Histamine H3 receptor ( IC50 = 1.9 μM )

Betaistine (0-10 μM) 抑制 [125I]iodoproxyfan 与 CHO (rH3(445)R) 和 CHO (hH3(445)R) 细胞膜的结合，IC50 值分别为 1.9 μM 和 3.3 μM。相应的 Ki 值为 2.5 μM 和 1.4 μM [2]。 CHO (rH3(445)R)、CHO (rH3(413)R) 和 CHO (hH3(445)R) 细胞中 cAMP 的生成受倍他司汀 (0-10 μM) 调节。倍他司汀在低剂量，逐渐增加 cAMP 的产生，EC50 值为 0.1 nM、0.05 nM 和 0.3 nM。另一方面，倍他司汀表现出完全激动剂活性，CHO (rH3(445)R) 中的 EC50 值为 0.1 μM ，并在浓度高于 10 nM 时抑制 cAMP 产生 [2]。

急性倍他司汀治疗（腹膜内或口服；0.1-30 mg/kg；单剂量）可提高远甲基组胺 (t-MeHA) 水平，ED50 为 0.4 mg/kg，表明具有反向激动作用。此外，在急性口服治疗后，雄性瑞士大鼠表现出升高的 t-MeHA 水平，ED50 为 2 mg/kg [2]。在 CIA 小鼠的爪组织中，倍他司汀（口服；1 和 5 mg/kg；每天一次，持续 3 周）可减少促炎细胞因子的量并减轻关节炎的严重程度 [3]。

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]。

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]。

Animal/Disease Models: Collagen-induced arthritis (CIA) DBA/1 male mouse model [3]
Doses: 1 mg/kg; 5 mg/kg
Route of Administration: oral; 21 days Results from day 21 to day 42 after CIA induction: Improves CIA in mice by reducing joint destruction.

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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]

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.

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

[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.

Pharmacodynamics
Through its actions on the histamine receptors, betahistine provides relief from vertigo associated with Ménière's disease.

C8H12N2

136.19428

136.1

C, 70.55; H, 8.88; N, 20.57

5638-76-6

Betahistine dihydrochloride;5579-84-0;Betahistine mesylate;54856-23-4; Betahistine; 5638-76-6; Betahistine-d3 dihydrochloride; 244094-72-2;

2366

Light yellow to yellow liquid

1.0±0.1 g/cm3

210.9±15.0 °C at 760 mmHg

150-144

96.7±0.0 °C

0.2±0.4 mmHg at 25°C

1.510

0.1

24.92

1

2

3

10

83.3

0

UUQMNUMQCIQDMZ-UHFFFAOYSA-N

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

N-methyl-2-pyridin-2-ylethanamine

betahistine; 5638-76-6; 2-(2-METHYLAMINOETHYL)PYRIDINE; N-methyl-2-(pyridin-2-yl)ethanamine; Vasomotal; 2-Pyridineethanamine, N-methyl-; Serc base; N-Methyl-2-pyridineethanamine;

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)

DMSO : ~100 mg/mL (~734.27 mM)

配方 1 中的溶解度: ≥ 2.5 mg/mL (18.36 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 (18.36 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 (18.36 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。