5 mg/kg infused over 10 min. One hour after the onset of occlusion, recanalization was initiated by intravenous infusion of recombinant human tissue-type plasminogen activator (rt-PA, 10 micrograms/kg/min for 30 min). Anatomic infarct size expressed as percent of the left ventricular mass (I/LV), global ejection fraction, and mean systolic shortening of the segmental radii (SS) of the infarcted area were measured either after 24 hr or 1 week in six groups of six dogs each: group I (rt-PA + metoprolol, evaluated at 24 hr), group II (rt-PA + metoprolol, evaluated at 1 week, group III (rt-PA alone, evaluated at 24 hr), group IV (rt-PA alone, evaluated at 1 week), group V (persistent occlusion, evaluated at 24 hr), and group VI (persistent occlusion, evaluated at 1 week). The smallest infarcts were found in reperfused dogs given metoprolol, but the differences from dogs receiving rt-PA alone were not statistically significant (I/LV, expressed as mean +/- SEM: 5.5 +/- 0.9% in group I, 6.7 +/- 1.9% in group II, 15.4 +/- 5.0% in group III, 11.4 +/- 3.5% in group IV, 23.6 +/- 2.5% in group V, and 26.9 +/- 2.3% in group VI).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Reduction in infarct size and enhanced recovery of systolic function after coronary thrombolysis with tissue-type plasminogen activator combined with beta-adrenergic blockade with metoprolol. 310 51

To evaluate functional recovery in 20 consecutive patients with acute myocardial infarction who received recombinant tissue-type plasminogen activator, serial two-dimensional echocardiograms were performed before and immediately after tissue plasminogen activator administration and at 1 and 10 days postinfarction. Tissue plasminogen activator was administered intravenously (17 patients) or by intracoronary infusion (3 patients) after angiographic confirmation of total occlusion. Reperfusion, documented by angiography, occurred in 13 of the 20 patients. The mean time from onset of chest pain to thrombolysis was 5.1 +/- 1.1 hours. Echocardiograms were evaluated for regional function with a visual semiquantitative scoring system by two independent observers who had no knowledge of patient identity, temporal sequence, therapy or effect of therapy. There was no immediate or 24 hour improvement in wall motion. At day 10 compared with pretreatment, 28 of 33 reperfused infarct zone segments versus 6 of 20 nonreperfused infarct segments demonstrated improved wall motion (p = 0.01). This improvement did not relate to time from onset of chest pain to successful thrombolysis. Of reperfused infarct zone segments in the distribution of coronary artery balloon dilation, 19 of 23 segments exhibited improvement versus 7 of 17 (reperfused, no angioplasty) and 6 of 20 (nonreperfused, no angioplasty) segments (p = 0.001). Infarct zone segments reperfused at the time of ongoing chest pain demonstrated functional recovery compared with segments reperfused in the absence of chest pain (18 of 23 versus 10 of 20, respectively; p = 0.05). Thus, in this uncontrolled series, there was echocardiographically detectable improvement in function of reperfused infarct segments 10 days after coronary thrombolysis with recombinant tissue plasminogen activator.
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PMID:Regional wall motion improvement after coronary thrombolysis with recombinant tissue plasminogen activator: importance of coronary angioplasty. 316 Jul 57

The most widely studied thrombolytic drugs in stroke have been streptokinase (SK) and alteplase. The three large trials with streptokinase were terminated prematurely. The combined results reveal an early increased risk of cerebral haemorrhage and death, with no net benefit at final follow-up, even in subgroups. Some controversy persists, however. The dose may have been inappropriately high, very early treatment has not been fully tested, and concomitant use of aspirin or heparin may have contributed to the deleterious effect. Even so, there is no evidence to guide the choice of a lower dose, streptokinase predisposes to a prolonged anticoagulant effect, and is associated with hypotension which may offset any benefit. The four large alteplase trials in acute stroke were more encouraging. The NINDS study was clearly positive and supporting evidence comes from the two ECASS trials when subjected to meta-analysis. The trials have shown additional functional recovery in 0.6% of patients receiving SK within 6 h and in 7.6% with alteplase, at the expense of excess mortality of 1.1% for alteplase and 11.7% for SK. There was an absolute cerebral haemorrhage excess of 10.7% with SK and 8% for alteplase. If alteplase use is restricted to < 3 h from stroke onset, the NNT is 10.7 with no excess mortality; later treatment (3-6 h) gives an NNT of 26 and absolute mortality of 3.4%. Finally, early fibrinogen depletion with ancrod also appears to have beneficial effects when treatment is started within 3 h of stroke onset. Further trials are still required to establish, inter alia, the outer limit of the therapeutic window, to identify sub-groups of patients in whom clear benefit (or harm) exists and to establish appropriate management protocols for concomitant treatment. Thrombolysis with alteplase within 3 h of stroke onset may be considered for patients in whom haemorrhage and established infarction have been excluded. Trained assessment is essential, since there is an increased risk of haemorrhagic conversion that may be fatal. Patients considering thrombolytic treatment should appreciate that 1 in 10 patients have improved outcome, 1 in 20 suffer haemorrhagic conversion and 1 in 100 may die as a result of treatment. Treatment much later than 3 h from stroke onset in unselected patients is as likely to kill as to cure.
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PMID:Thrombolysis. 1109 88

(1) Alteplase is the first thrombolytic drug to be approved in France for the treatment of ischaemic stroke within three hours of symptom onset. (2) The clinical evaluation dossier contains nine placebo-controlled trials, of which six were relatively large. In the two NINDS trials (624 patients in total), treatment was started within the first three hours and it showed no survival benefit. Near-complete functional recovery was more frequent in the alteplase group than in the placebo group. In the two ECASS trials (620 and 800 patients) and the ATLANTIS trials (142 patients and 613 patients), treatment was started within the first six hours and it showed no significant benefit in terms of survival or functional recovery. (3) There are two meta-analyses of these trials. They confirm the lack of a survival benefit with alteplase. Using a combined endpoint, one meta-analysis showed that treating 1000 patients with alteplase prevented death or major disability (dependency) in 55 patients. The other meta-analysis underlined the importance of a short interval between the onset of symptoms and the beginning of treatment. (4) Intracranial haemorrhage is the most important adverse effect. One meta-analysis showed that alteplase caused 62 additional symptomatic intracranial haemorrhages (including 25 deaths) per 1000 treated patients. (5) Various retrospective subgroup analyses have tentatively identified subgroups of patients at a particularly high risk of adverse effects, but subgroup analyses provide only weak evidence. The patients most likely to benefit from alteplase, started within three hours of symptom onset, remain to be defined. (6) The current health infrastructure in France would allow only a small number of stroke patients to be treated with alteplase under the kind of conditions prevailing in clinical trials (imaging to confirm ischaemic stroke, and treatment very soon after the onset of symptoms). (7) In practice, there is a narrow margin between the wanted and unwanted effects of alteplase. This treatment should be used only by specialised teams and for strictly selected patients. Research must continue, particularly to identify those patients most likely to benefit from alteplase, and those most likely to be harmed in whom thrombolysis is contraindicated.
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PMID:Alteplase: new indication. Inadequately assessed in ischaemic stroke. 1553 35

Neuroprotective therapies and tissue plasminogen activator (t-PA) have limited application for most stroke patients and thus rehabilitation is the primary treatment option for improving recovery of function. Following brain injury, environmental enrichment, pharmacological and rehabilitative treatments can markedly alter neuronal plasticity and behavioral recovery even when delayed by several weeks after the insult. Fluoxetine has been given to stroke patients to combat depression but its effects on recovery of function are not known. Functional magnetic resonance imaging reveals that fluoxetine alters brain activity and modulates motor performance in stroke patients in a use-dependent fashion. Several antidepressants, including fluoxetine, increase growth factors and other proteins associated with plasticity, such as brain-derived neurotrophic factor (BDNF). In this study, we examined whether chronic administration of fluoxetine combined with rehabilitation affected recovery of function on 3 separate tests of forelimb reaching, preference and limb coordination after focal ischemia in rats. Ischemia was induced in male Long-Evans rats by intracortical and striatal injections of endothelin-1. Fluoxetine (10 mg/kg/day) combined with rehabilitation therapy (6 h/day) for 4 weeks did not alter the degree or rate of recovery of function compared to non-treated animals. Despite the ability of fluoxetine to alter brain activity and increase growth factors, it does not appear to be an effective pharmacological adjunct to functional recovery after ischemia in rats.
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PMID:Fluoxetine and recovery of motor function after focal ischemia in rats. 1586 86

CNS axons rarely regenerate spontaneously back to original targets following spinal cord injury (SCI). Neuronal expression of the serine protease tissue-type plasminogen activator (tPA) enhances axon growth in vitro and following PNS injury. Here we test the hypothesis that neuronal overexpression of tPA in adult transgenic mice promotes CNS axon regeneration and functional recovery following SCI. Adult wild-type and transgenic mouse spinal cords were subjected to dorsal hemisection at the level of the T10/T11 vertebrae. PCR confirmed incorporation of the transgene. Immunolabeling revealed overexpression of tPA in transgenic mice in neurons, including large-diameter neurons in lumbar dorsal root ganglia that contribute axons to the dorsal columns. Immunolabeling also revealed the presence of tPA protein within axons juxtaposing the injury site in transgenics but not wild types. In situ zymography revealed abundant enzymatic activity of tPA in gray matter of thoracic spinal cords of transgenics but not wild types. Rotorod locomotor testing revealed no differences between groups in locomotor function up to 21 days postinjury. Transganglionic tracer was injected into the crushed right sciatic nerve 28 days postinjury, and mice were killed 3 days later. There was no evidence for regrowth of ascending dorsal column sensory axons through or beyond the injury site. In conclusion, despite neuronal overexpression of tPA in injured neurons of transgenics, neither locomotor recovery nor regeneration of ascending sensory axons was observed following thoracic dorsal hemisection.
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PMID:Neuronal overexpression of tissue-type plasminogen activator does not enhance sensory axon regeneration or locomotor recovery following dorsal hemisection of adult mouse thoracic spinal cord. 1691 39

Thrombolysis with intravenous alteplase (recombinant tissue-type plasminogen activator) continues to be the sole recourse for acute ischemic stroke therapy, provided that patients seek treatment preferably within 3 h of stroke onset. The narrow window of efficacy, coupled with the significant risk of hemorrhage and the high mortality rate, preclude the use of alteplase beyond this time frame. Moreover, in part because of safety concerns, only a small percentage (6-15%) of eligible patients is treated with alteplase. Clearly, safer and more effective treatments that focus on improving the shortcomings of the present thrombolysis for stroke need to be identified. Therefore, newer thrombolytics are being developed with the goal of minimizing side effects, while also shortening the time of cerebral reperfusion and extending the therapeutic window of efficacy. Besides thrombolytics, new and potentially useful drugs and devices are also being studied either as monotherapeutic agents or for use in conjunction with alteplase. In animal models of stroke, neuroprotective agents that affect various components of the ischemic injury cascade that results in neurodegeneration have shown promise for the latter. Examples of such agents include spin traps that block oxidative stress, metalloprotease inhibitors that prevent vascular damage, anti-inflammatory drugs that suppress inflammation and transcranial infrared laser irradiation, which promotes recovery of function. Ideally, a successful combination of neuroprotectant (drug or device) and thrombolytic therapy for stroke would minimize the side effects of thrombolysis followed by supplementary neuroprotection thereafter.
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PMID:Advances in ischemic stroke treatment: neuroprotective and combination therapies. 1735 16


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