Mg Of rt-PA Research Articles

Safety and Efficacy of Intrathecal Thrombolytic Therapy in a Primate Model of Cerebral Vasospasm

To test the safety of a large intrathecal dose of human recombinant tissue plasminogen activator (rt-PA), 6 cynomolgous monkeys were given 10 mg of rt-PA (mean, 2.7 mg/kg) through an Ommaya reservoir after craniectomy and dissection of the basal cisterns. Bleeding occurred briefly at the incision in 2 animals; otherwise the clinical condition of all 6 remained normal throughout the postoperative period. Systemic fibrinolysis did not occur, and gross and microscopic examination of the brain and meninges revealed no abnormality. Next, we evaluated the efficacy of unilateral administration of rt-PA suspension (0.5 mg) plus slow-release gel rt-PA (1.25 mg) in lysing a bilateral subarachnoid clot and preventing vasospasm in a randomized, placebo-controlled trial. Sixteen monkeys were divided randomly into 2 equal groups, each of which underwent baseline cerebral angiography, followed by frontotemporal craniectomy and induction of subarachnoid hemorrhage on the left side and then on the right. Before closure on the right side either rt-PA or an equal volume of placebo was injected into the subarachnoid space. On day 7 angiography was repeated, and the animals were killed under anesthesia for necropsy. One of the animals in the placebo group developed a cerebral infarction on day 5. In the placebo group significant vasospasm occurred in all major right and left-sided anterior cerebral vessels (P less than 0.01). No vasospasm occurred in the rt-PA-treated animals. Whereas gross subarachnoid clot was found in all animals in the placebo group (mean clot weight 1.13 g), only a small fragment of clot was found in a single rt-PA-treated animal.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of Invasive and Conservative Strategies after Treatment with Intravenous Tissue Plasminogen Activator in Acute Myocardial Infarction

We treated 3262 patients with intravenous recombinant tissue plasminogen activator (rt-PA) within four hours of the onset of chest pain thought to be caused by myocardial infarction. Of these patients, 1636 were then randomly assigned to treatment according to an invasive strategy consisting of coronary arteriography 18 to 48 hours after the administration of rt-PA, followed by prophylactic percutaneous transluminal coronary angioplasty (PTCA) if arteriography demonstrated suitable anatomy; 1626 patients were randomly assigned to treatment according to a conservative strategy, as part of which arteriography and PTCA were to be performed only in patients with spontaneous or exercise-induced ischemia. In the group assigned to the invasive strategy, PTCA was attempted in 928 of the 1636 patients (56.7 percent); the procedure was anatomically successful in 93.3 percent. In the group assigned to the conservative strategy, 216 patients (13.3 percent) underwent clinically indicated PTCA within 14 days of the onset of symptoms. Reinfarction or death within 42 days, the primary end point, occurred in 10.9 percent of the group assigned to the invasive strategy and in 9.7 percent of those assigned to the conservative strategy (P not significant). There were no significant differences between the two groups in the ejection fraction at rest or during exercise, either at hospital discharge or six weeks after randomization. Eleven of 582 patients (1.9 percent) who received 150 mg of rt-PA and 15 of 2952 patients (0.5 percent) who received 100 mg of rt-PA had intracranial hemorrhage. A subgroup of 1390 patients who were eligible for short-term intravenous beta-blockade were randomly assigned to receive 15 mg of intravenous metoprolol immediately, followed by oral metoprolol, or oral metoprolol begun on day 6. The ejection fraction and the incidence of death in the two groups were similar during the hospital period. Total mortality within the first 6 days and at 42 days was also similar. However, in the group that received intravenous metoprolol, 16 patients had nonfatal reinfarctions and 107 patients had recurrent ischemic episodes by six days after entry into the study, as compared with 31 and 147 patients, respectively, among those randomly assigned to deferred oral beta-blockade (P = 0.02 and P = 0.005, respectively); the latter comparison was considered statistically significant according to the study criteria.(ABSTRACT TRUNCATED AT 400 WORDS)

Intrathecal Fibrinolytic Therapy after Subarachnoid Hemorrhage: Dosage Study in a Primate Model and Review of the Literature

Because of the naturally low fibrinolytic activity of CSF many erythrocytes entrapped in subarachnoid blood clot undergo hemolysis in situ, releasing vasogenic oxyhemoglobin (OxyHb) in high concentrations around the basal cerebral arteries. In order to promote more rapid clearance of erythrocytes from the basal subarachnoid cisterns we are currently investigating intrathecal thrombolytic therapy with human, recombinant, tissue plasminogen activator (rt-PA) in a primate model of subarachnoid hemorrhage (SAH) and cerebral vasospasm (VSP). In the present study 16 monkeys were divided into 4 groups of 4, and each group received a different dose of sustained-release gel rt-PA at the time of experimental SAH. Cerebral angiography seven days later showed that whereas no VSP occurred in the groups receiving 0.5 or 0.75 mg of rt-PA, mild to moderate VSP occurred in the groups receiving 0.125 or 0.25 mg of rt-PA. Analysis of the combined 2 smaller dosage groups revealed significant (P less than 0.05) reduction of lumen caliber in the clot-side internal carotid (C3 and C4), proximal anterior cerebral (A1) and middle cerebral (MCA) arteries. Gross subarachnoid clot remained in all of the animals in the 0.125 and 0.25 mg dose groups, in 2 of the animals in the 0.5 mg dose group, and none of the animals in the 0.75 mg dose group. It was concluded that 0.75 mg of gel rt-PA is sufficient to completely lyse a 4.25 ml SAH and prevent VSP in our primate model. The literature on fibrinolysis and erythrocyte clearance in cerebrospinal fluid (CSF) is reviewed.

Monitoring of Hemostasis Parameters During Coronary Thrombolysis with Recombinant Tissue-Type Plasminogen Activator

The monitoring of changes in the blood coagulation and fibrinolytic systems during thrombolytic therapy with recombinant tissue-type plasminogen activator (rt-PA) may be complicated by artifacts due to in vitro activation after blood collection and to interference of other agents (e.g., heparin) in the assays. In 106 patients with early acute myocardial infarction, infused with 150 mg of rt-PA (G11044) intravenously over 5 to 8 hours, blood samples were collected into liquid citrate supplemented with the plasmin inhibitor aprotinin (200 KIU/ml plasma) or on a lyophilized mixture of acidified citrate and the synthetic t-PA inhibitor D-Phe-Pro-Arg-CH2Cl (PPACK). A good correlation between precipitable (sulphite) and functional (clotting rate) fibrinogen levels was observed in plasma collected on citrate before therapy (r = 0.76) and in samples collected after 3 hours on either aprotinin (r = 0.87) or PPACK (r = 0.82). Precipitable fibrinogen levels were approximately 10% higher than functional level, in baseline samples collected on citrate alone and approximately 20% higher in 3 hour samples collected on either PPACK or aprotinin. Fibrinogen levels measured with both assays correlated well, but were somewhat higher in samples collected on PPACK than on aprotinin. rt-PA antigen levels assayed in plasma collected in either inhibitor correlated well (r = 0.90) but were 10-20% higher in PPACK containing samples. Addition of heparin up to 9 units/ml to plasma had no effect on the functional fibrinogen assay.(ABSTRACT TRUNCATED AT 250 WORDS)

The thrombolysis in myocardial infarction (TIMI) phase II pilot study: Tissue plasminogen activator followed by percutaneous transluminal coronary angioplasty

The Thrombolysis in Myocardial Infarction (TIMI) Study Group is investigating whether percutaneous transluminal coronary angioplasty or intravenous beta-receptor blockers, or both, are useful adjuncts to recombinant tissue-type plasminogen activator (rt-PA) in the treatment of patients with acute myocardial infarction (TIMI II study). A total of 317 patients with acute myocardial infarction were treated an average of 2.7 hours after the onset of chest pain during the course of a nonrandomized pilot investigation with 150 mg of rt-PA given over 6 hours. This dose of rt-PA resulted in a high rate of infarct-related coronary artery patency (82 and 87% of patients catheterized an average of either 1 or 32 hours after entry, respectively) and a low 21 day mortality rate of 4.4%. Coronary angioplasty was performed successfully in greater than 90% of patients with appropriate anatomy and in greater than 50% of those treated with rt-PA. In 75 patients treated within 2 hours of the onset of chest pain only 2 (2.7%) were dead by 6 weeks. However, five cases of intracranial hemorrhage were noted, and the rt-PA dose was subsequently reduced to 100 mg given over 6 hours. The TIMI II design and the results of the TIMI II pilot study are discussed.

Coronary arterial thrombolysis with low-dose synergistic combinations of recombinant tissue-type plasminogen activator (rt-PA) and recombinant single-chain urokinase-type plasminogen activator (rscu-PA) for acute myocardial infarction

The effect of combined intravenous infusion of 10 mg of recombinant tissue-type plasminogen activator (rt-PA) and 10 mg of recombinant single-chain urokinase-type plasminogen activator over 1 hour on coronary artery recanalization and on the blood fibrinolytic system was studied in 9 patients with acute myocardial infarction and angiographically confirmed coronary artery occlusion. In 3 of these patients, prior infusion of 10 mg of rt-PA over 1 hour before the first angiogram had not produced coronary artery reperfusion. Complete recanalization was achieved in 7 patients and transient recanalization with reocclusion in 1 patient, whereas coronary artery occlusion persisted in 1 patient. At the end of the infusion, the fibrinogen level remained unchanged and no increase in fibrinogen degradation products was observed, whereas the α 2 antiplasmin level had decreased to 61 ± 16 % (mean ± standard deviation) of the preinfusion level. Thus, combined intravenous infusion of rt-PA and recombinant single-chain urokinase-type plasminogen activator induces fibrin-specific coronary thrombolysis at approximately one-fourth of the dose currently used for each agent alone, which further documents the pharmacologic synergism of these agents.

Acute coronary thrombolysis with recombinant human tissue-type plasminogen activator: Initial patency and influence of maintained infusion on reocclusion rate

An intravenous infusion of 40 mg of recombinant tissue-type plasminogen activator (rt-PA) was given intravenously over 90 minutes to 123 patients with acute myocardial infarction (AMI) of less than 4 hours' duration. A coronary angiogram was recorded at the end of the infusion in 119 patients. Central assessment of the angiograms revealed a patent infarct-related artery in 78 patients (patency rate 66%, 95% confidence limits 57 to 74%). Patients with a patent infarct-related artery at the first angiogram were randomized in a double-blind manner to receive a subsequent 6-hour infusion of either 30 mg of rt-PA or placebo. All patients had received an initial bolus of 5,000 IU of heparin and then 1,000 IU/hour until a second angiogram was recorded 6 to 24 hours after the start of the second perfusion. At central assessment of the second coronary angiogram the reocclusion rate was 2 of 36 patients who received rt-PA at the second infusion and 3 of 37 patients not receiving this drug (or the 2 groups combined 7%, 95% confidence limits 2 to 15%). Three of 60 patients (5%, 95% confidence limits 1 to 14%) with patent arteries on both previous angiograms had a later occlusion as judged on the angiogram recorded at hospital discharge. No difference in late reocclusion rates between the 2 treatment groups was observed.

Acute coronary reocclusion after thrombolysis with recombinant human tissue-type plasminogen activator: prevention by a maintenance infusion.

Twenty-nine patients with acute myocardial infarction were treated with recombinant human tissue-type plasminogen activator (rt-PA). The incidence of acute coronary reocclusion and its prevention by a maintenance infusion of rt-PA were studied. Intravenous rt-PA was given at a rate of 0.4 to 0.75 mg/kg over 60 to 120 min after angiographic documentation of complete coronary occlusion. Reperfusion was accomplished within 1 hr in 24 of 29 patients (83%) and was associated with a decrease of the plasma fibrinogen level by 20%. In a first group of 13 patients, 11 of whom were successfully reperfused, prevention of reocclusion was attempted with heparin anticoagulation. However, acute reocclusion within 1 hr after cessation of rt-PA was demonstrated angiographically in five of these patients (45%). Quantitative angiographic analysis indicated that acute reocclusion only occurred in patients with 80% or greater residual stenosis. In patients with less than 80% residual stenosis, heparin anticoagulation was sufficient to maintain patency during the hospital stay in four of five patients. In a second group of patients (n = 16), 13 of whom underwent reperfusion with intravenous rt-PA, seven demonstrated a residual stenosis of 80% or greater. These patients were given heparin and, in addition, 10 mg of rt-PA per hour for 4 hr. None developed acute angiographic reocclusion or clinical signs of reocclusion during the hospital stay. Repeat angiography at 10 to 14 days confirmed persistent patency in six of the seven patients. The maintenance infusion resulted in only a moderate additional drop in fibrinogen, while a steady-state plasma rt-PA level of 750 +/- 250 ng/ml was maintained.(ABSTRACT TRUNCATED AT 250 WORDS)