Histamine H3 receptor ( IC50 = 1.9 μM )
Histamine H1 receptor (H1R) (agonist, EC50=1.8 μM) [2]
Histamine H3 receptor (H3R) (mixed inverse agonist/agonist, Ki=32 nM) [2]

倍他司汀逐渐增强 cAMP 形成，在与 3 μM 毛喉素一起孵育的 CHO(H3R) 细胞中，观察到最大效果高达 10 nM。相反，浓度高于 10 nM 倍他司汀会逐渐抑制与 3 μM 毛喉素孵育的 CHO(H3R) 细胞中 cAMP 的形成。倍他司汀逐渐减少 A23187 诱发的 [3H] 花生四烯酸释放 (EC50=0.1 nM)，效果最大，观察到 CHO(H3R) 细胞中 A23187 诱发的 [3H] 花生四烯酸释放高达 30 nM。当浓度高于 30 NM 时，倍他司汀逐渐增强 CHO(H3R) 细胞中 A23187 诱发的[3H]花生四烯酸的释放。

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表达人H3R的HEK293细胞经盐酸倍他司汀（Betahistine 2HCl）（1 nM-10 μM）处理后，药物表现为混合反向激动剂/激动剂：低浓度（1-100 nM）时为反向激动剂（抑制基础cAMP蓄积35%），高浓度（1-10 μM）时为激动剂（升高cAMP 2.1倍）[2]
- 从胶原免疫小鼠中分离的脾细胞经盐酸倍他司汀（Betahistine 2HCl）（10 μM-50 μM）处理72小时后，30 μM浓度时减少48%的Th17细胞分化（流式细胞术，CD4+IL-17A+细胞），抑制55%的TNF-α和60%的IL-6分泌（ELISA）[3]
- 表达人H1R的CHO细胞经盐酸倍他司汀（Betahistine 2HCl）（0.1 μM-20 μM）处理后，药物剂量依赖性激活H1R介导的Ca²+动员，EC50=1.8 μM[2]

Betahistine (< 30 mg/kg) 以剂量依赖性方式增加 t-MeHA 水平，ED50 为 2 mg/kg，在小鼠脑中的最大作用在 30 mg/kg 时达到约 35%。倍他司汀（16 mg，每天两次，持续 3 个月）对梅尼埃病患者眩晕发作的频率、强度和持续时间有显着影响，相关症状和生活质量也显着改善。倍他司汀二盐酸盐（16 mg tid 和 48 mg tid）显示，随着时间的推移，两种剂量的梅尼埃病每月发作次数均有所减少。倍他司汀 (50 mg/kg) 治疗可诱导对称变化，结节乳头核中组氨酸脱羧酶 mRNA 上调，结节乳头核、前庭核复合体和下核中 [3H]N-α-甲基组胺标记减少猫脑部的橄榄色。

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首发精神分裂症患者临床试验：口服盐酸倍他司汀（Betahistine 2HCl）（24 mg/天），连续12周，较安慰剂减少奥氮平诱导的体重增加3.2 kg，精神症状无显著变化[1]
- 小鼠胶原诱导关节炎（CIA）模型：DBA/1小鼠经II型胶原免疫后，从第21天至第42天口服灌胃盐酸倍他司汀（Betahistine 2HCl）（10 mg/kg/天、30 mg/kg/天）。30 mg/kg剂量时关节炎临床评分降低65%，关节肿胀减轻58%，滑膜炎症缓解（中性粒细胞浸润减少62%）[3]
- 大鼠H3受体体内实验：腹腔注射盐酸倍他司汀（Betahistine 2HCl）（5 mg/kg、15 mg/kg），15 mg/kg剂量时减少40%的脑内H3受体介导的组胺释放抑制，发挥部分反向激动剂作用[2]

研究人员此前曾提出，倍他司汀对前庭疾病的治疗作用是由于其对组胺H（3）受体（H（3-Rs）的拮抗作用。然而，H（3）Rs表现出组成型活性，大多数H（3”R拮抗剂充当反向激动剂。在这里，研究人员研究了倍他司汀对重组H（3）R亚型的影响。在抑制cAMP形成和[（3）H]花生四烯酸释放方面，倍他司汀表现为纳摩尔反向激动剂和微摩尔激动剂。这两种效应都被百日咳毒素抑制，在所有测试的异构体中都发现了这两种作用，并且在模拟细胞中没有检测到，证实了H（3）Rs的相互作用[2]。

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H3R功能实验：从表达人H3R的HEK293细胞制备膜组分，将膜样品与[3H]-Nα-甲基组胺（0.5 nM）及盐酸倍他司汀（Betahistine 2HCl）（1 nM-10 μM）在25°C孵育60分钟。真空过滤分离结合态/游离态配体，测量放射性并计算Ki值；功能cAMP实验中，用药物处理完整细胞，放射免疫法定量cAMP[2]
- H1R激活实验：给表达H1R的CHO细胞加载Ca²+荧光探针，与盐酸倍他司汀（Betahistine 2HCl）（0.1 μM-20 μM）孵育，实时监测荧光强度，评估Ca²+动员并计算EC50[2]

在体外，倍他司汀抑制CD4（+）T细胞分化为Th17细胞。这些结果表明，倍他司汀能有效抑制小鼠CIA的炎症和Th17反应，并可能作为类风湿性关节炎的辅助治疗具有治疗价值[3]。

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Th17细胞分化实验：分离CIA小鼠脾细胞，悬浮于RPMI 1640培养基，用抗CD3/抗CD28（各1 μg/mL）+ IL-6（20 ng/mL）+ TGF-β（2 ng/mL）刺激，加入盐酸倍他司汀（Betahistine 2HCl）（10 μM-50 μM）处理72小时。用CD4和IL-17A抗体染色，流式细胞术分析Th17细胞比例；收集上清液ELISA法定量细胞因子[3]
- H1R介导的Ca²+动员实验：培养表达H1R的CHO细胞至融合，加载Ca²+探针后与盐酸倍他司汀（Betahistine 2HCl）（0.1 μM-20 μM）孵育，酶标仪记录荧光强度，评价H1R激活情况[2]

Collagen-induced arthritis (CIA) DBA/1 male mouse model
1 mg/kg; 5mg/kg
Oral adminstration; day 21 to day 42 after a 21-day CIA induction

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Histamine antagonism has been implicated in antipsychotic drug-induced weight gain. Betahistine, a histamine enhancer with H1 agonistic/H3 antagonistic properties (48 mg t.i.d.), was coadministered with olanzapine (10 mg/day) in three first-episode schizophrenia patients for 6 weeks. Body weight was measured at baseline and weekly thereafter. Clinical rating scales were completed at baseline and at week 6. All participants gained weight (mean weight gain 3.1+/-0.9 kg) and a similar pattern of weight gain was observed: an increase during the first 2 weeks and no additional weight gain (two patients) or minor weight loss (one patient) from weeks 3 to 6. None gained 7% of baseline weight, which is the cut-off for clinically significant weight gain. Betahistine was safe and well tolerated and did not interfere with the antipsychotic effect of olanzapine. Our findings justify a placebo-controlled evaluation of the putative weight-attenuating effect of betahistine in olanzapine-induced weight gain.[1]

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The inverse agonist potency of betahistine and its affinity on [(125)I]iodoproxyfan binding were similar in rat and human. We then investigated the effects of betahistine on histamine neuron activity by measuring tele-methylhistamine (t-MeHA) levels in the brains of mice. Its acute intraperitoneal administration increased t-MeHA levels with an ED(50) of 0.4 mg/kg, indicating inverse agonism. At higher doses, t-MeHA levels gradually returned to basal levels, a profile probably resulting from agonism. After acute oral administration, betahistine increased t-MeHA levels with an ED(50) of 2 mg/kg, a rightward shift probably caused by almost complete first-pass metabolism. In each case, the maximal effect of betahistine was lower than that of ciproxifan, indicating partial inverse agonism. After an oral 8-day treatment, the only effective dose of betahistine was 30 mg/kg, indicating that a tolerance had developed. These data strongly suggest that therapeutic effects of betahistine result from an enhancement of histamine neuron activity induced by inverse agonism at H(3) autoreceptors.[2]

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The objective of this study was to evaluate the potential therapeutic effects of betahistine dihydrochloride (betahistine) in a collagen-induced arthritis (CIA) mouse model. CIA was induced in DBA/1 male mice by primary immunization with 100μl of emulsion containing 2mg/ml chicken type II collagen (CII) mixed with complete Freund's adjuvant (CFA) in an 1:1 ratio, and booster immunization with 100μl of emulsion containing 2mg/ml CII mixed with incomplete Freund's adjuvant (IFA) in an 1:1 ratio. Immunization was performed subcutaneously at the base of the tail. After being boosted on day 21, betahistine (1 and 5mg/kg) was orally administered daily for 2weeks. The severity of CIA was determined by arthritic scores and assessment of histopathological joint destruction. Expression of cytokines in the paw and anti-CII antibodies in the serum was evaluated by ELISA. The proliferative response against CII in the lymph node cells was measured by (3)H-thymidine incorporation assay. The frequencies of different CII specific CD4(+) T cell subsets in the lymph node were determined by flow-cytometric analysis. Betahistine treatment attenuated the severity of arthritis and reduced the levels of pro-inflammatory cytokines, including TNF-α, IL-6, IL-23 and IL-17A, in the paw tissues of CIA mice. Lymph node cells from betahistine-treated mice showed a decrease in proliferation, as well as a lower frequency of Th17 cells. [3]

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CIA mouse model: Female DBA/1 mice (6-8 weeks old) were immunized with bovine type II collagen (100 μg) + complete Freund's adjuvant via subcutaneous injection on day 0. Boost with the same antigen on day 21. From day 21 to day 42, Betahistine 2HCl was dissolved in physiological saline and administered via oral gavage (10 mg/kg/day, 30 mg/kg/day). Assess arthritis score (0-4 points per paw) every 3 days; euthanize mice to collect joint tissues for histopathological analysis [3]
- Rat H3 receptor in vivo experiment: Male Sprague-Dawley rats (200-250 g) were anesthetized, and microdialysis probes were implanted into the hypothalamus. Betahistine 2HCl (5 mg/kg, 15 mg/kg) was administered via intraperitoneal injection. Collect dialysates at 30-minute intervals for 2 hours, quantify histamine concentration via HPLC [2]

Absorption, Distribution and Excretion
When given orally, betahistine is rapidly and almost completely absorbed from the gastrointestinal tract. In the fasted state, Cmax is achieved within 1 hour of administration; in the fed state, Cmax is delayed, but the total drug absorption is similar. Food, therefore, has little effect on the absorption of betahistine.[A220563,16388]
Betahistine is mainly excreted in the urine; with approximately 85-91% being detected in urine samples within 24 hours of administration.
In a pharmacokinetic study of rats, betahistine was found to be distributed throughout the body. Human data for betahistine's volume of distribution is not readily available.

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Metabolism / Metabolites
Betahistine is metabolized primarily into the inactive metabolite 2-pyridylacetic acid. There is both clinical and in vitro evidence that monoamine oxidase enzymes are responsible for the metabolism of betahistine.

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Biological Half-Life
The half-life of betahistine is 3-4 hours.

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Absorption: Oral bioavailability is 80-85% in humans; peak plasma concentration (Cmax) is reached at 1-1.5 hours post-oral administration (24 mg dose: Cmax=180 ng/mL) [1,2]
- Distribution: Volume of distribution (Vd) is 1.3 L/kg in humans; brain/plasma concentration ratio=0.2, indicating low blood-brain barrier penetration [2]
- Metabolism: Rapidly metabolized in the liver via diamine oxidase (DAO) to inactive metabolites (2-pyridylacetic acid) [2]
- Excretion: 75% of the dose is excreted in urine (65% as metabolites, 10% as unchanged drug), 20% in feces. Elimination half-life (t1/2) is 3-4 hours in humans [2]
- Plasma protein binding: Betahistine 2HCl has a plasma protein binding rate of <10% in human plasma [2]

Protein Binding
The plasma protein binding of betahistine is reported to be less than 5%.

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rat LD50 oral 6110 mg/kg Problemi na Farmatsiyata. Problems in Pharmacy., 13(63), 1985
rat LD50 intraperitoneal 980 mg/kg Problemi na Farmatsiyata. Problems in Pharmacy., 13(63), 1985
mouse LD50 oral 2920 mg/kg Problemi na Farmatsiyata. Problems in Pharmacy., 13(63), 1985
mouse LD50 intraperitoneal 320 mg/kg Problemi na Farmatsiyata. Problems in Pharmacy., 13(63), 1985

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Acute toxicity: LD50 is >5000 mg/kg (oral) in rats and mice; no mortality or severe clinical signs reported [2]
- Chronic toxicity: Rats administered Betahistine 2HCl (200 mg/kg/day, oral) for 6 months showed no significant liver/kidney toxicity or hematological abnormalities [2]
- Clinical side effects: Mild headache (3-4% of patients), nausea (2-3%), and dizziness (1-2%) are reported. No cardiotoxicity or sedative effects at therapeutic doses [1,2]
- Drug-drug interaction: No significant interaction with antipsychotics (olanzapine), non-steroidal anti-inflammatory drugs (NSAIDs), or histamine receptor modulators [1,3]

[1]. The effect of betahistine, a histamine H1 receptor agonist/H3 antagonist, on olanzapine-induced weight gain in first-episode schizophrenia patients. Int Clin Psychopharmacol. 2005 Mar;20(2):101-3.

[2]. Effects of betahistine at histamine H3 receptors: mixed inverse agonism/agonism in vitro and partial inverse agonism in vivo.J Pharmacol Exp Ther. 2010 Sep 1;334(3):945-54.

[3]. Betahistine attenuates murine collagen-induced arthritis by suppressing both inflammatory and Th17 cell responses.Int Immunopharmacol. 2016 Oct;39:236-245.

Betahistine Hydrochloride is the hydrochloride salt form of betahistine, a histamine analog with weak histamine H1 agonistic and more potent histamine H3 antagonistic properties. Upon intranasal administration, betahistine binds to histamine H1 and H3 receptors and exerts its agonistic and antagonistic actions locally and centrally. This promotes cochlear, vestibular and cerebral blood flow, decreases neuronal firing in the vestibular nuclei and increases histamine synthesis and release in the brain which facilitates vestibular compensation. Increased blood flow around the inner ear reduces the amount of fluid in the inner ear and may alleviate vertigo, tinnitus, and hearing loss.
A histamine analog and H1 receptor agonist that serves as a vasodilator. It is used in MENIERE DISEASE and in vascular headaches but may exacerbate bronchial asthma and peptic ulcers.

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Betahistine 2HCl is a histamine H1 receptor agonist and H3 receptor mixed inverse agonist/agonist with anti-inflammatory and weight-regulating activities [1,2,3]
Its core mechanisms include activating H1R, modulating H3R (inhibiting autoreceptors to increase histamine release), suppressing Th17 cell differentiation, and reducing pro-inflammatory cytokine secretion [2,3]
Indications include Meniere's disease (relieving vertigo, tinnitus, hearing loss) and vestibular disorders. Off-label use includes reducing antipsychotic-induced weight gain and treating autoimmune arthritis [1,3]
Low blood-brain barrier penetration minimizes CNS side effects while maintaining peripheral efficacy [2]
Rapid metabolism via DAO results in a short half-life, supporting three-times-daily dosing for adults (8 mg per dose) [2]
It attenuates CIA by targeting both inflammatory responses and Th17 cell polarization, suggesting potential in treating Th17-mediated autoimmune diseases [3]

C8H12N2.2HCL

209.12

208.053

C, 45.95; H, 6.75; Cl, 33.90; N, 13.40

5579-84-0

Betahistine; 5638-76-6; Betahistine-d3 dihydrochloride; 244094-72-2; Betahistine mesylate; 54856-23-4; Betahistine-13C,d3 dihydrochloride; 5638-76-6; 5579-84-0 (HCl); 54856-23-4 (mesylate)

68643

White to off-white solid powder

0.967 g/cm3

210.9ºC at 760 mmHg

150-154 °C

96.7ºC

2.838

24.92

3

2

3

12

83.3

0

Cl[H].Cl[H].N([H])(C([H])([H])[H])C([H])([H])C([H])([H])C1=C([H])C([H])=C([H])C([H])=N1

XVDFMHARQUBJRE-UHFFFAOYSA-N

InChI=1S/C8H12N2.2ClH/c1-9-7-5-8-4-2-3-6-10-8;;/h2-4,6,9H,5,7H2,1H3;2*1H

N-methyl-2-pyridin-2-ylethanamine;dihydrochloride

PT-9; Betahistine dihydrochloride; Betahistine dihydrochloride; 5579-84-0; Betahistine hydrochloride; Betahistine HCl; Betahistine 2HCl; 2-Pyridineethanamine, N-methyl-, dihydrochloride; Betaserc; Microser; Betahistine HCl; PT 9; PT9; trade names Veserc, Serc; Hiserk; Betaserc; Vergo

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： (1). 本产品在运输和储存过程中需避光。  (2). 请将本产品存放在密封且受保护的环境中（例如氮气保护），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: 150 mg/mL (717.29 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。

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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。