Histamine-stimulated gastric acid secretion can be antagonized in animals [i] and in man [2] by burimamide given intravenously. This effect appears to be related to the specific blockade of histamine H2-receptors by burimamide which was demonstrated on certain tissues in vitro [1]. Potential clinical interest was aroused by the finding that burimamide also inhibited gastric acid secretion evoked by pentagastrin or gastrin. However, because of difficulties found in studying the oral effectiveness of burimamide in experimental animals, no proposal for its clinical evaluation was made. A new compound, metiamide, has now been developed which has properties suitable for evaluation of the therapeutic potential of histamine H2-receptor blockade in man, namely, high specific activity, low toxicity and good oral bioavailability. methylene group (-CH2-) with an isosteric thios ether (-S-) link in the side chain and by the addition of a methyl group in the imidazole ring. These changes alter the electron densities of the ring nitrogens and were introduced to make the preferred tautomer of the imidazole ring similar to that found in histamine in solution. These changes also alter the ionisation and lipid solubility of the compound and hence may influence its absorption from the intestine. Thus the pKa for metiamide of 6.8 implies that when the pH is below 4 in the stomach almost all the molecules will be charged due to protonation of the imidazole ring but when the pH approaches neutrality in the small intestine about half of the molecules will now be uncharged. Since uncharged molecules are much more lipid soluble than charged ones the lipid solubility ofmetiamide at pH 7 is over 40 times greater than at pH 4. Chemistry of metiamideThe molecular weight of metiamide is 244.4. Therefore doses expressed in this paper as

Cimetidine, a new H2‐receptor antagonist, was safely administered to eighteen healthy man by the intravenous, intraduodenal or oral route. 2 When gastric secretion was maximally stimulated by either histamine or pentagastrin, the simultaneous administration of cimetidine produced marked inhibition of both acid and pepsin secretion. 3 Cimetidine was well absorbed by mouth and had a blood half‐life of 2 hours. 4 Cimetidine was rapidly excreted via the kidneys and about 70% of the excreted material was unchanged drug. 5 Clinical evaluation of cimetidine in patients with peptic ulceration is recommended.

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