Histamine 2HCl (Ergamine), the dihydrochloride salt of histamine, is an organic nitrogen compound and an endogenous metabolite involved in local immune responses, as well as regulating physiological function in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus.

Physicochemical Properties

Molecular Formula	C5H11CL2N3
Molecular Weight	184.07
Exact Mass	183.033
CAS #	56-92-8
Related CAS #	Histamine phosphate; 51-74-1; Histamine; 51-45-6; 51-45-6; 56-92-8 (HCl)
PubChem CID	5818
Appearance	White to off-white Solid powder
Density	1.14 g/cm3
Boiling Point	331ºC at 760 mmHg
Melting Point	249-252 °C(lit.)
Flash Point	180.3ºC
LogP	2.215
Hydrogen Bond Donor Count	4
Hydrogen Bond Acceptor Count	2
Rotatable Bond Count	2
Heavy Atom Count	10
Complexity	64.7
Defined Atom Stereocenter Count	0
SMILES	Cl[H].Cl[H].N1([H])C([H])=NC([H])=C1C([H])([H])C([H])([H])N([H])[H]
InChi Key	PPZMYIBUHIPZOS-UHFFFAOYSA-N
InChi Code	InChI=1S/C5H9N3.2ClH/c6-2-1-5-3-7-4-8-5;;/h3-4H,1-2,6H2,(H,7,8);2*1H
Chemical Name	2-(1H-imidazol-5-yl)ethanamine;dihydrochloride
Synonyms	Histamine 2HCl; 2-(1H-Imidazol-4-yl)ethanamine dihydrochloride; 1H-Imidazole-4-ethanamine dihydrochloride; peremin; 2-(4-Imidazolyl)ethylamine dihydrochloride; Ceplene; Histamine dihydrochloride
HS Tariff Code	2934.99.9001
Storage	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.
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

Targets	Histamine H1 receptor; Histamine H2 receptor
ln Vitro	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]
ln Vivo	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 Cmax of 167 mM, tmax of 0.5 hour, t1/2 of 0.95 and AUC of 186 mmol-h/L in male Sprague-Dawley rats.[5]
Enzyme Assay	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].
Animal Protocol	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
References	[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.
Additional Infomation	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.

Solubility Data

Solubility (In Vitro)

DMSO: 3~100 mg/mL (16.3~543.3 mM) Water: ~37 mg/mL (~201.0 mM) Ethanol: <1 mg/mL

Solubility (In Vivo)

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

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	5.4327 mL	27.1636 mL	54.3272 mL
	5 mM	1.0865 mL	5.4327 mL	10.8654 mL
	10 mM	0.5433 mL	2.7164 mL	5.4327 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.