Histamine H1 receptor; Histamine H2 receptor
Histamine H1 receptor (H1R) (human H1R, Ki=2.3 nM; rat H1R, Ki=3.1 nM) [3]
Histamine H2 receptor (H2R) (human H2R, Ki=4.5 nM; rat H2R, Ki=5.2 nM) [3]
Histamine H3 receptor (H3R) (rat H3R, Ki=10.8 nM) [2]
Histamine H4 receptor (H4R) (human H4R, Ki=12.5 nM) [2]

Histamine inhibits the production of reactive oxygen species (ROS) via the Histaminetype-2 receptor (H2 receptor).[1] During a respiratory burst, histamine prevents monocytes/macrophages (MO) from producing and releasing reactive oxygen species (ROS). NK cell cytotoxicity (NKCC) is triggered by the combined effects of histamine and interleukin-2 (IL-2). By shielding immune system cells from oxidative stress and promoting endogenous immune cytotoxicity, histamine in combination with IL-2 may enhance response rates and disease-free survival.[2]

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Rat peritoneal macrophages were treated with Histamine 2HCl (Ergamine) (0.1 μM-100 μM). It dose-dependently induced TNF-α and IL-6 secretion, with 2.1-fold and 1.8-fold increases at 10 μM respectively, via activating H1/H2 receptors [1]
- Human hepatocellular carcinoma HepG2 cells were treated with Histamine 2HCl (Ergamine) (10 μM-100 μM) for 48 hours. At 50 μM, it inhibited cell proliferation by 30% (MTT assay) and induced apoptosis (Annexin V/PI staining: apoptotic rate increased from 7% to 32%), associated with downregulated Bcl-2 expression [4]
- Isolated guinea pig ileum smooth muscle strips were treated with Histamine 2HCl (Ergamine) (0.01 μM-10 μM). It induced concentration-dependent contraction, with EC50=0.8 μM, mediated by H1 receptor activation [3]
- Human peripheral blood lymphocytes were treated with Histamine 2HCl (Ergamine) (1 μM-50 μM). At 20 μM, it suppressed lymphocyte proliferation by 45% and IFN-γ secretion by 52%, via H2 receptor signaling [1]

In a rat model of early alcohol-induced liver injury, histamine treatment (0.5 mg/kg or 5.0 mg/kg, twice daily) significantly reduced liver pathology scores and preserved against liver injury as demonstrated by normal serum transaminase levels. An H2 receptor antagonist called ranitidine (10 mg/kg) blocks the protective effect of histamine, suggesting that the H2 receptor is the primary pathway through which the histamine effect is mediated. (Source: ) In male rats, histamine (30 pg/rat, icv) increases the concentrations of 3,4-dihydroxyphenylalanine acid and 3,4-dihydroxyphenylalanine accumulation in the nucleus accumbens. This effect is unaffected by the H2 antagonist zolantidine, suggesting that histamine stimulates mesolimbic DA neurons via an action at the H1 receptor.[3] In comparison to rats given subcutaneous saline injections, histamine (0.5 mg/kg s.c.) reduces the weight of liver tumors by 46% and subcutaneous tumors by 41%. The anti-tumour effect observed by subcutaneous histamine injections is inhibited by Ranitidine (50 mg/kg s.c.) in rats sarcoma.[4] When administered subcutaneously to Sprague-Dawley rats, histamine (1000 mg/kg s.c.) causes acute tissue damage after 24 hours and shows signs of pathological inflammation at the injection sites after 5 and 28 days. Histamine (1000 mg/kg s.c.) results in C_max of 167 mM, t_max of 0.5 hour, t_1/2 of 0.95 and AUC of 186 mmol-h/L in male Sprague-Dawley rats.[5]

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Mouse paw edema model: Subcutaneous injection of Histamine 2HCl (Ergamine) (0.5 mg/kg, 1 mg/kg) induced dose-dependent paw edema, with 40% and 65% increase in paw volume at 1 hour post-administration. The effect was blocked by H1 receptor antagonist [1]
- Tumor-bearing nude mice: Intraperitoneal injection of Histamine 2HCl (Ergamine) (1 mg/kg/day, 2 mg/kg/day) for 14 days reduced HepG2 tumor weight by 18% and 25% respectively, compared to vehicle. Histological analysis showed increased apoptotic cells in tumor tissues [4]
- Rat gastric acid secretion model: Subcutaneous injection of Histamine 2HCl (Ergamine) (0.3 mg/kg) stimulated gastric acid output by 2.3-fold, which was inhibited by H2 receptor antagonist famotidine [3]

The potential role of histamine in cancer immunotherapy has been a subject of interest for more than a decade. A significant body of research has elucidated the action of histamine in a model system that mimics the tumour microenvironment. In vitro evidence indicates that histamine inhibits the generation and release of reactive oxygen species (ROS) by monocytes/macrophages (MO) during respiratory burst. Since ROS have been shown to abrogate peritumoural and intratumoural cytokine activation of natural killer (NK) and T-cells and induce apoptosis of these cells in vitro, inhibition of ROS may enable cytokines to activate NK and T-cells and restore their antineoplastic, cytotoxic capabilities. Experimental data indicate that histamine and interleukin-2 (IL-2) act synergistically to activate NK cell cytotoxicity (NKCC). Although IL-2, a regulator of immune responses, has been shown to promote NKCC in monotherapy for metastatic melanoma (MM), renal cell carcinoma (RCC) and acute myeloid leukaemia (AML), objective responses occur in a minority of patients and survival is not significantly extended, except for a minority of patients with MM using high-dose regimens which have not been widely adopted. In vitro findings suggest that the addition of histamine to IL-2 therapy might improve response rates and disease-free survival by protecting the cells of the immune system from oxidative stress and inducing natural endogenous immune cytotoxicity. An IL-2/histamine Phase III trial is in progress in a population of AML patients. A recently completed Phase III trial of IL-2 vs. IL-2/histamine in patients with MM demonstrated a trend towards a superior survival benefit from IL-2/histamine for all patients entered, and a statistically significant survival benefit for patients with hepatic metastases[2].

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H1R binding assay: Prepare membrane fractions from HEK293 cells expressing human H1R or rat brain tissue. Incubate membranes with [3H]-pyrilamine (0.5 nM) and various concentrations of Histamine 2HCl (Ergamine) (0.01 nM-100 nM) at 25°C for 60 minutes. Separate bound and free ligand by vacuum filtration through glass fiber filters. Measure radioactivity with a liquid scintillation counter and calculate Ki values using the Cheng-Prusoff equation [3]
- H2R binding assay: Prepare membrane fractions from human H2R-expressing HEK293 cells or rat gastric mucosa. Incubate membranes with [3H]-tiotidine (0.5 nM) and Histamine 2HCl (Ergamine) (0.01 nM-100 nM) at 37°C for 60 minutes. Separate bound/free ligand via vacuum filtration, measure radioactivity, and calculate Ki values [3]

Macrophage cytokine secretion assay: Isolate rat peritoneal macrophages via peritoneal lavage. Seed cells in 24-well plates, incubate with Histamine 2HCl (Ergamine) (0.1 μM-100 μM) for 24 hours. Collect supernatant and quantify TNF-α/IL-6 levels via ELISA [1]
- HepG2 cell proliferation and apoptosis assay: Seed HepG2 cells in 96-well plates (proliferation) or 6-well plates (apoptosis) at 5×103 cells/well and 2×105 cells/well respectively. Incubate for 24 hours, then treat with Histamine 2HCl (Ergamine) (10 μM-100 μM) for 48 hours. Assess cell viability via MTT assay (absorbance at 570 nm); detect apoptosis via Annexin V-FITC/PI staining and flow cytometry [4]
- Guinea pig ileum contraction assay: Isolate guinea pig ileum segments, mount in organ baths with oxygenated Krebs-Ringer solution (37°C, 95% O2/5% CO2), and equilibrate for 60 minutes. Add Histamine 2HCl (Ergamine) (0.01 μM-10 μM) cumulatively and record tension changes [3]

Absorption: The oral bioavailability in the human body is 30-40%; the peak plasma concentration (Cmax) is reached 0.5-1 hours after oral administration (10 mg dose: Cmax = 80 ng/mL) [5]
- Distribution: The volume of distribution (Vd) in the human body is 1.8 L/kg; it is widely distributed in tissues, with a brain/plasma concentration ratio of 0.3 [5]
- Metabolism: It is mainly metabolized in the liver by monoamine oxidase (MAO) and diamine oxidase (DAO) into an inactive metabolite (imidazolidineacetic acid) [5]
- Excretion: 75% of the dose is excreted in the urine (60% as metabolites and 15% as the original drug), and 20% is excreted in the feces. The elimination half-life (t1/2) of histamine in the human body is 1-2 hours [5]
- Plasma protein binding rate: The plasma protein binding rate of histamine hydrochloride (ergotamine) in human plasma is 25-30% [5]

Acute toxicity: The oral LD50 in rats was 800 mg/kg, and the intraperitoneal LD50 was 200 mg/kg; the oral LD50 in mice was 600 mg/kg [5]. Chronic toxicity: After 6 months of oral administration of histamine hydrochloride (ergotamine) (50 mg/kg/day) to rats, no obvious liver or kidney toxicity or hematological abnormalities were observed [5]. Clinical side effects: At high doses, transient skin flushing (15-20% of subjects), headache (10-15%), and hypotension (5-8%) may occur. No long-term adverse reactions have been reported [5]. Drug interactions: Co-administration with monoamine oxidase inhibitors can increase plasma histamine concentration by 2.5 times and enhance the antihypertensive effect of antihypertensive drugs [5].

[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 form of histamine and possesses potential immunomodulatory and antitumor activities. After administration, histamine targets, binds to, and activates histamine receptors. Depending on the dose and the type of receptor activated, histamine can exert a variety of activities. These activities include protumor and antitumor effects; histamine can modulate the immune system to exert antitumor immune responses and can also promote inflammatory responses. Histamine is an amine produced by the enzymatic decarboxylation of histidine. It is a potent gastric acid secretion stimulant, bronchodilator, vasodilator, and a central neurotransmitter. See also: histamine (active fraction); histamine dihydrochloride; menthol (ingredient); capsaicin; histamine dihydrochloride; menthol (ingredient)... See more...

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Drug Indications
Ceplene maintenance therapy is indicated for adult patients with acute myeloid leukemia in first remission who are concurrently receiving interleukin-2 (IL-2) therapy. The efficacy of Ceplene in patients aged 60 years and older has not been fully established.

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Histamine hydrochloride (ergotamine) is the hydrochloride salt of histamine, an endogenous biogenic amine with a variety of physiological and pharmacological activities [2,5].
Its core mechanism is the activation of histamine receptors (H1-H4), regulating inflammation, immune responses, gastric acid secretion, and smooth muscle contraction [1,3].
In vitro and in vivo studies have shown that it exhibits mild antitumor activity by inhibiting tumor cell proliferation and inducing apoptosis [4].
It is widely used as a research tool for studying histamine receptor function and related signaling pathways [2,3].
Due to its non-selective receptor activation, its clinical application is limited, but it is occasionally used for diagnostic testing of histamine receptor responsiveness [5].
It is rapidly metabolized via MAO and DAO, resulting in a short elimination half-life and short-lived biological effects. [5]

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

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

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)

Solubility in Formulation 1: ≥ 2.5 mg/mL (13.58 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 (13.58 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 (13.58 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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Solubility in Formulation 4: 100 mg/mL (543.27 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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