Br. J. Surg. Vol. 63 (1976) 788-792
Inhibitors of gastric secretion : current progress D. C. C A R T E R * SUMMARY
Several new compounds have become available recently which are potent inhibitors of gastric secretion. The therapeutic potential of these inhibitors in the peptic ulcer diathesis is reviewed and it is concluded that the histamine H,-receptor antagonists show most promise at present. The prostaglandins and gastro-intestinal polypeptides are of considerable physiological interest but are unlikely to have clinical importance in the immediate future.
ANTACIDSand anticholinergic compounds remain the mainstays of conventional medical treatment for the patient with duodenal ulceration. While it is freely acknowledged that antacids can relieve ulcer pain, there is little hard evidence to suggest that they accelerate the rate of ulcer healing. Anticholinergic drugs are among the most potent inhibitors of gastric secretion, but their potentially beneficial effects are offset by dose-limiting side-effects ; indeed, until such side-effects are produced it cannot be assumed that a pharmacologically effective dose is being administered. New compounds are constantly arriving on the scene with impressive claims for use in the peptic ulcer diathesis, but the continuing use of surgery to reduce acid and pepsin secretion remains the ultimate indictment of the inadequacy of medical treatment. All too often the new candidate compound passes through a period of enthusiastic acclaim, only to be rejected as useless or potentially dangerous after a more critical appraisal. It is against this rather gloomy background that all new inhibitors of gastric secretion must be assessed. The past few years have seen the development of a number of potent inhibitors, but three groups of compounds have excited particular interest and will be reviewed, not only in terms of their therapeutic potential but in the light of their contribution to our understanding of the pathophysiology of gastric secretion.
The prostaglandins The prostaglandins (PGs) are a group of unsaturated hydroxy fatty acids now known to be widely distributed through animal tissues. Initial medical interest centred on their role in human reproduction, but it was soon appreciated that PG E, is present in human gastric mucosa (Bennett et al., 1968), and Dozois and Thomson (1974) have reported the presence of both PG E, and PG A, in canine gastric secretions. Attempts to influence gastric secretion by administration of naturally occurring prostaglandins have been limited by their rapid degradation in the body 788
by the enzyme PG 15-OH dehydrogenase. Thus, while inhibition of human gastric secretion has been reported following administration of PG Al (Wilson et al., 1971) and PG El (Classen et al., 1971), the degree of inhibition has been unimpressive and apparent only after continuous intravenous infusion of relatively large doses of these compounds. Similarly, oral administration of P G A l and P G E , does not reduce basal secretion in man, although a transient rise in pH was observed following oral administration of PG A, (Bhana et al., 1973; Karim et al., 1973a). Analogues of PG E, have recently been synthesized in which the parent compound is modified by methylation at the crucial C-15 or neighbouring C-16 position. The resulting compounds are no longer substrates for PG 15-OH dehydrogenase, and an increase in biological activity might be anticipated. This is borne out by the fact that the analogues are potent inhibitors of gastric secretion, reducing both basal and stimulated acid and pepsin secretion when given orally to human volunteers (Carter et al., 1973; Karim et al., 1973a, b). The inhibitory action of one of these analogues is exemplified by Fig. 1, which illustrates the reduction in basal acid output which follows oral administration of 200 pg to healthy volunteers. Complementary animal studies have shown that the analogues are not only potent inhibitors of gastric secretion (Robert and Magerlein, 1973), but that the 15(R) analogue will protect the rat against gastric ulcers induced by indomethacin (Lippmann, 1974) or pyloric ligation (Carter, Ganesan et al., 1974). However, despite this accumulation of data, the mode of action of the prostaglandin analogues remains obscure. It is possible that the parent P G E , compound has a physiological role as a natural inhibitor of secretion, and that the analogues merely mimic this function. In other experimental systems, prostaglandins have been shown to influence cell function by affecting intracellular nucleotides such as the cyclic AMP system, but there is continuing debate as to whether cyclic AMP is responsible for the mediation of mammalian gastric secretion (Bieck et al., 1973; Mao et al., 1973). Of the other possible explanations for the inhibition of gastric secretion by the analogues (Fig. 2), a primary effect on mucosal blood flow is unlikely (Jacobson, 1970), and it is hardly conceivable that the compounds act by blockade of receptors on the cell surface. The remaining possibility is that the analogues damage the integrity of the gastric mucosal barrier, allowing hydrogen ions to diffuse back into the
* Department
of Clinical Surgery, University of Edinburgh.
Gastric secretion inhibitors mucosa from the lumen of the stomach and producing an apparent rather than real inhibition of secretion. In the case of the 16,16 dimethyl analogue, mucosal barrier damage has been demonstrated after local administration in an animal model (O'Brien and Carter, 1975), but the 15(R) analogue actually protects the mucosa from aspirin and bile salt damage in the rat (Carmichael et al., 1976). Until these uncertainties regarding the possible side-effects and mode of action have been resolved, it is unlikely that the prostaglandin analogues will be employed in large scale therapeutic trials in peptic ulcer patients. In a small pilot study Fung et al. (1974) have claimed that oral administration of the 15(R) analogue gave significant benefit in terms of the endoscopic healing of gastric ulcer, but these results must be interpreted with caution in view of the small numbers involved. It may be that the prostaglandin analogues will further our understanding of the pathophysiology of peptic ulceration and prove valuable in treatment, but at the present time more basic research is required before this promise can be fulfilled.
PG 15(R) 15 methyl E l methyl ester 200 pg orally
Gastro-intestinal hormones and related peptides A number of intestinal mucosal hormones, such as secretin, gastric inhibitory peptide and vasoactive intestinal peptide, are inhibitors of gastric secretion and have been considered as potential anti-ulcer compounds. With the exception of secretin, none of these hormones has been submitted to clinical trial in the ulcer diathesis. Secretin is an attractive theoBasal 0 I 2 3 retical proposition in that it stimulates secretion of Time (h) pancreatic bicarbonate, thereby neutralizing acid in the duodenal bulb, and also inhibits gastric secretion. Fig. 1. Effect of oral administration of 200 pg prostaglandin 15(R)15 methyl E2methyl ester on basal acid output in I 1 Konturek (1968) has shown that pentagastrin-induced healthy volunteers. duodenal ulcers in cats can be prevented by simultaneous infusion of secretin, but preliminary trials in PARIETAL CELL LUMEN man have failed to show any acceleration of duodenal SUBMUCOSA ulcer healing in secretin-treated patients when com0 Dared with controls receiving a Dlacebo (Henn et al.. Alter mucosal Jbloodflaw i975). Pancreatic glucagon aiso inhibits gastric secre: ATP tion and has been shown to protect the rat against Inhibit adenyl stress-induced haemorrhagic gastritis (Guth et al., 1975), but no clinical trials have been undertaken. Urogastrone is an interesting compound which has ,*' cAmP Hi been extracted from human urine and shown to consist of two polypeptides, one with 52 and the other *-Alter m e $ t $ e permeability D~~~~~mUcDsal with 53 amino acids. When infused intravenously, Mg++ barrier urogastrone is a potent inhibitor of both basal and Fig. 2. Possible mechanisms of action for inhibitors of stimulated gastric acid and intrinsic factor secretion gastric secretion. in human volunteers, but has little effect on pepsin output and does not affectserumgastrinconcentrations considerable interest. This is a hypothalamic tetra(Elder et al., 1975a). Urogastrone has also been infused decapeptide which suppresses growth hormone release, in 4 patients with the Zollinger-Ellison syndrome, but in addition is now known to be a potent inhibitor and although acid secretion was again markedly of several types of endocrine cell outwith the pituitary. reduced, the concentrations of intrinsic factor, Bloom et al. (1974) have reported that GH-RIH pepsin and serum gastrin were all increased (Elder lowered the plasma gastrin level and almost comet al., 1975b). Ulcer pain was relieved in all 4 patients pletely inhibited acid secretion in a patient with the within 3G60 minutes of commencing urogastrone Zollinger-Ellison syndrome, raising the possibility infusion, and this effect persisted for up to 24 hours. that GH-RIH might prove valuable clinically. At Finally, in this group of peptides, growth hormone first sight the inhibition of acid secretion might be release-inhibiting hormone (GH-RIH) has aroused attributed wholly to reduced gastrin production by 789
D. C. Carter the gastrinoma, but there is now good evidence that the compound also acts directly on the parietal cell (Barros D'Sa et al., 1975). GH-RIH-like immunoreactivity has recently been demonstrated in pancreatic D cells and morphologically similar cells in the stomach, duodenum, jejunum and upper ileum (Polak et al., 1975), opening a potential physiological role for this compound in the control of gastrointestinal function, including the control of gastric secretion. Thus, there are several gastro-intestinal hormones and related peptides which can inhibit gastric secretion and which may have therapeutic as well as physiological importance. However, clinical application of these compounds to the peptic ulcer problem remains limited by the difficulties of preparation coupled to the need for parenteral administration. At the present time their ultimate value to the patient with peptic ulcer disease is uncertain, regardless of their interest as research tools in the elucidation of the pathophysiology of gastric secretion.
Insulin infusion 0.03 u. k-' h-1
Control
Cirnetidine
I
Basal 0
I
30
I
I
90 Time (rnin)
60
I
I
I20
150
Fig. 3. Effect of cimetidine infusion on the mean acid output induced by simultaneous insulin infusion in 6 healthy volunteers.
Cimetidine 100 mg h
'
Cimetidine 100 rng h
Time ( h ) Fig. 4. Effect of cirnetidine on gastric acid output and pH in a patient with the Zollinger-Ellison syndrome.
790
'
Histamine H,-receptor antagonists Certain actions of histamine in the body, such as the stimulation of smooth muscle in the gut and bronchus, can be antagonized by the conventional histamine antagonist, mepyramine maleate, these actions being mediated by Hi-receptors (Ash and Schild, 1966). The stimulation of gastric secretion by histamine is unaffected by mepyramine maleate and is mediated by H,-receptors. In 1972 Black et al. published a description of the properties of a selective H,-receptor antagonist, burimamide, which had been developed after a painstaking search of some 700 synthesized compounds, all based on the structure of histamine. Burimamide was capable of inhibiting gastric secretion in several experimental situations, but was rapidly superseded by the more potent, and orally effective, metiamide. This new compound inhibited secretion induced by histamine, pentagastrin and insulin hypoglycaemia (Wyllie et al., 1973; Carter, Forrest et al., 1974; Thjodleifsson and Wormsley, 1974), profoundly decreased nocturnal acid secretion (Milton-Thompson et al., 1974) and reduced mealstimulated acid secretion (Mainardi et al., 1974) in both normal volunteers and patients with duodenal ulceration. Clinical trials were soon undertaken to assess its value in a clinical context. Pounder et al. (1975a) reported on 30 patients with duodenal ulcer treated for 5-8 weeks with either metiamide or a placebo as part of a double blind trial. In the 15 patients receiving oral metiamide there was a significant reduction in nocturnal pain and antacid consumption, and day-time pain was diminished although not to a significant degree. In a multicentre double blind trial in 68 patients with endoscopically proved duodenal ulceration (Multicentre Trial, 1975), ulcer healing was significantly greater in the patients receiving metiamide (67 per cent) when compared with the rate of healing in patients receiving a placebo (25 per cent). Metiamide also proved effective in the management of the Zollinger-Ellison syndrome (Thompson
Gastric secretion inhibitors et al., 1975) and seemed certain of an established place in the pharmacopoeia. Unfortunately, this early promise will not now be fulfilled as transient granulocytopenia has occurred in 7 patients receiving the drug. This marrow depression has been readily reversible on cessation of therapy in 6 patients but there has been one fatality, and the problem has been sufficient to curtail the use of the drug. Fortunately, a new H,-receptor antagonist is now available which appears at least as potent as metiamide as an inhibitor of gastric secretion (Burland, Duncan et al., 1975) without sharing its deleterious effect on the bone marrow. Indeed, the new compound, cimetidine, has been used successfully in a patient with metiamide-induced agranulocytosis (Burland, Sharpe et al., 1975). It seems likely that the thiourea residue in the metiamide molecule was responsible for marrow depression, and this has been replaced by a cyanoguanidine moiety in cimetidine. The potency of cimetidine as an inhibitor is illustrated by Fig. 3, which shows its effect on acid secretion induced by insulin infusion in paired tests in healthy volunteers in our own laboratory. Pounder and his colleagues (Pounder et al., 1975b; Pounder, Williams et al., 1976) have reported that cimetidine diminishes 24-hour intragastric hydrogen ion activity to levels compatible with ulcer healing, when given in four divided oral doses to healthy volunteers or duodenal ulcer patients. In a preliminary trial in 10 patients with gastric ulcer, oral cimetidine rapidly relieved symptoms and ulcer healing was complete at endoscopy in all subjects by the end of the 6-week trial (Pounder, Hunt et al., 1976). Ivey et al. (1976) have reported that cimetidine raises the potential difference across the gastric mucosa in man, and suggested that the compound protects the gastric mucosal barrier. This suggestion appears unwarranted and has not been confirmed by studies of ionic flux across the gastric mucosa in our own laboratories (Kenyon and Carter, 1976). However, our results in no way detract from the therapeutic promise of cimetidine as an inhibitor of secretion. We have had the opportunity of using cimetidine in a patient with the Zollinger-Ellison syndrome, and Fig. 4 demonstrates the profound reduction of acid secretion which can be achieved. Metiamide was less effective in controlling secretion in this case, but there is every indication that cimetidine will prove useful in this context, not only as an aid in preparation for gastrectomy, but as a possible alternative to surgery in selected cases. The H,-receptor antagonists have raised intriguing questions about the role of histamine in the control of gastric secretion. There is still debate as to whether histamine serves as the final common pathway in the mediation of secretion, or whether the effects of the H,-receptor antagonists can be explained by some form of interaction between receptors at the parietal cell. Formal clinical trials of cimetidine are now under way in patients with duodenal ulcer and the results will be awaited with interest. There is no doubt that the compound is a potent inhibitor and at the present 74
time it appears free of restrictive side-effects. Cimetidine must be regarded as the most promising of the currently available inhibitors of secretion but time alone will tell whether this promise will be fulfilled.
Conclusions The ideal inhibitor for therapeutic use in the peptic ulcer diathesis should be able to maintain effective reduction of gastric secretion without undesirable side-effects. It should relieve ulcer pain, speed ulcer healing and prove acceptable to the patient. Of the available inhibitors, cimetidine appears the most promising provided that it remains free from toxicity and proves effective in clinical trials. It is likely that inhibitors of gastric secretion will prove valuable during acute exacerbations of peptic ulceration and they may have a valuable role in the management of gastro-intestinal haemorrhage and the rare ZollingerEllison syndrome. However, it remains to be seen whether any inhibitor will materially affect the long term cause of the peptic ulcer diathesis, and surgery seems likely to retain a major role in management in the foreseeable future. References ASH A. s. F. and SCHILD H. 0. (1976) Receptors mediating some actions of histamine. Br. J. Pharmacol. 27, 427-439. BARROS D’SA A. A. J., BLOOM s. R. and BARON J. H. (1975) Direct inhibition of gastric acid by growthhormone release-inhibiting hormone in dogs. Lancet 1, 886-887. BENNETT A., MURRAY J. G . and WYLLIE J. H. (1968) Occurrence of prostaglandin El in human stomach, and a study of its effect on human isolated gastric muscle. Brit,J. Pharmacol. Chemother. 32, 339349. BHANA D., KARIM s. M. M., CARTER D. c . et al. (1973) The effect of orally administered prostaglandin Al, A, and 15-epi-A, on human basal secretion. Prostaglandins 3, 307-3 16. BIECK P. R., OATES J. A., ROBISON G. A . et al. (1973) Cyclic AMP in the regulation of gastric secretion in dogs and humans. Am. J. Physiol. 224, 158164. BLACK J. w . , DUNCAN w. M., DURANT c. J. et al. (1972) Definition and antagonism of histamine H,receptors. Nature (Lond.) 236, 355-390. BLOOM s. R., MORTIMER c . H., THORNER M. 0. et al. (1974) Inhibition of gastric acid secretion by growthhormone release-inhibiting hormone. Lancet 2, 1106-1 109. BURLAND w. L., DUNCAN w . A, M., HESSELBO T. et al. (1 975) Pharmacological evaluation of cimetidine, a new histamine H,-receptor antagonist in healthy man. Br. J . Clin. Pharmacol. 2, 481486. BURLAND w. L., SHARPE P. c . , COLIN-JONES D. G. et al. (1975) Reversal of metiamide-induced agranulocytosis during treatment with cimetidine. (Letter to the Editor.) Lancet 2, 1085. 791
D. C. Carter et al. (1976) Effect of prostaglandin 15(R)15methyl-E, methyl ester on aspirin and taurocholic acid-induced gastric mucosal haernorrhage in rats. Gut 17, 33-36. CARTER D. c., FORREST J. A, H., WERNER R. et al. (1974) Effect of histamine H,-receptor blockage on vagally induced gastric secretion in man. Br. Med. J. 2, 554556. CARTER D. c., GANESAN P. A., BHANA D. et al. (1974) The effect of locally administered prostaglandin 15(R)15 methyl-E, methyl ester on gastric ulcer formation in the Shay rat preparation. Prostaglandins 5, 455-463. CARTER D. c., KARIM s. M. M., BHANA D. et al. (1973) Inhibition of human gastric secretion by prostaglandin. Br. J . Surg. 60, 828-831. CLASSEN M., KOCH H., BICICHARDT J. et al. (1971) The effect of prostaglandin El on the pentagastrinstimulated gastric secretion in man. Digestion 4,333-344. DOZOIS R. R. and THOMPSON c. J. (1974) Presence of prostaglandins E, and A, in canine gastric secretions. Life Sci. 15, 975-986. ELDER J. B., GANGULI P. c., GILLESPIE I. E. et al. (1975a) Effect of urogastrone on gastric secretion and plasma gastrin levels in normal subjects. Gut 16, 887-893. ELDER J. B., GANGULI P. c., GILLESPIE I. E. et al. (1975b) Effect of urogastrone in the Zollinger-Ellison syndrome. Lancet 2, 424427. FUNG w. P., KARIM s. M. M. and TYE c. Y. (1974) Effect of 15(R)15 methyl prostaglandin Ez methyl ester on healing of gastric ulcers. Lancet 2, 10-12. GUTH R. H., MEEROFF J. C., PAULSEN G. et a]. (1975) Prevention of experimental stress induced haemorrhagic gastritis. (Abstr.) Clin. Res. 23, 130. HENN R., SELCON S., ISENBERG J. et d. (1975) Experience with synthetic secretin in treatment of duodenal ulcer. (Abstr.) Clin. Res. 23, 98. IVEY K. J., BASKIN W. and JEFFREY G. (1975) Effect O f cimetidine on gastric potential difference in man. Lancet 2, 1072-1073. JACOBSON E. D. (1970) Comparison of prostaglandin El and nor-epinephrine on the gastric mucosal circulation. Proc. SOC.Exp. Biol. Med. 133, 516519. KARIM S. M. M., CARTER D. C., BHANA D. et al. (1973a) Effect of orally administered prostaglandin E, and its 15-methyl analogues on gastric secretion. Br. Med. J. 1, 143-146. KARIM s. M. M., CARTER D. c., BHANA D. et al. (1973b) The effect of orally and intravenously administered prostaglandin 16,16 dimethyl-E, methyl ester on human gastric acid secretion. Prostaglandins 4, 71-83. KENYON G. s. and CARTER D. c. (1976) Unpublished observations. CARMICHAEL H. A,, NELSON L., RUSSELL R. I.
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s. J. (1968) The effect of secretin on gastric acid secretion and peptic ulcers induced by pentagastrin in cats with intact or resected duodenum. Am. J. Dig. Dis. 13, 874881. LIPPMANN w. (1974) Inhibition of indomethacininduced gastric ulceration in the rat by perorallyadministered synthetic and natural prostaglandin analogues. Prostaglandins 7 , 1-10. MAINARDI M., MAXWELL v., STURDEVANT R. A. L. et al. (1974) Metiamide, an H,-receptor blocker as inhibitor of basal and meal-stimulated gastric acid secretion in patients with duodenal ulcer. New Engl. J. Med. 291, 373-376. MAO c. c., JACOBSON E. D. and SHANBOUR L. L. (1973) Mucosal cyclic AMP and secretion in the dog stomach. Am. J. Physiol. 225, 893-895. KONTUREK
MILTON-THOMPSON C. J., WILLIAMS J. G., JENKINS D. J. A.
et al. (1974) Inhibition of nocturnal acid secretion in duodenal ulcer by one oral dose of metiamide. Lancet 1, 693-694. MULTICENTRE TRIAL (1975) Treatment of duodenal ulcer by metiamide. Lancet 2, 779-781. O’BRIEN P. E. and CARTER D. c. (1975) Effect of gastric secretory inhibitors on the gastric mucosal barrier. Gut 16, 437-442. POLAK J. M., PEARSE A. G. E., GRIMELIUS L. et al. (1975) Growth-hormone release-inhibiting hormone in gastrointestinal and pancreatic D cells. Lancet 1, 1220-1 222. POUNDER R. E., HUNT R. H., STEKELMAN M. et al. (1976) Healing of gastric ulcer during treatment with cimetidine. Lancet 1, 337-339. POUNDER R. E., WILLIAMS J. G., MILTON-THOMPSON J. G.
et aI. (1975a) Relief of duodenal ulcer symptoms by oral metiamide. Br. Med. J. 1, 307-309. POUNDER R. E., WILLIAMS J. G., MILTON-THOMPSON G. J.
et al. (1975b) 24-Hour control of intragastric acidity by cimetidine in duodenal ulcer patients. Lancet 2, 1069-1072. POUNDER R. E., WILLIAMS J. G., MILTON-THOMPSON J. G.
et al. (1976) Effect of cimetidine on 24-hour intragastric acidity in normal subjects. Gut 17, 133-138. ROBERT A. and MAGERLEIN B. J. (1973) 15-Methyl PGE, and 16,16-dimethyl PGE,: potent inhibitors of gastric secretion. Adu. Biosci. 9, 247-253. THJODLEIFSSON B. and WORMSLEY K. G. (1974) Gastric response to metiamide. Br. Med. J. 2, 304-306. THOMPSON M. H., VENABLES C. W., MILLER C. W. et a]. (1975) Metiamide in Zollinger-Ellison syndrome. (Letter to the Editor.) Lancet 1, 35. WILSON D. E., PHILLIPS c. and LEVINE R. A. (1971) Inhibition of gastric secretion in man by prostaglandin A,. Gastroenterology 61, 201-206. WYLLIE J. H., EALDING w. D. P., HESSELBO T. et al. (1973) Inhibition of gastric secretion in man by metiamide: a new orally active histamine H,-receptor antagonist. Gut 14, 423.
Inhibitors of gastric secretion : current progress D. C. C A R T E R * SUMMARY
Several new compounds have become available recently which are potent inhibitors of gastric secretion. The therapeutic potential of these inhibitors in the peptic ulcer diathesis is reviewed and it is concluded that the histamine H,-receptor antagonists show most promise at present. The prostaglandins and gastro-intestinal polypeptides are of considerable physiological interest but are unlikely to have clinical importance in the immediate future.
ANTACIDSand anticholinergic compounds remain the mainstays of conventional medical treatment for the patient with duodenal ulceration. While it is freely acknowledged that antacids can relieve ulcer pain, there is little hard evidence to suggest that they accelerate the rate of ulcer healing. Anticholinergic drugs are among the most potent inhibitors of gastric secretion, but their potentially beneficial effects are offset by dose-limiting side-effects ; indeed, until such side-effects are produced it cannot be assumed that a pharmacologically effective dose is being administered. New compounds are constantly arriving on the scene with impressive claims for use in the peptic ulcer diathesis, but the continuing use of surgery to reduce acid and pepsin secretion remains the ultimate indictment of the inadequacy of medical treatment. All too often the new candidate compound passes through a period of enthusiastic acclaim, only to be rejected as useless or potentially dangerous after a more critical appraisal. It is against this rather gloomy background that all new inhibitors of gastric secretion must be assessed. The past few years have seen the development of a number of potent inhibitors, but three groups of compounds have excited particular interest and will be reviewed, not only in terms of their therapeutic potential but in the light of their contribution to our understanding of the pathophysiology of gastric secretion.
The prostaglandins The prostaglandins (PGs) are a group of unsaturated hydroxy fatty acids now known to be widely distributed through animal tissues. Initial medical interest centred on their role in human reproduction, but it was soon appreciated that PG E, is present in human gastric mucosa (Bennett et al., 1968), and Dozois and Thomson (1974) have reported the presence of both PG E, and PG A, in canine gastric secretions. Attempts to influence gastric secretion by administration of naturally occurring prostaglandins have been limited by their rapid degradation in the body 788
by the enzyme PG 15-OH dehydrogenase. Thus, while inhibition of human gastric secretion has been reported following administration of PG Al (Wilson et al., 1971) and PG El (Classen et al., 1971), the degree of inhibition has been unimpressive and apparent only after continuous intravenous infusion of relatively large doses of these compounds. Similarly, oral administration of P G A l and P G E , does not reduce basal secretion in man, although a transient rise in pH was observed following oral administration of PG A, (Bhana et al., 1973; Karim et al., 1973a). Analogues of PG E, have recently been synthesized in which the parent compound is modified by methylation at the crucial C-15 or neighbouring C-16 position. The resulting compounds are no longer substrates for PG 15-OH dehydrogenase, and an increase in biological activity might be anticipated. This is borne out by the fact that the analogues are potent inhibitors of gastric secretion, reducing both basal and stimulated acid and pepsin secretion when given orally to human volunteers (Carter et al., 1973; Karim et al., 1973a, b). The inhibitory action of one of these analogues is exemplified by Fig. 1, which illustrates the reduction in basal acid output which follows oral administration of 200 pg to healthy volunteers. Complementary animal studies have shown that the analogues are not only potent inhibitors of gastric secretion (Robert and Magerlein, 1973), but that the 15(R) analogue will protect the rat against gastric ulcers induced by indomethacin (Lippmann, 1974) or pyloric ligation (Carter, Ganesan et al., 1974). However, despite this accumulation of data, the mode of action of the prostaglandin analogues remains obscure. It is possible that the parent P G E , compound has a physiological role as a natural inhibitor of secretion, and that the analogues merely mimic this function. In other experimental systems, prostaglandins have been shown to influence cell function by affecting intracellular nucleotides such as the cyclic AMP system, but there is continuing debate as to whether cyclic AMP is responsible for the mediation of mammalian gastric secretion (Bieck et al., 1973; Mao et al., 1973). Of the other possible explanations for the inhibition of gastric secretion by the analogues (Fig. 2), a primary effect on mucosal blood flow is unlikely (Jacobson, 1970), and it is hardly conceivable that the compounds act by blockade of receptors on the cell surface. The remaining possibility is that the analogues damage the integrity of the gastric mucosal barrier, allowing hydrogen ions to diffuse back into the
* Department
of Clinical Surgery, University of Edinburgh.
Gastric secretion inhibitors mucosa from the lumen of the stomach and producing an apparent rather than real inhibition of secretion. In the case of the 16,16 dimethyl analogue, mucosal barrier damage has been demonstrated after local administration in an animal model (O'Brien and Carter, 1975), but the 15(R) analogue actually protects the mucosa from aspirin and bile salt damage in the rat (Carmichael et al., 1976). Until these uncertainties regarding the possible side-effects and mode of action have been resolved, it is unlikely that the prostaglandin analogues will be employed in large scale therapeutic trials in peptic ulcer patients. In a small pilot study Fung et al. (1974) have claimed that oral administration of the 15(R) analogue gave significant benefit in terms of the endoscopic healing of gastric ulcer, but these results must be interpreted with caution in view of the small numbers involved. It may be that the prostaglandin analogues will further our understanding of the pathophysiology of peptic ulceration and prove valuable in treatment, but at the present time more basic research is required before this promise can be fulfilled.
PG 15(R) 15 methyl E l methyl ester 200 pg orally
Gastro-intestinal hormones and related peptides A number of intestinal mucosal hormones, such as secretin, gastric inhibitory peptide and vasoactive intestinal peptide, are inhibitors of gastric secretion and have been considered as potential anti-ulcer compounds. With the exception of secretin, none of these hormones has been submitted to clinical trial in the ulcer diathesis. Secretin is an attractive theoBasal 0 I 2 3 retical proposition in that it stimulates secretion of Time (h) pancreatic bicarbonate, thereby neutralizing acid in the duodenal bulb, and also inhibits gastric secretion. Fig. 1. Effect of oral administration of 200 pg prostaglandin 15(R)15 methyl E2methyl ester on basal acid output in I 1 Konturek (1968) has shown that pentagastrin-induced healthy volunteers. duodenal ulcers in cats can be prevented by simultaneous infusion of secretin, but preliminary trials in PARIETAL CELL LUMEN man have failed to show any acceleration of duodenal SUBMUCOSA ulcer healing in secretin-treated patients when com0 Dared with controls receiving a Dlacebo (Henn et al.. Alter mucosal Jbloodflaw i975). Pancreatic glucagon aiso inhibits gastric secre: ATP tion and has been shown to protect the rat against Inhibit adenyl stress-induced haemorrhagic gastritis (Guth et al., 1975), but no clinical trials have been undertaken. Urogastrone is an interesting compound which has ,*' cAmP Hi been extracted from human urine and shown to consist of two polypeptides, one with 52 and the other *-Alter m e $ t $ e permeability D~~~~~mUcDsal with 53 amino acids. When infused intravenously, Mg++ barrier urogastrone is a potent inhibitor of both basal and Fig. 2. Possible mechanisms of action for inhibitors of stimulated gastric acid and intrinsic factor secretion gastric secretion. in human volunteers, but has little effect on pepsin output and does not affectserumgastrinconcentrations considerable interest. This is a hypothalamic tetra(Elder et al., 1975a). Urogastrone has also been infused decapeptide which suppresses growth hormone release, in 4 patients with the Zollinger-Ellison syndrome, but in addition is now known to be a potent inhibitor and although acid secretion was again markedly of several types of endocrine cell outwith the pituitary. reduced, the concentrations of intrinsic factor, Bloom et al. (1974) have reported that GH-RIH pepsin and serum gastrin were all increased (Elder lowered the plasma gastrin level and almost comet al., 1975b). Ulcer pain was relieved in all 4 patients pletely inhibited acid secretion in a patient with the within 3G60 minutes of commencing urogastrone Zollinger-Ellison syndrome, raising the possibility infusion, and this effect persisted for up to 24 hours. that GH-RIH might prove valuable clinically. At Finally, in this group of peptides, growth hormone first sight the inhibition of acid secretion might be release-inhibiting hormone (GH-RIH) has aroused attributed wholly to reduced gastrin production by 789
D. C. Carter the gastrinoma, but there is now good evidence that the compound also acts directly on the parietal cell (Barros D'Sa et al., 1975). GH-RIH-like immunoreactivity has recently been demonstrated in pancreatic D cells and morphologically similar cells in the stomach, duodenum, jejunum and upper ileum (Polak et al., 1975), opening a potential physiological role for this compound in the control of gastrointestinal function, including the control of gastric secretion. Thus, there are several gastro-intestinal hormones and related peptides which can inhibit gastric secretion and which may have therapeutic as well as physiological importance. However, clinical application of these compounds to the peptic ulcer problem remains limited by the difficulties of preparation coupled to the need for parenteral administration. At the present time their ultimate value to the patient with peptic ulcer disease is uncertain, regardless of their interest as research tools in the elucidation of the pathophysiology of gastric secretion.
Insulin infusion 0.03 u. k-' h-1
Control
Cirnetidine
I
Basal 0
I
30
I
I
90 Time (rnin)
60
I
I
I20
150
Fig. 3. Effect of cimetidine infusion on the mean acid output induced by simultaneous insulin infusion in 6 healthy volunteers.
Cimetidine 100 mg h
'
Cimetidine 100 rng h
Time ( h ) Fig. 4. Effect of cirnetidine on gastric acid output and pH in a patient with the Zollinger-Ellison syndrome.
790
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Histamine H,-receptor antagonists Certain actions of histamine in the body, such as the stimulation of smooth muscle in the gut and bronchus, can be antagonized by the conventional histamine antagonist, mepyramine maleate, these actions being mediated by Hi-receptors (Ash and Schild, 1966). The stimulation of gastric secretion by histamine is unaffected by mepyramine maleate and is mediated by H,-receptors. In 1972 Black et al. published a description of the properties of a selective H,-receptor antagonist, burimamide, which had been developed after a painstaking search of some 700 synthesized compounds, all based on the structure of histamine. Burimamide was capable of inhibiting gastric secretion in several experimental situations, but was rapidly superseded by the more potent, and orally effective, metiamide. This new compound inhibited secretion induced by histamine, pentagastrin and insulin hypoglycaemia (Wyllie et al., 1973; Carter, Forrest et al., 1974; Thjodleifsson and Wormsley, 1974), profoundly decreased nocturnal acid secretion (Milton-Thompson et al., 1974) and reduced mealstimulated acid secretion (Mainardi et al., 1974) in both normal volunteers and patients with duodenal ulceration. Clinical trials were soon undertaken to assess its value in a clinical context. Pounder et al. (1975a) reported on 30 patients with duodenal ulcer treated for 5-8 weeks with either metiamide or a placebo as part of a double blind trial. In the 15 patients receiving oral metiamide there was a significant reduction in nocturnal pain and antacid consumption, and day-time pain was diminished although not to a significant degree. In a multicentre double blind trial in 68 patients with endoscopically proved duodenal ulceration (Multicentre Trial, 1975), ulcer healing was significantly greater in the patients receiving metiamide (67 per cent) when compared with the rate of healing in patients receiving a placebo (25 per cent). Metiamide also proved effective in the management of the Zollinger-Ellison syndrome (Thompson
Gastric secretion inhibitors et al., 1975) and seemed certain of an established place in the pharmacopoeia. Unfortunately, this early promise will not now be fulfilled as transient granulocytopenia has occurred in 7 patients receiving the drug. This marrow depression has been readily reversible on cessation of therapy in 6 patients but there has been one fatality, and the problem has been sufficient to curtail the use of the drug. Fortunately, a new H,-receptor antagonist is now available which appears at least as potent as metiamide as an inhibitor of gastric secretion (Burland, Duncan et al., 1975) without sharing its deleterious effect on the bone marrow. Indeed, the new compound, cimetidine, has been used successfully in a patient with metiamide-induced agranulocytosis (Burland, Sharpe et al., 1975). It seems likely that the thiourea residue in the metiamide molecule was responsible for marrow depression, and this has been replaced by a cyanoguanidine moiety in cimetidine. The potency of cimetidine as an inhibitor is illustrated by Fig. 3, which shows its effect on acid secretion induced by insulin infusion in paired tests in healthy volunteers in our own laboratory. Pounder and his colleagues (Pounder et al., 1975b; Pounder, Williams et al., 1976) have reported that cimetidine diminishes 24-hour intragastric hydrogen ion activity to levels compatible with ulcer healing, when given in four divided oral doses to healthy volunteers or duodenal ulcer patients. In a preliminary trial in 10 patients with gastric ulcer, oral cimetidine rapidly relieved symptoms and ulcer healing was complete at endoscopy in all subjects by the end of the 6-week trial (Pounder, Hunt et al., 1976). Ivey et al. (1976) have reported that cimetidine raises the potential difference across the gastric mucosa in man, and suggested that the compound protects the gastric mucosal barrier. This suggestion appears unwarranted and has not been confirmed by studies of ionic flux across the gastric mucosa in our own laboratories (Kenyon and Carter, 1976). However, our results in no way detract from the therapeutic promise of cimetidine as an inhibitor of secretion. We have had the opportunity of using cimetidine in a patient with the Zollinger-Ellison syndrome, and Fig. 4 demonstrates the profound reduction of acid secretion which can be achieved. Metiamide was less effective in controlling secretion in this case, but there is every indication that cimetidine will prove useful in this context, not only as an aid in preparation for gastrectomy, but as a possible alternative to surgery in selected cases. The H,-receptor antagonists have raised intriguing questions about the role of histamine in the control of gastric secretion. There is still debate as to whether histamine serves as the final common pathway in the mediation of secretion, or whether the effects of the H,-receptor antagonists can be explained by some form of interaction between receptors at the parietal cell. Formal clinical trials of cimetidine are now under way in patients with duodenal ulcer and the results will be awaited with interest. There is no doubt that the compound is a potent inhibitor and at the present 74
time it appears free of restrictive side-effects. Cimetidine must be regarded as the most promising of the currently available inhibitors of secretion but time alone will tell whether this promise will be fulfilled.
Conclusions The ideal inhibitor for therapeutic use in the peptic ulcer diathesis should be able to maintain effective reduction of gastric secretion without undesirable side-effects. It should relieve ulcer pain, speed ulcer healing and prove acceptable to the patient. Of the available inhibitors, cimetidine appears the most promising provided that it remains free from toxicity and proves effective in clinical trials. It is likely that inhibitors of gastric secretion will prove valuable during acute exacerbations of peptic ulceration and they may have a valuable role in the management of gastro-intestinal haemorrhage and the rare ZollingerEllison syndrome. However, it remains to be seen whether any inhibitor will materially affect the long term cause of the peptic ulcer diathesis, and surgery seems likely to retain a major role in management in the foreseeable future. References ASH A. s. F. and SCHILD H. 0. (1976) Receptors mediating some actions of histamine. Br. J. Pharmacol. 27, 427-439. BARROS D’SA A. A. J., BLOOM s. R. and BARON J. H. (1975) Direct inhibition of gastric acid by growthhormone release-inhibiting hormone in dogs. Lancet 1, 886-887. BENNETT A., MURRAY J. G . and WYLLIE J. H. (1968) Occurrence of prostaglandin El in human stomach, and a study of its effect on human isolated gastric muscle. Brit,J. Pharmacol. Chemother. 32, 339349. BHANA D., KARIM s. M. M., CARTER D. c . et al. (1973) The effect of orally administered prostaglandin Al, A, and 15-epi-A, on human basal secretion. Prostaglandins 3, 307-3 16. BIECK P. R., OATES J. A., ROBISON G. A . et al. (1973) Cyclic AMP in the regulation of gastric secretion in dogs and humans. Am. J. Physiol. 224, 158164. BLACK J. w . , DUNCAN w. M., DURANT c. J. et al. (1972) Definition and antagonism of histamine H,receptors. Nature (Lond.) 236, 355-390. BLOOM s. R., MORTIMER c . H., THORNER M. 0. et al. (1974) Inhibition of gastric acid secretion by growthhormone release-inhibiting hormone. Lancet 2, 1106-1 109. BURLAND w. L., DUNCAN w . A, M., HESSELBO T. et al. (1 975) Pharmacological evaluation of cimetidine, a new histamine H,-receptor antagonist in healthy man. Br. J . Clin. Pharmacol. 2, 481486. BURLAND w. L., SHARPE P. c . , COLIN-JONES D. G. et al. (1975) Reversal of metiamide-induced agranulocytosis during treatment with cimetidine. (Letter to the Editor.) Lancet 2, 1085. 791
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s. J. (1968) The effect of secretin on gastric acid secretion and peptic ulcers induced by pentagastrin in cats with intact or resected duodenum. Am. J. Dig. Dis. 13, 874881. LIPPMANN w. (1974) Inhibition of indomethacininduced gastric ulceration in the rat by perorallyadministered synthetic and natural prostaglandin analogues. Prostaglandins 7 , 1-10. MAINARDI M., MAXWELL v., STURDEVANT R. A. L. et al. (1974) Metiamide, an H,-receptor blocker as inhibitor of basal and meal-stimulated gastric acid secretion in patients with duodenal ulcer. New Engl. J. Med. 291, 373-376. MAO c. c., JACOBSON E. D. and SHANBOUR L. L. (1973) Mucosal cyclic AMP and secretion in the dog stomach. Am. J. Physiol. 225, 893-895. KONTUREK
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et al. (1974) Inhibition of nocturnal acid secretion in duodenal ulcer by one oral dose of metiamide. Lancet 1, 693-694. MULTICENTRE TRIAL (1975) Treatment of duodenal ulcer by metiamide. Lancet 2, 779-781. O’BRIEN P. E. and CARTER D. c. (1975) Effect of gastric secretory inhibitors on the gastric mucosal barrier. Gut 16, 437-442. POLAK J. M., PEARSE A. G. E., GRIMELIUS L. et al. (1975) Growth-hormone release-inhibiting hormone in gastrointestinal and pancreatic D cells. Lancet 1, 1220-1 222. POUNDER R. E., HUNT R. H., STEKELMAN M. et al. (1976) Healing of gastric ulcer during treatment with cimetidine. Lancet 1, 337-339. POUNDER R. E., WILLIAMS J. G., MILTON-THOMPSON J. G.
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