Requirement of Site-Specific Tyrosine Phosphorylation of Cortactin in Retinal Neovascularization and Vascular Leakage.

BACKGROUND: Retinal neovascularization is a major cause of vision impairment. Therefore, the purpose of this study is to investigate the mechanisms by which hypoxia triggers the development of abnormal and leaky blood vessels. METHODS: A variety of cellular and molecular approaches as well as tissue-specific knockout mice were used to investigate the role of Cttn (cortactin) in retinal neovascularization and vascular leakage. RESULTS: We found that VEGFA (vascular endothelial growth factor A) stimulates Cttn phosphorylation at Y421, Y453, and Y470 residues in human retinal microvascular endothelial cells. In addition, we observed that while blockade of Cttn phosphorylation at Y470 inhibited VEGFA-induced human retinal microvascular endothelial cell angiogenic events, suppression of Y421 phosphorylation protected endothelial barrier integrity from disruption by VEGFA. In line with these observations, while blockade of Cttn phosphorylation at Y470 negated oxygen-induced retinopathy-induced retinal neovascularization, interference with Y421 phosphorylation prevented VEGFA/oxygen-induced retinopathy-induced vascular leakage. Mechanistically, while phosphorylation at Y470 was required for its interaction with Arp2/3 and CDC6 facilitating actin polymerization and DNA synthesis, respectively, Cttn phosphorylation at Y421 leads to its dissociation from VE-cadherin, resulting in adherens junction disruption. Furthermore, whereas Cttn phosphorylation at Y470 residue was dependent on Lyn, its phosphorylation at Y421 residue required Syk activation. Accordingly, lentivirus-mediated expression of shRNA targeting Lyn or Syk levels inhibited oxygen-induced retinopathy-induced retinal neovascularization and vascular leakage, respectively. CONCLUSIONS: The above observations show for the first time that phosphorylation of Cttn is involved in a site-specific manner in the regulation of retinal neovascularization and vascular leakage. In view of these findings, Cttn could be a novel target for the development of therapeutics against vascular diseases such as retinal neovascularization and vascular leakage.

Severe thrombocytopenia induced by tirofiban after percutaneous coronary intervention: a case report.

BACKGROUND: Tirofiban is a nonpeptide glycoprotein IIb/IIIa receptor antagonist used widely in patients subjected to percutaneous coronary intervention. While the usage of tirofiban sets an important clinical benefit, severe thrombocytopenia can occur with use of this agent. CASE PRESENTATION: A 76-year-old Chinese man was admitted with 1-month history of sudden onset of chest tightness. He was diagnosed as having subacute inferior myocardial infarction, and percutaneous coronary intervention was performed. After the procedure, patient received tirofiban at 0.15 µg/kg/minute for 4 h. A blood sample was obtained for a complete blood count; severe thrombocytopenia was reported according to routine orders at our hospital. All antiplatelet drugs including tirofiban, aspirin, and clopidogrel were immediately discontinued. The patient received platelet transfusions and was treated with immunoglobulin G. Two days later, the patient's platelet count had increased to 75 × 109/L. There was a significant improvement after day 5, and the platelet count was 112 × 109/L. Seven days after the acute thrombocytopenia, he was discharged with normal platelet count. CONCLUSIONS: Clinicians should be particularly aware of tirofiban-induced thrombocytopenia in routine practice.

Tirofiban-induced thrombocytopenia.

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.

Tirofiban-induced thrombocytopenia usually occurred within the first 24 h of treatment, frequently accompanied by bleeding symptoms. The majority of the time, supportive care is used to manage this adverse event, and the platelet count often returns to normal in a few days.Although the exact cause of this adverse response is unknown, it is thought to be due to drug-dependent antibodies that bind to GP IIb/IIIa, presumably after tirofiban-induced conformational change.Age ≥ 65 years, white blood cell ≥ 12 × 10⁹/L, diabetes mellitus, congestive heart failure, and chronic kidney disease were identified as the risk factors for tirofiban-induced thrombocytopenia. Further investigations are needed for this.

[Efficacité du tirofiban intracoronaire avant pose d'un stent suivi d'une perfusion dans une charge de thrombus importante prouvée par angiographie : une étude randomisée]. / Efficacy of pre stenting intracoronary tirofiban followed by infusion in angiographically proven large thrombus burden : A randomized controlled study.

BACKGROUND: The presence of angiographic thrombus is associated with poor outcomes in contemporary cardiology practice. Percutaneous coronary intervention (PCI) in such lesions is associated with slow flow and no-reflow phenomenon which translate into poor clinical outcomes. METHODS: This was a single-centre, prospective, open-label, randomized controlled study with 50 patients each in intervention group and control group. Patients with angiographically proven large thrombus burden were recruited. In the intervention group, patients were given loading dose of intracoronary tirofiban (25 mcg/kg infused over 5 minutes) followed by prolonged infusion of tirofiban (0.15 mcg/kg/min for 12-18 hours) followed by PCI after 48-72 hours interval. In control group patients were taken up directly for PCI during the index procedure. Outcomes were assessed angiographically and in terms of clinical endpoints. RESULTS: The primary composite-endpoint of recurrent angina, myocardial infarction, cardiovascular death, target lesion revascularization and unscheduled CABG was significantly lower in the intervention arm compared to control arm (4% vs 16%, p = 0.04). Amongst the secondary endpoints, a statistically significant 30-day increase in ejection fraction from baseline was observed in the intervention group compared to the control group (1.6 ± 1.3 vs 0.2 ± 0.4, p = 0.0001). Overall mortality was similar in the two groups (4% vs 8%, p = 0.39). The primary safety endpoint of major bleeding was also similar in the 2 groups (2% vs 0%, p = 0.31). CONCLUSIONS: Tirofiban use prior to PCI in high thrombus burden was associated with improved clinical and angiographic endpoints with similar adverse events compared to controls.

Tyrosine sulphation of CXCR4 induces the migration of fibroblast in OSF.

Oral submucous fibrosis (OSF) caused by areca nut chewing is a prevalent fibrotic disease in Asia-Pacific countries. Arecoline-induced migration of fibroblasts (FBs) plays a vital role in the development of OSF. However, the specific molecular mechanisms involved remain unclear. Many studies have shown that tyrosine sulphation of chemokines can influence cell migration. Herein, we demonstrated that arecoline stimulates tyrosine sulphation of the chemokine receptor 4 (CXCR4) through the tyrosylprotein sulphotransferase-1 (TPST-1) to enhance the migration ability of FBs. Moreover, by RNA-Seq analysis, we found that the most significantly altered pathway was the EGFR pathway after the arecoline stimulation for FBs. After the knockdown of arecoline-induced EGFR expression, the tyrosine sulphation of CXCR4 was significantly decreased by the inhibition of TPST-1 induction. Finally, in human OSF specimens, TPST-1 expression was directly correlated with the expression of CXCR4. These data indicate that the arecoline-induced tyrosine sulphation of CXCR4, which is regulated by TPST-1, might be a potential mechanism that contributes to FB migration in OSF.

Comparison of intracoronary versus intravenous tirofiban in acute ST-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention.

OBJECTIVE: This study aimed to investigate the effect of intracoronary (IC) tirofiban compared to intravenously administered tirofiban in STEMI patients treated with PPCI. METHODS: This study included 180 STEMI patients who were underwent PPCI. Patients were randomized into an IC group ( n = 90) and intravenous (IV) group ( n = 90). During the procedure, the both groups were administered IC or IV injections of tirofiban, respectively, followed by an IV infusion of tirofiban for 24 hours. Changes in TIMI flow grading, TMP grade 3, Sum-STR two hours after the operation, the number of thrombus aspirations during the operation, myocardial enzyme, inflammatory factors,cardiac functional parameters, MACE and bleeding were investigated. RESULTS: Following treatment, TIMI flow grading and TMP grade 3 were improved in the IC tirofiban compared to the IV group ( P = 0.022 and P = 0.014, respectively). Additionally, the Sum-STR two hours after operation, the incidence of MACEs, levels of AST, CRP, ESR, and TNI in the IC group was improved, compared with the IV group (all P < 0.05). Furthermore. Cardiac function including CO and LVEF were significantly improved in the IC group 6 months after discharge. CONCLUSION: This study found that IC administration of tirofiban in patients with STEMI who underwent PPCI improved TIMI, TMP flow and cardiac function 6 months after discharge, and reduced CRP, ESR, and TNI. However, the incidence of bleeding between the two groups was comparable. These findings suggest that IC administration should be applied in certain acute STEMI patients.

Safety and Efficacy of Irradiation Boost Based on 18F-FET-PET in Patients with Newly Diagnosed Glioblastoma.

PURPOSE: Dual timepoint fluoro-ethyl-tyrosine (FET)-PET acquisition (10 and 60 minutes after FET injection) improves the definition of glioblastoma (GBM) location and shape. Here we evaluated the safety and efficacy of simultaneous integrated boost (SIB) planned using dual FET-PET for postoperative GBM treatment. PATIENTS AND METHODS: In this prospective pilot study (March 2017-December 2020), 17 patients qualified for FET-PET-based SIB intensity-modulated radiotherapy after resection. The prescribed dose was 78 and 60 Gy (2.6 and 2.0 Gy per fraction, respectively) for the FET-PET- and magnetic resonance (MR)-based target volumes. Eleven patients had FET-PET within 9 months to precisely define biological responses. Progression-free survival (PFS), overall survival (OS), toxicities, and radiation necrosis were evaluated. Six patients (35%) had tumors with MGMT promoter methylation. RESULTS: The 1- and 2-year OS and PFS rates were 73% and 43% and 53% and 13%, respectively. The median OS and PFS were 24 [95% confidence interval (CI), 9-26] and 12 (95% CI, 6-18) months, respectively. Two patients developed uncontrolled seizures during radiotherapy and could not receive treatment per protocol. In patients treated per protocol, 7 of 15 presented with new or increased neurologic deficits in the first month after irradiation. Radiation necrosis was diagnosed by MRI 3 months after SIB in 5 patients and later in another 2 patients. In 2 patients, the tumor was larger in FET-PET images after 6 months. CONCLUSIONS: Survival outcomes using our novel dose-escalation concept (total 78 Gy) were promising, even within the MGMT unmethylated subgroup. Excessive neurotoxicity was not observed, but radionecrosis was common and must be considered in future trials.

Primary Percutaneous Coronary Intervention with High-Bolus Dose Tirofiban: The FASTER (Favorite Approach to Safe and Effective Treatment for Early Reperfusion) Multicenter Registry.

Objectives: To investigate the safety and clinical efficacy of tirofiban during primary percutaneous coronary interventions (pPCI). Background: Gp IIb/IIIa inhibitors (GPI) use during pPCI has declined over years, mainly for the increased hemorrhagic risk associated to their use and for the availability of potent, fast-acting oral antiplatelet drugs. However, several pharmacodynamic studies showed suboptimal platelet inhibition with P2Y12-blockers, such as prasugrel or ticagrelor. Methods: Patients with ST-segment elevation myocardial infarction (STEMI) undergoing pPCI were prospectively enrolled in a multicenter registry conducted in high-volume centers in Italy. All patients received intraprocedural tirofiban. The primary safety endpoint was the occurrence of in-hospital bleedings according to the Bleeding Academic Research Consortium definition. In-hospital major adverse coronary events (MACE, defined as death, reinfarction, stent thrombosis, and target vessel revascularization), final TIMI flow, myocardial blush grade, and ST-segment resolution were also evaluated. Results: A total of 472 patients (mean age 61 ± 11 years, 83% males) were enrolled in 16 Italian centers from October 2015 to June 2018. Mean basal thrombus grade score was 3.47 ± 1.25. PCI was performed by transradial approach in 88% of patients. We observed a very low rate of 30 days BARC bleedings (2.1%) and MACE (0.8%). Complete (>70%) ST-segment resolution was observed in 67% of patients. Conclusions: In the FASTER registry, the use of tirofiban during primary PCI, performed with a transradial approach in most cases, in patients with high thrombus burden was associated with high rates of complete ST-segment resolution and low rates of in-hospital bleeding and MACE.

Efficacy and safety of a bridging strategy that uses intravenous platelet glycoprotein receptor inhibitors for patients undergoing surgery after coronary stent implantation: a meta-analysis.

BACKGROUND: Current guidelines indicate we can consider a bridging strategy that uses intravenous, reversible glycoprotein inhibitors for patients that required surgery following recent stent implantation. However, no strong clinical evidence exists that demonstrates the efficacy and safety of this treatment. Therefore, in this study, the efficacy and safety of a bridging strategy that uses intravenous platelet glycoprotein receptor inhibitors will be evaluated. METHODS: A meta-analysis was performed on preoperative bridging studies in patients undergoing coronary stent surgery. The primary outcome was the success rate of no major adverse cardiovascular events (MACE). The secondary outcomes were the success rate of no reoperations to stop bleeding. RESULTS: A total of 10 studies that included 382 patients were used in this meta-analysis. For the primary endpoint, the success rate was 97.7% (95% CI 94.4-98.0%) for glycoprotein IIb/IIIa inhibitors, 98.8% (95% CI 96.0-100%) for tirofiban (6 studies) and 95.8% (95% CI 90.4-99.4%) for eptifibatide (4 studies). For secondary endpoints, the success rate was 98.0% (95% CI 94.8-99.9%) for glycoprotein IIb/IIIa inhibitors, 99.7% (95% CI 97.1-100%) for tirofiban (5 studies), and 95.3% (95% CI 88.5-99.4%) for eptifibatide (4 studies). CONCLUSION: The results of this study showed that the use of intravenous platelet glycoprotein IIb/IIIa inhibitors as a bridging strategy might be safe and effective for patients undergoing coronary stent implantation that require surgery soon after.

Phase II trial of SM-88, a cancer metabolism based therapy, in non-metastatic biochemical recurrent prostate cancer.

Background Androgen deprivation therapy (ADT) is a standard treatment for high-risk biochemically-recurrent, non-metastatic prostate cancer (BRPC) but is not curative and associated with toxicity. Racemetyrosine (SM-88) is an amino-acid analogue used with methoxsalen, phenytoin, and sirolimus (MPS) to enhance SM-88 activity. Method A phase 1b/2, open-label trial in BRPC and rising PSA. Patients were given daily SM-88 (230 mg BID), methoxsalen (10 mg), phenytoin (50 mg), and sirolimus (0.5 mg)). Outcome measures included changes in PSA, circulating tumor cells (CTCs) and imaging. Results 34 subjects were screened, 23 treated and 21 remained on study for ≥12 weeks. The median PSA was 6.4 ng/ml (range 1.7-80.1); doubling-time 6.2 months (range 1.4-36.6) and baseline testosterone 319.1 ng/ml (range 2.5-913.7). Median duration of therapy was 6.5 months (2.6-14.0). CTCs (median 48.5 cells/4 ml (range 15-268) at baseline) decreased a median of 65.3% in 18 of 19 patients. For patients who achieved an absolute CTC nadir count of <10 cells/4 ml (n = 10), disease control was 100% i.e. no metastases or PSA progression, while on trial (p = 0.005). PSA fell by ≥50% in 4.3% (1 subject). No patients developed metastatic disease while on treatment (metastases free survival =100%). There were no treatment-related adverse events (AEs) and quality of life was unchanged from baseline on the EORTC QLQ-C30 and QLQ-PR25. Testosterone levels rose slightly on SM-88 and were unrelated to efficacy or toxicity. Conclusions Use of SM-88 was associated with disease control while maintaining QOL. SM-88 may delay the need for ADT and the associated hormonal side effects. Larger trials are planned.Trial registration number, date of registration - NCT02796898, June 13, 2016.

First-in-human phase I study of JPH203, an L-type amino acid transporter 1 inhibitor, in patients with advanced solid tumors.

This open-label first-in-human study evaluated JPH203, which is a novel selective L-type amino acid transporter 1 inhibitor. We also evaluated the association between the N-acetyltransferase 2 phenotype and outcomes. Japanese patients with advanced solid tumors received daily intravenous JPH203 treatment for 7 days, followed by a 21-day rest period, at escalating doses of 12-85 mg/m2. Dose-limiting toxicities were evaluated during the first cycle using a 3 + 3 design. The study enrolled 17 patients, although grade 3 liver dysfunction was detected in one of six patients receiving 60 mg/m2 and in the first patient to receive 85 mg/m2. Further enrollment was terminated and the maximum tolerated dose was defined as 60 mg/m2. The AUC∞ increased between 12 mg/m2 and 25 mg/m2, although no differences were observed at 25-40 mg/m2. Partial response was observed for one patient with biliary tract cancer (BTC) at the 12 mg/m2 dose, and disease control was achieved by 3 of 6 patients at the 12 mg/m2 and 25 mg/m2 dose levels. Based on these results, we recommend a phase II dose of 25 mg/m2. The disease control rate for BTC was 60%. Two patients with grade 3 liver dysfunction had the rapid N-acetyltransferase 2 phenotype, and disease control was more common for the non-rapid phenotype (50% vs. 12.5%). It appears that JPH203 was well-tolerated and provided promising activity against BTC. The N-acetyltransferase 2 phenotype might help predict the safety and efficacy of JPH203. Clinical trial registration: UMIN000016546.

Spatial Learning and Memory Impairment in Growing Mice Induced by Major Oxidized Tyrosine Product Dityrosine.

This study focused on the effects of oxidized tyrosine products (OTPs) and major component dityrosine (DT) on the brain and behavior of growing mice. Male and female mice were treated with daily intragastric administration of either tyrosine (Tyr; 420 µg/kg body weight), DT (420 µg/kg body weight), or OTPs (1909 µg/kg body weight) for 35 days. We found that pure DT and OTPs caused redox state imbalance, elevated levels of inflammatory factors, hippocampal oxidative damage, and neurotransmitter disorders while activating the mitochondrial apoptosis pathway in the hippocampus and downregulating the genes associated with learning and memory. These events eventually led to growing mice learning and memory impairment, lagging responses, and anxiety-like behaviors. Furthermore, the male mice exhibited slightly more oxidative damage than the females. These findings imply that contemporary diets and food-processing strategies of the modern world should be modified to reduce oxidized protein intake.

Neuro-Cognitive Effects of Acute Tyrosine Administration on Reactive and Proactive Response Inhibition in Healthy Older Adults.

The aging brain is characterized by altered dopamine signaling. The amino acid tyrosine, a catecholamine precursor, is known to improve cognitive performance in young adults, especially during high environmental demands. Tyrosine administration might also affect catecholamine transmission in the aging brain, thereby improving cognitive functioning. In healthy older adults, impairments have been demonstrated in two forms of response inhibition: reactive inhibition (outright stopping) and proactive inhibition (anticipatory response slowing) under high information load. However, no study has directly compared the effects of a catecholamine precursor on reactive and load-dependent proactive inhibition. In this study we explored the effects of tyrosine on reactive and proactive response inhibition and signal in dopaminergically innervated fronto-striatal regions. Depending on age, tyrosine might lead to beneficial or detrimental neurocognitive effects. We aimed to address these hypotheses in 24 healthy older human adults (aged 61-72 years) using fMRI in a double blind, counterbalanced, placebo-controlled, within-subject design. Across the group, tyrosine did not alter reactive or proactive inhibition behaviorally but did increase fronto-parietal proactive inhibition-related activation. When taking age into account, tyrosine affected proactive inhibition both behaviorally and neurally. Specifically, increasing age was associated with a greater detrimental effect of tyrosine compared with placebo on proactive slowing. Moreover, with increasing age, tyrosine decreased fronto-striatal and parietal proactive signal, which correlated positively with tyrosine's effects on proactive slowing. Concluding, tyrosine negatively affected proactive response slowing and associated fronto-striatal activation in an age-dependent manner, highlighting the importance of catecholamines, perhaps particularly dopamine, for proactive response inhibition in older adults.

Aumento de estresse oxidativo no sangue de pacientes com ostomia / Increased oxidative stress in the blood of ostomy patients

ABSTRACT BACKGROUND: Ostomy is a surgical procedure that creates a stoma that aims to construct a new path for the output of feces or urine. The relationship of oxidative stress (OxS) markers in patients with ostomy is still poorly described. OBJECTIVE: The present study was aimed at investigating the changes in oxidative stress parameters in peripheral blood collected from ostomy patients when compared with a healthy control group. METHODS: It was evaluated 29 ostomy patients and 30 healthy control patients. The oxidative stress parameters evaluated were: lipid peroxidation [lipid hydroperoxide (LPO), 8-isoprostane (8-ISO) and 4-hydroxynonenal (4-HNE)], protein oxidation and nitration [carbonyl and 3-nitrotyrosine (3-NT)] and DNA oxidation [8-hydroxy-2'-deoxyguanosine (8-OHDG)] in serum from ostomy patients compared to health controls. RESULTS: The data showed an increase of LPO, 8-ISO, 4-HNE, 3-NT and 8-OHDG in serum collected from ostomy patients when compared to healthy controls. CONCLUSION: The findings support the hypothesis that ostomy triggers the oxidative stress observed in the blood collected from these patients.

RESUMO CONTEXTO: Ostomia é um procedimento cirúrgico que cria um estoma com objetivo de construir um novo caminho para a saída das fezes ou urina. A relação dos marcadores de estresse oxidativo em pacientes ostomizados ainda é pouco descrita. OBJETIVO: O presente estudo tem como objetivo investigar as alterações dos parâmetros de estresse oxidativo em sangue de pacientes ostomizados comparados a controles saudáveis. MÉTODOS: Foram avaliados 29 pacientes ostomizados e 30 controles saudáveis. Os parâmetros de estresse oxidativo avaliados foram: peroxidação lipídica [hidroperóxido de lipídio (LPO), 8-isoprostano (8-ISO) e 4-hidroxinonenal (4-HNE)], oxidação e nitração de proteínas [carbonila e 3-nitrotirosina (3-NT)] e oxidação do DNA [8-hidroxi-2'-desoxiguanosina (8-OHDG)] em soro de pacientes ostomizados comparados a controles saudáveis. RESULTADOS: Os dados mostraram um aumento de LPO, 8-ISO, 4-HNE, 3-NT e 8-OHDG em soro de pacientes ostomizados em comparação a controles saudáveis. CONCLUSÃO: Os achados sustentam a hipótese de que a ostomia desencadeia o estresse oxidativo observado no sangue coletado destes pacientes.

Efficacy and safety of quadruple therapy including tirofiban in the treatment of Chinese NSTE-ACS patients failing to receive timely percutaneous coronary intervention.

BACKGROUND: Although it has been shown to be superior to simple antithrombotic drug therapy, most patients are unable to receive timely percutaneous coronary intervention (PCI) and are treated with conventional triple antithrombotic therapy (aspirin, clopidogrel, low-molecular-weight heparin). Here, we evaluate the efficacy and safety of adding low-dose tirofiban to this regimen. METHODS: A total of 1,783 patient records (unable to receive PCI) indicating non-ST-segment elevation acute coronary syndrome (NSTE-ACS) were included. A total of 882 received conventional triple antithrombotic therapy; 901 received quadruple antithrombotic therapy. Efficacy was evaluated in terms of major adverse cardiovascular event (MACE) parameters. Safety was evaluated based on the occurrence of bleeding events. Data were collected over a 6-month period post treatment. RESULTS: The rate of occurrence of MACE was significantly lower in the quadruple antithrombotic group (10.5% versus 14.1% at 6 months, P=0.02). The log-rank test showed improved survival in the quadruple antithrombotic group. Total bleeding events were higher in the quadruple antithrombotic group (9.7%) than in the triple antithrombotic group (7.1%) (P=0.04); however, this may be attributed to increased clinically insignificant minor bleeding events. CONCLUSION: Quadruple antithrombotic therapy demonstrated a superior alternative for the treatment of high-risk NSTE-ACS patients failing to receive PCI.

Safety and preliminary efficacy of intravenous tirofiban in acute ischemic stroke patient without arterial occlusion on neurovascular imaging studies.

BACKGROUND: There has been no effective treatment for acute ischemic stroke (AIS) patients who presented to the Emergency Department >4.5h without a visible arterial occlusion on the neurovascular imaging studies. In this study, we aimed to investigate whether intravenous antiplatelet agent tirofiban was safe and potentially effective in AIS patients who had no visible arterial occlusion and was outside of treatment window for Alteplase. The goal of this study was to collect preliminary data to plan a future phase II study. METHOD: Twenty-five patients received intravenous tirofiban therapy. The safety outcomes were assessed by the incidence of symptomatic intracerebral hemorrhage (sICH), systematic bleeding and mortality. Efficacy outcomes were evaluated with National Institutes of Health Stroke Scale (NIHSS) score at day 7 (or discharge) and modified Rankin Scale (mRS) at 90days. Outcomes for these patients were compared with a historical age-gender-admission-NIHSS matched cohort treated with aspirin and/or clopidogrel. RESULTS: The rate of intracerebral hemorrhage, systematic bleedings, and death were not found in both groups. At day 7 or discharge, the neurological function improved significantly in both treatment groups. However, the NIHSS score was lower in tirofiban group compared with the control group (2 vs.3, p=0.045). At 3months, more patients in tirofiban group had favorable outcomes (mRS 0-1) compared with control group (84% vs. 52%; adjusted odds ratio: 10.57; 95% CI: 1.54-72.33; p=0.016). CONCLUSIONS: Intravenous tirofiban appears to be safe and potentially effective for the ischemic stroke patients with no artery occlusion on neurovascular imaging studies and being out of the window for thrombolytic therapy. A next logic step is to plan for a phase II study.

[Long-lasting thrombocytopenia induced by glycoprotein IIb/IIIa inhibitor]. / Thrombopénie sévère et prolongée induite par un inhibiteur de la glycoprotéine IIb/IIIa.

INTRODUCTION: Glycoprotein IIb/IIIa inhibitors (anti-GPIIbIIIa) prevent platelet binding to fibrinogen. Transient sometimes-severe thrombocytopenia is a well-known side effect. OBSERVATION: A 71-year-old patient presented severe thrombocytopenia after the administration of tirofiban (anti-GPIIbIIIa). Corticosteroid treatment was initiated at day 10 because of persistence of severe thrombocytopenia with poor platelet transfusion efficacy. Corticosteroid treatment led to platelet recovery evoking an immune mediated mechanism for thrombocytopenia. CONCLUSION: Anti-GPIIbIIIa are associated with a risk of dramatic thrombocytopenia. The underlying mechanism is poorly understood. The management of these usually transient thrombocytopenias is based on platelet transfusion. As report here, in some cases persistent thrombocytopenia can respond to corticosteroids.

Short-term efficacy and safety of three different antiplatelet regimens in diabetic patients treated with primary percutaneous coronary intervention: a randomised study.

BACKGROUND AND AIM: This study aimed to investigate the efficacy and safety of dual and triple antiplatelet therapy (DAPT and TAPT) in patients with diabetes and acute ST segment elevation myocardial infarction (D-STEMI), who had undergone primary percutaneous coronary intervention (PCI). METHODS: We designed a phase IV, single-centre, randomised, double-blind, placebo-controlled study. The D-STEMI patients (n = 258) were randomly divided into three groups. Control group A (85 patients), was treated with aspirin and clopidogrel; group B (87 patients) received aspirin, clopidogrel, and tirofiban; and group C (86 patients) were treated with aspirin, ticagrelor, and tirofiban. Patients in all three groups received oral DAPT, and patients in groups B and C received intravenous tirofiban when primary PCI was performed. RESULTS: Compared to the findings in group A, the post-PCI Thrombolysis in Myocardial Infarction (TIMI) grade 3 blood flow in groups B and C increased significantly (TIMI grade 3 in groups A, B, C: 74%, 91%, and 98%, respectively; TIMI myocardial perfusion grade [TMPG] grade 3 in groups A, B, C: 59%, 86%, and 97%, respectively), and the incidence of major adverse cardiac events (MACE) decreased significantly (p < 0.05). Compared to the findings in group B, the rate of TMPG 3 in group C was significantly higher (p < 0.05) and the incidence of MACE was significantly lower (p < 0.05). Patients in group B exhibited minor bleeding; however, the incidence of mild to moderate bleeding in group C increased significantly (p < 0.05). CONCLUSIONS: TAPT effectively improved the TIMI blood flow and TMPG and reduced the occurrence of MACE. Ticagrelor was more effective than clopidogrel in TAPT; however, when using the combination of aspirin, ticagrelor, and tirofiban, close monitoring is required for possible bleeding complications.