Scottish Symposium-Peptic Ulceration
1977); the claim that it does so by protecting the ulcer surface as a result of chelation with protein of the necrotic tissue remains to be demonstrated convincingly. REFERNCES
Bank, S., Marks, I. N. (1973). Evaluation of new drugs for peptic ulcer. In Clinics in Gastroenterology, Vol. 2, number 2 Peptic Ulceration, p.379. Edited by W. Sircus. London, Philadelphia and Toronto: W. B. Saunders and Co. Buchmann, E. Kaung, D. T., Dolan, K., Knapp, R. N. (1969). Gastroenterology, 56, 1016 Doll, R., Jones, F. A., Pygott, F. (1958). Effect of smoking on the production and maintenance of gastric and duodenal ulcers. Lancet, 1, 657 Enquvist, A., Von. Feiltzen, F., Pyk, E., Richard, H. (1973). Double-blind trial of deglycyrrhizinated liquorice in gastric ulcer. Gut, 14, 711 Fordtran, J. S. (1968). Acid rebound. New England Journal of Medicine, 279, 900 Fordtran, J. S. (1973). Reduction of acidity by diet antacids and anticholinergics. In Gastrointestinal disease p.718. Edited by M. H. Sleisenger and J. S. Fordtran. Philadelphia, London, Toronto: W. B. Saunders and Co.
Fordtran, J. S., Morawski, S. G., Richardson, C. T (1973). In vivo evaluation of liquid antacids. New England Journal of Medicine, 288, 923 Hunt, T. (1974). Carbenoxelone and duodenal ulcer. In Fourth Symposium on Carbenoxelone, p.235. Edited by Sir Francis Avery Jones and D. V. Paeker. London and Boston: Butterworths Jones, Sir F. A. (1972). Gastric ulcer aetiology and management with special reference to biogastrone, Symposium on carbenoxelone sodium, British Medical Week, Tokyo Lee, S. P., Nicholson, G. I. (1977). Increased healing of gastric and duodenal ulcers using tripotassium dicitrato-bismuthate, Medical Journal of Australasia, 1, 808 Lennard-Jones, J. E., Barbouris, N. (1965). Effects of different foods on the acidity of the gastric contents. Gut, 6, 113 Piper, D. W. (1973). Antacid and anticholinergic drug therapy. In Clinics in Gastroenterology, vol. 2, number 2. 'Peptic Ulceration' p.361. Edited by W. Sircus. London, Philadelphia and Toronto: W. B. Saunders and Co. Turpie, A. G. G., Runcie, J., Thomson, T. J. (1969). Clinical trial of deglycyrrhizinised liquorice in gastric ulcer. Gut, 10, 299
DEVELOPMENT AND APPLICATION OF H-2 RECEPTOR ANTAGONISTS
M. E. Parsons Research Institute, Smith Kline and French Laboratories, Welwyn Garden City
The gastric secretory response to a meal is in part the result of central vagal activation leading to acetylcholine release from the nerve endings in the stomach. This acetylcholine can directly stimulate acid secretion from the fundic part of the stomach but of greater importance is its ability to release the hormone gastrin from the pyloric antrum which circulates in the blood stream to the fundus and there stimulates gastric secretion. The presence of food in the stomach continues the gastrin release process by both mechanical distension of the antrum and through chemical action of the digestion products and this gastrin sustains the gastric secretory response. Although exogenously administered histamine is a potent stimulant of gastric acid secretion its role in the normal physiological control described above has always been controversial. McIntosh in 1938 suggested 292
that histamine was the final common mediator for all secretory stimulants but the evidence to support this hypothesis was mainly circumstantial. The absence of an antagonist of the gastric secretory stimulant action of histamine was a serious barrier to the studies directed towards substantiating the hypothesis. The failure of conventional antihistamines (now called HI histamine receptor antagonists) to inhibit this and other actions of histamine such as its effects on the heart and uterus suggested that, as in the adrenergic system, there may be 2 types of histamine receptor. The advent in 1972 of the specific competitive histamine H.- receptor antagonist burimamide allowed histamine receptors to be classified as either HI or H. receptors and provided an important tool for investigating McIntosh's hypothesis. The Hs-receptor anta-
Scottish Symposium-Peptic Ulceration
gonists inhibited histamine-stimulated gastric secretion in all species studied. In addition they were effective inhibitors of pentagastrin (or gastrin) stimulated secretion in the same species. Quantitatively the inhibition of pentagastrin-stimulated secretion was very similar to that found against histamine. The fact that in vitro studies on non-gastric tissues showed the compounds to be specific competitive histamine Hs-receptor antagonists plus their failure to inhibit debAMPstimulated secretion indicates that they are not non-specific anti secretory agents and provides important evidence to support the hypothesis that pentagastrin acts by mobilisation of endogenous mucosal histamine which in turn acts at H 2 receptors. Animal studies showed that in addition the H. antagonists could inhibit acid secretion stimulated by other secretagogues for example stable choline esters, insulin 2 deoxyglucosz and feeding.
From these data together with studies on in vitro mucosal preparations it appears that there are both histamine H. and acetylcholine receptors on the gastric mucosa. Although burimamide was administered to human volunteers, difficulties found in studying its oral activity led to the development of a more potent H. antagonist, metiamide. Clinical pharmacological studies confirmed the secretory inhibitory activity of metiamide which had been established in animal experiments, but in controlled clinical trials in duodenal ulcer patients a small number of cases of reversible granulocytopenia occurred. Since this was thought to be due to the chemical structure of metiamide rather than its properties as an H 2 antagonist, a new compound, Cimetidine, was developed which has proved a valuable therapeutic agent in diseases in which gastric acid secretion forms part of the aetiology.
THE USE OF CIMETIDINE IN SEVERE DUODENAL ULCERATION G. Gray, I. S. Smith, I. Mackenzie and G. Gillespie Department of Surgery, Victoria Infirmary, Glasgow
The Histamine H 2 receptor antagonist Cimetidine (Tagamet) has been shown to be effective in inhibiting gastric acid secretion produced in response to all known stimulants and thereby to have potential use in controlling duodenal ulceration. In the first of 2 consecutive controlled clinical trials 40 adult outpatients with active endoscopically proven duodenal ulceration, who would otherwise have undergone surgery, entered a 4-week double-blind trial of oral Cimetidine (1 g./day) ingested after meals, 200 mg. thrice daily and 400 mg. at bedtime, or placebo. After 28 days, 17 of 20 (85 %) patients receiving Cimetidine had healed ulcers compared with 5 of 20 patients receiving placebo (p
1977); the claim that it does so by protecting the ulcer surface as a result of chelation with protein of the necrotic tissue remains to be demonstrated convincingly. REFERNCES
Bank, S., Marks, I. N. (1973). Evaluation of new drugs for peptic ulcer. In Clinics in Gastroenterology, Vol. 2, number 2 Peptic Ulceration, p.379. Edited by W. Sircus. London, Philadelphia and Toronto: W. B. Saunders and Co. Buchmann, E. Kaung, D. T., Dolan, K., Knapp, R. N. (1969). Gastroenterology, 56, 1016 Doll, R., Jones, F. A., Pygott, F. (1958). Effect of smoking on the production and maintenance of gastric and duodenal ulcers. Lancet, 1, 657 Enquvist, A., Von. Feiltzen, F., Pyk, E., Richard, H. (1973). Double-blind trial of deglycyrrhizinated liquorice in gastric ulcer. Gut, 14, 711 Fordtran, J. S. (1968). Acid rebound. New England Journal of Medicine, 279, 900 Fordtran, J. S. (1973). Reduction of acidity by diet antacids and anticholinergics. In Gastrointestinal disease p.718. Edited by M. H. Sleisenger and J. S. Fordtran. Philadelphia, London, Toronto: W. B. Saunders and Co.
Fordtran, J. S., Morawski, S. G., Richardson, C. T (1973). In vivo evaluation of liquid antacids. New England Journal of Medicine, 288, 923 Hunt, T. (1974). Carbenoxelone and duodenal ulcer. In Fourth Symposium on Carbenoxelone, p.235. Edited by Sir Francis Avery Jones and D. V. Paeker. London and Boston: Butterworths Jones, Sir F. A. (1972). Gastric ulcer aetiology and management with special reference to biogastrone, Symposium on carbenoxelone sodium, British Medical Week, Tokyo Lee, S. P., Nicholson, G. I. (1977). Increased healing of gastric and duodenal ulcers using tripotassium dicitrato-bismuthate, Medical Journal of Australasia, 1, 808 Lennard-Jones, J. E., Barbouris, N. (1965). Effects of different foods on the acidity of the gastric contents. Gut, 6, 113 Piper, D. W. (1973). Antacid and anticholinergic drug therapy. In Clinics in Gastroenterology, vol. 2, number 2. 'Peptic Ulceration' p.361. Edited by W. Sircus. London, Philadelphia and Toronto: W. B. Saunders and Co. Turpie, A. G. G., Runcie, J., Thomson, T. J. (1969). Clinical trial of deglycyrrhizinised liquorice in gastric ulcer. Gut, 10, 299
DEVELOPMENT AND APPLICATION OF H-2 RECEPTOR ANTAGONISTS
M. E. Parsons Research Institute, Smith Kline and French Laboratories, Welwyn Garden City
The gastric secretory response to a meal is in part the result of central vagal activation leading to acetylcholine release from the nerve endings in the stomach. This acetylcholine can directly stimulate acid secretion from the fundic part of the stomach but of greater importance is its ability to release the hormone gastrin from the pyloric antrum which circulates in the blood stream to the fundus and there stimulates gastric secretion. The presence of food in the stomach continues the gastrin release process by both mechanical distension of the antrum and through chemical action of the digestion products and this gastrin sustains the gastric secretory response. Although exogenously administered histamine is a potent stimulant of gastric acid secretion its role in the normal physiological control described above has always been controversial. McIntosh in 1938 suggested 292
that histamine was the final common mediator for all secretory stimulants but the evidence to support this hypothesis was mainly circumstantial. The absence of an antagonist of the gastric secretory stimulant action of histamine was a serious barrier to the studies directed towards substantiating the hypothesis. The failure of conventional antihistamines (now called HI histamine receptor antagonists) to inhibit this and other actions of histamine such as its effects on the heart and uterus suggested that, as in the adrenergic system, there may be 2 types of histamine receptor. The advent in 1972 of the specific competitive histamine H.- receptor antagonist burimamide allowed histamine receptors to be classified as either HI or H. receptors and provided an important tool for investigating McIntosh's hypothesis. The Hs-receptor anta-
Scottish Symposium-Peptic Ulceration
gonists inhibited histamine-stimulated gastric secretion in all species studied. In addition they were effective inhibitors of pentagastrin (or gastrin) stimulated secretion in the same species. Quantitatively the inhibition of pentagastrin-stimulated secretion was very similar to that found against histamine. The fact that in vitro studies on non-gastric tissues showed the compounds to be specific competitive histamine Hs-receptor antagonists plus their failure to inhibit debAMPstimulated secretion indicates that they are not non-specific anti secretory agents and provides important evidence to support the hypothesis that pentagastrin acts by mobilisation of endogenous mucosal histamine which in turn acts at H 2 receptors. Animal studies showed that in addition the H. antagonists could inhibit acid secretion stimulated by other secretagogues for example stable choline esters, insulin 2 deoxyglucosz and feeding.
From these data together with studies on in vitro mucosal preparations it appears that there are both histamine H. and acetylcholine receptors on the gastric mucosa. Although burimamide was administered to human volunteers, difficulties found in studying its oral activity led to the development of a more potent H. antagonist, metiamide. Clinical pharmacological studies confirmed the secretory inhibitory activity of metiamide which had been established in animal experiments, but in controlled clinical trials in duodenal ulcer patients a small number of cases of reversible granulocytopenia occurred. Since this was thought to be due to the chemical structure of metiamide rather than its properties as an H 2 antagonist, a new compound, Cimetidine, was developed which has proved a valuable therapeutic agent in diseases in which gastric acid secretion forms part of the aetiology.
THE USE OF CIMETIDINE IN SEVERE DUODENAL ULCERATION G. Gray, I. S. Smith, I. Mackenzie and G. Gillespie Department of Surgery, Victoria Infirmary, Glasgow
The Histamine H 2 receptor antagonist Cimetidine (Tagamet) has been shown to be effective in inhibiting gastric acid secretion produced in response to all known stimulants and thereby to have potential use in controlling duodenal ulceration. In the first of 2 consecutive controlled clinical trials 40 adult outpatients with active endoscopically proven duodenal ulceration, who would otherwise have undergone surgery, entered a 4-week double-blind trial of oral Cimetidine (1 g./day) ingested after meals, 200 mg. thrice daily and 400 mg. at bedtime, or placebo. After 28 days, 17 of 20 (85 %) patients receiving Cimetidine had healed ulcers compared with 5 of 20 patients receiving placebo (p
