Cimetidine

Cimetidine is a histamine-2 (H2) receptor antagonist.Cimetidine, a partial agonist for H2R, has a pharmacological profile different from ranitidine and famotidine, possibly contributing to its antitumor activity on gastrointestinal cancers [1]. Cimetidine

Radioprotective effects of cimetidine on rats irradiated by long-term, low-dose-rate neutrons and (60)Co gamma-rays.[Pubmed:28261494]

Mil Med Res. 2017 Feb 27;4:7.

BACKGROUND: Cimetidine, an antagonist of histamine type II receptors, has shown protective effects against gamma-rays or neutrons. However, there have been no reports on the effects of Cimetidine against neutrons combined with gamma-rays. This study was carried out to evaluate the protective effects of Cimetidine on rats exposed to long-term, low-dose-rate neutron and gamma-ray combined irradiation (n-gamma LDR). METHODS: Fifty male Sprague-Dawley (SD) rats were randomly divided into 5 groups: the normal control group, radiation model group, 20 mg/(kg . d) Cimetidine group, 80 mg/(kg . d) Cimetidine group and 160 mg/(kg . d) Cimetidine group (10 rats per group). Except for the normal control group, 40 rats were simultaneously exposed to fission neutrons ((252)Cf, 0.085 mGy/h) for 22 h every day and gamma-rays ((60)Co, 0.097 Gy/h) for 1.03 h once every three days, and the Cimetidine groups were administered intragastrically with Cimetidine at doses of 20, 80 and 160 mg/kg each day. Peripheral blood WBC of the rats was counted the day following exposure to gamma-rays. The rats were anesthetized and sacrificed on the day following exposure to (252)Cf for 28 days. The spleen, thymus, testicle, liver and intestinal tract indexes were evaluated. The DNA content of bone marrow cells and concanavalin A (ConA)-induced lymphocyte proliferation were measured. The frequency of micronuclei in polychromatic erythrocytes (fMNPCEs), superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione peroxidase (GSH-Px) in the serum and liver tissues were detected. RESULTS: The peripheral blood WBC in the Cimetidine groups was increased significantly on the 8th day and the 26th day compared with those in the radiation model group. The spleen, thymus and testicle indexes of the Cimetidine groups were higher than those of the radiation model group. The DNA content of bone marrow cells and lymphocyte proliferation in the Cimetidine groups were increased significantly, and fMNPCE was reduced 1.41-1.77 fold in Cimetidine treated groups. The activities of SOD and GSH-Px in the Cimetidine groups were increased significantly, and the content of MDA in the Cimetidine groups was decreased significantly. CONCLUSIONS: The results suggested that Cimetidine alleviated damage induced by long-term, low-dose-rate neutron and gamma combined irradiation via antioxidation and immunomodulation. Cimetidine might be useful as a potent radioprotector for radiotherapy patients as well as for occupational exposure workers.

The topological phase diagram of cimetidine: A case of overall monotropy.[Pubmed:28160941]

Ann Pharm Fr. 2017 Mar;75(2):89-94.

Cimetidine is a histamine H2-receptor antagonist used against peptic ulcers. It is known to exhibit crystalline polymorphism. Forms A and D melt within 0.35 degrees from each other and the enthalpies of fusion are similar as well. The present paper demonstrates how to construct a pressure-temperature phase diagram with only calorimetric and volumetric data available. The phase diagram provides the stability domains and the phase equilibria for the phases A, D, the liquid and the vapor. Cimetidine is overall monotropic with form D the only stable solid phase.

The Slow Relaxation Dynamics in the Amorphous Pharmaceutical Drugs Cimetidine, Nizatidine, and Famotidine.[Pubmed:27773524]

J Pharm Sci. 2016 Dec;105(12):3573-3584.

The slow molecular mobility in the amorphous solid state of 3 active pharmaceutical drugs (Cimetidine, nizatidine, and famotidine) has been studied using differential scanning calorimetry and the 2 dielectric-related techniques of dielectric relaxation spectroscopy and thermally stimulated depolarization currents. The glass-forming ability, the glass stability, and the tendency for crystallization from the equilibrium melt were investigated by differential scanning calorimetry, which also provided the characterization of the main relaxation of the 3 glass formers. The chemical instability of famotidine at the melting temperature and above it prevented the preparation of the amorphous for dielectric studies. In contrast, for Cimetidine and nizatidine, the dielectric study yielded the main kinetic features of the alpha relaxation and of the secondary relaxations. According to the obtained results, nizatidine displays the higher fragility index of the 3 studied glass-forming drugs. The thermally stimulated depolarization current technique has proved useful to identify the Johari-Goldstein relaxation and to measure taubetaJG in the amorphous solid state, that is, in a frequency range which is not easily accessible by dielectric relaxation spectroscopy.

Transdermal Delivery of Cimetidine Across Microneedle-Treated Skin: Effect of Extent of Drug Ionization on the Permeation.[Pubmed:28161442]

J Pharm Sci. 2017 May;106(5):1285-1292.

The objective of this work was to optimize a gel formulation of Cimetidine to maximize its transdermal delivery across microporated skin. Specifically, the effect of extent of ionization in formulation on permeation of Cimetidine across microporated skin was studied. Cimetidine was formulated into a gel using propylene glycol, water, and carbopol 980NF. Three strengths of gels (0.1% w/w, 0.5% w/w, and 0.8% w/w) were made and Tris base was used to adjust the pH of formulations to pH 5, pH 6.8, and pH 7.5. In vitro permeation testing was performed on vertical Franz cells with dermatomed porcine ear skin. Permeation studies suggested that pH 5 gels showed highest permeation through microchannels. This trend was more prominent with an increase in drug loading. The total amount of Cimetidine delivered from 0.8% w/w gel at pH 5 at 24 h was 28.20 +/- 4.63 mug, which was significantly higher than that from pH 6.8 (16.89 +/- 3.56 mug) and pH 7.5 (12.03 +/- 1.66 mug) gels. Cimetidine permeation across microporated skin was found to be pH dependent, with lower pH/highest ionization resulting in greatest permeation. The effect of ionization contributing to faster release was more pronounced when drug concentration was increased.

Inverse agonism of histamine H2 antagonist accounts for upregulation of spontaneously active histamine H2 receptors.[Pubmed:8692899]

Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6802-7.

Histamine H2 receptors transfected in Chinese hamster ovary (CHO) cells are time- and dose-dependently upregulated upon exposure to the H2 antagonists Cimetidine and ranitidine. This effect appears to be H2 receptor-mediated as no change in receptor density was observed after H1 or H3 antagonist treatment or after incubation with the structural analogue of Cimetidine, VUF 8299, which has no H2 antagonistic effects. By using transfected CHO cells expressing different densities of wild-type H2 receptors or an uncoupled H2Leu124Ala receptor, the histamine H2 receptor was found to display considerable agonist-independent H2 receptor activity. Cimetidine and ranitidine, which both induce H2 receptor upregulation, actually functioned as inverse agonists in those cell lines displaying spontaneous agonist-independent H2 receptor activity. Burimamide, on the other hand, was shown to act as a neutral antagonist and did as expected not induce H2 receptor upregulation after long-term exposure. The displayed inverse agonism of H2 antagonists appears to be a mechanistic basis for the observed H2 antagonist-induced H2 receptor upregulation in transfected CHO cells. These observations shed new light on the pharmacological classification of the H2 antagonists and may offer a plausible explanation for the observed development of tolerance after prolonged clinical use.

The imidazoline I1 receptor agonist, moxonidine, inhibits insulin secretion from isolated rat islets of Langerhans.[Pubmed:8549627]

Eur J Pharmacol. 1995 Sep 15;284(1-2):199-203.

In order to study the pharmacology of the putative imidazoline receptor involved in stimulation of insulin secretion, the potent and selective imidazoline I1 receptor agonist, moxonidine, was employed. Surprisingly, this agent caused a rapid and complete inhibition of glucose-induced insulin secretion in isolated rat islets of Langerhans. This response was reversible upon removal of the compound but was only partially attenuated under conditions of complete alpha 2 blockade, suggesting that it did not derive entirely from the weak alpha 2-adrenoceptor agonist activity of moxonidine. Furthermore, the response could not be attributed to activation of imidazoline I1 receptors since it was not reproduced by a second potent imidazoline I1 receptor agonist, Cimetidine, and could not be alleviated by the imidazoline I1 receptor antagonist efaroxan. The results confirm that the imidazoline receptor involved in control of insulin secretion differs from the I1 subclass and suggest that moxonidine inhibits insulin secretion by a mechanism unrelated to imidazoline I1 receptor agonism.

Distribution, properties, and functional characteristics of three classes of histamine receptor.[Pubmed:2164693]

Pharmacol Rev. 1990 Mar;42(1):45-83.

It is clear from the preceding overview of histamine receptor pharmacology that research into the pharmacology of histamine receptors is at an exciting stage of development. The rapid advance of molecular biology should soon see the structural identification and cloning of all three of the major vertebrate histamine receptors. Further work will continue toward enhancing our understanding of the control by histamine of intracellular signaling via H1- and H2-receptors, and the rapid explosion of work on the H3-receptor should begin to unravel the mechanisms underlying its actions, perhaps via effects on ionic channels. The potential role of histamine as an intracellular second messenger raises exciting possibilities, as does the search for a histamine receptor analogous to the ligand-gated ion channel in the invertebrate nervous system.