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1.
Iran Biomed J ; 24(1): 15-23, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31454859

RESUMO

Background: Streptokinase (SK), a heterogeneous plasminogen activator (PA) protein from groups A, C, and G streptococci (GAS, GCS, GGS, respectively) contains three structural domains (SKα, SKß, and SK). Based on the variable region of SKß, GAS-SK (ska) are clustered as SK1 and SK2 (including cluster2-streptokinase (SK2a)/SK2b), which show low and high fibrinogen (FG)-dependent plasminogen (Plg) activation properties, respectively. Despite being co-clustered as SK2a, GCS/GGS-SK (skcg) variants display properties similar to SK1. Herein, by SKß exchange between GGS (G88) and GAS-SK2a (STAB902) variants, the potential roles of SK domains in amidolytic/proteolytic activity and FG-bound-Plg activation are represented. Methods: Two parental SKG88 and SKSTAB902 genes were cloned into the NdeI/XhoI site of pET26b expression vector. The two chimeric SKß-exchanged constructs (SKC1: αG88-ßSTAB-γG88 and SKC2; αSTAB-ßG88-γSTAB) were constructed by BstEII/BsiWI digestion/cross-ligation in parental plasmids. SK were expressed in E. coli and purified by nickel-nitriloacetic acid chromatography. PA potencies of SKs were measured by colorimetric assay. Results: SDS-PAGE and Western-blot analyses confirmed the proper expression of 47-kDa SK. Analyses indicated that the catalytic efficiency (Kcat/Km) for amidolytic and proteolytic activity were less and moderately dependent on SKß, respectively. The increase of FG-bound-Plg activation for SKSTAB902/SKC1 containing SK2aß was around six times, whereas for SKG88/SKC2 containing skcgß, it was four times. Conclusion: Although SKß has noticeable contribution in FG-bound-Plg activation activity, it had minor contribution in fibrin-independent, amidolytic activity. These data might be of interest for engineering fibrin-specific versions of SK.


Assuntos
Amidas/metabolismo , Fibrina/metabolismo , Plasminogênio/metabolismo , Proteólise , Streptococcus/enzimologia , Estreptoquinase/química , Cinética , Domínios Proteicos , Estreptoquinase/genética , Estreptoquinase/isolamento & purificação
2.
Cochrane Database Syst Rev ; 2019(10)2019 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-31684683

RESUMO

BACKGROUND: Pleural infection, including parapneumonic effusions and thoracic empyema, may complicate lower respiratory tract infections. Standard treatment of these collections in adults involves antibiotic therapy, effective drainage of infected fluid and surgical intervention if conservative management fails. Intrapleural fibrinolytic agents such as streptokinase and alteplase have been hypothesised to improve fluid drainage in complicated parapneumonic effusions and empyema and therefore improve treatment outcomes and prevent the need for thoracic surgical intervention. Intrapleural fibrinolytic agents have been used in combination with DNase, but this is beyond the scope of this review. OBJECTIVES: To assess the benefits and harms of adding intrapleural fibrinolytic therapy to standard conservative therapy (intercostal catheter drainage and antibiotic therapy) in the treatment of complicated parapneumonic effusions and empyema. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase, ClinicalTrials.gov and the World Health Organization (WHO) trials portal. We contacted trial authors for further information and requested details regarding the possibility of unpublished trials. The most recent search was conducted on 28 August 2019. SELECTION CRITERIA: Parallel-group randomised controlled trials (RCTs) in adult patients with post-pneumonic empyema or complicated parapneumonic effusions (excluding tuberculous effusions) who had not had prior surgical intervention or trauma comparing an intrapleural fibrinolytic agent (streptokinase, alteplase or urokinase) versus placebo or a comparison of two fibrinolytic agents. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data. We contacted study authors for further information. We used odds ratios (OR) for dichotomous data and reported 95% confidence intervals (CIs). We used Cochrane's standard methodological procedures of meta-analysis. We applied the GRADE approach to summarise results and to assess the overall certainty of evidence. MAIN RESULTS: We included in this review a total of 12 RCTs. Ten studies assessed fibrinolytic agents versus placebo (993 participants); one study compared streptokinase with urokinase (50 participants); and one compared alteplase versus urokinase (99 participants). The primary outcomes were death, requirement for surgical intervention, overall treatment failure and serious adverse effects. All studies were in the inpatient setting. Outcomes were measured at varying time points from hospital discharge to three months. Seven trials were at low or unclear risk of bias and two at high risk of bias due to inadequate randomisation and inappropriate study design respectively. We found no evidence of difference in overall mortality with fibrinolytic versus placebo (OR 1.16, 95% CI 0.71 to 1.91; 8 studies, 867 participants; I² = 0%; moderate certainty of evidence). We found evidence of a reduction in surgical intervention with fibrinolysis in the same studies (OR 0.37, 95% CI 0.21 to 0.68; 8 studies, 897 participants; I² = 51%; low certainty of evidence); and overall treatment failure (OR 0.16, 95% CI 0.05 to 0.58; 7 studies, 769 participants; I² = 88%; very low certainty of evidence, with evidence of significant heterogeneity). We found no clear evidence of an increase in adverse effects with intrapleural fibrinolysis, although this cannot be excluded (OR 1.28, 95% CI 0.36 to 4.57; low certainty of evidence). In a sensitivity analysis, the reduction in referrals for surgery and overall treatment failure with fibrinolysis disappeared when the analysis was confined to studies at low or unclear risk of bias. In a moderate-risk population (baseline 14% risk of death, 20% risk of surgery, 27% risk of treatment failure), intra-pleural fibrinolysis leads to 19 more deaths (36 fewer to 59 more), 115 fewer surgical interventions (150 fewer to 55 fewer) and 214 fewer overall treatment failures (252 fewer to 93 fewer) per 1000 people. A single study of streptokinase versus urokinase found no clear difference between the treatments for requirement for surgery (OR 1.00, 95% CI 0.13 to 7.72; 50 participants; low-certainty evidence). A single study of alteplase versus urokinase showed no clear difference in requirement for surgery (OR alteplase versus urokinase 0.46, 95% CI 0.04 to 5.24) but an increased rate of adverse effects, primarily bleeding, with alteplase (OR 5.61, 95% CI 1.16 to 27.11; 99 participants; low-certainty evidence). This translated into 154 (6 to 499 more) serious adverse events with alteplase compared with urokinase per 1000 people treated. AUTHORS' CONCLUSIONS: In patients with complicated infective pleural effusion or empyema, intrapleural fibrinolytic therapy was associated with a reduction in the requirement for surgical intervention and overall treatment failure but with no evidence of change in mortality. Discordance between the negative largest trial of this therapy and other studies is of concern, however, as is an absence of significant effect when analysing low risk of bias trials only. The reasons for this difference are uncertain but may include publication bias. Intrapleural fibrinolytics may increase the rate of serious adverse events, but the evidence is insufficient to confirm or exclude this possibility.


Assuntos
Empiema Pleural/terapia , Fibrinolíticos/uso terapêutico , Derrame Pleural/terapia , Terapia Trombolítica/métodos , Antibacterianos/uso terapêutico , Drenagem , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Estreptoquinase/uso terapêutico , Ativador de Plasminogênio Tecidual/uso terapêutico , Ativador de Plasminogênio Tipo Uroquinase/uso terapêutico
3.
Pediatrics ; 144(6)2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31757859

RESUMO

CONTEXT: Thrombotic occlusion is 1 of the most frequent complications in catheters implanted in children. OBJECTIVE: To identify the interventions used to treat thrombotic events in long-term central venous catheters in pediatric patients with cancer. DATA SOURCES: Electronic searches were performed in the Cumulative Index to Nursing and Allied Health Literature, Cochrane Central Register of Controlled Trials, Latin American and Caribbean Health Sciences Literature, LIVIVO, PubMed, Scopus, Web of Science, Google Scholar, OpenGrey, and ProQuest databases. There were no restrictions on language or publication period. STUDY SELECTION: This systematic review was performed in 2 phases and included clinical trials and observational studies on drugs used to treat thrombotic catheter events in pediatric patients with cancer. The review was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis checklist, and the protocol was registered at PROSPERO (identifier CRD42018083555). DATA EXTRACTION: The authors evaluated the quality of included studies using the Methodological Index for Nonrandomized Studies and Grading of Recommendations Assessment, Development and Evaluation methods. The meta-analysis was performed by using Stata software. RESULTS: Ten studies were included. The drugs used to restore catheter function were alteplase, urokinase, and streptokinase. A meta-analysis of 6 studies revealed an overall restoration rate of 88% for alteplase. LIMITATIONS: Reference studies were excluded when it was not possible to reliably extract data that met the inclusion criteria of this review. Sampling issues (absence of randomization, blinding, or a control group) were the main methodologic concerns for the included articles. CONCLUSIONS: On the basis of the evidence obtained, thrombolysis is effective and potentially safe in this population.


Assuntos
Cateteres Venosos Centrais/efeitos adversos , Fibrinolíticos/uso terapêutico , Terapia Trombolítica , Trombose/tratamento farmacológico , Trombose/etiologia , Humanos , Estreptoquinase/uso terapêutico , Ativador de Plasminogênio Tecidual/uso terapêutico , Ativador de Plasminogênio Tipo Uroquinase/uso terapêutico
5.
J Coll Physicians Surg Pak ; 29(8): 749-752, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31358097

RESUMO

OBJECTIVE: To evaluate the presentation, diagnosis, management and outcome of acute pulmonary embolism for assessing the factors impacting mortality in such patients. STUDY DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: Rawalpindi Institute of Cardiology, Rawalpindi, Pakistan, from July 2015 to July 2018. METHODOLOGY: Patients presenting with clinical suspicion of pulmonary embolism were subjected to a diagnostic algorithm consisting of Wells Rule, D-Dimer testing, echocardiography and CT pulmonary angiogram. Patients diagnosed with pulmonary embolism were subdivided into massive and submassive pulmonary embolism groups. Most patients diagnosed with massive pulmonary embolism were treated with streptokinase injection. For those diagnosed as submassive pulmonary embolism, the standard therapy remained anticoagulation with intravenous heparin, both the subsets of patients were further put on oral warfarin. Clinical outcome was defined as combined end-point including death during hospital stay, recurrence of PE and meed for repeat thrombolysis. RESULTS: A total of 174 patients diagnosed with pulmonary embolism were studied. The mean age was 49.1 +14.8 years (range 23-88 years) with 109 (62.6%) patients being male. The in-hospital clinical course was uneventful in 144 (83%) patients. Twenty-two patients (12.6%) patients died, of whom 3 died from major bleeding, one from cancer, and 18 from the pulmonary embolism process (14 patients from refractory shock and 4 patients from recurrent PE). A total of 8 (4.6%) had fatal or non-fatal recurrent PE. In patients who had echocardiography both pre- and post-thrombolysis, initial RV dysfunction was reversible in 136 (78%) within 48h following thrombolytic therapy. By univariate analysis, only shock (SBP) and delay in diagnosis for more than 6 hours were associated with adverse event. CONCLUSION: Early diagnosis by doing urgent CTPA in patients with suspected acute PE is the cornerstone in reducing mortality in acute PE patients.


Assuntos
Anticoagulantes/uso terapêutico , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/tratamento farmacológico , Estreptoquinase/uso terapêutico , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paquistão/epidemiologia , Embolia Pulmonar/mortalidade , Recidiva , Atenção Terciária à Saúde , Terapia Trombolítica
6.
Kardiologiia ; 59(6): 91-96, 2019 Jun 06.
Artigo em Russo | MEDLINE | ID: mdl-31242846

RESUMO

Thrombolytic therapy (TLT), as a method of treatment, began to develop in the second half of the 50s of the last century. At that time, there was an accumulation of data on its effectiveness, side effects and contraindications, as well as the development of fibrinolytic drugs, such as fibrinolysin, streptokinase, urokinase, and the conditions for their administration. Official recognition of TLT in regulatory documents began only in the 80s after the development of more effective and safe tissue plasminogen activators. However, on the threshold of an era of development in this area in the treatment of patients with thrombosis of the coronary, carotid, and other peripheral vascular regions, the researchers obtained conflicting data on the results of the use of thrombolytics. There was no concept of a therapeutic window for the use of TLT, there was no data on possible combinations of thrombolytic drugs with anticoagulants, the high probability of bleeding prevented widespread introduction of the method into clinical practice. At that time, vascular imaging and laboratory diagnostics were not sufficiently developed, there was no consensus of the world's leading experts on the benefits of thrombolysis. The use of TLT in acute arterial thrombosis required not only clinical experience, but also courage and ability to make non-standard decisions. The authors of the article analyze in detail the case of rescuing a patient with progressive thrombotic occlusion of the arteries of the brain stem. Then the pioneer in the field of thrombolytic therapy E. I. Chazov and his colleagues took responsibility for the application in this situation of an insufficiently studied treatment method with uncertain consequences. This decision was not due to the identity of the patient or the threat of an internal investigation. Marshal or soldier - it did not matter for E. I. Chazov and his colleagues. If doctors in this clinical situation relied on recommendations, orders and standards, then such a patient would have to wait thrombolysis for another 30 years.


Assuntos
Terapia Trombolítica , Fibrinólise , Fibrinolíticos , Humanos , Neurologia , Estreptoquinase , Ativador de Plasminogênio Tecidual
7.
FEBS Open Bio ; 9(7): 1259-1269, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31087538

RESUMO

Streptokinase (SK) is a plasminogen activator which converts inactive plasminogen (Pg) to active plasmin (Pm), which cleaves fibrin clots. SK secreted by groups A, C, and G Streptococcus (SKA/SKC/SKG) is composed of three domains: SKα, SKß and SKγ. Previous domain-swapping studies between SK1/SK2b-cluster variants revealed that SKß plays a major role in the activation of human Pg. Here, we carried out domain-swapping between skcg-SK/SK2-cluster variants to determine the involvement of SKß in several SK functionalities, including specific/proteolytic activity kinetics, fibrinogen-bound Pg activation and α2 -antiplasmin resistance. Our results indicate that SKß has a minor to determining role in these diverse functionalities for skcg-SK and SK2b variants, which might potentially be accompanied by few critical residues acting as hot spots. Our findings enhance our understanding of the roles of SKß and hot spots in different functional characteristics of SK clusters and may aid in the engineering of fibrin-specific variants of SK for breaking down blood clots with potentially higher efficacy and safety.


Assuntos
Domínios Proteicos/fisiologia , Estreptoquinase/metabolismo , Proteínas de Bactérias/química , Fibrinogênio , Fibrinolisina/química , Fibrinolisina/metabolismo , Cinética , Plasminogênio/química , Plasminogênio/metabolismo , Ativadores de Plasminogênio/química , Ativadores de Plasminogênio/metabolismo , Ligação Proteica , Engenharia de Proteínas/métodos , Proteólise , Streptococcus/metabolismo , Estreptoquinase/química , Estreptoquinase/fisiologia
8.
Microbiol Spectr ; 7(2)2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30873932

RESUMO

Of the eight phylogenetic groups comprising the genus Streptococcus, Lancefield group C and G streptococci (GCS and GGS, resp.) occupy four of them, including the Pyogenic, Anginosus, and Mitis groups, and one Unnamed group so far. These organisms thrive as opportunistic commensals in both humans and animals but may also be associated with clinically serious infections, often resembling those due to their closest genetic relatives, the group A streptoccci (GAS). Advances in molecular genetics, taxonomic approaches and phylogenomic studies have led to the establishment of at least 12 species, several of which being subdivided into subspecies. This review summarizes these advances, citing 264 early and recent references. It focuses on the molecular structure and genetic regulation of clinically important proteins associated with the cell wall, cytoplasmic membrane and extracellular environment. The article also addresses the question of how, based on the current knowledge, basic research and translational medicine might proceed to further advance our understanding of these multifaceted organisms. Particular emphasis in this respect is placed on streptokinase as the protein determining the host specificity of infection and the Rsh-mediated stringent response with its potential for supporting bacterial survival under nutritional stress conditions.


Assuntos
Filogenia , Streptococcus/classificação , Streptococcus/genética , Fatores de Virulência/genética , Animais , Antígenos de Bactérias/classificação , Antígenos de Bactérias/genética , Antígenos de Superfície/classificação , Proteínas de Bactérias/classificação , Proteínas de Bactérias/genética , Membrana Celular , Parede Celular , DNA Bacteriano , Exotoxinas/classificação , Exotoxinas/genética , Genes Bacterianos , Especificidade de Hospedeiro , Humanos , Infecções Estreptocócicas/microbiologia , Streptococcus/patogenicidade , Estreptoquinase/genética , Simbiose
10.
Curr Pharm Biotechnol ; 20(1): 76-83, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30734674

RESUMO

BACKGROUND: Despite the extensive use of streptokinase in thrombolytic therapy, its administration may have some shortcomings like allergic reactions and relatively low half life. Specific PEGylation on cysteine at desired sites of streptokinase may alleviate these deficiencies and improve the quality of treatment. OBJECTIVE: This study was carried out to create a new cystein variant of streptokinase and compare its activity with formerly mutated SK263cys, SK45cys and intact streptokinase (Ski) to introduce superior candidates for specific PEGylation. METHOD: In silico study was carried out to select appropriate amino acid for cysteine substitution and accordingly mutagenesis was carried out by SOEing PCR. The mutated gene was cloned in E. coli, expressed, and purified by affinity chromatography. Activity of the purified proteins was assayed and kinetic parameters of enzymatic reaction were analyzed. RESULTS: According to in silico data, Arginine319 was selected for substitution with cysteine. SK319cys was achieved with 98% purity after cloning, expression and purification. It was shown that the enzymatic efficiency of SK319Cys and SK263cys was increased 18 and 21%, respectively, when compared to SKi (79.4 and 81.3 vs. 67.1µM-1min-1), while SK45cys showed 7% activity decrease (62.47µM-1min-1) compared to SKi. According to time-based activity assay, SK319Cys and SK263cys exhibited higher activity at lower substrate concentrations (100 and 200 µM), but at higher concentrations of substrate (400 and 800 µM), the proteins showed a very close trend of activity. CONCLUSION: SK319cys, as the new cysteine variant of streptokinase, together with SK263cys and SK45cys can be considered as appropriate molecules for specific PEGylation.


Assuntos
Cisteína/genética , Variação Genética/genética , Estreptoquinase/genética , Estreptoquinase/metabolismo , Cisteína/química , Escherichia coli/genética , Humanos , Reação em Cadeia da Polimerase/métodos , Estrutura Terciária de Proteína
11.
Ann Cardiol Angeiol (Paris) ; 68(2): 65-70, 2019 Apr.
Artigo em Francês | MEDLINE | ID: mdl-30292445

RESUMO

OBJECTIVE: To describe the management and evolution of high risk of death pulmonary embolism associated with right heart thrombi. MATERIAL AND METHODS: We conducted a prospective cohort survey over a 54 month-period, from March 1st, 2012 to September 30th 2015. Were included all patients with pulmonary embolism and having high or intermediate-high risk of death. Patients were divided into two groups according to whether cardiac Doppler-echography found a thrombus in the right chambers or not (ICT+ vs. ICT-). The survival curves for the patients were obtained using the software STATA. RESULTS: The prevalence of pulmonary embolism associated with right heart thrombi was 4% in our study. Thrombi were mobile, straight localization in all cases. The ICT+group was characterized by a significantly higher proportion of congestive heart and chronic lung disease. The proportion of patients' thrombolysis was significantly higher in the ICT-group. In the ICT+group, thrombolysis significantly reduced mortality giving a 30-day survival of 80% against 20% among patients receiving only heparin. CONCLUSION: Pulmonary embolism associated with right heart thrombi including the atrium are not exceptional. These patients are at high risk of early death. Thrombolysis is significantly improving the mortality of pulmonary embolism associated with right-sided heart thrombi.


Assuntos
Cardiopatias/complicações , Embolia Pulmonar/complicações , Trombose/complicações , Burkina Faso , Distribuição de Qui-Quadrado , Ecocardiografia , Feminino , Fibrinolíticos/uso terapêutico , Átrios do Coração/diagnóstico por imagem , Cardiopatias/diagnóstico por imagem , Cardiopatias/mortalidade , Cardiopatias/terapia , Heparina/uso terapêutico , Hospitais Universitários , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Embolia Pulmonar/diagnóstico por imagem , Embolia Pulmonar/mortalidade , Embolia Pulmonar/terapia , Risco , Estreptoquinase/uso terapêutico , Terapia Trombolítica/métodos , Terapia Trombolítica/mortalidade , Trombose/diagnóstico por imagem , Trombose/mortalidade , Trombose/terapia
12.
J Trop Pediatr ; 65(3): 231-239, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30053189

RESUMO

OBJECTIVES: The purposes of this paper are to study clinicobacteriological profile, treatment modalities and outcome of pediatric empyema thoracis and to identify changes over a decade. DESIGN: This is a retrospective study. SETTING: Department of Pediatrics of a tertiary care hospital in North India. PATIENTS: We enrolled 205 patients (1 month-12 years) of empyema thoracis admitted over 5 years (2007-11) and compared the profile with that of a previous study from our institute (1989-98). RESULTS: Pleural fluid cultures were positive in 40% (n = 82) cases from whom 87 isolates were obtained. Staphylococcus aureus was the most common isolate (66.7%). Methicillin-sensitive S. aureus accounted for 56%, Methicillin-resistant S. aureus (MRSA) 10% and gram-negative organisms 18.3% of isolates. Intercostal drainage tube (ICDT) was inserted in 97.5%, intrapleural streptokinase was administered in 33.6%, and decortication performed in 27.8% cases. Duration of hospital stay was 17.2 (±6.3) days, duration of antibiotic (intravenous and oral) administration was 23.8 (±7.2) days and mortality rate was 4%. In the index study (compared with a previous study), higher proportion of cases received parenteral antibiotics (51.7% vs. 23.4%) and ICDT insertion (20.5% vs. 7%) before referral and had disseminated disease (20.5% vs. 14%) and septic shock (11.2% vs. 1.6%), less culture positivity (40% vs. 48%), more MRSA (10.3% vs. 2.5%) and gram-negative organisms (18.4% vs. 11.6%), increased use of intrapleural streptokinase and surgical interventions (27.8% vs. 19.7%), shorter hospital stay (17 vs. 25 days) and higher mortality (3.9% vs. 1.6%). CONCLUSIONS: Over a decade, an increase in the incidence of empyema caused by MRSA has been noticed, with increased use of intrapleural streptokinase and higher number of surgical interventions.


Assuntos
Drenagem/métodos , Empiema Pleural/terapia , Fibrinolíticos/administração & dosagem , Estreptoquinase/administração & dosagem , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Infecções Bacterianas/complicações , Criança , Pré-Escolar , Esquema de Medicação , Empiema Pleural/diagnóstico , Empiema Pleural/tratamento farmacológico , Empiema Pleural/mortalidade , Feminino , Fibrinolíticos/uso terapêutico , Bactérias Gram-Negativas/isolamento & purificação , Humanos , Incidência , Tempo de Internação/estatística & dados numéricos , Masculino , Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas/complicações , Staphylococcus aureus/isolamento & purificação , Estreptoquinase/uso terapêutico , Resultado do Tratamento
13.
Ann Cardiol Angeiol (Paris) ; 68(1): 28-31, 2019 Feb.
Artigo em Francês | MEDLINE | ID: mdl-30290914

RESUMO

INTRODUCTION: High-risk pulmonary embolism (PE) accounts for 5% of total acute PE and is a life-threatening emergency requiring immediate therapeutic management by fibrinolysis. The objective of this work is to describe the experience of thrombolysis in high-risk PE in a cardiology department in Togo. PATIENTS AND METHODS: This is an analytical and descriptive study carried out in the cardiology department of the Campus teaching hospital of Lomé over a period of 5 years (August 2012 to July 2017) concerning patients hospitalized for high-risk mortality PE and having undergone streptokinase thrombolysis. RESULTS: Twenty-eight of the 102 PE were at high risk of mortality (27.5%). They were 9 men and 19 women with an average age of 61.9±14.1 years. The mean systolic blood pressure was 65mmHg and 50% of the patients were placed on dobutamine. Thrombolysis was performed in 22 of the 28 patients (78.6%). Eighteen patients had a short protocol and 4 a long protocol. The mortality rate was 32.1% or 13.6% in the thrombolysis PE versus 100% in the non-thrombolysis PE (P=0.01). Causes of death in thrombolysis were persistent shock (2 cases) at the end of thrombolysis and sudden death occurred 1 month after hospitalization. The average hospital stay was 18.8 days. CONCLUSION: The high-risk PE remains today a pathology burdened with heavy mortality. Thrombolysis remains the first treatment to reduce this mortality.


Assuntos
Embolia Pulmonar/tratamento farmacológico , Embolia Pulmonar/mortalidade , Terapia Trombolítica/estatística & dados numéricos , Adulto , Idoso , Serviço Hospitalar de Cardiologia , Cardiotônicos/uso terapêutico , Dobutamina/uso terapêutico , Esquema de Medicação , Feminino , Fibrinolíticos/administração & dosagem , Hospitais de Ensino , Humanos , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Estreptoquinase/administração & dosagem , Togo/epidemiologia
14.
Cardiovasc Drugs Ther ; 33(6): 749-753, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31897763

RESUMO

Ever since tissue plasminogen activator (tPA) was approved for therapeutic fibrinolysis in 1987, it has been the fibrinolytic of choice. At the same time, it is also recognized that tPA never lived up to its clinical expectations and has more recently been replaced by percutaneous coronary intervention (PCI) as the treatment of choice for acute myocardial infarction (AMI). For other occlusive vascular diseases and for patients in remote areas, tPA remains an essential option. In view of the continued importance of fibrinolysis, it is disappointing that fibrinolysis never evolved beyond what it was when tPA replaced streptokinase (SK) 32 years ago. The endovascular procedure replacement for AMI treatment suffers from being technically demanding, time-consuming, and costly. An untested alternative fibrinolytic paradigm is that of the endogenous, physiological system, which is initiated by tPA but then is followed by the other natural plasminogen activator, urokinase plasminogen activator (uPA). In this combination, it is uPA rather than tPA that has the dominant function. This is also evident from gene knockout studies where deletion of uPA that it has the dominant effect. The fibrinolytic properties of tPA and uPA are complementary so that their combined effect is synergistic, especially when they are administered sequentially starting with tPA. Endogenous fibrinolysis functions without bleeding side effects and is ongoing. This is evidenced by the invariable presence in blood of the fibrin degradation product, D-dimer (normal concentration 110-250 ng/ml). This activator combination, consisting of a mini bolus of tPA followed by a 90-min proUK infusion, was once used to treat 101 AMI patients. Compared with the best of the tPA mega trials, this regimen resulted in an almost a doubling of the infarct artery patency rate and reduced mortality sixfold. To date, a second trial has not yet been done.


Assuntos
Fibrinólise/efeitos dos fármacos , Fibrinolíticos/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Estreptoquinase/uso terapêutico , Terapia Trombolítica , Ativador de Plasminogênio Tecidual/uso terapêutico , Ativador de Plasminogênio Tipo Uroquinase/uso terapêutico , Animais , Quimioterapia Combinada , Fibrinolíticos/efeitos adversos , Hemorragia/induzido quimicamente , Humanos , Infarto do Miocárdio/sangue , Infarto do Miocárdio/mortalidade , Fatores de Risco , Estreptoquinase/efeitos adversos , Terapia Trombolítica/efeitos adversos , Ativador de Plasminogênio Tecidual/efeitos adversos , Resultado do Tratamento , Ativador de Plasminogênio Tipo Uroquinase/efeitos adversos
15.
Appl Microbiol Biotechnol ; 102(24): 10561-10577, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30298450

RESUMO

Streptokinase, a therapeutically important thrombolytic agent, is prone to C-terminal degradation and plasmin-mediated proteolytic processing. Since the protein was glycosylated during secretion from Pichia pastoris, therefore, the role of carbohydrate moieties on its stability was analyzed via in vivo blocking of N-glycosylation using tunicamycin where an increased degradation of streptokinase was observed. Further, the in vitro site-directed mutagenesis of the three putative N-glycosylation sites at asparagine residues 14, 265, and 377 to alanine revealed the essentiality of glycosylation of the 14th amino acid residue in its post-translational proteolytic stability without significantly affecting its biological activity. However, the mutation of both Asn265 and Asn377 did not seem to contribute toward its glycosylation but resulted in a 39% lower specific activity in case of the rSK-N265,377A. Moreover, the mutation of all three glycosylation positions drastically reduced the secretory expression of native streptokinase from 347 to 186.6 mg/L for the triple mutant with a 14% lower specific activity of 56,738 IU/mg from 65,808 IU/mg. The secondary structure, tertiary structure, and thermal transition point (45-55 °C) of all the deglycosylated variants did not show any significant differences when compared with fully glycosylated native streptokinase using CD and fluorescence spectroscopy. Furthermore, the longer acting plasmin-resistant variants were also developed via the mutation of lysine residues 59 and 386 to glutamine which enhanced its biological stability as a ~ 1.5-fold increase in the caseinolytic zone size was observed in case of rSK-K59Q and also in rSK-K59,386Q mutant without affecting the structural properties.


Assuntos
Fibrinolisina/metabolismo , Pichia/genética , Engenharia de Proteínas/métodos , Proteínas Recombinantes/metabolismo , Estreptoquinase/metabolismo , Dicroísmo Circular , Meios de Cultura/farmacologia , Estabilidade Enzimática/genética , Glicosilação , Mutagênese Sítio-Dirigida , Mutação , Pichia/efeitos dos fármacos , Pichia/metabolismo , Proteínas Recombinantes/genética , Espectrometria de Fluorescência , Estreptoquinase/genética , Tunicamicina/farmacologia
16.
J Am Chem Soc ; 140(45): 15516-15524, 2018 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-30347143

RESUMO

Although the functional specificity and catalytic versatility of enzymes have been exploited in numerous settings, controlling the spatial and temporal activity of enzymes remains challenging. Here we describe an approach for programming the function of streptokinase (SK), a protein that is clinically used as a blood "clot buster" therapeutic. We show that the fibrinolytic activity resulting from the binding of SK to the plasma proenzyme plasminogen (Pg) can be effectively regulated (turned "OFF" and "ON") by installing an intrasteric regulatory feature using a DNA-linked protease inhibitor modification. We describe the design rationale, synthetic approach, and functional characterization of two generations of intrasterically regulated SK-Pg constructs and demonstrate dose-dependent and sequence-specific temporal control in fibrinolytic activity in response to short predesignated DNA inputs. The studies described establish the feasibility of a new enzyme-programming approach and serves as a step toward advancing a new generation of programmable enzyme therapeutics.


Assuntos
DNA/farmacologia , Desenho de Fármacos , Ativadores de Plasminogênio/farmacologia , Inibidores de Proteases/farmacologia , Estreptoquinase/antagonistas & inibidores , DNA/química , Humanos , Ativadores de Plasminogênio/síntese química , Ativadores de Plasminogênio/química , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , Estreptoquinase/metabolismo
17.
Indian Heart J ; 70(4): 506-510, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30170645

RESUMO

OBJECTIVE: Prosthetic valve thrombosis (PVT) is a dreadful complication of mechanical prosthetic valves. Thrombolytic therapy (TT) for PVT is an alternative to surgery and currently making a leading role. This study compares TT with tenecteplase (TNK) and streptokinase (SK) head to head in patients with mitral PVT. METHODS: In this single center, observational study, patients with mitral PVT diagnosed by clinical data, transthoracic echocardiography, transesophageal echocardiography, and fluoroscopy were included. After excluding patients with contraindications for thrombolysis, they were randomly assigned to receive either SK or TNK regimen. Patients were monitored for success or failure of TT and for any complications. RESULTS: Among 52 episodes (47 patients with 5 recurrences) of mechanical mitral PVT, 40 patients were thrombolyzed with SK and 12 patients were thrombolyzed with TNK. Baseline characteristics including demographic profile, clinical and echocardiographic features, and valve types were not statistically significant between the groups. Complete success rate was 77.5% in SK group and 75% in TNK group (p=0.88). Partial success rate, failure rate, and major complications were not statistically significant between the two groups. Within 12h of therapy, TNK showed complete success in 33.3% of patients compared to 15% in SK group (p-value <0.02). Minor bleeding was more common in TNK group. CONCLUSION: Slow infusion of TNK is equally efficacious but more effective than SK in the management of mitral mechanical PVT. 75% to 77.5% of PVT patients completely recovered from TT and it should be the first line therapy where the immediate surgical options were remote.


Assuntos
Próteses Valvulares Cardíacas/efeitos adversos , Valva Mitral/diagnóstico por imagem , Estreptoquinase/administração & dosagem , Terapia Trombolítica/métodos , Trombose/tratamento farmacológico , Ativador de Plasminogênio Tecidual/administração & dosagem , Adolescente , Adulto , Ecocardiografia Transesofagiana , Feminino , Fibrinolíticos/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Valva Mitral/cirurgia , Estudos Retrospectivos , Tenecteplase , Trombose/diagnóstico , Trombose/etiologia , Resultado do Tratamento , Adulto Jovem
18.
Pak J Pharm Sci ; 31(4(Supplementary)): 1597-1602, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30058554

RESUMO

Streptokinase (SK) is a fibrinolytic protein used for the treatment of cardiovascular disorders. In the present study, enhanced production of SK was achieved by determining the optimum fermentation conditions for the maximum growth of Streptococcus agalactiae EBL-31 using response surface methodology (RSM). Four process variables (pH, temperature, incubation time and inoculum size) with five levels were evaluated in 30 experimental runs. Central composite rotatable design (CCRD) was employed to predict the effect of independent variables on SK activity. The statistical evaluation by ANOVA showed that the model was fit as the effect of single factors, quadratic effects and most of the interactions among variables. The value ofR2 (0.9988) indicated the satisfactory interaction between the experimental and predicted responses. Furthermore, the model F value (902.67) and coefficient of variation (1.92) clearly showed that the model is significant (p =>0.0001). The functional activity of SK was determined by spectrophotometric analysis and maximum SK production was obtained at pH-7.0, temperature- 37.5oC, an incubation time of 36 hours and 2.5 mL inoculum size. Hence it was concluded that the optimization of culture conditions through RSM increases the production of SK by 2.01-fold. Production of SK by fermentation is an economical choice to be used for the treatment of cardiovascular diseases.


Assuntos
Química Farmacêutica/métodos , Fermentação/fisiologia , Streptococcus agalactiae/enzimologia , Estreptoquinase/biossíntese , Humanos , Streptococcus agalactiae/genética , Estreptoquinase/genética
19.
BMJ Case Rep ; 20182018 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-29930186

RESUMO

A 45-year-old man without previous comorbidity presented to us with acute onset right-sided flank pain for last 14 hours. His general physical and systemic examination was unremarkable, and there were no clinical signs of peritonitis. The ultrasonography did not reveal any evidence of nephrolithiasis or hydronephrosis. His contrast-enhanced CT scan revealed hypoattenuated areas of right kidney and evidence of right renal artery thrombosis. He was immediately shifted to cardiac catheterisation lab, and his renal angiography showed thrombotic occlusion of right renal artery. The bolus dose of streptokinase (250 000 IU) was given locally in renal artery by right judkins catheter followed by systemic infusion of streptokinase (100 000 IU/hour) for 24 hours. After that he was started on low molecular weight heparin. Repeat renal angiography done after 5 days showed completely normal right renal artery. His cardiac and thrombophilia work up was negative, and he was discharged on antiplatelets, oral anticoagulants and statins.


Assuntos
Anticoagulantes/administração & dosagem , Artéria Renal/diagnóstico por imagem , Trombose/diagnóstico por imagem , Trombose/tratamento farmacológico , Angiografia , Anticoagulantes/uso terapêutico , Meios de Contraste , Heparina de Baixo Peso Molecular/administração & dosagem , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Estreptoquinase/administração & dosagem , Estreptoquinase/uso terapêutico , Tomografia Computadorizada por Raios X , Resultado do Tratamento
20.
Acta Paediatr ; 107(12): 2165-2171, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29782063

RESUMO

AIM: This study compared the efficacy of administering intrapleural streptokinase to children with multi-loculated empyema within 14 days or at any time after disease onset. METHODS: We studied children under 12 years with multi-loculated empyema who were admitted to a teaching hospital in Chandigarh, India, from July 2013 to June 2017. They received antibiotics, pleural drainage and intrapleural streptokinase. The first group received three doses within 14 days of disease onset, the second received three doses regardless of time after onset and the third group received four to six doses regardless of time after onset. The three phases lasted 18, 18 and 12 months, respectively. RESULTS: Of 195 children, 133 (68%) received streptokinase within 14 days, 46 (24%) beyond 14 days and 16 (8%) did not receive it. There was no difference in surgical decortication (14/133 versus 7/46, p > 0.05) and median hospitalisation duration (15 versus 14 days, p > 0.05) between administration before versus after 14 days. Median hospitalisation was shorter with four to six doses than three doses (11 versus 16 days, p < 0.01). CONCLUSION: Intrapleural streptokinase was effective for multi-loculated empyema even when it was administered more than 14 days after disease onset and four to six doses were superior to three doses.


Assuntos
Empiema Pleural/tratamento farmacológico , Fibrinolíticos/administração & dosagem , Estreptoquinase/administração & dosagem , Criança , Pré-Escolar , Humanos , Lactente
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