EDITORIALS
ANNALS of Internal Medicine
Histamine H-2 Receptor Antagonists
Volume 87 • Number 3 September 1 9 7 7 T H E ACTIONS OF HISTAMINE are mediated by two types of receptors that P U B L I S H E D monthly by the American College of Physicians under the direction of the Publications Committee of t h e Board of Regents; see advertising page 1-5 for listing of the Committee, the Editorial Staff, the Editorial Board, and the Business Staff. Editorial Policy A N N A L S O F I N T E R N A L M E D I C I N E pub-
lishes original papers, topical reviews, editorials, book reviews, and medical news in the broad field of internal medicine a n d allied sciences. Detailed information on t h e kinds of papers that will be considered for publication, the proper form and style for manuscripts, and submission of manuscripts to the Editor are given in " I N F O R M A T I O N F O R A U T H O R S " on advertising page 1-6. Selected books will be reviewed monthly. Review copies should be sent to the Editor. T h e content of this journal is protected by copyright. Manuscripts are accepted for publication with t h e understanding that their contents, all or in part, have not been published elsewhere a n d will not be published elsewhere, except in abstract form or by t h e express consent of the Editor. A N N A L S O F I N T E R N A L M E D I C I N E accepts no
responsibility for statements made by contributors. Subscriptions A N N A L S O F I N T E R N A L M E D I C I N E is is-
sued monthly; new volumes begin with the January a n d July issues each year. Subscription price per year, net postpaid: $25.00 in N o r t h and Central American countries, Puerto Rico, and Canal Zone; $28.00 in other countries; half price to medical students a n d to physicians within four years after graduation from medical school. Single copies of recent issues: $3.00 in N o r t h a n d Central American countries, Puerto Rico, and Canal Zone; $3.25 in other countries; price of supplements provided on request. Checks should be made payable to the American College of Physicians and remitted to the Circulation Manager. Communications to the Editor or the Circulation Manager should be sent to
Annals of Internal Medicine 4 2 0 0 Pine St. Philadelphia, PA 1 9 1 0 4 USA Phone: 2 1 5 / 2 4 3 - 1 2 0 0
are present on a number of morphologically distinct cell types (1). Those mediating mepyramine-sensitive histamine responses are defined as H-1 receptors. H-2 receptors, which mediate histamine effects on gastric acid secretion, cardiac pacemaker, and a growing list of other actions (1), are blocked by a new class of compounds first synthesized by Black and colleagues (2). They have also described specific agonists for H-1 (2-methyl histamine) and H-2 (4-methyl histamine) receptors. These and newer H-1 and H-2 specific agonists and antagonists have been used in a large number of fundamental and clinical studies, with several hundred publications on this subject in the last 5 years. As described by Durant, Emmett, and Ganellin (3), there are marked chemical distinctions between the H-2 and H-1 receptor antagonists. The H-1 antagonists possess aryl or heteroaryl rings that replace, but need not have structural relations to, the imidazole ring of histamine. The aryl groups make the compounds lipohophilic and probably act in hydrophobic bonding. These antihistamines resemble histamine in that they have a side chain (usually ammonium) that is positively charged at physiologic pH. In marked contrast, the H-2 antagonists are hydrophilic and resemble histamine in having an imidazole ring but differ in the side chain, which though polar is uncharged. These chemical differences confer considerable selectivity on the antagonists. The selectivity at the H-1 receptor is determined by the ammonium group and at the H-2 receptor by the imidazole ring. Furthermore, the H-2 receptor antagonists, being uncharged in the side chain, are unable to mimic the stimulant actions of histamine—they are not agonists. The low lipophilicity limits access to the central nervous system, avoiding some potential cerebral effects such as may be associated with the H-1 antihistamines. The H-2 receptor antagonists strongly inhibit gastric acid secretion in all species under basal conditions and block the stimulation by histamine as well as by nonhistamine stimuli, including gastrin, food, caffeine, distension, vagal and other cholinergic agonists (4, 5). This broad antagonism raises the question of a critical physiologic, perhaps intermediary role of histamine in the stimulation of gastric acid secretion by all stimuli. The obvious application of the antisecretory effect is to the treatment of supposed acid-peptic diseases of the upper gastrointestinal tract—duodenal and gastric ulcer, reflux esophagitis, acute hemorrhagic gastritis, and duodenitis. The first of the H-2 antagonists to be used in widescale clinical testing, metiamide, resulted in a number of cases of agranulocytosis, one of which was irreversible and fatal and led to its withdrawal from use. Its successor, cimetidine (Tagamet®), differs from metiamide in having a cyanoguanidine rather than a thiourea side chain. Cimetidine has not shown any hematologic effects, even when given to one patient who had had agranulocytosis with metiamide (6). The results of a number of clinical trials in the United States and abroad have been reported in two symposia (7, 8). In general these have been randomized and double-blind, depending 373
Downloaded from https://annals.org by Tulane University user on 01/21/2019
upon endoscopy as the objective criterion of diagnosis and healing. The results to date allow tentative conclusions on their likely use. Worldwide, 71 % of more than 600 patients with duodenal ulcer given cimetidine were healed endoscopically in 2 to 6 weeks, while only 37% of more than 300 patients given placebo were healed in the same time. In one study intensive antacid therapy did as well as cimetidine, suggesting that suppression of acid secretion was necessary to promote the healing of duodenal ulcer. The results so far suggest that a minimum of 3 and up to 6 weeks is necessary to secure healing in 65% to 70% of active duodenal ulcers but that treatment for longer than 6 weeks or additional measures may be needed in as many as 25% of patients with duodenal ulcer to secure healing. Recurrence of ulcer in various series within a month of stopping the trial at 2, 4, or 6 weeks ranged from 53% to 67%, with no significant difference between cimetidine and control. The reasons for the recurrences are not clear, especially in the placebo group, but the fact underscores the difficulties of interpreting any therapeutic trial in which positive placebo effects occur; for example, in the United States, healing with placebo is twice as high as in most European studies (60% versus 30% at 6 weeks, respectively). Early results on maintenance therapy in patients with healed duodenal ulcers using 400 mg of cimetidine orally twice daily show that relapse rates in 6 to 18 months' follow-up are reduced from greater than 50% to 10%. These results suggest that there may well be a place for cimetidine in the long-term treatment of duodenal ulcer. Further efficacy and safety data in larger numbers and for longer periods are needed to answer this important question, especially because such treatment may possibly be an alternative to surgical treatment. The latter has the advantage of permanency. Since cimetidine suppresses secretion stimulated by either histamine or gastrin, its use in gastric hypersecretory states—Zollinger-Ellison syndrome (gastrin excess) and systemic mastocytosis (histamine excess)—is logical and offers a reasonable alternative to total gastrectomy, the only effective treatment so far for Zollinger-Ellison syndrome. In fact, in most there is ulcer healing with adequate control of pain and diarrhea (9). Most patients need normal doses of cimetidine (1 to 1.6 g/day), though some may need up to 2.4 g/day or the additional use of antacids or anticholinergics to control pain or diarrhea. A few patients have shown loss of efficacy, while others on metiamide and then cimetidine for up to V/2 years have maintained control without change in dose. Acute erosive gastritis is the principal cause for major gastrointestinal bleeding in seriously ill or stressed patients with various illnesses, including acute renal, pulmonary, or hepatic failure, trauma, burns, sepsis, and shock. Thus far there are no adequately controlled studies on the use of cimetidine in this important disease entity. Such studies that are published (9) provide no reliable data on which to judge its potential use. In one prospective but unblinded study of fulminant hepatic failure, 374
only one of 26 patients given cimetidine bled, compared with 13 of 24 controls (10). Further properly designed double-blind studies in the prevention and treatment of bleeding from acute erosive gastritis are needed before any conclusions can be drawn. In gastric ulcer and reflux esophagitis, conditions considered to belong to the group of acid/peptic diseases, the results with cimetidine have been disappointing. In gastric ulcer trials involving more than 300 patients with benign gastric ulcers rigorously controlled by endoscopy, cimetidine-treated patients consumed less antacid than controls, but healing was not statistically better within the 2 to 6 weeks of the trial. Neither age, sex, rates of acid secretion, nor size of ulcer seemed to influence outcome. After 8 weeks of treatment of reflux esophagitis, cimetidine showed no advantage over placebo by subjective or objective endoscopic criteria. It is obviously not enough to only reduce acid output in treating esophagitis or gastric ulcer, though acid reduction is still the prime physiologic objective in duodenal ulcer and Zollinger-Ellison syndrome but less certainly so in erosive gastritis. What we have learned is that our understanding of the pathophysiology of acid-peptic diseases is still fragmentary. Cimetidine reduces stimulated acid output by 50% at blood levels between 1.5 and 4 jwM/litre (5), levels that are achieved for a 6-h period by oral doses between 2.5 and 3.5 mg/kg. Absorption is good and bioavailability the same as by the intravenous route. Since the principal excretion route is renal, 70% being excreted unchanged in 6 h, dosage schedules should be adjusted in renal failure. With normal renal function, 4 doses a day are needed for 24-h control of gastric acidity (6). Although atropine does not increase effectiveness of cimetidine in suppressing postprandial or nocturnal acid output, it offers the theoretical and a possible practical advantage of inhibiting pepsin secretion, which the H-2 antagonists do not. Cimetidine has little or no effect in man on esophageal motility or the lower esophageal sphincter, gastric contractility or emptying, gastrin release, or biliary or pancreatic secretion, nor does it have any major effect on intrinsic factor or mucin secretion. It has no lasting effect on gastric acid secretion, and rebound is not seen. Side effects have been few and the margin of safety good. Especially with doses above 1 g/day and starting by the third day, serum creatinine increases by up to 0.4 mg/dl in 60% of patients treated with cimetidine. In 11%, creatinine rises above the normal range, transiently in half of these. In the other half, values return to normal rapidly after cimetidine treatment is discontinued. The mechanism remains unexplained by studies of muscle and kidney function. Ley dig-cell tumors have been seen in rat testes on long-term cimetidine, but the significance of this small increase in what is a normal aging phenomenon is not yet clear. A handful of men with Zollinger-Ellison syndrome have developed gynecomastia while taking cimetidine. N o other endocrine changes have yet been measured or observed. The effects of cimetidine antagonism of other H-2 ac-
September 1977 • Annals of Internal Medicine • Volume 87 • Number 3
Downloaded from https://annals.org by Tulane University user on 01/21/2019
tions—such as those on gut, endocrine, pulmonary, hematopoietic, musculoskeletal, cardiovascular, and nervous systems, in smooth muscle, skin, adipocyte, leukocyte, and mast-cell function, fetal growth, tissue repair, allergy, inflammation, and immune reactions—in longterm and wide-scale use have yet to be delineated. The discoveries of Black and colleagues (2) have provided a powerful impetus and the tools for these investigations for years to .come. (BASIL I. HIRSCHOWITZ, M . D . , F.A.C.P., F.R.C.P., F.R.C.P. (EDIN); Gastroenterology Divi-
sion, The Medical Center, University of Alabama in Birmingham; Birmingham, Alabama) References 1. C H A N D N, EYRE P: Classification and biological distribution of histamine receptor subtypes. Agents Actions 5:277-295, 1975 2. BLACK JW, D U N C A N W A M , D U R A N T GJ, G A N E L L I N CR, PARSONS
ME: Definition and antagonism of histamine H-2 receptors. 236:385-390, 1972
Nature
3. D U R A N T GJ, E M M E T T JC, G A N E L L I N CR: The chemical origin and
properties of histamine H-2 receptor antagonists, in Cimetidine: Proceedings of the Second International Symposium on Histamine H-2 Receptor Antagonists, edited by BURLAND WL, SIMKINS MA. Amster-
dam, Excerpta Medica, 1977, pp. 1-12 4. G I B S O N R, H I R S C H O W I T Z BI, H U T C H I S O N G A : Actions of metiamide,
an H-2 histamine receptor antagonist, on gastric H + and peptic secretion in dogs. Gastroenterology 67:93-99, 1974 5. P O U N D E R RE, W I L L I A M S JG, H U N T R H , V I N C E N T SH, M I L T O N -
THOMPSON GJ, MISCIEWICZ JJ: The effects of oral cimetidine on foodstimulated gastric acid secretion and 24 hour intragastric acidity, in Cimetidine: Proceedings of the Second International Symposium on Histamine H-2 Receptor Antagonists edited by BURLAND WL, SIMKINS MA. Amsterdam, Excerpta Medica, 1977, pp. 189-204 6. B U R L A N D WL, S H A R P E PC, C O L I N - J O N E S D G , T U R N B U L L D R G ,
BOWSKILL P: Reversal of metiamide-induced agranulocytosis during treatment with cimetidine (letter). Lancet 2:1085, 1975 7. BURLAND WL, SIMKINS MA (eds.): Cimetidine: Proceedings of the Second International Symposium on Histamine H-2 Receptor Antagonists. Amsterdam, Excerpta Medica, 1977, p. 392 8. GROSSMAN MI, FORDTRAN J (eds.): Third Symposium on Histamine H-2 Receptor Antagonists—Clinical Results with Cimetidine. To be published as a supplement in Gastroenterology, December 1977 9. BURLAND WL, PARR SN: Experiences with cimetidine in the treatment of seriously ill patients, in Cimetidine: Proceedings of the Second International Symposium on Histamine H-2 Receptor Antagonists, edited by BURLAND WL, SIMKINS MA. Amsterdam, Excerpta Medica, 1977, pp. 345-357 10. M A C D O U G A L L BRD, B A I L E Y RJ, W I L L I A M S R: H-2 Receptor antago-
nists and antacids in the prevention of acute gastrointestinal haemorrhage in fulminant hepatic failure. Lancet 1:617-619, 1977
Editorials
Downloaded from https://annals.org by Tulane University user on 01/21/2019
3 7 5
ANNALS of Internal Medicine
Histamine H-2 Receptor Antagonists
Volume 87 • Number 3 September 1 9 7 7 T H E ACTIONS OF HISTAMINE are mediated by two types of receptors that P U B L I S H E D monthly by the American College of Physicians under the direction of the Publications Committee of t h e Board of Regents; see advertising page 1-5 for listing of the Committee, the Editorial Staff, the Editorial Board, and the Business Staff. Editorial Policy A N N A L S O F I N T E R N A L M E D I C I N E pub-
lishes original papers, topical reviews, editorials, book reviews, and medical news in the broad field of internal medicine a n d allied sciences. Detailed information on t h e kinds of papers that will be considered for publication, the proper form and style for manuscripts, and submission of manuscripts to the Editor are given in " I N F O R M A T I O N F O R A U T H O R S " on advertising page 1-6. Selected books will be reviewed monthly. Review copies should be sent to the Editor. T h e content of this journal is protected by copyright. Manuscripts are accepted for publication with t h e understanding that their contents, all or in part, have not been published elsewhere a n d will not be published elsewhere, except in abstract form or by t h e express consent of the Editor. A N N A L S O F I N T E R N A L M E D I C I N E accepts no
responsibility for statements made by contributors. Subscriptions A N N A L S O F I N T E R N A L M E D I C I N E is is-
sued monthly; new volumes begin with the January a n d July issues each year. Subscription price per year, net postpaid: $25.00 in N o r t h and Central American countries, Puerto Rico, and Canal Zone; $28.00 in other countries; half price to medical students a n d to physicians within four years after graduation from medical school. Single copies of recent issues: $3.00 in N o r t h a n d Central American countries, Puerto Rico, and Canal Zone; $3.25 in other countries; price of supplements provided on request. Checks should be made payable to the American College of Physicians and remitted to the Circulation Manager. Communications to the Editor or the Circulation Manager should be sent to
Annals of Internal Medicine 4 2 0 0 Pine St. Philadelphia, PA 1 9 1 0 4 USA Phone: 2 1 5 / 2 4 3 - 1 2 0 0
are present on a number of morphologically distinct cell types (1). Those mediating mepyramine-sensitive histamine responses are defined as H-1 receptors. H-2 receptors, which mediate histamine effects on gastric acid secretion, cardiac pacemaker, and a growing list of other actions (1), are blocked by a new class of compounds first synthesized by Black and colleagues (2). They have also described specific agonists for H-1 (2-methyl histamine) and H-2 (4-methyl histamine) receptors. These and newer H-1 and H-2 specific agonists and antagonists have been used in a large number of fundamental and clinical studies, with several hundred publications on this subject in the last 5 years. As described by Durant, Emmett, and Ganellin (3), there are marked chemical distinctions between the H-2 and H-1 receptor antagonists. The H-1 antagonists possess aryl or heteroaryl rings that replace, but need not have structural relations to, the imidazole ring of histamine. The aryl groups make the compounds lipohophilic and probably act in hydrophobic bonding. These antihistamines resemble histamine in that they have a side chain (usually ammonium) that is positively charged at physiologic pH. In marked contrast, the H-2 antagonists are hydrophilic and resemble histamine in having an imidazole ring but differ in the side chain, which though polar is uncharged. These chemical differences confer considerable selectivity on the antagonists. The selectivity at the H-1 receptor is determined by the ammonium group and at the H-2 receptor by the imidazole ring. Furthermore, the H-2 receptor antagonists, being uncharged in the side chain, are unable to mimic the stimulant actions of histamine—they are not agonists. The low lipophilicity limits access to the central nervous system, avoiding some potential cerebral effects such as may be associated with the H-1 antihistamines. The H-2 receptor antagonists strongly inhibit gastric acid secretion in all species under basal conditions and block the stimulation by histamine as well as by nonhistamine stimuli, including gastrin, food, caffeine, distension, vagal and other cholinergic agonists (4, 5). This broad antagonism raises the question of a critical physiologic, perhaps intermediary role of histamine in the stimulation of gastric acid secretion by all stimuli. The obvious application of the antisecretory effect is to the treatment of supposed acid-peptic diseases of the upper gastrointestinal tract—duodenal and gastric ulcer, reflux esophagitis, acute hemorrhagic gastritis, and duodenitis. The first of the H-2 antagonists to be used in widescale clinical testing, metiamide, resulted in a number of cases of agranulocytosis, one of which was irreversible and fatal and led to its withdrawal from use. Its successor, cimetidine (Tagamet®), differs from metiamide in having a cyanoguanidine rather than a thiourea side chain. Cimetidine has not shown any hematologic effects, even when given to one patient who had had agranulocytosis with metiamide (6). The results of a number of clinical trials in the United States and abroad have been reported in two symposia (7, 8). In general these have been randomized and double-blind, depending 373
Downloaded from https://annals.org by Tulane University user on 01/21/2019
upon endoscopy as the objective criterion of diagnosis and healing. The results to date allow tentative conclusions on their likely use. Worldwide, 71 % of more than 600 patients with duodenal ulcer given cimetidine were healed endoscopically in 2 to 6 weeks, while only 37% of more than 300 patients given placebo were healed in the same time. In one study intensive antacid therapy did as well as cimetidine, suggesting that suppression of acid secretion was necessary to promote the healing of duodenal ulcer. The results so far suggest that a minimum of 3 and up to 6 weeks is necessary to secure healing in 65% to 70% of active duodenal ulcers but that treatment for longer than 6 weeks or additional measures may be needed in as many as 25% of patients with duodenal ulcer to secure healing. Recurrence of ulcer in various series within a month of stopping the trial at 2, 4, or 6 weeks ranged from 53% to 67%, with no significant difference between cimetidine and control. The reasons for the recurrences are not clear, especially in the placebo group, but the fact underscores the difficulties of interpreting any therapeutic trial in which positive placebo effects occur; for example, in the United States, healing with placebo is twice as high as in most European studies (60% versus 30% at 6 weeks, respectively). Early results on maintenance therapy in patients with healed duodenal ulcers using 400 mg of cimetidine orally twice daily show that relapse rates in 6 to 18 months' follow-up are reduced from greater than 50% to 10%. These results suggest that there may well be a place for cimetidine in the long-term treatment of duodenal ulcer. Further efficacy and safety data in larger numbers and for longer periods are needed to answer this important question, especially because such treatment may possibly be an alternative to surgical treatment. The latter has the advantage of permanency. Since cimetidine suppresses secretion stimulated by either histamine or gastrin, its use in gastric hypersecretory states—Zollinger-Ellison syndrome (gastrin excess) and systemic mastocytosis (histamine excess)—is logical and offers a reasonable alternative to total gastrectomy, the only effective treatment so far for Zollinger-Ellison syndrome. In fact, in most there is ulcer healing with adequate control of pain and diarrhea (9). Most patients need normal doses of cimetidine (1 to 1.6 g/day), though some may need up to 2.4 g/day or the additional use of antacids or anticholinergics to control pain or diarrhea. A few patients have shown loss of efficacy, while others on metiamide and then cimetidine for up to V/2 years have maintained control without change in dose. Acute erosive gastritis is the principal cause for major gastrointestinal bleeding in seriously ill or stressed patients with various illnesses, including acute renal, pulmonary, or hepatic failure, trauma, burns, sepsis, and shock. Thus far there are no adequately controlled studies on the use of cimetidine in this important disease entity. Such studies that are published (9) provide no reliable data on which to judge its potential use. In one prospective but unblinded study of fulminant hepatic failure, 374
only one of 26 patients given cimetidine bled, compared with 13 of 24 controls (10). Further properly designed double-blind studies in the prevention and treatment of bleeding from acute erosive gastritis are needed before any conclusions can be drawn. In gastric ulcer and reflux esophagitis, conditions considered to belong to the group of acid/peptic diseases, the results with cimetidine have been disappointing. In gastric ulcer trials involving more than 300 patients with benign gastric ulcers rigorously controlled by endoscopy, cimetidine-treated patients consumed less antacid than controls, but healing was not statistically better within the 2 to 6 weeks of the trial. Neither age, sex, rates of acid secretion, nor size of ulcer seemed to influence outcome. After 8 weeks of treatment of reflux esophagitis, cimetidine showed no advantage over placebo by subjective or objective endoscopic criteria. It is obviously not enough to only reduce acid output in treating esophagitis or gastric ulcer, though acid reduction is still the prime physiologic objective in duodenal ulcer and Zollinger-Ellison syndrome but less certainly so in erosive gastritis. What we have learned is that our understanding of the pathophysiology of acid-peptic diseases is still fragmentary. Cimetidine reduces stimulated acid output by 50% at blood levels between 1.5 and 4 jwM/litre (5), levels that are achieved for a 6-h period by oral doses between 2.5 and 3.5 mg/kg. Absorption is good and bioavailability the same as by the intravenous route. Since the principal excretion route is renal, 70% being excreted unchanged in 6 h, dosage schedules should be adjusted in renal failure. With normal renal function, 4 doses a day are needed for 24-h control of gastric acidity (6). Although atropine does not increase effectiveness of cimetidine in suppressing postprandial or nocturnal acid output, it offers the theoretical and a possible practical advantage of inhibiting pepsin secretion, which the H-2 antagonists do not. Cimetidine has little or no effect in man on esophageal motility or the lower esophageal sphincter, gastric contractility or emptying, gastrin release, or biliary or pancreatic secretion, nor does it have any major effect on intrinsic factor or mucin secretion. It has no lasting effect on gastric acid secretion, and rebound is not seen. Side effects have been few and the margin of safety good. Especially with doses above 1 g/day and starting by the third day, serum creatinine increases by up to 0.4 mg/dl in 60% of patients treated with cimetidine. In 11%, creatinine rises above the normal range, transiently in half of these. In the other half, values return to normal rapidly after cimetidine treatment is discontinued. The mechanism remains unexplained by studies of muscle and kidney function. Ley dig-cell tumors have been seen in rat testes on long-term cimetidine, but the significance of this small increase in what is a normal aging phenomenon is not yet clear. A handful of men with Zollinger-Ellison syndrome have developed gynecomastia while taking cimetidine. N o other endocrine changes have yet been measured or observed. The effects of cimetidine antagonism of other H-2 ac-
September 1977 • Annals of Internal Medicine • Volume 87 • Number 3
Downloaded from https://annals.org by Tulane University user on 01/21/2019
tions—such as those on gut, endocrine, pulmonary, hematopoietic, musculoskeletal, cardiovascular, and nervous systems, in smooth muscle, skin, adipocyte, leukocyte, and mast-cell function, fetal growth, tissue repair, allergy, inflammation, and immune reactions—in longterm and wide-scale use have yet to be delineated. The discoveries of Black and colleagues (2) have provided a powerful impetus and the tools for these investigations for years to .come. (BASIL I. HIRSCHOWITZ, M . D . , F.A.C.P., F.R.C.P., F.R.C.P. (EDIN); Gastroenterology Divi-
sion, The Medical Center, University of Alabama in Birmingham; Birmingham, Alabama) References 1. C H A N D N, EYRE P: Classification and biological distribution of histamine receptor subtypes. Agents Actions 5:277-295, 1975 2. BLACK JW, D U N C A N W A M , D U R A N T GJ, G A N E L L I N CR, PARSONS
ME: Definition and antagonism of histamine H-2 receptors. 236:385-390, 1972
Nature
3. D U R A N T GJ, E M M E T T JC, G A N E L L I N CR: The chemical origin and
properties of histamine H-2 receptor antagonists, in Cimetidine: Proceedings of the Second International Symposium on Histamine H-2 Receptor Antagonists, edited by BURLAND WL, SIMKINS MA. Amster-
dam, Excerpta Medica, 1977, pp. 1-12 4. G I B S O N R, H I R S C H O W I T Z BI, H U T C H I S O N G A : Actions of metiamide,
an H-2 histamine receptor antagonist, on gastric H + and peptic secretion in dogs. Gastroenterology 67:93-99, 1974 5. P O U N D E R RE, W I L L I A M S JG, H U N T R H , V I N C E N T SH, M I L T O N -
THOMPSON GJ, MISCIEWICZ JJ: The effects of oral cimetidine on foodstimulated gastric acid secretion and 24 hour intragastric acidity, in Cimetidine: Proceedings of the Second International Symposium on Histamine H-2 Receptor Antagonists edited by BURLAND WL, SIMKINS MA. Amsterdam, Excerpta Medica, 1977, pp. 189-204 6. B U R L A N D WL, S H A R P E PC, C O L I N - J O N E S D G , T U R N B U L L D R G ,
BOWSKILL P: Reversal of metiamide-induced agranulocytosis during treatment with cimetidine (letter). Lancet 2:1085, 1975 7. BURLAND WL, SIMKINS MA (eds.): Cimetidine: Proceedings of the Second International Symposium on Histamine H-2 Receptor Antagonists. Amsterdam, Excerpta Medica, 1977, p. 392 8. GROSSMAN MI, FORDTRAN J (eds.): Third Symposium on Histamine H-2 Receptor Antagonists—Clinical Results with Cimetidine. To be published as a supplement in Gastroenterology, December 1977 9. BURLAND WL, PARR SN: Experiences with cimetidine in the treatment of seriously ill patients, in Cimetidine: Proceedings of the Second International Symposium on Histamine H-2 Receptor Antagonists, edited by BURLAND WL, SIMKINS MA. Amsterdam, Excerpta Medica, 1977, pp. 345-357 10. M A C D O U G A L L BRD, B A I L E Y RJ, W I L L I A M S R: H-2 Receptor antago-
nists and antacids in the prevention of acute gastrointestinal haemorrhage in fulminant hepatic failure. Lancet 1:617-619, 1977
Editorials
Downloaded from https://annals.org by Tulane University user on 01/21/2019
3 7 5
