替罗非班（0.25、1、3 μg/mL；72 小时）可增加 HAEC 细胞的增殖 [1]。 HUVEC 迁移划痕通过替罗非班（24 小时）在 18 小时内闭合[1]。 30 分钟后，替罗非班（0.25，1 μg/mL；1 小时）增加内皮细胞增殖并导致 VEGF 的产生 [1]。

通过提高 HR、LVESP、dp/dtmax 和降低 LVEDP，替罗非班（60 μg/kg；静脉注射；一次）表现出增强收缩力、心室顺应性和心脏功能的活性 [2]。替罗非班（60 μg/kg；静脉注射；一次）可减少急性心肌梗死后再灌注后的无复流区，并增加 eNOS 活性 [2]。在挤压模型中，替罗非班（50 μg/次；冲洗；单剂量）显示出抗凝作用，微血管吻合术后 24 小时通畅率为 59% [3]。

细胞增殖测定[1]
细胞类型： HAEC 细胞
测试浓度： 0.25、1、3 μg/mL
孵育时间：72小时
实验结果：HAEC细胞增殖增加。

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细胞迁移测定 [1]
细胞类型： HUVEC 细胞
测试浓度：
孵育持续时间：24小时
实验结果：刺激内皮细胞的迁移能力。

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蛋白质印迹分析[1]
细胞类型： HAEC 细胞
测试浓度： 0.05、0.12、0.25、1 μg/mL
孵育时间：1小时
实验结果：诱导产生VEGF，刺激内皮细胞增殖。

Animal/Disease Models: Male SD (Sprague-Dawley) rats (10 to 15-week-age; 270-330 g)[2].
Doses: 60 μg/kg
Route of Administration: intravenous (iv) injection; once.
Experimental Results: Increased contraction force, ventricular compliance, and improved heart function. decreased the size of no-reflow and infarct.

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Animal/Disease Models: SD (Sprague-Dawley) rats (350-400 g; crush injury model)[3]
Doses: 50 µg/per (50 µg/mL, 1 mL for each)
Route of Administration: Irrigate 1 mL within the vessel lumen (before placement of the last suture); once.
Experimental Results: demonstrated anticoagulant effect with patency rates of 59%.

Absorption, Distribution and Excretion
It is cleared from the plasma largely by renal excretion, with about 65% of an administered dose appearing in urine and about 25% in feces, both largely as unchanged tirofiban.
22 to 42 L
213 - 314 mL/min [Healthy subjects]
152 - 267 mL/min [patients with coronary artery disease]
Not highly bound to plasma proteins; protein binding is concentration-independent over the range of 0.01 to 25 ug/mL. Unbound fraction in human plasma is 35%.
Tirofiban is approximately 65% bound to plasma proteins ... The steady-state volume of distribution of tirofiban ranges from 22-42 L. It is not known whether tirofiban is distributed into milk or crosses the placenta in humans; however, the drug is distributed into milk in rats and crosses the placenta in pregnant rats and rabbits.
About 65 and 25% of a single dose of tirofiban is excreted in urine and feces, respectively, principally as unchanged parent drug. Plasma clearance of tirofiban in healthy individuals ranges from 213-314 mL/minute, with renal clearance accounting for 39-69% of plasma clearance. In patients with coronary artery disease, the plasma clearance of tirofiban ranges from 152-267 mL/minute and does not appear to be influenced by gender or race; renal clearance in these patients accounts for 39% of plasma clearance. Plasma clearance is about 19-26% lower in geriatric patients (those exceeding 65 years of age) with coronary artery disease than in younger patients. Plasma clearance appears to be independent of dose in healthy individuals and is not appreciably affected by mild to moderate hepatic insufficiency. In patients with renal impairment (creatinine clearance less than 30 mL per minute), including those requiring hemodialysis, plasma clearance of tirofiban is decreased by greater than 50% compared with that in individuals with normal renal function. Tirofiban is removed by hemodialysis.

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Metabolism / Metabolites
Metabolism appears to be limited.
Metabolism appears to be limited.

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Biological Half-Life
2 hours
Elimination: Approximately 2 hours.

Protein Binding
65%

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Interactions
Concurrent use /with other platelet aggregation inhibitors (especially inhibitors of platelet receptor GP IIb/IIIa) is not recommended.
Data from a large clinical study indicate that concomitant administration of tirofiban and levothyroxine or omeprazole was associated with a higher clearance of tirofiban; the clinical importance of this effect is not known.

[1]. Tirofiban induces VEGF production and stimulates migration and proliferation of endothelial cells. Vascul Pharmacol. 2014 May-Jun;61(2-3):63-71.

[2]. Effects of tirofiban on the reperfusion-related no-reflow in rats with acute myocardial infarction. J Geriatr Cardiol. 2013 Mar;10(1):52-8.

[3]. The effect of tirofiban on microvascular thrombosis: crush model. Plast Reconstr Surg. 2005 Jul;116(1):205-8.

Tirofiban is a member of the class of piperidines that is L-tyrosine in which a hydrogen attached to the amino group is replaced by a butylsulfonyl group and in which the hydrogen attached to the phenolic hydroxy group is replaced by a 4-(piperidin-4-yl)butyl group. It has a role as a fibrin modulating drug, a platelet glycoprotein-IIb/IIIa receptor antagonist and an anticoagulant. It is a member of piperidines, a sulfonamide and a L-tyrosine derivative.
Tirofiban prevents the blood from clotting during episodes of chest pain or a heart attack, or while the patient is undergoing a procedure to treat a blocked coronary artery. It is a non-peptide reversible antagonist of the platelet glycoprotein (GP) IIb/IIIa receptor, and inhibits platelet aggregation.
Tirofiban is a Platelet Aggregation Inhibitor. The physiologic effect of tirofiban is by means of Decreased Platelet Aggregation.
Tirofiban is a non-peptide tyrosine derivative, with anticoagulant activity. Upon administration, tirofiban antagonizes fibrinogen binding to the platelet cell surface receptor, glycoprotein (GP) IIb/IIIA complex, one of the two purinergic receptors activated by ADP. This prevents the GP IIb/IIIa receptor complex-mediated activation of adenylyl cyclase. This results in decreased levels of cAMP, interferes with the platelet membrane function and subsequent platelet-platelet interaction, prevents the release of platelet granule constituents and prolongs bleeding time.
Tyrosine analog and PLATELET GLYCOPROTEIN GPIIB-IIIA COMPLEX antagonist that inhibits PLATELET AGGREGATION and is used in the treatment of ACUTE CORONARY SYNDROME.
See also: Tirofiban Hydrochloride (has salt form).

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Drug Indication
For treatment, in combination with heparin, of acute coronary syndrome, including patients who are to be managed medically and those undergoing PTCA or atherectomy.
FDA Label

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Mechanism of Action
Tirofiban is a reversible antagonist of fibrinogen binding to the GP IIb/IIIa receptor, the major platelet surface receptor involved in platelet aggregation. Platelet aggregation inhibition is reversible following cessation of the infusion of tirofiban.
Tirofiban inhibits platelet aggregation by reversibly binding to the platelet receptor glycoprotein (GP) IIb/IIIa of human platelets, thus preventing the binding of fibrinogen. Inhibition of platelet aggregation occurs in a dose- and concentration-dependent manner.

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Therapeutic Uses
Antithrombotic; in treatment of unstable angina.
Tirofiban is indicated, in combination with heparin, for the prevention of acute cardiac ischemic complications in patients with acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction). these patients are at high risk for myocardial infarction and sudden death due to progression of total coronary artery occlusion, whether managed medically or with percutaneous coronary intervention (PCI). Note: Acute coronary syndrome is defined as prolonged (>/= 10 minutes) or repetitive symptoms of cardiac ischemia occurring at rest or with minimal exertion, associated with either ST-T wave changes on electrocardiogram or elevated cardiac enzymes. This definition includes unstable angina and non-Q-wave myocardial infarction but excludes myocardial infarction that is associated with Q waves or nontransient ST-segment elevation. /Included in US product labeling/

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Drug Warnings
Adverse cardiovascular effects that occurred in greater than 1% of patients receiving tirofiban plus heparin in clinical trials were bradycardia (4%) or dissection of the coronary artery (5%). Edema/swelling or vasovagal reactions were reported in 2% of patients receiving tirofiban and heparin in these trials.
Sweating was reported in 2% of patients receiving tirofiban and heparin in controlled clinical trials. Anaphylaxis and/or urticaria requiring discontinuance of therapy was not reported in clinical trials of tirofiban, but anaphylaxis and other severe allergic reactions have been reported during postmarketing experience. Such reactions have occurred on the first day of tirofiban infusion, during initial treatment, and during readministration of the drug. Some severe allergic reactions have been associated with severe thrombocytopenia (platelet counts less than 10,000/cu mm).
Pelvic pain occurred in 6%, leg pain in 3%, and dizziness in 3% of patients receiving tirofiban plus heparin in clinical trials. Other adverse effects reported in greater than 1% of patients receiving tirofiban plus heparin in clinical trials include headache, nausea, and fever.
The administration of tirofiban in patients with acute unstable angina or non-ST-segment elevation myocardial infarction has been associated with a small increase in the frequency of major bleeding compared with heparin and aspirin therapy alone.
For more Drug Warnings (Complete) data for TIROFIBAN (11 total), please visit the HSDB record page.

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Pharmacodynamics
Tirofiban prevents the blood from clotting during episodes of chest pain or a heart attack, or while the patient is undergoing a procedure to treat a blocked coronary artery. It is a non-peptide antagonist of the platelet glycoprotein (GP) IIb/IIIa receptor, and inhibits platelet aggregation. When administered intravenously, tirofiban inhibits ex vivo platelet aggregation in a dose- and concentration-dependent manner. When given according to the recommended regimen, >90% inhibition is attained by the end of the 30-minute infusion. Tirofiban has been recently shown in patients with unstable angina to reduce ischemic events at 48 hours following infusion when compared to standard heparin therapy.

C22H36N2O5S

440.6

440.234

144494-65-5

Tirofiban hydrochloride monohydrate;150915-40-5;Tirofiban hydrochloride;142373-60-2;Tirofiban-d9;1332075-40-7

60947

White to off-white solid powder

1.2±0.1 g/cm3

611.7±65.0 °C at 760 mmHg

223-225ºC

323.7±34.3 °C

0.0±1.8 mmHg at 25°C

1.532

4.14

113.11

3

7

14

30

579

1

CCCCS(=O)(=O)N[C@@H](CC1=CC=C(C=C1)OCCCCC2CCNCC2)C(=O)O

COKMIXFXJJXBQG-NRFANRHFSA-N

InChI=1S/C22H36N2O5S/c1-2-3-16-30(27,28)24-21(22(25)26)17-19-7-9-20(10-8-19)29-15-5-4-6-18-11-13-23-14-12-18/h7-10,18,21,23-24H,2-6,11-17H2,1H3,(H,25,26)/t21-/m0/s1

(2S)-2-(butylsulfonylamino)-3-[4-(4-piperidin-4-ylbutoxy)phenyl]propanoic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
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