Scandinavian Journal of Gastroenterology
ISSN: 0036-5521 (Print) 1502-7708 (Online) Journal homepage: http://www.tandfonline.com/loi/igas20
High Doses of Ranitidine in Patients with Reflux Oesophagitis J. B. M. J. Jansen & C. B. H. W. Lamers To cite this article: J. B. M. J. Jansen & C. B. H. W. Lamers (1990) High Doses of Ranitidine in Patients with Reflux Oesophagitis, Scandinavian Journal of Gastroenterology, 25:sup178, 42-46, DOI: 10.3109/00365529009093149 To link to this article: http://dx.doi.org/10.3109/00365529009093149
Published online: 08 Jul 2009.
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Date: 18 March 2016, At: 20:09
High Doses of Ranitidine in Patients with Reflux Oesophagit is J. B. M. J . JANSEN & C. B. H . W . LAMERS Dept. of Gastroenterology-Hepatology. University of Leiden, Leiden, The Netherlands
Downloaded by [ECU Libraries] at 20:09 18 March 2016
Jansen JBMJ, Lamers CBHW. High doses of ranitidine in patients with reHux oesophagitis. Scand J Gastroenterol 1990. 25(suppl 178). 42-46 As in duodenal and gastric ulcer patients, a highly significant correlation between suppression of 24-h intragastric acidity and healing rates in reHux oesophagitis patients was demonstrated by meta-analysis of data obtained from the literature ( r = 0.90: p < 0.001). Furthermore, we have demonstrated in eight patients with reHux orsophagitis that 2-week treatment courses with 300 nig ranitidine twice daily and 3OU mg four times daily progressively decreased 24-h intraoesophageal acidity but only moderately elevated basal and meal-stimulated serum gastrin concentrations, signilicantly below gastrin values obtained after a 2-week treatment course with 20mg omeprazole once daily. Further studies are awaited to demonstrate long-term effects on both healing rates and serum gastrin responses with high doses of histamine H,-receptor antagonists.
Key words: Gastrin; omeprazole; pH-recording; ranitidine: rcHux ocsophagitis
J . B. M . J . Jansen, M . D . . Dept. of Gastroenterology and Hepatology. University Hospital, Rijnsburgerweg 1 0 , P. 0. Box 9600. Building I , C4-PO17, 2300 RC Leiden, The Netherlands
Since reflux of gastric contents into the oesophagus is, to a certain degree, a physiologic event, reflux oesophagitis is the result of a prolonged contact time between contents of the gastric refluent, in particular gastric acid ( l ) , and the oesophageal mucosa. Gastro-oesophageal reflux is facilitated by a low pressure in the lower oesophageal sphincter (LOS) and by inappropriate relaxations of the LOS (2). An increased contact time between gastric contents and the oesophageal mucosa may further result from a disturbed oesophageal motor function (3), reduced salivary bicarbonate production (4), and delayed gastric emptying (5). Symptoms resulting from gastro-oesophageal reflux are initially best treated by simple life style modifications (6). However, a considerable number of patients with reflux symptoms and reflux oesophagitis need further medical support,
for which a variety of drugs, such as antacids, anti-secretory drugs, prokinetic drugs, and mucosa-protecting agents, are available. Gastric acid is believed to be of critical importance in the pathogenesis of reflux oesophagitis. However, standard doses of histamine H2-receptor antagonists have repeatedly been reported to leave a considerable number of patients with reflux oesophagitis unhealed and with incomplete symptom relief (7-20). On the other hand, more profound inhibition of gastric acid secretion by the H+/K+-ATPase antagonist omeprazole has been demonstrated to augment healing rates and symptom relief in reflux oesophagitis patients considerably (21-27), at the cost of hypergastrinaemia due to interference with the feedback system between intragastric acidity and antral gastrin release. We have therefore investigated the relationship between the suppression of gastric acidity by
Ranitidine in Heflux Oesoph(igiris
Downloaded by [ECU Libraries] at 20:09 18 March 2016
anti-secretory drugs and their corresponding oesophagitis healing rates. Furthermore, we have investigated, in a limited number of patients with severe reflux oesophagitis. whether increasing the dose of the histamine H2-receptor antagonist ranitidine also increases basal and mealstimulated serum gastrin concentrations. and we have compared these gastrin concentrations with those obtained after 2 weeks' administration of omeprazole in the same patients. RELATIONSHIP BETWEEN SUPPRESSION O F ACIDITY A N D OESOPHAGITIS HEALING RATES Previous studies have demonstrated that there is a linear relationship between suppression of 24-h intragastric acidity and duodenal and gastric ulcer healing rates (28,29). We have investigated
whether such a relationship also exists in patients with reflux oesophagitis. Healing rates were derived from trials which included only patients with erosive or ulcerative reflux oesophagitis and were calculated for at least 8 weeks of treatment (21-27. 34, 35). Information on suppression o f intragastric acidity was mainly derived from a review of published clinical pharmacologic trials of antisecretory drugs in ulcer patients (28, 29). With suppression of 24-h acidity as an independent variable and with corresponding oesophagitis healing rates as a dependent variable, the relationship between the two sets of variables has been investigated by using correlation and linear regression analysis. After 8 weeks of treatment healing rates were significantly (p < 0.001) correlated ( r = 0.90) with suppression of 24-h acidity (Fig. 1).
acid
reduction (Yo)
40 20
t
01 0
A
I
20
43
40
60
80
100
healed (%)
Fig. I. Relation hetween X-week healing rates of erosive or ulcerative reflux oesophagitis and gastric acid reduction hy anti-ulcer drugs ( y = 0 . 6 ~+ 40; N = X; r = 0.90; p < 0.001). P=placebo; A=antacids. INN)mmoV24 h; C = cimetidine, 400mg four times daily; F = famotidine, 40mg; R = ranitidine, 150mg twice daily; RR = ranitidine. 300mg four times daily; 0 = omeprazole, 60, 20, and 40 mg, respectively.
J . B . M . J . Jansen & C. B. H . W . Lamers
44
Basal serum gastrin levels during the placebo study period (63 +. 9ng/l) were not significantly different from basal serum gastrin levels during In eight reflux oesophagitis patients (five women, the 300-mg ranitidine twice daily period (67 & three men; mean age, 52 f 5 years) resistant to 10 ng/l). During the 300-mg ranitidine four times treatment with 150 mg ranitidine twice daily or daily period, basal serum gastrin levels signifi400 mg cimetidine four times daily for 12 weeks, cantly increased to 97 f 14ngll (p < 0.05). four 2-week study periods were performed in However, these levels were significantly lower random order. During these study periods, than those obtained after the 20-mg omeprazole placebo, 300 mg ranitidine twice daily, 300 mg study period (197 f 25 ng/l). Meal-stimulated ranitidine four times daily, or 20 mg omeprazole serum gastrin values showed a similar response once daily was administered. During the last day (Fig. 2). Integrated meal-stimulated serum gastrin reof each 2-week study period intraoesophageal pH sponses after the 300-mg ranitidine twice daily was recorded every 6 sec during 24 h using comperiod (6881.8 f 711.0ng/1.60 min) were not bined glass electrodes (model 440m 4, Ingold significantly different from those obtained after AG, Urdorf, Switzerland). These 6-sec pH tracings were stored on solid state devices with a 15- the placebo study period (6068.8 f 753.9 ng/l.60 Kbyte memory (Proxima Light, Mantova, Italy) min). Integrated meal-stimulated serum gastrin and subsequently transferred to floppy disks by responses after the 300-mg four times daily study period (8726.3 +. 682.3 ngIl.60 min), however, means of an Olivetti personal computer. Basal and stimulated serum gastrin levels were were significantly higher than those obtained after measured by radioimmunoassay before and at the placebo study period (p c 0.05), but signifiregular intervals after a meal containing 25 g fat, cantly lower (p < 0.05) than those obtained after the 20-mg omeprazole at bedtime study period 30 g protein, and 50 g carbohydrates. There was a gradual decline in the percentage (16607.3 f 2050.9 ngA.60 min). of time that intraoesophageal pH's were below 4 with increasing doses of ranitidine when comDISCUSSION pared with the placebo study. Although in four of the eight patients 24-h pH recordings reached the HZ-receptor antagonists are highly effective in normal range with the 300mg four times daily the treatment of gastric and duodenal ulcer dose of ranitidine (Table I), 20mg of omeprazole disease. However, in reflux oesophagitis was still significantly (p < 0.05) better in decreas- patients, overall healing rates achieved during ing intraoesophageal acid response in these treatment with conventional doses of HZ-receppatients when analysed by Wilcoxon's test for tor antagonists are suboptimal. with from half to paired results. two-thirds of patients remaining unhealed after 8
Downloaded by [ECU Libraries] at 20:09 18 March 2016
SERUM GASTRIN LEVELS DURING HIGH DOSES O F RANITIDINE
Table I. Twenty-four-hour intraoesophagel pH: percentage time below pH 4.0
Ranitidine
Patient no.
Age
Sex
Placebo
300 mg twice daily
300mg 4 times daily
Omeprazole 20 mg
1 2 3 4 5 6 7 8
30 39 60 35 61 51 73 64
F M M F M F F F
23.8 31 .0 15.1 49.0 5.3 16.4 28.6 32.2
6.6 0.2 7.4 21.1 4.5 14.0 18.3 16.3
1.7 0.0 3.7 9.4 3.3 10.2 12.1 9.3
1.2 0.0 3.9 2.9 1.9 9.0 8.9 3.5
Ranitidine in Reflux Oesophagitis
(31). In man, administration of omeprazole also induces slight to moderate reversible hypergastrinaemia (32, 33). Since further studies are needed to establish the long-term efficacy and &OO safety, omeprazole has not yet been registered for maintenance treatment. The knowledge that profound inhibition of gastric acid secretion results in nearly optimal healing rates in reflux oesophagitis patients has 300 motivated studies with higher doses of ranitidine in these patients (34). These studies have demonstrated that healing rates increase significantly, from 54% to 75%. after 8 weeks' treatment when 200 the dose of ranitidine was increased from 150 mg twice daily to 300 mg four times daily. The present study has demonstrated that these high doses of ranitidine only result in a slight, but significant, increase in basal and postprandial 100 serum gastrin concentrations, significantly below the gastrin values obtained with doses of omeprazole advised for the treatment of reflux oesophagitis patients. Until more information on the long-term efficacy and safety of omeprazole is available, higher than presently used doses of H2-is 0 i s i i s 60 min receptor antagonists may be a reasonable alterFig. 2. Basal and meal-stimulated serum gastrin con- native in patients with erosive or ulcerative reflux centrations in eight patients with reflux oesophagitis oesophagitis. These higher doses of H2-receptor after '-week treatment courses with placebo (0); 300 rng ranitidine twice daily ( A ) ; 300 mg ranitidine four antagonists significantly improve healing rates times daily (0); and 20mg omeprazole once daily ( x ) . and only moderately increase serum gastrin Results are expressed as mean k SEM. values, but studies are needed to demonstrate the long-term effects of this therapy. weeks of treatment (7-27). More profound and persistent inhibition of gastric acid secretion, as REFERENCES obtained with the H+/K+-ATPase antagonist 1. Jansen JBMJ, Lamers CBHW. Medical treatment omeprazole, has demonstrated that near optimal of reHux oesophagitis. J Drug Ther Res 1989, 14, 45-49 healing rates can be achieved in reflux oeso2. Vantrappen G. Janssens J. Pathophysiology and phagitis patients after 8 weeks' treatment. Howtreatment of gastro-oesophageal reflux disease. ever, after cessation of omeprazole therapy there Scand J Gastroenterol 1989, 24(suppl 165). 7-12 is a high relapse rate, necessitating maintenance 3. Stancin C, Bennet JR. Oesophageal acid clearing: one factor in the production of reflux oesophagitis. treatment in almost all reflux oesophagitis Gut 1974, 15, 852-857 patients (22). 4. Helm JF, Esophageal acid clearance. J Clin GastroIn rats, long-term administration of high doses enterol 1986, S(supp1 1). 5-1 1 5. McCallum RW, Berkowitz DM, Lerner E. Gastric of omeprazole has been demonstrated to result in emptying in patients with gastroesophageal reflux. enterochromaffin cell hyperplasia and subGastroenterology 1981, 80. 285-293 sequently carcinoid formation in some, mainly 6. Richter JE. A critical review of current medical therapy for gastroesophageal reflux disease. J Clin female, rats (30). These events are related to Gastroenterol 1984, 8(suppl l ) , 72-80 hypergastrinaemia induced by profound gastric 7. Wesdorp E, Bartelsman J. Pape K, Dekker W, acid inhibition during omeprazole administration Tijtgat GN . Oral eimetidine in reflux esophagitis:
SERUM GASTRIN ng/l
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45
Downloaded by [ECU Libraries] at 20:09 18 March 2016
46
J . B. M. J . Jansen & C. B. H . W . Lamers
a double blind controlled trial. Gastroenterology 1978, 74, 811-814 8. Behar J , Brand DL, Brown FC. Cimetidine in the treatment of symptomatic gastroesophageal reflux: a double blind controlled trial. Gastroenterology 1978. 74, 441-448 9. Powell-Jackson P. Barkley H, NorthfieldTC. Effect of cimetidine in symptomatic gastroesophageal reflux. Lancet 1978, 1068-1070 10. Fiasse R, Hanin C, Lepot A, Descamps C, Lamy F, Dive C. Controlled trial of cimetidine in reflux esophagitis. Dig Dis Sci 1980, 25. 750-755 11. Brown P. Cimetidine in the treatment of reflux esophagitis. Med J Aust 1979, 2, 96-97 12. Druguet M, Lambert R. Oral cimetidinc in reflux esophagitis: a double blind controlled trial. In: Dress A, Barbier F, Harvengt C. Tijtgat G, eds. Proceedings of the second national symposium. Exerpta Medica. Amsterdam, 1980. 30-36 13. Festen HPM. Driessen WMM, Lamers CBHW, van Tongeren JHM. Treatment of reflux esophagitis with cimetidine. Ned J Med 1980. 23, 237240 14. Bennett JR, Buckton G, Marrin MD. Cimetidine in gastroesophageal reflux. Digestion 1983, 25, 166-176 15. Wesdorp JC. Dekker W. Klinkenberg-Knol EC. Treatment of reflux oesophagitis with ranitidine. Gut 1983, 24, 921-924 16. Sherbanish R, Wensel R, Baily R . Ranitidine in the treatment of symptomatic gastroesophageal reflux disease. J Clin Gastroenterol 1984. 6, 9-15 17. Hine KR, Homes GKT, Melikian V, Lucey M, Fairclough PD. Ranitidine in reflux esophagitis. Digestion 1984, 29, 119-123 18. McCallum RW, Eskelman F, Nardi R. A doubleblind multicenter trial to compare the efficacy of ranitidine and placebo in the short-term treatment of chronic gastroesophageal reflux disease. Gastroenterology 1984, 86. 1179 19. Grove 0. Bekker C, Jeppe-Hanscn G . Ranitidine and high dose antacid in reflux esophagitis: a randomized placebo controlled trial. Scand J Gastroenterol 1985. 20. 457-461 20. Koelz HR, Birckler R, Oveholz A, et al. Healing and relapse in reflux esophagitis during treatment with ranitidine. Gastroenterology 1986, 91, 119% 12% 21. Klinkenberg-Knol EC, Jansen JBMJ, Festen HPM. Meuwissen SGM, Lamers CBHW. Doubleblind multicenter comparison of omeprazole and ranitidine in the treatment of oesophagitis. Lancet 1987, 1, 349-351
22. Hetzel DJ, Dent J , Reed WD, et al. Healing and relapse of severe peptic esophagitis after treatment with omeprazole. Gastroenterology 1988, 95, 303-3 12 23. Vantrappen G, Rutgeers L, Schurmans P. Coenegrachts JL. Omeprazole (40 mg) is superior to ranitidine in short-term treatment of ulcerative reflux esophagitis. Dig Dis Sci 1988, 33, 523-529 24. Zeitoun P, Desjars de KeranrouC M, lsal JP. Omeprazole versus ranitidine in erosive oesophagitis. Lancet 1987. 2, 621-622 25. Havelund T, Laursen LS, Skoubo-Kristensen E, et al. Omeprazole and ranitidine in treatment of reflux oesophagitis: double-blind comparative trial. Br Med J 1988. 296, 89-92 26. Sandmark S. Carlsson R, Fausa S, Lundell L. Omeprazole or ranitidine in the treatment of reflux esophagitis. Scand J Gastroenterol 1988. 23. 625-632 27. Dehn TC, Shephard HA, Collin-Jones D, Kettlewell MG. Double-blind comparative study of omeprazole (40mg)vscimetidine (400mgq.d.s.) in the treatment of erosive reflux oesophagitis. Gut 1988. A1440 28. Jones DB, Howden CW, Burget DW. Kerr GD, Hunt RH. Acid suppression in duodenal ulcer: a meta-analysis to define optimal dosing with antisecretory drugs. Gut 1987. 28, 1120-1 127 29. Howden CW, Hunt RH. The relationship between suppression of acidity and gastric ulcer healing rates. Aliment Pharmacol Ther 1990. 4. 25-33 30. Ekman L, Hansson E, Havn N , Carlsson E, Lundberg C. Toxicological studies on omeprazole. Scand J Gastroenterol 1985, 20(suppl 108). 5 S 6 9 31. Creutzfeldt W. The achlorhydria-carcinoid sequence: role of gastrin. Digestion 1988, 39. 61-79 32. Brunner G . Creutzfeldt W, Harke U. Lamberts R. Therapy with omeprazole in patients with peptic ulcerations resistant to extended high-dose ranitidine treatment. Digestion 1988. 39, 80-90 33. Jansen JBMJ. Klinkenberg-Knol EC, Meuwissen SGM. et al. Effect of long-term treatment with omeprazole on serum gastrin and serum group A and C pepsinogens in patients with reflux esophagitis. Gastroenterology 1990. 99, 621-628 34. Johnson NJ. Boyd EJS, Mills JG, Wood JR. Acute treatment of reflux oesophagitis: a multicentre trial to compare 150 mg ranitidine b.d. with 300 mg ranitidine q.d.s. Aliment Pharmacol Ther 1989, 3, 259-266 35. Sekiguchi T, Takasu Y, Miwa T. et al. Clinical study of famotidine in reflux esophagitis. Med Consult New Remedies 1983. 20, 2467-2485
ISSN: 0036-5521 (Print) 1502-7708 (Online) Journal homepage: http://www.tandfonline.com/loi/igas20
High Doses of Ranitidine in Patients with Reflux Oesophagitis J. B. M. J. Jansen & C. B. H. W. Lamers To cite this article: J. B. M. J. Jansen & C. B. H. W. Lamers (1990) High Doses of Ranitidine in Patients with Reflux Oesophagitis, Scandinavian Journal of Gastroenterology, 25:sup178, 42-46, DOI: 10.3109/00365529009093149 To link to this article: http://dx.doi.org/10.3109/00365529009093149
Published online: 08 Jul 2009.
Submit your article to this journal
Article views: 2
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=igas20 Download by: [ECU Libraries]
Date: 18 March 2016, At: 20:09
High Doses of Ranitidine in Patients with Reflux Oesophagit is J. B. M. J . JANSEN & C. B. H . W . LAMERS Dept. of Gastroenterology-Hepatology. University of Leiden, Leiden, The Netherlands
Downloaded by [ECU Libraries] at 20:09 18 March 2016
Jansen JBMJ, Lamers CBHW. High doses of ranitidine in patients with reHux oesophagitis. Scand J Gastroenterol 1990. 25(suppl 178). 42-46 As in duodenal and gastric ulcer patients, a highly significant correlation between suppression of 24-h intragastric acidity and healing rates in reHux oesophagitis patients was demonstrated by meta-analysis of data obtained from the literature ( r = 0.90: p < 0.001). Furthermore, we have demonstrated in eight patients with reHux orsophagitis that 2-week treatment courses with 300 nig ranitidine twice daily and 3OU mg four times daily progressively decreased 24-h intraoesophageal acidity but only moderately elevated basal and meal-stimulated serum gastrin concentrations, signilicantly below gastrin values obtained after a 2-week treatment course with 20mg omeprazole once daily. Further studies are awaited to demonstrate long-term effects on both healing rates and serum gastrin responses with high doses of histamine H,-receptor antagonists.
Key words: Gastrin; omeprazole; pH-recording; ranitidine: rcHux ocsophagitis
J . B. M . J . Jansen, M . D . . Dept. of Gastroenterology and Hepatology. University Hospital, Rijnsburgerweg 1 0 , P. 0. Box 9600. Building I , C4-PO17, 2300 RC Leiden, The Netherlands
Since reflux of gastric contents into the oesophagus is, to a certain degree, a physiologic event, reflux oesophagitis is the result of a prolonged contact time between contents of the gastric refluent, in particular gastric acid ( l ) , and the oesophageal mucosa. Gastro-oesophageal reflux is facilitated by a low pressure in the lower oesophageal sphincter (LOS) and by inappropriate relaxations of the LOS (2). An increased contact time between gastric contents and the oesophageal mucosa may further result from a disturbed oesophageal motor function (3), reduced salivary bicarbonate production (4), and delayed gastric emptying (5). Symptoms resulting from gastro-oesophageal reflux are initially best treated by simple life style modifications (6). However, a considerable number of patients with reflux symptoms and reflux oesophagitis need further medical support,
for which a variety of drugs, such as antacids, anti-secretory drugs, prokinetic drugs, and mucosa-protecting agents, are available. Gastric acid is believed to be of critical importance in the pathogenesis of reflux oesophagitis. However, standard doses of histamine H2-receptor antagonists have repeatedly been reported to leave a considerable number of patients with reflux oesophagitis unhealed and with incomplete symptom relief (7-20). On the other hand, more profound inhibition of gastric acid secretion by the H+/K+-ATPase antagonist omeprazole has been demonstrated to augment healing rates and symptom relief in reflux oesophagitis patients considerably (21-27), at the cost of hypergastrinaemia due to interference with the feedback system between intragastric acidity and antral gastrin release. We have therefore investigated the relationship between the suppression of gastric acidity by
Ranitidine in Heflux Oesoph(igiris
Downloaded by [ECU Libraries] at 20:09 18 March 2016
anti-secretory drugs and their corresponding oesophagitis healing rates. Furthermore, we have investigated, in a limited number of patients with severe reflux oesophagitis. whether increasing the dose of the histamine H2-receptor antagonist ranitidine also increases basal and mealstimulated serum gastrin concentrations. and we have compared these gastrin concentrations with those obtained after 2 weeks' administration of omeprazole in the same patients. RELATIONSHIP BETWEEN SUPPRESSION O F ACIDITY A N D OESOPHAGITIS HEALING RATES Previous studies have demonstrated that there is a linear relationship between suppression of 24-h intragastric acidity and duodenal and gastric ulcer healing rates (28,29). We have investigated
whether such a relationship also exists in patients with reflux oesophagitis. Healing rates were derived from trials which included only patients with erosive or ulcerative reflux oesophagitis and were calculated for at least 8 weeks of treatment (21-27. 34, 35). Information on suppression o f intragastric acidity was mainly derived from a review of published clinical pharmacologic trials of antisecretory drugs in ulcer patients (28, 29). With suppression of 24-h acidity as an independent variable and with corresponding oesophagitis healing rates as a dependent variable, the relationship between the two sets of variables has been investigated by using correlation and linear regression analysis. After 8 weeks of treatment healing rates were significantly (p < 0.001) correlated ( r = 0.90) with suppression of 24-h acidity (Fig. 1).
acid
reduction (Yo)
40 20
t
01 0
A
I
20
43
40
60
80
100
healed (%)
Fig. I. Relation hetween X-week healing rates of erosive or ulcerative reflux oesophagitis and gastric acid reduction hy anti-ulcer drugs ( y = 0 . 6 ~+ 40; N = X; r = 0.90; p < 0.001). P=placebo; A=antacids. INN)mmoV24 h; C = cimetidine, 400mg four times daily; F = famotidine, 40mg; R = ranitidine, 150mg twice daily; RR = ranitidine. 300mg four times daily; 0 = omeprazole, 60, 20, and 40 mg, respectively.
J . B . M . J . Jansen & C. B. H . W . Lamers
44
Basal serum gastrin levels during the placebo study period (63 +. 9ng/l) were not significantly different from basal serum gastrin levels during In eight reflux oesophagitis patients (five women, the 300-mg ranitidine twice daily period (67 & three men; mean age, 52 f 5 years) resistant to 10 ng/l). During the 300-mg ranitidine four times treatment with 150 mg ranitidine twice daily or daily period, basal serum gastrin levels signifi400 mg cimetidine four times daily for 12 weeks, cantly increased to 97 f 14ngll (p < 0.05). four 2-week study periods were performed in However, these levels were significantly lower random order. During these study periods, than those obtained after the 20-mg omeprazole placebo, 300 mg ranitidine twice daily, 300 mg study period (197 f 25 ng/l). Meal-stimulated ranitidine four times daily, or 20 mg omeprazole serum gastrin values showed a similar response once daily was administered. During the last day (Fig. 2). Integrated meal-stimulated serum gastrin reof each 2-week study period intraoesophageal pH sponses after the 300-mg ranitidine twice daily was recorded every 6 sec during 24 h using comperiod (6881.8 f 711.0ng/1.60 min) were not bined glass electrodes (model 440m 4, Ingold significantly different from those obtained after AG, Urdorf, Switzerland). These 6-sec pH tracings were stored on solid state devices with a 15- the placebo study period (6068.8 f 753.9 ng/l.60 Kbyte memory (Proxima Light, Mantova, Italy) min). Integrated meal-stimulated serum gastrin and subsequently transferred to floppy disks by responses after the 300-mg four times daily study period (8726.3 +. 682.3 ngIl.60 min), however, means of an Olivetti personal computer. Basal and stimulated serum gastrin levels were were significantly higher than those obtained after measured by radioimmunoassay before and at the placebo study period (p c 0.05), but signifiregular intervals after a meal containing 25 g fat, cantly lower (p < 0.05) than those obtained after the 20-mg omeprazole at bedtime study period 30 g protein, and 50 g carbohydrates. There was a gradual decline in the percentage (16607.3 f 2050.9 ngA.60 min). of time that intraoesophageal pH's were below 4 with increasing doses of ranitidine when comDISCUSSION pared with the placebo study. Although in four of the eight patients 24-h pH recordings reached the HZ-receptor antagonists are highly effective in normal range with the 300mg four times daily the treatment of gastric and duodenal ulcer dose of ranitidine (Table I), 20mg of omeprazole disease. However, in reflux oesophagitis was still significantly (p < 0.05) better in decreas- patients, overall healing rates achieved during ing intraoesophageal acid response in these treatment with conventional doses of HZ-receppatients when analysed by Wilcoxon's test for tor antagonists are suboptimal. with from half to paired results. two-thirds of patients remaining unhealed after 8
Downloaded by [ECU Libraries] at 20:09 18 March 2016
SERUM GASTRIN LEVELS DURING HIGH DOSES O F RANITIDINE
Table I. Twenty-four-hour intraoesophagel pH: percentage time below pH 4.0
Ranitidine
Patient no.
Age
Sex
Placebo
300 mg twice daily
300mg 4 times daily
Omeprazole 20 mg
1 2 3 4 5 6 7 8
30 39 60 35 61 51 73 64
F M M F M F F F
23.8 31 .0 15.1 49.0 5.3 16.4 28.6 32.2
6.6 0.2 7.4 21.1 4.5 14.0 18.3 16.3
1.7 0.0 3.7 9.4 3.3 10.2 12.1 9.3
1.2 0.0 3.9 2.9 1.9 9.0 8.9 3.5
Ranitidine in Reflux Oesophagitis
(31). In man, administration of omeprazole also induces slight to moderate reversible hypergastrinaemia (32, 33). Since further studies are needed to establish the long-term efficacy and &OO safety, omeprazole has not yet been registered for maintenance treatment. The knowledge that profound inhibition of gastric acid secretion results in nearly optimal healing rates in reflux oesophagitis patients has 300 motivated studies with higher doses of ranitidine in these patients (34). These studies have demonstrated that healing rates increase significantly, from 54% to 75%. after 8 weeks' treatment when 200 the dose of ranitidine was increased from 150 mg twice daily to 300 mg four times daily. The present study has demonstrated that these high doses of ranitidine only result in a slight, but significant, increase in basal and postprandial 100 serum gastrin concentrations, significantly below the gastrin values obtained with doses of omeprazole advised for the treatment of reflux oesophagitis patients. Until more information on the long-term efficacy and safety of omeprazole is available, higher than presently used doses of H2-is 0 i s i i s 60 min receptor antagonists may be a reasonable alterFig. 2. Basal and meal-stimulated serum gastrin con- native in patients with erosive or ulcerative reflux centrations in eight patients with reflux oesophagitis oesophagitis. These higher doses of H2-receptor after '-week treatment courses with placebo (0); 300 rng ranitidine twice daily ( A ) ; 300 mg ranitidine four antagonists significantly improve healing rates times daily (0); and 20mg omeprazole once daily ( x ) . and only moderately increase serum gastrin Results are expressed as mean k SEM. values, but studies are needed to demonstrate the long-term effects of this therapy. weeks of treatment (7-27). More profound and persistent inhibition of gastric acid secretion, as REFERENCES obtained with the H+/K+-ATPase antagonist 1. Jansen JBMJ, Lamers CBHW. Medical treatment omeprazole, has demonstrated that near optimal of reHux oesophagitis. J Drug Ther Res 1989, 14, 45-49 healing rates can be achieved in reflux oeso2. Vantrappen G. Janssens J. Pathophysiology and phagitis patients after 8 weeks' treatment. Howtreatment of gastro-oesophageal reflux disease. ever, after cessation of omeprazole therapy there Scand J Gastroenterol 1989, 24(suppl 165). 7-12 is a high relapse rate, necessitating maintenance 3. Stancin C, Bennet JR. Oesophageal acid clearing: one factor in the production of reflux oesophagitis. treatment in almost all reflux oesophagitis Gut 1974, 15, 852-857 patients (22). 4. Helm JF, Esophageal acid clearance. J Clin GastroIn rats, long-term administration of high doses enterol 1986, S(supp1 1). 5-1 1 5. McCallum RW, Berkowitz DM, Lerner E. Gastric of omeprazole has been demonstrated to result in emptying in patients with gastroesophageal reflux. enterochromaffin cell hyperplasia and subGastroenterology 1981, 80. 285-293 sequently carcinoid formation in some, mainly 6. Richter JE. A critical review of current medical therapy for gastroesophageal reflux disease. J Clin female, rats (30). These events are related to Gastroenterol 1984, 8(suppl l ) , 72-80 hypergastrinaemia induced by profound gastric 7. Wesdorp E, Bartelsman J. Pape K, Dekker W, acid inhibition during omeprazole administration Tijtgat GN . Oral eimetidine in reflux esophagitis:
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