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)

In this study, we evaluated the efficacy of postoperative intrathecal injections of tissue-type plasminogen activator (tPA) in preventing cerebral vasospasm in cases with a diffuse severe subarachnoid hemorrhage. All 10 cases were graded Group 3 according to the classification of Fisher and associates, and the CT number (Hounsfield number) of the subarachnoid clot was over 75. After clipping the aneurysm and removing the clot, three cisternal drainage catheters were inserted into both sylvian cisterns and the prepontine cistern, and continuous ventricular drainage was performed routinely. Postoperatively, tPA (0.5 mg/2.5 ml) was infused as a bolus into both basal cisterns and the lateral ventricle twice daily for about 6 days. Angiography and cerebral blood flow studies using single photon emission computed tomography were performed on Day 4 or 5 and between Days 7 and 10 after onset of the hemorrhage. To date, there have been no cases that have shown angiographic vasospasm or delayed ischemic neurological deficits. This preliminary study indicates that the intrathecal bolus injection of tPA produces a marked effect on vasospasm.
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PMID:Prevention of vasospasm by clot removal and intrathecal bolus injection of tissue-type plasminogen activator: preliminary report. 190 42

Recent laboratory studies have demonstrated that intracisternal administration of recombinant tissue plasminogen activator (rt-PA) can facilitate the normal clearing of blood from the subarachnoid space and prevent or ameliorate delayed arterial spasm. The results of a preliminary Phase I trial of intracisternal rt-PA in 10 patients are reported with documented aneurysmal subarachnoid hemorrhage (SAH). All patients enrolled were classified as clinical Grade III or IV (according to Hunt and Hess) with thick clots or layers of blood in the basal cisterns and major cerebral fissures (Fisher Grade 3). Ventriculostomy and surgery for clipping of the aneurysms were performed within 48 hours of hemorrhage. In one patient, 10 mg rt-PA was instilled into the subarachnoid cisterns prior to closing the dura. In the remaining nine patients, a small silicone catheter was left in the subarachnoid space and rt-PA (5 mg in four cases or 1.5 mg (0.5 mg every 8 hours for three infusions) in five cases) was instilled 12 to 24 hours after surgery. Minor local bleeding complications were noted in all patients receiving 5 or 10 mg rt-PA. Oozing was noted at the operative incision site in four of five patients and at the ventriculostomy site in two patients. One patient developed a small epidural hematoma that was treated by delayed drainage. No bleeding complications were noted in the patients receiving the lower regimen of rt-PA (three infusions of 0.5 mg each). Serial coagulation studies demonstrated no evidence of systemic fibrinolysis. Analysis of cisternal cerebrospinal fluid samples revealed thrombolytic tissue plasminogen activator (t-PA) levels for 24 to 48 hours. Follow-up cerebral angiography 7 to 8 days after rupture disclosed mild to moderate spasm in nine patients, while one patient with hemorrhage from a posterior inferior cerebellar artery aneurysm had severe focal spasm of the vertebral arteries that was not symptomatic. These results suggest that postoperative treatment with rt-PA may be effective in reducing the severity of delayed cerebral vasospasm. The results of serial t-PA levels suggest that the lower dosage regimen with divided dosages at 8-hour intervals is well tolerated and that even lower dosages may be effective. Further studies are clearly indicated.
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PMID:Phase I trial of tissue plasminogen activator for the prevention of vasospasm in patients with aneurysmal subarachnoid hemorrhage. 190 34

The safety and efficacy of the thrombolytic agent tissue-type plasminogen activator (tPA) in the elimination of subarachnoid clot and prevention of chronic vasospasm were evaluated in a blind randomized placebo-controlled trial. Twenty-four monkeys were randomly assigned to one of two groups of 12. Each group underwent baseline cerebral angiography and coagulation analysis followed by right-sided craniectomy and experimental subarachnoid hemorrhage (SAH). An Ommaya reservoir was inserted with its catheter placed into the subarachnoid space. Twenty-four hours later one group (the tPA group) received 0.5 mg of tPA in 0.5 ml of buffer injected into the reservoir every 8 hours for three doses, while the second group (the placebo group) received the same volume of normal saline. On Day 7, angiography was repeated and the animals were sacrificed. One animal from the placebo group developed a delayed ischemic neurological deficit on Day 5 after SAH. Moderate to severe vasospasm (greater than 30% reduction in vessel caliber) was present on Day 7 in the internal carotid and middle cerebral arteries of the animals in the placebo group (p less than 0.01), while in the tPA group only mild narrowing of the anterior cerebral artery was seen. No significant change in coagulation status occurred in either group. All animals in the placebo group had a large amount of subarachnoid clot remaining at the time of sacrifice, but 11 of the 12 animals in the tPA group were completely free of clot. The results of electron microscopic studies of the cerebral arteries correlated with angiography, and there was no histological evidence of brain inflammation associated with the intrathecal use of tPA.
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PMID:Effect of intrathecal thrombolytic therapy on subarachnoid clot and chronic vasospasm in a primate model of SAH. 314 95

Two randomised controlled clinical trials in patients with recently ruptured intracranial aneurysms were undertaken using tranexamic acid (AMCA) to prevent early recurrent bleeding. In our accumulated series of 105 patients 53 were given AMCA and 52 were controls. 13% of the AMCA-treated patients and 31% of the controls rebled. In patients treated with AMCA the recurrent bleeding took place later than the rebleeding in the control patients. Vasospasm and delayed cerebral ischaemic deficits were seen more frequently in patients treated with AMCA. Total mortality from rebleeding and cerebral ischaemia was 25% in AMCA-treated patients and 19% in the controls during the six weeks' observation time. Coagulation factors remained unaffected by the drug. Local fibrinolysis in the cerebrospinal fluid decreased after one week in patients treated with AMCA. After two weeks the fibrinolytic activity was similar in AMCA-treated patients and in the controls. After experimental subarachnoid haemorrhage in 90 rabbits, AMCA was found to suppress plasminogen activator activity, mainly in the leptomeninges. This occurred however only during the first few postbleeding days. Antifibrinolytic agents only appear to reduce the risk of recurrent bleeding during the first ten day period after the primary aneurysm rupture. However they also seem to produce delayed cerebral ischaemia in patients with subarachnoid haemorrhage. Synthetic antifibrinolytics evidently shift the incidence of rebleeding curve to the right but these drugs are probably of diminished value in the subsequent weeks of risk.
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PMID:Antifibrinolytic treatment in subarachnoid haemorrhage: present state. 704 63

The influence of tranexamic acid (AMCA) on the fibrinolytic activity induced by plasminogen activators (PA) of the cerebral leptomeninges, arteries and choroid plexus after artificial subarachnoid haemorrhage (SAH) was studied in 90 rabbits. SAH was induced by injection of 1-2 ml autologous blood into the suboccipital cistern. Half of the rabbits were given AMCA, 200 mg per kg body weight, in daily single i.v. injections. The rabbits were sacrificed after 3-5, 8-10 and 14-15 days respectively. Part of the leptomeninges, basilar artery and choroid plexus were removed for assaying PA by the histochemical fibrin slide and fibrin plate methods, using thiocyanate for extraction of plasminogen activator from the tissues. Quantitative assays for the fibrin plate method showed high PA in the arterial and meningeal tissues from the untreated animals 3-5 days after SAH. The PA had decreased to normal levels 8-10 days after SAH but increased again 14-15 days after SAH. A lower PA in the choroid plexus followed the same pattern. The concentration of the primary plasmin inhibitor in plasma had decreased to half of the normal value 8 days after SAH when compared to the concentration in pooled plasma from normal rabbits. In AMCA treated animals the meningeal PA, assayed by both methods, was decreased 3-5 days after SAH while no or an insignificant decrease in PA was seen 8-10 and 14-15 days after SAH. The PA of the arterial vessel wall and choroid plexus in the AMCA treated animals, assayed by the histochemical method, was moderately decreased 3-5 days after SAH, while no significant differences between untreated and AMCA treated animals were seen after 8-10 or 14-15 days when the tissues were assayed by either method. These findings indicate that AMCA suppresses PA primarily in the leptomeninges during the first few days after SAH and presumably before the meningeal fibrosis has developed.
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PMID:Fibrinolytic activity of cerebral tissue after experimental subarachnoid haemorrhage: inhibitory effect of tranexamic acid (AMCA). 719 59

The results of a Phase II clinical trial of intrathecal recombinant tissue-type plasminogen activator for the prevention of vasospasm were reported. The subjects were 53 patients with aneurysmal subarachnoid hemorrhage (SAH), Groups 2 to 4 in Fisher's preoperative computed tomography classification and Grades II to IV in the Hunt-Kosnik classification. Twenty-four hours after surgery, tissue-type plasminogen activator (TD-2061) was intracisternally administered via a catheter (0.1, 0.2, or 0.4 mg, three times daily for 5 days). The clot-dissolving effects assessed as "effective" and "markedly effective" were virtually the same in the 0.1- and 0.2-mg groups (66.7% and 64.3%, respectively) but slightly lower (53.3%) in the 0.4-mg group, suggesting an adequate effect in the 0.1- and 0.2-mg groups. Severe angiographic vasospasm was not observed in any of three groups. No intergroup differences were noted in the incidence of symptomatic vasospasm, low density on computed tomography 1 month after SAH, and functional prognosis. Bleeding complications were noted in 4 patients (7.5%), including 1 case of SAH in the low 0.1-mg group, 2 cases of SAH in the 0.2-mg group, and 1 case of epidural hematoma in the 0.4-mg group. In overall safety rating, 3 cases with increased SAH and 1 case of epidural hematoma were assessed as "safety doubtful." Other minor side effects such as headache and hepatic dysfunction attributed to the effect of other simultaneously used drugs were assessed as "almost safe," and the rate of "almost safe" and "better" for all dose groups was about 90%, suggesting a safe dose level for all groups. These results suggest that repeated intrathecal administration of tissue-type plasminogen activator is useful for preventing vasospasm even in the low dose of 0.1 mg.
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PMID:A phase II clinical trial of recombinant human tissue-type plasminogen activator against cerebral vasospasm after aneurysmal subarachnoid hemorrhage. 780 2

Safety and efficacy of the thrombolytic agent urokinase (URO) in the elimination of subarachnoid clot and prevention of chronic vasospasm was compared with tissue-type plasminogen activator (rt-PA) in a blind, randomized placebo-controlled trial. Twenty monkeys were randomly assigned to one of five groups of four. Each group underwent baseline cerebral angiography followed by bilateral craniectomy and experimental subarachnoid hemorrhage. An Ommaya reservoir was inserted on the right side with its catheter placed into the ipsilateral subarachnoid space. Twenty-four hours later, depending upon group assignment, the animals received 100,000 IU URO, 200,000 IU URO, 1 mg rt-PA, 2 mg rt-PA, or the equivalent volume of normal saline (control group). On Day 7, angiography was repeated and the animals were killed. One animal died as a result of complications during the baseline angiography, presumably due to blood loss and prolonged anesthesia, and a replacement animal was obtained. No animals demonstrated any delayed neurological deficits. The study demonstrated that a single intracisternal bolus injection of rt-PA, 2.0 mg in 2 ml sterile water, or URO, 200,000 IU in 2 ml sterile water, 24 hours after induction of experimental subarachnoid hemorrhage in primates, was equally effective in thrombolysing ipsilateral clot, but neither dosage prevented angiographic vasospasm. Vasospasm occurred bilaterally in all groups. Whereas gross subarachnoid clot was found bilaterally in all animals in the placebo group and both smaller-dose URO and rt-PA groups, right-sided subarachnoid clot was virtually absent and left-sided clot reduced in both higher-dose URO and rt-PA groups.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparison of intrathecal administration of urokinase and tissue plasminogen activator on subarachnoid clot and chronic vasospasm in a primate model. 823 10

The authors have evaluated the efficacy of postoperative intrathecal injections of tissue-type plasminogen activator (tPA) in preventing cerebral vasospasm in patients with a diffuse thick subarachnoid hemorrhage (SAH). The present study examined 105 patients who underwent direct surgery within 48 hours of SAH and whose computerized tomography (CT) findings were classified as Fisher CT Group 3. Patients showing diffuse thick subarachnoid blood clots on CT with greater than 75 Hounsfield units (HU) were included in the tPA therapy group and those with below 75 HU comprised the control group. The surgical method was the same in both groups, and both groups had cisternal drainage instituted. On the day following the operation, the tPA group was given an intrathecal injection of tPA (2 mg), and this was continued for several days until all of the cisterns exhibited low density on CT scans. Follow-up angiography showed that 26 cases (87%) in the tPA group had no vasospasm, three (10%) had moderate vasospasm, and one (3%) had severe vasospasm. All four patients showing spasm on angiography were asymptomatic, and there were no cases of delayed ischemic neurological deficits (DIND). In contrast, there were 11 cases (15%) with DIND in the control group. In the tPA group, there was one case of SAH caused by drainage catheter removal, one with a small epidural hematoma, and one with subgaleal fluid accumulation; all of these were treated conservatively with favorable results. Overall, there were no infectious complications related to cisternal drainage and intrathecal injection of tPA. These results indicate that multiple intrathecal injections of small doses of tPA are effective and safe in preventing vasospasm. On the basis of this experience, the authors conclude that injection of 2 mg of tPA daily for 5 days (a total of 10 mg) is effective in preventing the development of vasospasm.
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PMID:Prospective study on the prevention of cerebral vasospasm by intrathecal fibrinolytic therapy with tissue-type plasminogen activator. 843 45

Aneurysmal subarachnoid hemorrhage (SAH) affects approximately 30,000 people each year in North America. At least 30% of these patients will develop vasospasm as a result of the initial hemorrhage, and two thirds of these develop permanent disabilities or die. Blood deposited into the basal cisterns from the ruptured aneurysm can form thick clots around the major cerebral vessels. The by-products of the hemolyzed clots are believed to be responsible for the subsequent development of vasospasm. Hypervolemic, hypertensive, hemodilution therapy (HHHT) and nimodipine may improve outcome in some cases but there is no therapy known to prevent vasospasm in all patients. One potential therapeutic agent under investigation is tissue plasminogen activator (t-PA), a fibrinolytic enzyme. Instilled into the basal cisterns at time of aneurysm clipping, t-PA dissolves the clot so spasmogenic substances may be removed, thus preventing or reducing the severity of vasospasm.
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PMID:Innovations in aneurysmal subarachnoid hemorrhage: intracisternal t-PA for the prevention of vasospasm. 871 59

New therapies of cerebral vasospasm aim to prevent the effects of subarachnoid haemorrhage. These effects result in red blood cell haemolysis and release of oxyhaemoglobin, free radicals formation and lipid peroxidations, imbalance in endothelial modulation of vasomotor tone and activation of the complement system. Low doses of fibrinolytic agents administered intrathecally accelerate the fibrinolysis of the clot and reduce the oxyhaemoglobin release. The tissue-type plasminogen activator has proven to be effective in preventing vasospasm, but the modalities of this therapy remain to be defined. Free radical reactions may be inhibited by free radical scavengers and inhibitors of lipid peroxidations. Tirilazad is a potent inhibitor of lipid peroxidations, which improves the patients' outcome and has gone to Phase III human trials. Superoxide dismutase and tropolone derivatives are currently evaluated in animal models. Vasomotor tone can be modified in experimental models either by blocking endothelin receptors (BQ-123), or by facilitating the release and enhancing the effect of nitric oxide using protein kinase C inhibitors, drugs that increase intracellular calcium (cyclopiazonic acid, LP-805) and free radicals scavengers (superoxide dismutase). These possibilities are being investigated. Finally, preliminary studies have demonstrated the efficacy of FUT-175, an inhibitor of the complement system, in the prevention of vasospasm. In the next years, these new therapies have to be validated by prospective and randomized clinical trials to propose guidelines for the management of patients at risk of cerebral vasospasm after aneurysmal rupture.
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PMID:[Pharmacological therapeutic prospects of cerebral vasospasm]. 875 98


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