Anti-ulcer and secretion-inhibitory properties of the tricyclic derivative doxepin in rats and dogs.
The anti-ulcer and antisecretory properties of 3-(dibenz[b,e] oxepin - 11(6H)-ylidene)-N,N- dimethylpropylamine hydrochloride (doxepin) were investigated in a series of acute experiments in rats with gastric and duodenal ulcer. Acute gastric ulceration induced by immobilisation and stress (waterbath), and by non-steroidal anti-inflammatory agents, was reduced by doxepin to the same extent as by pirenzepine and cimetidine. Doxepin and cimetidine showed a weak but significant effect against serotonin-induced ulcers in the rat, but pirenzepine did not. Duodenal ulcer caused by increased acid production (pentagastrin plus carbachol induced) was suppressed by pirenzepine, doxepin and cimetidine. The inhibition of gastric secretion by doxepin was studied in anaesthetised rats and conscious dogs. In the Lai rat, doxepin decreased carbachol-induced secretion of hydrochloric acid more effectively than cimetidine. Doxepin was as ineffective as pirenzepine against histamine- or pentagastrin-induced secretion. In the dog with gastric fistula, doxepin inhibited the acid production induced by 2-desoxy-d-glucose more effectively, and for longer periods, than that induced by pentagastrin or histamine. In the dog with a Heidenhain pouch, doxepin reduced the acid secretion stimulated by pentagastrin and carbachol, and by histamine, less effectively and for a shorter time, than cimetidine. The antagonism of doxepin to the action of carbachol in the rat and that of 2-desoxy-d-glucose in the dog appears to be an important factor in its mode of action. To inhibit the secretion of saliva and to delay intestinal transport, a dose of doxepin 3-10 times greater than that required for anti-ulcerative and secretion-inhibitory effects was necessary.
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000009:adverse effects; D000897:Anti-Ulcer Agents; D001570:Benzodiazepinones / Q000494:pharmacology; D002217:Carbachol / Q000037:antagonists & inhibitors; D002927:Cimetidine / Q000494:pharmacology; D003864:Depression, Chemical; D004285:Dogs; D004316:Doxepin / Q000494:pharmacology*; D004381:Duodenal Ulcer / Q000517:prevention & control; D005260:Female; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism; D005769:Gastrointestinal Motility / Q000187:drug effects; D006801:Humans; D007274:Injections, Intraperitoneal; D008297:Male; D010418:Pentagastrin / Q000037:antagonists & inhibitors; D010890:Pirenzepine; D051381:Rats; D011919:Rats, Inbred Strains; D012472:Salivation / Q000187:drug effects; D012702:Serotonin Antagonists; D013045:Species Specificity; D013315:Stress, Psychological / Q000503:physiopathology
D000893:Anti-Inflammatory Agents; D000897:Anti-Ulcer Agents; D001570:Benzodiazepinones; D012702:Serotonin Antagonists; D004316:Doxepin; D010890:Pirenzepine; D002927:Cimetidine; D002217:Carbachol; D010418:Pentagastrin