Histamine H1 receptor

Bepotastine（10、100、1000 µM；预孵育 120 分钟）可减少 A23187 治疗诱导的组胺释放，在 1000 µM 时达到统计学上显着的减少水平[1]。 Bepotastine（50 µM；1 小时）可抑制 NHEK 中 NGF mRNA 的表达[2]。细胞活力测定[1] 细胞系：RPMC 浓度：10、100、1000 µM 孵育时间：120 分钟（预孵育） 结果：组胺释放减少。 Western Blot 分析[2] 细胞系：NHEK 浓度：50 µM（预孵育） 孵育时间：1 小时 结果：抑制 NHEK 中 NGF mRNA 的表达。

贝托斯汀（10 g/L；滴眼剂；一只眼睛 3 次，间隔 20 分钟）显示出对 PAF 诱导的结膜嗜酸性粒细胞浸润的显着抑制作用[1]。贝托斯汀（3 mg/kg；口服；一次）抑制抓挠行为的频率为 59.0，持续时间为 14.57 秒，与对照组相比几乎处于相同水平[3]。 Bepotastine（10 mg/kg；口服；一次）在出现皮疹的 NC/Nga 小鼠中显着抑制血清 LTB 4 水平，1 小时时为 711.3 pg/mL，2 小时时为 858.8 pg/mL[3]。动物模型：豚鼠（6周龄）[1]。剂量：10 µL 为 10 g/L (1.0% (w/v))。给药方法：滴眼剂； 3次，间隔20分钟（一只眼睛）。结果：抑制PAF诱导的结膜嗜酸性粒细胞浸润。动物模型：雄性BALB/c小鼠（12周龄）； NC/Nga 小鼠[3]。剂量：3、10 mg/kg 给药方法：口服；一次（诱导雄性 BALB/c 小鼠抓挠行为前 1 小时）。结果：显着抑制雄性 BALB/c 小鼠组胺介导的抓挠行为。显着抑制出现皮疹的 NC/Nga 小鼠的血清 LTB 4 水平。

细胞系：RPMC
浓度：10、100、1000 µM
孵育时间：120 分钟（预孵育）
结果：组胺释放减少

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).

Absorption, Distribution and Excretion
Tmax, after single dose, opthalmic = 1.2 hours; Cmax, 1.5%, opthalmic dose = 7.3 ±1.9 ng/mL; After 24 hours post-installation, levels of bepotastine are below quantifiable limit of 2 ng/mL. Minimal systemic absorption with opthalmic dosage form.
When a oral dose of 2.5 - 40 mg bepotastine is given, 75%-90% of the dose was excreted unchanged in the urine by 24 hours.

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Metabolism / Metabolites
Minimal metabolism via CYP enzymes

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Biological Half-Life
Elimination half life = 2.5 hours

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
There are no reports of infants breastfed during maternal therapy with bepotastine. Because absorption from the eye is limited, bepotastine would not be expected to cause any adverse effects in breastfed infants. To substantially diminish the amount of drug that reaches the breastmilk after using eye drops, place pressure over the tear duct by the corner of the eye for 1 minute or more, then remove the excess solution with an absorbent tissue.
◉ Effects in Breastfed Infants
Relevant published information on bepotastine was not found as of the revision date. In one telephone follow-up study, mothers reported irritability and colicky symptoms in 10% of infants exposed to various antihistamines and drowsiness was reported in 1.6% of infants. None of the reactions required medical attention and none of the patients were using bepotastine.
◉ Effects on Lactation and Breastmilk
Antihistamines in relatively high doses given by injection can decrease basal serum prolactin in nonlactating women and in early postpartum women. However, suckling-induced prolactin secretion is not affected by antihistamine pretreatment of postpartum mothers. The prolactin level in a mother with established lactation may not affect her ability to breastfeed. Low ophthalmic doses of bepotastine are unlikely to have the same effect on serum prolactin.

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Protein Binding
55.4% mean plasma protein binding with 10 mg oral dose. Extent of protein binding is 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 that is (S)-(4-chlorophenyl)(pyridin-2-yl)methanol in which the hydroxyl hydrogen is substituted by a 1-(3-carboxypropyl)piperidin-4-yl group. A topical, selective and non-sedating histamine (H1) receptor antagonist used (as its benzenesulfonate salt) for treatment of itching associated with allergic conjunctivitis. It has a role as a H1-receptor antagonist and an anti-allergic agent. It is a member of pyridines, a monocarboxylic acid, a member of piperidines, an ether and a member of monochlorobenzenes. It is a conjugate base of a bepotastine(1+).
Bepotastine is a non-sedating, selective antagonist of the histamine 1 (H1) receptor. Bepotastine was approved in Japan for use in the treatment of allergic rhinitis and uriticaria/puritus in July 2000 and January 2002, respectively, and is marketed by Tanabe Seiyaku Co., Ltd. under the brand name Talion. It is available in oral and opthalmic dosage forms in Japan. The opthalmic solution is FDA approved since Sept 8, 2009 and is under the brand name Bepreve.
Bepotastine is a Histamine-1 Receptor Antagonist.

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Drug Indication
For the symptomatic treatment of itchy eyes (caused by IgE-induced mast cell degranulation) due to allergic conjunctivitis.
FDA Label

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Mechanism of Action
Because of a type 1 hypersensitivity reaction cascade that is triggered by antigen exposure, allergic conjunctivitis occurs. Allergen exposure is followed by conjunctival mast cell degranulation and histamine released as a result of the formation of complementary IgE cross-links on the conjunctiva. Due to the release of histamine, symptoms such as itching can be observed. Bepotastine works to relieve itchy eyes by three primary mechanisms of action. It is a non-sedating, selective antagonist of the histamine 1 (H1) receptor, a mast cell stabilizer, and it suppresses the migration of eosinophils into inflamed tissues to prevent tissue damage and worsening of allergic inflammation of the conjunctiva.

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Pharmacodynamics
Bepotastine is a non-sedating, selective antagonist of the histamine 1 (H1) receptor. It belongs to the second-generation piperidine chemical class. It is a mast cell stabilizer and suppresses the migration of eosinophils into inflamed tissues. Furthermore, bepotastine does not interact with serotonin, muscarinic, benzodiazepine, and beta-adrenergic receptor that would otherwise result in adverse reactions such as dry mouth or sonmolence. 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

62.66

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

注意： 请将本产品存放在密封且受保护的环境中，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: 78~100 mg/mL (200.6~257.1 mM)
Water: ~78 mg/mL
Ethanol: ~78 mg/mL

配方 1 中的溶解度: ≥ 2.5 mg/mL (6.43 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 (6.43 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 (6.43 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。