低分子量肝素对体内、体外血栓的溶解作用

目的：探讨低分子量肝素（ＬＭＷＨ）对体内、外血栓的溶解作用。方法：（１）取雄性家兔动脉血，制备人工血栓，放入贫血小板血浆中，观察ＬＭＷＨ对血栓的溶解作用；（２）于家兔一侧颈外静脉制备血栓，观察耳缘静脉用药（８００，４００，２００ＩＵ·ｋｇ－１）后静脉血栓溶解情况；同时测定ＡＰＴＴ、ＥＬＴ和血浆纤维蛋白原的含量。结果：不同于尿激酶，ＬＭＷＨ体外无溶栓作用；体内给药２００～８００ＩＵ·ｋｇ－１能有效地溶解体内血栓，降低纤维蛋白原的含量，缩短优球蛋白溶解时间（ＥＬＴ），并呈剂量依赖性，４００ＩＵ·ｋｇ－１溶栓作用与尿激酶５０００Ｕ·ｋｇ－１相似。结论：ＬＭＷＨ通过激活体内纤溶系统发挥溶栓作用。     

利伐沙班等治疗脊柱融合术后下肢肌间静脉血栓的疗效观察

目的探讨利伐沙班、伊诺肝素和低分子肝素钙对脊柱融合术后下肢肌间静脉血栓的治疗效果。方法回顾性分析40例脊柱融合术后发生下肢肌间静脉血栓的患者62例肢体的临床资料,分别用利伐沙班(20例),伊诺肝素(21例)和低分子肝素钙(21例)治疗,疗程均为1~3个月,用彩超观察血栓的消失情况,观察治疗过程中的不良反应。结果治疗后,利伐沙班组和低分子肝素钙组的总有效率均高于伊诺肝素组(P<0.05);利伐沙班组和低分子肝素钙组血小板功能相关参数、内皮细胞功能相关参数与不良反应发生率均低于伊诺肝素组(P<0.05);而利伐沙班组和低分子肝素钙组之间差异均无统计学意义。结论低分子肝素钙和利伐沙班治疗脊柱融合术后急性肌间静脉血栓疗效强,安全性较高,但服药方式不同,可根据患者的需要灵活使用。     

低分子肝素相对分子质量与抗凝活性关系研究*

目的:研究低分子肝素相对分子质量与抗凝活性之间的关系。方法:用生色底物法测定不同相对分子质量的低分子肝素6个分级和未分级样品的抗Ⅹa因子和抗Ⅱa因子效价,相对分子质量采用高效体积排阻色谱法(high performance size exclusion chromatography,HPSEC)测定。结果:抗Ⅹa因子与抗Ⅱa因子效价比随着相对分子质量的降低而增大。结论:在测定范围内,低分子肝素相对分子质量降低,抗凝活性降低,抗栓作用增强。     

Tetradecylmaltoside (TDM) enhances in vitro and in vivo intestinal absorption of enoxaparin,a low molecular weight heparin

Tetradecylmaltoside (TDM) was evaluated as a potential gastrointestinal absorption enhancer for low molecular weight heparin (LMWH), enoxaparin. The in vitro efficacy of TDM (0.0625, 0.125 and 0.25% w/v) in enhancing transport of ³H-enoxaparin or ¹⁴C-mannitol was investigated in human colonic epithelial cells (C2_BBel). Metabolic stability of the drug was determined in C2_BBel cell extracts. Transepithelial electrical resistance (TEER) was measured before and after exposure of the cells to TDM. Enoxaparin was further administered to anesthetized Sprague–Dawley rats in oral formulations in the absence or presence of increasing concentrations of TDM and drug absorption was monitored by measuring anti-factor Xa activity in rat blood. In vitro permeability study shows that apparent permeability (P_app) of ³H-enoxaparin across C2_BBe1 cells was increased by 8-fold in the presence of 0.0625% TDM compared to untreated cells. The movement of ¹⁴C-mannitol across the cell monolayer followed a similar pattern in the presence of increasing concentrations of TDM. No degradation or depolymerization of enoxaparin was observed when the drug was incubated in C2_BBel cell extract. TEER was reversible after 60 min exposure of the cells to 0.0625% (w/v) TDM. Oral formulations of enoxaparin containing TDM administered to anesthetized rats significantly and rapidly increased gastrointestinal absorption as compared to those animals which received enoxaparin plus saline (p<0.05). In the presence of 0.125% TDM in the formulation, enoxaparin oral bioavailability was increased by 2.5-fold compared to the saline control group. Overall, the data on the effect of TDM on the in vitro and in vivo intestinal permeation of enoxaparin suggest that TDM may represent a promising excipient for use in oral LMWH formulations.     

低分子量肝素对白细胞黏附和黏附分子表达的影响

目的研究低分子量肝素对白细胞与血管内皮细胞体内外黏附和细胞间黏附分子 1(ICAM 1)表达的影响。方法倒置显微镜观察在致敏豚鼠肠系膜微循环中白细胞的滚动和黏附情况 ,体外观察大鼠中性粒细胞对培养的脐静脉内皮细胞的黏附情况 ,流式细胞仪测定ICAM 1的表达。结果低分子量肝素 2 0、4 0u kg对白细胞黏附有明显抑制作用 ;0 .5、1.0u ml(终浓度 )对中性粒细胞体外黏附有明显抑制作用 ;0 .12 5、0 .2 5、0 .5、1.0u ml对脐静脉内皮ICAM 1的表达有明显抑制作用。结论低分子量肝素有明显抑制白细胞黏附及降低ICAM 1表达的作用。     

低分子肝素钙对过敏性紫癜患儿T细胞亚群的影响

目的 探讨低分子肝素钙对过敏性紫癜(HSP)血T细胞亚群的影响.方法 随机分低分子肝素钙治疗组(Ⅰ组,32例),普通治疗组(Ⅱ组,30例),并设健康对照(Ⅲ组,30例).采用流式细胞术观察CD4 细胞,CD8 细胞,部分凝血活酶时间(APTT),D-二聚体(D-D)变化和临床症状改善情况.结果 CD4 治疗前Ⅰ、Ⅱ两组均显著高于Ⅲ组,1个月后Ⅰ组降至Ⅲ组水平,Ⅱ组与Ⅲ组仍有差异,CD8 与CD4 的改变相反.治疗10d后Ⅰ组APTT、D-D恢复,Ⅱ组APTT恢复,D-D仍显著高于Ⅲ组.Ⅰ组临床症状改善优于Ⅱ组.结论 低分子肝素钙对CD4 ,CD8 细胞有调节作用,能抑制血栓形成,改善临床症状.     

国产相对低分子质量肝素钠在常规血透中的应用

目的:比较国产与进口相对低分子质量肝素钠(LMWH)注射液在常规血透患者中应用的有效性和安全性。方法:90例维持性血透患者随机分为2组,分别接受国产或进口LMWH治疗,观察透析器和透析管路的凝血情况、内瘘穿刺点压迫时间、血Xa因子活性和活化的部分凝血酶时间(APTT)变化以及药物不良反应。结果:2组患者均能顺利完成4-5.5 h的血透治疗,仅少数患者发生轻微透析器和管路凝血,2组患者在内瘘穿刺点压迫时间、血浆抗Xa因子和APTT的变化方面均相似;2组药物不良反应如肝功能损害、出血性并发症、血小板减少、过敏反应等发生率均较低;以上指标2组间比较P均>0.05。结论:国产与进口IMWH的有效性和安全性相似。     

肝素雾化吸入对豚鼠凝血时间及小鼠尾出血时间的影响

目的 :研究雾化吸入低分子量肝素 (LMWH )和标准肝素 (SH)对动物凝血时间和出血时间的影响。方法 :LMWH和SH超声雾化后经简易面罩吸入 ,连用7d ,观察对豚鼠凝血时间和小鼠尾出血时间的影响。结果 :与N S组比较 ,LMWH800IU/L、400IU/L和SH800IU/L、400IU/L对豚鼠凝血时间和小鼠尾出血时间均无显著影响 (P>0.05) ;LMWH800IU/L、400IU/L和SH800IU/L、400IU/L之间也无显著性差异 (P>0.05)。结论 :LMWH和SH雾化吸入是抗哮喘治疗的一种安全的给药途径     

Preliminary safety evaluation of a taurocholate‐conjugated low‐molecular‐weight heparin derivative (LHT7): a potent angiogenesis inhibitor

In our previous studies, taurocholic acid (TA)‐conjugated low‐molecular‐weight heparin derivative (LHT7) has been proven to be a potent anti‐angiogenic agent by demonstrated successful blockage capability of vascular endothelial growth factors (VEGF). Preliminary safety evaluations were conducted based on its mechanism of action and chemical behavior. For this purpose, acute toxicity study, and hematological and serological evaluations were carried out. Additionally, in order to evaluate mechanism‐related side effects, both blood pressure and the occurrence of proteinuria were measured using a treatment regime of multiple high doses of LHT7 in a biodistribution study. LD₅₀ values for LHT7 in female and male mice were 56.9 and 64.7 mg kg^–1 doses, respectively. There were no vital fluctuations in the serological and hematological parameters, except for the elevated levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) at 100 and 200 mg kg^–1 doses of LHT7, representing vital changes in the liver function. Moreover, the results of mechanism‐related studies showed that blood pressure at 50 mg kg^–1 did not change but showed elevated levels of protein in urine. In the biodistribution study, a slight accumulation of LHT7 in the kidney and the liver were observed at the 50 mg kg^–1 repeated dose owing to the presence of bile acid. No fatal damage was observed in this study; most observations were related to the chemical composition or the mechanism of action of the material. Copyright © 2014 John Wiley & Sons, Ltd.     

Movement of Heparins Across Rat Gastric Mucosa is Dependent on Molecular Weight and pH

Purpose  Movement of unfractionated (UFH) and low molecular weight heparins (LMWHs) through gastric mucosa was compared to determine effect of molecular weight on absorption. Methods  Rat gastric mucosa, mounted in an Ussing chamber, was bathed in oxygenated Kreb’s buffer, containing mannitol on the mucosal (lumen) at pH 7.4 or 4, and glucose on the serosal side (circulation) at pH 7.4. Heparins (10 mg/ml) were added to the mucosal side. Potential difference (PD), resistance, and short circuit current (Isc), were determined. Buffers and tissues were extracted to measure heparin by gel electrophoresis. Results  PD increased on heparin addition and following a lag period, that was longer for UFH at pH 7.4 and LMWHs at pH 4.0, returned to baseline. Isc increased slightly for UFH at pH 4.0 but significantly for LMWHs at pH 7.4. More UFH or LMWHs were recovered from serosal buffers at pH 4.0 and pH 7.4 respectively. Results suggest UFH and LMWHs cross gastric mucosa faster, and active transport is involved, at pH 4.0 and pH 7.4, respectively. Conclusions  Decreasing heparin size, increases movement through gastric mucosa at mucosal buffer pH 7.4 but not pH 4.0. The stomach environment may favor UFH absorption while the intestine environment favors LMWH absorption.     

低分子肝素对原代培养神经细胞缺血性损伤的保护作用

目的观察低分子肝素(LMWH)对原代培养低糖和谷氨酸损伤大鼠大脑皮层神经细胞的作用。方法将血清药理学方法与神经细胞体外培养技术结合在一起,制备低糖和谷氨酸损伤模型,以细胞形态学、培养液吸光度(A)值以及乳酸脱氢酶(LDH)活性作为观察指标,研究LMWH所产生的保护作用。结果LMWH可改善损伤神经细胞的形态、升高培养液A值、降低培养液中LDH活性。结论LMWH可提高低糖和谷氨酸损伤状态下神经细胞的活性,对损伤神经细胞有保护作用。     

低分子肝素凝胶处方优化及对瘙痒模型小鼠的作用

目的:优化低分子肝素(low molecular weight heparin,LMWH)凝胶处方,并观察其对蛋白酶活化受体2(proteinase activated receptor 2,PAR-2)激动剂SLIGRL-NH2引起小鼠瘙痒的作用.方法:选用L9(3 4)正交设计,优化LMWH凝胶处方.32只BALB/c小鼠随机分成对照组、模型组、地塞米松乳膏组和LMWH凝胶组,每组8只.分别在脱毛部位给予空白凝胶、空白凝胶、复方醋酸地塞米松乳膏和LMWH凝胶各0.1g,2次/d×3d.最后一次给药后2h,除对照组小鼠用药局部皮内注射生理盐水外,其余3组小鼠皮内注射PAR-2激动剂SLIGRL-NH2.观察皮内注射后30 min内小鼠的搔抓次数.结果:最佳处方是LMWH3％、月桂氮(艹卓)酮5％、卡波姆1.5％.模型组小鼠搔抓次数比对照组显著增多(P＜0.01);复方醋酸地塞米松乳膏组小鼠搔抓次数比模型组小鼠显著减少(P＜0.05);LMWH凝胶组小鼠搔抓次数比模型组和地塞米松乳胶组小鼠均显著减少(P＜0.01).结论:LMWH凝胶能减轻PAR-2激动剂SLIGRL-NH2引起的瘙痒,其作用可能优于地塞米松乳膏.     

Review of enoxaparin and its clinical applications in venous and arterial thromboembolism

Venous and arterial thromboembolic disorders are common medical conditions that are associated with considerable morbidity and mortality. Unfractionated heparin (UFH) and its derivatives, the low molecular weight heparins (LMWHs), are the anticoagulants of choice when a rapid anticoagulant effect is required. LMWHs have several advantages over UFH, including a longer plasma halflife and higher bioavailability; a predictable dose response, which enables once- or twice-daily dosing; and a more convenient route of administration (subcutaneous instead of intravenous), which enables patients to self-inject in an out-patient setting. Enoxaparin is a LMWH prepared by alkaline hydrolysis of the benzylin ester of UFH. The efficacy of enoxaparin in the management of venous and arterial thromboembolism has been shown in a wide range of patient groups using doses ranging from fixed doses of 20 – 60 mg o.d. and 0.75 – 1.5 mg/kg b.i.d. Other doses, such as 80 mg/day for pregnant women with combined thrombophilic defects, have also been studied. The use of subcutaneous enoxaparin as an effective and safe home treatment for patients with acute proximal deep vein thrombosis (DVT) has been demonstrated. The benefits of preventing venous thromboembolic events with enoxaparin include reducing the costs associated with investigating the symptoms of DVT, acute treatment and hospitalisation, and potentially preventing the development of post-thrombotic syndrome, while improving quality of life and so making the treatment cost effective. In contrast to other LMWHs, enoxaparin has been shown to provide better outcomes than UFH in the treatment of unstable angina and non-ST-segment elevation myocardial infarction, without increasing major bleeding. Adverse events with enoxaparin are infrequent; the most common events are minor bleeding complications. It should be noted that different doses or indications are approved in each country.     

不同剂量瑞舒伐他汀对冠心病合并高胆固醇血症患者血脂及血清高敏C反应蛋白的影响

目的综述低分子肝素口服给药的国内外研究进展。方法对近十年来国内外发表的具有代表性的相关文章进行分析、整理和归纳。结果低分子肝素被制成胶囊、脂质体、微乳等制剂后,口服吸收增加,抗凝抗栓作用增强,作用时间延长,安全性提高。结论低分子肝素口服制剂有望成为高效安全的抗血栓新制剂。     

低分子肝素联合糖皮质激素治疗小儿肾病综合征疗效及安全性的Meta 分析

目的:评估低分子肝素联合糖皮质激素治疗小儿肾病综合征(NS)的疗效及安全性。 方法:检索 PubMed、the Cochrane Library、EMBase、中国知网、中国生物医学文献数据库、维普、万方数据库,检索时间从建库至 2021 年 3 月,收集低分子肝素联合 糖皮质激素治疗小儿 NS 的临床随机对照试验(RCT),根据 Cochrane 推荐的偏倚风险评估方法对纳入的 RCT 研究进行风险评估,使用 RevMan 5. 3 软件进行统计学分析。 结果:共纳入 16 篇 RCT,病例共计 1 348 例。 Meta 分析结果显示:与单用糖皮质激素(泼尼松)治疗小儿 NS 相比,低分子肝素+泼尼松治疗在活化部分凝血活酶时间、血浆凝血酶原时间、不良反应发生率方面差异无统计学意义(P 均>0. 05),在改善 24 h 尿蛋白定量、血清白蛋白、尿素氮、血肌酐清除率、血肌酐及血浆胆固醇水平方面差异有统计学意义(P 均<0. 05)。 结论:低分子肝素联合糖皮质激素较单用激素治疗小儿 NS 疗效更优,但仍需大样本、多指标的RCT 对远期疗效及药物不良反应等展开深入评估。     

低分子肝素及利伐沙班预防全髋关节置换术后失血的观察

探讨人工全髋关节置换患者术后应用低分子肝素或利伐沙班对术后出血量的影响。回顾性分析2012年2月至2014年2月共240例行人工全髋关节置换患者,按术后是否应用低分子肝素或利伐沙班分为空白对照组、低分子肝素组及利伐沙班组。统计比较各组术后血红蛋白、血小板的变化及术后总失血量、显性失血量及隐性失血量。 低分子肝素组总失血量明显高于对照组（P＜0.01）,利伐沙班组总失血量明显高于对照组（P＜0.01）。低分子肝素组及利伐沙班组的显性失血量及隐性失血量也明显高于对照组。低分子肝素组与利伐沙班组出血量无明显差异。3组患者中隐性失血量占总失血量的比例无明显差异。髋骨关节置换术后应用低分子肝素及利伐沙班可增加失血量,包括隐性失血量的增加,2种抗凝药物的疗效相当,应密切关注血红蛋白及血小板的变化,充分认识隐性失血,对患者有效血容量的丢失作出正确评估。     

用低分子肝素急性抗凝再用伊布利特或普罗帕酮复律治疗心房颤动/扑动患者多中心临床研究

目的　评价发作持续48h余的房颤/房扑患者用低分子肝素急性抗凝后再用伊布利特与普罗帕酮复律的有效性及安全性。方法　共入选持续时间<90天的房扑/房颤患者212例(房颤151例,房扑61例),发作持续时间≥48h为试验组(51例), <48h为对照组(161例)。试验组经心脏超声除外血栓后,静推低分子肝素1. 7mg·kg-1行急性全身肝素化,对照组不抗凝治疗; 2组均于10min内静推伊布利特1mg或普罗帕酮70mg;给药结束10min后未复律者,重复给药1次。观察给药1. 5h内的转复率及4h内药物不良反应。结果　伊布利特对房扑的转复率明显高于房颤(78. 1% vs48. 3%,P<0. 01),对房颤的转复率、平均转复时间等, 2种药比较无显著性差异(P>0. 05)。试验组药物不良反应发生率无明显增加。结论　发作持续时间≥48h的房扑/房颤患者,用低分子肝素急性抗凝后再用伊布利特与普罗帕酮复律安全、有效。     

Effects of cadmium alone and in combination with low molecular weight chitosan on metallothionein,glutathione‐S‐transferase,acid phosphatase,and ATPase of freshwater crab Sinopotamon yangtsekiense

Cadmium (Cd) is an environmental contaminant showing a variety of deleterious effects, including the potential threat for the ecological environment and human health via food chains. Low molecular weight chitosan (LMWC) has been demonstrated to be an effective antioxidant. Metallothionein (MT) mRNA levels and activities of glutathione‐S‐transferase (GST), superoxide dismutase (SOD), acid phosphatase (ACP), Na⁺,K⁺‐ATPase, and Ca²⁺‐ATPase as well as malondialdehyde (MDA) contents in the gills of the freshwater crab Sinopotamon yangtsekiense were analyzed in vivo in order to determine the injury of Cd exposure on the gill tissues as well as the protective effect of LMWC against this injury. The results showed that there was an apparent accumulation of Cd in the gills, which was lessened by the presence of LMWC. Moreover, Cd²⁺ significantly increased the gill MT mRNA levels, ACP activity and MDA content while decreasing the activities of SOD, GST, Na⁺,K⁺‐ATPase, and Ca²⁺‐ATPase in the crabs relative to the control. Cotreatment with LMWC reduced the levels of MT mRNA and ACP but raised the activities of GST, Na⁺,K⁺‐ATPase, and Ca²⁺‐ATPase in gill tissues compared with the crabs exposed to Cd²⁺ alone. These results suggest that LMWC may exert its protective effect through chelating Cd²⁺ to form LMWC‐Cd²⁺ complex, elevating the antioxidative activities of GST, Na⁺,K⁺‐ATPase, and Ca²⁺‐ATPase as well as alleviating the stress pressure on MT and ACP, consequently protecting the cell from the adverse effects of Cd. © 2012 Wiley Periodicals, Inc. Environ Toxicol 29: 298–309, 2014.     

低分子量肝素乙酰化物的理化特性及其体外抗肿瘤活性研究

目的合成低抗凝血性低分子量肝素乙酰化物(ALMWH),并对其理化性质、抗肿瘤活性进行检测。方法采用高碘酸钠氧化,硼氢化钠还原法对普通肝素(UFH)进行选择性裂解,制得低抗凝血性低分子肝素(LMWH),以N,N二环己基碳二亚胺和二甲氨基吡啶(DCC/DMAP)为催化剂,对其进行乙酰化,制得ALMWH,经X线衍射(XRD)和差示扫描量热(DSC)试验,分析其构型和理化性质。以乳腺癌MDA-MB-231、MCF-7细胞为模型,检测其抗增殖、抗侵袭转移能力。利用家兔全血激活凝血时间实验(ACT)检测其抗凝血活性。结果 XRD测得ALMWH与LMWH同属无定形结构,但DSC热损失曲线和LMWH明显不同。与LMWH比较,ALMWH含有更多的结合水较低的抗凝血活性。更有意义的是,在低浓度下ALMWH即表现出较LMWH强的抗肿瘤细胞增殖、转移的活性。结论 ALMWH抗凝血活性低,具有一定的抗肿瘤增殖及侵袭转移的作用。本研究为低毒性抗肿瘤药物筛选提供了基础方法。     

超低分子肝素对原代培养大鼠大脑皮质神经元化学诱导损伤的保护作用

目的探讨超低分子肝素(ULMWH)对不同化学诱导损伤大脑皮质神经元的保护作用。方法谷氨酸、叠氮钠、KCl和咖啡因诱导损伤原代培养的大鼠大脑皮质神经元,观察神经元存活率、培养液中乳酸脱氢酶(LDH)漏出量及细胞内游离钙离子浓度([Ca2+]i)。结果ULMWH(0.01～1.0mg.L-1)预处理24h可显著提高谷氨酸损伤神经元的存活率,降低细胞LDH的漏出量和[Ca2+]i,高浓度(1.0mg.L-1)时对叠氮钠引起的神经元损伤也有一定的保护作用,但对咖啡因和KCl所致的神经元损伤无影响。结论ULMWH对谷氨酸和叠氮钠所致大鼠大脑皮质神经元损伤有一定的保护作用,可能与其抑制[Ca2+]i升高有关;但不能对抗KCl和咖啡因所致的皮质神经元损伤。