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Biomedical subjects

A A Sasahara

Publications and source records attributed to A A Sasahara.

At least 19 recordsLinked to original sources
PubMed2000

Long-term benefit of thrombolytic therapy in patients with pulmonary embolism.

A total of 23 of the 40 patients who had angiographically proven pulmonary embolism and who had initially been randomized to an IV infusion of heparin (n = 11) or a thrombolytic agent (urokinase or streptokinase, n = 12) were restudied after a mean follow-up of 7.4 years to measure the right-sided pressures and to evaluate their response to exercise during supine bicycle ergometry. Results showed that, at rest, the pulmonary artery (PA) mean pressure and the pulmonary vascular resistance (PVR) were significantly higher in the heparin group compared with the thrombolytic group (22 vs. 17 mmHg, p<0.05, and 351 vs. 171 dynes s(-1) cm(-5), p<0.02, respectively). During exercise both parameters rose to a significantly higher level in the heparin group (from rest to exercise, PA: 22-32 mmHg, p<0.01; PVR: 351-437 dynes s(-1) cm 5, p<0.01, respectively), but not in the thrombolytic group (rest to exercise, PA: 17-19 mm Hg, p = NS; PVR: 171-179 dynes s(-1) cm(-5), p = NS). It is concluded that thrombolytic therapy preserves the normal hemodynamic response to exercise in the long term and may prevent recurrences of venous thromboembolism and the development of pulmonary hypertension.

Blood Pressure↗
PubMed1998

A comparison of recombinant urokinase with vascular surgery as initial treatment for acute arterial occlusion of the legs. Thrombolysis or Peripheral Arterial Surgery (TOPAS) Investigators.

BACKGROUND: Recent controlled trials suggest that thrombolytic therapy may be an effective initial treatment for acute arterial occlusion of the legs. A major potential benefit of initial thrombolytic therapy is that limb ischemia can be managed with less invasive interventions. METHODS: In this randomized, multicenter trial conducted at 113 North American and European sites, we compared vascular surgery (e.g., thrombectomy or bypass surgery) with thrombolysis by catheter-directed intraarterial recombinant urokinase; all patients (272 per group) had had acute arterial obstruction of the legs for 14 days or less. Infusions were limited to a period of 48 hours (mean [+/-SE], 24.4+/-0.86), after which lesions were corrected by surgery or angioplasty if needed. The primary end point was the amputation-free survival rate at six months. RESULTS: Final angiograms, which were available for 246 patients treated with urokinase, revealed recanalization in 196 (79.7 percent) and complete dissolution of thrombus in 167 (67.9 percent). Both treatment groups had similar significant improvements in mean ankle-brachial blood-pressure index. Amputation-free survival rates in the urokinase group were 71.8 percent at six months and 65.0 percent at one year, as compared with respective rates of 74.8 percent and 69.9 percent in the surgery group; the 95 percent confidence intervals for the differences were -10.5 to 4.5 percentage points at six months (P=0.43) and -12.9 to 3.1 percentage points at one year (P=0.23). At six months the surgery group had undergone 551 open operative procedures (excluding amputations), as compared with 315 in the thrombolysis group. Major hemorrhage occurred in 32 patients in the urokinase group (12.5 percent) as compared with 14 patients in the surgery group (5.5 percent) (P= 0.005). There were four episodes of intracranial hemorrhage in the urokinase group (1.6 percent), one of which was fatal. By contrast, there were no episodes of intracranial hemorrhage in the surgery group. CONCLUSIONS: Despite its association with a higher frequency of hemorrhagic complications, intraarterial infusion of urokinase reduced the need for open surgical procedures, with no significantly increased risk of amputation or death.

Acute Disease↗
PubMed1998

Interventional use of plasminogen activators in central nervous system diseases.

Still an experimental approach, the direct intra-arterial infusion of plasminogen activators in the setting of acute thrombotic stroke has received impetus from successful clinical trials of intravenous infusion therapy. Direct therapy, employing catheter delivery, has successfully produced evidence of recanalization in carotid artery territory and vertebrobasilar artery territory thrombotic occlusions. One very recent prospective randomized study has demonstrated the success and limitations of this approach. Attention to safety concerns will be important to the future success of direct intra-arterial delivery of plasminogen activators in acute thrombotic stroke.

Central Nervous System Diseases↗
PubMed1996

Thrombolysis or peripheral arterial surgery: phase I results. TOPAS Investigators.

PURPOSE: Thrombolytic therapy is widely used in the treatment of peripheral arterial occlusion, but prospective, randomized comparisons with standard therapy remain few. A multicenter trial of thrombolysis or peripheral arterial surgery (TOPAS) was organized to compare critically the use of recombinant urokinase (rUK) or surgery for the initial treatment of acute lower-extremity ischemia. Phase I of the trial was designed as a dose-ranging trial to evaluate the safety and efficacy of three doses of rUK in comparison with surgery. METHODS: In a multicenter, prospective, double-blind comparison, 213 patients who had acute lower-extremity ischemia for 14 days or fewer were randomized to one of two groups. The first group received one of three dosages of rUK (catheter-directed at 2000, 4000, or 6000 IU/min for 4 hours, then 2000 IU/min to a maximum of 48 hours). The second group underwent surgery. Successful thrombolysis was followed by surgical or endovascular interventions when anatomic lesions responsible for the occlusion were unmasked. Patients were followed-up for 1 year; data were evaluated on an intent-to-treat basis. RESULTS: The 4000 IU/min rUK dosage was chosen as the most appropriate thrombolytic regimen because it maximized lytic efficacy against the risk of bleeding. Complete (> 95%) lysis of thrombus was achieved in 71% of the 49 patients who were randomized to the 4000 IU/min group, with a mean infusion time of 23 hours. In contrast, complete lysis was achieved in 67% of patients who received 2000 IU/min and in 60% of patients who received 6000 IU/min. Hemorrhagic complications occurred in 2% of the 4000 IU/min group versus 13% of the 2000 IU/min group (p = 0.05) and 16% of the 6000 IU/min group (p = 0.03). In a comparison of the 4000 IU/min group with the surgical group, the 1-year mortality rate (14% vs 16%) or amputation-free survival rate (75% vs 65%) did not differ significantly. The frequency and magnitude of surgery in the patients randomized to rUK were decreased (p < 0.001). CONCLUSION: The preliminary results suggest that an initial rUK dose of 4000 IU/min is safe and efficacious in the treatment of acute lower-extremity ischemia. rUK therapy is associated with limb salvage and patient survival rates similar to those achieved with surgery, concurrent with a reduced requirement for complex surgery after thrombolytic intervention.

Acute Disease↗
PubMed1994

New recombinant glycosylated prourokinase for treatment of patients with acute myocardial infarction. Prourokinase Study Group.

OBJECTIVES: Three dosage regimens of a new recombinant glycosylated prourokinase (A-74187) were evaluated by measuring coronary artery patency at 90 min in patients with acute myocardial infarction. BACKGROUND: Prourokinase is a thrombolytic drug with unique pharmacologic properties that may be clinically advantageous. METHODS: Aspirin (325 mg), intravenous heparin and prourokinase (60- or 80-mg monotherapy or 60 mg "primed" with a preceding bolus dose of 250,000 IU of recombinant urokinase) were administered to 128 patients. Coronary angiography was performed at 60 min (wherever possible), 90 min (primary end point) and 24 h to determine arterial patency and reocclusion rates. Plasma was collected serially to measure fibrinogen, plasminogen, thrombin antithrombin III and fibrinopeptide A. Clinical events until hospital discharge were recorded. RESULTS: The coronary artery patency rate at 90 min was similar for all three regimens, averaging 73% (95% confidence interval [CI] 64% to 80%); Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow rates averaged 52% (95% CI 42% to 61%). Arterial patency at 60 min was 62% (95% CI 50% to 73%), and reocclusion occurred in 1.4% (95% CI 0.1% to 4.1%). Prourokinase demonstrated relative fibrin specificity at all doses studied. Fibrinopeptide A and thrombin antithrombin III levels were elevated at baseline and declined rapidly during the 1st 12 h. There was no difference in the baseline values of these thrombin markers between patients with patent versus closed arteries at 90 min. There was one death; no strokes occurred. CONCLUSIONS: A-74187 prourokinase is a rapid-acting, effective fibrin-specific thrombolytic agent. Reocclusion was unusual, possibly because of aggressive anticoagulation with intravenous heparin or unique features of the drug. Full definition of the clinical effectiveness of this drug merits examination in future randomized trials evaluating clinical and angiographic effectiveness.

Aspirin↗
PubMed1993

Effect of recombinant-tissue plasminogen activator, low molecular weight urokinase and unfractionated heparin on platelet aggregation.

We studied the interaction of two thrombolytic agents, recombinant-tissue plasminogen activator (r-TPA) and low molecular weight urokinase (UK), with platelet aggregation in the absence or presence of unfractionated heparin (UH). With platelet rich plasma (PRP), a dose dependent inhibition was seen for both r-TPA and UK. However, this effect was more evident in the presence of r-TPA. UH did not modify this effect. However, it enhanced platelet aggregation induced by ADP and decreased the aggregation induced by collagen (COL) as already shown by us. With washed platelets, only r-TPA decreased platelet aggregation in a dose dependent manner in the presence of COL and only at the highest dose (100 micrograms) in the presence of TH. The presence of ten units of plasminogen (PLG) together with 10 micrograms of r-TPA or 1250 units of UK totally inhibited TH-induced platelet aggregation. UH reversed this effect. In contrast, when COL was the aggregating agent, the inhibition of platelet aggregation in presence of PLG, seems to be further increased by UH. Since UH is an adjunct of thrombolytic therapy to prevent rethrombosis, this double edged sword could partially explain the lack of therapeutic effect in some patients.

Adenosine Diphosphate↗
PubMed1992

New developments in thrombolytic therapy.

Pharmacologic lysis of occlusive, ischemia-producing thrombi has become widely accepted during the past decade. New developments in this field have centered around increasing the efficacy of the known plasminogen activators while employing methods to minimize the risk of hemorrhage and decrease the incidence of rethrombosis. Such methods have included the use of thrombus-directed antibodies linked to plasminogen activators, increased plasminogen (substrate) concentration at the thrombus site, anticoagulant and antiplatelet therapy to prevent thrombus propagation and reformation following lysis, and combination plasminogen activator therapy designed to increase efficacy and safety. These new strategies have been extensively tested in vitro and in a variety of animal models. As we have indicated, extrapolation of such results to human patients cannot be done with confidence. However, the strategies are based on sound rationale and the reported findings should serve as the basis for controlled human trials.

Humans↗
PubMed1992

Approach to the patient with venous thromboembolism. Treatment with thrombolytic agents.

This article reviews the different thrombolytic agents currently available and the different mechanisms by which they activate the body's fibrinolytic system. The discussion is confined to the approach to the patient with venous thromboembolism using the different thrombolytic agents. Data are presented supporting the use of thrombolytic therapy and its long-term benefits, especially in patients with pulmonary embolism. A substantial portion of this article is devoted to practical considerations involved in the administration of thrombolytic therapy.

Amino Acid Sequence↗
PubMed1991

Enhancement of the thrombolytic efficacy of prourokinase by lys-plasminogen in a dog model of arterial thrombosis.

Current findings suggest that the efficacy of thrombolytic therapy may be limited by the availability of active forms of plasminogen at the thrombus site. The purpose of this study was to determine if the systemic administration of 0.5 mg kg-1 glu-plasminogen (glu-plg) or 0.5 mg kg-1 lys-plasminogen (lys-plg) could safely increase the efficacy of a single intravenous bolus injection of 50,000 U kg-1 prourokinase (proUK) in a dog model of arterial thrombosis. Thrombolysis was measured by monitoring the continuous decrement of 125I-gamma emissions from a radiolabeled thrombus. Reflow was evaluated by direct visual examination. Forty dogs (mean wt 10.3 +/- 2 kg) were randomly sorted into 4 groups of 10 each. The dogs in each group were given either saline plus saline, saline plus proUK, glu-plg plus proUK, or lys-plg plus proUK 60 minutes after formation of an occlusive arterial thrombus. Ninety minutes after drug administration the dogs receiving saline plus proUK, glu-plg plus proUK, and the lys-plg plus proUK showed greater thrombolysis (41%, 43%, and 66%, respectively) than the control (saline plus saline) group (15%, P less than 0.01). The lys-plg plus proUK treatment caused greater lysis than the saline plus proUK or the glu-plg plus proUK treatment (P less than 0.05). All of the dogs (10/10) receiving lys-plg plus proUK had patent vessels at the end of the 90 minute monitoring period, whereas only 4/10 and 5/10 vessels were patent in the saline plus proUK and glu-plg plus proUK groups, respectively. None of the dogs in the saline plus saline group had patent vessels. No significant changes were observed in the various coagulation parameters tested for any of the 4 treatment groups. The results show that lys-plg can safely increase the thrombolytic efficacy of proUK.

Analysis of Variance↗
PubMed1991

The beneficial effect of lys-plasminogen upon the thrombolytic efficacy of urokinase in a dog model of peripheral arterial thrombosis.

The efficacy of thrombolytic therapy may be limited by local availability of plasminogen near a poorly perfused thrombus. The purpose of this study was to determine if the local (i.e., clot site) administration of 0.5 mg glu-plasminogen (glu-plg) or 0.5 mg lysplasminogen (lys-plg) could safely increase the thrombolytic efficacy of a 30-min intraarterial injection of 3,500 U kg-1 of two-chain urokinase plasminogen activator (UK) in a dog model of arterial thrombosis. Thrombolysis was measured by monitoring the continuous decrement of 125I-gamma emissions from a radiolabeled thrombus. Reflow was evaluated by a distally placed flowmeter and by direct visual examination. Forty-two dogs (mean weight 10.1 +/- 1.9 kg) were randomly sorted into six groups of 7 each. The dogs in each group were given either saline plus saline (group 1), saline plus UK (group 2), glu-plg plus saline (group 3), glu-plg plus UK (group 4), lys-plg plus saline (group 5), or lys-plg plus UK (group 6) by selective arterial catheterization 60 min after formation of an occlusive thrombus. Ninety minutes following drug administration, all groups which received UK (groups 2, 4, and 6) showed greater lysis (p less than 0.05) than the groups which received only saline or either glu- or lys-plg plus saline. Group 6, which received lys-plg plus UK, showed significantly greater lysis (34 +/- 4%) than both group 2 (23 +/- 2%), which received saline plus UK, and group 4 (19 +/- 3%), which received glu-plg plus UK (p less than 0.05). All dogs (7/7) in group 6 had reflow at 90 min whereas only 3/7 dogs had reflow in both groups 2 and 4.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Prospective study of a standardized questionnaire to improve clinical estimate of pulmonary embolism.

A standardized questionnaire was administered to 100 patients suspected of having pulmonary embolism to investigate whether clinical data may be reliably used in the decision-making process of such patients. Questionnaire data were compared with lung scintigraphy outcome and 16 variables were selected as significantly associated with the scintigraphic diagnosis. Based on these variables, patients with abnormal scintigraphy compatible with pulmonary embolism and patients with scintigraphy not compatible with embolism were classified in accordance with the scintigraphic diagnosis. When these 16 variables were tested in an additional validation group, clinical and scintigraphic diagnosis matched in most cases. These results show that clinical data can be used to predict the outcome of lung perfusion scintigraphy in patients suspected of pulmonary embolism. Use of a standardized questionnaire can improve the accuracy of pretest assessment of such patients and positively influence the decisions to start heparin coverage or obtain pulmonary angiography.

Electrocardiography↗
PubMed1988

Serial determinations of PF4 and beta TG: comparisons between multiple venipunctures vs a catheter infusion system.

Platelet factor 4 (PF4) and beta thromboglobulin (beta TG) are platelet-specific proteins which are released upon platelet aggregation and which can be accurately measured by radioimmunoassay. We devised a catheter-infusion system that enables serial determinations of these proteins. In 20 subjects (10 healthy volunteers and 10 patients with stable coronary artery disease), we compared samples collected by individual venipunctures with those simultaneously obtained by means of a simple catheter-infusion system. At least 5 samples were obtained over a period of time which was as long as 60 min, and at least 30 min. Subjects with stable coronary artery disease were selected so that they would be expected to have stable and normal PF4 and beta TG levels. Thus, elevations of either PF4 or beta TG would represent artifacts secondary to sampling technique. Analysis of the results demonstrated that the catheter-infusion system was equivalent to individual venipunctures for determination of PF4 and beta TG. 16.8% of samples obtained via the catheter and 17.2% of those obtained by individual venipunctures were spuriously elevated. A second series of studies were performed to refine the technique further by examining the impact of infusion rate and the addition of citrate phosphate dextrose (CPD) to the infusate. Ten additional subjects had catheter systems utilized in both arms simultaneously. The addition of CPD resulted in significantly less abnormal values at slower infusion rates (1 and 2.5 cc/min). At 5 cc/min D5/w or saline alone are suitable. These investigations confirm that this simple catheter system is equivalent to individual venipunctures for determination of PF4 and beta TG while avoiding patient discomfort.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1988

Fundamentals of fibrinolytic therapy.

The fibrinolytic system is activated by the conversion of plasminogen to plasmin by mediators such as tissue extract, plasma factor XII, or the exogenous activators urokinase (UK) and streptokinase (SK). The foreign protein composition of SK is responsible for the allergic response observed in some patients following administration. Clinical and investigational evidence has also shown a higher incidence of hemorrhagic complications with SK compared with UK. In general, thrombolytic therapy is a safe, effective way to resolve thrombotic obstruction in patients with such problems as acute pulmonary embolism, acute myocardial infarction, or occluded intravascular lines.

Fibrinolytic Agents↗
PubMed1988

Dihydroergotamine/heparin in the prevention of deep-vein thrombosis after total hip replacement. A controlled, prospective, randomized multicenter trial.

In a randomized, double-blind, placebo-controlled multicenter trial, the efficacy and safety of dihydroergotamine mesylate/heparin sodium as a prophylactic agent for deep-vein thrombosis were evaluated in 148 patients who were forty years old or more and who underwent total hip replacement. The incidence of venographically proved postoperative deep-vein thrombosis was 52 per cent in the placebo group and 25 per cent in the dihydroergotamine mesylate/heparin sodium group (p = 0.002). Proximal thrombi developed in only 5 per cent and extensive thrombi, in only 10 per cent of the patients who received dihydroergotamine mesylate/heparin sodium. In contrast, proximal thrombi and extensive thrombi developed in 19 and 25 per cent, respectively, of the patients in the placebo group (p less than 0.05). Adverse reactions in the two groups did not differ significantly: in the treatment group they consisted primarily of hematoma at the site of injection (9 per cent), hematoma at the wound (5 per cent), and excessive postoperative bleeding, and in the placebo group there was hematoma at the site of injection (3 per cent). It was concluded that the combination agent dihydroergotamine mesylate/heparin sodium was effective and safe prophylaxis against deep-vein thrombosis for the patients who underwent total hip replacement in this study.

Adult↗