Discovery of novel (6S/12aS)-heptachpyridone capable of inhibiting thrombosis in vivo

The in vitro conversion of (1S,3S)-1-dimethoxylethyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid, (1S,3S)-DCCA, in rat plasma is monitored by HPLC-FT-ICR-MS. We show that the in vitro conversion of (1S,3S)-DCCA in rat plasma for 1 h leads to forming (6S/12aS)-bisdimethoxyethylheptachpyridone, reflecting intermolecular condensation of (1S,3S)-DCCA, and the in vitro conversion of (6S/12aS)-bisdimethoxyethylheptachpyridone in rat plasma for 1 h leads to forming (6S/12aS)-heptachpyridone, reflecting hydrolysis of (6S/12aS)-bisdimethoxyethylheptachpyridone. At a dose of 1.0 μmol/kg (6S/12aS)-heptachpyridone orally inhibits venous thrombosis and arterial thrombosis in vivo. Bleeding time, clotting time and international normalized ratio show that at this dose (6S/12aS)-heptachpyridone has no bleeding risk, does not lengthen clotting time and does not change the exogenous coagulation pathway. We also show that the reactions promoted by rat plasma are easy to practice by chemical synthesis. Thus our findings build a bridge across the in vivo conversion and the application.     

PCI术后是否抗凝治疗的临床疗效比较

目的：研究PCI术后是否应用依诺肝素抗凝治疗对患者临床疗效的影响。方法：于2011年5月至2012年1月间,连续入选在我院行冠状动脉造影并置入了支架的患者158例,将符合标准的患者随机分为非抗凝组或抗凝组两组各79名。非抗凝组术后常规应用阿司匹林和氯吡格雷。抗凝组术后加用依诺肝素。对入选患者进行院内随访记录其主要心脏不良事件及出血事件。结果：支架植入成功率100%。术后抗凝组113处病变共置入支架135枚;非抗凝组109处病变置入支架115枚。院内随访：主要心脏不良事件和严重出血差异无统计学意义。小出血事件抗凝组多于非抗凝组（P=0.007）。结论：冠状动脉支架置入术后非抗凝治疗组缺血不良事件发生率较抗凝组无明显增加,小出血并发症明显减少。该研究结果表明,对PCI术无特殊并发症的患者术后无需常规抗凝治疗。     

Anti-thrombosis effect of diosgenyl saponins in vitro and in vivo

Thrombosis in coronary or cerebral arteries is the major cause of morbidity and mortality worldwide. Diosgenin and total steroidal saponins extracted from the rhizome of Dioscorea zingiberensis C.H. Wright are demonstrated to have anti-thrombotic activity. However, few studies describe the anti-thrombotic activity of the diosgenyl saponin monomer. In the present study, a simple and convenient method for the preparation of a new disaccharide saponin, diosgenyl β-d-galactopyranosyl-(1 → 4)-β-d-glucopyranoside (3), is described. We evaluated the anti-thrombotic effects of diosgenin and four diosgenyl saponins by measuring the bleeding time; the results showed that compound 3 exhibits outstanding efficiency in prolonging the bleeding time. Furthermore, we assessed whether compound 3 could alter platelet aggregation in vitro and in vivo. In addition, activated partial thromboplastin time (APTT), thrombin time (TT), prothrombin time (PT), coagulation factors and protection rate in mice were measured to evaluate the anti-thrombotic effect of compound 3. The results show that compound 3 inhibited platelet aggregation, prolonged APTT, inhibited factor VIII activities in rats, and increased the protection rate in mice in a dose-dependent manner. Taken together, these findings suggested that diosgenyl saponins, especially compound 3, had anti-thrombotic activity. It may execute anti-thrombotic activity through inhibiting factor VIII activities and platelet aggregation.     

Actin exposure upon tissue injury is a targetable wound site-specific protein marker

BackgroundIdentification of wound-specific markers would represent an important step toward damaged tissue detection and targeted delivery of biologically important materials to injured sites. Such delivery could minimize the amount of therapeutic materials that must be administered and limit potential collateral damage on nearby normal tissues. Yet, biological markers that are specific for injured tissue sites remain elusive.MethodsIn this study, we have developed an immunohistological approach for identification of protein epitopes specifically exposed in wounded tissue sites.ResultsUsing ex-vivo tissue samples in combination with fluorescently-labeled antibodies we show that actin, an intracellular cytoskeletal protein, is specifically exposed upon injury. The targetability of actin in injured sites has been demonstrated in vivo through the specific delivery of anti-actin conjugated particles to the wounded tissue in a lethal rat model of grade IV liver injury.ConclusionsThese results illustrate that identification of injury-specific protein markers and their targetability for specific delivery is feasible.General significanceIdentification of wound-specific targets has important medical applications as it could enable specific delivery of various products, such as expression vectors, therapeutic drugs, hemostatic materials, tissue healing, or scar prevention agents, to internal sites of penetrating or surgical wounds regardless of origin, geometry or location.     

光动力疗法辅助治疗轻中度牙周炎的疗效观察

目的:探讨光动力疗法(PDT)辅助治疗轻中度牙周炎患者的临床疗效。方法:选取我院2016年1月-2017年8月收治的轻中度牙周炎患者46例为研究对象,共选取患牙276颗,随机分为观察组与对照组,每组138颗患牙,对照组予以龈下刮治术和根面平整术(SRP)治疗,观察组在对照组的基础上联合PDT治疗,比较治疗前、治疗后1个月、2个月、3个月观察两组患者的牙周袋探诊深度(PD)、探诊出血(BOP)阳性率、出血指数(BI)。结果:治疗后1个月、2个月、3个月,两组PD均随着时间的推移逐渐变浅(P0.05),且观察组治疗后各时间点均浅于对照组(P0.05);两组BOP阳性率均较治疗前降低,且观察组治疗后各时间均低于对照组(P0.05);两组BI随着时间的推移呈逐渐下降趋势(P0.05),且观察组治疗后各时间点BI均低于对照组(P0.05)。结论:PDT辅助治疗轻中度牙周炎患者的临床疗效较好,其能减小PD,降低BI和BOP阳性率。     

氨甲环酸联合利伐沙班对单侧全膝关节置换术后患者出血量、凝血功能以及膝关节功能的影响

目的:探讨氨甲环酸联合利伐沙班对单侧全膝关节置换术后患者出血量、凝血功能及膝关节功能的影响。方法:选取2015年1月-2016年1月在解放军425医院骨科初次行单侧全膝关节置换术的患者66例为研究对象,按照随机数字表法分为治疗组与对照组,每组各33例。治疗组患者在止血带释放前向关节腔内注射氨甲环酸,对照组患者则给予氯化钠注射液进行静脉滴注,在术后6-12h内两组患者均口服利伐沙班。记录并对比两组患者总失血量、隐性出血量、输血率、输血量,对比两组患者手术前后凝血功能指标、膝关节功能评分、膝关节活动度、疼痛视觉模拟评分(VAS),并观察两组患者并发症发生情况。结果:与对照组对比,治疗组患者的总失血量、隐性出血量、输血量及输血率均明显降低(P0.05);治疗组与对照组患者术前与术后3 d的活化部分凝血酶时间(APTT)、凝血酶原时间(PT)、纤维蛋白原(FG)水平比较均无显著差异(P0.05);术前两组患者的美国膝关节协会评分(AKSS)及膝关节活动度比较无显著差异(P0.05),术后7 d,治疗组与对照组患者的AKSS评分及膝关节活动度均较术前升高(P0.05),且治疗组患者的AKSS评分及膝关节活动度高于同时期对照组(P0.05);术前两组VAS评分比较无显著差异(P0.05),术后1 d,两组患者的VAS评分比较及与同组术前比较均无显著差异(P0.05),术后7 d,两组患者的VAS评分明显较术前及术后1 d降低(P0.05),但两组之间比较无显著差异(P0.05)。两组患者并发症总发生率对比无显著差异(P0.05)。结论:氨甲环酸联合利伐沙班可有效降低行单侧全膝关节置换术患者的出血量,加快关节功能的恢复,且不影响患者的凝血功能,值得临床推广。     

通道大小对经皮肾镜取石患者出血的影响

目的:探讨通道大小对经皮肾镜取石患者围手术期出血的影响及治疗策略。方法:回顾性分析2016年1月至2017年1月在我院行F24和F18通道的经皮肾镜取石术的189例患者临床资料,分别比较具有不同临床特征患者围手术期出血的发生情况。结果:95例F24通道患者平均出血量为125±19.6 m L,其中5人进行输血治疗;94例F18通道患者平均出血量为103±17.6m L,其中3人进行输血治疗。F18通道经皮肾镜取石术的出血组和非出血组糖尿病、高血压的发生率、结石表面积、通道数量、手术时间比较差异均具有统计学意义(P0.05)。F24通道经皮肾镜取石术的出血组和非出血组孤立肾、高血压发生率、结石面积、肾实质厚度、通道数量和手术时间比较差异均具有统计学意义(P0.05)。F18通道经皮肾镜取石围手术期出血量显著少于F24通道(P0.05)。结论:孤立肾、高血压、结石面积大、肾实质厚、肾积水轻、通道数量多和手术时间长均会导致经皮肾镜围手术期出血几率和出血量增加,并且F24通道相较于F18通道出血量更多。     

Design,synthesis and biological evaluation of anthranilamide derivatives as potential factor Xa (fXa) inhibitors

Factor Xa (fXa) is a crucial player in various thromboembolic disorders. Inhibition of fXa can provide safe and effective antithrombotic effects. In this study, a series of anthranilamide compounds were designed by utilizing structure-based design strategies. Optimization at P1 and P4 groups led to the discovery of compound 16g: a highly potent, selective fXa inhibitor with pronounced in vitro anticoagulant activity. Moreover, 16g also displayed excellent in vivo antithrombotic activity in the rat venous thrombosis (VT) and arteriovenous shunt (AV-SHUNT) models. The bleeding risk evaluation showed that 16g had a safer profile than that of betrixaban at 1?mg/kg and 5?mg/kg dose. Additionally, 16g also exhibited satisfactory PK profiles. Eventually, 16g was selected to investigate its effect on hypoxia-reoxygenation- induced H9C2 cell viability. MTT results showed that H9C2 cell viability can be remarkably alleviated by 16g.     

内镜与药物治疗肝硬化伴食管静脉曲张破裂出血的疗效比较

目的:比较内镜与药物治疗肝硬化伴食管静脉曲张破裂出血(EVB)的疗效。方法:选择2012年1月-2013年8月我院收治的肝硬化伴EVB患者70例,依据随机数字表法将所有患者分为对照组和观察组,各35例。两组患者入院后均给予纠正贫血、扩充血容量治疗,观察组待患者病情稳定后,在咽部麻醉下行内镜下食管静脉曲张套扎疗法(EVL),对照组患者应用生长抑素3mg+50 m L生理盐水泵入,兰索拉唑40 mg+100 m L生理盐水静脉滴注治疗。比较两种治疗方法的临床总有效率、复发率以及不良反应发生率。结果:观察组治疗总有效率91.43%,显著高于对照组71.43%(P0.05);观察组的出血复发率仅为5.71%,低于对照组的22.86%(P0.05);观察组食管溃疡、发热和胸骨后疼痛发生率均低于对照组,但差异未见统计学意义(均P0.05)。结论:EVL治疗肝硬化伴EVB疗效显著,减少复发率和不良发应发生率,效果优于单纯药物治疗,值得在临床上推广。     

Effects of combined nitrogen on anapleurotic carbon assimilation and bleeding sap composition in Phaseolus vulgaris L.

Dwarf french beans, Phaseolus vulgaris L., were grown with or without inoculation with rhizobia (strain 3644), and with or without a combined nitrogen source (nitrate or ammonium ions). The distribution of radioactivity into products of dark ¹⁴CO₂ assimilation was studied in roots or nodules from these plants. A detailed study was also made of the distribution and rates of excretion of nitrogen in xylem bleeding sap in 28 day old plants grown on the various sources of nitrogen. Whereas detached nodules accumulated radioactive glycine, serine and glutamate when incubated with ¹⁴CO₂, bleeding sap from plants root fed ¹⁴CO₂ contained low levels of radioactivity in these compounds but higher levels in allantoin. Chemical analysis showed allantoin to be the major compound transported in the xylem of nodulated plants, whether or not they were fed on combined nitrogen. In contrast uninoculated plants accumulated mainly amino acids in the bleeding sap, the amount and chemical composition of which depended on the combined nitrogen source.Abbreviations PEP phosphoenol pyruvate - OAA oxaloacetate