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The role of streptokinase in induction of posterior vitreous detachment: a scanning and transmission electron microscopic study of the retina in rabbits.

PURPOSE: To evaluate the possibility of inducing a posterior vitreous detachment (PVD) by intravitreal injection of streptokinase using electron microscopy and electrophysiological study. METHODS: The current study was performed on 30 eyes of 15 male white rabbits. The rabbits were divided into three equal groups. The right eye of the three groups received an intravitreal injection of streptokinase at three different concentrations (150, 1,500 and 15,000 IU in 0.1 mL balanced salt solution) in the mid vitreous cavity. The left eye in all animals received an intravitreal injection of balanced salt solution and was considered the control group. Electroretinography was performed 1 day and 1 week after injection. The rabbits were killed after 10 days, and the enucleated eyes were processed for transmission and scanning electron microscopic examination. RESULTS: In Group 1, scanning electron microscopy showed the retinal surface covered with thin collagen fibers, whereas in Group 2, a complete PVD with bare retinal surface was seen. Group 3 showed a bare retinal surface with hemorrhagic reaction and toxic effects on the retina by transmission electron microscopy. CONCLUSION: An intravitreal injection of 1,500 IU of streptokinase can lead to a PVD without major toxic effects on the retina.

Animals↗

Streptokinase reperfusion and early surgical revascularization in patients with acute myocardial infarction.

During a 21-month period, 150 patients with acute myocardial infarction were offered entry into a study comprising emergency cardiac catheterization, streptokinase infusion for thrombus if present, and coronary artery bypass surgery where appropriate. Forty refused or were excluded, and served as a control group. Approximately 80% of the remainder had coronary thrombosis and obtained benefit as a group from streptokinase reperfusion. Among the 44 who had coronary artery bypass mortality was low except in those having cardiogenic shock at the time of operation. Those without coronary thrombosis appeared to have a better result from early than from delayed operative revascularization. It appears that both streptokinase reperfusion and early coronary artery bypass have a beneficial role in the management of patients with acute myocardial infarction.

Cardiac Catheterization↗

Coronary thrombolysis in a community hospital: experience with an intravenous streptokinase protocol.

To determine whether intravenous streptokinase can be delivered safely and effectively in a community hospital without acute angiography, we treated 120 patients with intravenous infusion of 1.5 million units of streptokinase shortly after arrival in the emergency room. Average time from onset of pain to treatment was 2.7 hours. Therapy was well tolerated without significant complication. Reperfusion was clinically suspected in 78% of patients. Coronary angiography was done at referral hospitals in 94% of the surviving patients two to ten days after treatment. The infarcted vessel was patent in 74% of these patients. Of these, coronary angioplasty was performed in 36%, and 32% had bypass grafting. We conclude that intravenous streptokinase can be safely and effectively used in community hospitals without acute angiography in carefully selected patients with acute myocardial infarction.

Adult↗

Detection of nephritis strain-associated streptokinase by monoclonal antibodies.

Monoclonal antibodies (MAbs) N-59 and RU-1 were produced by immunisation of mice with streptokinase secreted by Streptococcus group A, type 12, strain A374 isolated from a patient with post-streptococcal glomerulonephritis (PSGN) and were characterised by Western blot analysis. MAb N-59 recognised antigenic determinants shared by both nephritis strain-associated streptokinase (NSA-SKase) and streptokinase of Streptococcus group C (C-SKase); MAb RU-1 reacted only with NSA-SKase. All nephritis-associated group A streptococcal strains tested reacted with MAb N-59; 87.5% of these strains reacted with MAb RU-1. MAb N-59 reacted with SKase produced by group G streptococcal strains isolated from patients with PSGN, and MAb RU-1 recognised SKase in two out of three of these strains.

Animals↗

Enhanced platelet function in acute myocardial infarction is attenuated by streptokinase treatment.

The aim of this study was to determine whether platelets are activated and aggregation is increased in myocardial infarction treated with streptokinase. Twelve consecutive patients were studied. Before streptokinase infusion (1.5 x 10(6) IU i.v. over a period of 1 h), 7 +/- 4 h after the onset of symptoms, fibrinogen, leucocyte and platelet functions were enhanced compared to reference values. Plasma fibrinogen was 3.1 +/- 0.6 g 1-1 (P less than 0.03), leucocyte count was 14.3 +/- 3.3 x 10(3) l-1 (P less than 0.0005), elastase was 39 +/- 8 micrograms l-1 (P less than 0.0002), beta-thromboglobulin was 68 +/- 71 micrograms 1-1 (P less than 0.0001) and filtragometer platelet aggregation time was 137 +/- 40 s (P less than 0.0001). After streptokinase the leucocyte count, elastase and beta-thromboglobulin levels increased further, by about 40% (P less than 0.02), 130% (P less than 0.02) and 140% (P less than 0.005), respectively. Fibrinogen was almost eliminated. Despite signs of increased activation, platelet aggregation was decreased as indicated by both filtragometer aggregation time, which increased by about 480% (P less than 0.003), and whole-blood aggregometry, in which electrical impedance decreased by about 65% (P less than 0.01).

Female↗

In vitro enhancement of AA-degrading activity in human plasma with the plasminogen activator streptokinase.

Radiolabelled protein AA was coupled to cyanogen-bromide-activated Sepharose 6 MB and used as a substrate to determine the AA-degrading activity of enzymes in solution. The applicability of the substrate was tested with an elastase preparation known to have AA-degrading activity. The substrate was used to determine the AA-degrading activity in fractions of normal human serum in the presence and absence of the plasminogen activator streptokinase. The AA-degrading activity was increased in fractions in which streptokinase-induced plasminogen activation had occurred. The increase in activity could be inhibited with antibodies to plasminogen. AA-degrading activity could also be increased in whole human plasma by the addition of streptokinase.

Amyloid↗

Purification and cloning of a streptokinase from Streptococcus uberis.

A bovine plasminogen activator was purified from the culture supernatant of the bovine pathogen Streptococcus uberis NCTC 3858. After the final reverse-phase high-performance liquid chromatography step a single protein with a molecular mass of 32 kDa was detected in the active fraction. A partial peptide map was established, and degenerate primers were designed and used for amplification of fragments of the gene encoding the activator. Inverse PCR was subsequently used for obtaining the full-length gene. The S. uberis plasminogen activator gene (skc) encodes a protein consisting of 286 amino acids including a signal peptide of 25 amino acids. In an amino acid sequence comparison the cloned activator showed an identity of approximately 26% to the streptokinases isolated from Streptococcus equisimilis and Streptococcus pyogenes. Interestingly, the activator from S. uberis was found to lack the C-terminal domain possessed by the streptokinase from S. equisimilis. This is apparently a general feature of the streptokinases of this species; biochemical and genetic analysis of 10 additional strains of S. uberis revealed that 9 of these were highly similar to strain NCTC 3858. Sequencing of the skc gene from three of these strains indicated that the amino acid sequence of the protein is highly conserved within the species.

Amino Acid Sequence↗

Streptokinase mutations relieving Escherichia coli K-12 (prlA4) of detriments caused by the wild-type skc gene.

A novel phenotype is described for Escherichia coli K-12 carrying the prlA4 allele determining a membrane component of the protein export mechanism. It is manifest as transformation deficiency for plasmids containing the cloned group C streptococcal streptokinase gene, skc. Streptokinase plasmid mutations relieving the prlA4 strain of this deficiency fell into three classes. Class 1 included skc::IS5 insertions, with IS5 integrated in a region encoding the Skc signal sequence and inactivating skc. Class 2 included IS1 insertions leaving skc intact but reducing skc expression, presumably by altering the function of the skc promoter as judged by an insertion site close to the -35 region. The most interesting class, 3, included skc deletions removing the entire signal sequence or a tetrapeptide from its hydrophobic core. The tetrapeptide deletion reduced the size, hydrophobicity, and predicted alpha-helicity of the central region of the Skc signal sequence but facilitated the export of mature Skc in both the wild type and the prlA4 mutant. These findings indicate that the incompatibility between prlA4 and skc is related to deleterious effects of the Skc signal sequence. The tetrapeptide deletion may function by altering the conformation of the signal sequence so as to render interaction with both the PrlA wild-type protein and the PrlA4 mutant protein less detrimental to the export mechanism. These findings also provide an explanation for the difficulties encountered in cloning streptokinase genes in E. coli plasmids and maintaining their structural stability.

DNA Mutational Analysis↗

Comparison of streptokinase and heparin in treatment of isolated acute massive pulmonary embolism.

Massive pulmonary embolism was confirmed by pulmonary arteriography in 23 patients. All were seen between 2 and 48 hours after the onset of embolism and none had pre-existing cardiorespiratory disease. Fifteen were treated with streptokinase and eight with heparin. Factors which might influence prognosis and rate of resolution were similar in the patients in each group, and there was no significant difference between the groups in terms of pretreatment haemodynamic or arteriographic findings. Haemodynamic and arteriographic findings after treatment for 72 hours provided an objective measurement of resolution, which was significantly greater in the streptokinase-treated patients. There was no mortality in either group, but treatment had to be changed in two heparin-treated patients because of clinical deterioration. The principal complication of treatment, seen more often in the streptokinase-treated patients, was bleeding from cut-down or operation sites.

Acute Disease↗

Streptokinase and deep vein thrombosis.

Five patients with deep vein thrombosis were given streptokinase. Five others with similar phlebograms were given anticoagulants, and the results assessed by examining changes in the iliac, femoral, and calf segments of the phlebograms when repeated 7-10 days later. Those of the anticoagulant group were unchanged. Four of the five given streptokinase had a reduction in the size and extent of their thrombosis. Fresh thrombus surrounded by flowing blood was lysed. Thrombus completely blocking a vein was not lysed.The indications for the use of streptokinase in deep vein thrombosis are reviewed.

Adolescent↗

Streptokinase versus alteplase and other treatments for acute and delayed thrombolysis of blood stains in clothing.

OBJECTIVE: To assess the usefulness of heparin, alteplase, and streptokinase in removing blood stains. DESIGN: Randomised controlled trial. SETTING: Hospital laundry. INTERVENTIONS: Blood stains were allocated to treatment with alteplase, streptokinase, heparin, a commercial enzymatic stain remover, or no treatment at all after three or seven hours and then washed in hot or cold water two hours later. RESULTS: Both hot water and early treatment were strongly associated with improved stain removal. All four treatments were associated with a worse outcome than no treatment at all, although for streptokinase this trend did not reach significance. The commercial stain remover gave the worst results of all treatments tested. CONCLUSIONS: Contrary to popular wisdom, hot water is much more effective than cold in removing blood stains. Methodologically rigorous research and evidence based principles are needed within the laundry industry, and the role of thrombolytic drugs should be assessed further.

Blood Stains↗

Outcome of recent thromboembolic occlusions of limb arteries treated with streptokinase.

All our patients with a recent thromboembolic occlusion of limb arteries treated with streptokinase have been reviewed retrospectively. Clearing of the main artery, as judged by arteriography or reappearance of arterial pulsations, occurred more often when treatment was started early. If only patients with an iliac, femoral, or popliteal artery occlusion are considered, those who received a lower initial dose had a significantly higher clearing rate and a significantly lower mortality than those who received a high initial dose (500,000 units of streptokinase or more). Therefore an initial standard dose of 1,200,000 units of streptokinase is no longer recommended in these conditions, and even an individually titrated initial dose of more than half a million units could be hazardous. If no neurological abnormalities were present on admission amputation was never necessary, even if clearing of the main artery did not occur. If there was sensory loss of at least part of a limb, amputation was avoided only if the pulsations returned in at least one artery of hand or foot.

Amputation, Surgical↗

Neutralising antibodies after streptokinase treatment for myocardial infarction: a persisting puzzle.

OBJECTIVE: To determine the development of titres of streptokinase (SK) neutralising antibodies after a single dose of SK, to establish when titres decrease to levels at which a second dose might be effective. DESIGN: Analyses of blood samples taken from patients at intervals after SK administration. SETTING: Australian public hospital. PATIENTS: 104 patients with acute myocardial infarction who were treated with SK and 27 controls who were not. OUTCOME MEASURE: SK neutralising antibodies were measured once in each of the 27 controls and on 166 occasions in the 104 treated patients. RESULTS: Titres of SK neutralising antibodies rose after SK administration but returned to control levels by 2 years. CONCLUSIONS: SK might be effective again as a thrombolytic agent as early as 2 years after a single dose. These results are at variance with most previously published data and the reasons for this are not clear. Data evaluating patency rates after standard doses of streptokinase in patients with increased titres of neutralising antibodies are necessary before re-exposure to streptokinase can be recommended.

Antibodies↗

Circadian fluctuations in the efficacy of thrombolysis with streptokinase.

This study was designed to investigate possible diurnal fluctuations in the efficacy of thrombolysis with streptokinase and whether they follow the circadian periodicity which has already been well documented for the time of onset of acute myocardial infarction, transient myocardial ischaemia, sudden cardiac death, thrombotic stroke, and for the efficacy of thrombolysis with tissue-type plasminogen and urokinase. A total of 156 consecutive patients treated with streptokinase were studied retrospectively; success or failure of thrombolysis was determined according to accepted clinical and angiographic criteria. A definite time peak for successful thrombolysis could be detected at the late afternoon and early evening hours; between 16.00 and 20.00 h, 30.2% of all successful thrombolysis cases were observed compared with 7.0% between 20.00 and 24.00 (p < 0.05) or 10.5% between 00.00 and 04.00 (p < 0.05). Between 16.00 and 20.00 h, 75.8% of treated patients had successful thrombolysis compared to 15.2% of failed treatments and 9% equivocal results (p < 0.001). Multiple regression analysis showed that the independent factor with the major impact on successful reperfusion was the actual time of thrombolysis (p = 0.037), followed by the time delay from pain onset to streptokinase administration (p = 0.020), while age and gender had much lesser impact (p = 0.328 and 0.215, respectively) and the individual risk factors even less. These findings may have several clinical implications; dose adjustment for the time of day may be required, with higher doses during morning hours, or preference for primary coronary angioplasty in order to avoid the increase in bleeding complications related to higher doses of thrombolytic agents.

Adult↗

Subacute massive pulmonary embolism treated with plasminogen and streptokinase.

Major pulmonary embolism occurring insidiously over several weeks (subacute massive pulmonary embolism) has a high mortality and may not respond well to standard anticoagulant or thrombolytic treatment. A priming dose of plasminogen was used to enhance thrombolysis produced by a streptokinase infusion in five consecutive patients with subacute massive pulmonary embolism. In each patient a dramatic clinical improvement occurred with a substantial increase in pulmonary blood flow. All five patients survived to leave hospital. Malignant disease was the underlying cause of embolism in three patients, two of whom died of their malignant disease in the six months after treatment of their pulmonary embolism. The third patient with malignant disease had a choriocarcinoma; at least some of the pulmonary obstruction may have been tumour tissue but this obstruction was dramatically cleared by the treatment. The use of a combination of plasminogen with streptokinase should be considered in severely ill patients with subacute massive pulmonary embolism, particularly if other treatment, including streptokinase alone, has failed.

Adult↗

Investigation on the interaction of commercial forms of streptokinase and human plasminogen: a potential screening procedure for fibrinolytic inhibitors.

Streptokinase activation of human plasminogen is known to produce several enzymatic entities. Initially, the identification and characterization of these various entities were based on molecular model studies which necessitated highly purified biological materials and sophisticated techniques. However, these conditions cannot always be adhered to when alacrity, precision, and cost are often the prime factors governing the choice of a method for the evaluation of therapeutic agents. Our concern was therefore to find a suitable method of investigating inhibitors of the fibrinolytic system without compromising on accuracy, reliability, and reproducibility. We found that the activation of human plasminogen by streptokinase was dependent both on the duration of the activation step and the concentration of streptokinase used. By combining these two factors, activation could be visualized as a dual phase phenomenon. Each phase revealed distinct kinetic parameters and reactivity toward inhibitors such that their identity with the known enzymatic entities could be established. Inhibitors were further assessed with respect to their kinetic profile and were found to conform to known data. Therefore, the proposed method not only allows for direct visualization of the activation process but also meets the requirements for the routine screening of potential therapeutic inhibitors of the fibrinolytic system.

Antifibrinolytic Agents↗

Fibrinolysis in chronic arteriosclerotic occlusions: intrathrombotic injections of streptokinase. Work in progress.

Forty-seven patients with chronic arteriosclerotic occlusions of iliac and femoropopliteal arteries were treated by intrathrombotic fibrinolysis. The occlusions were 10-65 cm (mean, 22 cm) long and 6 weeks to 2 years (mean, 4.5 months) old. By means of consistent intrathrombotic injections of 2,500 units of streptokinase every 5 minutes, the thrombi were recanalized within 1-7 hours (mean, 2.5 hours). The primary recanalization rate was 75% (35/47), the patency rate after 2 weeks, 68%. In 29 patients (62%), a residual stenosis had to be dilated by balloon angioplasty. Because of the low total dose of streptokinase (mean, 70,000 units), the thrombin time was elevated up to twice the normal value in only one patient. Bleeding that required transfusions was observed in only two patients (4%). Advantages of intrathrombotic fibrinolysis include higher recanalization rate, lower total dose of streptokinase, fewer bleeding complications, and shorter therapy time than previously reported with other treatments.

Adult↗

Renal artery embolism treated with intra-arterial streptokinase infusion results in patent but small renal arteries.

A low intra-arterial dose of streptokinase was used to dissolve a renal artery embolus in 2 patients. Angiography at the end of the streptokinase therapy disclosed patent renal arteries. Arteriograms performed 3 months and 2 years later demonstrated patent but small renal arteries. These cases confirm the limited experience reported in the literature that even though initial restoration of renal artery patency is possible, the ultimate renal function is poor after intra-arterial streptokinase therapy.

Adult↗