Digestive Diseases and Sciences, Vol. 35, No. 8 (August 1990), pp. 976-983

Tolerance to Oral H2-Receptor Antagonists C. H. WILDER-SMITH, MD, T. ERNST, MD, M. G E N N O N I, MD, B. ZEYEN, MD, F. H A L T E R, MD, and H. S. MERKI, MD

The acid-inhibitory action of H2-receptor antagonists was shown to decrease after one to two weeks o f dosing in healthy volunteers. This tolerance was evaluated in three randomized, placebo-controlled trials with the He-receptor antagonists famotidine, 40 mg given after the evening meal for 28 days; ranitidine, 300 mg four times a day for seven days followed by 300 mg at night until day 28; and ranitidine, 300 mg three times a day vs 300 mg at night for 14 days. Continuous 24-hr p H monitoring with glass electrodes was performed underfed conditions. The median 24-hr p H decreased from 3.2 on day 1 with famotidine 40 mg to 1.9 on day 28 (P < 0.0012). After seven days of dosing with ranitidine 300 mg four times a day the median 24-hr p H dropped from 5.0 on day 1 to 3.0 on day 7 (P < 0.00l) and then to 2.2 with ranitidine 300 mg at night on day 28. With ranitidine 300 mg three times a day the median 24-hr p H fell from 4.3 on day 1 to 2.4 on day 14 (P < 0.0005). With ranitidine 300 mg at night the respective p H values were 2.5 and 1.8 (P < 0.003). Tolerance to He-receptor antagonists given in a single evening dose was only evident during the night, whereas tolerance occurred throughout the day and night with the three- and four-times-a-day regimens. A large increase in the interindividual variability o f p H response was seen during the nighttime. KEY WORDS: 24-hour pH-metry; tolerance; ranitidine; famotidine; acid inhibition; pharmacodynamics; H 2receptor antagonists.

A decrease in the pharmacodynamic effect of different H2-receptor antagonists after repetitive dosing has been reported (1-5). This tolerance seems to occur after only a few days of treatment with doses used in clinical practice (6). Most studies reported so far have used designs that did not allow conclusive evaluation of tolerance. The incidence, time of onset, and magnitude of tolerance remain unclear. The extent to which intragastric acidity recovers during different dosing regimens with He-receptor antagonists may be important, as there is a good correlation between inhibition of nocturnal acidity and healing of duodenal ulcer (7). Tolerance might be implicated in failure of ulcers to heal or in early relapses during maintenance therapy in a selected Manuscript received November 29, 1989; revised manuscript received April 4, 1990; accepted April 13, 1990. From the Gastrointestinal Unit, Department of Medicine, University of Berne, Inselspital, Berne, Switzerland. Address for reprint requests: Dr. H. S. Merki, Gastrointestinal Unit, Inselspital, CH-3010 Berne, Switzerland.

976

group of patients. Three studies were performed in 41 healthy volunteers, lasting 14-28 days, to assess the development of tolerance occurring during therapeutically relevant He-receptor antagonist dosage regimens. MATERIALS AND METHODS Study A. Fourteen healthy volunteers, five females and nine males, between 18 and 35 years of age, underwent continuous 24-hr pH-metry on four separate occasions. The study design was open. A baseline 24-hr study without active drug was performed three to seven days before the start of the 28-day dosing period with famotidine 40 mg after the evening meal. On days 1, 14, and 28 of the study, combined glass electrodes (Ingold 440 M4) were introduced transnasally and positioned by advancing the tube a further 8-10 cm after the pH drop was registered on passing through the cardia, pH monitoring was begun at 1600 hr and famotidine 40 mg was taken under supervision at 1830 hr. Standardized meals were given at 1600, 1800, 2200, 0800, and 1300 hr. Only sips of tap water were allowed intercurrently. Volunteers smoked the same number of cigarettes on each study day. Digestive Diseases and Sciences, Vol. 35, No. 8 (August 1990)

0163-2116/90/0800-0976506.00/09 1990PlenumPublishingCorporation

TOLERANCE TO H2-RECEPTOR ANTAGONISTS At the end of the study subjects were required to return the tablet dispensers to document compliance. Exclusion criteria were known hypersensitivity to H 2receptor antagonists, active and past gastrointestinal disease, concurrent medication, more than 15% over ideal body weight, and a clinically significant abnormal blood test. Gastrograph Mark I pH data-loggers and Pack2 software (MIC, Solothurn, Switzerland) for data processing were used. The intraindividual median pH for the total 24-hr (1600-1600 hr) and nighttime (1800-0800 hr) periods was predefined for confirmative analysis. The Wilcoxon signed-rank test was used for comparison of days 14 and 28 with day 1 and with each other. The baseline pH-metry was purely for descriptive comparison. All P values were corrected for multiple testing according to HolmBonferroni (8). Study B. This randomized, placebo-controlled, twoway crossover, double-blind study was carried out in 13 healthy volunteers between 18 and 40 Years of age. The drug regimen consisted of either ranitidine 300 mg four times a day given for seven days (at 2300, 0830, 1330, and 1830 hr) and followed by ranitidine 300 mg at night (at 2300 hr) from day 8 to 28, or identical placebo tablets. On either treatment arm, 24-hr pH monitoring was performed on days 1, 7, and 28, beginning at 2300 hr. There was a washout period of two weeks between the two study arms. Study procedures were identical to those in study A. An updated, miniaturized pH logger, the Gastrograph Mark2, was used. The predefined primary variable for comparison of days 1, 7, and 28 was the areaunder-the-curve (AUC) of H § ion activity for the total 24 hr (2300-2300 hr), daytime (0800-2300 hr), and nighttime (2300-0800 hr). Descriptive analysis of the median pH for the above periods was also performed. Statistical tests were the same as in study A. Study C. Fourteen healthy volunteers, of which two were females, between 18 and 40 years of age, were recruited for this double-blind, placebo-controlled, randomized, three-way crossover trial to compare the development of tolerance with ranitidine 300 mg three times a day, 300 mg at night, an d placebo given for 14 days. Studies were conducted as described for study A. The pH recordings began at 2300 hr on days 1 and 14 of the study, Coded tablets were taken under supervision at 2300, 0830, and 1230 hr on every study day. The Washout period between treatment arms was two weeks. The 24-hr AUC of H § activity was defined as the primary efficacy variable. Nighttime (2300-0800 hr) and daytime (08002300 hr) AUCs of H + activity and the median pH for all time periods were analyzed descriptively. Statistical tests were as in the above studies. Hospital ethics committee approval and the subjects' written informed consent were obtained for all three studies.

RESULTS Study A. Complete data from 12 subjects were available for evaluation. One volunteer discontinued the study after the first day. The baseline 24-hr study was missing in another subject because of Digestive Diseases and Sciences, Vol. 35, No. 8 (August 1990)

day 0

day 1

day 14

day 28

pH m

4.543.53~I

2.52-

I~176176 i

/_

1.5-

I L

1

_

_

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--

n=13 Fig

I

t

n=13

n=13

n=13

1. Box-Whisker plots o f median nighttime p H before and on

days 1, 14, and 28 of famotidine 40 mg after the evening meal treatment in healthy volunteers. Ip < 0.001 (days 1 vs 14) zp < 0.0012 (days 1 vs 28).

equipment failure from 1330 to 1600 hr. The baseline median p H values (interquartile range) were 1.5 (1.3-1.75) for the 24-hr period and 1.3 (1.25-1.7) for the nighttime. With famotidine 40 mg after the evening meal, the median 24-hr p H declined from 3.2 (2.15-3.7) on day 1 to 2.2 (1165-2,6) on day 14 (P < 0.0004) and to 1.9 (1.75-2.5) on day 28 (P < 0.0012 day 1 vs 28). The median nighttime p H is shown in Figure 1. T h e r e were no significant differences in p H between days 14 and 28 in either the 24-hr or nighttime period. The 24-hr group median p H profiles are shown in Figure 2. Study B. T e n volunteers completed all study arms. One subject withdrew before receiving any study medication, in two further subject s t h e datalogger malfunctioned on day 7. The median 24-hr p H dropped significantly from 5.0 (4.4-5.5) on day 1 to 3.0 (2:3-4.8) on day 7 and to 2.2 (1.8-2.9) on day 28 (1 vs 7: P < 0.001; 7 vs 28: P < 0.012; 1 vs 28: P < 0.0002) (Figure 3). During the daytime, the corresponding median p H fell from 4.2 (4.0-5.1) to 3.3 (3.1-4.1) and to 2.0 (1.7-2.6) (1 vs 7: P < 0.0005, 7 vs 28: P < 0.002, 1 vs 28: P < 0.0002). Median nighttime pHs a r e shown in BoxWhisker plots in Figure 4. The interindividual variability in response increased after 7 days treatment with ranitidine 300 mg four times a day. During dosing with placebo, the median 24-hr p H did not change significantly from 1.3 (1.1-2.2) on

977

WILDER-SMITH ET AL pH n=13 8--

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Fig 2. 24-Hour median pH profiles before (dotted line) and on days 1 (solid line) and 14 (broken line) of famotidine treatment, 40 mg after the evening meal, in healthy volunteers. Meals were taken at 1600, 1800, 2200, 0800, and 1300 hr.

day 1 to 1.4 (1.3-1.9) on day 7 and 1.7 (1.4-1.8) on day 28. Study C. Ten volunteers completed all the study arms. In two the data-logger malfunctioned on

study day 4, two others withdrew from the study (one was unable to swallow the tube on day 2 and the other decided to discontinue for personal reasons).

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Fig 3.24-Hour median pH profiles in healthy volunteers on ranitidine 300 mg four times a day (day 1: solid line, day 7: broken line) or placebo (dotted line) for seven days. Meals were taken at 1600, 1800, 2200, 0800, and 1300 hr.

978

Digestive Diseases and Sciences, Vol. 35, No. 8 (August 1990)

TOLERANCE TO H2-RECEPTOR ANTAGONISTS Ranitidine 300 mg qds day 1

day 7

Ranitidine 300 mg noc

Placebo

day 28

1 6---eooooo

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3-

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Fig 4. Box-Whisker plots of median nighttime pH on ranitidine 300 mg four times a day for seven days followed by ranitidine 300 nag at night until day 28, and placebo, lp < 0.0005 (day 1 vs day 7); ZNS (day 7 vs day 28); 3p < 0.0005 (day 1 vs day 28).

The median 24-hr pH fell from 4.3 (3.6-4.6) on day 1 to 2.4 (2.0-2.6) on day 14 with 300 mg three times a day (P < 0.0005) and from 2.5 (2.1-3.1) to 1.8 (1.62.6) with 300 mg at night, respectively (P < 0.003). There were no significant changes in median pH in the placebo group throughout the study period. The 24-hr group median profiles are shown in Figure 5. The daytime median pH declined from 3.6 (3.34.1) to 2.1 (1.8-2.6) after 14 days of dosing with ranitidine 300 mg three times a day (P < 0.0005), but remained unchanged at 1.7 (1.5-1.8) and 1.6 (1.5-1.8) with 300 mg at night, respectively. The effects of 14 days of dosing with ranitidine and placebo on median nighttime pH are shown in Figure 6. A substantial increase in interindividual variability of pH was observed after 14 days of dosing with ranitidine. Digestive Diseases and Sciences, Vol. 35, No. 8 (August 1990)

DISCUSSION In this series of studies the development of tolerance to oral HE-receptor antagonist regimens was investigated in 41 healthy subjects. Marked tolerance developed after one to two weeks in the dayand nighttime periods with the ranitidine 300 mg three- and four-times-a-day regimens, which have recently been recommended for the treatment of reflux esophagitis (9). The sustained action of these dosing schemes leads to inhibition of acidity throughout the entire 24-hr period. Consequently, counterregulatory mechanisms, whether they are hormonal or cellular, are constantly stimulated and tolerance would be expected to develop rapidly. However, even with the evening application of famotidine or ranitidine, significant tolerance was observed during the night but not during the day. With these dosing regimens the profound nocturnal antisecretory effects are interrupted by daytime periods of uninhibited acid secretion, because of the limited duration of pharmacodynamic action of the drugs. The development of tolerance despite interspersed periods of normal acidity indicates that the counterregulatory mechanisms to profound acid inhibition persist longer than the primary antisecretory action at the HE-receptor. The interindividual variability of pH-response in all studies increased substantially as tolerance developed. This was especially evident during the night, when some subjects continued to attain a high intragastric pH, whereas others no longer responded adequately. In the daytime variability was smaller, as the antisecretory effect of HE-blockers was overcome by the postprandial acid secretion in most subjects, irrespective of responder type (10). The results corroborate an earlier randomized, double-blind study comparing ranitidine 300 mg four times a day with ranitidine 300 mg after the evening meal, where significant tolerance, dependent on the time of drug administration, was seen after seven days in a similar study design (6). The data gathered in our studies are difficult to compare with earlier trials reporting tolerance in duodenal ulcer patients either in the active or quiescent phase of the disease. The interpretation of these trials is problematic for several reasons: tolerance to oral Hz-receptor antagonists develops and may also disappear within several days (11-13). Tolerance therefore may be missed if there is a delay in the pH measurements at the start or end of dosing with HE-antagonists (1, 4, 5, 14, 15). There

979

WILDER-SMITH

ET AL

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Fig 5. (A) 24-Hour median pH profiles in healthy volunteers on ranitidine 300 mg three times a day (day 1: solid line, day 14: broken line) or placebo (dotted line) for 14 days. (B) 24-Hour median pH profiles in healthy volunteers on ranitidine 300 mg at night (day 1: solid line, day 14: broken line) or placebo (dotted line) for 14 days. Meals were taken at 1600, 1800, 2200, 0800, and 1300 hr.

were no measurements for comparison on day 1 of dosing (1, 2, 5, 15); the doses or potencies of drugs used were low, possibly not suppressing acidity sufficiently for tolerance to be observed (1, 3, 4, 14, 15). Tolerance in response to acute intravenous H 2receptor antagonist was tested after chronic oral dosing, but tolerance in response to intravenous or

980

oral dosing may be different (1, 3, 5, 15). The regulating mechanism behind tolerance is unclear. Several factors, including counterregulatory hormonal mechanisms, cellular and receptor modulation, may be involved. Changes in the pharmacokinetics of H2-receptor antagonists have not been reported (3, 16). Digestive Diseases and Sciences, Vol. 35, No, 8 (August 1990)

TOLERANCE TO H2-RECEPTOR ANTAGONISTS Ranitidine 300 mg tds

Ranitidine 300 mg nocte

day 1

day 14

I_

I

day 1

Placebo

day 14

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There are some indications that gastrin may be involved in the development of the tolerance phenomenon. In a previous study, gastrin either remained constantly elevated after seven days of

dosing with ranitidine 300 mg four times a day or 14 days of dosing with sufotidine 300 mg twice a day, or increased further after 14 days of dosing with sufotidine 600 mg twice a day, despite increasing acidity (6). Other studies have also shown hypergastrinemia, especially postprandially, after chronic H2-blockade in duodenal ulcer patients (1, 4, 17). However, as intragastric acidity increases as a result of tolerance, the plasma gastrin levels would be expected to decrease. This acute negative feedback relationship, well known in both animal and human studies, is probably not valid during protracted hypoacidity (18-20). It is conceivable that in man chronic hypoacidity could lead to increased G-cell activation, as has been shown to occur in the rat (21-23). The resulting hypergastrinemia could increase the number of gastrin or H2-receptors by its trophic and up-regulatory effects on the parietal cell (24-26). An increased reaction to intravenous impromidine, a specific H2-agonist, after chronic oral H2-blocker dosing has been reported and postulated to signify H2-receptor up-regulation (5). Alternatively, gastrin may not be causally related to the development of tolerance. No clear relationship between 24-hr intragastric acidity and gastrin levels was reported in a previous study (17). Upregulation of H2-receptors on the parietal cell may theoretically occur, independent of gastrinergic mechanisms. The reduced efficacy of Hz-receptor antagonists in suppressing intragastric acidity could be expected to be of clinical significance, as a good correlation between intragastric acidity and healing

TABLE 1. INTEGRATED MEDIAN (INTERQUART1LE RANGE) AREA-UNDER-CURVE OF H + ACTIVITY WITH RANTIDINE 300 MG FOUR TIMES A DAY FOR 7 DAYS FOLLOWED BY 300 MG AT NIGHT UNTIL DAY 28, OR PLACEBO FOR 28 DAYS*

Day A U C 24 hr (mmol/1) 300 mg qds 300 mg qds 300 mg noc Placebo Placebo Placebo A U C night (mmol/1) 300 mg qds 300 mg qds 300 mg noc Placebo Placebo Placebo

Median

Interquartile range

N

1 7 28 1 7 28

155.5] ] 266.0~ I t 3 602.5J 2 1434.0] 1125.0 / 4 965.0 a

66.5-309.0 111.5-605.5 532.5-868.5 739.5-1672.0 694.5-1409.5 667.0-1136.5

12 11 12 12 11 12

1 7 28 1 7 28

59.0] ] 97.0~ 5 217.5J 6 ] 3 680.0 575.0 371.5

14.5-104.0 5.5-216.5 62.0-238.0 387.0-869.0 470.5-705.5 279.5-622.5

12 11 12 12 1t 12

J

*qds = four times a day; noc = at night. t l = p < 0.027; 2 = p < 0.007; 3 = p < 0.0002; 4 = p < 0.013; 5 = p < 0.019; 6 = NS.

Digestive Diseases and Sciences, Vol. 35, No. 8 (August 1990)

981

WILDER-SMITH ET AL TABLE 2. INTEGRATED MEDIAN (INTERQUARTILE RANGE) AREA-UNDER-CURVE OF H + ACTIVITY WITH RANIT1D1NE 300 MG THREE TIMES A DAY, RANITID1NE 300 MG AT NIGHT, OR PLACEBO FOR 14 DAYS* Day

AUC 24 hr (mmol/liter) Placebo Placebo 300 mg tds 300 mg tds 300 mg noc 300 mg noc AUC night (mmol/liter) Placebo Placebo 300 mg tds 300 mg tds 300 mg noc 300 mg noc

Median

Interquartile range

N

1 14 1 14 1 14

1204.5 1249.0 283.5 ] 1 537.0 J 693.0 ] 695.0 J 2

1049.0-1406.5 1025.0-1388.0 212.5-337.0 476.0-658.5 529.0-893.0 579.5-928.0

12 12 12 11 12 11

1 14 1 14 1 14

484 506 54 ]J 3 151 92 1 136 J 2

388.0-653.5 376.0-607.5 35.0-72.5 106.5-253.5 68.5-157.5 80.0-248.0

12 12 12 11 12 11

*tds = three times a day; noc = night. t l = P < 0.001; 2 = NS; 3 = P < 0.0005.

of duodenal ulcers has been demonstrated (7, 27). However, if tolerance were clinically relevant, unhealed ulcers should be more common than the 10-15% remaining after four to six weeks treatment with H2-receptor antagonists. Recent analyses indicate that the acid inhibition remaining after development of tolerance may still suffice to heal ulcers in most patients (7, 26). Tolerance may be important, however, in a specific subgroup of patients responding insufficiently to the normal H2-receptor antagonist dosage regimens. In conclusion, significant tolerance and increased interindividual variability in pH-responses to different H2-receptor antagonists occurred in healthy volunteers. Tolerance occurred with both single evening and multiple daily dosing.

6.

7. 8. 9.

10.

11.

REFERENCES 12. 1. Sewing KF, Hagie L, Ippoliti AF, Isenberg JI, Samloff IM, Sturdevant RAL: Effect of one month treatment with cimetidine on gastric secretion and serum gastrin and pepsinogen levels. Gastroenterology 74:376-379, 1978 2. Meyrick Thomas JU, Misiewicz JJ, Cook AR, Hill MJ, Smith PLR, Walters CL, Forster JK, Martin LE, Woodings DF: Effect of one year's treatment with ranitidine and of truncal vagotomy on gastric contents. Gut 28:726-738, 1987 3. Prichard PJ, Jones DB, Yeomans ND, Mihaly GW, Smallwood RA, Louis WJ: The effectiveness of ranitidine in reducing gastric acid-secretion decreases with continued therapy. Br J Clin Pharmacol 22:663-668, 1986 4. Frislid K, Aadland E, Berstad A: Augmented postprandial gastric acid secretion due to exposure to ranitidine in healthy subjects. Scand J Gastroenterol 21:119-122, 1986 5. Jones DB, Howden CW, Burget DW, Silletti C, Hunt RH: Alteration of H2-receptor sensitivity in duodenal ulcer pa-

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13.

14. 15.

16.

17.

tients after maintenance treatment with an H2-receptor antagonist. Gut 29:890-893, 1988 Wilder-Smith CH, Halter F, Ernst T, Gennoni M, Zeyen B, Varga L, Rrhmel JJ, Merki HS: Rapid reduction of acid suppression of H2-receptor antagonists. Aliment Pharmacol Ther 1990 (in press) Jones DB, Howden CW, Burget DW, Kerr GD, Hunt RH: Acid suppression in duodenal ulcer. Gut 28:1120-1128, 1987 Holm SA: A simple sequentially rejective multiple test procedure. Scand J Stat 6:65-70, 1979 Johnson NJ, Boyd EJS, Mills JG, Wood JR: Acute treatment of reflux oesophagitis: A multicentre trial to compare 150 mg ranitidine bd with 300 mg ranitidine qds. Aliment Pharmacol Ther 3:259-267, 1989 Merki HS, Halter F, Wilder-Smith CH, Allemann P, Witzel L, Kempf M, Roehmel JJ, Walt RP: The effect of food on H2-receptor blockade in normal subjects and duodenal ulcer patients. Gut 31:148-150, 1990 Gespach C, Emami S: Histamine H2-receptors and gastric cells. In Frontiers in Histamine Research. CR Ganellin, JC Schwartz (eds). Oxford, Pergamon Press, 1985, pp 265-274 Aadland E, Berstad A, Semb LS: Effect of cimetidine on pentagastrin-stimulated gastric secretion in healthy man. Scand J Gastroenterol 12:501-506, 1977 Konturek S J, Obtulowicz W, Kwiecien N, Kopp B, Oleksy J: Dynamics of gastric acid inhibition by ranitidine in duodenal ulcer patients. Digestion 22:119-125, 1988 Barbezat GO, Bank S: Effect of prolonged cimetidine therapy on gastric acid secretion. Gut 19:151-154, 1987 Aadland E, Berstad A: Effect of cimetidine on pentagastrinstimulated gastric acidity and pepsin secretion before and after 6 weeks of cimetidine treatment. Scand J Gastroenterol 13:193-197, 1978 Mihaly GW, Jones DB, Anderson JA, Smallwood RA, Louis WJ: Pharmacolginetic studies of cimetidine and ranitidine before and after treatment in peptic ulcer patients. Br J Clin Pharmacol 17:109-111, 1984 Lanzon-Miller S, Pounder RE, Hamilton MR, Chronos NAF, Ball S, Mercieca JE, Olausson M, Cederberg C: Digestive Diseases and Sciences, Vol. 35, No. 8 (August 1990)

TOLERANCE TO H2-RECEPTOR ANTAGONISTS

18.

19.

20.

21.

22.

23.

24.

25. 26. 27.

Twenty-four hour intragastric acidity and plasma gastrin concentration in healthy subjects and patients with duodenal or gastric ulcer, or pernicious anaemia. Aliment Pharmacol Ther 1:225-237, 1987 Lind T, Cederberg C, ForsseU H, Olausson M, Olbe L: Relationship between reduction of gastric acid secretion and plasma gastrin concentration during omeprazole treatment. Scand J Gastroenterol 23:1259-1266, 1988 Lanzon-Miller S, Pounder RE, Hamilton MR, Ball S, Chronos NAF, Raymond F, Olausson M, cederberg C: Twentyfour hour intragastric acidity and plasma gastrin concentration before and during treatment with either ranitidine or omeprazole. Aliment Pharmacol Ther 1:239-251, 1987 McGuigan J: Inhibition of Hydrogen-Potassium-stimulated adenosine triphosphatase: effects on acid secretion, plasma gastrin and the gastric mucosa. Gastroenterology 97:10451048, 1989 Stockbrugger R, Larsson LI, Lundqvist G, Angervall L: Antral gastrin cells and serum gastrin in achlorhydria. Scand J Gastroenterol 12:209-213, 1977 Koop H, Willemer S, Steinbach F, Eissele R, Tuch K, Arnold R: Influence of chronic drug-induced achlorhydria by substituted benzimidazoles on the endocrine stomach of rats. Gastroenterology 92:406-413, 1987 Arnold R, Hillse MV, Neuhof CH, Schwarting H, Becker HD, Creutzfeld EW: Antral gastrin-producing G-cells and somatostatin-producing D-cells in different states of gastric acid secretion. Gut 23:285-291, 1982 Bertaccini G, Coruzzi G: Regulation of receptors on parietal cells on acid secretion. Scand J Gastroenterol 23(suppl 146):22-33, 1988 Johnson LR: Regulation of gastrointestinal growth. World J Surg 3:477-487, 1979 Bertaccini G: Receptors involved in the regulation of gastric acid secretion. S Afr Med J 74:3-14, 1988 Burget DW, Chiverton SG, Hunt RH: Is there an optimal degree of acid suppression for healing duodenal ulcer? Gut (in press)

Digestive Diseases and Sciences, Vol. 35, No. 8 (August 1990)

APPENDIX

The

Box-Whisker-Plots

2 values further than 2 times the IQD

~

+

9

4-

2 4 _ from the 3rd quartile --

Value within 1.5 to 2 times the IQD from the 3rd quartile Value within 1 to 1.5 times the IQD from the 3rd quartile

Greatest value within one IQD from the 3rd quartile

- - 3rd quartile

It" 4

Average

4

Median

4

1st quartile

T

1

Interquartile distance (IQD)

Smallest value within one IQD from the 1st quartile Value within 1 to 1.5 times the IQD from the 1st quartile 92

4

i

9

2 values within 1,5 to 2 times the IQD from the 1st quartile One value further than 2 times the IQD from the 1st quartile

983