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...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.展开更多
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 inhibitor...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.展开更多
In both Traditional Chinese Medicine(TCM)and modern medicine,they agree that the integrity and healthy structure of the vascular endothelium are essential for normal hemodynamics.Damage to the vascular endothelium can...In both Traditional Chinese Medicine(TCM)and modern medicine,they agree that the integrity and healthy structure of the vascular endothelium are essential for normal hemodynamics.Damage to the vascular endothelium can quickly activate the extrinsic coagulation pathway by triggering the tissue factor(TF)and lead to coagulation.This damage,along with a loss of anticoagulant properties through antithrombinⅢ(ATⅢ),TF pathway inhibitors,and the protein C system,can result in a hypercoagulable state and even thrombosis.Hypercoagulability is not only a common feature of many cancers but also an important factor promoting tumor development and metastasis,which corresponds to the TCM theory of“blood stasis leading to tumors.”The pharmacological effects of heparin and aspirin have similarities with TCM's“activating blood circulation and removing blood stasis”theory in improving blood circulation,treating related diseases,and their anti-inflammatory effects.展开更多
Heparin,a glycosaminoglycan,is a stable source of carbon that supports the growth of microorganisms in the human intestine.It is also a commonly used anticoagulant drug in clinical practice,with significant therapeuti...Heparin,a glycosaminoglycan,is a stable source of carbon that supports the growth of microorganisms in the human intestine.It is also a commonly used anticoagulant drug in clinical practice,with significant therapeutic effects.Low molecular weight heparin(LMWH)is a highly active low molecular weight fragment obtained via enzymatic reaction or the chemical degradation of heparin.LMWH has been applied globally in the prevention and treatment of venous thromboembolism in thrombosis patients.Simultaneously,as a potential prebiotic,because of its low molecular weight,LMWH can be well degraded by the gut microbiota to maintain intestinal balance.Enzymatic heparin degradation has recently emerged as a viable disposal method for LMWH preparation;however,only very few benchmark enzymes have been thoroughly described and subjected to protein engineering to improve their properties over the past few years.The commercialization of enzymes will require the development of robustly engineered enzymes that meet the demands of industrial processes.Herein,we report a rational protein engineering strategy that includes molecular dynamic simulations of flexible amino acid mutations and disulfide bond screening.Several Bacteroides thetaiotaomicron heparanase I(Bt-HepI)mutants were obtained and screened for high thermal stability.We obtained the Bt-HepI^(D204C/K208C/H189W/Q198R)variant,which features a stabilized protein surface structure,with a 1.3-fold increase in catalytic constant/michaelis-menten constant(k_(cat)/K_(m)),a 2.44-fold increase in thermal stability at 50℃,and a 1.8-fold decrease in the average molecular weight of LMWH produced at 40℃compared with that seen with Bt-HepI^(WT).Our study establishes a strategy to engineer thermostable HepI to underpin its industrial applications.展开更多
Subcutaneous administration of low-molecularweight heparin(LMWH)has been widely accepted as an effective anticoagulation therapy and is frequently used for patients to prevent thromboembolic events.While the usually s...Subcutaneous administration of low-molecularweight heparin(LMWH)has been widely accepted as an effective anticoagulation therapy and is frequently used for patients to prevent thromboembolic events.While the usually seen bruising around the injection site during subcutaneous LMWH treatment,the abdominal wall(AW)hematoma(AWH)was scarcely observed and reported.A previous study demonstrated the usual etiological risk of AWH involved anticoagulation therapy,chronic kidney disease,and trauma.^([1])Most of these cases had a favorable prognosis after conservative treatment.展开更多
BACKGROUND The risk and mortality rate of venous thromboembolism(VTE)following gastrointestinal surgery remain high,and the symptoms are atypical.Therefore,it is necessary to identify the risk factors associated with ...BACKGROUND The risk and mortality rate of venous thromboembolism(VTE)following gastrointestinal surgery remain high,and the symptoms are atypical.Therefore,it is necessary to identify the risk factors associated with the occurrence of VTE following gastrointestinal surgery and to implement appropriate prevention and treatment measures.AIM To assess the efficacy of perioperative anticoagulation for the prevention of postoperative VTE.METHODS This retrospective study enrolled 205 patients who underwent gastrointestinal surgery.In the observation group(n=101),prophylactic anticoagulation was administered via hypodermic injection of low-molecular-weight heparin during the perioperative period,whereas the control group(n=104)only received lowmolecular-weight heparin treatment postoperatively.Blood coagulation parameters and the incidence of VTE of the bilateral lower limbs pre-and post-surgery were compared between groups.Postoperative VTE was transformed into a dichotomous variable,and influencing factors were explored using multivariate logistic regression analyses.RESULTS On the 7th day postoperatively,the incidence of VTE of the bilateral lower limbs was significantly lower in the observation group than in the control group,as were the D-dimer levels(P<0.05).At 1 month postoperatively,the incidence of VTE was significantly lower in the observation group than in the control group(P<0.05).An age≥65 years,a body mass index≥24 kg/m^(2),and malignant diseases of the digestive system were identified as risk factors for the occurrence of postoperative VTE in patients undergoing gastrointestinal surgery.CONCLUSION The incidence of VTE in patients who underwent gastrointestinal surgery peaked within 1 week postoperatively.The findings confirmed perioperative anticoagulation can safely and effectively reduce the incidence of postoperative VTE.展开更多
Objective To analyze the market environment of heparin,and to provide reference for the development of the heparin industry in China.Methods The international market size and competition pattern of heparin was investi...Objective To analyze the market environment of heparin,and to provide reference for the development of the heparin industry in China.Methods The international market size and competition pattern of heparin was investigated first.Then,environmental analysis of it was made based on the PEST model.Results and Conclusion There is room for optimization of the relevant policies for the development of heparin industry in China.The use of heparin drugs and regulation should be further improved.In addition,the research and development ability of pharmaceutical enterprises should be enhanced,and the development strategy of heparin industry needs to be adjusted.展开更多
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-functiona...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.展开更多
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 p...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.展开更多
The treatment of gastric carcinoma consists of neoadjuvant chemoradiation,partial gastrectomy,subtotal gastrectomy,total gastrectomy,extended resection,and postoperative chemotherapy.Currently,gastrectomy and extended...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.展开更多
基金Supported by the Natural Science Fund for Colleges and Universities in Jiangsu Province(No.18KJB350009)the Natural Science Fund for Colleges and Universities in Jiangsu Province(No.17KJB350009)the Natural Science Foundation of Jiangsu Province(No.BK20170445).
文摘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.
文摘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.
基金supported by the Guizhou Provincial Basic Research Program(Natural Science)Youth Guidance Project{Qian Kehe Foundation-[2024]Youth 307}。
文摘In both Traditional Chinese Medicine(TCM)and modern medicine,they agree that the integrity and healthy structure of the vascular endothelium are essential for normal hemodynamics.Damage to the vascular endothelium can quickly activate the extrinsic coagulation pathway by triggering the tissue factor(TF)and lead to coagulation.This damage,along with a loss of anticoagulant properties through antithrombinⅢ(ATⅢ),TF pathway inhibitors,and the protein C system,can result in a hypercoagulable state and even thrombosis.Hypercoagulability is not only a common feature of many cancers but also an important factor promoting tumor development and metastasis,which corresponds to the TCM theory of“blood stasis leading to tumors.”The pharmacological effects of heparin and aspirin have similarities with TCM's“activating blood circulation and removing blood stasis”theory in improving blood circulation,treating related diseases,and their anti-inflammatory effects.
基金supported by the Natural Science Foundation of Jiangsu Province(BE2021623,BK20220155)Natural Science Foundation of Jiangsu Province(BE2021623)+4 种基金National Natural Science Foundation of China(32001665,U1903205,32021005)the National Key Research and Development Program of China(2017YF0400303)the Key Scientific and Technological Research Projects in the Key Areas of the Xinjiang Production and Construction Corps(2018AB010)the Key Research and Development 303 Program of Ningxia(2020BFG02012)Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province。
文摘Heparin,a glycosaminoglycan,is a stable source of carbon that supports the growth of microorganisms in the human intestine.It is also a commonly used anticoagulant drug in clinical practice,with significant therapeutic effects.Low molecular weight heparin(LMWH)is a highly active low molecular weight fragment obtained via enzymatic reaction or the chemical degradation of heparin.LMWH has been applied globally in the prevention and treatment of venous thromboembolism in thrombosis patients.Simultaneously,as a potential prebiotic,because of its low molecular weight,LMWH can be well degraded by the gut microbiota to maintain intestinal balance.Enzymatic heparin degradation has recently emerged as a viable disposal method for LMWH preparation;however,only very few benchmark enzymes have been thoroughly described and subjected to protein engineering to improve their properties over the past few years.The commercialization of enzymes will require the development of robustly engineered enzymes that meet the demands of industrial processes.Herein,we report a rational protein engineering strategy that includes molecular dynamic simulations of flexible amino acid mutations and disulfide bond screening.Several Bacteroides thetaiotaomicron heparanase I(Bt-HepI)mutants were obtained and screened for high thermal stability.We obtained the Bt-HepI^(D204C/K208C/H189W/Q198R)variant,which features a stabilized protein surface structure,with a 1.3-fold increase in catalytic constant/michaelis-menten constant(k_(cat)/K_(m)),a 2.44-fold increase in thermal stability at 50℃,and a 1.8-fold decrease in the average molecular weight of LMWH produced at 40℃compared with that seen with Bt-HepI^(WT).Our study establishes a strategy to engineer thermostable HepI to underpin its industrial applications.
文摘Subcutaneous administration of low-molecularweight heparin(LMWH)has been widely accepted as an effective anticoagulation therapy and is frequently used for patients to prevent thromboembolic events.While the usually seen bruising around the injection site during subcutaneous LMWH treatment,the abdominal wall(AW)hematoma(AWH)was scarcely observed and reported.A previous study demonstrated the usual etiological risk of AWH involved anticoagulation therapy,chronic kidney disease,and trauma.^([1])Most of these cases had a favorable prognosis after conservative treatment.
文摘BACKGROUND The risk and mortality rate of venous thromboembolism(VTE)following gastrointestinal surgery remain high,and the symptoms are atypical.Therefore,it is necessary to identify the risk factors associated with the occurrence of VTE following gastrointestinal surgery and to implement appropriate prevention and treatment measures.AIM To assess the efficacy of perioperative anticoagulation for the prevention of postoperative VTE.METHODS This retrospective study enrolled 205 patients who underwent gastrointestinal surgery.In the observation group(n=101),prophylactic anticoagulation was administered via hypodermic injection of low-molecular-weight heparin during the perioperative period,whereas the control group(n=104)only received lowmolecular-weight heparin treatment postoperatively.Blood coagulation parameters and the incidence of VTE of the bilateral lower limbs pre-and post-surgery were compared between groups.Postoperative VTE was transformed into a dichotomous variable,and influencing factors were explored using multivariate logistic regression analyses.RESULTS On the 7th day postoperatively,the incidence of VTE of the bilateral lower limbs was significantly lower in the observation group than in the control group,as were the D-dimer levels(P<0.05).At 1 month postoperatively,the incidence of VTE was significantly lower in the observation group than in the control group(P<0.05).An age≥65 years,a body mass index≥24 kg/m^(2),and malignant diseases of the digestive system were identified as risk factors for the occurrence of postoperative VTE in patients undergoing gastrointestinal surgery.CONCLUSION The incidence of VTE in patients who underwent gastrointestinal surgery peaked within 1 week postoperatively.The findings confirmed perioperative anticoagulation can safely and effectively reduce the incidence of postoperative VTE.
文摘Objective To analyze the market environment of heparin,and to provide reference for the development of the heparin industry in China.Methods The international market size and competition pattern of heparin was investigated first.Then,environmental analysis of it was made based on the PEST model.Results and Conclusion There is room for optimization of the relevant policies for the development of heparin industry in China.The use of heparin drugs and regulation should be further improved.In addition,the research and development ability of pharmaceutical enterprises should be enhanced,and the development strategy of heparin industry needs to be adjusted.
基金Project (31100693/C100302) supported by the National Natural Science Foundation of ChinaProject (31011120049) supported by the Australia-China Special Fund, International Science Linkages Program co-supported by the Department of Innovation, Industry, Science and Research of Australia, and the Ministry of Science and Technology and National Science Foundation of China+1 种基金Project(2010ZDKG-96) supported by the Major Subject of "13115" Programs of Shaan’xi Province, ChinaProject (2012CB619102) supported by the National Basic Research Program of China
文摘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.
文摘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.
文摘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.
