Histamine H1 receptor; Histamine H2 receptor

体外活性：组胺通过组胺 2 型受体（H2 受体）抑制 ROS 的产生。组胺抑制呼吸爆发期间单核细胞/巨噬细胞 (MO) 产生和释放活性氧 (ROS)。组胺和白细胞介素 2 (IL-2) 协同作用，激活 NK 细胞的细胞毒性 (NKCC)。组胺与 IL-2 结合可能会保护免疫系统细胞免受氧化应激并诱导天然内源性免疫细胞毒性，从而提高缓解率和无病生存率。

组胺治疗（0.5 mg/kg 或 5.0 mg/kg，每日两次）可防止肝损伤，血清转氨酶水平正常即可证明，并且在早期酒精性肝损伤的大鼠模型中显着降低肝脏病理评分。组胺的保护作用被 H2 受体拮抗剂雷尼替丁 (10 mg/kg) 阻断，表明组胺作用主要通过 H2 受体介导。组胺（30 pg/大鼠，icv）增加雄性大鼠伏隔核中 3,4-二羟基苯丙氨酸的积累和 3,4-二羟基苯丙氨酸的浓度，并且这种作用不受 H2 拮抗剂唑兰替丁的影响，表明组胺刺激中脑边缘 DA神经元通过 H1 受体的作用。与皮下注射盐水的大鼠相比，组胺（0.5 mg/kg sc）可将肝脏肿瘤重量减少 46%，皮下肿瘤重量减少 41%。在大鼠肉瘤中，皮下注射组胺所观察到的抗肿瘤作用被雷尼替丁（50 mg/kg sc）抑制。组胺 (1000 mg/kg sc) 在 24 小时后显示出急性组织损伤，并在第 5 天和 28 天时在注射部位出现病理性炎症迹象。组胺（1000 mg/kg sc）导致雄性 Sprague-Dawley 大鼠的 Cmax 为 167 mM，tmax 为 0.5 小时，t1/2 为 0.95，AUC 为 186 mmol-h/L。

十多年来，组胺在癌症免疫疗法中的潜在作用一直是人们感兴趣的主题。大量研究阐明了组胺在模拟肿瘤微环境的模型系统中的作用。体外证据表明，组胺在呼吸爆发期间抑制单核细胞/巨噬细胞（MO）产生和释放活性氧（ROS）。由于ROS已被证明可以消除自然杀伤（NK）和T细胞的瘤周和瘤内细胞因子激活，并在体外诱导这些细胞凋亡，因此抑制ROS可能使细胞因子激活NK和T细胞，恢复其抗肿瘤、细胞毒性能力。实验数据表明，组胺和白细胞介素-2（IL-2）协同作用，激活NK细胞毒性（NKCC）。尽管IL-2作为免疫反应的调节因子，已被证明在转移性黑色素瘤（MM）、肾细胞癌（RCC）和急性髓系白血病（AML）的单一疗法中促进NKCC，但少数患者会出现客观反应，生存期没有显著延长，除了少数使用高剂量方案的MM患者，这些方案尚未被广泛采用。体外研究结果表明，在IL-2治疗中添加组胺可能通过保护免疫系统细胞免受氧化应激和诱导天然内源性免疫细胞毒性来提高反应率和无病生存率。一项IL-2/组胺III期试验正在AML患者群体中进行。最近完成的一项在多发性骨髓瘤患者中进行的IL-2与IL-2/组胺的III期试验表明，IL-2/组胺对所有入选患者的生存益处都有提高的趋势，对肝转移患者的生存效益也有统计学意义[2]。

Inflammation of the liver may be caused by a variety of factors that include infectious agents and toxins. Reactive oxygen species (ROS) generated by the NADPH oxidase in Kupffer cells and infiltrating leukocytes play an important role in the pathogenesis of early alcohol-induced hepatitis. Histamine dihydrochloride (histamine) suppresses the generation of ROS through the histamine type-2 receptor (H2 receptor). Histamine was studied as a potential protective treatment against early alcohol-induced liver injury in an experimental hepatitis model. Female Wistar rats were given ethanol (5 g/kg) intragastrically by gavage once daily for 4 weeks, while a control group not receiving ethanol was fed an isocaloric high-fat diet. Animals receiving ethanol had elevated serum levels of alanine and aspartate transaminase (ALT/AST) and developed steatosis, inflammation, and necrosis of the liver. Histamine treatment (0.5 or 5.0 mg/kg, twice daily) protected against this liver injury as evident by normal serum transaminase levels and significantly reduced liver pathology scores. Ranitidine (10 mg/kg), an H2 receptor antagonist, blocked the protective effect of histamine, indicating that the histamine effect is predominantly mediated through the H2 receptor. In conclusion, these results suggest that histamine protects against early alcohol-induced liver injury in rats.[1]

---

Subcutaneous injections of histamine (0.5 mg/kg) reduced the liver tumour weight by 46+/-8% (p=0.0002) and subcutaneous tumour weight by 41+/-12% (p=0.026) versus animals receiving subcutaneous saline injections. Histamine continuously administered by osmotic pumps at doses of 0.5, 2 and 20 mg/kg/24 hour, did not reduce tumour growth. Ranitidine (50 mg/kg s.c.), inhibited the anti-tumour effect observed by subcutaneous histamine injections. In conclusion, H2-receptor-mediated tumour growth inhibition was accomplished by bolus injections of histamine.[4]

---

Histamine dihydrochloride is currently being evaluated as an adjuvant to immunotherapy regimens in neoplastic and infectious diseases. The no-observed-effect-level (NOEL), no-observable-adverse-effect-level (NOAEL), and pharmacokinetics of subcutaneously administered histamine dihydrochloride were determined via 5 and 28 day repeated dose studies in Sprague-Dawley rats. In the five day study, male rats received 0 (vehicle), 5, 30, 500, or 1000 mg/kg BID. Acute tissue damage was observed at one or more injection sites in the two highest dose groups after 24 h. At five days, animals in these groups displayed indications of pathological inflammation at the injection sites. In the 28 day study, male and female rats received 0 (vehicle), 0.5, 5, or 100 mg/kg BID. The most significant treatment-related pathological findings were signs of inflammation at the injection sites for animals in the 100 mg/kg BID group. Hematology and clinical chemistry changes in the highest dose groups in both studies were consistent with inflammation and anemia but were found to be reversible following a 14-day recovery. Plasma histamine levels were quantified from male and female animals receiving 0.5, 5, and 100 mg/kg injections on Day 1 and 28 of the twenty-eight day study. Cmax was achieved within 0.25 h and was dose-proportional. The elimination half-life and tmax were longer at the 100 mg/kg dose than the lower doses. No marked differences between genders or between Day 1 and 28 were found. Based on these findings, the NOEL and NOAEL were established at 0.5 mg/kg BID and 5 mg/kg BID, respectively. When converted to human equivalent dose, the NOAEL is 0.81 mg/kg which is 54 times the intended human dose. These studies support a wide safety margin for histamine dihydrochloride.[5]

0.5 mg/kg or 5.0 mg/kg

Rats

[1]. Inflammation . 2003 Oct;27(5):317-27.

[2]. Expert Opin Biol Ther . 2001 Sep;1(5):869-79.

[3]. Naunyn Schmiedebergs Arch Pharmacol . 1993 Jan;347(1):50-4.

[4]. Anticancer Res . 2002 Jul-Aug;22(4):1943-8.

[5]. Drug Chem Toxicol . 2003 Feb;26(1):35-49.

Histamine Dihydrochloride is the hydrochloride salt form of histamine, with potential immunomodulatory and antineoplastic activities. Upon administration, histamine targets, binds to and activates histamine receptors. Depending on the amount of histamine administered and the type of receptor that is activated, histamine may exert a wide variety of activities. These can range from pro-tumorigenic to anti-tumor effects and may modulate the immune system to exert anti-tumor immune effects or may contribute to an inflammatory response.
An amine derived by enzymatic decarboxylation of HISTIDINE. It is a powerful stimulant of gastric secretion, a constrictor of bronchial smooth muscle, a vasodilator, and also a centrally acting neurotransmitter.
See also: Histamine (has active moiety); Histamine dihydrochloride; menthol (component of); Capsaicin; histamine dihydrochloride; menthol (component of) ... View More ...

---

Drug Indication
Ceplene maintenance therapy is indicated for adult patients with acute myeloid leukaemia in first remission concomitantly treated with interleukin-2 (IL-2). The efficacy of Ceplene has not been fully demonstrated in patients older than age 60.

C5H11CL2N3

184.07

183.033

56-92-8

Histamine phosphate; 51-74-1; Histamine; 51-45-6; 51-45-6; 56-92-8 (HCl)

5818

White to off-white Solid powder

1.14 g/cm3

331ºC at 760 mmHg

249-252 °C(lit.)

180.3ºC

2.215

54.7

4

2

2

10

64.7

0

Cl[H].Cl[H].N1([H])C([H])=NC([H])=C1C([H])([H])C([H])([H])N([H])[H]

PPZMYIBUHIPZOS-UHFFFAOYSA-N

InChI=1S/C5H9N3.2ClH/c6-2-1-5-3-7-4-8-5;;/h3-4H,1-2,6H2,(H,7,8);2*1H

2-(1H-imidazol-5-yl)ethanamine;dihydrochloride

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)

配方 1 中的溶解度: ≥ 2.5 mg/mL (13.58 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。

---

配方 2 中的溶解度: ≥ 2.5 mg/mL (13.58 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。

---

View More

配方 3 中的溶解度: ≥ 2.5 mg/mL (13.58 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。

---

配方 4 中的溶解度: 100 mg/mL (543.27 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶.

---

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。