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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 黃德富(Tur-Fu Huang) | |
| dc.contributor.author | Chia-I Yen | en |
| dc.contributor.author | 顏嘉怡 | zh_TW |
| dc.date.accessioned | 2021-06-07T17:50:55Z | - |
| dc.date.copyright | 2013-03-04 | |
| dc.date.issued | 2012 | |
| dc.date.submitted | 2012-10-30 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/15731 | - |
| dc.description.abstract | 血管栓塞是由一系列血小板與凝血因子的異常所導致，對於心血管、腦血管及周邊血管造成一定程度的影響。經過一系列化合物的篩選，我們發現化合物Ctkf6f2具抑制血小板凝集的活性，並且在測試濃度中不影響細胞膜完整性。在人類血小板懸浮液中，Ctkf6f2呈濃度相關性的抑制由膠原蛋白(collagen)，花生四烯酸(A.A.)及U46619(TXA2類似物)所引起的血小板凝集，其IC50分別為3.4±0.6μM，3.2±1.0μM及1.17±0.2μM。 Ctkf6f2呈濃度相關抑制由collagen引起的 P-selectin表現量及TXB2的形成。在酵素活性分析方面，Ctkf6f2部分抑制thromboxane synthase的活性，但不影響COX-1酵素活性。且發現在U46619誘發血小板凝集的濃度反應曲線圖上，Ctkf6f2及5185對於TP受體呈現競爭性的拮抗作用。另一方面， 靜脈注射Ctkf6f2 (10 μg/g) 能顯著的抑制螢光素前處理之小鼠腸繫膜小靜脈血栓生成，且不影響小鼠的出血時間。同時，Ctkf6f2能有效抑制老鼠PRP之凝集反應，且更優於化合物5185。在肺栓塞實驗中，Ctkf6f2 能增加小鼠存活率及減少循環阻塞與栓子形成的數目。當口服給予Ctkf6f2 (80 mg/kg/day) 三天，Ctkf6f2證明能抑制血小板凝集且不會引起急性胃部之損傷，顯示其為口服有效之化合物。總結上述結果，Ctkf6f2於體內及體外實驗皆呈現強效抑制血小板之活性，此化合物具潛力進入未來的抗血栓藥物之研發。 | zh_TW |
| dc.description.abstract | Atherothrombosis is a systemic process that affects the cardiovascular, cerebrovascular, and peripheral arterial systems. The abnormality of platelet activation plays a key role in its pathogenesis. We screened a series of synthetic compounds and found Ctkf6f2, a derivative of compound 5185, possesses concentration-dependent inhibition on platelet aggregation of washed human platelets induced by collagen (IC50=3.4±0.6μM) , arachidonic acid (IC50=3.2±1.0μM) and U46619 (IC50=1.17±0.2μM). Ctkf6f2 inhibited P-selectin expression and TXB2 formation induced by collagen in a concentration-dependent manner. In the enzyme assay, we found Ctkf6f2 partially inhibited thromboxane synthase activity and had little effect on COX-1 enzyme. Moreover, Ctkf6f2 produced a right-shift of the concentration- response curve of U46619, indicating a competitive antagonism on TP receptor. On the other hand, Ctkf6f2 significantly inhibited thrombus formation of the irradiated mesenteric vessels in fluorescein sodium-pretreated mice without significantly affecting the bleeding time induced by tail transaction. In addition, Ctkf6f2 significantly impaired platelet aggregation of mice PRP induced by collagen and U46619 compared to compound 5185. In the pulmonary embolism model, Ctkf6f2 was proved to increase the survival rate, reduce the circulation obstruction and number of emboli formation. Also, it exerts antiplatelet potent upon oral administration. Taken together, Ctkf6f2 may become a new potent antithrombotic agent. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-07T17:50:55Z (GMT). No. of bitstreams: 1 ntu-101-R99443014-1.pdf: 2976986 bytes, checksum: ba174a5825121b77fe0fadc48c64eddf (MD5) Previous issue date: 2012 | en |
| dc.description.tableofcontents | 中文摘要 i
Abstract ii Abbreviation table iii Chapter1 Introduction 1 1.1 Atherothrombosis 1 1.2 Platelet adhesion, activation and aggregation 2 1.3 Arachidonic acid derivatives and Eicosanoids 3 1.4 Biosynthesis of thromboxane A2 6 1.5 Physiological role of thromboxane A2 7 1.6 Thromboxane A2 receptor 9 1.7 Therapeutic targeting of thromboxane receptor 11 1.8 Cyclooxygenase inhibitors 12 1.9 Limitations of aspirin 12 1.10 Inhibitors of thromboxane synthase 14 1.11 Antagonists of thromboxane A2 receptor 15 1.12 Dual-acting drugs 17 1.13 TP receptor antagonist and TXS synthase inhibitor 18 1.14 Aim of the research 19 Chapter 2 Materials and methods 33 2.1 Reagents and Animals 33 2.2 Preparaion of washed human platelets and platelet-rich plasma 34 2.3 Measurements of platelet aggregation 35 2.4 LDH assay 35 2.5 Measurement of thromboxane B2 formation 36 2.6 Flow cytometric analysis of P-selectin expression 36 2.7 Measurement of intracellular Ca2+ mobilization 37 2.8 Western blotting and immunoprecipitation 37 2.9 Ex vivo mouse platelet aggregation 38 2.10 Fluorescein sodium-induced platelet thrombus formation in mesenteric venules 39 2.11 Pulmonary embolism 40 2.12 Tail bleeding time in mice 40 2.13 Gastric ulcer assay 41 2.14 Statistic analysis 41 Chapter 3 Results 42 3.1 Ctkf6f2 was selected from 5185 derivatives for further study 42 3.2 Effect of Ctkf6f2 on platelet aggregation 43 3.3 Effect of Ctkf6f2 on platelet LDH release 44 3.4 Effect of Ctkf6f2 on collagen and U46619–induced intracellular Ca2+ mobilization 44 3.5 Effect of Ctkf6f2 on collagen and U46619–induced granule secretion 45 3.6 Effect of Ctkf6f2 on TXB2 formation of human platelets by collagen 45 3.7 Effect of competitive inhibition of compound 5185 and Ctkf6f2 on U46619-induced platelet aggregation 45 3.8 Effect of Ctkf6f2 on in vivo thrombosis mouse model 46 3.9 Effect of Ctkf6f2 on ex vivo mouse platelet aggregation 47 3.10 Effect of Ctkf6f2 on pulmonary histology 48 3.11 Effect of Ctkf6f2 on pulmonary thromboembolism 48 3.12 Effect of orally given Ctkf6f2 on ex vivo mouse platelet aggregation 49 3.13 Lack of gastric lesion in mice as Ctkf6f2 was orally administrated 49p; 3.14 Effect of Ctkf6f2 on tail bleeding time in mouse model 49 Chapter 4 Discussion 75 Chapter 5 Conclusion and perspective 83 References 87 | |
| dc.language.iso | en | |
| dc.subject | 凝集 | zh_TW |
| dc.subject | 血栓 | zh_TW |
| dc.subject | 血小板 | zh_TW |
| dc.subject | platelet | en |
| dc.subject | thrombus | en |
| dc.subject | aggregation | en |
| dc.title | 新穎抗血栓藥物Ctkf6f2之藥理作用及機轉之探討 | zh_TW |
| dc.title | Action Mechanism and Pharmacological Effects of the Novel Antithrombotic Agent Ctkf6f2 | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 101-1 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 鄧哲明(Che-Ming Teng),顏茂雄(Mao-Hsiung Yen),楊春茂,陳文彬 | |
| dc.subject.keyword | 血栓,血小板,凝集, | zh_TW |
| dc.subject.keyword | thrombus,platelet,aggregation, | en |
| dc.relation.page | 96 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2012-10-30 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 藥理學研究所 | zh_TW |
| 顯示於系所單位： | 藥理學科所 | |
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