Metiamide

Abstract: Metiamide has been found to be about 10 times more active than burimamide in vitro in antagonizing histamine H2-receptors and nearly 5 times more active in vivo as an antagonist of histamine or pentagastrin-stimulated secretion. Effective oral ED50 doses for inhibition have been estimated as 25 μmole kg−1 against basal secretion in rats and 16 μmole kg−1 against maximal histamine-stimulated secretion in dogs. Administration of metiamide orally daily for 90 days with doses of 1,500 μmole kg−1 to rats and 700 μmole kg−1 to dogs produced signs of kidney damage as the dominant lesion in both species. These toxic doses are roughly 60 and 44 times greater than the ED50 doses in the rat and dog, respectively. These results show that metiamide has the degree of activity and safety needed for a compound to be a candidate for through clinical evaluation.

Abstract: Antigen-induced, IgE-mediated release of histamine from human basophiles is an in vitro model of allergic reacttions; it is blocked by extracellular histamine, presumably as a result of its ability to increase adenosine 3',5'-monophosphate (cyclic AMP) levels. The H1 antihistamines do not antagonize these effects of histamine but at approximately equal to 1 mM cause histamine release and at approximately equal to 0.1mM inhibit antigen-induced histamine release. The phenothiazine antihistamines are 10-30 fold more potent inhibitors than the rest; other tricyclic antidepressant drugs share this activity. The mechanism of this inhibition, which occurs in both the 1 degree and 2 degree stages of histamine release, is not known but it is not due to partial agonist activity since the anti-H1 drugs cause a significant fall in cyclic AMP levels. The anti-anaphylactic effects of the H1 antagonists probably play no therapeutic role but we suggest that drugs structurally similar to the phenothiazine antihistamines should be developed for clinical testing. The H2 antihistamines block histamine-induced inhibition of histamine release and the increase in cyclic AMP levels, but neither cause nor inhibit histamine release. The K-B values for the anti-H2 drugs (burimamide approximately equal to 5 muM); metiamide approximately equal to 0.5muM); are similar to those described for other H2 receptors.