5-lipoxygenase (5-LO)

当齐留通钠（A 64077 钠）添加到抗 CD3 处理的细胞中时，经过处理和未处理的细胞中的 IL-2 水平随着孵育时间的延长而下降。通过阻断 5-脂氧合酶，齐留通钠 (sodium A 64077) 可以通过阻止白三烯 B4（一种 IL-2 诱导剂）的合成来降低 IL-2 水平 [2]。

在 I/R 大鼠中，齐留通钠（钠 A 64077）（5 mg/kg，口服）降低 NF-κB 表达的作用不受 COX 抑制剂的显着影响。此外，该组的 NF-κB 染色水平明显较低。用齐留通（5 mg/kg，口服）治疗的 I/R 大鼠的细胞凋亡指数可以显着降低。对于 I/R 组血清 TNF-α 水平的升高，齐留通没有显示出明显的影响 [1]。在 APCΔ468 的结肠和小肠中，zileutonodium（A 64077 钠）（1200 mg/kg）抑制息肉的形成。在大鼠息肉中，齐留通治疗可增加非上皮细胞的凋亡率并降低其增殖率。用齐留通处理的小肠和结肠显示凋亡细胞数量显着增加。在齐留通喂养的 APCΔ468 小鼠中，增殖率降低可能在减少小肠和结肠息肉病方面发挥重要作用 [3]。

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I/R组左心室MDA含量高于假手术组；然而，与齐留通相比，没有显示出显著的变化。尽管I/R组的组织损伤在所有治疗组中都不那么严重，但没有统计学意义。与假I/R组相比，I/R组NF-κB H评分和凋亡指数较高，但应用齐留通后降低（H评分：p<0.01；凋亡指数：p<0.001）。Zileuton对I/R组血清TNF-α水平升高没有显著影响。 结论：5-LOX抑制大鼠心肌梗死模型可减轻左心室NF-κB表达和凋亡的增加，这些作用不受COX抑制剂的调节。[1]

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Zileuton喂养的小鼠出现的息肉较少，全身和息肉相关炎症明显减少。病变和全身的促炎细胞因子和促炎先天性和适应性免疫细胞均减少。作为肿瘤相关炎症的一部分，5-LO活性的产物白三烯B4（LTB4）在人类发育不良病变中局部增加。Zileuton治疗的息肉病小鼠血清中5-LO酶活性降低。 结论：本研究表明，在息肉病小鼠模型中，5-LO特异性抑制剂的饮食给药可降低息肉负担，并表明Zileuton可能是癌症高危患者的潜在化疗抑制剂[3]。

从11只4个月大的C57BL/6雌性小鼠中获得的脾细胞在没有和有10μg/mL HU或齐留通、2.5μg/mL刀豆球蛋白A（ConA）、20μg/mL植物血凝素（PHA）和50 ng/mL抗CD3抗体的情况下孵育12-48小时。通过酶联免疫吸附试验在上清液中测量IL-2，通过（3）h-胸苷摄取测量细胞增殖[2]。 结果：HU降低了淋巴细胞对丝裂原的增殖反应（P<0.05），而齐留通没有。两种药物均未对基线IL-2浓度和PHA诱导的IL-2产生显著影响。与我们的预期相反，在抗CD3抗体处理的细胞中，HU将IL-2上清液水平提高了1.17倍至6.5倍（P<0.05），而齐留通将其降低了35%-65%（P<0.05）。齐留通可能通过抑制5-脂氧合酶降低IL-2水平，从而抑制IL-2诱导剂白三烯B4的产生。HU没有减少IL-2的分泌，可能是因为它对mRNA和蛋白质合成没有影响。[2] 结论：齐留通调节IL-2分泌和/或HU减少淋巴细胞增殖可能会损害镰状细胞病患者的免疫反应，但也可能通过减轻炎症而有益于胎儿血红蛋白诱导[2]。

Male Wistar rats (200-250 g; n=12 per group) were used in the study. I/R was performed by occluding the left coronary artery for 30 minutes and 2 hours of reperfusion of the heart. Experimental groups were I/R group, sham I/R group, zileuton (5 mg/kg orally, twice daily)+I/R group, zileuton+indomethacin (5 mg/kg intraperitoneally)+I/R group, zileuton+ketorolac (10 mg/kg subcutaneously)+I/R group, and zileuton+nimesulide (5 mg/kg subcutaneously)+I/R group. Following I/R, blood samples were collected to measure tumor necrosis factor alpha (TNF-α), and left ventricles were excised for evaluation of microscopic damage; malondialdehyde (MDA), glutathione, nuclear factor (NF)-κB assays; and evaluation of apoptosis.[1]

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In the current study, we inhibited 5-LO by dietary administration of Zileuton in the APCΔ468 mouse model of polyposis and analyzed the effect of in vivo 5-LO inhibition on tumor-associated and systemic inflammation.[3]

[1]. Inhibition of 5-lipoxygenase by zileuton in a rat model of myocardial infarction. Anatol J Cardiol. 2016 Nov 10.

[2]. Hydroxyurea and Zileuton Differentially Modulate Cell Proliferation and Interleukin-2 Secretion by Murine Spleen Cells: Possible Implication on the Immune Function and Risk of Pain Crisis in Patients with Sickle Cell Disease. Ochsner.

[3]. Zileuton, 5-lipoxygenase inhibitor, acts as a chemopreventive agent in intestinal polyposis, by modulating polyp and systemic inflammation. PLoS One. 2015 Mar 6;10(3):e0121402.

Zileuton belongs to the 1-benzothiophene class of compounds, with its structure consisting of a hydrogen atom at the 2-position of the 1-benzothiophene molecule replaced by a 1-[carbamoyl(hydroxy)amino]ethyl group. It is a selective 5-lipoxygenase inhibitor that inhibits the production of leukotrienes LTB4, LTC4, LDT4, and LTE4. Zileuton is used to treat chronic asthma. It possesses various pharmacological activities, including as an EC 1.13.11.34 (arachidonic acid 5-lipoxygenase) inhibitor, a nonsteroidal anti-inflammatory drug, an anti-asthmatic drug, a leukotriene antagonist, and a ferroptosis inhibitor. It belongs to the urea and 1-benzothiophene classes of compounds. It is derived from the hydride of 1-benzothiophene. Leukotrienes are a class of substances that can induce a variety of biological effects, including enhancing the migration of neutrophils and eosinophils, promoting the aggregation of neutrophils and monocytes, enhancing leukocyte adhesion, increasing capillary permeability, and inducing smooth muscle contraction. These effects lead to airway inflammation, edema, mucus secretion, and bronchoconstriction in asthma patients. Zileuton alleviates these symptoms by selectively inhibiting 5-lipoxygenase (an enzyme that catalyzes the conversion of arachidonic acid into leukotrienes). Specifically, it inhibits the production of leukotrienes LTB4, LTC4, LTD4, and LTE4. Both R(+) and S(-) enantiomers exhibit pharmacological activity as 5-lipoxygenase inhibitors in in vitro systems. Zileuton immediate-release tablets have been withdrawn from the US market. Zileuton is a 5-lipoxygenase inhibitor. Its mechanism of action is the inhibition of 5-lipoxygenase. Its physiological effect is through reducing leukotriene production. Zileuton is an anti-inflammatory leukotriene pathway inhibitor, belonging to the 5-lipoxygenase inhibitor class, used to treat asthma and allergic rhinitis. Zileuton has been associated with rare cases of drug-induced liver disease and is therefore considered contraindicated in patients with active liver disease.

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Ziliutone is a synthetic derivative of hydroxyurea with anti-asthmatic properties. As a leukotriene inhibitor, ziliutone blocks 5-lipoxygenase (which catalyzes the formation of leukotrienes from arachidonic acid), thereby causing bronchodilation, reducing bronchial mucus secretion and edema, and may prevent or alleviate asthma symptoms. (NCI04)
Depending on state or federal labeling requirements, ziliutone may cause cancer, developmental toxicity, and female reproductive toxicity.

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Drug Indications
For the prevention and chronic treatment of asthma in adults and children aged 12 years and older.

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Pharmacodynamics
Ziliutone is an asthma medication with chemical and pharmacological properties that differ from other anti-asthma medications. It blocks leukotriene synthesis by inhibiting 5-lipoxygenase (an enzyme in the eicosate synthesis pathway). Current data indicate that asthma is a chronic inflammatory airway disease involving the production and activity of various endogenous inflammatory mediators, including leukotrienes. Thiopeptide leukotrienes (LTC4, LTD4, LTE4, also known as sustained-release substances of anaphylactic reactions) and LTB4 (a chemokine for neutrophils and eosinophils) are both derived from the initial unstable product of arachidonic acid metabolism, leukotriene A4 (LTA4), and can be detected in various biological fluids, including bronchoalveolar lavage fluid (BALF) from asthmatic patients. In humans, pretreatment with zileutone reduces bronchoconstriction induced by cold air provocation in asthmatic patients.

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Absorption
Absorption is rapid and almost complete. Absolute bioavailability is unknown.

Elimination pathway
Zileutone is primarily eliminated through metabolism, with a mean terminal half-life of 2.5 hours. The urinary excretion of both the inactive N-dehydroxylated metabolite and the unchanged zileuton is less than 0.5% of the administered dose.

Volume of distribution
1.2 L/kg

Clearance
Apparent oral clearance = 7 mL/min/kg

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Metabolites/Metabolites
Hepatic metabolism. Zileuton and its N-dehydroxylated metabolite are oxidatively metabolized by cytochrome P450 isoenzymes 1A2, 2C9, and 3A4.

Known human metabolites of zileuton include zileuton O-glucuronide.
S73 | METXBIODB | Metabolite Response Database from BioTransformer | DOI:10.5281/zenodo.4056560

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Biological Half-Life
2.5 hours

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Mechanism of Action
Leukotrienes are a class of substances that can induce a variety of biological effects, including enhancing neutrophil and eosinophil migration, promoting neutrophil and monocyte aggregation, enhancing leukocyte adhesion, increasing capillary permeability, and causing smooth muscle contraction. These effects lead to airway inflammation, edema, mucus secretion, and bronchoconstriction in asthmatic patients. Ziliutone alleviates these symptoms by selectively inhibiting 5-lipoxygenase (an enzyme that catalyzes the conversion of arachidonic acid into leukotrienes). Specifically, it inhibits the production of leukotrienes LTB4, LTC4, LTD4, and LTE4. Both R(+) and S(-) enantiomers exhibit pharmacological activity as 5-lipoxygenase inhibitors in in vitro systems. Since leukotrienes play a role in the pathogenesis of asthma, regulating leukotriene production by blocking 5-lipoxygenase activity may alleviate airway symptoms, reduce bronchial smooth muscle tone, and improve asthma control.

C11H11N2O2S-.NA+

258.272

258.044

118569-21-4

Zileuton;111406-87-2;Zileuton-d4;1189878-76-9

78357785

White to off-white solid powder

3.541

97.63

1

3

2

17

280

0

USURPRPAYRQEOV-UHFFFAOYSA-N

InChI=1S/C11H11N2O2S.Na/c1-7(13(15)11(12)14)10-6-8-4-2-3-5-9(8)16-10;/h2-7H,1H3,(H2,12,14);/q-1;+1

sodium;1-[1-(1-benzothiophen-2-yl)ethyl]-1-oxidourea

Zileuton (sodium); 118569-21-4; sodium;1-[1-(1-benzothiophen-2-yl)ethyl]-1-oxidourea; Zileutonsodium; A 64077 (sodium);

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。

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

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

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！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。