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体内抗凝血和抗血栓活性的聚多糖糖胺聚糖和动态效应-暴露关系在大鼠血浆。

In Vivo Anticoagulant and Antithrombic Activity of Depolymerized Glycosaminoglycan from and Dynamic Effect-Exposure Relationship in Rat Plasma.

机构信息

Key Laboratory of Marine Drugs, Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.

Laboratory of Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology, Qingdao 266237, China.

出版信息

Mar Drugs. 2022 Oct 2;20(10):631. doi: 10.3390/md20100631.

DOI:10.3390/md20100631
PMID:36286455
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9605468/
Abstract

Glycosaminoglycan from (AHG) and its depolymerized fragments (DAHGs) are anticoagulant fucosylated chondroitin sulfate. The aim of this study was to further evaluate the anticoagulant and antithrombic activity of AHG and DAHGs, as well as reveal the dynamic relationship between exposure and effect in vivo. The results demonstrated that AHG100 (Mw100 kDa), DAHG50 (Mw50 kDa), and DAHG10 (Mw~10 kDa) exhibited potent anticoagulant activity by inhibiting intrinsic factor Xase complex (FXase) as well as antithrombin-dependent factor IIa (FIIa) and factor Xa (FXa). These glycosaminoglycans markedly prevented thrombosis formation and thrombin-induced platelet aggregation in a dose- and molecular weight-dependent manner in vitro and in vivo. The further bleeding time measurement indicated that DAHG10 exhibited obviously lower hemorrhage risks than native AHG100. Following oral administration, DAHG10 could be absorbed into blood, further dose-dependently prolonging activated partial thromboplastin time (APTT) and thrombin time (TT) as well as inhibiting FXa and FIIa partially through FXase. Anticoagulant activity was positively associated with plasma concentration following oral administration of DAHG10. Our study proposed a new point of view to understand the correlation between effects and exposure of fucosylated chondroitin sulfate as an effective and safe oral antithrombotic agent.

摘要

糖胺聚糖来自鲨鱼（AHG）及其解聚片段（DAHGs）是具有抗凝作用的岩藻糖基硫酸软骨素。本研究旨在进一步评估 AHG 和 DAHGs 的抗凝和抗血栓活性，并揭示体内暴露与效应之间的动态关系。结果表明，AHG100（Mw100 kDa）、DAHG50（Mw50 kDa）和 DAHG10（Mw~10 kDa）通过抑制内源性因子 Xa 酶复合物（FXase）以及抗凝血酶依赖性因子 IIa（FIIa）和因子 Xa（FXa），表现出很强的抗凝活性。这些糖胺聚糖在体外和体内以剂量和分子量依赖性方式显著防止血栓形成和凝血酶诱导的血小板聚集。进一步的出血时间测量表明，DAHG10 比天然 AHG100 表现出明显更低的出血风险。口服给予 DAHG10 后，可被吸收到血液中，进一步通过 FXase 剂量依赖性地延长活化部分凝血活酶时间（APTT）和凝血酶时间（TT），并部分抑制 FXa 和 FIIa。抗凝活性与口服 DAHG10 后的血浆浓度呈正相关。我们的研究提出了一个新的观点，以了解作为有效和安全的口服抗血栓药物的岩藻糖基硫酸软骨素的效应与暴露之间的相关性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fa9/9605468/71152860a385/marinedrugs-20-00631-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fa9/9605468/1e56a632b87a/marinedrugs-20-00631-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fa9/9605468/ec2fdaffd3be/marinedrugs-20-00631-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fa9/9605468/63c01cd06e6e/marinedrugs-20-00631-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fa9/9605468/3d757f14e60a/marinedrugs-20-00631-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fa9/9605468/9509c925d2f1/marinedrugs-20-00631-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fa9/9605468/6ec391aee35d/marinedrugs-20-00631-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fa9/9605468/486aa099d762/marinedrugs-20-00631-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fa9/9605468/71152860a385/marinedrugs-20-00631-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fa9/9605468/1e56a632b87a/marinedrugs-20-00631-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fa9/9605468/ec2fdaffd3be/marinedrugs-20-00631-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fa9/9605468/63c01cd06e6e/marinedrugs-20-00631-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fa9/9605468/3d757f14e60a/marinedrugs-20-00631-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fa9/9605468/9509c925d2f1/marinedrugs-20-00631-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fa9/9605468/6ec391aee35d/marinedrugs-20-00631-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fa9/9605468/486aa099d762/marinedrugs-20-00631-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fa9/9605468/71152860a385/marinedrugs-20-00631-g008.jpg

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