Streptokinase-induced Thrombolysis Research Articles

Efficiency of targeted delivery of streptokinase based on fibrin-specific liposomes in the in vivo experiment.

Acute thrombosis has a narrow therapeutic window and remains the leading cause of morbidity and mortality, while thrombolytic therapy has limited efficacy and risk of side effects. We have developed and investigated new fibrin-specific systems for local drug delivery to increase efficiency while minimizing the side effects of streptokinase. The experiment was carried out on dogs with 2-h thrombi in the femoral artery received intravenous injections of streptokinase, liposome-bound and free streptokinase at 40/60% ratio, and immunoliposomes. The completeness of the vessel lumen restoration affected by the thrombus, and the risks of side effects were assessed. Fibrinolytic parameters (plasminogen, fibrinogen, alpha2-antiplasmin, and D-dimers levels) were measured at several time points after thrombus induction and the administration of the drug. There was a strong activation of fibrinolysis and consumption of fibrinolysis inhibitors after therapy with all liposomal forms of streptokinase. According to the ultrasound data, immunoliposomal form of streptokinase significantly reduces the degree of residual stenosis to 32% [30.5; 33.7] in 180min after injection. The high fibrinolytic effect of liposomal forms of streptokinase is not accompanied by a sharp drop in the fibrinogen concentration in the blood compared to the native streptokinase by 60min. The morphometric evaluation of the artery samples showed that immunoliposomal form of streptokinase induces a significant increase in the degree of free vascular lumen compared to the native streptokinase (71.3% (62.7; 77.5) vs. 47.7% (39.6; 55.7), p < 0.001). Thus, the study shows the efficacy of streptokinase-induced thrombolysis using immunoliposomal form of drug delivery system. Mechanism of action of the immunoliposomal delivery system.

Frequency of retinal hemorrhage after thrombolysis with streptokinase in patients presenting with ST-elevation myocardial infarction: A single-center experience at a large tertiary care center in Lahore, Pakistan

Background: Thrombolytic therapy with streptokinase is the mainstay of pharmacological treatment in acute myocardial infarction in Pakistan. Retinal hemorrhage is a common complication of streptokinase-induced thrombolysis and is often overlooked which can lead to permanent vision loss. Therefore, this study was carried out to determine the frequency of retinal hemorrhage after thrombolysis with streptokinase in patients presenting with ST-elevation myocardial infarction (STEMI).&#x0D; Patients and methods: It was an observational, cross-sectional study conducted at the Emergency Department of Mayo Hospital Lahore from 11-08-2015 to 10-02-2016. The patients underwent injection of streptokinase (1.5 million U) intravenously over 60 min and intravenous heparin 5,000 U bolus followed by 1,000 U/hour. Then patients were followed up for 24 hours followed by the ophthalmoscopy to confirm the presence of retinal hemorrhage. The data were entered and analyzed using SPSS version 20.&#x0D; Results: A total of 130 patients were included in this study. The mean age of patients was 62±9.86 years. The male to female ratio was 1.6:1. The retinal hemorrhage was present in 17 (13.08%) patients. About 80 (61.5%) were diabetics and 96 (73.8%) were hypertensive. Stratified variables like age, gender, hypertension, and diabetes were not found associated with retinal hemorrhage (p-value ≥0.05). &#x0D; Conclusion: Retinal hemorrhage was found in 13.08% after streptokinase injection in patients presenting with STEMI. Although the association was statistically insignificant but still the proportion of retinal hemorrhage was substantially high in these patients. This higher percentage demands vigilant monitoring with the drug for timely diagnosis of this ignored complication which latter can be proved hazardous to the vision.

Hemodynamic changes determine the efficacy of thrombolysis: results from an in-vitro flow model.

The efficacy of thrombolytic therapy might be influenced by changes in the hemodynamic status. The aim of the study was to examine whether changes in perfusion pressure could affect the time to reflow in an in-vitro model. The in-vitro flow system comprised flexible plastic tubes that enclosed a blood clot formed in one of the circuit arms. Streptokinase (125,000 U) or saline (control) was injected from a proximal side branch to induce thrombolysis. The protocol comprised four treatments: A, perfusion pressure 150/90 mmHg with streptokinase infusion; B, perfusion pressure 150/90 mmHg with saline; C, perfusion pressure 120/60 mmHg with streptokinase; D, perfusion pressure 120/60 mmHg with saline. Reflow was defined as flow restoration determined by the ultrasonic flowmeter. Successful recanalization was obtained in six of six samples subjected to treatment A (100%), two of seven samples subjected to treatment B (28%), three of five samples subjected to treatment C (60%) and none of six samples subjected to treatment D (0%). Time to reflow was 23 +/- 11 min with treatment A, 76 +/- 24 min with treatment B, 66 +/- 25 min with treatment C, and > 90 min with treatment D. Our data suggest that the hemodynamic status determines the efficacy of streptokinase-induced thrombolysis, and that spontaneous clot lysis is more likely to occur at greater perfusion pressures. It is conceivable that the hypotensive reaction induced by streptokinase in the clinical setting may adversely affect angiographic patency, compared with that observed with other lytic agents such as tissue-type plasminogen activator.

Preclinical and Clinical Pharmacology of Efegatran (LY294468) : A Novel Antithrombin for the Treatment of Acute Coronary Syndromes

Efegatran (LY294468), a tripeptide arginal in hibitor of the catalytic site of thrombin, is being devel oped as a parenteral anticoagulant for the treatment of acute coronary syndromes. Efegatran was studied in a canine model of coronary artery thrombosis to determine its ability to prevent thrombus formation and as an ad junctive anticoagulant to thrombolysis, in phase I clinical studies, and phase II clinical studies in unstable angina. In the preclinical in vivo studies in dogs, efegatran pro duced a dose-dependent increase in clotting times and demonstrated a selectivity for thrombin time (TT) changes. The activated partial thromboplastin time (APTT)-TT ratio (that is, based on the dose to double each clotting time) determined in dogs from ex vivo blood samples was 8: 1. This observation was similar to that obtained during the phase I studies in normal volunteers where the APTT-TT ratio was 12:1. The canine and hu man clotting systems responded similarly at doses of efe gatran where comparisons could be made (0.25-1.0 mg/ kg/h). The kinetics of the anticoagulant activity of efega tran in dogs and humans were linear and nonsaturable over the dose ranges studied. Efegatran was also found to be an effective adjunctive anticoagulant during streptoki nase-induced thrombolysis in dogs, preventing reocclu sion without increasing bleeding risk. The novel an tithrombin, efegatran, has demonstrated dose-dependent and safe anticoagulation in animal and human studies. Efegatran is presently undergoing phase II clinical studies in unstable angina and acute myocardial infarction pa tients.

Pro- and antifibrinolytic effects of ultrasound on streptokinase-induced thrombolysis

We have earlier documented that ultrasound can enhance the fibrinolytic effect of streptokinase and shorten the reperfusion time under experimental conditions. The present study concerns the magnitude of the effect in relation to ultrasound frequency, intensity and exposure time. The effect of ultrasound on the structural properties of the fibrin network was evaluated by scanning electron microscopy. Whole blood clots were created and exposed to streptokinase (5000 U/mL). In paired experiments, one clot was also exposed to pulsed ultrasound. Lysis is expressed as the percentage decrease in clot weight. Clot lysis was equally affected by ultrasound in the range of 0.5 to 2.3 MHz. Below 0.5 W/cm 2 no enhancing effect was observed, while intensities between 0.5 and 1.5 W/cm 2 resulted in a singnificant enhancement of clot lysis. Intensities above 4 W/cm 2 inhibited the fibrinolytic effect of streptokinase but not of rt-PA. From scanning electron microscopy there was no evidence that ultrasound disrupted the clot surface or damaged the fibrin structure.

Beneficial effects of combined thromboxane synthase inhibition/receptor blockade with CGS 22652 in a canine model of coronary thrombosis

Various antiplatelet agents were examined for their effectiveness as adjuncts to thrombolytic therapy in a canine model of thrombin-induced coronary thrombosis. Aspirin (5 mg/kg i.v. bolus), CGS 15435A (thromboxane synthase inhibitor (TxSI), 0.1 mg/kg i.v. bolus + 0.04 mg/kg per h) and BM 13.505 (thromboxane receptor antagonist (TxRA), 0.5 mg/kg i.v. bolus + 0.2 mg/kg per h) administered concurrently with streptokinase (750 000 units/h) were examined for their effects on reperfusion and reocclusion, as were a combination therapy with CGS 15435A + BM 13.505 or the dual TxRA/TxSI inhibitor, CGS 22652 (1 mg/kg i.v. bolus + 0.4 mg/kg per h). All dogs received heparin (150 U/kg bolus + 50 U/kg per h) throughout the experimental protocol. Survival analysis at reperfusion indicated that thrombolysis was significantly improved in dogs treated with CGS 15435A, BM 13.505, CGS 15435A + BM 13.505 or CGS 22652 over that of vehicle-treated animals. Both dual inhibitor groups and the BM 13.505 group were significantly different from aspirin. Aspirin-treated dogs were not different from vehicle. Otherwise, all treatments differed from the vehicle-treated group at reocclusion. Time and incidence of reocclusion for CGS 22652 was significantly improved over that of BM 13.505. Residual thrombus weight was significantly reduced in the CGS 22652-treated and BM 13.505 + CGS 15435A-treated animals. These findings demonstrate that streptokinase-induced thrombolysis is accompanied by TxA 2/prostaglandin H 2 synthesis and platelet activation and suggest a role for platelet activation during reocclusion following clot lysis. These studies also show it is possible to combine the beneficial effects of both a TxRA and TxSI into a single chemical entity, CGS 22652, which, when administered as adjunctive therapy to streptokinase, results in an apparent synergistic antithrombotic effect.

Potentiating Effect of Clopidogrel and SR 46349, a Novel 5-HT2 Antagonist, on Streptokinase-Induced Thrombolysis in the Rabbit

Current thrombolytic strategies have a number of important shortcomings including resistance to recanalization and development of acute reocclusion. The purpose of this study was to investigate whether the lysis of venous thrombi by streptokinase could be enhanced by SR 46349, a novel 5-HT2 receptor antagonist, or clopidogrel, an analogue of ticlopidine. The activity of these compounds was evaluated by following the lysis of radiolabelled fibrin under a continuous infusion of streptokinase (4,000 IU kg-1 h-1 over 4 h). Streptokinase alone induced 42% thrombolysis when compared to saline. The i.v. co-administration of SR 46349 or clopidogrel (10 mg/kg) enhanced significantly streptokinase-induced thrombolysis. Thrombolysis measured by [125I]-fibrinogen lysis increased to 65 and 59% respectively. This efficacy was achieved without additional prolongation of the template bleeding time observed with streptokinase alone. Thus, the concomitant use of a 5-HT2 receptor antagonist or an anti-ADP agent during streptokinase therapy may facilitate clot lysis.

Potentiating effects of anticoagulants and antiplatelet agents on streptokinase-induced thrombolysis in the rabbit

Current thrombolytic strategies have a number of important shortcomings including resistance to recanalisation, development of acute reocclusion and serious haemorrhage. The purpose of this study was to investigate whether the lysis of venous thrombi by streptokinase could be enhanced by standard heparin, hirudin (rHV2-Lys 47), aspirin or clopidogrel, an analogue of ticlopidine. The activity of these compounds was evaluated by following the lysis of radiolabelled fibrin under a continuous infusion of streptokinase (4000 U/kg/h-4h). Streptokinase alone induced 45% thrombolysis when compared to saline. The i.v. bolus co-administration of hirudin (75–150–750 μg/kg), heparin (100 IU/kg), aspirin (100 mg/kg) or clopidogrel (10 mg/kg) enhanced thrombolysis with streptokinase. Under these various treatments, thrombolysis as measured by [ 125I]-fibrinogen lysis increased to 55%, 64%, 79%, 60%, 54% and 59% respectively. These effects were related to the respective antithrombotic activities of these compounds, as evidenced by their anticoagulant or antiaggregant activities measured in parallel. However, efficacy of these compounds was achieved without additional prolongation of the template bleeding time observed with streptokinase alone. Thus, the concomitant use of antithrombotic agents during streptokinase therapy may prove to be helpful in preventing thrombus accretion and thus facilitating clot lysis.

Effect of Thromboxane Antagonism on Recanalization During Streptokinase-Induced Thrombolysis in Anesthetized Monkeys

The effect of a selective thromboxane A2 (TxA2) receptor antagonist, SQ 30,741, on streptokinase-induced thrombolysis was examined in pentobarbital-anesthetized cynomolgus monkeys. The intimal surface of a stenosed carotid artery was stimulated with 100 microA anodal current to produce an occlusive thrombus. After 45 min of zero blood flow, a 1-h intraarterial (i.a.) infusion of streptokinase (680 U/min) was injected proximal to the thrombus. Five minutes before streptokinase (SK) intravenous (i.v.) infusions of heparin (200 U/kg + 120 U/h) and either SQ 30,741 (2 mg/kg + 2 mg/kg/min, n = 8) or vehicle (1 ml/h saline, n = 7) were started and maintained for 3 h. In four monkeys not given streptokinase or heparin, no recanalization was detected and occlusive thrombi were observed after 3 h. All animals receiving streptokinase were recanalized. SQ 30,741 had no effect on return of flow during streptokinase infusion, but increased average reflows during the second (60%, p less than 0.05) and third hours (159%, p less than 0.01). Average blood flows were decreased from the second to third hours with vehicle (p less than 0.001) and remained stable with SQ 30,741. Thromboxane antagonism also increased minimal blood flows during the third hour (438%, p less than 0.01) and decreased the total time reoccluded by 73% (p less than 0.05). However, SQ 30,741 had no effect on the time to recanalization, the maximum reflow, and both number of animals reoccluded and average number of reocclusions. Fibrinogen levels were equivalently diminished (8%, p less than 0.05), and platelet counts were unaffected in both treatment groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Enhanced Streptokinase-Induced Thrombolysis Using Heparin in a Rabbit Model

Heparin potentiation of clot lysis by streptokinase was studied in a rabbit model. Clot was initiated in the rabbit aorta with stasis and thrombin and allowed to naturally propagate proximally until stasis met flow. The clot was allowed to age for 1 h before assigning treatment. Fifteen rabbits (group I) were given streptokinase (10,000 IU/h) and 11 rabbits (group II) were given streptokinase (10,000 IU/h) plus sodium-heparin (120 IU/h). Thrombolytic therapy was continued for 5 h. Clot lysis averaged 30% in group I and 70% in group II. Ten of 11 rabbits in group II had more than 50% clot lysis, whereas only 4 of 15 in group I had this degree of lysis. One group II rabbit and four group I rabbits died prematurely; each was noted to have clot propagation at the time of death. While a trend for amelioration of hypofibrinogenemia was observed in the group receiving both streptokinase and heparin, this difference was not statistically significant. We conclude, in the animal model, that thrombolysis by a combination of heparin and streptokinase is more effective than streptokinase alone. Systemic effects are apparently no worse with the combination.

Thromboxane synthetase inhibition with CGS 13080 improves coronary blood flow after streptokinase-induced thrombolysis

The focus of this investigation was to examine the potential beneficial effects of the selective thromboxane synthetase inhibitor CGS 13080 (imidazo [1,5-a] pyridine-5-hexanoic acid) on coronary blood flow after streptokinase-induced thrombolysis. Thrombotic occlusion of the circumflex coronary artery was produced by electrolytic (100 μA anodal current) injury to the intimal surface of the circumflex coronary artery at the site of a noncircumferential stenosis in dogs anesthetized with pentobarbital to have open-chest surgery. Intracoronary streptokinase, 6000 IU/kg in 3 ml saline solution, was infused at 0.05 ml/min for 1 hour, beginning 30 minutes after the formation of an occlusive thrombus. The animals were assigned randomly to two groups. In group I (n = 10) the intravenous infusion of vehicle was begun simultaneously with the intracoronary administration of streptokinase and continued for 2 hours after thrombolysis had been achieved. The animals in group II (n = 10) received intravenous CGS 13080 (1 mg/kg/hr) along with intracoronary streptokinase. Infarct size was assessed by a dual perfusion technique with Evans blue and triphenyltetrazolium stains to demarcate the normally perfused myocardium from the area at risk and the infarct zone within the risk region. The two groups did not differ with respect to baseline coronary blood flow, time to the development of coronary artery thrombotic occlusion, or time to achieve thrombolysis. Oscillations in coronary blood flow were more frequent in group I than in group II (group I, 9 ± 2.2; group II, 4.4 ± 0.8 oscillation/min × 100, p < 0.05 [mean ± SEM]). Reocclusion was observed more frequently in group I than in group II (8 of 10 [80%] vs 2 of 10 [20%], p < 0.05). Infarct size expressed as a percent of the total left ventricular mass was similar ([IZLV] group I, 5% ± 2%; group II, 4% ± 1%), as was the percent of the left ventricle dependent on the blood flow distribution from the left circumflex coronary artery or the area at risk of infarction ([ARLV] 37% ± 2% vs 40% ± 3%, respectively). These results demonstrate that the thromboxane synthetase inhibitor CGS 13080, in combination with the thrombolytic agent streptokinase, is able to maintain patency of the injured coronary artery after thrombolysis and to decrease the frequency of oscillatory flow responses. The results suggest a possible role for thromboxane as a contributor to the process of thrombotic reocclusion after successful thrombolysis.

Augmentation of Streptokinase-Induced Thrombolysis by Heparin and Prostacyclin

The ability of heparin and prostacyclin to improve streptokinase-induced recanalization was examined in open-chest dogs subjected to thrombotic occlusion of the left circumflex coronary artery. Vessel injury was produced by electrical stimulation of the intimal surface at the site of a noncircumferential fixed stenosis. Animals were divided into three treatment groups as follows: group 1 received intracoronary streptokinase alone (75,000 units/80 min starting 30 min postocclusion; n = 8); group 2 received streptokinase plus heparin (300 units/kg i.v. at 20 min postocclusion; n = 7); group 3 received streptokinase plus heparin plus prostacyclin (500 ng/kg/min, intracoronary, given intermittently during reperfusion; n = 7). Overall, the groups did not differ with respect to preocclusion coronary blood flow (27 +/- 1 ml/min; +/- SEM), the duration of streptokinase infusion required to achieve reflow (15 +/- 2 min), and the percentage of animals recanalized (85%). They did differ in the average rate of reflow, which was greater in group 2 (16 +/- 2 ml/min) and group 3 (20 +/- 4 ml/min) as compared with group 1 (6 +/- 1 ml/min; p less than 0.05). The intermittent reocclusions which persisted during reperfusion in group 1 and 2 dogs were diminished during the periodic infusions of prostacyclin. Thrombus mass at the site of injury was comparable among groups. In contrast, distal circumflex thrombi, about twice the weight of the proximal mass, were observed in all group 1 dogs and were undetectable in group 2 and 3 animals. Transient improvements in contractile force during reperfusion were observed only with groups 2 and 3.(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial surgical revascularization after streptokinase treatment for acute myocardial infarction

Eighty-six patients admitted with evolving myocardial infarction within 6 hours of symptom onset were treated with streptokinase. Thirty-nine received intracoronary streptokinase, and 47 received intravenous streptokinase. There were no streptokinase-related complications. Twenty-three patients treated with intracoronary streptokinase and 28 patients receiving intravenous streptokinase underwent coronary artery bypass grafting. On admission, 16 patients receiving intracoronary streptokinase had electrocardiographic evidence of anterolateral evolving myocardial infarction and seven had evidence of inferior evolving myocardial infarction. Time from first symptom to intracoronary streptokinase was 4.4 +/- 1.6 hours. In seven patients, intracoronary streptokinase failed to open the obstructed coronary. All developed severe left ventricular hypokinesia in the area supplied by that coronary artery. In spite of recanalization, nine of 14 patients developed severe hypokinesia in the supplied area, and one an apical aneurysm. Four patients developed mild to moderate hypokinesia, and one had no left ventricular damage. On admission, 14 patients receiving intravenous streptokinase had electrocardiographic evidence of anterolateral evolving myocardial infarction and four had evidence of inferior evolving myocardial infarction. Time from first symptom to intravenous streptokinase was 3.2 +/- 1.5 hours. In seven patients, intravenous streptokinase failed to open the coronary, and all developed severe hypokinesia of the supplied area, with formation of apical left ventricular aneurysm in three. In 21 patients, intravenous streptokinase opened the artery. Eighteen angiographies performed 9.6 +/- 7.9 days after therapy showed a normal left ventricle in eight patients, moderate hypokinesia in seven, and severe hypokinesia in three. Time from first symptom to therapy was shorter in the patients receiving intravenous therapy (p less than 0.01). Coronary artery bypass grafting and four resections after left ventricular aneurysm were performed without operative death. Two patients receiving intracoronary therapy died in the hospital, and one died 2 months later from arrhythmias. Freedom from angina and rehabilitation (New York Heart Association Class I) were achieved in 69.5% of patients receiving intracoronary streptokinase and in 75% of patients receiving intravenous streptokinase. Thus streptokinase-induced thrombolysis salvages myocardium, and the intravenous route seems as effective as the intracoronary. Advantages of the former are earlier administration that might increase myocardial salvage, no invasive procedure, and lesser cost.