Gut: first published as 10.1136/gut.29.1.81 on 1 January 1988. Downloaded from Gut, 1988, 29, 81-84 Double blind comparison of the effects of cimetidine, ranitidine, famotidine, and placebo on intragastric acidity in 30 normal volunteers

H S MERKI, L WITZEL, R P WALT, J NEUMANN, E SCHEURLE, A MAPPES, H KRAMMISCH, J HEIM, D KAUFMANN, AND J ROEHMEL From the DRK Hospital Mark Brandenburg, Department ofGastroenterology Berlin, FRG, Department-of Therapeutics, Queens Medical Centre, Nottingham, and Department ofStatistics, Arzneimittelforschung Berlin (AFB) Berlin, FRG

SUMMARY Continuous measurement of 24 hour intragastric acidity was carried out in 30 normal volunteers during treatment with placebo, cimetidine 800 mg, ranitidine 300 mg, and famotidine 40 mg in a double blind study. Medication was taken after the evening meal (post cenam nocte, PCN). Median 24 hour acidity decreased with all H2-receptor antagonists from 25 1 mmol/l on placebo to 10 mmol/l (-60. 1%) during cimetidine, to 3.2 mmol/l (-87.25%) during ranitidine and to 2.5 mmol/l (-90.0%) during famotidine treatment (p<0.0005). All drugs significantly inhibited night time acidity but only famotidine decreased acidity during the late morning compared with placebo. Significantly greater acid reduction was seen with famotidine and ranitidine compared with cimetidine but no difference was found between famotidine and ranitidine. http://gut.bmj.com/

It has become standard practice to assess the effects week apart in Berlin. Half the subjects were non- of new antisecretory agents by measuring gastric smokers and the mean age was 25.5 years (19-39 acidity over 24 hours.'-" Famotidine is a new H2- range). Clinical, biochemical and haematological receptor antagonist which is more potent than parameters were normal before study and all subjects ranitidine (approximately eight times weight for gave informed consent. Ethical committee approval weight).'"'5 Early clinical results with famotidine for the study was obtained before the start. Subjects on October 1, 2021 by guest. Protected copyright. show it to be as effective as either cimetidine or took apparently identical capsules containing ranitidine. h 7 No previous study, however, has com- cimetidine 800 mg, ranitidine 300 mg, famotidine pared the effects of single doses of these three drugs 40 mg or placebo in random order at 1900 h after the on 24 hour gastric acidity in a double blind study of evening meal. No other drugs were allowed during adequate size although in one study of seven sub- the study which compared single doses of the H2- jects, famotidine 40 mg appeared more effective in receptor antagonists. reducing nocturnal acidity than ranitidine 300 mg.x The technique used for the measurement of 24 We have done repeated studies of 24 hour acidity in hour acidity has been previously described.1" 2"1 30 volunteers in order to be confident that observed Normal fixed diets were used unrestricted after the differences were real. first four hours. Drugs were administered in the investigation ward and thereafter subjects returned Methods to their own homes, intragastric acidity being monitored continuously using intragastric electrodes SUBJECTS allowing accurate and reproducible measure- Thirty healthy volunteers (15 women, 15 men) each ments."'M 21 Each study started at 1500 h and lasted underwent four separate 24 hour studies at least one until 1500 h the next day. Address for correspondence: Dr Hans Merki, Department of Gastroenter- Results have been displayed as frequency distribu- ology, Inseispital Bern, CH-3010 Bern, Switzerland. tion and time sequence arrays of.pH values and as Received for publication 10 June 1987. medians, means, and ranges (Box-Whisker-Plots). 81 Gut: first published as 10.1136/gut.29.1.81 on 1 January 1988. Downloaded from 82 Merki, Witzel, Walt, Neumann, Scheurle, Mappes, Krammisch, Heim, Kaufmann, and Roehmel

7.0. 65 60 5.5. 5*0. 4.5. pH 40. 3.5, 30 2.5 ~~~~~~~~~~~1 I 20 1l5 1 0 15 16 18 20 22 24 2 4 6 81 0 12 14 15 Time (h) 05 Fig. 1 Median 24 hour intragastric acidity in 30 normal Placebo Cimetidine Famotidine Ranitidine volunteers receivingplacebo, cimetidine 800mg, ranitidine 800 mg 300 300 mg andfamotidine 40 mg. Medianfive min values are 40mg mg plotted. Drugs were taken as shown at 1900 h and meal times Fig. 3 Box-whisker-plots ofnight time acidity (2200-0600) are shown at the bottom, tea (T), dinner (D), snack (S), during all treatments. All drugs producedsignificant breakfast (B), and lunch (L). inhibition ofacidity compared with placebo (p<0.0005) and ranitidine andfamotidine had significantly greater effects Median pH during the four treatments was compared than cimetidine (p<0005). for the following predefined time periods, 24 hours, night (2200-0600), early morning (0600-1000), late Results morning (1000-1200) and afternoon (1200-1500). Wilcoxon's signed rank tests were applied with The median pH profile of the 30 subjects are shown correction of significance for multiple testing when for the four treatments in Figure 1. All H2-receptor appropriate. 24 antagonists inhibited hour acidity compared with http://gut.bmj.com/ placebo (p<0.0005). Median 24 hour acidity was 50i 25-1 mmol/l (44.7-15.8 interquartile range) on 4.5 5.5- 40 .3 5*0- 3.5 .2 A 4.5- on October 1, 2021 by guest. Protected copyright. pH 3.0l 40- t 2.5 3.5. 20 pH 3.0- 1.5 1*0 2.5- 2.0- Ubl Placebo Cimetidine Famotidine Ranitidine 800mg 40 mg 300mg 15- Fig. 2 Box-whisker-plots ofevening acidity (1800-2200) 1*0- during all treatments. The box shows the median (solid line), the mean (dotted line) and the interquartile ranges (extremes 0.5 ofbox). Whiskers show the greatest or smallest values within Placebo Cimetidine Famotidine Ranitidine one interquartile distancefrom the quartiles. Outliers are 800 mg 40 mg 300 mg shown separately.25 Similarplots are shown in Figures 3 and 4. Fig. 4 Box-whisker-plots ofacidity in the early morning All drugs decreased acidity compared with placebo but (0600-1000) during all treatments. All drugs produced statistical testing ofthese differences was not done as it had significant inhibition ofacidity compared with placebo not been planned in theprotocol. (p<00()5). Gut: first published as 10.1136/gut.29.1.81 on 1 January 1988. Downloaded from Comparison ofthe effects ofcimetidine, ranitidine, famotidine, andplacebo on intragastric acidity 83

100- effects of antisecretory drugs has previously been 90- successfully collected by this and other techniques assessing only intragastric pH. '" 19 1 80 This study confirms that famotidine and ranitidine 70 , \* Famotidine are more potent inhibitors of gastric acidity than cimetidine. In the recommended dosages for clinical 60- use, ranitidine and famotidine decrease 24 hour %50 * intragastric acidity to a similar degree. We have not 40 * been able to confirm the findings of a small study which suggested that famotidine 40 mg was more 30 -Ranitidine effective than ranitidine 300 mg during the night 20 Placebo - when taken in the early evening.'8 Famotidine 40 mg had significant activity over a slightly longer time 10 * Cimet ine * period than the other drugs. Although this effect was 0 small and the size of this 0 1 2 3 4 5 6 7 8 possibly unimportant, study pH was adequate to detect such a change. No anti- Fig. 5 Frequency distribution curves offpH in 30 normal secretory effects, however, were found after midday volunteers receiving H,-receptor antagonists. The with any drug. proportion oftime during 24 hours with pH values above any Post cenam nocte dosing is not the standard given level are shown. recommended regimen for these drugs. Five separate studies have now shown that inhibition of gastric placebo, and decreased after cimetidine 800 mg to acidity during the evening and night is significantly 10 mmol/l (15-8-6-6), after ranitidine 300 mg to 3-2 greater after early evening dosing with H2-receptor mmol/l (5.6-1-0) and after famotidine 40 mg to antagonists compared with 'bedtime' dosing,'8"18212 2-5 mmol/l (5-6-1-0). The effect of cimetidine was Pounder RE (personal communication). The more significantly less than either ranitidine or famotidine potent drugs given in adequate doses show this best (p<0.001), but there was no significant difference while the activity of the least potent (cimetidine) between famotidine and ranitidine during any pre- weakens towards the morning and PCN dosing with defined time period. Box-whisker-plots showing the 800 mg cimetidine would not be recommended. A distribution, median, interquartile ranges and means similar increased effect is possible, however, with http://gut.bmj.com/ for the evening (Fig. 2), night (Fig. 3) and the early cimetidine given in a large dose (1600 mg).'2 morning acidity (Fig. 4) are shown. All three drugs Although the majority of these studies were done on significantly decreased gastric acidity during the normal volunteers it seems reasonable to extrapolate latter two periods compared with placebo (p<0-005). the findings to ulcer patients as it appears that data During the late morning (1000-1200) median pH was from normal volunteers do predict the responses of 1-5 with placebo, 1-3 with cimetidine (NS), 1-5 with ulcer patients.2. Preliminary data also suggest that ranitidine (NS) and, after a consistent response with this increased pharmacodynamic effect is associated on October 1, 2021 by guest. Protected copyright. famotidine, was 1-7 (significant compared with with better clinical results.24 On the basis of these placebo (p<0-005)). No significant inhibition of findings it is likely that famotidine and ranitidine acidity was found with any drug during the afternoon. would be equally effective in ulcer healing when The pH frequency distribution curves (Fig. 5) clearly prescribed in these PCN doses. show that the overall effects of ranitidine and famotidine are indistinguishable. References Discussion I Pounder RE, Williams JG, Milton-Thompson GJ, Misiewicz JJ. 24-hour control of intragastric acidity by Continuous intragastric pH monitoring is becoming cimetidine in duodenal ulcer patients. Lancet 1975; ii: more popular as an accurate assessment of gastric pH 1069-72. over prolonged periods. The equipment and tech- 2 Pounder RE, Hunt RH, Vincent SH, Milton-Thompson nique used here have been validated' " and are able GJ, Misiewicz JJ. 24-hour intragastric acidity and to detect changes of pH during predefined time nocturnal acid secretion in patients with duodenal ulcer during oral administration of cimetidine and atropine. periods of 0-1 unit or greater.2 In common with other Gut 1977; 18: 85-90. methods where only pH is measured the volume of 3 Peterson WL, Barnett C, Feldman M, Richardson CT. gastric secretion cannot be assessed and information Reduction of 24-hour intragastric acidity with combina- about peptic activity and bile salt concentrations tion drug therapy in patients with duodenal ulcer. is not collected. Important information about the Gastroenterology 1979; 77: 1t)15-20. Gut: first published as 10.1136/gut.29.1.81 on 1 January 1988. Downloaded from 84 Merki, Witzel, Walt, Neumannl, Scheurle, Mappes, Krammlisch, Heim, Kaufmann, and Roehmel

4 Walt RP, Male JP, Rawlings J, Hunt RH, Milton- Takeuchi T. Effect of famotidine on gastric secretion, Thompson GJ, Misiewicz JJ. Comparison of the effects and on 24-hour intragastric pH in duodenal ulcer of ranitidine, cimetidine and placebo on the 24-hour patients [Abstract]. Gastroenterology 1984; 86: 1250. intragastric acidity and nocturnal acid secretion in 15 Smith JL. Clinical pharmiacology of famotidine. patients with duodenal ulcer. Gut 1981; 22: 49-54. Digestion 1985; 32: suppl 1: 15-23. 5 Walt RP, Gomes M, Wood EC, Logan LH, Pounder 16 Simon B, Damman HG, Jakob G, et al. Famotidine RE. Effect of daily oral omeprazole on 24-hour intra- versus ranitidine for the short term treatment of gastric acidity. Br Med J 1983; 287: 12-4. duodenal ulcer. Digestion 1985; 32: suppl 1: 32-7. 6 Gledhill T, Howard OM, Buck M, Paul A, Hunt RH. 17 Paoluzi P, Torsoli A, Bianchi Porro G, et al. Famotidine Single nocturnal dose of an H-receptor antagonist for in the treatment of gastric ulcer. Results of a multicenter treatment of duodenal ulcer. Gut 1983; 24: 904-8. double-blind controlled study. Digestion 1985; 32: suppl 7 Gledhill T, Buck M, Paul A, Hunt RH. Cimetidine or 1: 38-44. vagotomy'? Comparison of the effects of proximal gastric 18 Bauerfeind P, Cilluffo T, Emde C, et al. H1-antagonists vagotomy, cimetidine or placebo on nocturnal intra- are more effective after early evening intake than gastric acidity and acid secretion in patients with after late intake [Abstract]. Gastroenterology 1986; 90: cimetidine resistant duodenal ulcer. Br J Surg 1983; 70: 1340. 704-6. 19 Merki HS, Witzel L, Harre K, Scheurle E, Neumann J,. 8 Sharma BK, Walt RP, Pounder RE, Gomes M, Wood Rohmel J. Single dose treatment with H-receptor EC, Logan KH. Optimal dose of oral omeprazole for antagonists: Is bedtime administration too late'? Gut maximal 24-hour decrease of intragastric acidity. Gut 1987; 28: 451-4. 1984; 25: 957-64. 20 Merki HS, Witzel L, Walt RP, et al. Day to day variation 9 Prichard PJ, Yeomans ND, Mihaly GW, et al. of 24-hour intragastric acidity. Gastroenterology (In Omeprazole: a study of its inhibition of gastric pH and press). oral pharmacokinetics after morning or evening doses. 21 Warzee PL, CoppensJP, Fiasse R, Dive CH. Ranitidine Gastroenterology 1985; 88:64-9. single dose 300 mg. Influence of the time of administra- 10 Etienne A, Fimmel CJ, Bron BA, Loizeau E, Blum A. tion on gastric acidity [Abstract]. Dig Dis Sci 1986; 31: Evaluation of pirenzepine on gastric acidity in healthy suppl: 333. volunteers using ambulatory 24-hour intragastric pH- 22 Deakin M, Glenny H, Ramage JK, et al. Treatment of monitoring. Gut 1985; 26: 241-5. duodenal ulcer by H, blockade, large single daily dose, 11 Fimmel CJ, Etienne A, Cillufo T, et al. Long-term how much and when'? [Abstract]. Gut 1985; 26: A 1 120. ambulatory gastric pH-monitoring: validation of a new 23 Howden CW, Jones DB, Burget DW, Hunt RH. method and effect of H,-antagonists. Gastroenterology Comparison of the effects of gastric antisecretory agents 1985;88: 1842-51. in healthy volunteers and patients with duodenal ulcer. http://gut.bmj.com/ 12 Damman HG, Walter THA, Muller P, Simon B. H2- Gut 1986; 27: 1058-61. Rezeptor-Antagonisten und intragastrale Aciditat. 24 Merki HS, Witzel L, Hiittemann W, et al. Single dose Dtsch Med Wochenschr 1984; 109: 1767-9. treatment with H2-receptor antagonists. A comparison 13 McCallum RW, Kuljian B, Chremos AN, Tupy-Visich, of an early evening dose vs bedtime administration Huber PB. Prolonged gastric antisecretory effect of a of ranitidine in the treatment of duodenal ulcer novel H2-receptor inhibitor, MK-208 [Abstract]. [Abstract]. Gastroenterology 1986; 90: 1550. Gastroenterology 1983; 84: 1245. 25 McGill R, Tukey JW, Larsen WA. Variations of box

14 Shiratori K, Watanabe S, Maruyama M, Kurokawa K, plots. Am Statistician 1978; 32: 12-7. on October 1, 2021 by guest. Protected copyright.