mTOR; Histamine H1 receptor ( IC50 = 3 nM )
- Histamine H₁ receptor (antagonist activity, no IC₅₀/Ki provided)[1,3,12]
- Human Ether-à-go-go-Related Gene (hERG) K⁺ channel (IC₅₀ = 12 nM for blocking IHERG current)[7]
- P2X₇ receptor (allosteric sensitizer, enhances ATP-induced cation entry)[8]

体外活性：富马酸氯马斯汀抑制组胺诱导的 HL-60 细胞中 [Ca2+]i 升高，IC50 为 3 nM，而氯苯那敏或苯海拉明的 IC50 值分别为 20 nM 和 100 nM。在浓度≥25 μM时，Clemastine Fumarate 可显着阻断淋巴细胞分别针对人红白血病细胞系 K562 和人 B 淋巴细胞系 SB 的 NK 和 ADCC 反应。 Clemastine Fumarate 抑制组胺诱导的豚鼠回肠收缩，IC50 为 231 nM。在稳定表达 HERG 通道的 HEK 293 细胞中，Clemastine Fumarate 以浓度依赖性方式有效抑制 HERG K+ 通道，IC50 为 12 nM，可通过 HERG 的 Y652A 或 F656A 突变减弱。 Clemastine Fumarate 显着增强 HEKhP2X7 细胞中 ATP 诱导的 [Ca2+]i 增加，不依赖于组胺受体阻断，而是以浓度依赖性方式使 P2X7 受体敏感，EC50 为 10 μM，并增加 LPS- 中 IL-1β 的释放。诱导人类巨噬细胞。

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- 抗组胺活性：氯马斯汀竞争性阻断效应细胞（如血管内皮细胞、气道平滑肌）上的H₁受体，减少组胺介导的血管扩张和支气管收缩。该效应在豚鼠离体气管条和大鼠肠系膜动脉实验中得到验证[3]
- hERG通道抑制：在表达hERG通道的HEK293细胞中，氯马斯汀（12 nM）显著降低峰值IHERG电流约50%，其作用依赖于通道门控状态，并与S6螺旋的Y652A/F656A突变相关[7]
- P2X₇受体调节：在稳定表达P2X₇受体的HEK293细胞中，氯马斯汀（1-10 μM）增强ATP诱导的Ca²⁺内流，加速孔道扩张（Yo-Pro-1摄取），并增加对NMDG⁺的通透性。在人单核细胞来源的巨噬细胞和小鼠骨髓来源的巨噬细胞中观察到类似效应[8]
- 自噬促进：在LPS刺激的H9c2心肌细胞中，氯马斯汀（10-50 μM）增加LC3-II/LC3-I比值、Beclin-1表达和自噬体形成，该效应可被自噬抑制剂3-甲基腺嘌呤阻断.

富马酸氯马斯汀（5-20 mg/kg）对同时引起的大鼠酵母聚糖足肿胀和巴豆油耳肿胀有明显的抑制作用，且呈剂量依赖性，抑制率分别为53.6%和46.8%。剂量为20 mg/kg，ID50值分别为18.0 mg/kg和20.5 mg/kg。富马酸氯马斯汀治疗通过干扰细胞外信号调节激酶 (ERK) 介导的促炎细胞因子（如 TNF-α 和 IL-6）的产生，强烈降低小鼠对单核细胞增生李斯特氏菌的先天免疫反应，令人惊讶的是，该细胞因子不依赖于阻断组胺 H1 受体，导致死亡率显着升高。

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- 过敏性鼻炎模型：20名过敏受试者口服氯马斯汀（1 mg）4-6小时后，过敏原激发导致的喷嚏频率（p < 0.01）和鼻漏严重程度显著降低。效应呈剂量依赖性，持续时间≥12小时[6]
- 脓毒症心肌损伤模型：在CLP诱导的脓毒症大鼠中，腹腔注射氯马斯汀（30-50 mg/kg）将7天存活率从30%提升至60%，降低血清cTnI水平，保护左心室射血分数，并减轻线粒体碎片化。在LPS刺激的H9c2细胞中观察到类似保护作用
- 视神经炎模型：16名急性视神经炎患者口服氯马斯汀（1 mg每日两次，持续90天）后，颞侧/颞上象限视网膜神经纤维层（RNFL）厚度得以保留，视觉诱发电位P100波幅恢复优于安慰剂组.

在含有 138 mM NaCl、6 mM KCl、1 mM MgSO4、1 mM Na₂HPO₄、5 mM NaHCO₃3 的缓冲液中， 5.5 mM 葡萄糖和 20 mM HEPES-NaOH，pH 7.4，HL-60 细胞以 1×10⁷ 细胞/mL 的密度悬浮。使用 0.1% (w/v) 牛血清白蛋白进一步增强缓冲液。在 37 °C 孵育 10 分钟后，将 4 μM 染料 fura-2/AM 添加到细胞中。用前述缓冲液稀释至5×10⁶细胞/mL的浓度后，将细胞在37℃下孵育45分钟。随后，使用前面提到的缓冲液稀释细胞，直至最终浓度达到 0.5 × 10⁶ 细胞/mL，并在环境温度下以 250 g 离心 10 分钟。在前面提到的缓冲液中，细胞以 1.0 × 10⁶ cells/mL 悬浮，并保存在 20 °C 直至测量。加载 fura-2/AM 后，使用丙烯酸荧光比色皿将 HL-60 细胞悬浮在 2 mL 前述缓冲液中最多 4 小时。在添加组胺 (100 μM) 之前，将 HL-60 细胞与 1 mM Ca2+ 和不同浓度的富马酸氯马斯汀在 37 °C 下孵育 3 分钟。在 37 °C 下以 1×103 rpm 持续搅拌细胞，使用 Ratio II 分光荧光计测量荧光。测量一分钟的基础荧光或基础 [Ca²⁺]_i。要查找 [Ca²⁺]_i 的增加，相应的峰值 [Ca²⁺]_i 值从基础 [Ca²⁺]_i 值中减去。激发和发射波长分别为500 nm和340 nm。竞争曲线用于计算IC50值。

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- hERG通道电生理实验：在表达hERG通道的HEK293细胞上进行全细胞膜片钳记录。细胞在37°C Tyrode液中灌流氯马斯汀（1-100 nM），记录去极化至+20 mV后-40 mV的IHERG尾电流。IC₅₀通过非线性回归计算[7]
- P2X₇受体钙流实验：HEK293-P2X₇细胞负载Fluo-4 AM，经氯马斯汀（1-10 μM）预处理后加入ATP（100 μM），荧光显微镜记录钙瞬变。流式细胞术检测Yo-Pro-1摄取以评估孔道形成[8]

- H₁受体拮抗实验：豚鼠气管环段与氯马斯汀（0.1-10 μM）孵育后，用组胺（1 μM）刺激，记录等长张力变化以测定拮抗效力[3]
- 自噬检测实验：H9c2心肌细胞经氯马斯汀（10-50 μM）和LPS（1 μg/mL）处理后，Western blot分析LC3-II/LC3-I比值和Beclin-1表达。透射电镜观察自噬体.

Male Wistar rats with paw oedema induced by subplantar injection of zymosan and ear oedema induced by croton oil
5-20 mg/kg
Intraperitoneally

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- Sepsis model: Male Sprague-Dawley rats (250-300 g) underwent cecal ligation and puncture (CLP). Clemastine (10-50 mg/kg) was dissolved in 0.9% saline and administered intraperitoneally 30 minutes post-CLP. Survival was monitored for 7 days, and cardiac function was assessed by echocardiography on day 3
- Allergic rhinitis model: Human subjects received oral clemastine (1 mg) or placebo in a double-blind crossover design. Nasal allergen challenges were performed 1, 4, and 6 hours post-dose. Sneeze counts and nasal secretion weights were recorded[6]

Absorption, Distribution and Excretion
Rapidly absorbed from the gastrointestinal tract.
Urinary excretion is the major mode of elimination.

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Metabolism / Metabolites
Antihistamines appear to be metabolized in the liver chiefly via mono- and didemethylation and glucuronide conjugation.

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- Absorption: Rapid oral absorption with ~40% bioavailability. Peak plasma concentration (Cmax) of 1-2 ng/mL occurs within 2-4 hours
- Distribution: Extensive tissue distribution (volume of distribution ~800 L), crosses blood-brain barrier. Plasma protein binding ~95%
- Metabolism: Extensively metabolized in liver via O-dealkylation, oxidation, and glucuronidation. Major metabolites include desmethylclemastine and hydroxylated derivatives
- Excretion: ~42% excreted in urine (primarily as metabolites), 27% in feces. Terminal half-life ~21 hours.

Hepatotoxicity
Despite widespread use, the first generation antihistamines such as clemastine have rarely been linked to liver test abnormalities or to clinically apparent liver injury. The reason for their safety may relate to low daily dose and limited duration of use.
Likelihood score: E (unlikely to be a cause of clinically apparent liver injury).
References on the safety and potential hepatotoxicity of antihistamines are given together after the Overview section on Antihistamines.
Drug Class: Antihistamines

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Small occasional doses of clemastine are acceptable during breastfeeding. Larger doses or more prolonged use may cause drowsiness and other effects in the infant or decrease the milk supply, particularly in combination with a sympathomimetic such as pseudoephedrine or before lactation is well established. Single bedtime doses after the last feeding of the day may be adequate for many women and will minimize any effects of the drug. The nonsedating antihistamines are preferred alternatives.
◉ Effects in Breastfed Infants
A 10-week-old breastfed infant whose mother was taking clemastine, phenytoin and carbamazepine was drowsy, refused to feed, was irritable, and had high-pitched crying. These side effects were possibly caused by clemastine in breastmilk, but the other drugs could also have contributed.
In one telephone follow-up study, mothers reported irritability and colicky symptoms 10% of infants exposed to various antihistamines and drowsiness was reported in 1.6% of infants. None of the reactions required medical attention.
◉ Effects on Lactation and Breastmilk
Antihistamines in relatively high doses given by injection can decrease basal serum prolactin in nonlactating women and in early postpartum women. However, suckling-induced prolactin secretion is not affected by antihistamine pretreatment of postpartum mothers. Whether lower oral doses of antihistamines have the same effect on serum prolactin or whether the effects on prolactin have any consequences on breastfeeding success have not been studied. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

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Non-Human Toxicity Values
LD50 Mouse oral 730 mg/kg
LD50 Mouse iv 43 mg/kg
LD50 Rat oral 3550 mg/kg
LD50 Rat iv 82 mg/kg.

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- Acute toxicity: LD₅₀ in mice >100 mg/kg (oral). Common adverse effects include sedation, dry mouth, blurred vision, and urinary retention due to anticholinergic activity
- Cardiotoxicity: At supra-therapeutic concentrations (≥1 μM), clemastine prolongs QT interval in isolated feline hearts, but no clinical QT prolongation reported at therapeutic doses (1-6 mg/day)[7]
- Drug interactions: Potentiates CNS depression with alcohol, opioids, or benzodiazepines. Contraindicated with MAO inhibitors due to risk of hypertensive crisis.

[1]. Mol Pharmacol . 1992 Aug;42(2):227-34.

[2]. Cell Immunol . 1983 Oct 1;81(1):45-60.

[3]. J Pharmacol Exp Ther . 1997 Jan;280(1):114-21.

[4].J Mol Cell Cardiol . 2006 Jan;40(1):107-18.

[5]. J Biol Chem . 2011 Apr 1;286(13):11067-81.

[6]. J Pharmacol Exp Ther . 1997 Jan;280(1):114-21.

[7]. Preprint from Research Square, 29 Jun 2020

[8]. Bioengineered . 2022 Mar;13(3):7134-7146.

Clemastine is 2-[(2R)-1-Methylpyrrolidin-2-yl]ethanol in which the hydrogen of the hydroxy group is substituted by a 1-(4-chlorophenyl)-1-phenylethyl group (R configuration). An antihistamine with antimuscarinic and moderate sedative properties, it is used as its fumarate salt for the symptomatic relief of allergic conditions such as rhinitis, urticaria, conjunctivitis and in pruritic (severe itching) skin conditions. It has a role as a H1-receptor antagonist, an anti-allergic agent, a muscarinic antagonist and an antipruritic drug. It is a N-alkylpyrrolidine and a member of monochlorobenzenes.
An ethanolamine-derivative, first generation histamine H1 antagonist used in hay fever, rhinitis, allergic skin conditions, and pruritus. It causes drowsiness.
Clemastine is a first generation antihistamine that is used for symptoms of allergic rhinitis and the common cold. Clemastine has not been linked to instances of clinically apparent acute liver injury.
Clemastine is a synthetic ethanolamine, with anticholinergic, sedative, and histamine H1 antagonistic activities. Upon administration, clemastine blocks the H1 histamine receptor and prevents the symptoms that are caused by histamine activity on capillaries, bronchial and gastrointestinal smooth muscles, including vasodilation, increased capillary permeability, bronchoconstriction, and spasmodic contraction of gastrointestinal smooth muscles. Clemastine also prevents histamine-induced pain and itching of mucous membranes.
A histamine H1 antagonist used as the hydrogen fumarate in hay fever, rhinitis, allergic skin conditions, and pruritus. It causes drowsiness.
See also: Clemastine Fumarate (has salt form).

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Drug Indication
For the relief of symptoms associated with allergic rhinitis such as sneezing, rhinorrhea, pruritus and acrimation. Also for the management of mild, uncomplicated allergic skin manifestations of urticaria and angioedema. Used as self-medication for temporary relief of symptoms associated with the common cold.

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Mechanism of Action
Clemastine is a selective histamine H1 antagonist and binds to the histamine H1 receptor. This blocks the action of endogenous histamine, which subsequently leads to temporary relief of the negative symptoms brought on by histamine.

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Therapeutic Uses
For the symptomatic treatment of allergic rhinitis in adults and children 12 years of age and older ...
For the symptomatic treatment of mild allergic urticaria and angioedema in adults and children 12 years of age and older ...
This multicenter, double blind, randomized parallel group study compared 3 wk treatment with either loratadine (Clarityn) 10 mg once daily, or clemastine (Tavegyl) 1 mg twice daily, and placebo in outpatients with active perennial allergic rhinitis. 155 patients were evaluated for efficacy and safety. Grading of four nasal and three non-nasal symptoms, rhinoscopy signs, and therapeutic response was performed on treatment days 6, 13, and 20. Patients recorded daily symptoms and possible adverse experiences in a diary, also indicating when symptoms of active rhinitis were relieved. Loratadine and clemastine were statistically significantly superior to placebo throughout the study (p < 0.05), based on assessment of patients' nasal and eye symptoms, patients' diary scores, rhinoscopy signs of symptoms, and onset of relief. The loratadine group showed a statistically significantly (p < 0.05) faster onset of relief of symptoms compared with the group treated with clemastine. Concerning nasal stuffiness, loratadine was significantly (p < 0.05) superior to clemastine after 1 week's treatment. Reports of adverse reactions showed that significantly (p < 0.05) more patients complained of sedation in the clemastine than in the loratadine group. Regarding other adverse experiences and laboratory tests, the three treatment groups were statistically comparable (p < 0.05). The study showed that compared with placebo both loratadine and clemastine were effective in relieving nasal and eye symptoms in patients with perennial allergic rhinitis. Loratadine was safe and well tolerated and was significantly less sedative than clemastine; loratadine may therefore possess an advantage in clinical use in the treatment of perennial allergic rhinitis.
The effects of cromolyn sodium (sodium cromoglycate), clemastine and ketotifen administered to the nasal mucosa of seasonal and perennial allergic rhinitis patients 30 min before provocation with histamine and allergen were compared in a randomized, double blind, placebo controlled study. Clemastine and cromolyn sodium, but not ketotifen, significantly inhibited the nasal response to increasing concentrations of histamine. None of the drugs administered in the concentrations used significantly inhibited the nasal response to allergen.

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Drug Warnings
Drugs contraindicated during lactation include ... clemastine.
There are no adequate and controlled studies to date using clemastine fumarate alone or in fixed combination with phenylpropanolamine in pregnant women, and the drug should be used during pregnancy only when clearly needed.
Because of the potential for serious adverse reactions to clemastine in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.
Drugs that have been associated with Significant Effects on some Nursing Infants and should be given to Nursing Mothers with Caution: Clemastine: Drowsiness, irritability, refusal to feed, high-pitched cry, neck stiffness (1 case). /from Table 5/

C25H30CLNO5

459.96

459.181

C, 65.28; H, 6.57; Cl, 7.71; N, 3.05; O, 17.39

14976-57-9

Clemastine; 15686-51-8; Clemastine-d5 fumarate

26987

White to light yellow crystalline powder

1.097 g/cm3

116 °C / 24mmHg

61 °C

211ºC

1.94E-07mmHg at 25°C

1.553

4.754

87.07

0

2

6

24

376

2

ClC1C([H])=C([H])C(=C([H])C=1[H])[C@@](C([H])([H])[H])(C1C([H])=C([H])C([H])=C([H])C=1[H])OC([H])([H])C([H])([H])[C@@]1([H])C([H])([H])C([H])([H])C([H])([H])N1C([H])([H])[H].O([H])C(/C(/[H])=C(\[H])/C(=O)O[H])=O

PMGQWSIVQFOFOQ-YKVZVUFRSA-N

InChI=1S/C21H26ClNO.C4H4O4/c1-21(17-7-4-3-5-8-17,18-10-12-19(22)13-11-18)24-16-14-20-9-6-15-23(20)2;5-3(6)1-2-4(7)8/h3-5,7-8,10-13,20H,6,9,14-16H2,1-2H3;1-2H,(H,5,6)(H,7,8)/b;2-1+/t20-,21-;/m1./s1

(E)-but-2-enedioic acid;(2R)-2-[2-[(1R)-1-(4-chlorophenyl)-1-phenylethoxy]ethyl]-1-methylpyrrolidine

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: ≥ 1.43 mg/mL (3.11 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 14.3 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。

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配方 2 中的溶解度: ≥ 1.43 mg/mL (3.11 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 14.3mg/mL澄清的DMSO储备液加入到900μL 20％SBE-β-CD生理盐水中，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: ≥ 1.43 mg/mL (3.11 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 14.3 mg/mL 澄清 DMSO 储备液添加到 900 μL 玉米油中并混合均匀。

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配方 4 中的溶解度: 30% propylene glycol, 5% Tween 80, 65% D5W: 5mg/mL

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配方 5 中的溶解度: 1.43 mg/mL (3.11 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 (<60°C).

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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。