阿加曲班抑制脑出血大鼠血肿周围组织蛋白酶激活受体-1的表达

目的：探讨凝血酶与脑出血后蛋白酶激活受体-1（PAR-1）表达的关系,以及观察阿加曲班对脑出血后PAR-1表达的影响.方法：60只大鼠随机分为5组：假手术对照组,脑出血组（ICH组）,脑出血＋阿加曲班干预组（ICH＋Arg 组）,凝血酶注入组（TH组）和凝血酶＋阿加曲班干预组（TH＋Arg组）,每组6只.建立大鼠自体血脑出血模型以及凝血酶注入模型,术后3 和12 h经腹腔分别注入阿加曲班0.9 mg·kg-1体重.术后24 h处死大鼠取脑,分别用免疫组化、West ern blot和RT-PCR检测PAR-1的表达.结果： ICH组血肿周围和TH组尾状核区PAR-1阳性细胞数明显高于假手术对照组,ICH＋Arg和TH＋Arg组PAR-1阳性细胞数明显低于ICH和TH组.Western blot和RT-PCR法检测显示ICH＋Arg和TH＋Arg组的PAR-1蛋白和PAR-1 mRNA表达水平明显低于ICH和TH组（P〈0.01或P 〈0.05）.结论：脑出血后PAR-1的表达水平与凝血酶有关,阿加曲班可抑制脑出血后的PAR-1表达.     

阿加曲班联合阿司匹林治疗早期进展性缺血性脑卒中的疗效观察

目的 探讨阿加曲班联合阿司匹林在早期进展性缺血性脑卒中治疗中的应用效果。方法 纳入2019年1月—2022年1月火箭军特色医学中心收治的发病24 h内、未接受静脉溶栓治疗和血管内介入治疗的急性进展性缺血性脑卒中患者120例为对象进行回顾性研究。根据治疗方案的不同分为对照组（阿司匹林联合氢硫酸氯吡格雷）及试验组（阿加曲班联合阿司匹林）,每组各60例。对照组口服阿司匹林肠溶片每次100 mg,每天1次,同时联合口服硫酸氢氯吡格雷片每次75 mg,每天1次,共3周。试验组予以阿司匹林肠溶片,用法用量同对照组,在此基础上联合阿加曲班注射液,治疗前48 h给予阿加曲班注射液60 mg,每天1次,24 h持续静脉泵入,第3～7天予以阿加曲班注射液每次10 mg,每天2次,3 h静脉滴注。两组住院治疗时间均≥14 d。分别采用美国国立卫生研究院卒中量表（NIHSS）评分及根据Barthel指数（BI）评分比较治疗前后两组患者神经功能缺损情况及日常生活能力改善情况,并观察两组的症状性脑出血及消化道出血等不良反应情况。结果 试验组与对照组治疗的总有效率分别为82.67%和65.00%,差异有统计学意义（P＜0.05）。治疗前两组NIHSS比较,差异有统计学意义（P＜0.05）。治疗后两组患者NIHSS评分均较治疗前显著降低（P＜0.05）,试验组降低程度更加明显,治疗后两组 NIHSS评分比较,差异无统计学意义（P＞0.05）。治疗前,试验组 BI评分低于对照组,但差异无统计学意义（P＞0.05）;治疗后,两组患者BI评分均较同组治疗前显著增加（P＜0.05）,且试验组BI评分显著高于对照组（P＜0.05）。治疗期间出现消化道出血的患者对照组有3例,试验组有2例;两组患者均无症状性脑出血出现。两组间主要不良反应比较,差异无统计学意义（P＞0.05）。结论 阿加曲班联合阿司匹林较常规双抗治疗更有助于改善早期急性进展性缺血性脑卒中患者的神经功能预后,同时不增加不良反应风险。     

阿加曲班不同给药方式超早期治疗急性缺血性脑卒中的疗效及安全性观察

目的 探索阿加曲班不同给药方式对超早期急性缺血性脑卒中患者的疗效及安全性。方法 回顾性选取2019年2月—2020年11月在肇庆市第一人民医院神经内科住院的急性缺血性脑卒中患者64例为研究对象,根据给药方式不同将患者分为静脉滴注组（静滴组）和微泵＋静脉滴注组（微泵＋静滴组）,静滴组患者给予阿加曲班注射液,10 mg阿加曲班注射液加入0.9%氯化钠注射液250 mL中,静脉滴注给药,每天2次,连续给药（7±1）d;微泵＋静滴组患者给予阿加曲班注射液,持续微泵（10 mL·h^-1）24 h或者48 h,其后采用10 mg阿加曲班注射液加入0.9%氯化钠注射液250 mL中,静脉滴注给药,每天2次,连续给药（5±2）d。比较两组患者临床治疗效果及不良反应。结果 静滴组总有效率（55.88%）高于微泵＋静滴组（53.55%）,但差异无统计学意义（P＞0.05）。两组患者出院时美国国立卫生研究院卒中量表（NIHSS）评分均低于本组入院时NIHSS评分（P＜0.05）,两组间出院时NIHSS评分比较,差异无统计学意义（P＞0.05）。两组患者出院时改良Rankin量表（MRS）≤1分的患者占比比较,差异有统计学意义（P＜0.05）,静滴组占比更高。两组患者出院时MRS评分≤2分的患者占比比较,差异无统计学意义（P＞0.05）。两组均未发生出血事件及新发心脑血管事件。结论 阿加曲班静脉滴注给药治疗急性缺血性脑卒中的疗效显著,安全性高。     

阿加曲班对大鼠脑出血后脑损伤的作用

目的:观察阿加曲班对大鼠脑出血后脑损伤的作用。方法:采用自体血注入法建立大鼠脑出血模型,于脑出血后3 h颅内原位注入阿加曲班(0．5 mg·L~(-1))。分别用伊文思蓝(EB)测血脑屏障(BBB)通透性,干-湿重法测组织含水量,同时进行组织病理学观察和神经功能评定,并与对照组相比较。结果:应用阿加曲班干预,可以明显减轻大鼠脑出血后的脑水肿、BBB通透性增加以及炎性细胞浸润的程度(P＜0．05,P＜0．01),并显著改善神经功能(P＜0．01)。结论:阿加曲班对大鼠脑出血后血肿周围组织的脑损伤具有明显的改善作用。     

Argatroban and Alteplase in Patients with Acute Myocardial Infarction: The ARGAMI Study

ARGAMI was designed to assess safety and efficacy of argatroban compared with heparin as adjunctive treatment to alteplase in the treatment of patients with acute myocardial infarction. ARGAMI consisted of an open-dose finding study (35 patients) followed by a placebo-controlled study with double dummy technique and 2:1 (argatroban:heparin) randomization. An argatroban dosage of 100g/kg bolus plus 3g/kg/min infusion for 72 hours was selected for the randomized study in which 82 patients were allocated to argatroban and 45 to heparin (5000U intravenous bolus, 1000U/h infusion). Patency of the infarct-related artery (Thrombolysis in Myocardial Infarction [TIMI] grade 2 or 3 flow) after 90 minutes was obtained in 62 patients (76%) allocated to argatroban versus 37 patients (82%) allocated to heparin (p=ns). Angiograms after 24 hours and 5 to 10 days showed low reocclusion rates in both groups. Bleeding complications were observed in 16 patients allocated to argatroban (19.5%) and in 9 patients allocated to heparin (20.0%). One patient allocated to heparin suffered from hemorrhage stroke. Argatroban, given as adjunctive treatment to alteplase, is tolerated well in patients with acute myocardial infarction. Safety and efficacy of the combination alteplase and argatroban (with this dose regimen) are similar to those of alteplase and heparin.     

Safety and Feasibility of Argatroban,Recombinant Tissue Plasminogen Activator,and Intra-Arterial Therapy in Stroke (ARTSS-IA Study)

Background

A randomized trial of concurrent recombinant tissue-type plasminogen activator (r-tPA)?+?thrombin-inhibition with Argatroban in stroke patients recently demonstrated safety and signal of efficacy compared to r-tPA alone, but patients having endovascular therapy (EVT) were excluded. The current study intended to study feasibility and safety of concurrent r-tPA and Argatroban in patients undergoing EVT.

通迪胶囊联合双氯芬酸二乙胺乳胶剂治疗膝关节软组织损伤的临床研究

目的 观察阿加曲班联合阿替普酶治疗急性脑卒中的疗效及其对氧化应激和炎症因子的影响。方法 回顾性选取2018年6月—2020年12月徐州医科大学附属连云港东方医院收治的急性脑卒中患者84例,发病均在4.5 h内,根据治疗方法将患者分为对照组（n=42）和观察组（n=42）。对照组给予注射用阿替普酶（0.9 mg/kg为其标准剂量,最大使用剂量不超过90 mg）静脉溶栓及常规治疗,观察组在对照组的基础上静脉溶栓24 h后加用阿加曲班注射液治疗,第1～2天,阿加曲班注射液60 mg静脉滴注24 h;第3～7天,阿加曲班注射液10 mg静脉滴注3 h,2次/d,两组患者治疗疗程均为14 d。分别于治疗前和治疗14 d后采用美国国立卫生研究院卒中量表（NIHSS）和改良Barthel指数量表（MBI）对两组患者神经功能缺损和日常生活能力进行评分,检测两组患者的氧化应激标志物超氧化物歧化酶（SOD）和丙二醛（MDA）水平,检测血清炎症标志物白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）水平,监测出血性转化（HT）发生率及药物的不良反应。结果 治疗14 d后,观察组的总有效率高于对照组（P<0.05）;两组患者的NIHSS评分及血清MDA、IL-6及TNF-α水平均较治疗前明显下降（P<0.01）,MBI评分及SOD水平较治疗前明显升高（P<0.01）,且观察组相比对照组改善作用更加明显（P<0.01）。两组患者治疗14 d内,HT发生率及不良反应发生率比较差异均无统计学意义。结论 阿加曲班注射液具有抗炎、抑制氧化应激作用,联合阿替普酶治疗急性脑卒中安全有效,与单独阿替普酶静脉溶栓治疗相比,可显著改善预后,且未增加HT风险及不良反应发生率。     

Argatroban use during pediatric interventional cardiac catheterization.

Argatroban is a synthetic direct thrombin inhibitor that does not interact with or induce heparin-dependent antibodies. It is approved for use in adults for prevention and treatment of thrombosis associated with heparin-induced thrombocytopenia (HIT). It has been administered safely in adults with HIT during coronary interventions. There are no reports of argatroban use for anticoagulation in pediatric patients. The present case describes the use of argatroban during coil embolization of a Fontan fenestration in a child with a history of HIT. The patient received a single bolus dose of 150 microg/kg of argatroban at the onset of the intervention. The fenestration was successfully occluded with a detachable coil. The activated clotting time (ACT) was > 200 sec throughout the procedure. The ACT returned to baseline 72 min after the bolus. No complications occurred. This case demonstrates the safe and successful use of argatroban during a transcatheter intervention in a pediatric patient with a history of HIT. The use of argatroban is promising for anticoagulation in children who require an alternative to heparin.     

Effect of thrombin inhibition on patients with peripheral arterial obstructive disease: A multicenter clinical trial of argatroban

Background: Enhanced thrombin generation has been found in patients with peripheral arterial obstructive disease (PAOD). The objective of this study is to investigate the effect of thrombin inhibition in PAOD patients.Methods: Argatroban (20 mg/day) was infused intravenously over 2 hours for 14–68 days in 27 patients with chronic PAOD of the lower extremities. Plasma thrombin-antithrombin III complex (TAT) levels and clinical signs were assessed.Results: TAT levels before argatroban therapy were significantly higher in the PAOD patients than in age- and gender-matched controls. In the PAOD patients, TAT levels increased stepwise in the presence of rest pain classified as Fontain HI and IV. To assess the effect of thrombin inhibition, we divided the patients into a high-TAT group (pretreatment TAT level >-5 ng/ml, n=12) and a low-TAT group (pretreatment TAT level <5 ng/ml, n=15). In the high-TAT group, TAT levels were suppressed in 8 of 12 patients after the administration of argatroban, along with improvement of their clinical symptoms and a decrease in the size of ischemic skin ulcers, indicating that argatroban clearly inhibited thrombin generation in vivo. Even in the low-TAT group, argatroban improved the clinical signs and symptoms, and also reduced the size of ischemic skin ulcers although TAT levels remained within the low range (<5 ng/ml) in 13 of the 15 patients, indicating that PAOD signs and/or symptoms may be related to small amounts of thrombin generated locally at the sites of atherothrombotic stenotic lesion.Conclusions: These results suggest that thrombin generation was enhanced in PAOD and that the amount was related to disease severity. Thrombin inhibition by argatroban may break this vicious cycle and lead to clinical improvement in PAOD.     

Combination of a Direct Thrombin Inhibitor and a Platelet Glycoprotein IIb/IIIa Blocking Peptide Facilitates and Maintains Reperfusion of Platelet-Rich Thrombus with Alteplase

We sought to determine the efficacy of the combination of argatroban, a direct thrombin inhibitor, and G4120, a platelet glycoprotein (GP) IIb/IIIa blocker, to enhance thrombolysis with alteplase. Platelet-rich thrombus in the rabbit arterial thrombosis model is relatively resistant to alteplase despite the addition of aspirin and heparin. The adjunctive use of either direct thrombin inhibitors or GP IIb/IIIa inhibitors in thrombolysis has been investigated with encouraging, but limited, success. The usefulness of combining both agents as adjunctive therapy to thrombolysis has not been fully explored. Following platelet-rich thrombus formation in the rabbit, argatroban (3mg/kg), G4120 (0.5mg/kg), G4120 plus heparin (200U/kg), or G4120 plus argatroban were intravenously infused over 60 minutes. Alteplase was given as intravenous boluses (0.45mg/kg) at 15-minute intervals up to 4 doses or until reperfusion. Blood flow and bleeding time were monitored for 2 hours. The combination of G4120 plus argatroban resulted in a persistent patency in 5 of 7 animals compared with 0 of 6 for argatroban alone (p=0.02), 1 of 6 for G4120 alone (p=0.08), and 2 of 6 for G4120 plus heparin (p=0.2). Although during the infusion the bleeding times were longer in the groups that received G4120 (26±7.7 minutes vs. 14±10 minutes, p<0.05), by the end of the experiment there were no statistically significant differences. Similarly, during the infusion the activated partial thromboplastin times (aPTT) was higher in groups that received heparin or argatroban (99±51 seconds vs. 32±7.6 seconds, p<0.001), but by the end of the experiment the aPTTs had returned to close to baseline in all groups except the G4120 plus heparin group. These results suggest that lysis of platelet-rich thrombus with alteplase requires the addition of both potent platelet and thrombin inhibitors. Specifically designed agents, G4120 and argatroban, are effective without additional increased risk for bleeding.