Metiamide

Metiamide is a high-selective and oral bioavailable antagonist of histamine H2-receptor with ED50 value of 25 μmol/kg [1].
Unlike the traditional antihistaminics which are H1-receptor antagonists, metiamide is an antagonist of H2-receptor. It is developed from burimamide which is a previously found antagonist of H2-receptor. Metiamide acts as a competitive antagonist and blocks the combination of histamine and its receptor. This blockade results in the inhibition of gastric acid secretion stimulated by histamine and other hormone such as pentagastrin and gastrin. Compared with burimamide, metiamide showed higher activity and good oral bioavailability [1 and 2].
In the in vitro assays, metiamide displayed about 10-fold higher activity than burimamide on rat uterine muscle and guinea-pig heart muscle with Kb values of 0.75 and 0.92 μM, respectively. The Kb value of burimamide on the atrial muscle was 7.8 μM. Besides that, metiamide showed no efficacy on H1-receptor and isoprenaline even at the concentration of 1 mM suggested that metiamide was also a selective antagonist. Moreover, metiamide was found to cause increase in chemokinesis and random migration in PMN cells similar to histamine. It was different that metiamide had no effects on the true chemotaxis whereas histamine significantly suppressed the chemotaxis, which demonstrated histamine affected neutrophil motility through the H2-receptor site [1 and 3].
In dogs, the administration of metiamide inhibited acid secretion stimulated by histamine from both the Heidenhain pouch and the gastric fistula. It also inhibited acid secretion stimulated by pentagastrin and liver extract from both the Heidenhain pouch and the main stomach. When metiamide was given by intravenous injection, the doses of it to cause 50% inhibition of the maximal histamine- and pentagastrin-stimulated acid secretion were 3.1 and 6.1 μmol/kg. When metiamide was given by oral administration, the ED50 value of it to cause inhibition was 16 μmol/kg [1 and 2].
References:
[1] Black J W, Duncan W A M, Emmett J C, et al. Metiamide—an orally active histamine H2-receptor antagonist. Agents and Actions, 1973, 3(3): 133-137.
[2] Grossman M I, Konturek S J. Inhibition of acid secretion in dog by metiamide, a histamine antagonist acting on H2 receptors. Gastroenterology, 1974, 66(4): 517-521.
[3] Anderson R, Glover A, Rabson A R. The in vitro effects of histamine and metiamide on neutrophil motility and their relationship to intracellular cyclic nucleotide levels. The Journal of Immunology, 1977, 118(5): 1690-1696.

Toxic effects of the histamine H(2) receptor antagonist metiamide on bone-marrow haemopoietic and stromal progenitor cells in vitro.[Pubmed:20702338]

Toxicol In Vitro. 1988;2(3):221-4.

The histamine H(2)-receptor antagonist, Metiamide has been shown to cause agranulocytosis in vivo. In vitro colony forming assays for bone-marrow stromal fibroblast progenitors (CFU-F) and granulocyte/macrophage progenitor cells (CFU-GM) were performed, using murine bone marrow, to assess the relative sensitivity of committed haemopoietic cells, and the marrow stromal microenvironment to Metiamide toxicity. CFU-F were more susceptible than CFU-GM to inhibition by Metiamide, with 50% inhibition of colony formation (ID(50)) at 17 and 180 mug/ml in the CFU-F and CFU-GM assays, respectively. Inhibition of CFU-GM required the continuous presence of the drug, while CFU-F were inhibited similarly by either short-term (20-hr) or prolonged (10-day) incubation with Metiamide (ID(50) 27 and 17 mug/ml, respectively). It is suggested that bone-marrow stromal cell damage may be an important contributory factor in the haemopoietic toxicity of Metiamide.

Orthogonal arrays of particles in the gastric parietal cell of the rat: differences between superficial and basal cells in the gland and after pentagastrin or metiamide treatment.[Pubmed:3085548]

Anat Rec. 1986 May;215(1):28-34.

The basolateral plasma membrane of gastric parietal cells is characterized by the presence of orthogonal arrays of particles revealed by the freeze-fracture technique. These arrays were quantitatively assessed in freeze-fracture replicas of the gastric mucosa at two different levels of the gastric gland and after pentagastrin and Metiamide treatment. The arrays were small and scarce in parietal cells located in the upper part of the gland, while they were markedly more abundant in parietal cells situated at the base of the gland. In both superficial and basal cells, the concentration of the arrays was significantly decreased after pentagastrin or Metiamide treatment. This decrease was not due to an increase in the surface area of the basal plasma membrane. These results indicate that the concentration of the orthogonal arrays is a distinctive feature between superficial and basal parietal cells and that the arrays can be modulated by parietal cell function.

Antagonism of hypotensive and bradycardic effects of centrally administered guanfacine by metiamide in anesthetized rabbits.[Pubmed:2865383]

Jpn Heart J. 1985 Jul;26(4):577-84.

In anesthetized rabbits, intracerebroventricular (ICV) administration of the alpha-adrenoceptor agonist, guanfacine, like clonidine, elicited dose-related falls in arterial blood pressure and heart rate. ICV pretreatment with the histamine H2-receptor antagonist, Metiamide, significantly reduced the hypotensive and bradycardic responses caused by ICV injection of either guanfacine or clonidine. The present results seem to indicate that the antagonistic effect of Metiamide against either guanfacine or clonidine is probably due to its alpha-adrenoceptor blocking action rather than its histamine H2-receptor blocking action, suggesting that these interactions might be of central origin.