Symposium on New Methods of Treatment of Gastrointestinal Disease
Cimetidine in the Management of Peptic Ulcer Disease Walter P. Dyck, M.D.
Background and Physiology Two classes of histamine receptors, H 1 and H 2 , have been pharmacologically identified by means of specific competitive antagonists. The classical antihistamines (Hj-receptor antagonists) developed several decades ago competitively antagonize the action of histamine on smooth muscle but have no inhibitory effect on histamine-stimulated gastric acid secretion. This suggested the existence of an additional histamine receptor and prompted a search for competitive inhibitors for additional receptor site(s). Beginning with the structure of histamine, stepwise chemical modification of various compounds" 3. 25 ultimately led to the development of cimetidine, a specific histamine H 2receptor antagonist which has been shown to be an effective inhibitor of basal and nocturnal acid secretion as well as acid secretion stimulated by histamine, pentagastrin, caffeine, insulin, sham feeding, and food.v " Treatment of Acute Duodenal Ulcer The worldwide experience with cimetidine has clearly shown the efficacy of this drug in promoting acute duodenal ulcer healing, and this constitutes the chief indication for its use at present. Results of numerous clinical trials in the United States and abroad have been summarized elsewhere.v>' At least three to four weeks of cimetidine therapy appear to be required to achieve healing rates of about 70 per cent. The accepted dosage regimen consists of 300 mg of cimetidine taken four times a day, with meals and at bedtime. In one randomized double-blind multicenter trial, patients treated with cimetidine or an intensive antacid program had similar rates of healing of duodenal ulcers and of pain relief. 15 Prevention of Recurrence of Duodenal Ulcers Several multicenter studies are presently examining the efficacy of cimetidine in doses smaller than those used for the treatment of acute From the Division of Gastroenterology, Scott and White Clinic, Temple, Texas
Surgical Clinics of North America - Vol. 59, No.5, October 1979
863
864
WALTER
P.
DYCK
duodenal ulcer disease, in preventing duodenal ulcer recurrence. Limited available data suggest that continuous maintenance therapy with cimetidine is effective in preventing recurrence of ulcers!" but does not protect the patient from relapse on cessation of therapy." The relapse rate after prolonged use of cimetidine (one year) was similar to that after six weeks of cimetidine, suggesting that if cimetidine is to be used to prevent recurrence of ulcers it may require continued use. Treatment of Gastric Ulcers The role of cimetidine in the management of gastric ulcers is not nearly as clear as its obvious usefulness in the management of duodenal ulcer disease. Several multicenter studies in the United States have failed to show a clear beneficial effect of cimetidine on healing of gastric ulcers." 9. 11 Limited data from abroad suggests that cimetidine is effective in promoting the healing of gastric ulcers," and that maintenance therapy with cimetidine may be effective in reducing the incidence of gastric ulcer relapse. 17 Ongoing studies will hopefully clarify the potential role of these agents in the management of gastric ulcer disease. Treatment of Hypersecretory States Until recently, the only acceptable therapeutic modality for the management of the Zollinger-Ellison syndrome was total gastrectomy with or without an attempt at resection of the gastrin-secreting tumor. The inability to excise all tumor tissue in most cases made it attractive to try to control the production of acid by nonsurgical means. Until the advent of the Hj-receptor blockers, satisfactory long-term suppression of acid secretion was not possible in the majority of such patients. Cimetidine has now been shown to provide a viable alternative to total gastrectomy for patients with Zollinger-Ellison syndrome, and appears to control acid-peptic disease in the large majority at least as effectively as total gastrectomy but without the attendant morbidity of that procedure. 18 While each patient must be approached individually, it seems appropriate now to recommend that cimetidine therapy be used as the initial therapeutic modality in all patients with Zollinger-Ellison syndrome. Those patients who do not respond to cimetidine therapy and those patients who are unable to use the drug on a continuing basis under careful supervision should undergo total gastrectomy. The availability of cimetidine also makes it reasonable now to attempt simple excision of the tumor as a curative procedure in some cases without demonstrable metastases, with the understanding that an effective anti-secretory agent is available in the event of recurrence of the tumor. A longer follow-up of patients presently being treated with H 2receptor blockers will be needed before a more definitive statement can be made on the appropriate long-term management of such hypersecretory states. Cimetidine for Anastomotic Ulceration Anastomotic ulceration occurring in a patient who has previously undergone partial gastrectomy usually results from an inadequate sur-
CIMETIDINE IN PEPTIC ULCER DISEASE
865
gical procedure (incomplete vagotomy and/or inadequate resection). Consequently it is generally accepted that this complication requires surgical correction. The efficacy of cimetidine in patients with endoscopically proved anastomotic ulcer arising after partial gastrectomy has recently been studied;" Healing rate after one month of treatment with cimetidine was 67 per cent and increased to 86 per cent after two months of therapy. Three of 19 patients relapsed during one year of maintenance therapy with 800 mg of cimetidine daily. It could be recommended therefore that in high-risk patients, particularly the debilitated or bleeding patient, cimetidine be used as an initial therapeutic approach until the patient can be prepared for elective corrective surgery under optimal conditions. Cimetidine for Reflux Esophagitis Although endoscopic and histologic improvement of reflux esophagitis during cimetidine therapy has not been conclusively shown, significant subjective improvement in terms of decreased frequency and severity of symptoms as well as a significant improvement in esophageal acid sensitivity has been shown to result from cimetidine therapy.1 Since cimetidine fails to alter basal lower esophageal sphincter pressure;" the effectiveness of cimetidine in relieving symptoms of gastroesophageal reflux are felt to result from the inhibitory effect on gastric acid secretion with resultant decrease in the reflux of gastric acid into the esophagus. Hemorrhagic Gastritis The efficacy of Hj-receptor blockers in preventing experimental gastric mucosal ulceration produced by stress'" and topical aspirin" has been demonstrated. The precise mechanism whereby cimetidine affords such a protective action has not been defined. Cimetidine has been shown to result in a significant reduction in fecal blood loss in patients with aspirin-induced occult gastrointestinal bleeding." Studies are in progress to further define the efficacy of cimetidine in acute upper gastrointestinal hemorrhage of erosive gastritis and hepatic failure. Safety and Side Effects Considering the widespread use of cimetidine in the treatment of acute duodenal ulcer disease over the last several years, relatively few side effects have been reported. Accordingly, the United States Food and Drug Administration has ruled that cimetidine is safe for shortterm use (up to eight weeks) in the treatment of acute duodenal ulcer disease. As anticipated, increased population exposure, particularly of subjects receiving long-term therapy, has resulted in the recognition of certain side effects. Unilateral or bilateral gynecomastia has been observed in a significant number of patients, with complete resolution upon discontinuance of the drug. While some case reports of granulocytopenia have been reported to the Food and Drug Administration, most case reports involved complex other factors and it is impossible. to presently conclude that cimetidine ever affects granulocytes." Al-
866
WALTER
P.
DYCK
though some increase in serum creatinine is commonly observed, blood urea concentrations are not altered and presently available data do not offer evidence of nephrotoxicity. Cimetidine occasionally produces a confusional syndrome. 21 In all reported cases the mental symptoms resolve quickly upon discontinuance of drug use. A flurry of interest has recently been generated by a report of hypothalamicpituitary-gonadal dysfunction in a small group of men treated with cimetidine. A 43 per cent mean reduction in sperm count was observed. 22 Judgment on the clinical significance of these endocrine changes must await further observations. Considerable controversy has recently arisen over a possible link between cimetidine (a notrosable drug) and gastric cancer. To date, an assumption for such a relationship is based on scattered anecdotal case reports and a great deal of conjecture.
REFERENCES 1. Behar, J., Brand, D. L., Brown, F. C., et al.: Cimetidine in the treatment of symptomatic gastroesophageal reflux. A double blind controlled trial. Gastroenterology, 74:441-448, 1978. 2. Black, J. W., Duncan, W. A. M., Durant, G. J., et al.: Definition and antagonism of histamine Hj-receptors. Nature, 236:385-390, 1972. 3. Black, J. W., Duncan, W. A. M., Emmett, J. C., et al.: Metiamide - an orally active histamine Hj-receptor antagonist. Agents Actions 3:133-137, 1973. 4. Brimblecombe, R. W., Duncan, W. A. M., Durant, G. J., et al.: Cimetidine-a nonthiourea Hj-receptor antagonist. J. Intern. Med. Res., 3:86-92, 1975. 5. Brown, P. A., Brown, T. H., and Vernihos-Danellis, I.: Histamine Hj-receptor: involvement in gastric ulceration. Life Sci., 18:339-344, 1976. 6. Burland, W. L., and Simkins, M. A.: Cimetidine: Proceedings of the Second International Symposium on Histamine Hj-receptcr Antagonists. Amsterdam, Excerpta Medica, 1977, p. 392. 7. Ciclitira, P. J., Machell, R. J., Farthing, M. J., et al.: A controlled trial of cimetidine in the treatment of gastric ulcer. In Burland, W. L., and Simkins, M. A. (eds.): Cimetidine: Proceedings of the Second International Symposium on Histamine Hj-receptor Antagonists. Amsterdam, Excerpta Medica, 1977, pp. 283-286. 8. Dyck, W. P., Belsito, A., FleshIer, B., et al.: Cimetidine and placebo in the treatment of benign gastric ulcer. A multicenter double blind study. Gastroenterology, 74:410415, 1978. 9. Englert, E., Jr., Freston, J. W., Graham, D. Y., et al.: Cimetidine, antacid and hospitalization in the treatment of benign gastric ulcer. A multicenter double blind study. Gastroenterology, 74 :416-425, 1978. 10. Festen, J. P. M., Lamers, C. B. H., Driessen, W. M. M., et al.: Cimetidine in anastomotic ulceration after partial gastrectomy. Gastroenterology, 77:83-85, 1979. 11. Freston, J. W.: Cimetidine in the treatment of gastric ulcer. Review and commentary. Gastroenterology, 74:426-430, 1978. 12. Freston, J. W.: Cimetidine and granulocytopenia. Ann. Intern. Med., 90:264-265, 1979. 13. Hansky, J., Korman, M. G., Hetzel, D. J., et al.: Relapse rate after cessation of 12 months cimetidine in duodenal ulcer (abstract). Gastroenterology, 76:1151, 1979. 14. Hetzel, D. J., Hanskey, J., Sheannan, D. J. C., et al.: Cimetidine treatment of duodenal ulceration. Short term clinical trial and maintenance study. Gastroenterology, 74:389-392, 1978. 15. Ippolitia, A. F., Sturdevant, R. A. L., Isenberg, J. I., et al.: Cimetidine versus intensive antacid therapy for duodenal ulcer. A multicenter trial. Gastroenterology, 74 :393395,1978. 16. Kravitz, J. J., Snape, W. J., Jr., and Cohen, S.: Effect of histamine and histamine antagonists on human lower esophageal sphincter function. Gastroenterology;' 74 :435-440, 1978. 17. Machell, R. J., Ciclitira, P. J., Farthing, M. G. J., et al.: The prevention of gastric ulcer 'relapse with cimetidine (abstract). Gastroenterology, 76:1191, 1979.
CIMETIDINE IN PEPTIC ULCER DISEASE
867
18. McCarthy, D. M.: Report on the United States experience with cimetidine in ZollingerEllison syndrome and other hypersecretory states. Gastroenterology, 74 :453458, 1978. 19. Richardson, C. T.: Effect of Hs-receptor antagonists on gastric acid secretion and serum gastrin concentration. A review. Gastroenterology, 74:366-370,1978. 20. Safaie-Sharizi, S., Foster, L. D., and Hardy, B. M.: The effect of metiamide, an H 2receptor antagonist, in the prevention of experimental stress ulcer. Gastroenterology, 71 :421425, 1976. 21. Schentag, J. J., Cerra, F. B., Calleri, G., et al.: Pharmacokinetic and clinical studies in patients with cimetidine-associated mental confusion. Lancet, 1 :177-181, 1979. 22. Van Thiel, D. H., Gavaler, J. S., Smith, W. I., Jr., et al.: Hypothalamic-pituitary-gonadal dysfunction in men using Cimetidine. New Engl. J. Med., 300:1012-1015,1979. 23. Welch, W., Bentch, H. L., and Harris, S. C.: Reduction of Aspirin-induced gastrointestinal bleeding with Cimetidine. Gastroenterology, 74 :459463. 24. Winship, D. H.: Cimetidine in the treatment of duodenal ulcer. Review and commentary. Gastroenterology, 74:402406, 1978. 25. Wyllie, J. H., Hesselbo, T., and Black, J. W.: Effects in man of histamine Hj-receptor blockade by burimamide. Lancet, 2:1117-1120, 1972. Division of Gastroenterology Scott and White Clinic Temple, Texas 76501
Cimetidine in the Management of Peptic Ulcer Disease Walter P. Dyck, M.D.
Background and Physiology Two classes of histamine receptors, H 1 and H 2 , have been pharmacologically identified by means of specific competitive antagonists. The classical antihistamines (Hj-receptor antagonists) developed several decades ago competitively antagonize the action of histamine on smooth muscle but have no inhibitory effect on histamine-stimulated gastric acid secretion. This suggested the existence of an additional histamine receptor and prompted a search for competitive inhibitors for additional receptor site(s). Beginning with the structure of histamine, stepwise chemical modification of various compounds" 3. 25 ultimately led to the development of cimetidine, a specific histamine H 2receptor antagonist which has been shown to be an effective inhibitor of basal and nocturnal acid secretion as well as acid secretion stimulated by histamine, pentagastrin, caffeine, insulin, sham feeding, and food.v " Treatment of Acute Duodenal Ulcer The worldwide experience with cimetidine has clearly shown the efficacy of this drug in promoting acute duodenal ulcer healing, and this constitutes the chief indication for its use at present. Results of numerous clinical trials in the United States and abroad have been summarized elsewhere.v>' At least three to four weeks of cimetidine therapy appear to be required to achieve healing rates of about 70 per cent. The accepted dosage regimen consists of 300 mg of cimetidine taken four times a day, with meals and at bedtime. In one randomized double-blind multicenter trial, patients treated with cimetidine or an intensive antacid program had similar rates of healing of duodenal ulcers and of pain relief. 15 Prevention of Recurrence of Duodenal Ulcers Several multicenter studies are presently examining the efficacy of cimetidine in doses smaller than those used for the treatment of acute From the Division of Gastroenterology, Scott and White Clinic, Temple, Texas
Surgical Clinics of North America - Vol. 59, No.5, October 1979
863
864
WALTER
P.
DYCK
duodenal ulcer disease, in preventing duodenal ulcer recurrence. Limited available data suggest that continuous maintenance therapy with cimetidine is effective in preventing recurrence of ulcers!" but does not protect the patient from relapse on cessation of therapy." The relapse rate after prolonged use of cimetidine (one year) was similar to that after six weeks of cimetidine, suggesting that if cimetidine is to be used to prevent recurrence of ulcers it may require continued use. Treatment of Gastric Ulcers The role of cimetidine in the management of gastric ulcers is not nearly as clear as its obvious usefulness in the management of duodenal ulcer disease. Several multicenter studies in the United States have failed to show a clear beneficial effect of cimetidine on healing of gastric ulcers." 9. 11 Limited data from abroad suggests that cimetidine is effective in promoting the healing of gastric ulcers," and that maintenance therapy with cimetidine may be effective in reducing the incidence of gastric ulcer relapse. 17 Ongoing studies will hopefully clarify the potential role of these agents in the management of gastric ulcer disease. Treatment of Hypersecretory States Until recently, the only acceptable therapeutic modality for the management of the Zollinger-Ellison syndrome was total gastrectomy with or without an attempt at resection of the gastrin-secreting tumor. The inability to excise all tumor tissue in most cases made it attractive to try to control the production of acid by nonsurgical means. Until the advent of the Hj-receptor blockers, satisfactory long-term suppression of acid secretion was not possible in the majority of such patients. Cimetidine has now been shown to provide a viable alternative to total gastrectomy for patients with Zollinger-Ellison syndrome, and appears to control acid-peptic disease in the large majority at least as effectively as total gastrectomy but without the attendant morbidity of that procedure. 18 While each patient must be approached individually, it seems appropriate now to recommend that cimetidine therapy be used as the initial therapeutic modality in all patients with Zollinger-Ellison syndrome. Those patients who do not respond to cimetidine therapy and those patients who are unable to use the drug on a continuing basis under careful supervision should undergo total gastrectomy. The availability of cimetidine also makes it reasonable now to attempt simple excision of the tumor as a curative procedure in some cases without demonstrable metastases, with the understanding that an effective anti-secretory agent is available in the event of recurrence of the tumor. A longer follow-up of patients presently being treated with H 2receptor blockers will be needed before a more definitive statement can be made on the appropriate long-term management of such hypersecretory states. Cimetidine for Anastomotic Ulceration Anastomotic ulceration occurring in a patient who has previously undergone partial gastrectomy usually results from an inadequate sur-
CIMETIDINE IN PEPTIC ULCER DISEASE
865
gical procedure (incomplete vagotomy and/or inadequate resection). Consequently it is generally accepted that this complication requires surgical correction. The efficacy of cimetidine in patients with endoscopically proved anastomotic ulcer arising after partial gastrectomy has recently been studied;" Healing rate after one month of treatment with cimetidine was 67 per cent and increased to 86 per cent after two months of therapy. Three of 19 patients relapsed during one year of maintenance therapy with 800 mg of cimetidine daily. It could be recommended therefore that in high-risk patients, particularly the debilitated or bleeding patient, cimetidine be used as an initial therapeutic approach until the patient can be prepared for elective corrective surgery under optimal conditions. Cimetidine for Reflux Esophagitis Although endoscopic and histologic improvement of reflux esophagitis during cimetidine therapy has not been conclusively shown, significant subjective improvement in terms of decreased frequency and severity of symptoms as well as a significant improvement in esophageal acid sensitivity has been shown to result from cimetidine therapy.1 Since cimetidine fails to alter basal lower esophageal sphincter pressure;" the effectiveness of cimetidine in relieving symptoms of gastroesophageal reflux are felt to result from the inhibitory effect on gastric acid secretion with resultant decrease in the reflux of gastric acid into the esophagus. Hemorrhagic Gastritis The efficacy of Hj-receptor blockers in preventing experimental gastric mucosal ulceration produced by stress'" and topical aspirin" has been demonstrated. The precise mechanism whereby cimetidine affords such a protective action has not been defined. Cimetidine has been shown to result in a significant reduction in fecal blood loss in patients with aspirin-induced occult gastrointestinal bleeding." Studies are in progress to further define the efficacy of cimetidine in acute upper gastrointestinal hemorrhage of erosive gastritis and hepatic failure. Safety and Side Effects Considering the widespread use of cimetidine in the treatment of acute duodenal ulcer disease over the last several years, relatively few side effects have been reported. Accordingly, the United States Food and Drug Administration has ruled that cimetidine is safe for shortterm use (up to eight weeks) in the treatment of acute duodenal ulcer disease. As anticipated, increased population exposure, particularly of subjects receiving long-term therapy, has resulted in the recognition of certain side effects. Unilateral or bilateral gynecomastia has been observed in a significant number of patients, with complete resolution upon discontinuance of the drug. While some case reports of granulocytopenia have been reported to the Food and Drug Administration, most case reports involved complex other factors and it is impossible. to presently conclude that cimetidine ever affects granulocytes." Al-
866
WALTER
P.
DYCK
though some increase in serum creatinine is commonly observed, blood urea concentrations are not altered and presently available data do not offer evidence of nephrotoxicity. Cimetidine occasionally produces a confusional syndrome. 21 In all reported cases the mental symptoms resolve quickly upon discontinuance of drug use. A flurry of interest has recently been generated by a report of hypothalamicpituitary-gonadal dysfunction in a small group of men treated with cimetidine. A 43 per cent mean reduction in sperm count was observed. 22 Judgment on the clinical significance of these endocrine changes must await further observations. Considerable controversy has recently arisen over a possible link between cimetidine (a notrosable drug) and gastric cancer. To date, an assumption for such a relationship is based on scattered anecdotal case reports and a great deal of conjecture.
REFERENCES 1. Behar, J., Brand, D. L., Brown, F. C., et al.: Cimetidine in the treatment of symptomatic gastroesophageal reflux. A double blind controlled trial. Gastroenterology, 74:441-448, 1978. 2. Black, J. W., Duncan, W. A. M., Durant, G. J., et al.: Definition and antagonism of histamine Hj-receptors. Nature, 236:385-390, 1972. 3. Black, J. W., Duncan, W. A. M., Emmett, J. C., et al.: Metiamide - an orally active histamine Hj-receptor antagonist. Agents Actions 3:133-137, 1973. 4. Brimblecombe, R. W., Duncan, W. A. M., Durant, G. J., et al.: Cimetidine-a nonthiourea Hj-receptor antagonist. J. Intern. Med. Res., 3:86-92, 1975. 5. Brown, P. A., Brown, T. H., and Vernihos-Danellis, I.: Histamine Hj-receptor: involvement in gastric ulceration. Life Sci., 18:339-344, 1976. 6. Burland, W. L., and Simkins, M. A.: Cimetidine: Proceedings of the Second International Symposium on Histamine Hj-receptcr Antagonists. Amsterdam, Excerpta Medica, 1977, p. 392. 7. Ciclitira, P. J., Machell, R. J., Farthing, M. J., et al.: A controlled trial of cimetidine in the treatment of gastric ulcer. In Burland, W. L., and Simkins, M. A. (eds.): Cimetidine: Proceedings of the Second International Symposium on Histamine Hj-receptor Antagonists. Amsterdam, Excerpta Medica, 1977, pp. 283-286. 8. Dyck, W. P., Belsito, A., FleshIer, B., et al.: Cimetidine and placebo in the treatment of benign gastric ulcer. A multicenter double blind study. Gastroenterology, 74:410415, 1978. 9. Englert, E., Jr., Freston, J. W., Graham, D. Y., et al.: Cimetidine, antacid and hospitalization in the treatment of benign gastric ulcer. A multicenter double blind study. Gastroenterology, 74 :416-425, 1978. 10. Festen, J. P. M., Lamers, C. B. H., Driessen, W. M. M., et al.: Cimetidine in anastomotic ulceration after partial gastrectomy. Gastroenterology, 77:83-85, 1979. 11. Freston, J. W.: Cimetidine in the treatment of gastric ulcer. Review and commentary. Gastroenterology, 74:426-430, 1978. 12. Freston, J. W.: Cimetidine and granulocytopenia. Ann. Intern. Med., 90:264-265, 1979. 13. Hansky, J., Korman, M. G., Hetzel, D. J., et al.: Relapse rate after cessation of 12 months cimetidine in duodenal ulcer (abstract). Gastroenterology, 76:1151, 1979. 14. Hetzel, D. J., Hanskey, J., Sheannan, D. J. C., et al.: Cimetidine treatment of duodenal ulceration. Short term clinical trial and maintenance study. Gastroenterology, 74:389-392, 1978. 15. Ippolitia, A. F., Sturdevant, R. A. L., Isenberg, J. I., et al.: Cimetidine versus intensive antacid therapy for duodenal ulcer. A multicenter trial. Gastroenterology, 74 :393395,1978. 16. Kravitz, J. J., Snape, W. J., Jr., and Cohen, S.: Effect of histamine and histamine antagonists on human lower esophageal sphincter function. Gastroenterology;' 74 :435-440, 1978. 17. Machell, R. J., Ciclitira, P. J., Farthing, M. G. J., et al.: The prevention of gastric ulcer 'relapse with cimetidine (abstract). Gastroenterology, 76:1191, 1979.
CIMETIDINE IN PEPTIC ULCER DISEASE
867
18. McCarthy, D. M.: Report on the United States experience with cimetidine in ZollingerEllison syndrome and other hypersecretory states. Gastroenterology, 74 :453458, 1978. 19. Richardson, C. T.: Effect of Hs-receptor antagonists on gastric acid secretion and serum gastrin concentration. A review. Gastroenterology, 74:366-370,1978. 20. Safaie-Sharizi, S., Foster, L. D., and Hardy, B. M.: The effect of metiamide, an H 2receptor antagonist, in the prevention of experimental stress ulcer. Gastroenterology, 71 :421425, 1976. 21. Schentag, J. J., Cerra, F. B., Calleri, G., et al.: Pharmacokinetic and clinical studies in patients with cimetidine-associated mental confusion. Lancet, 1 :177-181, 1979. 22. Van Thiel, D. H., Gavaler, J. S., Smith, W. I., Jr., et al.: Hypothalamic-pituitary-gonadal dysfunction in men using Cimetidine. New Engl. J. Med., 300:1012-1015,1979. 23. Welch, W., Bentch, H. L., and Harris, S. C.: Reduction of Aspirin-induced gastrointestinal bleeding with Cimetidine. Gastroenterology, 74 :459463. 24. Winship, D. H.: Cimetidine in the treatment of duodenal ulcer. Review and commentary. Gastroenterology, 74:402406, 1978. 25. Wyllie, J. H., Hesselbo, T., and Black, J. W.: Effects in man of histamine Hj-receptor blockade by burimamide. Lancet, 2:1117-1120, 1972. Division of Gastroenterology Scott and White Clinic Temple, Texas 76501
