Histamine H3 receptor ( IC50 = 1.9 μM )

Betahistine mesylate (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。 Ki 值分别为 1.4 μM 和 2.5 μM[2]。甲磺酸倍他司汀 (0-10 μM) 对 CHO (rH3(445)R)、CHO (rH3(413)R) 和 CHO (hH3(445)R) 细胞中的 cAMP 形成具有调节功能。在低浓度下，Betahistine mesylate 表现出明显的反向激动剂，并逐渐增强 cAMP 形成，EC50 值分别为 0.1 nM、0.05 nM 和 0.3 nM。相比之下，在浓度高于 10 nM 时，Betahistine mesylate 可抑制 cAMP 形成，在 CHO (rH3(445)R) 中的 EC50 值为 0.1 μM，并具有完全激动剂活性[2]。

甲磺酸倍他司汀（腹膜内或口服给药；0.1-30 mg/kg；单剂量）急性给药可增加远甲基组胺 (t-MeHA) 水平，ED50 为 0.4 mg/kg，表明具有反向激动作用。此外，急性口服给药后，雄性瑞士鼠的 t-MeHA 水平增加，ED50 为 2 mg/kg[2]。甲磺酸倍他司汀（口服；1 和 5 mg/kg；每天一次，持续 3 周）可减轻 CIA 小鼠爪组织中关节炎的严重程度并降低促炎细胞因子的水平[3]。动物模型：胶原诱导关节炎（CIA）DBA/1雄性小鼠模型[3] 剂量：1 mg/kg； 5mg/kg 给药方式：口服； 21 天 CIA 诱导后第 21 天至第 42 天 结果：通过减少关节破坏改善小鼠 CIA。

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]。

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]

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

Betahistine mesilate is an aralkylamine.
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 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.

C₁₀H₂₀N₂O₆S₂

328.41

328.076

C, 36.57; H, 6.14; N, 8.53; O, 29.23; S, 19.53

54856-23-4

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

198334

White to off-white solid powder

210.9ºC at 760 mmHg

112°C

96.7ºC

2.404

150.42

3

8

3

20

176

0

S(C([H])([H])[H])(=O)(=O)O[H].N([H])(C([H])([H])[H])C([H])([H])C([H])([H])C1=C([H])C([H])=C([H])C([H])=N1

ZBJJDYGJCNTNTH-UHFFFAOYSA-N

InChI=1S/C8H12N2.2CH4O3S/c1-9-7-5-8-4-2-3-6-10-8;2*1-5(2,3)4/h2-4,6,9H,5,7H2,1H3;2*1H3,(H,2,3,4)

methanesulfonic acid;N-methyl-2-pyridin-2-ylethanamine

PT9; PT-9; BRN0112294; BRN-0112294; Betahistine mesylate; 54856-23-4; Betahistine mesilate; Meginalisk; Merislon; Riptonin; Betahistine Methanesulfonate; betahistine dimesylate; BRN 0112294; beta-Histine; Betahistine; NSC 42617; PT 9 base; Serc base

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)

DMSO: 65~100 mg/mL (197.9~304.5 mM))

配方 1 中的溶解度: ≥ 2.5 mg/mL (7.61 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 (7.61 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 (7.61 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。