ABSTRACT
VI. DEVELOPMENTS SINCE CIMETIDINE Since cimetidine, nearly 30 histamine Hrreceptor antagonists have been taken into development although only four have made it to the marketplace. The first was ranitidine (Zantac) in which a furan ring replaces the imidazole in cimetidine and the cyano-guanidine group is replaced by a 1,1-diamino-nitroethine. Ranitidine is more potent than cimetidine and has a somewhat superior side effect profile. Subsequently famotidine (Pepcid), a guanidinothiazole structure, came on to the market and remains the most potent Hz antagonist available for clinical use. The other two marketed compounds, nizatidine and roxatidine, do not represent a significant advance over the already available compounds. Because of the short half-life of both cimetidine and ranitidine, coupled with the perception that gastric acid secretion needed to be controlled throughout a 24-hr period, both SK&F and Glaxo successfully synthesized and started to develop longacting Hz antagonists (Lupitidine at SK&F, Loxtidine at Glaxo ). Lupitidine was some 16 times more potent than cimetidine in the dog and had an extended duration of antisecretory activity (19). Loxtidine behaved as an unsurmountable Hz antagonist in vitro and had a very prolonged duration of action in the dog (20). In humans a dose of 40 mg twice daily maintained intragastric pH at values above 4.5 throughout 24 hr (21).
