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Signal Transduction and Targeted Therapy Jan 2023Integrins are considered the main cell-adhesion transmembrane receptors that play multifaceted roles as extracellular matrix (ECM)-cytoskeletal linkers and transducers... (Review)
Review
Integrins are considered the main cell-adhesion transmembrane receptors that play multifaceted roles as extracellular matrix (ECM)-cytoskeletal linkers and transducers in biochemical and mechanical signals between cells and their environment in a wide range of states in health and diseases. Integrin functions are dependable on a delicate balance between active and inactive status via multiple mechanisms, including protein-protein interactions, conformational changes, and trafficking. Due to their exposure on the cell surface and sensitivity to the molecular blockade, integrins have been investigated as pharmacological targets for nearly 40 years, but given the complexity of integrins and sometimes opposite characteristics, targeting integrin therapeutics has been a challenge. To date, only seven drugs targeting integrins have been successfully marketed, including abciximab, eptifibatide, tirofiban, natalizumab, vedolizumab, lifitegrast, and carotegrast. Currently, there are approximately 90 kinds of integrin-based therapeutic drugs or imaging agents in clinical studies, including small molecules, antibodies, synthetic mimic peptides, antibody-drug conjugates (ADCs), chimeric antigen receptor (CAR) T-cell therapy, imaging agents, etc. A serious lesson from past integrin drug discovery and research efforts is that successes rely on both a deep understanding of integrin-regulatory mechanisms and unmet clinical needs. Herein, we provide a systematic and complete review of all integrin family members and integrin-mediated downstream signal transduction to highlight ongoing efforts to develop new therapies/diagnoses from bench to clinic. In addition, we further discuss the trend of drug development, how to improve the success rate of clinical trials targeting integrin therapies, and the key points for clinical research, basic research, and translational research.
Topics: Integrins; Cell Adhesion; Cell Communication; Signal Transduction; Peptides
PubMed: 36588107
DOI: 10.1038/s41392-022-01259-6 -
Journal of Hematology & Oncology Mar 2019Integrins are a family of transmembrane glycoprotein signaling receptors that can transmit bioinformation bidirectionally across the plasma membrane. Integrin αIIbβ3... (Review)
Review
Integrins are a family of transmembrane glycoprotein signaling receptors that can transmit bioinformation bidirectionally across the plasma membrane. Integrin αIIbβ3 is expressed at a high level in platelets and their progenitors, where it plays a central role in platelet functions, hemostasis, and arterial thrombosis. Integrin αIIbβ3 also participates in cancer progression, such as tumor cell proliferation and metastasis. In resting platelets, integrin αIIbβ3 adopts an inactive conformation. Upon agonist stimulation, the transduction of inside-out signals leads integrin αIIbβ3 to switch from a low- to high-affinity state for fibrinogen and other ligands. Ligand binding causes integrin clustering and subsequently promotes outside-in signaling, which initiates and amplifies a range of cellular events to drive essential platelet functions such as spreading, aggregation, clot retraction, and thrombus consolidation. Regulation of the bidirectional signaling of integrin αIIbβ3 requires the involvement of numerous interacting proteins, which associate with the cytoplasmic tails of αIIbβ3 in particular. Integrin αIIbβ3 and its signaling pathways are considered promising targets for antithrombotic therapy. This review describes the bidirectional signal transduction of integrin αIIbβ3 in platelets, as well as the proteins responsible for its regulation and therapeutic agents that target integrin αIIbβ3 and its signaling pathways.
Topics: Abciximab; Amino Acid Sequence; Animals; Blood Platelets; Eptifibatide; Humans; Molecular Targeted Therapy; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Signal Transduction; Tirofiban
PubMed: 30845955
DOI: 10.1186/s13045-019-0709-6 -
JAMA Aug 2022Tirofiban is a highly selective nonpeptide antagonist of glycoprotein IIb/IIIa receptor, which reversibly inhibits platelet aggregation. It remains uncertain whether... (Comparative Study)
Comparative Study Randomized Controlled Trial
Effect of Intravenous Tirofiban vs Placebo Before Endovascular Thrombectomy on Functional Outcomes in Large Vessel Occlusion Stroke: The RESCUE BT Randomized Clinical Trial.
IMPORTANCE
Tirofiban is a highly selective nonpeptide antagonist of glycoprotein IIb/IIIa receptor, which reversibly inhibits platelet aggregation. It remains uncertain whether intravenous tirofiban is effective to improve functional outcomes for patients with large vessel occlusion ischemic stroke undergoing endovascular thrombectomy.
OBJECTIVE
To assess the efficacy and adverse events of intravenous tirofiban before endovascular thrombectomy for acute ischemic stroke secondary to large vessel occlusion.
DESIGN, SETTING, AND PARTICIPANTS
This investigator-initiated, randomized, double-blind, placebo-controlled trial was implemented at 55 hospitals in China, enrolling 948 patients with stroke and proximal intracranial large vessel occlusion presenting within 24 hours of time last known well. Recruitment took place between October 10, 2018, and October 31, 2021, with final follow-up on January 15, 2022.
INTERVENTIONS
Participants received intravenous tirofiban (n = 463) or placebo (n = 485) prior to endovascular thrombectomy.
MAIN OUTCOMES AND MEASURES
The primary outcome was disability level at 90 days as measured by overall distribution of the modified Rankin Scale scores from 0 (no symptoms) to 6 (death). The primary safety outcome was the incidence of symptomatic intracranial hemorrhage within 48 hours.
RESULTS
Among 948 patients randomized (mean age, 67 years; 391 [41.2%] women), 948 (100%) completed the trial. The median (IQR) 90-day modified Rankin Scale score in the tirofiban group vs placebo group was 3 (1-4) vs 3 (1-4). The adjusted common odds ratio for a lower level of disability with tirofiban vs placebo was 1.08 (95% CI, 0.86-1.36). Incidence of symptomatic intracranial hemorrhage was 9.7% in the tirofiban group vs 6.4% in the placebo group (difference, 3.3% [95% CI, -0.2% to 6.8%]).
CONCLUSIONS AND RELEVANCE
Among patients with large vessel occlusion acute ischemic stroke undergoing endovascular thrombectomy, treatment with intravenous tirofiban, compared with placebo, before endovascular therapy resulted in no significant difference in disability severity at 90 days. The findings do not support use of intravenous tirofiban before endovascular thrombectomy for acute ischemic stroke.
TRIAL REGISTRATION
Chinese Clinical Trial Registry Identifier: ChiCTR-IOR-17014167.
Topics: Administration, Intravenous; Aged; Arterial Occlusive Diseases; Brain Ischemia; Double-Blind Method; Endovascular Procedures; Female; Humans; Intracranial Hemorrhages; Ischemic Stroke; Male; Platelet Aggregation Inhibitors; Stroke; Thrombectomy; Tirofiban; Treatment Outcome
PubMed: 35943471
DOI: 10.1001/jama.2022.12584 -
Frontiers in Pharmacology 2022Ischemic stroke is a leading cause of morbidity and mortality in neurological diseases. Numerous studies have evaluated the efficacy and safety of ischemic stroke...
Ischemic stroke is a leading cause of morbidity and mortality in neurological diseases. Numerous studies have evaluated the efficacy and safety of ischemic stroke therapies, but clinical data were largely inconsistent. Therefore, it is necessary to summarize and analyze the published clinical research data in the field. We aimed to perform an umbrella review to evaluate the efficacy and safety of ischemic stroke therapies. We conducted a search for meta-analyses and systematic reviews on PubMed, the Cochrane Library, and the Web of Science to address this issue. We examined neurological function deficit and cognitive function scores, quality of life, and activities of daily living as efficacy endpoints and the incidence of adverse events as safety profiles. Forty-three eligible studies including 377 studies were included in the umbrella review. The results showed that thrombolytic therapy (tPA; alteplase, tenecteplase, and desmoteplase), mechanical thrombectomy (MTE), edaravone with tPA, stem cell-based therapies, stent retrievers, acupuncture with Western medicines, autologous bone marrow stromal cells, antiplatelet agents (aspirin, clopidogrel, and tirofiban), statins, and Western medicines with blood-activating and stasis-dispelling herbs (NaoShuanTong capsule, Ginkgo biloba, Tongqiao Huoxue Decoction, Xuesaitong injection) can improve the neurological deficits and activities of daily living, and the adverse effects were mild for the treatment of ischemic stroke. Moreover, ligustrazine, safflower yellow, statins, albumin, colchicine, MLC601, salvianolic acids, and DL-3-n-butylphthalide showed serious adverse events, intracranial hemorrhage, or mortality in ischemic stroke patients. Our study demonstrated that tPA, edaravone and tPA, tPA and MTE, acupuncture and Western medicines, and blood-activating and stasis-dispelling herbs with Western medicines are the optimum neurological function and activities of daily living medication for patients with ischemic stroke. : https://inplasy.com/, identifier [INPLASY202250145].
PubMed: 35935837
DOI: 10.3389/fphar.2022.924747 -
Annals of Medicine Dec 2023Tirofiban is a small non-peptide ligand-mimetic Glycoprotein (GP) IIb/IIIa inhibitor which can reversibly bind to the arginine-glycine-aspartic acid (RGD) recognition... (Review)
Review
Tirofiban is a small non-peptide ligand-mimetic Glycoprotein (GP) IIb/IIIa inhibitor which can reversibly bind to the arginine-glycine-aspartic acid (RGD) recognition site of GP IIb/IIIa to prevent platelet aggregation. It reduces the incidence of thrombotic cardiovascular events in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS). Although generally considered safe, tirofiban has been reported to be associated with thrombocytopenia in several case reports and clinical trials. The pathogenesis for this adverse reaction is not entirely understood, is thought to be due to immune-mediated reaction. This side effect caused by tirofiban is especially concerning given how frequently it is used in the practice of contemporary cardiovascular care. The present review provides an overview of the pathophysiology, clinical presentation, management, and risk factors associated with tirofiban-induced thrombocytopenia.
Topics: Humans; Tirofiban; Platelet Aggregation Inhibitors; Tyrosine; Thrombocytopenia; Platelet Glycoprotein GPIIb-IIIa Complex; Acute Coronary Syndrome
PubMed: 37439782
DOI: 10.1080/07853890.2023.2233425 -
Neurology May 2023To investigate the efficacy and safety of IV infusion of tirofiban before endovascular thrombectomy for patients with large vessel occlusion due to intracranial... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND OBJECTIVE
To investigate the efficacy and safety of IV infusion of tirofiban before endovascular thrombectomy for patients with large vessel occlusion due to intracranial atherosclerotic disease. The secondary objective was to identify potential mediators for the clinical effect of tirofiban.
METHODS
Post hoc exploratory analysis of the Endovascular Treatment With versus Without Tirofiban for Patients with Large Vessel Occlusion Stroke (RESCUE BT) trial, which was a randomized, double-blinded, placebo-controlled trial at 55 centers in China from October 2018 to October 2021. Patients with occlusion of the internal carotid artery or middle cerebral artery due to intracranial atherosclerosis were included. The primary efficacy outcome was the proportion of patients achieving functional independence (defined as modified Rankin scale 0-2) at 90 days. Binary logistic regression and causal mediation analyses were used to estimate the treatment effect of tirofiban and the potential mediators.
RESULTS
This study included 435 patients, of whom 71.5% were men. The median age was 65 (interquartile range [IQR] 56-72) years, with a median NIH Stroke Scale of 14 (IQR 10-19). Patients in the tirofiban group had higher rates of functional independence at 90 days than patients in the placebo group (adjusted odds ratio 1.68; 95% CI 1.11-2.56, = 0.02) without an increased risk of mortality or symptomatic intracranial hemorrhage. Tirofiban was associated with fewer thrombectomy passes (median [IQR] 1 [1-2] vs 1 [1-2], = 0.004), which was an independent predictor of functional independence. Mediation analysis showed tirofiban-reduced thrombectomy passes explained 20.0% (95% CI 4.1%-76.0%) of the effect of tirofiban on functional independence.
DISCUSSION
In this post hoc analysis of the RESCUE BT trial, tirofiban was an effective and well-tolerated adjuvant medication of endovascular thrombectomy for patients with large vessel occlusion due to intracranial atherosclerosis. These findings need to be confirmed in future trials.
TRIAL REGISTRATION INFORMATION
The RESCUE BT trial was registered on the Chinese Clinical Trial Registry: chictr.org.cn, ChiCTR-INR-17014167.
CLASSIFICATION OF EVIDENCE
This study provides Class II evidence that tirofiban plus endovascular therapy improves 90-day outcome for patients with large vessel occlusion due to intracranial atherosclerosis.
Topics: Male; Humans; Middle Aged; Aged; Female; Tirofiban; Stroke; Ischemic Stroke; Treatment Outcome; Thrombectomy; Intracranial Arteriosclerosis; Endovascular Procedures; Brain Ischemia
PubMed: 36941074
DOI: 10.1212/WNL.0000000000207194 -
EuroIntervention : Journal of EuroPCR... May 2014Optimal perioperative antiplatelet therapy in patients with coronary stents undergoing surgery still remains poorly defined and a matter of debate among cardiologists,...
Perioperative management of antiplatelet therapy in patients with coronary stents undergoing cardiac and non-cardiac surgery: a consensus document from Italian cardiological, surgical and anaesthesiological societies.
Optimal perioperative antiplatelet therapy in patients with coronary stents undergoing surgery still remains poorly defined and a matter of debate among cardiologists, surgeons and anaesthesiologists. Surgery represents one of the most common reasons for premature antiplatelet therapy discontinuation, which is associated with a significant increase in mortality and major adverse cardiac events, in particular stent thrombosis. Clinical practice guidelines provide little support with regard to managing antiplatelet therapy in the perioperative phase in the case of patients with non-deferrable surgical interventions and/or high haemorrhagic risk. Moreover, a standard definition of ischaemic and haemorrhagic risk has never been determined. Finally, recommendations shared by cardiologists, surgeons and anaesthesiologists are lacking. The present consensus document provides practical recommendations on the perioperative management of antiplatelet therapy in patients with coronary stents undergoing surgery. Cardiologists, surgeons and anaesthesiologists have contributed equally to its creation. On the basis of clinical and angiographic data, the individual thrombotic risk has been defined. All surgical interventions have been classified according to their inherent haemorrhagic risk. A consensus on the optimal antiplatelet regimen in the perioperative phase has been reached on the basis of the ischaemic and haemorrhagic risk. Aspirin should be continued perioperatively in the majority of surgical operations, whereas dual antiplatelet therapy should not be withdrawn for surgery in the case of low bleeding risk. In selected patients at high risk for both bleeding and ischaemic events, when oral antiplatelet therapy withdrawal is required, perioperative treatment with short-acting intravenous glycoprotein IIb/IIIa inhibitors (tirofiban or eptifibatide) should be taken into consideration.
Topics: Anesthesiology; Aspirin; Cardiac Surgical Procedures; Cardiology; Clopidogrel; Eptifibatide; Hemorrhage; Humans; Italy; Myocardial Ischemia; Peptides; Perioperative Care; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Risk Assessment; Societies, Medical; Stents; Surgical Procedures, Operative; Thoracic Surgery; Ticlopidine; Tirofiban; Tyrosine
PubMed: 24832636
DOI: 10.4244/EIJV10I1A8 -
Frontiers in Neurology 2022The clinical efficacy and safety of tirofiban in the treatment of large hemispheric infarction (LHI) remain controversial.
BACKGROUND
The clinical efficacy and safety of tirofiban in the treatment of large hemispheric infarction (LHI) remain controversial.
METHODS
This study prospectively enrolled patients with acute LHI who were admitted to Putuo Hospital affiliated with Shanghai University of Traditional Chinese Medicine from June 2021 to December 2021. The patients were randomly assigned to the tirofiban group [3-4 μg/(kg·h)] or control group (clopidogrel 75 mg/d).
RESULTS
A total of 71 patients with acute LHI were selected: 36 in the tirofiban group and 35 in the control group. The reduction of the NIHSS score in the tirofiban group was 2.92 ± 9.31 at discharge, and that of the control group was -3.23 ± 12.06 ( = 0.021, , 0.006; 95% , 0.004-0.008). Six patients (16.7%) in tirofiban group and 14 patients (40%) in control group died during hospitalization ( = 0.029, , 0.300; 95% , 0.099-0.908). There was significant difference in Modified Rankin Scale (mRS) 5-6 scores at 90 days between the two groups ( = 0.023, , 0.327; 95% , 0.124-0.867). However, there was no significant difference in mRS 0-1 ( = 0.321, , 0.972; 95% , 0.920-1.027), mRS 2 ( = 0.572, , 2.00; 95% , 0.173-23.109), mRS 3 ( = 0.225, , 2.214; 95% , 0.601-8.161), or mRS 4( = 0.284, , 1.859; 95% , 0.593-5.825) scores between the two groups. There was no difference in symptomatic intracranial hemorrhage ( = 0.29, , 0.305; 95% , 0.030-3.081), asymptomatic intracranial hemorrhage ( = 0.123, , 0.284; 95% , 0.053-1.518). There was a significant difference in systemic bleeding events during hospitalization ( = 0.044, , 0.309; 95% , 0.096-1.000).
CONCLUSIONS
Low-dose and long-course tirofiban treatment may significantly improve the early neurological function and reduce the in-hospital mortality in LHI patients. Meanwhile, tirofiban does not increase the risk of any type of bleeding events.
PubMed: 36158948
DOI: 10.3389/fneur.2022.987859