Betahistine impurity

Betahistine (0-10 μM) has IC50 values of 1.9 μM and 3.3 μM, respectively, that prevent [¹²⁵I]iodoproxyfan from binding to the membranes of CHO (rH₃₍₄₄₅₎R) and CHO (hH₃₍₄₄₅₎R) cells. result in Ki values that are, respectively, 2.5 μM and 1.4 μM3].

[1]. Characterization and in silico Mutagenic Assessment of a New Betahistine Degradation Impurity. J. Braz. Chem. Soc. vol.30 no.7 São Paulo July 2019 Epub July 04, 2019.

[2]. 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.

[3]. 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.

Currently, the pharmaceutical industry is highly concerned about drug degradation products because these compounds may pose a risk to patients. A previous study on the degradation of betahistine (N-α-methyl-2-pyridylethylamine) under different stress conditions detected three major impurities, named A, B and C. The degradation products were analyzed by electrospray ionization time-of-flight mass spectrometry (ESI-TOF) and nuclear magnetic resonance (NMR). The mutagenicity of the impurities was assessed using Derek Nexus and Sarah Nexus software. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of forced degradation samples of betahistine revealed the presence of a new impurity, named impurity C1. The new impurity was fully structurally characterized by two-dimensional nuclear magnetic resonance experiments. Computer simulation mutagenicity studies showed that neither the active pharmaceutical ingredient nor the degradation impurity was active. A new betahistine impurity was identified by a systematic study of forced degradation samples. Computer simulation mutagenicity studies of betahistine degradation impurities may help in the risk assessment of drug products. [1]

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Histamine antagonism is associated with weight gain caused by antipsychotic drugs. Betahistine, a histamine enhancer with H1 agonist/H3 antagonist properties (48 mg, three times daily), was used in combination with olanzapine (10 mg/day) for 6 weeks in three patients with first-episode schizophrenia. Weight was measured at baseline and weekly thereafter. Clinical rating scales were completed at baseline and week 6. All participants experienced weight gain (mean weight gain 3.1 ± 0.9 kg), and a similar pattern of weight gain was observed: weight gain in the first 2 weeks, followed by no further weight gain (2 patients) or a slight decrease (1 patient) between weeks 3 and 6. Weight gain did not exceed 7% of baseline weight in any participant, which is the clinically significant threshold for weight gain. Betahistine is safe and well-tolerated and does not interfere with the antipsychotic effects of olanzapine. Our results support a placebo-controlled evaluation of the potential weight-loss effect of betahistine in olanzapine-induced weight gain. [2] We previously proposed that betahistine's mechanism of action in treating vestibular disorders is its antagonistic effect on histamine H₃ receptors (H₃Rs). However, H₃Rs are constitutively active, and most H₃R antagonists act as inverse agonists. This study investigated the effects of betahistine on recombinant H₃R subtypes. Betahistine inhibits cAMP production and [³H]arachidonic acid release, acting as both a nanomolar inverse agonist and a micromolar agonist. Pertussis toxin inhibited both of these effects and was observed in all tested subtypes but not detected in mock cells, confirming the interaction between betahistine and H₃Rs. The inverse agonist potency of betahistine and its affinity for binding to [¹²⁵I]iodopropoxyphene were similar in rats and humans. Subsequently, we investigated the effect of betahistine on the activity of histaminergic neurons by measuring distal methylhistamine (t-MeHA) levels in the mouse brain. Acute intraperitoneal injection of betahistine increases t-MeHA levels with an ED₅₀ of 0.4 mg/kg, indicating a reverse agonist effect. At high doses, t-MeHA levels gradually return to baseline levels, a change that may be a result of agonist effects. After acute oral administration, betahistine increases t-MeHA levels with an ED50 of 2 mg/kg, a rightward shift that may be due to almost complete first-pass metabolism. In all cases, the maximum effect of betahistine was lower than that of ciproxifen, indicating a partial reverse agonist effect. After 8 days of oral administration, the only effective dose of betahistine was 30 mg/kg, indicating tolerance. These data strongly suggest that the therapeutic effect of betahistine stems from its enhancement of histaminergic neuronal activity through reverse agonist activation of H3 autoreceptors. [3]

C15H19N3

241.338

241.158

C, 74.65; H, 7.94; N, 17.41

5452-87-9

5452-87-9

227430

Solid powder

1.067g/cm3

371.9ºC at 760mmHg

178.7ºC

1.568

2.193

0

3

6

18

198

0

CN(CCC1=NC=CC=C1)CCC2=NC=CC=C2

PQHKIDBZBKQYMR-UHFFFAOYSA-N

InChI=1S/C15H19N3/c1-18(12-8-14-6-2-4-10-16-14)13-9-15-7-3-5-11-17-15/h2-7,10-11H,8-9,12-13H2,1H3

N-methyl-2-pyridin-2-yl-N-(2-pyridin-2-ylethyl)ethanamine

NSC19005; NSC-19005; 5452-87-9; N-Methyl-2-(pyridin-2-yl)-N-(2-(pyridin-2-yl)ethyl)ethanamine; Betahistine EP Impurity C; N-Methyl-N,N-bis(2-pyridylethyl)amine; Methylbis(2-pyridylethyl)amine; NSC-19005; Betahistine impurity C; NSC 19005

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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