H1 Receptor; antihistamine

据报道，Meclizine（Meclozine；50 µM；24 小时）可抑制 STHdh 细胞的凋亡，从血清撤药 24 小时后细胞存活率显着增加即可看出（基于 caspase 3 和 7 裂解）。 EC50 为 17.3 µm，救援效果呈剂量依赖性。与媒介物的最高功效进行比较时，存活率增加了 218%。 Meclizine 可防止突变型 (STHdhQ111/111) 和野生型 (STHdhQ7/7) 纹状体细胞中表达多聚谷氨酰胺 (polyQ) 扩增的亨廷顿蛋白的纹状体细胞中血清戒断诱导的细胞凋亡 [2]。

美克洛嗪 (Meclozine; 10-100 mg/kg; ip) 可保护小鼠免受肾缺血的影响。结果表明，在缺血前17或24小时用100 mg/kg Meclizine预处理小鼠肾脏具有保护作用。 Meclizine 增加糖酵解并直接抑制肯尼迪途径的磷脂酰乙醇胺产生，从而降低线粒体耗氧量 [4]。

细胞活力测定[2]
细胞类型：表达野生型 (STHdhQ7/7) 或突变型 (STHdhQ111/111) 亨廷顿蛋白的小鼠纹状体细胞
测试浓度： 50 µM
孵育持续时间： 24 小时
实验结果： STHdhQ111/111 中的细胞 细胞的存活率显着提高去除血清后24小时。

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蛋白质印迹分析[2]
细胞类型：突变体 (STHdhQ111/111) 和野生型 (STHdhQ7/7) 纹状体细胞
测试浓度： 50 µM
孵育时间：0、4、10、24 小时
实验结果： 抑制细胞凋亡 (基于 caspase 3) 和 7 切割。

Animal/Disease Models: 8-10 weeks old male C57BL/6 mice [4]
Doses: 10, 30, 60 or 100 mg/kg
Route of Administration: intraperitonealadministration
Experimental Results: Protect mice from renal ischemia-reperfusion injury .

Absorption, Distribution and Excretion
Most histamine H1 antagonists are reported to be readily absorbed following oral administration. Upon oral administration, the time to reach peak plasma concentrations (Cmax) of meclizine is about 3 hours post-dose, with the value ranging from 1.5 to 6 hours.
Meclizine is excreted in the urine as metabolites and in the feces as unchanged drug.
The volume of distribution of meclizine in humans has not been fully studied. It is proposed that meclizine may be excreted into breast milk.
There is limited data on the clearance of meclizine.
BENZHYDROLPIPERAZINES & THEIR N-DEALKYLATION PRODUCTS ARE DISTRIBUTED IN ALL TISSUES OF RATS & TRANSFERRED TO FETUS.
The drug is excreted in feces unchanged and in urine as norchlorcyclizine. /Meclizine hydrochloride/

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Metabolism / Metabolites
There is limited human data on meclizine metabolism. According to the findings of _in vitro_ studies, meclizine may undergo aromatic hydroxylation or benzylic oxidation mediated by the hepatic CYP2D6 enzyme.
OXIDATIVE N-DEALKYLATION IS MAIN METAB PATHWAY OF BENZHYDROLPIPERAZINES... NORCHLORCYCLIZINE IS...MAJOR METABOLITE OF MECLIZINE.
The metabolic fate of meclizine in humans in unknown. In rats, meclizine is metabolized (probably in the liver) to norchlorcyclizine. This metabolite is distributed throughout most body tissues and crosses the placenta.
Hepatic
Half Life: 6 hours

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Biological Half-Life
Meclizine has a plasma elimination half-life of about 5-6 hours in humans.
The drug has a plasma half-life of 6 hr. /Meclizine hydrochloride/

Toxicity Summary
Along with its actions as an antagonist at H₁-receptors, meclizine also possesses anticholinergic, central nervous system depressant, and local anesthetic effects. Meclizine depresses labyrinth excitability and vestibular stimulation and may affect the medullary chemoreceptor trigger zone.

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Toxicity Data
LD50: 1600 mg/kg (oral) (A701)
LD50: 659 mg/kg (i.p.) (A701)

[1]. Safety and Efficacy in the Treatment and Prevention of Motion Sickness.

[2]. Meclizine is neuroprotective in models of Huntington's disease. Hum Mol Genet. 2011 Jan 15;20(2):294-300.

[3]. Meclizine Is an Agonist Ligand for Mouse Constitutive Androstane Receptor (CAR) and an Inverse Agonist for Human CAR.

[4]. Meclizine Preconditioning Protects the Kidney Against Ischemia-Reperfusion Injury. EBioMedicine. 2015 Jul 29;2(9):1090-101.

Therapeutic Uses
Anti-Allergic Agents; Antiemetics; Histamine H1 Antagonists
A LONG-ACTING ANTIHISTAMINIC AGENT WHICH IS EFFECTIVE IN PREVENTION OR TREATMENT OF NAUSEA, VOMITING & DIZZINESS ASSOC WITH MOTION SICKNESS. ... ACTION OF SINGLE DOSE PERSISTS FOR 9-24 HR. /MECLIZINE HYDROCHLORIDE/
... H1 antagonists, notably dimenhydrinate and meclizine, are often of benefit in vestibular disturbances, such as Meniere's disease, and in other types of true vertigo.
...LARGE DRUG SURVEILLANCE PROGRAMS HAVE NOT DEMONSTRATED BIRTH DEFECTS CLINICALLY IN DOSAGE RANGES EMPLOYED.
For more Therapeutic Uses (Complete) data for MECLIZINE (10 total), please visit the HSDB record page.

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Drug Warnings
CHILDREN DOSAGE HAS NOT BEEN ESTABLISHED.
WOMAN WITH CIRRHOSIS HAD EXTRAPYRAMIDAL DISORDERS PRIOR TO DEATH IN COMA, FOLLOWING 1 TABLET/DAY FOR 4 DAYS OF ANCOLOXIN (MECLIZINE 25 MG & PYRIDOXINE 50 MG). EXTREME CAUTION IS EMPHASIZED IN PRESCRIBING DRUGS METAB IN LIVER TO PT WITH CHRONIC LIVER DISEASE.
... Meclizine may impair their ability to perform hazardous activities requiring mental alertness or physical coordination (e.g., operating machinery or driving ... ). In addition, additive CNS depression may occur when antihistamines, such as meclizine, are admin concomitantly with other CNS depressants including barbiturates, tranquilizers, and alcohol. If meclizine is used concomitantly with other depressant drugs, caution should be used to avoid overdosage. The anticholinergic effects of the drug should be considered when admin meclizine to patients with angle-closure glaucoma or prostatic hypertrophy. Meclizine is contraindicated in patients who are hypersensitive to it.
Safety and efficacy of meclizine in children younger than 12 yr of age have not been established; therefore ... use ... is not recommended.
Meclizine is teratogenic in animals. Although retrospective studies in humans suggest that the use of meclizine during pregnancy is probably not assoc with teratogenic effects, the manufacturers state that the drug is contraindicated in women who are or may become pregnant.

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Pharmacodynamics
Meclizine works on the higher centres of the brain to reduce nausea, vomiting, or vertigo. It is effective against nausea and vomiting arising from many causes, including motion sickness and disorders affecting the vestibular system. The onset of action of meclizine is about 1 hour, with effects lasting between 8 to 24 hours. Meclizine is reported to cause drowsiness due to its anticholinergic actions.

C25H27N2CL

390.94828

426.163

C, 76.81; H, 6.96; Cl, 9.07; N, 7.17

569-65-3

Meclizine dihydrochloride;1104-22-9;Meclizine-d8 dihydrochloride;1432062-16-2;Meclizine dihydrochloride monohydrate;31884-77-2

4034

Typically exists as solid at room temperature

1.159 g/cm3

1.5 g/100 mL (25ºC)

153-157ºC

253.3ºC

6.233

6.48

0

2

5

28

448

0

CC1=CC(=CC=C1)CN2CCN(CC2)C(C3=CC=CC=C3)C4=CC=C(C=C4)Cl

OCJYIGYOJCODJL-UHFFFAOYSA-N

InChI=1S/C25H27ClN2/c1-20-6-5-7-21(18-20)19-27-14-16-28(17-15-27)25(22-8-3-2-4-9-22)23-10-12-24(26)13-11-23/h2-13,18,25H,14-17,19H2,1H3

1-[(4-chlorophenyl)-phenylmethyl]-4-[(3-methylphenyl)methyl]piperazine

meclizine; Meclozine; 569-65-3; HSDB3113; HSDB-3113; HSDB 3113; Parachloramine; Bonadettes; Histamethine; Histamethizine; Histametizine;

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)

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。