Melagatran
(Synonyms: 美拉加群) 目录号 : GC60240
Melagatran 是具有口服活性的 thrombin 直接抑制剂，除凝血酶外，它与凝血级联反应中的任何其他酶或纤溶酶没有相互作用。Melagatran 的抗凝血酶作用不需要内源性辅因子，可能有助于减轻内毒素血症的某些破坏作用。 Melagatran 具有预防动脉阻塞的潜能。
Cas No.:159776-70-2
Sample solution is provided at 25 µL, 10mM.
;)
,-1-7$$$37316672.jpg');)
;)
;)
$$$36806353.jpg');)
;33(7)%EF%BC%9A546-561$$$37156877.jpg');)
;)
;)
;)
%201124-1138.$$$35908550.jpg');)
%20766-780.$$$37100057.jpg');)
%20418-432.$$$36893736.jpg');)
%EF%BC%9A-240-255.$$$35108512.jpg');)
533-545$$$36543525.jpg');)
%201-13.$$$36600053.jpg');)
;)
Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Melagatran is a direct and orally active inhibitor of thrombin, without interacting with any other enzymes in the coagulation cascade or fibrinolytic enzymes aside from thrombin. Melagatran does not require endogenous co-factors for its antithrombin effect and may help to alleviate some of the damaging effects of endotoxemia[1]. Melagatran has the potential to provide a rational approach in the prevention of arterial occlusion[2].
[1]. Eriksson M, et al. Effects of melagatran, a novel direct thrombin inhibitor, during experimental septic shock. Expert Opin Investig Drugs. 2000 May;9(5):1129-37. [2]. Mehta JL, et al. Melagatran, an oral active-site inhibitor of thrombin, prevents or delays formation of electrically induced occlusive thrombus in the canine coronary artery. J Cardiovasc Pharmacol. 1998 Mar;31(3):345-51.
| Cas No. | 159776-70-2 | SDF | |
| 别名 | 美拉加群 | ||
| Canonical SMILES | NC(C(C=C1)=CC=C1CNC([C@@H]2CCN2C([C@@H](C3CCCCC3)NCC(O)=O)=O)=O)=N | ||
| 分子式 | C22H31N5O4 | 分子量 | 429.51 |
| 溶解度 | 储存条件 | ||
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
||
| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
 |
1 mg | 5 mg | 10 mg |
| 1 mM | 2.3282 mL | 11.6412 mL | 23.2823 mL |
| 5 mM | 0.4656 mL | 2.3282 mL | 4.6565 mL |
| 10 mM | 0.2328 mL | 1.1641 mL | 2.3282 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Ximelagatran/Melagatran: a review of its use in the prevention of venous thromboembolism in orthopaedic surgery
Drugs 2004;64(6):649-78.PMID:15018597DOI:10.2165/00003495-200464060-00010.
Ximelagatran (Exanta), the first available oral direct thrombin inhibitor, and its active form, Melagatran, have been evaluated in the prevention of venous thromboembolism (VTE) in patients undergoing hip or knee replacement. After oral administration ximelagatran is rapidly bioconverted to Melagatran. Melagatran inactivates both circulating and clot-bound thrombin by binding to the thrombin active site, thus, inhibiting platelet activation and/or aggregation and reducing fibrinolysis time. The efficacy of subcutaneous Melagatran followed by oral ximelagatran has been investigated in four European trials and the efficacy of an all oral ximelagatran regimen has been investigated in five US trials. In a dose-ranging European study, preoperatively initiated subcutaneous Melagatran 3 mg twice daily followed by oral ximelagatran 24 mg twice daily was significantly more effective than subcutaneous dalteparin sodium 5000IU once daily in preventing the occurrence of VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients undergoing hip or knee replacement. In one study, there were no significant differences in VTE prevention between subcutaneous Melagatran 3 mg administered after surgery followed by ximelagatran 24 mg twice daily and enoxaparin sodium (enoxaparin) 40 mg once daily. Compared with enoxaparin, significantly lower rates of proximal DVT and/or PE (major VTE) and total VTE were observed when Melagatran was initiated preoperatively (2mg) then postoperatively (3mg) and followed by ximelagatran 24 mg twice daily. In the US, four studies showed that postoperatively initiated ximelagatran 24 mg twice daily was of similar efficacy to enoxaparin or warfarin in the prevention of VTE in patients undergoing hip or knee replacement. However, ximelagatran 36 mg twice daily was superior to warfarin (target international normalised ratio of 2.5) at preventing the incidence of VTE in patients undergoing total knee replacement in two studies.Ximelagatran alone or after Melagatran was generally well tolerated. Overall, the incidence of bleeding events and transfusion rates were not markedly different from those documented for comparator anticoagulants. In a post-hoc analysis of one study, transfusion rates were lower in ximelagatran than enoxaparin recipients. Conclusions: Oral ximelagatran alone or in conjunction with subcutaneous Melagatran has shown good efficacy and was generally well tolerated in the prevention of VTE in patients undergoing orthopaedic surgery. Furthermore, patients receiving ximelagatran/Melagatran do not require anticoagulant monitoring. The drug has a low potential for drug interactions and can be administered either by subcutaneous injection or orally. Thus, on the basis of available evidence, ximelagatran/Melagatran appears poised to play an important role in the prophylaxis of VTE in patients undergoing orthopaedic surgery.
Clinical experience of Melagatran/ximelagatran in major orthopaedic surgery
Thromb Res 2003 Jul 15;109 Suppl 1:S23-9.PMID:12818631DOI:10.1016/s0049-3848(03)00248-2.
The oral direct thrombin inhibitor (oral DTI) ximelagatran (Exanta, AstraZeneca) is rapidly absorbed and bioconverted to its active form Melagatran, which also can be administered subcutaneously (s.c.). Two large-scale clinical trials (Melagatran for THRombin inhibition in Orthopaedic surgery [METHRO] II and III) have evaluated the safety and efficacy of s.c. Melagatran followed by oral ximelagatran compared with low-molecular-weight heparins (LMWH) for thromboprophylaxis following total hip (THR) and total knee replacement (TKR) surgery. In METHRO II, patients received either 5000 IU s.c. dalteparin once daily (od) or a combination of one of four doses (from 1 to 3 mg) of s.c. Melagatran twice daily (bid) started immediately before surgery, followed by one of four doses (from 8 to 24 mg) of oral ximelagatran bid started 1-3 days after surgery. In METHRO III, patients were randomized to receive either 40 mg s.c. enoxaparin od or 3 mg s.c. Melagatran bid started 4-12 h after surgery followed by 24 mg oral ximelagatran. In METHRO II, there was a highly significant dose-response relationship for s.c. Melagatran plus oral ximelagatran, with the highest dose combination superior to dalteparin in the prevention of venous thromboembolism (VTE). In METHRO III, a dosing regimen in which s.c. Melagatran was started postoperatively and followed by oral ximelagatran was not more effective than enoxaparin started preoperatively. Thus, the time interval between surgery and the first dose of anticoagulant may be important in ensuring optimal efficacy. The METHRO II and III studies demonstrate that s.c. Melagatran combined with oral ximelagatran are well tolerated and effective for the prevention of VTE following major orthopaedic surgery.
Effects of Melagatran, a novel direct thrombin inhibitor, during experimental septic shock
Expert Opin Investig Drugs 2000 May;9(5):1129-37.PMID:11060733DOI:10.1517/13543784.9.5.1129.
Sepsis and endotoxaemia initiate the generation of thrombin, which is responsible for the conversion of fibrinogen to fibrin, platelet aggregation and acts as an inflammatory mediator affecting numerous types of cells, including myocardial, smooth muscle and endothelial cells. Human Gram-negative septic shock, frequently seen in intensive care units, is a condition with high mortality. This condition can be replicated in the endotoxaemic pig. As many of the toxic effects of sepsis are due to thrombin generation, it was of interest to study, using this porcine experimental septic shock model, whether inhibition of thrombin could alleviate the effects of endotoxaemia. For this purpose Melagatran, a direct synthetic thrombin inhibitor with a molecular weight of 429 Da, was employed. Melagatran does not significantly interact with any other enzymes in the coagulation cascade or fibrinolytic enzymes aside from thrombin. Furthermore, Melagatran does not require endogenous co-factors such as antithrombin or heparin co-Factor II for its antithrombin effect, which is important, as these inhibitors are often consumed in septic patients. We have shown that Melagatran exerts a beneficial effect on renal function, as evaluated by plasma creatinine and urinary output, during experimental septic shock. These effects were most pronounced during the later phase of the experimental period, after the infusion of Melagatran had been discontinued. Prevention of intrarenal coagulation may be attributable to this finding. In addition, Melagatran had beneficial effects on systemic haemodynamics (left ventricular stroke work index, pulmonary capillary wedge pressure and systemic vascular resistance index) in endotoxaemic pigs. This result may be explained by the ability of Melagatran to inhibit thrombin, thereby counteracting thrombin's cellular effects. Thus, it can be seen, using this experimental model of septic shock, that Melagatran may help to alleviate some of the damaging effects of endotoxaemia, although more research is required to test this further.
The direct thrombin inhibitor Melagatran/ximelagatran
Med J Aust 2004 Oct 18;181(8):432-7.PMID:15487959DOI:10.5694/j.1326-5377.2004.tb06367.x.
Melagatran is a synthetic, small-peptide direct thrombin inhibitor with anticoagulant activity. Ximelagatran, an oral prodrug, undergoes rapid enzymatic conversion to Melagatran. Melagatran has rapid onset of action, fixed twice-daily dosing, stable absorption, apparent low potential for medication interactions, and no requirement for monitoring drug levels or dose adjustment. There is no specific antidote, but the drug has a short plasma elimination half-life (about 4 hours). In clinical studies, Melagatran/ximelagatran is not inferior to warfarin for stroke prevention in patients with non-valvular atrial fibrillation, to heparin-warfarin for acute treatment and extended secondary prevention of deep vein thrombosis, and superior to warfarin for prevention of venous thromboembolism after major orthopaedic surgery. Major bleeding with Melagatran/ximelagatran occurred at rates similar to those in patients treated with warfarin. 6%-12% of patients taking ximelagatran develop asymptomatic elevated liver enzyme levels (predominantly alanine aminotransferase) after 1-6 months of therapy; this usually resolves with cessation of therapy. Less than 1% of patients develop abnormal liver function while taking ximelagatran; this rarely persists or develops into clinical illness.
Low potential for interactions between Melagatran/ximelagatran and other drugs, food, or alcohol
Semin Vasc Med 2005 Aug;5(3):254-8.PMID:16123912DOI:10.1055/s-2005-916164.
Vitamin K antagonists including warfarin are associated with numerous interactions with other drugs and foods. In clinical practice, this complicates the task of maintaining plasma levels of warfarin within a narrow therapeutic window and so maximizing protection against thromboembolic events while minimizing the risk of complications, particularly bleeding. In contrast, ximelagatran has a low potential for pharmacokinetic drug:drug and food interactions. There is no significant metabolism of Melagatran, and the main route of elimination of Melagatran is renal excretion that appears to occur via glomerular filtration. Most importantly, cytochrome P450 isoenzymes that mediate many drug:drug interactions are not involved in the biotransformation of ximelagatran to Melagatran. No significant pharmacokinetic interactions have been observed when oral ximelagatran is administered with a range of agents, including diclofenac, diazepam, nifedipine, digoxin, atorvastatin, or amiodarone. The low potential for drug:drug interactions with ximelagatran is also supported by an analysis of the pharmacokinetic data from clinical studies in patients with atrial fibrillation receiving long-term treatment with oral ximelagatran. Increases of mean Melagatran area under the curve and maximum plasma concentration ( Cmax) of up to approximately 80% have been observed when ximelagatran is co-administered with the macrolide antibiotics erythromycin or azithromycin, and the mechanism for this interaction is currently under investigation. The bioavailability of Melagatran is not altered by co-administration with food or alcohol. The melagatran-induced prolongation of activated partial thromboplastin time (APTT), an ex vivo coagulation time assay used as a measure of thrombin inhibition, is not altered by other drugs [including digoxin, atorvastatin, acetylsalicylic acid (ASA), and amiodarone], food, or alcohol. The effect of Melagatran on capillary bleeding time, which is prolonged as a result of the inhibition of thrombin-induced platelet aggregation, is relatively low and additive to the platelet-inhibitory effect of ASA.