Histamine H1 receptor

Bepotastine (10, 100, 1000 µM; preincubates for 120 min) reduces the amount of histamine released when treated with A23187, reaching a statistically significant level at 1000 µM[1].
Bepotastine (50 µM; 1 h) inhibits the expression of NGF mRNA in NHEKs[2].

Bepotastine (10 g/L; eye drop; 3 times at intervals of 20 min in one eye) significantly reduces the infiltration of conjunctival eosinophils induced by PAF[1].
Bepotastine (3 mg/kg; p.o.; once) minimizes scratching to a frequency of 59.0 and a duration of 14.57 seconds, which is nearly identical to the control[3].
Bepotastine (10 mg/kg; p.o.; once) significantly suppresses serum LTB 4 levels to 711.3 pg/mL at 1 h and 858.8 pg/mL at 2 h in NC/Nga mice with a rash[3].

Cell Line: RPMCs
Concentration: 10, 100, 1000 µM
Incubation Time: 120 min (preincubate)
Result: Decreased the release of histamine

Guinea pigs (6-week-old)
10 g/L (1.0% (w/v)) for 10 µL
Eye drop; 3 times at intervals of 20 min (in one eye).

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Antigen-induced conjunctival vascular hyperpermeability in passively sensitized guinea pigs: Guinea pigs (6-week-old) were anesthetized with ketamine/xylazine. They were passively sensitized by subconjunctival injection of 50 μL of anti-ovalbumin antiserum (diluted 1:600) in one eye. 48 hours later, animals were challenged intravenously with ovalbumin (3 mg/kg) and Evans blue dye (20 mg/kg). 30 minutes before antigen challenge, animals received topical instillation of 10 μL of test article or saline. After 30 minutes, animals were euthanized, conjunctiva was excised, and extravasated dye was extracted and quantified by absorbance at 620 nm. [1]
- Histamine-induced conjunctival vascular hyperpermeability: Guinea pigs (5-week-old) were anesthetized. Immediately after intravenous injection of Evans blue dye (20 mg/kg), 50 μL of 0.2% histamine dihydrochloride was injected into the upper conjunctival sac. 30 minutes before histamine injection, animals received topical instillation of 10 μL of test article or saline. After 30 minutes, animals were euthanized, conjunctiva excised, and extravasated dye quantified. [1]
- PAF-induced eosinophil infiltration into guinea pig conjunctiva: Guinea pigs (6-week-old) received topical instillation of 10 μL of test article in one eye three times at 20-minute intervals. 20 minutes after the last instillation, 10 μL of 0.1% PAF was topically applied to the conjunctiva. 6 hours after PAF instillation, animals were euthanized, conjunctiva removed, and eosinophil peroxidase activity was determined as an index of eosinophil infiltration. [1]

Absorption, Distribution and Excretion
Following a single ophthalmic dose, the time to peak concentration (Tmax) is 1.2 hours; the peak concentration (Cmax) for a 1.5% ophthalmic dose is 7.3 ± 1.9 ng/mL. 24 hours after implantation, Bepotastine concentrations are below the limit of quantitation (LOQ) of 2 ng/mL. Systemic absorption of the ophthalmic formulation is minimal. Following oral administration of 2.5–40 mg Bepotastine, 75%–90% of the dose is excreted unchanged in the urine within 24 hours. Metabolism/Metabolites Primarily metabolized by CYP enzymes. Biological Half-Life Elimination half-life = 2.5 hours.

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
There are currently no reports of mothers breastfeeding their infants while receiving Bepotastine treatment. Due to limited absorption of Bepotastine through the eyes, no adverse effects are expected on breastfed infants. After using eye drops, to significantly reduce the amount of medication entering breast milk, press the tear duct at the corner of the eye for at least 1 minute, then blot away excess medication with absorbent tissue.
◉ Effects on Breastfed Infants
As of the revision date, no published information was found regarding Bepotastine. In a telephone follow-up study, mothers reported irritability and colic in 10% of infants exposed to various antihistamines, and lethargy in 1.6% of infants. All adverse reactions were non-medical, and none of the patients were using Bepotastine.
◉ Effects on Lactation and Breast Milk
Higher doses of antihistamines can lower baseline serum prolactin levels in non-lactating women and early postpartum women. However, pre-administration of antihistamines by postpartum mothers does not affect lactation-induced prolactin secretion. Prolactin levels in established lactating mothers are unlikely to affect their lactation capacity. Low-dose ophthalmic Bepotastine is unlikely to have the same effect on serum prolactin.

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Protein Binding
After oral administration of 10 mg, the mean plasma protein binding rate was 55.4%. The degree of protein binding was independent of plasma drug concentration.

[1]. Bepotastine besilate, a highly selective histamine H(1) receptor antagonist, suppresses vascular hyperpermeability and eosinophil recruitment in in vitro and in vivo experimental allergic conjunctivitis models. Exp Eye Res. 2010 Jul;91(1):8.

[2]. Bepotastine besilate downregulates the expression of nerve elongation factors in normal human epidermal keratinocytes. J Dermatol Sci. 2018 Apr 23:S0923-1811(18)30186-5.

[3]. Oral administration of bepotastine besilate suppressed scratching behavior of atopic dermatitis model NC/Nga mice. Int Arch Allergy Immunol. 2008;145(4):277-82.

[4]. Non-clinical pharmacology, pharmacokinetics, and safety findings for the antihistamine bepotastine besilate. Curr Med Res Opin. 2010 Oct;26(10):2329-38.

Bepotastine is an ether compound with the chemical name (S)-(4-chlorophenyl)(pyridin-2-yl)methanol, in which the hydroxyl hydrogen is replaced by a 1-(3-carboxypropyl)piperidin-4-yl group. It is a topical, selective, non-sedating histamine (H1) receptor antagonist, used in benzyl sulfonate form to treat itching caused by allergic conjunctivitis. It is both an H1 receptor antagonist and an antihistamine. It belongs to the Pyridalyl, monocarboxylic acid, piperidine, ether, and monochlorobenzene classes. It is the conjugate base of Bepotastine (1+). Bepotastine is a non-sedating, selective histamine 1 (H1) receptor antagonist. Bepotastine was approved in Japan in July 2000 and January 2002 for the treatment of allergic rhinitis and urticaria/pruritus, respectively, and is marketed by Tanabe Pharmaceutical Co., Ltd. under the brand name Talion. In Japan, it is available in oral and ophthalmic formulations. Bepreve ophthalmic solution was approved by the U.S. Food and Drug Administration (FDA) on September 8, 2009. Bepreve is a histamine-1 receptor antagonist. Indications: For the treatment of itchy eyes caused by IgE-induced mast cell degranulation in allergic conjunctivitis. FDA Label: Mechanism of Action: Allergic conjunctivitis occurs due to a type I hypersensitivity cascade triggered by antigen exposure. Upon contact with an allergen, conjunctival mast cells degranulate and form complementary IgE cross-links on the conjunctiva, releasing histamine. Histamine release leads to symptoms such as itching. Bepreve relieves itchy eyes through three main mechanisms of action. It is a non-sedating, selective histamine 1 (H1) receptor antagonist, a mast cell stabilizer, and inhibits the migration of eosinophils to inflamed tissues, thus preventing tissue damage and exacerbation of allergic conjunctival inflammation.

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Pharmacodynamics
Bepotastine is a non-sedating, selective histamine 1 (H1) receptor antagonist. It belongs to the second-generation piperidine class of compounds. It is a mast cell stabilizer and inhibits the migration of eosinophils to inflamed tissues. Furthermore, Bepotastine does not interact with serotonin receptors, muscarinic receptors, benzodiazepine receptors, or β-adrenergic receptors, therefore it does not cause adverse reactions such as dry mouth or drowsiness. Onset of action = 0.25 hours; duration of action = 12-24 hours.

C21H25CLN2O3

388.8878

388.155

C, 64.86; H, 6.48; Cl, 9.12; N, 7.20; O, 12.34

125602-71-3

Bepotastine besilate; 190786-44-8; Bepotastine tosylate; 1160415-45-1; 125602-71-3

164522

Light brown to brown liquid

1.3±0.1 g/cm3

546.8±50.0 °C at 760 mmHg

56-58 °C

284.5±30.1 °C

0.0±1.5 mmHg at 25°C

1.605

3.67

1

5

8

27

449

1

C1=CC=NC(=C1)[C@H](C2=CC=C(C=C2)Cl)OC3CCN(CCCC(=O)O)CC3

YWGDOWXRIALTES-NRFANRHFSA-N

InChI=1S/C21H25ClN2O3/c22-17-8-6-16(7-9-17)21(19-4-1-2-12-23-19)27-18-10-14-24(15-11-18)13-3-5-20(25)26/h1-2,4,6-9,12,18,21H,3,5,10-11,13-15H2,(H,25,26)/t21-/m0/s1

4-[4-[(S)-(4-chlorophenyl)-pyridin-2-ylmethoxy]piperidin-1-yl]butanoic acid

TAU-284; TAU 284; TAU284; Bepotastine band name: Talion; Bepreve

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: 78~100 mg/mL (200.6~257.1 mM)
Water: ~78 mg/mL
Ethanol: ~78 mg/mL

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.43 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 (6.43 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 (6.43 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.)