Efficacy of Low-Dose Streptokinase Infusion in Late-Onset Permanent Tunnel Catheter Dysfunction: A Single-Center Interventional Study.

Introduction Hemodialysis is a vital modality for patients with renal dysfunction, with venous access being a significant factor in its success. While arteriovenous fistulas are preferred, tunneled catheters serve as important alternatives, especially in challenging cases. Late-onset tunneled catheter dysfunction, often due to fibrin sheath formation, impedes hemodialysis efficiency. Streptokinase, a low-cost thrombolytic agent, has shown promise in resolving such complications, yet its efficacy in the Indian context remains unexplored. Methods We conducted a single-center interventional study at Mahatma Gandhi Mission (MGM) Hospital, Aurangabad, India, from May 2023 to October 2023. Ethical approval was obtained, and 10 eligible patients experiencing late-onset permanent tunnel catheter dysfunction were enrolled. Patients were treated with low-dose streptokinase, and outcomes were monitored for 60 days. Results Ten patients, evenly distributed by gender, participated, with a mean age of 48.2 ± 11.96 years. Diabetes was the predominant cause of chronic kidney disease (CKD) at 33% (3/10). All patients achieved the primary endpoint of blood flow rate (BFR) >300 ml/min post-streptokinase treatment, with an overall success rate of 100%. Group A had the highest average gain in catheter days (80.6 ± 7.59), followed by Group B (64 ± 1), while Group C showed variations in catheter days between the first (26.2 ± 6.8) and second insertion (32.5 ± 1.76). Eight patients maintained catheter patency during the 60-day follow-up. Adverse effects, primarily minor, were observed. The dosage rationale involved an eight-hour infusion at 4,000 units per hour. Conclusion Streptokinase emerges as cost-effective and efficacious for maintaining the patency of late-onset tunnel catheter dysfunction in resource-limited settings, particularly in younger patients. Caution is advised for older individuals with prolonged CKD.

Targeted drug delivery to the thrombus by fusing streptokinase with a fibrin-binding peptide (CREKA): an in silico study.

Aim: Streptokinase has poor selectivity and provokes the immune response. In this study, we used in silico studies to design a fusion protein to achieve targeted delivery to the thrombus. Materials & methods: Streptokinase was analyzed computationally for mapping. The fusion protein modeling and quality assessment were carried out on several servers. The enzymatic activity and the stability of the fusion protein and its complex with plasminogen were assessed through molecular docking analysis and molecular dynamics simulation respectively. Results: Physicochemical properties analysis, protein quality assessments, protein-protein docking and molecular dynamics simulations predicted that the designed fusion protein is functionally active. Conclusion: Our results showed that this fusion protein might be a prospective candidate as a novel thrombolytic agent with better selectivity.

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Diverse origins of fibrinolytic enzymes: A comprehensive review.

Fibrinolytic enzymes cleave fibrin which plays a crucial role in thrombus formation which otherwise leads to cardiovascular diseases. While different fibrinolytic enzymes have been purified, only a few have been utilized as clinical and therapeutic agents; hence, the search continues for a fibrinolytic enzyme with high specificity, fewer side effects, and one that can be mass-produced at a lower cost with a higher yield. In this context, this review discusses the physiological mechanism of thrombus formation and fibrinolysis, and current thrombolytic drugs in use. Additionally, an overview of the optimization, production, and purification of fibrinolytic enzymes and the role of Artificial Intelligence (AI) in optimization and the patents granted is provided. This review classifies microbial as well as non-microbial fibrinolytic enzymes isolated from food sources, including fermented foods and non-food sources, highlighting their advantages and disadvantages. Despite holding immense potential for the discovery of novel fibrinolytic enzymes, only a few fermented food sources limited to Asian countries have been studied, necessitating the research on fibrinolytic enzymes from fermented foods of other regions. This review will aid researchers in selecting optimal sources for screening fibrinolytic enzymes and is the first one to provide insights and draw a link between the implication of source selection and in vivo application.

Prehospital Fibrinolysis Therapy in Acute Myocardial Infarction: A Narrative Review.

Acute myocardial infarction is a fatal condition. Acute myocardial infarction requires appropriate timely reperfusion therapy to improve the outcomes. Fibrinolysis and percutaneous coronary intervention are the cornerstone strategies for managing such cases. In this review, our objective is to summarize the available evidence concerning the administration of prehospital fibrinolysis and its impact on patient outcomes in patients with acute myocardial infarction. We conducted a comprehensive literature search across PubMed, Cochrane Library, Scopus, and Web of Science databases. Our search strategy included the following terms: "Prehospital," "EMS," "Emergency Medical Services," "ambulance," "Fibrinolytic Therapy," "alteplase," "streptokinase," "reteplase," "tenecteplase," "Acute Myocardial Infarction," and "patient outcomes." We found prehospital administration of fibrinolysis may improve the outcomes and decrease the mortality rate. We found that some recommendations were to use prehospital fibrinolysis only if the percutaneous coronary intervention was not accessible within two hours. Additionally, we discussed recommendations to use newer prehospital fibrinolysis as they have better efficacy and safety outcomes. In conclusion, prehospital fibrinolysis decreases the total ischemic time and improves outcomes in acute myocardial infarction patients when timely percutaneous coronary intervention is not available. The guidelines strongly recommend it when the anticipated time for percutaneous coronary intervention exceeds two hours. Ongoing research optimizes patient selection, treatment tools, and prehospital systems of care.

Plasminogen activation and plasmin inhibition during in vitro fertilization in bovine: implications for fertilization parameters and early embryo development.

Components of the plasminogen/plasmin system, known to be present in the oocyte, play a key role in maturation and fertilization. The objective of this study was to examine the effect of plasminogen activation and plasmin inhibition by exogenous supplementation of the IVF medium with streptokinase (SK) or ɛ-aminocaproic acid (ε-ACA), respectively, on fertilization parameters and preimplantation embryo development. After in vitro maturation, bovine cumulus-oocyte complexes (COCs) were inseminated in the presence of SK or ε-ACA. The addition of SK to the IVF medium facilitated the adhesion of the spermatozoa to the zona pellucida without affecting the percentages of monospermy. Cleavage rates and blastocyst yield were similar between the SK and Control groups while they were lower with the ε-ACA treatment. Additionally, we found that the expression levels of embryo quality-related genes (SDHA and DNMT3A) could be modified in blastocysts by the addition of SK or ε-ACA during IVF. The results obtained indicate that supplementation of the IVF medium with SK did not greatly alter the embryonic developmental parameters related to embryo quality in blastocysts. Moreover, we noticed that ε-ACA treatment compromises the success of in vitro embryo development, thus highlighting the importance of the plasminogen/plasmin activity during the early stages of embryogenesis in bovine.

The Inhibitory Effects of Amylase and Streptokinase on Minimum Inhibitory Concentration of Antibiotics Used to Treat Gram Negative Bacteria Biofilm Infection on Indwelling Devices.

The study evaluated and compared the effect of adding streptokinase and amylase to antibiotics that are already used in clinical practice to treat Gram negative bacteria biofilm infection on indwelling devices on the antibiotics' minimum inhibitory concentration (MIC). 24 h-old biofilms were developed on 96-well plate with eight clinical isolates. MIC of amikacin, cefepime, ceftazidime, colistin, meropenem, and piperacillin-tazobactam, on biofilms were measured before and after the addition of 25 U/ml streptokinase and 25 µg/ml amylase with microplate reader. The addition of streptokinase reduces the MICs of cefepime, ceftazidime, colistin, meropenem from (16, 16, 8, 4 µg/ml) to (8, 1, 1, 0.5 µg/ml) in Escherichia coli (isolate 1). While the addition of amylase reduces the MICs of only cefepime, ceftazidime from (16, 16 µg/ml) to (2, 4 µg/ml) in E. coli (isolate 1). In Pseudomonas aeruginosa (isolate 4), the MICs of amikacin, cefepime, ceftazidime, colistin and meropenem (64, 16, 32, 4, 32 µg/ml) reduced to (2, 1, 0.5, 0.25, 0.5 µg/ml) with streptokinase and (4, 4, 4, 2, 0.5 µg/ml) with amylase respectively. Similar inhibitions were seen in Pseudomonas putida, Proteus mirabilis. We can conclude that the addition of streptokinase and amylase were effective in reducing the MICs of antibiotics that are commonly used to treat Gram negative bacteria biofilm infection on indwelling devices, thereby increasing susceptibility of bacteria to antibiotics. Streptokinase obviously had a greater effect than amylase, implying that it should be prioritized in future in vivo and clinical studies to obtain successful therapy with antibiotics on biofilm infections.

A Systematic Review of the Efficacy and Safety of Tenecteplase Versus Streptokinase in the Management of Myocardial Infarction in Developing Countries.

Myocardial infarction (MI) is a significant cause of morbidity and mortality in low- and middle-income countries. Fibrinolytic agents and percutaneous coronary intervention (PCI) are the main approaches for the recanalization and reperfusion of the myocardium following MI. Many studies have shown that PCI is superior to thrombolytics due to better outcomes and decreased mortality. Nevertheless, PCI's mortality gain over thrombolysis decreases as the time between presentation and PCI procedure increases. Furthermore, PCI is not widely available in most developing countries; thus, it cannot be delivered promptly. Most patients in developing countries cannot afford the cost of PCI. Thus, thrombolytic therapy remains essential to managing MI in developing countries and should not be disregarded. Tenecteplase (TNK) and streptokinase (SK) are the two most widely used fibrinolytics in managing MI in underdeveloped nations. Despite their widespread availability, comparative studies on them have been inconclusive. This study aims to review the available literature on the effectiveness and safety of TNK versus SK in managing MI in resource-poor nations. The study is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) extension and analyzed according to Cochrane guidelines on synthesis without meta-analysis. A comprehensive literature search for studies comparing TNK and STK was conducted on EMBASE, Cochrane Library, Web of Science, CINAHL, Scopus, Google Scholar, and Ovid version of MEDLINE databases. A reference list of the eligible articles and systematic reviews was also screened. A narrative synthesis of the available data was done by representing the data on the effect direction plot, followed by vote counting. Of the 2284 references retrieved from the databases, only 17 studies met the inclusion criteria and were selected for final analysis. The study suggested that TNK is more effective in complete ST-segment resolution (80% vs 10% on the effect direction plot) and symptom relief (80% vs 20%) than SK. SK and TNK were comparable in achieving successful fibrinolysis (50% vs 50%). For the safety parameters, TNK is associated with a lesser risk of major bleeding than SK (88.9% vs 11.1%) and minor bleeding (25% vs 75%). SK was linked with a higher risk of hypotension/shock (77.8% vs 11.1%) and anaphylaxis/allergy (100% vs 0%). Long-term mortality was higher in the SK arm (100% vs 0%). In-hospital mortality is comparable between the two agents (37.5% vs 37.5%). There is conflicting evidence regarding other safety and efficacy endpoints. Compared to SK, TNK results in better complete ST-segment resolution and symptom relief. A higher risk of long-term mortality, increased risk of major and minor bleeding, hypotension, and allergy/anaphylaxis was observed in patients who received SK. Both agents were comparable in terms of in-hospital mortality and successful fibrinolysis. Controversy exists regarding which agent is linked with increased risk of 30-35-day mortality benefit and stroke. Randomized controlled trials (RCTs) with large sample sizes are needed to establish TNK vs SK superiority in efficacy and safety. The long-term duration of follow-up of the mortality rate of the two agents is also essential, as most patients in these regions cannot afford the recommended PCI post-fibrinolysis.

Management of hemorrhagic pleural effusion with intrapleural streptokinase in a patient on peritoneal dialysis and dual antiplatelet therapy.

Key Clinical Message: Intrapleural streptokinase can be an option for loculated hemorrhagic pleural effusion among patients receiving CAPD and under DAPT. Its use can be individualized based on risk benefit analysis by the treating clinician. Abstract: Pleural effusion is seen in up to 10 percent of patients on peritoneal dialysis (PD). A hemorrhagic pleural effusion is a diagnostic dilemma and a therapeutic challenge. We report a complicated case of 67 years old man with end stage renal disease, with coronary artery disease and stent in situ under dual antiplatelet therapy and continuous ambulatory peritoneal dialysis. The patient presented with left-sided loculated hemorrhagic pleural effusion. He was managed with intrapleural streptokinase therapy. His loculated effusion resolved without any local and systemic bleeding manifestations. Therefore, in poor resource settings, Intrapleural streptokinase can be an option for loculated hemorrhagic pleural effusion among patients receiving CAPD and under DAPT. Its use can be individualized based on risk benefit analysis by the treating clinician.

Choice of intrapleural fibrinolytic agents in the treatment of adult complicated parapneumonic effusion and empyema: Network meta-analysis.

BACKGROUND: The appropriate use of intrapleural fibrinolytic agents in patients with complicated parapneumonic effusion and empyema remains unclear, especially regarding the choice of fibrinolytic agents. We conducted a network meta-analysis comparing outcomes of intrapleural fibrinolytic agents in patients with complicated parapneumonic effusion and empyema. METHODS: MEDLINE and EMBASE were searched through April 2022 to identify randomized controlled trials (RCTs) that investigated outcomes in patients with complicated parapneumonic effusion or empyema who were treated with intrapleural fibrinolytic agents. The outcomes of interest were surgical requirements, bleeding, length of hospital stay, and all-cause mortality. RESULTS: Our analysis included 10 RCTs that enrolled 1085 patients treated with intrapleural tissue plasminogen activator (TPA) (n = 138), TPA + deoxyribonuclease (DNase) (n = 52), streptokinase (n = 311), urokinase (n = 75), DNase (n = 51), or placebo (n = 458). The rates of surgical requirement were significantly lower with TPA and TPA + DNase than with placebo (risk ratio [RR]; 95% confidence interval [CI] = 0.36 [0.14-0.97], p = 0.038, RR [95% CI] = 0.25 [0.08-0.78], p = 0.017, respectively). The risk of bleeding was higher with TPA + DNase than with placebo (RR [95% CI] = 10.91 [1.53-77.99], p = 0.017), as well as TPA and TPA + DNase than with urokinase (RR [95% CI] = 17.90 [1.07-299.44], p = 0.044, RR [95% CI] = 89.3 [2.88-2772.49], p = 0.010, respectively). All-cause mortality was similar among the groups. CONCLUSION: TPA and TPA + DNase reduced the rates of surgical requirement compared with placebo. However, TPA + DNase increased the risk of bleeding compared with placebo. Intrapleural agents for complicated parapneumonic effusion and empyema should be selected with an individual risk assessment.

Guillain-Barre syndrome after myocardial infarction: a case report and literature review.

BACKGROUND: Guillain-Barre syndrome after myocardial infarction occurs infrequently, and its occurrence following percutaneous coronary intervention is extremely rare. Due to the high mortality rate of myocardial infarction and the disability of Guillain-Barre syndrome, early identification of Guillain-Barre syndrome after myocardial infarction and early intervention can decrease the mortality rate, lead to early recovery, and provide a better outcome. CASE PRESENTATION: Herein, we reported a rare case of Guillain-Barre syndrome after myocardial infarction treated with percutaneous coronary intervention. The patient was a 75-year-old woman from China who was admitted to hospital due to sudden loss of consciousness. Electrocardiography showed acute myocardial infarction in the right ventricle and inferior and posterior walls. The patient underwent emergency percutaneous intervention of the posterior collateral artery of the right coronary artery. Soon after, her condition worsened resulting in limb weakness and numbness. Unfortunately, she continued to develop respiratory failure, and treated with intravenous immunoglobulin and ventilator-assisted breathing. A physical examination showed hypotonia of all four limbs, complete quadriplegia, bulbar palsy, dysarthria, and tendon areflexia. Serum immunoglobulin (Ig) G anti-ganglioside antibody analysis was positive with anti-GT1a antibodies (+ +), anti-GM1 antibodies ( +), anti-GM2 antibodies ( +), and anti-GM4 antibodies ( +), and he was diagnosed with Guillain-Barre syndrome after myocardial infarction. She was discharged due to poor response to treatment. The patient died two days after being discharged. CONCLUSIONS: Myocardial infarction and/or percutaneous coronary intervention may activate immune-mediated response and cause severe complications. Clinician should be alert to Guillain-Barre syndrome after myocardial infarction and/or percutaneous coronary intervention.

Inactivation of the lysine binding sites of human plasminogen (hPg) reveals novel structural requirements for the tight hPg conformation, M-protein binding, and rapid activation.

Accelerated activation of the human plasminogen zymogen (hPg) to two-chain active plasmin (hPm) is achieved following conformational changes induced by ligand-binding at the lysine-binding sites (LBSs) in four of the five hPg kringle domains. In this manner, pattern D skin-trophic strains of Group A streptococci (GAS), through the expression of surface plasminogen-binding M-protein (PAM), immobilize surface hPg, thereby enabling rapid hPg activation by GAS-secreted streptokinase (SK). Consequently, GAS enhances virulence by digesting extracellular and tight cellular junctional barriers using hPm activity. Many studies have demonstrated the singular importance of the kringle-2 domain of hPg (K2hPg) to PAM-binding using hPg fragments. Recently, we showed, using full-length hPg, that K2hPg is critical for PAM binding. However, these studies did not eliminate any modulatory effects of the non-K2hPg LBS on this interaction. Moreover, we sought to establish the significance of the intramolecular interaction between Asp219 of the LBS of K2hPg and its serine protease domain binding partner, Lys708, to conformational changes in hPg. In the current study, selective inactivation of the LBS of K1hPg, K4hPg, and K5hPg revealed that the LBS of these kringle domains are dispensable for hPg binding to PAM. However, the attendant conformational change upon inactivation of K4hPg LBS increased the affinity of hPg for PAM by an order of magnitude. This finding suggests that the native hPg conformation encloses PAM-binding exosites or sterically hinders access to K2hPg. While simultaneous inactivation of the LBS of K1hPg, K4hPg, and K5hPg inhibited hPg/SK association alongside hPg activation, the replacement of Lys708 generated a slight conformational change that optimally accelerated hPg activation. Thus, we accentuate disparate functions of hPg LBS and conclude, using intact proteins, that K2hPg plays a central role in regulating hPg activation.

Generation and characterization of a plasminogen-binding group A streptococcal M-protein/streptokinase-sensitive mouse line.

BACKGROUND: Streptococcus pyogenes (GAS) is a human bacterial pathogen that generates various mild to severe diseases. Worldwide, there are approximately 700 million cases of GAS infections per year. In some strains of GAS, the surface-resident M-protein, plasminogen-binding group A streptococcal M-protein (PAM), binds directly to human host plasminogen (hPg), where it is activated to plasmin through a mechanism involving a Pg/bacterial streptokinase (SK) complex as well as endogenous activators. Binding to Pg and its activation are dictated by selected sequences within the human host Pg protein, making it difficult to generate animal models to study this pathogen. OBJECTIVES: To develop a murine model for studying GAS infection by minimally modifying mouse Pg to enhance the affinity to bacterial PAM and sensitivity to GAS-derived SK. METHODS: We used a targeting vector that contained a mouse albumin-promoter and mouse/human hybrid plasminogen cDNA targeted to the Rosa26 locus. Characterization of the mouse strain consisted of both gross and histological techniques and determination of the effects of the modified Pg protein through surface plasmon resonance measurements, Pg activation analyses, and mouse survival post-GAS infection. RESULTS: We generated a mouse line expressing a chimeric Pg protein consisting of 2 amino acid substitutions in the heavy chain of Pg and a complete replacement of the mouse Pg light chain with the human Pg light chain. CONCLUSION: This protein demonstrated an enhanced affinity for bacterial PAM and sensitivity to activation by the Pg-SK complex, making the murine host susceptible to the pathogenic effects of GAS.

Mortality outcomes and predictors of failed thrombolysis following STEMI thrombolysis in a non-PCI capable tertiary hospital: a 5-year analysis.

Pharmacological reperfusion remains the primary strategy for ST-elevation myocardial infarction (STEMI) in low- and medium-income countries. Literature has reported inconsistent incidences and outcomes of failed thrombolysis (FT). This study aimed to identify the incidence, mortality outcomes and predictors of FT in STEMI pharmacological reperfusion. This single-centre retrospective cohort study analyzed data on consecutive STEMI patients who received thrombolytic therapy from 2016 to 2020 in a public tertiary hospital. Total population sampling was used in this study. Logistic regression analyses were used to assess independent predictors of the mortality outcomes and FT. We analyzed 941 patients with a mean age of 53.0 ± 12.2 years who were predominantly male (n = 846, 89.9%). The in-hospital mortality was 10.3% (n = 97). FT occurred in 86 (9.1%) patients and was one of the predictors of mortality (aOR 3.847, p < 0.001). Overall, tenecteplase use (aOR 1.749, p = 0.021), pre-existing hypertension (aOR 1.730, p = 0.024), history of stroke (aOR 4.176, p = 0.004), and heart rate ≥ 100 bpm at presentation (aOR 2.333, p < 0.001) were the general predictors of FT. The predictors of FT with streptokinase were Killip class ≥ II (aOR 3.197, p = 0.004) and heart rate ≥ 100 bpm at presentation (aOR 3.536, p = 0.001). History of stroke (aOR 6.144, p = 0.004) and heart rate ≥ 100 bpm at presentation (aOR 2.216, p = 0.015) were the predictors of FT in STEMI patients who received tenecteplase. Mortality following STEMI thrombolysis remained high in our population and was attributed to FT. Identified predictors of FT enable early risk stratification to evaluate the patients' prognosis to manage them better.

Multiple Mutations on α, ß and γ Domains of Streptokinase Lead to the Generation of Highly Efficient Cysteine Analogues with Promising Features.

BACKGROUND: Streptokinase, one of the most widely used thrombolytic medicines, is a favorable protein for site-specific PEGylation as it lacks any cysteine residues in its amino acid sequence; however, any changes in the protein's structure should be carefully planned to avoid undesired changes in its function. OBJECTIVES: This study aimed to design and produce novel di/tri-cysteine variants of streptokinase from previously developed cysteine analogues, Arg45, Glu263, and Arg319, as candidates for multiple site-specific PEGylation. METHODS: Using bioinformatics tools and site-directed mutagenesis, we incorporated concurrent mutations at Arg45, Glu263, and Arg319 (carried out in our previous study) to create di/tri-cysteine variants of streptokinase proteins (SK45-319cys, SK263-319cys, and SK45-263-319cys) and evaluated their kinetic activity parameters by a colorimetric method, using H-D-Val-Leu-Lys-pNA.2HCl (S2251) as substrate. RESULTS: Based on the kinetic results, SK263-319cys with 44% enzyme efficiency increment compared to wild-type SK was the superior protein in terms of activity; as well, SK45-319cys and SK45-263-319cys showed 17 and 22% activity enhancement, respectively. Docking of the mutant streptokinase proteins with µ-plasmin demonstrated that changes in intermolecular interactions caused by amino acid substitution could be the reason for activity difference. CONCLUSION: The novel mutant proteins created in this study exhibit remarkable biological activity and may be uniquely suitable for simultaneous PEGylation on two/three domains. As well, PEGylated derivates of these variants might prove to be more proficient proteins, compared to the singlecysteine analogs of streptokinase; because of their more surface coverage and increased molecular weight.

Efficacy and Safety of Thrombolysis in COVID-19 Related ARDS.

INTRODUCTION: COVID-19 causes significant pulmonary microthrombi in some individuals, leading to ARDS and death. Thrombolysis could be an effective approach in some patients with severe ARDS. We describe our experience with the usage of thrombolytic agents in critically ill COVID-19 patients who were in worsening respiratory failure. METHODS: Retrospective chart analysis was done in patients who were thrombolysed between May 2020-Sept 2020. Analysis was done to find out factors associated with improvement in oxygenation and survival. RESULTS: Twenty-seven patients with severe ARDS [all had respiratory rate >30, FiO2 >0.6 (on NIV/HFNC) and PiO2/FiO2 ratio <120] were thrombolysed in our ICU for COVID19 causes. C.T. Pulmonary Angiography could not be done in any of the 27 patients due to poor general condition, but 2D echo was normal in most (5 had dilated RA, RV), and none of the patients was in shock. So, there was no conventional indication of thrombolysis in these patients, yet after thrombolysis, we observed dramatic changes in oxygenation (defined by a decrease in FiO2 by ≥0.2) in twenty patients. Five patients had a major bleed. Eleven patients survived (survival rate of 40.7%) and the survival rate was high {66% (8/12)} in patients who were thrombolysed within 2 days of oxygen requirement. CONCLUSION: In this unprecedented pandemic with high mortality rates, efficacy of early thrombolysis needs to be further explored in randomised controlled trials.

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 180 min 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 60 min. 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.

Ensayo controlado y aleatorizado del uso de Heberkinasa® en el derrame pleural paraneumónico en niños / Randomized Controlled Trial of the Use of Heberkinase® in Parapneumonic Pleural Effusion in Children

Introducción: El derrame pleural paraneumónico resulta la complicación más frecuente de la neumonía bacteriana, de manejo complejo y muchas veces quirúrgico. No existen publicaciones en Cuba provenientes de ensayos clínicos controlados y aleatorizados ni del uso de la estreptoquinasa recombinante (Heberkinasa®) en el derrame pleural. Objetivo: Evaluar la eficacia y la seguridad de la Heberkinasa® en el tratamiento del derrame pleural paraneumónico complicado complejo y el empiema en niños. Métodos: Ensayo clínico fase III, abierto, aleatorizado (2:1), en grupos paralelos y controlado. Se concluyó la inclusión prevista de 48 niños (1-18 años de edad), que cumplieron los criterios de selección. Los progenitores otorgaron el consentimiento informado. Los pacientes se distribuyeron en dos grupos: I- experimental: terapia estándar y administración intrapleural diaria de 200 000 UI de Heberkinasa® durante 3-5 días y II-control: tratamiento estándar. Las variables principales: necesidad de cirugía y la estadía hospitalaria. Se evaluaron los eventos adversos. Resultados: Ningún paciente del grupo I-experimental requirió cirugía, a diferencia del grupo II-control en el que 37,5 por ciento necesitó cirugía video-toracoscópica, con diferencia altamente significativa. Se redujo la estadía hospitalaria (en cuatro días), las complicaciones intratorácicas y las infecciones asociadas a la asistencia sanitaria en el grupo que recibió Heberkinasa®. No se presentaron eventos adversos graves atribuibles al producto. Conclusiones: La Heberkinasa® en el derrame pleural paraneumónico complicado complejo y empiema resultó eficaz y segura para la evacuación del foco séptico, con reducción de la necesidad de tratamiento quirúrgico, de la estadía hospitalaria y de las complicaciones, sin eventos adversos relacionados con su administración(AU)

Introduction: Paraneumonic pleural effusion is the most frequent complication of bacterial pneumonia, with complex and often surgical management. There are no publications in Cuba from randomized controlled clinical trials or the use of recombinant streptokinase (Heberkinase®) in pleural effusion. Objective: To evaluate the efficacy and safety of Heberkinase® in the treatment of complex complicated parapneumonic pleural effusion and empyema in children. Methods: Phase III, open-label, randomized (2:1), parallel-group, controlled clinical trial. The planned inclusion of 48 children (1-18 years of age), who met the selection criteria, was completed. Parents gave informed consent. The patients were divided into two groups: I-experimental: standard therapy and daily intrapleural administration of 200,000 IU of Heberkinase® for 3-5 days; and II-control: standard treatment. The main variables: need for surgery and hospital stay. Adverse events were evaluated. Results: No patient in group I-experimental required surgery, unlike group II-control in which 37.5 percent required video-assisted thoracoscopic surgery, with a highly significant difference. Hospital stay (to 4 days), intrathoracic complications and infections associated to healthcare in the group that received Heberkinase® was reduced. No serious adverse events attributable to the product occurred. Conclusions: Heberkinase® in complex complicated parapneumonic pleural effusion and empyema was effective and safe for the draining of the septic focus, with reduction of the need for surgical treatment, hospital stay and complications, with no adverse events related to its administration(AU)

Fibrinolytic Therapy in Thrombosis of Mechanical Valves: Outcomes and Complications.

INTRODUCTION: Valvular heart disease presents a significant and escalating global health challenge. Prosthetic valve thrombosis (PVT) following surgical valve replacement is a primary cause of valve failure. The aim of this study was to ascertain the outcomes and complications of fibrinolytic therapy in patients diagnosed with PVT. METHOD: This cross-sectional study enrolled 81 patients diagnosed with PVT who underwent fibrinolytic therapy between 2008 and 2018. Streptokinase was administered to 87.6% of patients, while 12.4% received reteplase. All demographic and clinical data were gathered from the patients' medical records. The incidence of successful recovery and complications were assessed. RESULTS: The records of 81 patients (43.2% male, mean age: 51.6 ± 13.9 years) were examined. The findings revealed that 59% and 35% of the patients had mitral and aortic PVT, respectively. While 12% of the patients experienced drug complications, 90% achieved successful recovery. Stroke and severe hemorrhage were complications frequently reported by the patients treated with streptokinase (8% and 4% respectively). The patients treated with reteplase demonstrated a 100% recovery rate. Conversely, 89% of the patients treated with streptokinase achieved successful recovery, and 7% of the patients experienced a partial recovery. CONCLUSION: Fibrinolytic agents can serve as an effective treatment with an excellent success rate for managing PVT in patients post-surgical valve replacement.

Factores pronósticos de fallo de trombólisis en pacientes con diagnóstico de infarto agudo de miocardio / Prognostic factors of thrombolytic failure in patients diagnosed with acute myocardial infarction

RESUMEN Introducción: La medida terapéutica más importante en pacientes con infarto agudo de miocardio con supradesnivel del segmento ST es la reperfusión del territorio isquémico; la fibrinólisis es la estrategia primaria en muchos hospitales. El diagnóstico temprano de aquellos pacientes con riesgo de fallo de trombólisis es vital. Objetivo: Identificar los factores pronósticos de fallo de trombólisis en pacientes con diagnóstico de infarto agudo de miocardio con supradesnivel del segmento ST. Métodos: Estudio descriptivo y prospectivo que incluyó a pacientes atendidos en la Emergencia del Hospital Clínico-Quirúrgico «Joaquín Albarrán¼, con diagnóstico de la enfermedad antes mencionada, y tratados con estreptoquinasa recombinante, entre noviembre de 2018 hasta mayo de 2020. Fueron incluidos 66 pacientes en la investigación. Las variables analizadas fueron: Edad, sexo, hipertensión arterial, diabetes mellitus, tiempo entre inicio de síntomas y comienzo de fibrinólisis, localización del infarto, duración del complejo QRS, duración y profundidad de onda. Resultados: Hubo fallo de trombólisis en 27 pacientes (40,9 %). Las variables: Tiempo de realización de trombólisis, duración y profundidad de la onda Q, así como la duración del QRS mostraron valores con diferencias significativas entre ambos grupos (p<0,05). El análisis multivariado confirmó la duración y profundidad de la onda Q como factores independientes, predictores de fallo de trombólisis: (OR= 14,50; IC 95 % 1,58-132,33); (OR: 1,69; IC 95 % 1,27-2,26), respectivamente. Conclusiones: El análisis de la profundidad y duración de la onda Q en el electrocardiograma inicial de los pacientes estudiados, permite predecir a una subpoblación de pacientes con riesgo de fallo de trombólisis.

ABSTRACT Introduction: the most important therapeutic measure in patients with ST-segment elevation acute myocardial infarction is reperfusion of the ischemic territory; fibrinolysis is the primary strategy in many hospitals. Early diagnosis of those patients with risk of failed thrombolysis is vital. Objective: to identify prognostic factors of thrombolytic failure in patients diagnosed with ST- segment elevation acute myocardial infarction. Methods: a descriptive and prospective study including patients treated in the Emergency department at "Joaquín Albarrán" Clinical and Surgical Hospital, who were diagnosed with the previously mentioned disease and treated with recombinant streptokinase, between November 2018 and May 2020. A number of 66 patients were included in the investigation. Age, gender, arterial hypertension, diabetes mellitus, time between onset of symptoms and onset of fibrinolysis, location of the infarction, QRS complex duration, duration and depth of the wave were the analyzed variables. Results: thrombolysis failed in 27 patients (40.9%). Time of performing thrombolysis, duration and depth of the Q wave, as well as the QRS duration showed values with significant differences between both groups (p<0.05). The multivariate analysis confirmed the duration and depth of the Q wave as independent factors, predictors of thrombolysis failure: (OR= 14.50; 95% CI 1.58-132.33); (OR: 1.69; 95% CI 1.27-2.26), respectively. Conclusions: the analysis of the depth and duration of the Q wave in the initial electrocardiogram of the studied patients allows us to predict a subpopulation of patients with risk of failed thrombolysis.

Intrapleural thrombolytics for parapneumonic effusion: A network meta-analysis.

OBJECTIVES: Intrapleural thrombolytics have been trialed for facilitating pleural fluid drainage in patients with complicated parapneumonic effusion. The present study is a network meta-analysis of randomized clinical trials (RCTs) that have evaluated these thrombolytics. METHODS: Electronic databases (Medline, Cochrane CENTRAL, and Google Scholar) were searched for appropriate RCTs evaluating the therapeutic effect of thrombolytics in patients with complicated parapneumonic effusion. Mortality, proportion of patients referred for surgical intervention, and serious adverse events were the outcome measures. Random-effects model was used for generating direct and mixed treatment comparison pooled estimates. Grading of the evidence for key comparisons was carried out. Odds ratio with 95% confidence intervals was used for representing the pooled estimates. RESULTS: Seventy-six studies were retrieved with the search strategy of which 16 were included. No significant differences were observed for mortality. Compared to normal saline, significantly less proportion of patients was referred for surgical intervention with streptokinase (0.4, 0.2 to 0.8), urokinase (0.4, 0.2 to 0.8), alteplase (0.3, 0.1 to 0.7), and alteplase + DNase (0.2, 0.1 to 0.7). DNase alone increased the risk of referral to surgical intervention (3.4, 1.5 to 7.6). Only streptokinase was observed with increased risk of serious adverse events compared to normal saline (2.8, 1.1 to 7.1) and alteplase (6.7, 1.1 to 39.9). Moderate quality of evidence was observed for streptokinase with normal saline for the proportion of patients referred for surgical intervention while either low or very low quality strength was observed for all other comparisons. CONCLUSION: Streptokinase, urokinase, alteplase, and alteplase + DNase was observed with reduced proportions of patients referred for surgical interventions when used intrapleural in patients with parapneumonic effusion. Alteplase + DNase is likely to outperform others as it was observed with the least risk of patients referred for surgical interventions. Until additional data emerges that changes the pooled estimates, thrombolytics other than streptokinase are preferred due to increased risk of serious adverse events.