Human neutrophil elastase (IC50 = 44 nM; Ki=200 nM)

即使浓度为 100 μM，西维来司他 (ONO-5046) 也不会抑制胰凝乳蛋白酶、组织蛋白酶 G、胰激肽释放酶、凝血酶、纤溶酶、血浆激肽释放酶或血浆激肽释放酶[1]。 Sivelestat (ONO-5046) 对人、兔、大鼠、仓鼠和小鼠中性粒细胞弹性蛋白酶的 IC50 值分别为 44 nM、36 nM、19 nM、37 nM 和 49 nM[1]。

当sivelestat（ONO-5046，0.021-2.1 mg/kg）时，人中性粒细胞弹性蛋白酶可抑制仓鼠肺出血（ID50 = 82 pg/kg），并增加豚鼠皮肤毛细血管通透性（ID50 = 9.6 mg/kg）。 kg，气管内）静脉内给药[1]。在大鼠中，通过尾静脉输注西维来司他 (10 mg/kg) 可减少失血性休克后的肺损伤[2]。在大鼠膀胱中，伊来司他（15、60 mg/kg，腹腔注射）可预防缺血再灌注损伤[3]。

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失血性休克后复苏（HSR）引起肺中性粒细胞隔离，导致急性肺损伤（ALI）。中性粒细胞弹性蛋白酶（NE）被认为在ALI的发病机制中起关键作用。本研究探讨特异性NE抑制剂西维司他是否能减轻HSR所致大鼠ALI。雄性Sprague-Dawley大鼠通过抽血使失血性休克维持平均动脉血压30+/-5 mm Hg 60 min，然后用流出的血复苏。hsr治疗的动物在复苏开始时静脉注射西司他（10 mg/kg），随后在复苏阶段或载药中连续注射60分钟（10 mg/kg/h）。通过肺组织学、肺干重比（W/D）、髓过氧化物酶（MPO）活性、肿瘤坏死因子(TNF)- α和诱导型一氧化氮合酶（iNOS）基因表达、核因子(NF)-kappaB DNA结合活性、细胞间粘附分子(ICAM)-1免疫组化分析评估肺损伤。HSR治疗引起肺损伤，表现为肺水肿伴中性粒细胞浸润，肺W/D比、MPO活性、tnf - α和iNOS基因表达、NF-kappaB dna结合活性升高，ICAM-1表达增强。相比之下，西司他治疗显著改善了hsr诱导的肺损伤，从所有这些指标的显着改善来判断。这些结果表明，除了对NE的直接抑制作用外，西司他至少在一定程度上通过抑制炎症信号通路来减轻hsr诱导的肺损伤。[2]

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本研究探讨了中性粒细胞弹性酶抑制剂西维司他钠对大鼠膀胱缺血再灌注损伤的影响。用小夹子夹住大鼠腹主动脉，诱导膀胱缺血再灌注损伤。8周龄雄性大鼠分为4组；假手术对照大鼠、30 min缺血-60 min再灌注（IR）大鼠和15、60 mg/kg西司他钠处理的IR大鼠。缺血诱导前60分钟，腹腔注射西司他钠。采用激光多普勒流量计和NO选择电极同时实时监测大鼠血流和一氧化氮（NO）释放。测定大鼠膀胱中NO2-NO3和丙二醛（MDA）的浓度。夹紧腹主动脉，血流量迅速减少，一氧化氮释放量逐渐增加。取下夹子后，血流量迅速增加，一氧化氮释放逐渐恢复到基础水平。这些血流运动和一氧化氮释放被西司他钠水合物以剂量依赖的方式抑制。IR诱导膀胱NO2-NO3和MDA浓度升高，高剂量西司他钠处理膀胱NO2-NO3和MDA浓度显著降低。我们的数据表明，西司他钠可以抑制IR引起的NO2-NO3和MDA浓度的升高，对大鼠膀胱IR损伤具有潜在的保护作用。［３］

ONO-5046，N-[2-[4-（2,2-二甲基丙酰氧基）苯磺酰氨基]氨基乙酸，竞争性抑制人中性粒细胞弹性蛋白酶（IC50=0.044微M，Ki=0.2微M）。它还抑制了从兔、大鼠、仓鼠和小鼠中获得的白细胞弹性蛋白酶。然而，ONO-5046即使在100微摩尔下也不会抑制胰蛋白酶、凝血酶、纤溶酶、血浆激肽释放酶、胰腺激肽释放蛋白酶、胰凝乳蛋白酶和组织蛋白酶G[1]。

Animal/Disease Models: Male Golden hamsters, weighing 90 to 110 g[1].
Doses: 0.021-2.1 mg/kg.
Route of Administration: Intratracheally five min before HNE injection.
Experimental Results: Dramatically and dosedependently suppressed the lung hemorrhage.

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Animal/Disease Models: Male SD (Sprague-Dawley) rats weighing 350-400 g[2].
Doses: 10 mg/kg.
Route of Administration: Continuous infusion via the tail vein at 10 mg/kg/h for 60 min during the resuscitation phase.
Experimental Results: Greatly suppressed lung injury, as revealed by the decreased histological damage. Dramatically ameliorated HSR-induced lung injury. Markedly diminished the levels of TNF-α and iNOS gene.

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Animal/Disease Models: Male Sprague Dawley rats, 8 weeks old and weighing 250-320 g[3].
Doses: 15 mg/kg or 60 mg/kg.
Route of Administration: IP.
Experimental Results: diminished the blood flow in the bladder during reperfusion phase compared to the IR group.

[1]. ONO-5046, a novel inhibitor of human neutrophil elastase. Biochem Biophys Res Commun. 1991 Jun 14;177(2):814-20.

[2]. A neutrophil elastase inhibitor, sivelestat, ameliorates lung injury after hemorrhagic shock in rats. Int J Mol Med. 2007 Feb;19(2):237-43.

[3]. Neutrophil elastase inhibitor, sivelestat sodium hydrate prevents ischemia-reperfusion injury in the rat bladder. Mol Cell Biochem. 2008 Apr;311(1-2):87-92.

[4]. Neutrophil elastase inhibitor (sivelestat) may be a promising therapeutic option for management of acute lung injury/acute respiratory distress syndrome or disseminated intravascular coagulation in COVID-19. J Clin Pharm Ther. 2020 Dec;45(6):1515-1519.

ONO-5046, N-[2-[4-(2,2-Dimethylpropionyloxy)phenylsulfonylamino] aminoacetic acid, competitively inhibited human neutrophil elastase (IC50 = 0.044 microM, Ki = 0.2 microM). It also inhibited leukocyte elastase obtained from rabbit, rat, hamster and mouse. However, ONO-5046 did not inhibit trypsin, thrombin, plasmin, plasma kallikrein, pancreas kallikrein, chymotrypsin and cathepsin G even at 100 microM. In in vivo studies, ONO-5046 suppressed lung hemorrhage in hamster (ID50 = 82 micrograms/kg) by intratracheal administration and increase of skin capillary permeability in guinea pig (ID50 = 9.6 mg/kg) by intravenous administration, both of which were induced by human neutrophil elastase.[1]

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What is known and objective: This article summarizes the effects of sivelestat on acute lung injury/acute respiratory distress syndrome (ALI/ARDS) or ARDS with coagulopathy, both of which are frequently seen in patients with COVID-19. Comment: COVID-19 patients are more susceptible to thromboembolic events, including disseminated intravascular coagulation (DIC). Various studies have emphasized the role of neutrophil elastase (NE) in the development of DIC in patients with ARDS and sepsis. It has been shown that NE inhibition by sivelestat mitigates ALI through amelioration of injuries in alveolar epithelium and vascular endothelium, as well as reversing the neutrophil-mediated increased vascular permeability. What is new and conclusions: Sivelestat, a selective NE inhibitor, has not been evaluated for its possible therapeutic effects against SARS-CoV-2 infection. Based on its promising beneficial effects in underlying complications of COVID-19, sivelestat could be considered as a promising modality for better management of COVID-19-induced ALI/ARDS or coagulopathy. Keywords: COVID-19; acute lung injury/acute respiratory distress syndrome; coagulopathy; neutrophil elastase inhibitor; sivelestat.[4]

C₂₀H₂₁N₂NAO₇S

456.44

456.096

C, 52.63; H, 4.64; N, 6.14; Na, 5.04; O, 24.54; S, 7.02

150374-95-1

Sivelestat;127373-66-4;Sivelestat sodium tetrahydrate;201677-61-4

23664980

Typically exists as white to off-white solids at room temperature

2.463

150.08

2

8

9

31

738

0

[O-]C(CNC(C1=CC=CC=C1NS(C2=CC=C(OC(C(C)(C)C)=O)C=C2)(=O)=O)=O)=O.[Na+]

ZAIFANJZUGNYCK-UHFFFAOYSA-M

InChI=1S/C20H22N2O7S.Na/c1-20(2,3)19(26)29-13-8-10-14(11-9-13)30(27,28)22-16-7-5-4-6-15(16)18(25)21-12-17(23)24;/h4-11,22H,12H2,1-3H3,(H,21,25)(H,23,24);/q;+1/p-1

sodium;2-[[2-[[4-(2,2-dimethylpropanoyloxy)phenyl]sulfonylamino]benzoyl]amino]acetate

Sivelestat sodium, ONO5046-Na, Sodium sivelestat, EI546 sodium, LY544349 sodium; ONO5046, LY544349, EI546; ONO 5046; ONO5046; ONO-5046; LY544349; LY-544349; Sivelestat sodium; 150374-95-1; Sivelestat sodium salt; Sivelestat sodium anhydrous; Sivelestat (sodium); Sivelestat sodium salt hydrate; sodium;2-[[2-[[4-(2,2-dimethylpropanoyloxy)phenyl]sulfonylamino]benzoyl]amino]acetate; 0CLL4232KD; LY 544349; EI 546 sodium salt hydrate, Elaspol sodium salt hydrate, LY 544349 sodium salt hydrate, Trade name: Elaspol.

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)

配方 1 中的溶解度: ≥ 2.5 mg/mL (5.48 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (5.48 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (5.48 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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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。