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| 靶点 |
Histamine receptor
Histamine H1 receptor (H1R) (human H1R, Ki=0.6 nM; rat H1R, Ki=0.8 nM) [1] Histamine H2 receptor (H2R), muscarinic receptors, adrenergic receptors (Ki>1000 nM, negligible affinity) [1] |
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| 体外研究 (In Vitro) |
在豚鼠回肠的受体结合研究中，依匹斯汀显示出与 H1 受体的高亲和力。 Epinastine 能够在低浓度下取代蝗虫神经组织中的特异性 [3H]NC-5Z 结合。 Epinastine 与蜜蜂神经元章鱼胺受体结合，Ki 为 1.1 nM。 Epinastine 拮抗昆虫大脑中章鱼胺诱导的 cAMP 形成。 Epinastine 可抑制由抗原抗体反应和化合物 48/80 诱导的大鼠腹膜肥大细胞释放组胺。 Epinastine 同样有效地抑制化合物 48/80 诱导的组胺释放，不仅从分离的大鼠腹膜肥大细胞中释放，而且从大鼠肠系膜碎片中释放。 Epinastine 不仅能有效抑制主动致敏豚鼠肺肥大细胞中 Ca2+ 的摄取，还能有效抑制暴露于化合物 48/80 和 P 物质的大鼠腹膜肥大细胞的细胞内 Ca2+ 释放 Ca2+。 Epinastine 显示剂量和时间对IL-8的依赖性抑制作用，IL-8是嗜酸性粒细胞的趋化因子之一，从特应性疾病分离的嗜酸性粒细胞中释放。
放射性配体结合实验显示，盐酸依匹斯汀（Epinastine HCl; WAL801）以高亲和力竞争性结合人及大鼠H1R，浓度依赖性置换[3H]-美吡拉敏[1] - 组胺（1 μM）预收缩的分离豚鼠气管平滑肌条经盐酸依匹斯汀（Epinastine HCl; WAL801）（0.1 μM-10 μM）处理后，药物呈浓度依赖性舒张平滑肌，IC50=1.1 μM，证实其H1R拮抗活性[2] - 抗IgE（1 μg/mL）刺激的人外周血嗜碱性粒细胞经盐酸依匹斯汀（Epinastine HCl; WAL801）（1 nM-10 μM）处理后，药物剂量依赖性抑制组胺释放，10 μM时最大抑制率达68%[3] - 化合物48/80（1 μg/mL）激活的培养大鼠腹腔肥大细胞经盐酸依匹斯汀（Epinastine HCl; WAL801）（0.5 μM-50 μM）处理后，50 μM浓度时抑制肥大细胞脱颗粒及组胺释放达55%，且不影响细胞活力[3] |
| 体内研究 (In Vivo) |
Epinastine 可抑制组胺引起的大鼠、狗和豚鼠皮肤或肺部反应。
大鼠被动皮肤过敏反应（PCA）模型：背部皮内注射抗卵清蛋白IgE（0.1 mL）的大鼠，48小时后口服灌胃盐酸依匹斯汀（Epinastine HCl; WAL801）（0.3 mg/kg、1 mg/kg、3 mg/kg），1小时后静脉注射卵清蛋白（1 mg/kg）+伊文思蓝（5 mg/kg）。30分钟后处死大鼠，测量皮肤风团面积，药物呈剂量依赖性抑制风团形成，3 mg/kg时抑制率达83%[1] - 豚鼠过敏性鼻炎模型：第0天和第7天腹腔注射卵清蛋白（100 μg）+氢氧化铝（2 mg）致敏豚鼠，第14天鼻内给予卵清蛋白（1%溶液）攻击前30分钟，腹腔注射盐酸依匹斯汀（Epinastine HCl; WAL801）（1 mg/kg）。记录攻击后10分钟内的喷嚏次数和鼻分泌物量，药物使喷嚏次数减少65%，鼻分泌物减少58%[2] - 小鼠急性荨麻疹模型：静脉注射盐酸依匹斯汀（Epinastine HCl; WAL801）（0.5 mg/kg、1 mg/kg）或生理盐水的小鼠，30分钟后耳皮内注射组胺（10 μg）。2小时后测量耳厚度评估水肿程度，药物分别抑制水肿42%和67%[1] |
| 酶活实验 |
H1R结合实验：从表达人H1R的HEK293细胞或大鼠脑组织制备膜组分，将膜样品与[3H]-美吡拉敏（0.5 nM）及不同浓度的盐酸依匹斯汀（Epinastine HCl; WAL801）（0.01 nM-100 nM）在25°C孵育60分钟。通过真空过滤玻璃纤维滤膜分离结合态和游离态配体，用液体闪烁计数器测量放射性，采用Cheng-Prusoff方程计算Ki值[1]
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| 细胞实验 |
嗜碱性粒细胞组胺释放实验：密度梯度离心法分离人外周血嗜碱性粒细胞，用缓冲液重悬后，加入盐酸依匹斯汀（Epinastine HCl; WAL801）（1 nM-10 μM）预处理30分钟，再用抗IgE（1 μg/mL）在37°C刺激60分钟。离心收集上清液，荧光法检测组胺浓度[3]
- 肥大细胞脱颗粒实验：腹腔灌洗法分离大鼠腹腔肥大细胞，用培养基重悬后，加入盐酸依匹斯汀（Epinastine HCl; WAL801）（0.5 μM-50 μM）预处理15分钟，再用化合物48/80（1 μg/mL）刺激30分钟。离心收集上清液，比色法检测组胺水平[3] - 气管平滑肌舒张实验：分离豚鼠气管条，置于含氧合Krebs-Ringer溶液（37°C，95% O2/5% CO2）的器官浴中平衡60分钟，用组胺（1 μM）预收缩后，累积加入盐酸依匹斯汀（Epinastine HCl; WAL801）（0.1 μM-10 μM），记录张力变化[2] |
| 动物实验 |
PCA rat model: Male Wistar rats (150-200 g) were intradermally injected with anti-ovalbumin IgE (0.1 mL) on the back. After 48 hours, Epinastine HCl (WAL801) was dissolved in physiological saline and administered via oral gavage (0.3 mg/kg, 1 mg/kg, 3 mg/kg). One hour later, intravenous injection of ovalbumin (1 mg/kg) + Evans blue (5 mg/kg) was given. Thirty minutes later, rats were euthanized, and skin wheal area was measured [1]
- Allergic rhinitis guinea pig model: Male Hartley guinea pigs (300-350 g) were sensitized with ovalbumin (100 μg) + aluminum hydroxide (2 mg) via intraperitoneal injection on days 0 and 7. On day 14, Epinastine HCl (WAL801) (1 mg/kg) was injected intraperitoneally 30 minutes before intranasal ovalbumin challenge (1% solution). Record sneezing frequency and nasal secretion volume for 10 minutes post-challenge [2] - Acute urticaria mouse model: Male ICR mice (20-25 g) were intravenously injected with Epinastine HCl (WAL801) (0.5 mg/kg, 1 mg/kg) or physiological saline. Thirty minutes later, histamine (10 μg) was injected intradermally into the ear. Two hours later, measure ear thickness to evaluate edema severity [1] - Pharmacokinetic rat experiment: Male Sprague-Dawley rats (200-250 g) were fasted for 12 hours. Epinastine HCl (WAL801) was administered via oral gavage (10 mg/kg) or intravenous injection (2 mg/kg). Blood samples were collected at predetermined time points, and plasma drug concentrations were determined by HPLC [1] |
| 药代性质 (ADME/PK) |
Absorption: The oral bioavailability in rats is 65-75%; peak plasma concentration (Cmax) is reached 1.5-2.5 hours after oral administration [1]
- Distribution: The volume of distribution (Vd) in rats is 10-12 L/kg; the brain/plasma concentration ratio is 0.08, indicating extremely low blood-brain barrier penetration [1] - Metabolism: Very little is metabolized in the liver (≤15% of the dose), and most (85%) is excreted unchanged [1] - Excretion: 60% of the dose is excreted in the urine (55% unchanged, 5% metabolites), and 35% is excreted in the feces. The elimination half-life (t1/2) in rats is 7-9 hours [1] |
| 毒性/毒理 (Toxicokinetics/TK) |
Plasma protein binding rate: The plasma protein binding rate of Epinastine HCl (WAL801) in human plasma is 88-92%, and the plasma protein binding rate in rat plasma is 85-90%[1]. Acute toxicity: The LD50 of rats is >2000 mg/kg (oral) and 1500 mg/kg (intraperitoneal injection); the LD50 of mice is >1800 mg/kg (oral)[1]. Chronic toxicity: No obvious hepatotoxicity or hematological abnormalities were observed in rats after oral administration of Epinastine HCl (WAL801) (100 mg/kg/day) for 6 consecutive months[1]. Clinical side effects: Mild headache (3-5% of patients) and dry mouth (1-2%) have been reported. Due to the extremely low blood-brain barrier penetration, no sedative effect or cognitive impairment was observed at therapeutic doses[1,2].
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| 参考文献 | |
| 其他信息 |
Epinastine hydrochloride is a histamine H1 receptor antagonist and has no sedative effect. Epinastine hydrochloride blocks histamine H1 receptors, inhibiting histamine release from mast cells. This prevents typical allergic reactions caused by histamine acting on capillary, skin, mucous membranes, and gastrointestinal and bronchial smooth muscle. Typical effects of histamine include vasodilation, bronchoconstriction, increased vascular permeability, pain, itching, and spasmodic contractions of gastrointestinal smooth muscle. Epinastine also has affinity for histamine H2, 5-HT2, and α1 and α2 adrenergic receptors.
See also: Epinastine (containing the active fraction). Epistine hydrochloride (WAL801) is a second-generation non-sedating histamine H1 receptor antagonist with a dual mechanism of action: competitive blocking of H1R and inhibition of histamine release from mast cells/basophils [1,3]. It is indicated for the treatment of allergic rhinitis (relieving sneezing, runny nose, and nasal itching) and chronic idiopathic urticaria (relieving wheals and itching) [1,2]. Compared to first-generation antihistamines, it has high selectivity for H1R and very low blood-brain barrier penetration, thus avoiding sedative side effects [1]. It has a rapid onset of action (within 1 hour of administration) and a long duration of action (12-24 hours), supporting once- or twice-daily administration [1]. |
| 分子式 |
C16H16CLN3
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| 分子量 |
285.77
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| 精确质量 |
285.103
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| 元素分析 |
C, 67.25; H, 5.64; Cl, 12.41; N, 14.70
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| CAS号 |
108929-04-0
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| 相关CAS号 |
Epinastine; 80012-43-7
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| PubChem CID |
157313
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| 外观&性状 |
White to off-white solid powder
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| 密度 |
1.32g/cm3
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| 沸点 |
428ºC at 760 mmHg
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| 熔点 |
>270ºC
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| 闪点 |
212.7ºC
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| 蒸汽压 |
1.56E-07mmHg at 25°C
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| LogP |
3.469
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| tPSA |
41.62
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| 氢键供体(HBD)数目 |
2
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| 氢键受体(HBA)数目 |
1
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| 可旋转键数目(RBC) |
0
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| 重原子数目 |
20
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| 分子复杂度/Complexity |
378
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| 定义原子立体中心数目 |
0
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| SMILES |
Cl[H].N12C(N([H])[H])=NC([H])([H])C1([H])C1=C([H])C([H])=C([H])C([H])=C1C([H])([H])C1=C([H])C([H])=C([H])C([H])=C21
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| InChi Key |
VKXSGUIOOQPGAF-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C16H15N3.ClH/c17-16-18-10-15-13-7-3-1-5-11(13)9-12-6-2-4-8-14(12)19(15)16;/h1-8,15H,9-10H2,(H2,17,18);1H
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| 化学名 |
2,4-diazatetracyclo[12.4.0.02,6.07,12]octadeca-1(18),3,7,9,11,14,16-heptaen-3-amine;hydrochloride
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| 别名 |
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| HS Tariff Code |
2934.99.9001
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| 存储方式 |
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。 |
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| 运输条件 |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| 溶解度 (体外实验) |
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| 溶解度 (体内实验) |
配方 1 中的溶解度: ≥ 2.08 mg/mL (7.28 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 20.8 mg/mL澄清DMSO储备液加入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。 配方 2 中的溶解度: ≥ 2.08 mg/mL (7.28 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 20.8 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。 View More
配方 3 中的溶解度: ≥ 2.08 mg/mL (7.28 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。 配方 4 中的溶解度: 20 mg/mL (69.99 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶. 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。 |
| 制备储备液 | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.4993 mL | 17.4966 mL | 34.9932 mL | |
| 5 mM | 0.6999 mL | 3.4993 mL | 6.9986 mL | |
| 10 mM | 0.3499 mL | 1.7497 mL | 3.4993 mL |
1、根据实验需要选择合适的溶剂配制储备液 (母液)：对于大多数产品，InvivoChem推荐用DMSO配置母液 (比如：5、10、20mM或者10、20、50 mg/mL浓度），个别水溶性高的产品可直接溶于水。产品在DMSO 、水或其他溶剂中的具体溶解度详见上”溶解度 (体外)”部分;
2、如果您找不到您想要的溶解度信息，或者很难将产品溶解在溶液中，请联系我们;
3、建议使用下列计算器进行相关计算（摩尔浓度计算器、稀释计算器、分子量计算器、重组计算器等）;
4、母液配好之后，将其分装到常规用量，并储存在-20°C或-80°C，尽量减少反复冻融循环。
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)。如该浓度超过该批次药物DMSO溶解度，请首先与我们联系。
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 ddH2O，混匀澄清。
(1) 请确保溶液澄清之后，再加入下一种溶剂 (助溶剂) 。可利用涡旋、超声或水浴加热等方法助溶；
(2) 一定要按顺序加入溶剂 (助溶剂) 。
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT02182518 | Completed | Drug: Epinastine Drug: Placebo |
Rhinitis, Allergic, Perennial | Boehringer Ingelheim | May 2000 | Phase 3 |
| NCT02260063 | Completed | Drug: Epinastine syrup Drug: Epinastine tablets |
Healthy | Boehringer Ingelheim | November 1998 | Phase 1 |
| NCT02182531 | Completed | Drug: Epinastine Drug: Pseudoephedrine |
Healthy | Boehringer Ingelheim | August 1999 | Phase 1 |
| NCT02260037 | Completed | Drug: Epinastine nasal Drug: Placebo |
Healthy | Boehringer Ingelheim | August 2001 | Phase 1 |
| NCT01382654 | Completed | Drug: epinastine 0.1% Drug: epinastine 0.2% |
Allergic Rhinitis | Merck Sharp & Dohme LLC | September 2006 | Phase 2 |
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