Histamine H3 receptor ( IC50 = 1.9 μM )
Histamine H1 receptor (agonist), Histamine H3 receptor (antagonist) [1]

With IC50 values of 1.9 μM and 3.3 μM, respectively, betahistine (0-10 μM) inhibits the binding of [125I]iodoproxyfan to CHO (rH3(445)R) and CHO (hH3(445)R) cell membranes. The corresponding Ki values are 2.5 μM and 1.4 μM [2]. The generation of cAMP in CHO (rH3(445)R), CHO (rH3(413)R, and CHO (hH3(445)R) cells is modulated by betahistine (0-10 μM). Betahistine exhibits clear inverse agonistic properties at low doses, progressively increasing the production of cAMP at EC50 values of 0.1 nM, 0.05 nM, and 0.3 nM. On the other hand, betahistine exhibits full agonist activity, with an EC50 value of 0.1 μM in CHO (rH3(445)R), and inhibits cAMP production at concentrations higher than 10 nM [2].

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In CHO cells expressing the rat H3(445)R isoform, Betahistine displayed a biphasic effect on forskolin-stimulated cAMP accumulation. At low concentrations (EC50 = 0.1 ± 0.1 nM), it acted as an inverse agonist, enhancing cAMP formation by a maximum of 32 ± 7%, similar to the inverse agonist thioperamide. At higher concentrations (EC50 = 0.1 ± 0.1 µM), it acted as an agonist, inhibiting cAMP formation by a maximum of 21 ± 3%, similar to the agonist histamine. [2]
- On A23187-evoked [3H]arachidonic acid release in CHO cells expressing the rat H3(445)R isoform, Betahistine again showed a biphasic effect. It acted as an inverse agonist at low concentrations (EC50 = 0.1 ± 0.1 nM), reducing release by a maximum of 47 ± 5%, similar to thioperamide. At higher concentrations (EC50 = 7 ± 1 µM), it acted as an agonist, increasing release by a maximum of 41 ± 11%, similar to histamine. [2]
- In CHO cells expressing the rat H3(413)R isoform, Betahistine also produced biphasic effects on both cAMP accumulation (inverse agonist EC50 = 0.05 ± 0.15 nM, maximal increase +17 ± 4%; agonist EC50 ≥15 ± 1 µM, maximal inhibition -73 ± 2%) and [3H]arachidonic acid release (inverse agonist EC50 = 0.06 ± 0.23 nM, maximal decrease -16 ± 5%; partial agonist EC50 = 4 ± 1 µM, maximal increase +51 ± 7%). [2]
- In CHO cells expressing the human H3(445)R isoform, Betahistine produced biphasic effects on cAMP accumulation (inverse agonist EC50 = 0.3 ± 1.4 nM, maximal increase +15 ± 4%; agonist EC50 ≥48 ± 2 µM, maximal inhibition -70 ± 3%) and [3H]arachidonic acid release (inverse agonist EC50 = 0.1 ± 0.3 nM, maximal decrease -25 ± 3%; agonist EC50 ≥65 ± 20 µM, maximal increase +180 ± 31%). [2]
- The inverse agonist and agonist effects of Betahistine on cAMP formation in CHO(hH3(445)R) cells were completely abolished by pre-treatment with pertussis toxin (PTX), confirming that these effects are mediated by Gi/o protein-coupled H3 receptors. [2]
- In a radioligand binding assay using [125I]iodoproxyfan, Betahistine inhibited binding to membranes of CHO(rH3(445)R) and CHO(hH3(445)R) cells with Ki values of 1.4 ± 0.1 µM and 2.5 ± 0.3 µM, respectively. For the CHO(rH3(413)R) isoform, the inhibition curve was shallow (Hill coefficient 0.5 ± 0.1), resolving into a high-affinity site with an IC50 of 0.9 ± 0.3 nM and a low-affinity site with an IC50 of 77 ± 42 µM. [2]

Telemethylhistamine (t-MeHA) levels are raised by acute betahistine treatment (i.p. or oral; 0.1–30 mg/kg; single dose), with an ED50 of 0.4 mg/kg, indicating a reverse agonistic effect. Furthermore, upon acute oral treatment, male Swiss rats showed elevated t-MeHA levels, with an ED50 of 2 mg/kg [2]. In the paw tissue of CIA mice, betahistine (orally given; 1 and 5 mg/kg; once daily for 3 weeks) decreases the amount of pro-inflammatory cytokines and lessens the severity of arthritis [3].

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In a 6-week clinical study involving three first-episode, drug-naive schizophrenia patients, co-administration of Betahistine (48 mg/day, three times daily) with olanzapine (10 mg/day) resulted in a mean weight gain of 3.1 ± 0.9 kg from baseline. None of the participants gained 7% or more of their initial body weight, which is the threshold for clinically significant weight gain. [1]
- A similar pattern of weight gain was observed across all three patients: weight increased during the first 2 weeks of treatment, with no further weight gain (two patients) or a minor weight loss (one patient) from weeks 3 to 6. [1]
- Clinical rating scales showed a significant decrease from baseline to week 6 in Clinical Global Impression (CGI) scores (4.0 ± 0.1 to 2.3 ± 0.6, P < 0.01) and Scale for the Assessment of Positive Symptoms (SAPS) scores (3.5 ± 1.4 to 0.5 ± 0.9, P < 0.05), indicating that Betahistine did not interfere with the antipsychotic effect of olanzapine. [1]

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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Radioligand Binding Assay: Membrane preparations from CHO cells stably expressing rat H3(445)R, rat H3(413)R, or human H3(445)R isoforms were incubated with 20 pM of the selective H3 receptor radioligand [125I]iodoproxyfan in the presence of increasing concentrations of Betahistine for 60 minutes at 25°C. Non-specific binding was determined using 1 µM imetit. The reaction was terminated by filtration, and bound radioactivity was measured. The specific binding represented approximately 80% of the total binding. The inhibition constant (Ki) values were calculated from the IC50 values using the Cheng-Prusoff equation. [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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cAMP Accumulation Assay: CHO cells stably expressing rat or human H3 receptor isoforms were incubated for 2 hours at 37°C with 0.5 µCi of [3H]arachidonic acid in culture medium containing 100 µM isobutyl-methyl-xanthine. The cells were then stimulated with 3 µM forskolin to induce cAMP formation. The effects of increasing concentrations of Betahistine on forskolin-stimulated cAMP accumulation were measured. The natural agonist histamine (10 µM) and the inverse agonist thioperamide (10 µM) were used as controls. The accumulated cAMP was extracted and quantified by radioimmunoassay. [2]
- [3H]Arachidonic Acid Release Assay: CHO cells stably expressing rat or human H3 receptor isoforms were pre-incubated for 2 hours at 37°C with 0.5 µCi of [3H]arachidonic acid in culture medium containing 0.2% bovine serum albumin. After washing, the cells were stimulated with 2 µM of the calcium ionophore A23187 in the presence or absence of increasing concentrations of Betahistine, histamine (10 µM), or thioperamide (10 µM) for 30 minutes. The release of [3H]arachidonic acid into the supernatant was then determined by liquid scintillation counting. [2]

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]

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Acute Intraperitoneal Administration:** Male Swiss mice (18-20 g) were administered Betahistine dissolved in saline solution (0.9% NaCl) via intraperitoneal injection. Control animals received saline only. Mice were sacrificed by decapitation 90 minutes after administration, and whole brains were collected for t-MeHA analysis. [2]
- **Acute and Repeated Oral Administration:** For acute oral studies, Betahistine was dissolved in 1% methylcellulose and administered by oral gavage to male Swiss mice. Animals were sacrificed 90 minutes post-administration. For repeated oral administration, Betahistine was given once daily for 8 days, with the final dose administered 90 minutes before sacrifice. Control animals received the vehicle (1% methylcellulose) only. [2]

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Acute Intraperitoneal Administration: Male Swiss mice (18-20 g) were administered Betahistine dissolved in saline solution (0.9% NaCl) via intraperitoneal injection. Control animals received saline only. Mice were sacrificed by decapitation 90 minutes after administration, and whole brains were collected for t-MeHA analysis. [2]
- Acute and Repeated Oral Administration: For acute oral studies, Betahistine was dissolved in 1% methylcellulose and administered by oral gavage to male Swiss mice. Animals were sacrificed 90 minutes post-administration. For repeated oral administration, Betahistine was given once daily for 8 days, with the final dose administered 90 minutes before sacrifice. Control animals received the vehicle (1% methylcellulose) only. [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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Betahistine crosses the blood-brain barrier and acts centrally by enhancing histamine synthesis in the tuberomammillary nuclei of the posterior hypothalamus. [1]

Protein Binding

It has been reported that the plasma protein binding rate of betahistine is less than 5%.

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Oral LD50 in rats: 6110 mg/kg, Pharmaceutical Issues, 13(63), 1985
Intraperitoneal LD50 in rats: 980 mg/kg, Pharmaceutical Issues, 13(63), 1985
Oral LD50 in mice: 2920 mg/kg, Pharmaceutical Issues, 13(63), 1985
Intraperitoneal LD50 in mice: 320 mg/kg, Pharmaceutical Issues, 13(63), 1985

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Betahistine was safe and well tolerated in the three patients when co-administered with olanzapine (48 mg/day, t.i.d., for 6 weeks). No clinically significant side-effects of the olanzapine-betahistine combination were revealed. [1]

[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
Betahistine relieves dizziness caused by Meniere's disease by acting on histamine receptors.

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Betahistine is a structural analog of histamine. It exerts H1 receptor agonistic and H3 receptor antagonistic properties. [1]
- The drug is used clinically in the treatment of vertigo. [1]
- The mechanism for potential weight gain attenuation is hypothesized to involve the marked antagonistic effect on the presynaptic H3 receptor, which may lead to enhanced histamine release, rather than the direct but weak agonistic effect on postsynaptic H1 receptors. [1]
- The findings of this study justify a placebo-controlled evaluation of the putative weight-attenuating effect of Betahistine in antipsychotic-induced weight gain. [1]

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

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

Note: Please store this product in a sealed and protected environment, 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)

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

Solubility in Formulation 1: ≥ 2.5 mg/mL (18.36 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (18.36 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (18.36 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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