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Stroke Nov 2020Tenecteplase is a fibrinolytic drug with higher fibrin specificity and longer half-life than the standard stroke thrombolytic, alteplase, permitting the convenience of... (Review)
Review
Tenecteplase is a fibrinolytic drug with higher fibrin specificity and longer half-life than the standard stroke thrombolytic, alteplase, permitting the convenience of single bolus administration. Tenecteplase, at 0.5 mg/kg, has regulatory approval to treat ST-segment-elevation myocardial infarction, for which it has equivalent 30-day mortality and fewer systemic hemorrhages. Investigated as a thrombolytic for ischemic stroke over the past 15 years, tenecteplase is currently being studied in several phase 3 trials. Based on a systematic literature search, we provide a qualitative synthesis of published stroke clinical trials of tenecteplase that (1) performed randomized comparisons with alteplase, (2) compared different doses of tenecteplase, or (3) provided unique quantitative meta-analyses. Four phase 2 and one phase 3 study performed randomized comparisons with alteplase. These and other phase 2 studies compared different tenecteplase doses and effects on early outcomes of recanalization, reperfusion, and substantial neurological improvement, as well as symptomatic intracranial hemorrhage and 3-month disability on the modified Rankin Scale. Although no single trial prospectively demonstrated superiority or noninferiority of tenecteplase on clinical outcome, meta-analyses of these trials (1585 patients randomized) point to tenecteplase superiority in recanalization of large vessel occlusions and noninferiority in disability-free 3-month outcome, without increases in symptomatic intracranial hemorrhage or mortality. Doses of 0.25 and 0.4 mg/kg have been tested, but no advantage of the higher dose has been suggested by the results. Current clinical practice guidelines for stroke include intravenous tenecteplase at either dose as a second-tier option, with the 0.25 mg/kg dose recommended for large vessel occlusions, based on a phase 2 trial that demonstrated superior recanalization and improved 3-month outcome relative to alteplase. Ongoing randomized phase 3 trials may better define the comparative risks and benefits of tenecteplase and alteplase for stroke thrombolysis and answer questions of tenecteplase efficacy in the >4.5-hour time window, in wake-up stroke, and in combination with endovascular thrombectomy.
Topics: Clinical Trials as Topic; Dose-Response Relationship, Drug; Fibrinolytic Agents; Humans; Intracranial Hemorrhages; Ischemic Stroke; Mortality; ST Elevation Myocardial Infarction; Tenecteplase; Thrombolytic Therapy; Time-to-Treatment; Tissue Plasminogen Activator; Treatment Outcome
PubMed: 33045929
DOI: 10.1161/STROKEAHA.120.029749 -
Neuroscience Bulletin Oct 2022Ischemic stroke caused by intracranial vascular occlusion has become increasingly prevalent with considerable mortality and disability, which gravely burdens the global... (Review)
Review
Ischemic stroke caused by intracranial vascular occlusion has become increasingly prevalent with considerable mortality and disability, which gravely burdens the global economy. Current relatively effective clinical treatments are limited to intravenous alteplase and thrombectomy. Even so, patients still benefit little due to the short therapeutic window and the risk of ischemia/reperfusion injury. It is therefore urgent to figure out the neuronal death mechanisms following ischemic stroke in order to develop new neuroprotective strategies. Regarding the pathogenesis, multiple pathological events trigger the activation of cell death pathways. Particular attention should be devoted to excitotoxicity, oxidative stress, and inflammatory responses. Thus, in this article, we first review the principal mechanisms underlying neuronal death mediated by these significant events, such as intrinsic and extrinsic apoptosis, ferroptosis, parthanatos, pyroptosis, necroptosis, and autophagic cell death. Then, we further discuss the possibility of interventions targeting these pathological events and summarize the present pharmacological achievements.
Topics: Brain Ischemia; Cell Death; Humans; Ischemic Stroke; Reperfusion Injury; Stroke; Tissue Plasminogen Activator
PubMed: 35513682
DOI: 10.1007/s12264-022-00859-0 -
EBioMedicine Sep 2022As aortic aneurysms (AAs) enlarge, they can become life-threatening if left undiagnosed or neglected. At present, there is a lack of radical treatments for preventing...
BACKGROUND
As aortic aneurysms (AAs) enlarge, they can become life-threatening if left undiagnosed or neglected. At present, there is a lack of radical treatments for preventing disease progression. Therefore, we aimed to identify effective drug targets that slow the progression of AAs.
METHODS
A Mendelian randomization (MR) analysis was conducted to identify therapeutic targets which are associated with AAs. Summary statistics for AAs were obtained from two datasets: the UK Biobank (2228 cases and 408,565 controls) and the FinnGen study (3658 cases and 244,907 controls). Cis-expression quantitative trait loci (cis-eQTL) for druggable genes were retrieved from the eQTLGen Consortium and used as genetic instrumental variables. Colocalization analysis was performed to determine the probability that single nucleotide polymorphisms (SNPs) associated with AAs and eQTL shared causal genetic variants.
FINDINGS
Four drug targets (BTN3A1, FASN, PLAU, and PSMA4) showed significant MR results in two independent datasets. Proteasome 20S subunit alpha 4 (PSMA4) and plasminogen activator, urokinase (PLAU) in particular, were found to have strong evidence for colocalization with AAs, and abdominal aortic aneurysm in particular. Additionally, except for the association between PSMA4 and intracranial aneurysms, no association between genetically proxied inhibition of PLAU and PSMA4 was detected in increasing the risk of other cardiometabolic risks and diseases.
INTERPRETATION
This study supports that drug-targeting PLAU and PSMA4 inhibition may reduce the risk of AAs.
FUNDING
This work was supported by National Key R&D Program of China (NO. 2017YFC0909400), Nature Science Foundation of China (No. 91839302, 81790624), Project supported by Shanghai Municipal Science and Technology Major Project (Grant No. 2017SHZDZX01), and Tongji Hospital Clinical Research Flagship Program (no. 2019CR207).
Topics: Antigens, CD; Aortic Aneurysm; Butyrophilins; China; Humans; Mendelian Randomization Analysis; Proteasome Endopeptidase Complex; Urokinase-Type Plasminogen Activator
PubMed: 35952493
DOI: 10.1016/j.ebiom.2022.104199 -
International Journal of Biological... 2022Gastric cancer (GC) is the most common gastrointestinal malignant tumor, and distant metastasis is a critical factor in the prognosis of patients with GC. Understanding...
Gastric cancer (GC) is the most common gastrointestinal malignant tumor, and distant metastasis is a critical factor in the prognosis of patients with GC. Understanding the mechanism of GC metastasis will help improve patient prognosis. Studies have confirmed that urokinase-type plasminogen activator receptor (PLAUR) promotes GC metastasis; however, its relationship with anoikis resistance and associated mechanisms remains unclear. In this study, we demonstrated that PLAUR promotes the anoikis resistance and metastasis of GC cells and identified transcription Factor 7 Like 2 (TCF7L2) as an important transcriptional regulator of PLAUR. We also revealed that TCF7L2 is highly expressed in GC and promotes the anoikis resistance and metastasis of GC cells. Moreover, we found that TCF7L2 transcription activates PLAUR. Finally, we confirmed that TCF7L2 is an independent risk factor for poor prognosis of patients with GC. Our results show that TCF7L2 and PLAUR are candidate targets for developing therapeutic strategies for GC metastasis.
Topics: Anoikis; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Metastasis; Plasminogen Activators; Receptors, Urokinase Plasminogen Activator; Signal Transduction; Stomach Neoplasms; Transcription Factor 7-Like 2 Protein
PubMed: 35864968
DOI: 10.7150/ijbs.69933 -
European Stroke Journal Mar 2023Within the last year, four randomised-controlled clinical trials (RCTs) have been published comparing intravenous thrombolysis (IVT) with tenecteplase and alteplase in...
Within the last year, four randomised-controlled clinical trials (RCTs) have been published comparing intravenous thrombolysis (IVT) with tenecteplase and alteplase in acute ischaemic stroke (AIS) patients with a non-inferiority design for three of them. An expedited recommendation process was initiated by the European Stroke Organisation (ESO) and conducted according to ESO standard operating procedure based on the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework. We identified three relevant Population, Intervention, Comparator, Outcome (PICO) questions, performed systematic reviews of the literature and meta-analyses, assessed the quality of the available evidence, and wrote evidence-based recommendations. Expert consensus statements were provided if insufficient evidence was available to provide recommendations based on the GRADE approach. For patients with AIS of <4.5 h duration who are eligible for IVT, tenecteplase 0.25 mg/kg can be used as a safe and effective alternative to alteplase 0.9 mg/kg (moderate evidence, strong recommendation). For patients with AIS of <4.5 h duration who are eligible for IVT, we recommend against using tenecteplase at a dose of 0.40 mg/kg (low evidence, strong recommendation). For patients with AIS of <4.5 h duration with prehospital management with a mobile stroke unit who are eligible for IVT, we suggest tenecteplase 0.25 mg/kg over alteplase 0.90 mg/kg (low evidence, weak recommendation). For patients with large vessel occlusion (LVO) AIS of <4.5 h duration who are eligible for IVT, we recommend tenecteplase 0.25 mg/kg over alteplase 0.9 mg/kg (moderate evidence, strong recommendation). For patients with AIS on awakening from sleep or AIS of unknown onset who are selected with non-contrast CT, we recommend against IVT with tenecteplase 0.25 mg/kg (low evidence, strong recommendation). Expert consensus statements are also provided. Tenecteplase 0.25 mg/kg may be favoured over alteplase 0.9 mg/kg for patients with AIS of <4.5 h duration in view of comparable safety and efficacy data and easier administration. For patients with LVO AIS of <4.5 h duration who are IVT-eligible, IVT with tenecteplase 0.25 mg/kg is preferable over skipping IVT before MT, even in the setting of a direct admission to a thrombectomy-capable centre. IVT with tenecteplase 0.25 mg/kg may be a reasonable alternative to alteplase 0.9 mg/kg for patients with AIS on awakening from sleep or AIS of unknown onset and who are IVT-eligible after selection with advanced imaging.
Topics: Humans; Tenecteplase; Stroke; Tissue Plasminogen Activator; Brain Ischemia; Ischemic Stroke
PubMed: 37021186
DOI: 10.1177/23969873221150022 -
Circulation. Cardiovascular Quality and... Aug 2019
Topics: Humans; Percutaneous Coronary Intervention; Stroke; Thrombolytic Therapy; Tissue Plasminogen Activator
PubMed: 31412736
DOI: 10.1161/CIRCOUTCOMES.119.005931 -
Journal of Thrombosis and Haemostasis :... Dec 2023Fibrinolysis is the system primarily responsible for removal of fibrin deposits and blood clots in the vasculature. The terminal enzyme in the pathway, plasmin, is... (Review)
Review
Fibrinolysis is the system primarily responsible for removal of fibrin deposits and blood clots in the vasculature. The terminal enzyme in the pathway, plasmin, is formed from its circulating precursor, plasminogen. Fibrin is by far the most legendary substrate, but plasmin is notoriously prolific and is known to cleave many other proteins and participate in the activation of other proteolytic systems. Fibrinolysis is often overshadowed by the coagulation system and viewed as a simplistic poorer relation. However, the primordial plasminogen activators evolved alongside the complement system, approximately 70 million years before coagulation saw the light of day. It is highly likely that the plasminogen activation system evolved with its roots in primordial immunity. Almost all immune cells harbor at least one of a dozen plasminogen receptors that allow plasmin formation on the cell surface that in turn modulates immune cell behavior. Similarly, numerous pathogens express their own plasminogen activators or contain surface proteins that provide binding sites for host plasminogen. The fibrinolytic system has been harnessed for clinical medicine for many decades with the development of thrombolytic drugs and antifibrinolytic agents. Our refined understanding and appreciation of the fibrinolytic system and its alliance with infection and immunity and beyond are paving the way for new developments and interest in novel therapeutics and applications. One must ponder as to whether the nomenclature of the system hampered our understanding, by focusing on fibrin, rather than the complex myriad of interactions and substrates of the plasminogen activation system.
Topics: Humans; Fibrinolysis; Fibrinolysin; Plasminogen Activators; Plasminogen; Fibrin; Serine Proteases
PubMed: 38000850
DOI: 10.1016/j.jtha.2023.09.012 -
Neurotherapeutics : the Journal of the... Apr 2023Alteplase has been the primary thrombolytic used in the treatment of acute ischemic stroke since thrombolysis was first established as an effective treatment of acute... (Review)
Review
Alteplase has been the primary thrombolytic used in the treatment of acute ischemic stroke since thrombolysis was first established as an effective treatment of acute ischemic stroke in 1995. Tenecteplase, a genetically modified tissue plasminogen activator, has gained attention as an attractive alternative to alteplase given its practical workflow advantages and possible superior efficacy in large vessel recanalization. As more data is analyzed both from randomized trials and non-randomized patient registries, there is mounting support that tenecteplase appears to be at least equally, if not more, safe and potentially more effective than alteplase in the treatment of acute ischemic stroke. Randomized trials investigating tenecteplase in the delayed treatment window and with thrombectomy are ongoing, and their results are eagerly awaited. This paper provides an overview of completed and ongoing randomized trials and nonrandomized studies analyzing tenecteplase in the treatment of acute ischemic stroke. Results reviewed support the safe use of tenecteplase in clinical practice.
Topics: Humans; Tissue Plasminogen Activator; Tenecteplase; Ischemic Stroke; Stroke; Brain Ischemia; Fibrinolytic Agents
PubMed: 37273127
DOI: 10.1007/s13311-023-01391-3 -
Pharmacology 2023Thrombolytic agents and anticoagulants are the two classes of medication used in the treatment of acute pulmonary embolism (PE). There is continuous renewal and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Thrombolytic agents and anticoagulants are the two classes of medication used in the treatment of acute pulmonary embolism (PE). There is continuous renewal and iteration of thrombolytic agents, and the efficacy and adverse effects of different agents have different effects on PE due to their different mechanisms of action.
OBJECTIVES
The aim of the study was to evaluate the efficacy and safety of different thrombolytic agents in the treatment of all types of acute PE: hemodynamically unstable PE (massive PE) and hemodynamically stable PE (submassive PE and low-risk PE), using a network meta-analysis.
METHODS
A search was conducted of the following databases: PubMed, The Cochrane Library, Embase, and Web of Science to collect randomized controlled trials (RCTs) comparing thrombolytic agents with heparin or other thrombolytic agents in patients with acute PE; the clinical outcomes included patient mortality, recurrent PE, pulmonary artery systolic pressure (PASP) after treatment, and major and minor bleeding. The measurement duration of outcome indicators was the longest follow-up period. Thereafter, a network meta-analysis was performed using a Bayesian network framework.
RESULTS
A total of 29 RCTs (3,067 patients) were included, of which 6 studies (304 patients) were massive PE, 14 studies (2,173 patients) were submassive PE, 1 study (83 patients) included massive and submassive PE, and 8 studies (507 patients) were PE of unknown type. The treatment regimens included thrombolytic therapy (alteplase, reteplase, tenecteplase, streptokinase, and urokinase) and anticoagulant therapy alone. The results showed that the mortality using thrombolytic agents (except tenecteplase) was significantly lower compared with heparin. The recurrence of PE with alteplase was significantly lower compared with heparin (RR = 0.23, 95% CI, 0.04, 0.65). The PASP after using alteplase was significantly lower compared with heparin (mean difference = -11.36, 95% CI, -21.45, -1.56). Compared with heparin, the incidence of minor bleeding associated with tenecteplase was higher (RR = 3.27, 95% CI, 1.36, 7.39); compared with streptokinase, the incidence of minor bleeding associated with tenecteplase was higher (RR = 3.22, 95% CI, 1.01, 11.10).
CONCLUSION
For patients with acute PE, four thrombolytic agents (alteplase, reteplase, streptokinase, and urokinase) appeared to be superior in efficacy compared with anticoagulants alone due to a reduction in mortality and no increase in bleeding risk. Alteplase may be a better choice because it not only reduced mortality but also reduced PE recurrence rate and treated PASP. Tenecteplase did not reduce mortality compared with anticoagulants alone and may not be a good choice of thrombolytic agent due to an increase in minor bleeding compared with streptokinase and anticoagulants alone. Thrombolytic drugs should be rationally selected to optimize the thrombolytic regimen and achieve as good a balance as possible between thrombolysis and bleeding.
Topics: Humans; Fibrinolytic Agents; Tissue Plasminogen Activator; Tenecteplase; Urokinase-Type Plasminogen Activator; Network Meta-Analysis; Pulmonary Embolism; Heparin; Streptokinase; Hemorrhage; Anticoagulants
PubMed: 36603558
DOI: 10.1159/000527668 -
Biomolecules Nov 2020The Gram-negative bacterium causes plague, a fatal flea-borne anthropozoonosis, which can progress to aerosol-transmitted pneumonia. overcomes the innate immunity of... (Review)
Review
The Gram-negative bacterium causes plague, a fatal flea-borne anthropozoonosis, which can progress to aerosol-transmitted pneumonia. overcomes the innate immunity of its host thanks to many pathogenicity factors, including plasminogen activator, Pla. This factor is a broad-spectrum outer membrane protease also acting as adhesin and invasin. uses Pla adhesion and proteolytic capacity to manipulate the fibrinolytic cascade and immune system to produce bacteremia necessary for pathogen transmission via fleabite or aerosols. Because of microevolution, invasiveness has increased significantly after a single amino-acid substitution (I259T) in Pla of one of the oldest phylogenetic groups. This mutation caused a better ability to activate plasminogen. In paradox with its fibrinolytic activity, Pla cleaves and inactivates the tissue factor pathway inhibitor (TFPI), a key inhibitor of the coagulation cascade. This function in the plague remains enigmatic. Pla (or ) had been used as a specific marker of , but its solitary detection is no longer valid as this gene is present in other species of . Though recovering hosts generate anti-Pla antibodies, Pla is not a good subunit vaccine. However, its deletion increases the safety of attenuated strains, providing a means to generate a safe live plague vaccine.
Topics: Animals; Antigens, Bacterial; Humans; Plague; Plague Vaccine; Plasminogen Activators; Point Mutation; Protein Interaction Maps; Protein Structure, Secondary; Yersinia pestis
PubMed: 33202679
DOI: 10.3390/biom10111554