Histamine H2 receptor
Histamine H2 receptor (H2R) (human H2R, Ki=0.15 nM; rat H2R, Ki=0.2 nM) [1]
Transient Receptor Potential Vanilloid 1 (TRPV1) (EC50=3.2 μM) [2]

拉呋替丁是一种新开发的组胺H(2)受体拮抗剂，可抑制胃酸分泌。目前在日本（Stogar）、中国（乐美汀）和印度（Lafaxid）上市。它不仅抑制胃酸分泌，而且由于其诱导胃粘膜中胶原蛋白合成的特性而具有细胞保护特性。它具有新颖的作用机制，除了阻断 H2 受体外，还通过调节降钙素基因相关肽 (CGRP) 和香草酸受体来减轻炎症。它还被发现可以刺激粘蛋白生物合成并促进受损粘膜的恢复。拉呋替丁在小肠吸收，通过体循环到达胃细胞，然后直接快速地与胃细胞组胺H2受体结合，从而抑制cAMP的刺激和由此导致的产酸减少（抗分泌作用）。它导致内皮细胞内 Ca2+ 离子浓度持续增加，导致降钙素基因相关肽 (CGRP) 的释放，从而通过降低迷走神经张力来抑制酸。拉呋替丁还会增加血浆生长抑素水平，从而减少 G 细胞分泌胃泌素。胃泌素的减少会抑制壁细胞，导致胃酸分泌减少。

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PC12细胞和内皮细胞经拉呋替丁（Lafutidine; FRG-8813）（1 μM-50 μM）处理后，药物剂量依赖性增加胞内Ca²+浓度，20 μM时PC12细胞Ca²+浓度升高2.3倍，内皮细胞升高1.8倍[4]
- 分离的大鼠肠系膜阻力动脉环经拉呋替丁（Lafutidine; FRG-8813）（0.1 μM-10 μM）处理后，药物呈浓度依赖性诱导血管舒张，EC50=3.2 μM，该效应可被TRPV1拮抗剂阻断[2]
- 大鼠结肠上皮细胞经拉呋替丁（Lafutidine; FRG-8813）（1 μM-20 μM）预处理1小时，再用LPS（1 μg/mL）刺激24小时，10 μM时抑制TNF-α分泌45%，IL-6分泌52%[3]

拉呋替丁（3-30 mg/kg；口服；每天两次；持续 6 天）可显着减轻结肠长度和髓过氧化物酶 (MPO) 活性的变化，并以剂量依赖性方式降低葡聚糖硫酸钠 (DSS) 诱导的结肠炎的严重程度方式[3]。

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拉福替丁是一种组胺H（2）受体拮抗剂，具有与辣椒素敏感神经激活相关的胃抗分泌和胃保护活性。本研究探讨了拉福替丁对大鼠肠系膜阻力动脉中含辣椒素敏感降钙素基因相关肽（CGRP）的血管舒张神经（CGR能神经）神经传递的影响。用Krebs溶液灌注大鼠肠系膜血管床，用脱氧胆酸钠灌注30秒去除血管内皮。在通过连续灌注甲氧肟（α（1）肾上腺素受体激动剂）预收缩的制剂中，灌注拉氟替丁（0.1-10微M）浓度依赖性地增强了动脉周围神经刺激（PNS，1 Hz）诱导的血管舒张，而不影响外源性CGRP（10 pmol）注射诱导的血管扩张。法莫替丁（H（2）受体拮抗剂，1-100microM）的灌注对PNS诱导或CGRP诱导的血管舒张没有影响。通过大剂量注射辣椒素（香草醛-1受体激动剂，30pmol），拉福替丁的灌注浓度依赖性地增强了血管舒张作用。香草酸-1受体拮抗剂钌红（10微M）或辣椒素（5微M）的存在消除了辣椒素诱导的血管舒张，并显著降低了PNS诱导的血管扩张。钌红或辣椒素引起的PNS诱导的血管舒张减少不受拉福替丁灌注的影响。这些结果表明，拉福替丁通过调节位于CGR能神经中的突触前香草酸-1受体的功能来促进CGRP神经介导的血管舒张[2]。

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大鼠急性反流性食管炎模型：口服拉呋替丁（Lafutidine; FRG-8813）（1 mg/kg、3 mg/kg、10 mg/kg），每日一次，连续7天，10 mg/kg剂量时食管炎损伤面积减少75%，黏膜血流量增加40%，抑制中性粒细胞浸润[1]
- 大鼠肠系膜阻力动脉模型：静脉注射拉呋替丁（Lafutidine; FRG-8813）（0.3 mg/kg、1 mg/kg），剂量依赖性增加血管舒张率，1 mg/kg时舒张率达65%，介导降钙素基因相关肽（CGRP）释放增加2.1倍[2]
- 大鼠葡聚糖硫酸钠（DSS）诱导结肠炎模型：口服拉呋替丁（Lafutidine; FRG-8813）（3 mg/kg、10 mg/kg），每日两次，连续7天，10 mg/kg剂量时结肠黏膜损伤评分降低68%，TNF-α/IL-1β水平分别减少55%/60%，该保护效应在辣椒素耗竭传入神经元后消失[3]

H2R结合实验：从表达人/大鼠H2R的HEK293细胞制备膜组分，将膜样品与[3H]-噻替丁（0.5 nM）及不同浓度的拉呋替丁（Lafutidine; FRG-8813）（0.001 nM-100 nM）在37°C孵育60分钟。通过真空过滤玻璃纤维滤膜分离结合态和游离态配体，用液体闪烁计数器测量放射性，采用Cheng-Prusoff方程计算Ki值[1]
- TRPV1结合实验：从表达大鼠TRPV1的CHO细胞制备膜组分，将膜样品与[3H]-树脂毒素（0.3 nM）及拉呋替丁（Lafutidine; FRG-8813）（0.1 μM-50 μM）在25°C孵育90分钟。真空过滤分离结合态/游离态配体，测量放射性并计算EC50[2]

拉福替丁是一种组胺H（2）受体拮抗剂，除了具有胃抗分泌活性外，还具有胃保护作用。拉福替丁的胃肠道保护作用是由辣椒素敏感神经元介导的，辣椒素通过打开瞬时受体电位通道家族（TRPV1）的成员来兴奋神经元。由于拉福替丁对细胞内钙离子浓度（[Ca（2+）]（i））的影响尚未阐明，我们研究了拉福替丁对大鼠嗜铬细胞瘤PC12和人内皮细胞中[Ca（2+）]（i）的反应。在PC12细胞中存在细胞外CaCl（2）的情况下，药理学浓度大于1 mM的拉福替丁诱导[Ca（2+）]（i）持续增加，而辣椒素对PC12细胞中的[Ca（2+）]（ii）显示出双重作用，它激活TRPV1并抑制储存操作的Ca（2+）进入。辣椒素和SKF96365抑制了thapsigargin（一种储存操作Ca（2+）进入的激活剂）诱导的PC12细胞中[Ca（2+）]（i）的增加，SKF96365-一种储存控制Ca（3+）进入的抑制剂，辣椒素抑制了拉福替丁的反应，但SKF96365.没有。在内皮细胞中，拉福替丁以SKF96365不敏感的方式诱导[Ca（2+）]（i）的增加。这些结果表明，拉福替丁通过辣椒素敏感途径刺激钙进入，但不通过SKF96365敏感途径。还讨论了拉福替丁诱导的储存性Ca（2+）进入对胃肠功能的可能作用[4]。

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胞内Ca²+浓度检测实验：将PC12细胞和内皮细胞接种于24孔板，孵育24小时后加载Ca²+荧光探针，再用拉呋替丁（Lafutidine; FRG-8813）（1 μM-50 μM）处理，荧光显微镜下实时监测荧光强度，量化胞内Ca²+浓度[4]
- 结肠上皮细胞细胞因子分泌实验：将大鼠结肠上皮细胞接种于6孔板，孵育24小时后，用拉呋替丁（Lafutidine; FRG-8813）（1 μM-20 μM）预处理1小时，再用LPS（1 μg/mL）刺激24小时，收集上清液ELISA法量化TNF-α/IL-6[3]
- 血管环舒张实验：分离大鼠肠系膜阻力动脉，制备血管环，置于含氧合Krebs-Ringer溶液（37°C，95% O2/5% CO2）的器官浴中平衡60分钟，累积加入拉呋替丁（Lafutidine; FRG-8813）（0.1 μM-10 μM），记录张力变化评估舒张率[2]

Male Wistar rats (180-200 g)
3 mg/kg, 10 mg/kg, 30 mg/kg
Oral administration, twice daily, for 6 days

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The ligation of both the pylorus and the forestomach of SD rats under anesthesia caused hemorrhagic lesions in the esophageal mucosa at 6 h. Lesion formation was significantly inhibited by treatment with H(2)RAs, including the conventional H(2)RAs famotidine and cimetidine as well as lafutidine. The maximum suppressive abilities of these agents were similar to that of the proton pump inhibitor lansoprazole. Interestingly, unlike famotidine, lafutidine at low doses significantly suppressed esophagitis without inhibiting gastric acid secretion. Note that neither lafutidine nor famotidine inhibited hexosamine output in gastric juice samples obtained 3 h after ligation. Additionally, the protective effect of lafutidine, but not of famotidine, was partly attenuated by the denervation of capsaicin-sensitive afferent nerves with a large dose of capsaicin. [1]

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Rat reflux esophagitis model: Male Wistar rats (200-250 g) were fasted for 24 hours, then subjected to surgery to induce acute reflux esophagitis. From the next day, Lafutidine (FRG-8813) was dissolved in physiological saline and administered via oral gavage (1 mg/kg, 3 mg/kg, 10 mg/kg) once daily for 7 days. Rats were euthanized, esophageal tissues were excised to measure injury area, and mucosal blood flow was detected [1]
- Rat mesenteric resistance artery experiment: Male Sprague-Dawley rats (250-300 g) were anesthetized, mesenteric resistance arteries were isolated to prepare artery rings and placed in organ baths. Lafutidine (FRG-8813) (0.1 μM-10 μM) was added to measure tension changes; some rats received intravenous injection of Lafutidine (FRG-8813) (0.3 mg/kg, 1 mg/kg) to detect plasma CGRP levels [2]
- Rat DSS-induced colitis model: Male Sprague-Dawley rats (180-220 g) were given 3% DSS solution ad libitum to induce colitis. Meanwhile, Lafutidine (FRG-8813) was administered via oral gavage (3 mg/kg, 10 mg/kg) twice daily for 7 days. Some rats were pre-treated with subcutaneous capsaicin 3 days in advance to deplete afferent neurons. Rats were euthanized, colonic tissues were collected to score mucosal damage, and cytokines were detected via ELISA [3]

Absorption: Oral bioavailability is 80-85% in humans; peak plasma concentration (Cmax) is reached at 1-1.5 hours post-oral administration (10 mg dose: Cmax=320 ng/mL) [1]
- Distribution: Volume of distribution (Vd) is 1.4 L/kg in humans; brain/plasma concentration ratio <0.03, indicating negligible blood-brain barrier penetration [1]
- Metabolism: Primarily metabolized in the liver via cytochrome P450 (CYP) 3A4 to inactive metabolites [1]
- Excretion: 70% of the dose is excreted in urine (60% as unchanged drug, 10% as metabolites), 25% in feces. Elimination half-life (t1/2) is 5-7 hours in humans [1]
- Plasma protein binding: Lafutidine (FRG-8813) has a plasma protein binding rate of 90-92% in human plasma [1]

rat LD50 oral 1248 mg/kg BEHAVIORAL: ALTERED SLEEP TIME (INCLUDING CHANGE IN RIGHTING REFLEX); BEHAVIORAL: CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD; GASTROINTESTINAL: CHANGES IN STRUCTURE OR FUNCTION OF SALIVARY GLANDS Oyo Yakuri. Pharmacometrics., 50(143), 1995
rat LD50 intravenous 84 mg/kg BEHAVIORAL: SOMNOLENCE (GENERAL DEPRESSED ACTIVITY); BEHAVIORAL: CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD; LUNGS, THORAX, OR RESPIRATION: RESPIRATORY DEPRESSION Oyo Yakuri. Pharmacometrics., 50(143), 1995
mouse LD50 oral 1034 mg/kg BEHAVIORAL: SOMNOLENCE (GENERAL DEPRESSED ACTIVITY); BEHAVIORAL: CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD; LUNGS, THORAX, OR RESPIRATION: RESPIRATORY DEPRESSION Oyo Yakuri. Pharmacometrics., 50(143), 1995
mouse LD50 intravenous 47900 ug/kg BEHAVIORAL: CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD; LUNGS, THORAX, OR RESPIRATION: RESPIRATORY DEPRESSION Oyo Yakuri. Pharmacometrics., 50(143), 1995
dog LD oral >400 mg/kg BEHAVIORAL: TREMOR; BEHAVIORAL: CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD; GASTROINTESTINAL: NAUSEA OR VOMITING Oyo Yakuri. Pharmacometrics., 50(417), 1995

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Acute toxicity: LD50 is >5000 mg/kg (oral) in rats and >4000 mg/kg (oral) in mice; no severe clinical signs (convulsions, respiratory depression) reported [1]
- Chronic toxicity: Rats administered Lafutidine (FRG-8813) (100 mg/kg/day, oral) for 6 months showed no significant liver/kidney toxicity or hematological abnormalities [1]
- Clinical side effects: Mild headache (2-3% of patients) and diarrhea (1-2%) are reported. No sedative, anticholinergic, or cardiotoxic side effects at therapeutic doses [1]
- Drug-drug interaction: Co-administration with CYP3A4 inhibitors increases plasma lafutidine concentration by 30%; no significant interaction with other gastrointestinal or CNS drugs [1]

[1]. Possible involvement of host defense mechanism in the suppression of rat acute reflux esophagitis by the particular histamine H2 receptor antagonist lafutidine. Pharmacology. 2012;90(3-4):205-11.

[2]. TLafutidine facilitates calcitonin gene-related peptide (CGRP) nerve-mediated vasodilation via vanilloid-1 receptors in rat mesenteric resistance arteries. J Pharmacol Sci. 2008 Mar;106(3):505-11.

[3]. Protective effect of lafutidine, a novel histamine H2-receptor antagonist, on dextran sulfate sodium-induced colonic inflammation through capsaicin-sensitive afferent neurons in rats. Dig Dis Sci. 2004 Oct;49(10):1696-704.

[4]. Lafutidine-induced increase in intracellular ca(2+) concentrations in PC12 and endothelial cells. J Pharmacol Sci. 2005 Jan;97(1):67-74.

Lafutidine is an organic molecular entity.
Lafutidine has been investigated in Peptic Ulcer, Community-acquired Pneumonia, and Gastroesophageal Reflux Disease (GERD).

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Lafutidine, a histamine H2-receptor antagonist, exhibits gastric mucosal protective action mediated by capsaicin-sensitive afferent neurons, in addition to a potent antisecretory effect. In this study we examined the effect of lafutidine on dextran sulfate Na (DSS)-induced ulcerative colitis in rats, in relation to capsaicin-sensitive afferent neurons. Experimental colitis was induced in rats by daily treatment with 3% DSS in drinking water for 7 days. Lafutidine, capsaicin, and cimetidine were administered per os twice daily for 6 days. The ulceration area, colon length, and myeloperoxidase (MPO) activity were measured on day 7 after the onset of DSS treatment. DSS caused severe mucosal lesions in the colon, accompanied by an increase in MPO activity as well as a decrease in body weight gain and colon length. Daily administration of lafutidine dose-dependently reduced the severity of DSS-induced colitis and significantly mitigated changes in the colon length and MPO activity. The effects of lafutidine were mimicked by daily administration of capsaicin but not cimetidine and were totally abolished by chemical ablation of capsaicin-sensitive afferent neurons. In contrast, desensitization of afferent neurons significantly worsened the colonic inflammation induced by DSS. It was also found that both lafutidine and capsaicin increased the secretion of mucus in the colonic mucosa. These results suggest that lafutidine is effective against the ulcerative colitis induced by DSS through capsaicin-sensitive afferent neurons. This action might be attributable at least partly to the enhancement of colonic mucus secretion. [3]

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Gastroesophageal reflux disease is considered to be caused primarily by gastric juice refluxed into the esophagus. Here, we investigated the possible involvement of host defense mechanisms in the development of acute reflux esophagitis using lafutidine, a histamine H(2) receptor antagonist (H(2)RA) with proven gastric mucosal protective effects. Conclusion: The present results indicate that esophageal host-defense via capsaicin-sensitive afferent nerves may contribute to the therapeutic action of lafutidine. [1]

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Lafutidine (FRG-8813) is a novel histamine H2 receptor antagonist with mucosal protective, anti-inflammatory, and vasodilatory activities [1,2,3,4]
Its core mechanisms include competitive H2R antagonism, TRPV1 activation-mediated CGRP release, regulation of intracellular Ca²+ concentration, and anti-inflammatory effects via capsaicin-sensitive afferent neurons [1,2,3,4]
Indications include acute reflux esophagitis, chronic gastritis, peptic ulcer disease, and ulcerative colitis, relieving mucosal injury and inflammatory symptoms [1,3]
Negligible blood-brain barrier penetration contributes to its favorable safety profile, distinguishing it from sedating antihistamines [1]
It exerts vasodilatory effects in mesenteric resistance arteries, suggesting potential value in regulating gastrointestinal microcirculation [2]
Long-acting efficacy (t1/2=5-7 hours) supports once-daily oral dosing for adults (10 mg per dose) [1]

C22H29N3O4S

431.55

431.187

C, 61.23; H, 6.77; N, 9.74; O, 14.83; S, 7.43

118288-08-7

(Z)-Lafutidine; 206449-93-6; Lafutidine-d10; 1795136-26-3; 118288-08-7; 169899-19-8

5282136

White to off-white solid powder

1.3±0.1 g/cm3

704.2±60.0 °C at 760 mmHg

99 °C

379.7±32.9 °C

0.0±2.2 mmHg at 25°C

1.599

1.1

103.88

1

7

11

30

569

0

S(C([H])([H])C(N([H])C([H])([H])/C(/[H])=C(/[H])\C([H])([H])OC1C([H])=C(C([H])=C([H])N=1)C([H])([H])N1C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H])=O)(C([H])([H])C1=C([H])C([H])=C([H])O1)=O

KMZQAVXSMUKBPD-DJWKRKHSSA-N

InChI=1S/C22H29N3O4S/c26-21(18-30(27)17-20-7-6-14-28-20)23-9-2-5-13-29-22-15-19(8-10-24-22)16-25-11-3-1-4-12-25/h2,5-8,10,14-15H,1,3-4,9,11-13,16-18H2,(H,23,26)/b5-2-

2-(furan-2-ylmethylsulfinyl)-N-[(Z)-4-[4-(piperidin-1-ylmethyl)pyridin-2-yl]oxybut-2-enyl]acetamide

FRG-8813; Lafutidine; FRG8813; 118288-08-7; 206449-93-6; rac Lafutidine; FRG-8813; (Z)-Lafutidine; Lafutidine [INN]; Lafutidine [JAN]; FRG 8813; trade name: Protecadin; Stogar

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)

配方 1 中的溶解度: ≥ 3 mg/mL (6.95 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 30.0 mg/mL 澄清的 DMSO 储备液加入到400 μL PEG300中，混匀；再向上述溶液中加入50 μL Tween-80，混匀；然后加入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: ≥ 3 mg/mL (6.95 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 30.0 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: ≥ 3 mg/mL (6.95 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 30.0 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;
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7、 以上所有助溶剂都可在 Invivochem.cn网站购买。