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]

In vitro activity: Betahistine dihydrochloride (0-10 μM) inhibits [ 125 I]iodoproxyfan binding to membranes of CHO (rH₃₍₄₄₅₎R) and CHO (hH₃₍₄₄₅₎R) cells with IC50 values of 1.9 μM and 3.3 μM, respectively. In CHO (rH₃₍₄₄₅₎R), CHO (rH₃₍₄₄₅₎R, and CHO (hH₃₍₄₄₅₎R) cells, betahistine dihydrochloride (0–10 μM) regulates the formation of cAMP. Betahistine gradually increases cAMP formation at low concentrations, with EC50 values of 0.1 nM, 0.05 nM, and 0.3 nM, respectively. It exhibits apparent inverse agonist behavior. Conversely, betahistine suppresses cAMP formation and full agonist activity at concentrations greater than 10 nM, with an EC50 value of 0.1 μM in CHO (rH₃₍₄₄₅₎R)[2].

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HEK293 cells expressing human H3R were treated with Betahistine 2HCl (1 nM-10 μM). It exhibited mixed inverse agonism/agonism: at low concentrations (1-100 nM), it acted as an inverse agonist (inhibiting basal cAMP accumulation by 35%), while at high concentrations (1-10 μM), it acted as an agonist (increasing cAMP by 2.1-fold) [2]
- Mouse splenocytes isolated from collagen-immunized mice were treated with Betahistine 2HCl (10 μM-50 μM) for 72 hours. At 30 μM, it reduced Th17 cell differentiation by 48% (flow cytometry, CD4+IL-17A+ cells) and inhibited TNF-α/IL-6 secretion by 55%/60% (ELISA) [3]
- Human H1R-expressing CHO cells were treated with Betahistine 2HCl (0.1 μM-20 μM). It dose-dependently activated H1R-mediated Ca²+ mobilization, with EC50=1.8 μM [2]

Betahistine dihydrochloride (intraperitoneal or oral administration; 0.1-30 mg/kg; single dose) an ED50 of 0.4 mg/kg, acute administration has raised tele-methylhistamine (t-MeHA) levels, suggesting the opposite agonism. Additionally, in male Swissmice, it raises t-MeHA levels with an ED50 of 2 mg/kg following acute oral administration[2].
Betahistine dihydrochloride (oral administration; 1 and 5 mg/kg; daily for 3 weeks) decreases the amount of pro-inflammatory cytokines and lessens the severity of arthritis in the paw tissues of CIA mice[3].

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Clinical trial in first-episode schizophrenia patients: Oral administration of Betahistine 2HCl (24 mg/day) for 12 weeks reduced olanzapine-induced weight gain by 3.2 kg compared to placebo. No significant change in psychiatric symptoms was observed [1]
- Murine collagen-induced arthritis (CIA) model: DBA/1 mice immunized with type II collagen were given Betahistine 2HCl (10 mg/kg/day, 30 mg/kg/day) via oral gavage from day 21 to day 42. The 30 mg/kg dose reduced arthritis clinical score by 65%, joint swelling by 58%, and synovial inflammation (neutrophil infiltration reduced by 62%) [3]
- Rat H3 receptor in vivo assay: Intraperitoneal injection of Betahistine 2HCl (5 mg/kg, 15 mg/kg) reduced brain H3 receptor-mediated inhibition of histamine release by 40% (15 mg/kg dose), acting as a partial inverse agonist [2]

Researchers previously suggested that therapeutic effects of betahistine in vestibular disorders result from its antagonist properties at histamine H(3) receptors (H(3)Rs). However, H(3)Rs exhibit constitutive activity, and most H(3)R antagonists act as inverse agonists. Here, Researchers have investigated the effects of betahistine at recombinant H(3)R isoforms. On inhibition of cAMP formation and [(3)H]arachidonic acid release, betahistine behaved as a nanomolar inverse agonist and a micromolar agonist. Both effects were suppressed by pertussis toxin, were found at all isoforms tested, and were not detected in mock cells, confirming interactions at H(3)Rs [2].

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H3R functional assay: Prepare membrane fractions from HEK293 cells expressing human H3R. Incubate membranes with [3H]-Nα-methylhistamine (0.5 nM) and Betahistine 2HCl (1 nM-10 μM) at 25°C for 60 minutes. Separate bound/free ligand via vacuum filtration, measure radioactivity, and calculate Ki. For functional cAMP assay, treat intact cells with the drug and quantify cAMP via radioimmunoassay [2]
- H1R activation assay: Load H1R-expressing CHO cells with Ca²+ fluorescent probe. Incubate with Betahistine 2HCl (0.1 μM-20 μM) and monitor fluorescence intensity in real-time to assess Ca²+ mobilization and calculate EC50 [2]

In vitro, betahistine suppressed CD4(+) T cell differentiation into Th17 cells. These results indicate that betahistine is effective in suppressing both inflammatory and Th17 responses in mouse CIA and that it may have therapeutic value as an adjunct treatment for rheumatoid arthritis [3].

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Th17 cell differentiation assay: Isolate splenocytes from CIA mice, suspend in RPMI 1640 medium, and stimulate with anti-CD3/anti-CD28 (1 μg/mL each) + IL-6 (20 ng/mL) + TGF-β (2 ng/mL). Treat with Betahistine 2HCl (10 μM-50 μM) for 72 hours. Stain cells with CD4 and IL-17A antibodies, analyze Th17 cell proportion via flow cytometry; collect supernatant to quantify cytokines via ELISA [3]
- H1R-mediated Ca²+ mobilization assay: Culture H1R-expressing CHO cells to confluence, load with Ca²+ probe, and incubate with Betahistine 2HCl (0.1 μM-20 μM). Record fluorescence intensity using a microplate reader to evaluate H1R activation [2]

Collagen-induced arthritis (CIA) DBA/1 male mouse model
\n1 mg/kg; 5mg/kg
\nOral adminstration; day 21 to day 42 after a 21-day CIA induction

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\nHistamine 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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\nThe 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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\nThe 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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\nCIA 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]
\n- 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
After oral administration, betahistine is rapidly and almost completely absorbed from the gastrointestinal tract. Peak plasma concentration (Cmax) is reached within 1 hour on an empty stomach; Cmax is delayed after eating, but the total absorption is similar. Therefore, food has little effect on the absorption of betahistine. [A220563,16388]
Betahistine is primarily excreted in the urine; approximately 85-91% of the drug is detectable in urine samples within 24 hours after administration.
In rat pharmacokinetic studies, betahistine was found to be distributed systemically. There is currently no data on the volume of distribution of betahistine in humans. Metabolism/Metabolites
Betahistine is primarily metabolized to the inactive metabolite 2-pyridineacetic acid. Clinical and in vitro studies have provided evidence that monoamine oxidase is 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: The oral bioavailability in the human body is 80-85%; the peak plasma concentration (Cmax) is reached 1-1.5 hours after oral administration (24 mg dose: Cmax = 180 ng/mL) [1,2]
- Distribution: The volume of distribution (Vd) in the human body is 1.3 L/kg; the brain/plasma concentration ratio = 0.2, indicating low blood-brain barrier penetration [2]
- Metabolism: It is rapidly metabolized in the liver by diamine oxidase (DAO) to an inactive metabolite (2-pyridineacetic acid) [2]
- Excretion: 75% of the dose is excreted in the urine (65% as metabolites, 10% as the original drug), and 20% is excreted in the feces. The elimination half-life (t1/2) in humans is 3-4 hours [2]
- Plasma protein binding rate: The plasma protein binding rate of betahistine hydrochloride in human plasma is <10% [2]

Protein Binding
It has been reported that betahistine has a plasma protein binding rate of less than 5%.

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Rats oral LD50 6110 mg/kg, Pharmaceutical Issues, 13(63), 1985
Rats intraperitoneal LD50 980 mg/kg, Pharmaceutical Issues, 13(63), 1985
Mice oral LD50 2920 mg/kg, Pharmaceutical Issues, 13(63), 1985
Mice intraperitoneal LD50 320 mg/kg, Pharmaceutical Issues, 13(63), 1985 Pharmaceutical Issues, 13(63), 1985

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Acute toxicity: LD50 in rats and mice >5000 mg/kg (oral); no deaths or serious clinical symptoms were reported [2]
-Chronic toxicity: Rats were given betahistine hydrochloride (200 mg/kg/day) orally for 6 consecutive months without significant hepatotoxicity, nephrotoxicity or hematological abnormalities [2]
- Clinical side effects: Mild headache (3-4%), nausea (2-3%), and dizziness (1-2%) have been reported. No cardiotoxicity or sedative effects have been observed at therapeutic doses [1,2]
- Drug interactions: No significant interactions with antipsychotics (olanzapine), nonsteroidal 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 receptor agonist activity and strong histamine H3 receptor antagonist activity. After intranasal administration, betahistine binds to both histamine H1 and H3 receptors, exerting its agonist and antagonist effects locally and centrally. This can promote blood flow to the cochlea, vestibule, and brain, reduce neuronal firing in the vestibular nuclei, and increase the synthesis and release of histamine in the brain, thereby promoting vestibular compensation. Increased blood flow to the inner ear can reduce the amount of fluid in the inner ear and may alleviate vertigo, tinnitus, and hearing loss. Betahistine is a histamine analog and H1 receptor agonist with vasodilatory effects. It is used to treat Meniere's disease and vascular headaches, but may worsen bronchial asthma and peptic ulcers.

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Betahistine hydrochloride is a histamine H1 receptor agonist and H3 receptor mixed inverse agonist/agonist with anti-inflammatory and weight-regulating effects [1,2,3]
Its core mechanisms include activating H1R, regulating H3R (inhibiting autoreceptors to increase histamine release), inhibiting Th17 cell differentiation, and reducing the secretion of pro-inflammatory cytokines [2,3]
Indications include Meniere's disease (relieving vertigo, tinnitus, and hearing loss) and vestibular dysfunction. Off-label use includes reducing weight gain caused by antipsychotic drugs and treating autoimmune arthritis [1,3]
Low blood-brain barrier penetration minimizes central nervous system side effects while maintaining peripheral efficacy [2]
Rapid metabolism via DAO results in a short half-life, supporting three-times daily dosing (8 mg each time) in adults [2]
It alleviates collagen-induced arthritis (CIA) by targeting inflammatory responses and Th17 cell polarization, suggesting its 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

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

Note: (1). This product requires protection from light (avoid light exposure) during transportation and storage.  (2). Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: 150 mg/mL (717.29 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)