A Study in Mice of Benzodiazepine-Anticholinergic Interaction: Protection against Restraint-Immersion and Forced Exertion-Induced Gastric Mucosal Erosion

Abstract

The effectiveness of benzodiazepines arid anticholinergics administered alone or in combination in preventing restraint-immersion and forced exertion-induced gastric mucosal erosion was investigated in mice. The benzodiazepines used were diazepam and chlordiazepoxide HCI and the anticholinergics were propantheline bromide and clidinium bromide. The administration of a benzodiazepine with an anticholinergic resulted in additive or supra-additive protective effects in both systems. In the restraint-immersion system, diazepam combined with propantheline bromide at a ratio of 1 to 13.7 yielded a 4.53-fold supra-additive effect. At ratios of 4.6 or 1.5 parts of propantheline bromide to 1 part of diazepam an additive effect was observed. One part of diazepam, when combined with 1.4 to 12.0 parts of clidinium bromide resulted in supra-additive effects of about 1.5-fold. The co-administration of chlordiazepoxide HCI and clidinium bromide in ratios of 2 to 1 or 2.5 to 1 resulted in supra-additive effects of 2.4- and 1.85-fold, respectively. At higher and lower ratios additive effects were demonstrated. In the forced exertion system, diazepam combined with either anticholinergic resulted in supra-additive effects of 2- to 3-fold which occurred at ratios of diazepam to the anticholinergic varying over an 8-fold range. The co-administration of 2 parts of chlordiazepoxide HCI and 1 part of clidinium bromide resulted in a 2.84-fold supra-additive effect in the forced exertion system. These results are discussed in relation to the use of benzodiazepine anticholinergic combinations in the treatment of human gastric and duodenal ulcer disease.

Benzodiazepines Reduce Gastric Ulcers Induced in Rats by Stress

“…In our experiments the lowest dose of chlordiazepoxide (5 mg/kg) was sedative but produced an increase in gastric ulceration and haemorrhage. This lack of protection contrasts with a previous report, that mucosal damage induced by restraint-immersion in the mouse was reduced by low doses of diazepam (ED50= 1.1 mg/kg) and chlordiazepoxide (ED50 = 4.0 mg/kg), although much higher doses (diazepam 33.7, chlordiazepoxide 132) were required for protection against the effects of forced exertion (Dairman & Juhasz, 1978). The separation of sedative and antiulcer effects after acute administration suggests that these two actions of benzodiazepines may not be related.…”

“…This improvement may be effected by the reduction in resting gastric secretion and acid production observed after treatment with diazepam (Birnbaum, Karmeli & Tefera, 1971). This observation is reinforced by animal studies which indicate that, even with acute treatment, diazepam and chlordiazepoxide reduce the formation of gastric lesions induced by a variety of stress situations (Haot, Djahanguiri & Richelle, 1964;Bimbaum, 1969;Bonfils & Dubrasquet, 1969;Schumpelick & Paschen, 1974;Dairman & Juhasz, 1978). However, the doses used in these studies (e.g.…”

General Pharmacology and Neuropharmacology of Benzodiazepine Derivatives

“…As already observed for chlordiazepoxide, diazepam at doses of 0.3-10 mg· kg -I p.o. effectively diminished the incidence of gastric mucosal erosions in mice under restrained stress or forced exercise (DAIRMAN and JUHASZ, 1978). The same authors also found that a combined injection of either diazepam or chlordiazepoxide with anticholinergics resulted in an additive or supraadditive effect.…”

“…Chlordiazepoxide was shown to reduce the number of ulcerations produced either by restrained stress in rats (50 mg· kg-I i.p., HAOT et aI., 1964), by restrained stress combined with immersion and forced exertion in mice (5-20 mg· kg-I p.o., DAIRMAN and JUHASZ, 1978) or by unescapable electroshock in rabbits (50 mg· kg-I i.p., DASGUPTA and MUKHERJEE, 1967 a). Nitrazepam (15 and 20 mg· kg -I s.c.) was shown by MERCIER and LUMBROSO (1967) to reduce the number of ulcerations occurring after restrained stress in both rats and mice.…”

The role of adenosinergic, GABAergic and benzodiazepine systems in hyperemotionality and ulcer formation in stressed rats

“…GABA agonists and benzodiazepines would exhibit similar pharmacological effects or would potentiate each other. Benzodiazepines reduce the formation of gastric lesions induced by a variety of stress situations (Dairman and Juhasz 1978;Gupta et al 1985); however, the doses used in these studies are higher than those observed to produce marked sedation with acute administration (File 1980). The present studies were designed to distinguish between the effects of low doses of benzodiazepines on hyperemotionality and ulceration induced by immobilization stress, and to assess the possible contribution of central purinergic, GABAergic and benzodiazepine systems involved in them.…”