Histamine H2 receptor

Ranitidine bismuth citrate (0.1–1 μM, 5 minutes) is a strong and irreversible inhibitor of DNA unwinding (IC50 = 0.74 μM, Ki = 0.39 μM) Agent-CoV-2 helicase and SARS ATPase (IC50 = 0.69 μM, Ki = 0.97 μM) [2]. With an EC50 value of 2.3 μM in Vero E6 cells, ranitidine bismuth citrate (24 hours) demonstrated strong efficacy against SARS-CoV-2 [2].

In the golden Syrian hamster model, ranitidine bismuth citrate (150 mg/kg; intranasally; thrice daily; 4 days) reduced SARS-CoV-2 replication and relieved virus-associated pneumonia [2]. Ranitidine bismuth citrate (48 mg/kg, intraperitoneally) is efficient in eliminating H. pylori in female ferrets and weasels, with MIC values of 8 ng/L and 1-2 ng/L, respectively [3] . Ranitidine bismuth citrate (0.1 mg/kg, 0.3 mg/kg; oral) significantly suppresses stomach acid secretion and (1.0 mM) inhibits human pepsin isoenzyme activity [4].

Cytotoxicity assay[2]
Cell Types: monkey kidney Vero E6 cells, human colorectal Caco-2 cells
Tested Concentrations: 400-3,740 μM
Incubation Duration: 48 hrs (hours)
Experimental Results: demonstrated low cytotoxicity, 50% cytotoxic concentration (CC50) range 2.2 mM and 2.5 mm.

Animal/Disease Models: Female Beagle dog (14-20 kg) [3]
Doses: 0.1 mg/kg
Route of Administration: Oral once hourly for 5 hrs (hrs (hours))
Experimental Results: Inhibition of gastric acid secretion.

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Animal/Disease Models: Female, randomly raised hooded rats (body weight range 90-120 g) [4]
Doses: 0.5 mL/100 g
Route of Administration: Pretreatment with indomethacin (5 mg/kg sc); oral Results of intragastric (po) (po)
Route of Administration: Inhibition of gastric mucosal damage in rats.

Metabolism / Metabolites
Ranitidine's known metabolites include desmethylranitidine.

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
Although there are individual differences, the dose of ranitidine in breast milk is lower than the dose for newborns. However, ranitidine has been withdrawn from the market in the United States and other countries due to the discovery that it spontaneously breaks down into carcinogenic chemicals. Alternative medications are recommended.
◉ Effects on Breastfed Infants
No adverse reactions were observed in a 54-day-old breastfed infant after the mother received 150 mg of ranitidine every 12 hours for two consecutive days.
◉ Effects on Lactation and Breast Milk
Histamine H2 receptor antagonists are known to stimulate prolactin secretion. Some studies have shown that intravenous administration of ranitidine exceeding 100 mg or prolonged oral administration of ranitidine can lead to elevated serum prolactin levels, with rare reports of gynecomastia. For mothers who have established lactation, prolactin levels may not affect their ability to breastfeed.

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Adverse Reactions
Occupational Hepatotoxicants - Secondary Hepatotoxicants: Potential toxic effects in the occupational environment based on human ingestion cases or animal studies. Skin Sensitizers - Substances that can induce allergic skin reactions.

[1]. Inhibition of 14C-aminopyrine accumulation in isolated rabbit gastric glands by the H2-receptor antagonist HOE 760 (TZU-0460). Agents Actions. 1987 Feb. 20(1-2):35-9.

[2]. Metallodrug ranitidine bismuth citrate suppresses SARS-CoV-2 replication and relieves virus-associated pneumonia in Syrian hamsters. Nat Microbiol. 2020 Nov. 5(11):1439-1448.

[3]. The actions of bismuth in the treatment of Helicobacter pylori infection. Aliment Pharmacol Ther. 1997 Apr. 11(Suppl 1):27-33.

[4]. Gastric anti-secretory, mucosal protective, anti-pepsin and anti-Helicobacter properties of ranitidine bismuth citrate. Aliment Pharmacol Ther. 1993 Jun. 7(3):237-46.

Ranitidine belongs to the furan class of drugs and is used to treat peptic ulcers and gastroesophageal reflux disease. It has multiple effects, including anti-ulcer action, H2 receptor antagonism, action against environmental pollutants, exogenous substances, and drug allergens. It belongs to the furan class of compounds, tertiary amine compounds, C-nitro compounds, and organosulfur compounds. Ranitidine is a histamine H2 receptor antagonist with antacid activity. Ranitidine is a competitive and reversible inhibitor of histamine released from enterochromaffin-like cells (ECL cells) binding to histamine H2 receptors on gastric parietal cells, thereby inhibiting normal gastric acid secretion and gastric acid secretion induced by food intake. Furthermore, when H2 receptors are blocked, the effects of other substances that promote gastric acid secretion on parietal cells are also weakened. Ranitidine hydrochloride belongs to the class of histamine H2 receptor antagonists. Ranitidine is a competitive and reversible inhibitor of histamine released from enterochromaffin-like cells (ECL cells) that binds to histamine H2 receptors on gastric parietal cells, thereby inhibiting normal gastric acid secretion and food-induced gastric acid secretion. Furthermore, when H2 receptors are blocked, the effects of other substances that promote gastric acid secretion on parietal cells are also weakened. Ranitidine is a non-imidazole histamine receptor (H2 receptor) blocker that mediates gastric acid secretion. It is used to treat gastrointestinal ulcers. See also: Ranitidine (note moved to). SARS-CoV-2 is causing the COVID-19 pandemic, characterized by high infectivity and significant mortality.¹ Currently, treatment options for COVID-19 are limited. Historically, metal compounds have been used as antibacterial agents, but their antiviral activity has been rarely studied. Here, we tested a range of metal drugs and related compounds and found that ranitidine bismuth citrate (a commonly used treatment for Helicobacter pylori infection) is a potent anti-SARS-CoV-2 agent, both in vitro and in vivo. Ranitidine bismuth citrate exhibits low cytotoxicity and protects SARS-CoV-2-infected cells with a high selectivity index of 975. Importantly, ranitidine bismuth citrate inhibits SARS-CoV-2 replication, thereby reducing viral load in the upper and lower respiratory tracts and alleviating virus-associated pneumonia in a golden hamster model. In vitro studies have shown that ranitidine bismuth citrate and related compounds inhibit the ATPase activity (IC50 = 0.69 µM) and DNA unwinding activity (IC50 = 0.70 µM) of SARS-CoV-2 helicases by irreversibly displacing zinc (II) ions in the enzyme with bismuth (III) ions. Our results highlight the value of viral helicases as drug targets and the clinical potential of bismuth (III) drugs or other metal drugs in the treatment of SARS-CoV-2 infection. [2]

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Bismuth citrate ranitidine is a novel compound formed by the complex of ranitidine and bismuth citrate. In conscious dogs, ranitidine bismuth citrate showed similar activity to ranitidine hydrochloride in inhibiting histamine-induced gastric acid secretion when compared with oral administration of equal doses of ranitidine base (0.1 or 0.3 mg/kg). In rats, oral administration of ranitidine bismuth citrate (3–30 mg/kg) prevented gastric mucosal damage induced by ethanol (fundus injury) and indomethacin (antral injury). Ranitidine hydrochloride and bismuth potassium citrate were also effective against indomethacin-induced damage, but their potency was significantly lower than that of ranitidine citrate in this model. Ranitidine hydrochloride was ineffective against ethanol-induced damage. In vitro experiments showed that ranitidine citrate (1 mmol/L) inhibited human pepsin isoenzymes 1, 2, 3, and 5. Bismuth citrate ranitidine, bismuth citrate, and bismuth citrate potassium at concentrations equivalent to 1 mmol/L bismuth showed similar inhibitory effects on pepsin 1, but ranitidine at 1 mmol/L was inactive. Bismuth citrate ranitidine was more potent than bismuth citrate tripotassium as an inhibitor of pepsin 2, 3, and 5. Bismuth citrate ranitidine inhibited Helicobacter pylori (effective concentrations of 4–32 μg/mL) and Haemophilus stolonifer (1–4 μg/mL); bismuth citrate tripotassium also yielded similar results. Bismuth citrate was slightly less potent, while ranitidine hydrochloride was inactive (>125 μg/mL). In ferrets naturally infected with Haemophilus stolonifer, oral administration of bismuth citrate ranitidine (12 or 24 mg/kg, twice daily for 4 weeks) resulted in dose-dependent clearance of Haemophilus stolonifer. Similar qualitative results were also obtained in a small study using bismuth citrate tripotassium and bismuth citrate. [4]

C13H22N4O3S.C6H5O7-3.BI+3

712.48348

712.125

C, 32.03; H, 3.82; Bi, 29.33; N, 7.86; O, 22.46; S, 4.50

128345-62-0

Ranitidine hydrochloride;66357-59-3; Ranitidine-d6 hydrochloride; 1185238-09-8; Ranitidine; 66357-35-5; Ranitidine bismuth citrate; 128345-62-0; 71130-06-8 (HCl)

62984

Typically exists as solid at room temperature

1.184g/cm3

437.1ºC at 760mmHg

218.2ºC

7.66E-08mmHg at 25°C

3

14

11

35

558

0

[Bi+3].CN/C(/NCCSCC1=CC=C(CN(C)C)O1)=C\[N+]([O-])=O.O=C(CC(C([O-])=O)(O)CC([O-])=O)[O-]

XAUTYMZTJWXZHZ-UHFFFAOYSA-K

InChI=1S/C13H22N4O3S.C6H8O7.Bi/c1-14-13(9-17(18)19)15-6-7-21-10-12-5-4-11(20-12)8-16(2)3;7-3(8)1-6(13,5(11)12)2-4(9)10;/h4-5,9,14-15H,6-8,10H2,1-3H3;13H,1-2H2,(H,7,8)(H,9,10)(H,11,12);/q;;+3/p-3

bismuth;1-N'-[2-[[5-[(dimethylamino)methyl]furan-2-yl]methylsulfanyl]ethyl]-1-N-methyl-2-nitroethene-1,1-diamine;2-hydroxypropane-1,2,3-tricarboxylate

Ranitidine bismuth citrate; Tritec; 128345-62-0; GR 122311X; GR-122311X; Azamplus; Elicodil; Helirad;

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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