Advanced delivery strategies facilitating oral absorption of heparins

Heparins show great anticoagulant effect with few side effects,and are administered by subcutaneous or intravenous route in clinics.To improve patient compliance,oral administration is an alternative route.Nonetheless,oral administration of heparins still faces enormous challenges due to the multiple obstacles.This review briefly analyzes a series of barriers ranging from poorly physicochemical properties of heparins,to harsh biological barriers including gastrointestinal degradation and pre-systemic metabolism.Moreover,several approaches have been developed to overcome these obstacles,such as improving stability of heparins in the gastrointestinal tract,enhancing the intestinal epithelia permeability and facilitating lymphatic delivery of heparins.Overall,this review aims to provide insights concerning advanced delivery strategies facilitating oral absorption of heparins.

Bivalirudin is superior to heparins alone with bailout GP Ⅱb / Ⅲa inhibitors in patients with ST-segment elevation myocardial infarction transported emergently for primary percutaneous coronary intervention: a pre-specified analysis from the EUROMAX tria

Aims In the HORIZONS trial, in-hospital treatment with bivalirudin reduced bleeding and mortality in primary percutaneous coronary intervention（PCI） compared with heparin and routine glycoprotein Ⅱb / Ⅲa inhibitors（GPI）. It is unknown whether this advantage of bivalirudin is observed in comparison with heparins only with GPI used as bailout. Methods and results In the EUROMAX study, 2198 patients with ST-segment elevation myocardial infarction（STEMI） were randomized during transport for primary PCI to bivalirudin or to heparins with optional GPI. Primary and principal outcome was the composites of death or nonCABG-related major bleeding at 30 days. This pre-specified analysis compared patients receiving bivalirudin（n = 1089） with those receiving heparins with routine upstream GPI（n = 649） and those receiving heparins only with GPI use restricted to bailout（n = 460）. The primary outcome death and major bleeding occurred in5.1% with bivalirudin, 7.6% with heparin plus routine GPI（HR 0.67 and 95% CI 0.46-0.97, P = 0.034）,and 9.8% with heparins plus bailout GPI（HR 0.52 and 95% CI 0.35-0.75, P = 0.006）. Following adjustment by logistic regression, bivalirudin was still associated with significantly lower rates of the primary outcome（odds ratio 0.53, 95% CI 0.33-0.87） and major bleeding（odds ratio 0.44, 95% CI 0.24 – 0.82） compared with heparins alone with bailout GPI. Rates of stent thrombosis were higher with bivalirudin（1.6 vs. 0.6 vs.0.4%, P = 0.09 and 0.09）. Conclusion Bivalirudin, started during transport for primary PCI, reduces major bleeding compared with both patients treated with heparin only plus bailout GPI and patients treated with heparin and routine GPI, but increased stent thrombosis.

Heparin is an effective treatment for preventing liver failure after hepatectomy

BACKGROUND Posthepatectomy liver failure(PHLF)is one of the most important causes of death following liver resection.Heparin,an established anticoagulant,can protect liver function through a number of mechanisms,and thus,prevent liver failure.AIM To look at the safety and efficacy of heparin in preventing hepatic dysfunction after hepatectomy.METHODS The data was extracted from Multiparameter Intelligent Monitoring in Intensive Care III(MIMIC-III)v1.4 pinpointed patients who had undergone hepatectomy for liver cancer,subdividing them into two cohorts:Those who were injected with heparin and those who were not.The statistical evaluations used were unpaired ttests,Mann-Whitney U tests,chi-square tests,and Fisher’s exact tests to assess the effect of heparin administration on PHLF,duration of intensive care unit(ICU)stay,need for mechanical ventilation,use of continuous renal replacement therapy(CRRT),incidence of hypoxemia,development of acute kidney injury,and ICU mortality.Logistic regression was utilized to analyze the factors related to PHLF,with propensity score matching(PSM)aiming to balance the preoperative disparities between the two groups.RESULTS In this study,1388 patients who underwent liver cancer hepatectomy were analyzed.PSM yielded 213 matched pairs from the heparin-treated and control groups.Initial univariate analyses indicated that heparin potentially reduces the risk of PHLF in both matched and unmatched samples.Further analysis in the matched cohorts confirmed a significant association,with heparin reducing the risk of PHLF(odds ratio:0.518;95%confidence interval:0.295-0.910;P=0.022).Additionally,heparin treatment correlated with improved short-term postoperative outcomes such as reduced ICU stay durations,diminished requirements for respiratory support and CRRT,and lower incidences of hypoxemia and ICU mortality.CONCLUSION Liver failure is an important hazard following hepatic surgery.During ICU care heparin administration has been proved to decrease the occurrence of hepatectomy induced liver failure.This indicates that heparin may provide a hopeful option for controlling PHLF.

Low-molecular-weight heparin and preeclampsia—does the sword cut both ways?Three case reports and review of literature

BACKGROUND Low-molecular-weight heparins(LMWH)are the most commonly used anticoagulants during pregnancy.It is considered to be the drug of choice due to its safety in not crossing placenta.Considering the beneficial effect in the improvement of microcirculation,prophylactic application of LMWH in patients with preeclampsia became a trend.However,the bleeding risk related with LMWH in preeclampsia patients has seldomly been evaluated.This current study aimed to identify the potential risks regarding LMWH application in patients with preeclampsia.CASE SUMMARY Herein we present a case series of three pregnant women diagnosed with preeclampsia on LMWH therapy during pregnancy.All the cases experienced catastrophic hemorrhagic events.After reviewing the twenty-one meta-analyses,the bleeding risk related with LMWH seems ignorable.Only one study analyzed the bleeding risk of LMWH and found a significantly higher risk of developing PPH in women receiving LMWH.Other studies reported minor bleeding risks,none of these were serious enough to stop LMWH treatment.Possibilities of bleeding either from uterus or from intrabdominal organs in preeclampsia patients on LMWH therapy should not be ignored.Intensive management of blood pressure even after delivery and homeostasis suture in surgery are crucial.CONCLUSION Consideration should be given to the balance between benefits and risks of LMWH in patients with preeclampsia.

Application of aspirin and low molecular weight heparin in major orthopedic surgery:Meta analysis of a randomized controlled trial

Objective:The perioperative period of major orthopedic surgery is associated with a high risk of thrombosis,but the best chemopreventive agent for thrombosis prophylaxis is still inconclusive.For this reason,this paper evaluated the efficacy and safety of aspirin versus low-molecular heparin using a Meta-analysis.Methods:Ten randomized controlled studies on the application of aspirin and low-molecular heparin for the prevention of deep vein thrombosis in orthopedic major surgery were retrieved by computer searches of PubMed,CochraneLibrary,WebofScience,China Knowledge Network,Wanfang,and Vipul databases according to inclusion and exclusion criteria,and the literature was managed using Endnote software,and the data were analyzed using Revman 5.3 software was used to perform Meta-analysis of the extracted data,focusing on the effects of these two drugs on pulmonary embolism,deep vein thrombosis,major bleeding events,minor bleeding events,wound complications,mortality and blood loss within 90 days after major orthopedic surgery.Results:(1)Ten randomized controlled trials of high quality were included,with a total of 12,974 patients,7,026 in the aspirin group and 5,948 in the low-molecular heparin group;(2)Meta-analysis showed that aspirin had a higher incidence of pulmonary embolism(OR=1.59,95%CI:1.02 to 2.49,P=0.04)and deep vein thrombosis(OR=1.60,95%CI:1.26 to 2.02,P=0.0001)than low molecular heparin;(3)The incidence of major bleeding events(OR=0.85,95%CI:0.47 to 1.55,P=0.60),minor bleeding events(OR=0.79,95%CI:0.55 to 1.12,P=0.18),adverse wound reactions(OR=0.79,95%CI:0.48 to 1.31,P=0.36),mortality within 90 days(OR=0.69,95%CI:0.20 to 2.31,P=0.55)and perioperative blood loss(MD=0.69,95%CI:0.20 to 2.31,P=0.55)in both drug groups,mortality within 90 days(OR=0.69,95%CI:0.20 to 2.31,P=0.55)and perioperative blood loss(MD=0.69,95%CI:0.20 to 2.31,P=0.55)were not statistically significant.Conclusion:Low-molecular heparin was superior to aspirin in the prevention of pulmonary embolism and lower extremity deep vein thrombosis after major orthopedic surgery,but the safety and adverse drug reactions of both groups were basically similar.Based on this,the authors recommend that low-molecular heparin should be preferred for the prevention of deep vein thrombosis in major orthopaedic surgery;however,the inclusion of randomized controlled trials remains limited,necessitating high-quality,large-sample,long-term follow-up clinical studies.

Effect of bivalirudin on myocardial microcirculation and adverse events after interventional therapy in older patients with acute coronary syndrome

BACKGROUND Bivalirudin,a direct thrombin inhibitor,is used in anticoagulation therapies as a substitute for heparin,especially during cardiovascular procedures such as percutaneous coronary intervention.AIM To explore the effect of bivalirudin on myocardial microcirculation following an intervention and its influence on adverse cardiac events in elderly patients with acute coronary syndrome(ACS).METHODS In total,165 patients diagnosed with acute myocardial at our hospital between June 2020 and June 2022 were enrolled in this study.From June 2020 to June 2022,elderly patients with ACS with complete data were selected and treated with interventional therapy.The study cohort was randomly divided into a study group(n=80,administered bivalirudin)and a control group(n=85,administered unfractionated heparin).Over a 6-mo follow-up period,differences in emergency processing times,including coronary intervention,cardiac function indicators,occurrence of cardiovascular events,and recurrence rates,were analyzed.RESULTS Significant differences were observed between the study cohorts,with the observation group showing shorter emergency process times across all stages:Emergency classification;diagnostic testing;implementation of coronary intervention;and conclusion of emergency treatment(P<0.05).Furthermore,the left ventricular ejection fraction in the observation group was significantly higher(P<0.05),and the creatine kinase-MB and New York Heart Association scores were CONCLUSION In elderly patients receiving interventional therapy for ACS,bivalirudin administration led to increased activated clotting time achievement rates,enhanced myocardial reperfusion,and reduced incidence of bleeding complications and adverse cardiac events.

Haemocompatibility of Ti-3Zr-2Sn-3Mo-25Nb biomedical alloy with surface heparinization using electrostatic self assembly technology

The haemocompatibility of Ti-3Zr-2Sn-3Mo-25Nb biomedical alloy was studied after surface heparinization. A layer of sol-gel TiO2 films was applied on the alloy samples followed by active treatment in the bio-functionalized solution for introducing the OH- and groups, and then the heparin was immobilized on the active TiO2 films through the electrostatic self assembly technology. It is shown that the heparinized films are mainly composed of anatase and rutile with smooth and dense surface. In vitro blood compatibility was evaluated by haemolysis test, clotting time and platelet adhesion behavior tests. The results show that the haemocompatibility of the alloy could be significantly improved by surface heparinization.

肝素诱导的血小板减少症--识别与处理

随着肝素和低分子肝素被广泛应用于临床,一种严重的肝素相关性并发症——肝素诱导的血小板减少症（heparin-induced thrombocytopenia,HIT）悄然危害着患者健康。HIT是在应用肝素（包括普通肝素、低分子肝素）过程中出现的以血小板计数降低及栓塞并发症为主要表现的临床疾病,可引起致命性的血栓栓塞并发症,包括肺栓塞、坏疽、急性心肌梗死及脑卒中等。

低分子肝素生物活性测定方法的比较研究

目的:对低分子肝素(low molecular weight heparin,LMWH)生物活性即抗活化10因子(抗-FXa)和抗活化2因子(抗-FⅡa)测定的不同方法进行比较与研究,建立国家标准。方法:(1)比较量反应平行线与标准曲线2种分析方法在发色底物的分光光度法即利用发色底物对 FXa 或 FⅡa特异的405 nm 显色反应测定抗-FXa 或抗-FⅡa效价的差异。(2)比较发色底物的分光光度法与血液凝固法(观察兔全血或兔血浆的凝结时间)测定 LMWH 的抗凝血酶(抗-FⅡa)效价的异同。结果:量反应平行线法比标准曲线法测定结果可靠、准确、精确;发色底物分光光度法与血液凝固法的实验结果相似,其差异无统计学意义(P>0.05),并且具有良好相关性(r=0.997 P<0.01和 r=0.976 P<0.01)。结论:对 LMWH 的抗-FXa 和抗-FⅡa效价测定采用发色底物的分光光度法;并以量反应平行线法进行分析。

一种快速大量纯化骨骼肌Ryanodine受体的方法

Ryanodine受体1(RyR1)在骨骼肌细胞的兴奋收缩偶联过程中扮演重要角色,是肌质网快速释放Ca2+的通道.RyR1的结构研究需要大量的且纯度很高的蛋白.目前,文献中的方法不能一次性得到大量的纯化蛋白,因而不能满足结构研究的需要.通过运用肝素(heparin,HP)层析与羟基磷灰石(hydroxyapatite,HA)层析,可以在1d内纯化获得毫克级RyR1.SDSPAGE显示,RyR1纯度达95%以上.在透射电子显微镜下观察到RyR1是一个正方形的结构,形态类似儿童玩具风车.这些结果表明,该纯化方法获得的RyR1不仅纯度高而且结构完整.

肝素诱导血小板减少症的诊治进展

肝素诱导的血小板减少症(heparin induced thrombocytopenia, HIT)是在应用肝素类药物过程中出现的不良反应,以普通肝素(unfractionated heparin,UFH)诱发的HIT为主,低分子肝素( low molecular weight heparin,LMWH)引起HIT的机率要低于普通肝素[1]。HIT临床上以血小板计数降低为主要表现,可引发静脉或动脉血栓形成,严重者甚至导致死亡。成人HIT发病率0.5%~5%,其中30%~60%的患者出现血栓事件[2]。近年回顾性分析儿童HIT总体发病率仅0.058%,伴血栓的发生率为0.047%,远低于成人[3],且多见于心脏手术体外循环或体外膜肺等重症患儿。另有系统性综述显示非新生儿心脏术后的HIT发生率0.33%,而新生儿未见HIT报道[4]。鉴于成人和儿童的差别,本文将简单阐述HIT的相关诊治进展。

低分子肝素配合生理盐水定时冲洗在连续性血液净化中的应用和护理

连续性血液净化（CBP）技术，已成为急危重症抢救不可缺少的重要手段，而抗凝则是保障其顺利进行的重要条件，目前最广泛应用的抗凝剂仍然是普通肝素（unfractionated heparin, UFH ） 或低分子肝素（Low molecular weight heparins, LMWH ）。但因UFH有并发出血的危险性，而LMWH在保证相同抗血栓形成效果的情况下，能较普通肝素减小出血的危险性，具有抗凝效果更好，明显降低出血次数，且对脂质代谢影响小的特点[1]，近年来广泛用于血液净化中。但在我国血液净化抗凝治疗方案多为经验性，缺乏标准化治疗方案。笔者比较了我院连续性静脉静脉血液滤过（CVVH）中应用UFH与LMWH的抗凝效果和安全性，现报道如下。

Bronchoalveolar Lavage and Histologic Characterization of Inhaled Heparin in Asthmatic Guinea Pigs

Objective: To survey the effects of inhaled heparin on airway inflammation inguinea pigs with asthma and investigate the possible mechanism of inhaled heparin in the treatmentof asthma. Methods: The asthma in guinea pigs induced by ovalbumin was treated with inhaled heparin.The changes of cellularities in bronchoalveolar lavage (BAL) fluid and the airway walls wereexamined. Histologic examinations were also done in the guinea pig controls. Results: The number ofeosinophils, lymphocytes, and ciliated epithelial cells in the BAL fluid from the group treated withheparin was significantly lower than that of the group of asthma controls (P<0.01). Within theairway watts of the heparin treated group, the eosinophil infiltration was less prominent than thatof the group of asthma controls (P<0.001) and the number of mast cell was significantly higher thanthat of the group of asthma controls (P<0.01). Histologic examination showed that airway damages inthe heparin treated group were mild. Conclusion: Heparin can inhibit airway inflammation andalleviate airway damage in guinea pigs with asthma.

低分子肝素联合血管转换酶抑制剂对糖尿病肾病显性蛋白尿的治疗观察

目的观察低分子肝素联合血管转换酶抑制剂对糖尿病肾病显性蛋白尿的治疗效果。方法将64例糖尿病肾病显性蛋白尿患者随机分为A、B、C3组。A组常规降血糖和饮食控制及对症治疗;B组在A组的基础上加用低分子肝素2500U皮下注射,2次/d;C组在A组的基础上加用洛汀新10mg口服,2次/d;D组在A组的基础上加用低分子肝素2500U皮下注射,2次/d,同时给予洛汀新10mg口服,2次/d。观察治疗前后24h尿蛋白定量、血清白蛋白(ALB)、血肌酐(Scr)、内生肌酐清除率(Ccr)的变化。结果A组病情改善不明显,部分病例有不同程度的恶化;B组及C组24h蛋白尿定量均有明显下降、ALB明显升高,Ccr有轻度下降,但不明显。D组24h蛋白尿明显下降,ALB及Ccr均明显升高。结论低分子肝素联合血管转换酶抑制剂对糖尿病肾病显性蛋白尿的治疗有明显效果,且优于单用LMWH或单用血管转换酶抑制剂。

Heparin和CRS-heparin对小鼠黑色素瘤细胞增殖和黏附的作用研究

本实验以小鼠黑色素瘤细胞为材料,通过细胞增殖和黏附的抑制实验,对比分析了肝素(Hep-arin)和羧基还原后再硫酸化肝素(CRS-heparin)对小鼠黑色素瘤细胞增殖和黏附的影响。体外实验表明,Heparin和CRS-heparin对小鼠黑色素瘤细胞增殖都有抑制作用,并且随浓度增加抑制作用加强,但两者之间的作用差异不大。Heparin和CRS-heparin对小鼠黑色素瘤细胞与血小板之间的黏附均有抑制作用,CRS-heparin的抑制作用要稍好于Heparin,两者的抑制效果都是浓度依赖的。由于CRS-heparin的抗凝血活性明显低于Heparin,本研究结果提示,CRS-heparin可能进一步被用来作为抗肿瘤药物进行研究。

Deep venous thrombosis after gastrectomy for gastric carcinoma:A case report

The treatment of gastric carcinoma consists of neoadjuvant chemoradiation,partial gastrectomy,subtotal gastrectomy,total gastrectomy,extended resection,and postoperative chemotherapy.Currently,gastrectomy and extended lymphadenectomy is the optimal choice for late gastric carcinoma.Postoperative complications are common after total gastrectomy including hemorrhage,anastomotic leakage,f istula,and obstruction.However,deep venous thrombosis(DVT) is an uncommon complication after gastrectomy for gastric carcinoma.We describe a case of a 68-year-old female patient with DVT after gastrectomy for gastric carcinoma.The patient was treated with anticoagulants and thrombolytics and subjected to necessary laboratory monitoring.The patient recovered well after treatment and was symptom-free during a 3-mo follow-up.We conclude that correct diagnosis and treatment of DVT are crucial.