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Gut, 1991,32, 1455-1460 1455 Rebound intragastric hyperacidity after abrupt withdrawal ofhistamine H2 receptor blockade Gut: first published as 10.1136/gut.32.12.1455 on 1 December 1991. Downloaded from

C U Nwokolo, J T L Smith, A M Sawyerr, R E Pounder

Abstract an extensive research programme investigating In a series of 24 hour studies, intragastric the phenomenon of tolerance during continued acidity and plasma gastrin concentration were H2 blockade.'2 '4 measured simultaneously in 46 healthy sub- jects before, during, and 24 to 48 hours after abrupt withdrawal of a H2 receptor Methods antagonist regimen. For 34 days subjects were given either 800 mg at night (n=8), SUBJECTS AND DRUG REGIMENS 150 mg twice daily (n= 10), ranitidine Forty six of48 healthy men completed the study. 300 mg at night (n= 12), 300 mg at Their median age was 21 years (range 19 to 24 night (n=8), or 40 mg at night years), median weight was 74 kg (range 60 to 96 (n=8). All subjects responded to H2 blockade kg), and median height was 1'80 m (range 1.67 to by a decrease in 24 hour intragastric acidity. 1-93 m). Twenty four smoked cigarettes (4-20 Withdrawal ofH2 blockade resulted in a signifi- cigarettes per day). None had been dosed with an cant rise in median nocturnal integrated intra- antisecretory drug for at least eight weeks before gastric acidity in 42 of46 subjects (+36%; 95% entry to this study. CI +19, +55%) compared with prestudy This study was 'open label,' and all the H2 values, but this rise was not associated with a blockers were supplied by the pharmacy of the significant change in the median integrated Royal Free Hospital, London. plasma gastrin concentration (+1%; 95% CI The subjects received no antisecretory drug -12, +13%). A statistically significant rise during the first 24 hour simultaneous study of in nocturnal acidity was observed after all intragastric acidity and plasma gastrin concen- regimens, except after dosing with famotidine. tration. They were then randomly assigned to After stopping, median daytime integrated receive one ofthe following regimens: cimetidine acidity and plasma gastrin concentrations in 800 mg at night (Smith Kline & French Labora- the whole group were raised, but not signifi- tories Ltd, n=8),'2 either ranitidine 300 mg at http://gut.bmj.com/ cantly: values were +15% (95% CI +4, +34%) night (n=12) or ranitidine 150 mg twice daily and +5% (95% CI -2, +12%), respectively. A (n= 10) (Glaxo Laboratories Ltd); nizatidine 300 statistically significant increase in daytime mg at night (n=8) (Eli Lilly and Co Ltd),'2 or acidity was observed only after dosing with famotidine 40 mg at night (n=8) (Thomas ranitidine. In conclusion, intragastric hyper- Morson Pharmaceuticals). 12 The experiments acidity occurs in most subjects after abrupt involving cimetidine, nizatidine, and famotidine withdrawal of a blocker, were extensions of previously published studies on September 29, 2021 by guest. Protected copyright. but this phenomenon is not associated with investigating 'tolerance,' but the ranitidine hypergastrinaemia. experiments were not part of the earlier 'tolerance' experiments. 12 The subjects were dosed with an H2 receptor antagonist for 34 days, When the histamine H2 receptor antagonists and 24 hour profiles of intragastric acidity and were introduced for the management of peptic plasma gastrin concentration were measured for ulceration, there was concern that they would assessment of antisecretory activity on day 29 of induce a surge of gastric acid secretion in the dosing. The final 24 hour study of acidity and days or weeks after their withdrawal.' Experi- plasma gastrin concentration was begun 24 hours ments were performed to explore this possibility, after the last oral dose ofeach H2 blocker. but most reported that no rebound hypersecre- tion could be detected.2"'A It came as a surprise when Fullarton et al" EXPERIMENTAL DESIGN reported rebound nocturnal hypersecretion of The subjects were studied using the Royal Fzee acid occurring after four weeks of treatment with Hospital protocol,'2"' with minor changes as University Department of nizatidine mg at a Medicine, Royal Free 300 night. They found, in specified below. The subjects began fasting at Hospital School of group of eight duodenal ulcer patients, that 1330 hours, and were provided with a standard Medicine, London mean nocturnal acid output was 39.4 mmol/10 light supper at 1815 hours. They had nothing to C U Nwokolo hours before treatment, but rose significantly to eat or drink until 2130 hours, when a 10 FG J T L Smith A M Sawyerr 74-1 mmol/10 hours when measured two days Salem Sump nasogastric tube (Argyle Medical, R E Pounder after stopping. They observed no significant Crawley, West Sussex) was positioned in the Correspondence to: change in daytime intragastric acidity. stomach; its position was checked by a water Dr R E Pounder, University Department of Medicine, The object of this series of experiments was to recovery test. Aliquots (5-10 ml) of intragastric Royal Free Hospital School of measure 24 hour intragastric acidity and plasma contents were aspirated hourly throughout the Medicine, Pond Street, London NW3 2QG. gastrin concentration before, during, and after study, and the pH of each aliquot was measured Accepted for publication five different regimens. These immediately to the nearest 0.01 pH unit by 18 March 1991 experiments were performed in conjunction with means of a glass electrode and digital pH meter 1456 Nwokolo, Smith, Sawyerr, Pounder

LU r , Day 0 Gut: first published as 10.1136/gut.32.12.1455 on 1 December 1991. Downloaded from 1001 N N Day 29 Day 36 801F Day 36 0 E E 60 V

ci Figure 1: 24 hour median 401F hourly intragastric acidity before dosing (), on day 29 ofdosing (-4--), and 24 20 hours after stopping cimetidine 800 mg at night (0 ), in eight healthy 5 a a a a 9 a a a a A a a a a a a a a a subjects. N=nightcap, B= 0 breakfast, C=coffee, L= 23 24 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 lunch, T=tea, D=dinner. Time (hours)

120 Day 0 0 100 Day 29

Day 36 80 ...... 0E E 60

40

Figure 2: 24 hour median 20 hourly acidity before dosing (-0-), on day 29 ofdosing (-4-), and 24 hours after 0 stopping ranitidine 150 mg http://gut.bmj.com/ twice daily( a , in 10 23 24 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 healthy subjects. Time (hours)

120 Day 0

Day 29 on September 29, 2021 by guest. Protected copyright. Day 36 ...... * ....

0 E E E

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Figure 3: 24 hour median hourly intragastric acidity before dosing (-0-), on day 29 ofdosing (-4), and 24 hours after stopping - ranitidine 300 mg at night (* a), in 12 healthy 23 24 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 subjects. Time (hours)

(Radiometer, Copenhagen). The electrode was Newbury). The tubes were centrifuged immedi- calibrated with standard buffers (pH 7-00, 4.01, ately, and the plasma transferred to plastic tubes and 1.09; Radiometer, Copenhagen) before and and frozen to -20°C. All the plasma samples after every six samples in each hourly batch of from each subject were analysed for gastrin in aspirates. one batch, by radioimmunoassay using the anti- Every hour from 2300 hours to 2300 hours the body GAS 179 in Professor Bloom's laboratory next day (apart from 0100, 0300, 0500, and 0700 at the Royal Postgraduate Medical School hours) blood was taken via a venous cannula for London. 16 assay of the plasma gastrin concentration. The The subjects were fully ambulant around the blood was collected in lithium heparin tubes ward during the study. The food and environ- which contained 0-2 ml aprotinin (Bayer UK Ltd, mental conditions for all studies were identical to Rebound intragastric hyperacidity after abrupt withdrawal ofhistamine H2 receptor blockade 1457

120 Day 0 Gut: first published as 10.1136/gut.32.12.1455 on 1 December 1991. Downloaded from 100 N A B Day 29 I Day 36 <80 l

60

< 40

Figure 4: 24 hour median 20 hourly intragastnc acidity before dosing (-4-), on day 29 ofdosing (-4), and 24 hours after stopping 0 * nizatidine 300mg at night 23 24 1 2 3 4 5 6 7 8 9 10 (- ),ineight healthy subjects. Time (hours)

120 _ Day 0 0 100oo N B C L T D N Day 29

Day 36 80 ...... * ..

0 E E 60

: a U 40 V Figure 5: 24 hour median hourly intragastric acidity 20 h before dosing (-4-), on day 29 ofdosing (@--), and 24 http://gut.bmj.com/ hours after stopping 0 famotidine 40 mg at night (* a), in eight healthy 23 24 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 subjects. Time (hours)

those used in earlier experiments at the Royal ing dose of ranitidine 150 mg was taken by one Free Hospital.'5 The standard meals (bedtime group at 0830 hours.

snack, breakfast, coffee, lunch, tea and dinner) on September 29, 2021 by guest. Protected copyright. were eaten at 2245, 0815, 1045, 1315, 1545, and 1815 hours, respectively. The bedtime doses of STATISTICAL ANALYSES medication were taken at 2305 hours; the morn- Profiles ofintragastric acidity and plasma gastrin concentration and were obtained for each sub- TABLE I Median integrated nocturnal (2400-0800 hours) intragastric acidity (mmol.hll) in 46 healthy subjects before, during, and after dosing with an H2 antagonist regimen ject. The area under the curve for each profile was calculated by the trapezoid rule, with inte- Cimetidine Ranitidine Ranitidine Nizatidine Famotidine grated acidity expressed as mmol.h/l and plasma (800 mg, (150 mg, (300 mg, (300 mg, (40 mg, nocte) bd) nocte) nocte) nocte) gastrin concentration as pmol.h/l. Values of integrated acidity and plasma gastrin concentra- tion were calculated for the night time (0000 to No 8 10 12 8 8 Value before dosing (day 0) 610 490 472 478 508 0800 hours), and daytime (0900 to 2300 hours). During dosing (day 29) 112t 153t 33t 50t 133t The significance ofobserved differences between (-82%) (-69%) (-93%) (-90%) (-74%) After dosing (day 36) 666* 700t 790t 614* 561 groups was assessed using the Wilcoxon matched (+9%) (+43%) (+67%) (+28%) (+ 10%) pair signed rank test. All statistical calculations were made using the Oxstat program (Walling- p value compared with before dosing *=0.05; t=0-01 (Wilcoxon rank sum test). ford Computing Services, Wallingford). TABLE II Median integrated daytime (0900-2300 hours) intragastric acidity (mmol.hll) in 46 healthy subjects before, during, and after dosing with an H2 antagonist regimen ETHICAL AND SAFETY ISSUES Cimetidine Ranitidine Ranitidine Nizatidine Famotidine (800 mg, (150 mg, (300 mg, (300 mg, (40 mg, The studies were approved by the Ethics Com- nocte) bd) nocte) nocte) nocte) mittee of the Royal Free Hospital, and written consent was obtained from each subject. Routine No 8 10 12 8 8 laboratory safety studies were performed before Value before dosing (day 0) 371 236 410 369 389 and after During dosing (day 29) 356 210 375* 353* 263 each study. (-4%) (- 1 1%) (-9%) (-4%) (-32%) After dosing (day 36) 364 475t 526t 420 426 (-2%) (+ 101%) (+28%) (+13%) (+ 10%) Results p value compared with before dosing *=0.05; t=0 01 (Wilcoxon rank sum test). Forty six subjects tolerated all the experiments 1458 Nwokolo, Smith, Sawyerr, Pounder

20 4 J '205 0426 0205 5 252 : Ranitidine 300 mg at bedtime (n = 12) a j a . 0 0 0 Ranitidine 150 mg twice daily (n - Gut: first published as 10.1136/gut.32.12.1455 on 1 December 1991. Downloaded from Figure 6: Changes in 1 0) integrated nocturnal acidity compared with changes in 1501- In p a Cimetidine 800 mg at bedtime (n = 8) integrated nocturnal plasma gastrin concentration (2400- A Nizatidine 300 mg at bedtime (n = 8) a) 0800 hours) in 46 healthy Ll 0 03 -8) subjects dosed with an H2 0 2431 Famotidine 40 mg at bedtime (n = antagonistfor 35 days. The innu L acidity or plasma gastrin 1- concentration after dosing is 50~~~~~~o expressed as a percentage of the value before dosing 5 (cimetidine 800 mg at night= l; ranitidine 150 mg twice daily=@; ranitidine 300 mg at night=O; nizatidine 300 mg at night= A;famotidine 40 mg at 0 50 100 150 20 night=-). Gastrin (% of predosing)

2C 30* 0306 1 Ranitidine 300 mg at bedtime (n = = 12) 308 :6234 Figure 7: Changes in * Ranitidine 150 mg twice daily (n - = 10) integrated daytime acidity CD 1 )0 _ . A Cimetidine 800 mg at bedtime )n = 8) compared with changes in C: ecn .~~~~0 integrated nocturnal plasma 0 10~~~~~~~~~~~~ A Nizatidine 300 mg at bedtime = 8) gastrin concentration (0900- (n a) o 2300 hours) in 46 healthy 0.. so * Famotidine 40 mg at bedtime (n = = 8) subjects dosed with an H2 0 o0 D antagonistfor 35 days. The 1C 0~~~~~~~~~~~ ~0 acidity or plasma gastrin -0 concentration is after dosing :L, expressed as a percentage of 50 O the value before dosing Q (cimetidine 800 mg at night=-; ranitidine 150 mg twice daily=-; ranitidine 300 mg at night=O; nizatidine 300 mg at night= 0 A;famotidine 40 mg at U 50 100 150 200 night=-). Gastrin (% of predosing) http://gut.bmj.com/

without any adverse event, but two subjects PLASMA GASTRIN CONCENTRATION allocated to receive ranitidine 150 mg twice daily Compared with values before dosing, the 24 hour were withdrawn from the study (one had tonsil- profiles of plasma gastrin concentration were litis and the other family commitments which raised during dosing with all of the antisecretory

precluded continuation in the study). Bio- drug regimens,'2 but there was no significant on September 29, 2021 by guest. Protected copyright. chemical and haematological profiles were change in the median integrated plasma gastrin normal before and after the experiments. Full concentration during the 24 hours after stopping compliance was reported by all the subjects. the drugs. The individual data points for all 46 subjects, correlating changes in either nocturnal or 24 HOUR INTRAGASTRIC ACIDITY daytime integrated intragastric acidity with Figures 1 to 5 show the profiles of 24 hour integrated plasma gastrin concentration after median hourly intragastric acidity for the five withdrawal ofH2 blockade, are shown in Figures different regimens of H2 blockade before, 6 and 7. Figure 6 shows that, compared with during, and immediately after abrupt with- before dosing, the rise (median +36%, 95% CI drawal of the antisecretory drugs. Compared +19, +55%) in nocturnal intragastric acidity, with values before dosing, each of the five H2 observed in 42 ofthe 46 subjects after withdrawal blocker regimens was associated with a signifi- of dosing with an H2 blocker regimen, was not cant decrease in median daytime acidity during associated with a significant change in the plasma dosing, and four of the five regimens were gastrin concentration (median + 1%; 95% CI followed by a significant rise in median inte- - 12, + 13%). Figure 7 shows that daytime grated nocturnal intragastric acidity after dosing acidity was increased in 33 of the 46 subjects (Table I). Analysis of variance could detect no (median + 15%; 95% CI +4, + 34%), but that the significant difference in the change in nocturnal integrated plasma gastrin concentration was intragastric acidity (expressed as a percentage of unchanged (median +5%; 95% CI -2, + 12%). pretreatment acidity) between the five H2 antagonist regimens. Two of the five regimens were associated with a significant rise in median integrated intragastric acidity during the day- Discussion time 34 to 48 hours after the last dose of an H2 The results of these studies confirm and extend antagonist (Table II), but analysis of variance Fullarton and colleagues' original report of detected no significant difference between the rebound nocturnal hyperacidity": increased groups. nocturnal intragastric acidity does occur after Rebound intragastric hyperacidity afterabrupt withdrawal ofhistamine H2 receptor blockade 1459

abruptly stopping short acting histamine H2 output increased from 1F2 to 2 8 mmollhour, and receptor antagonists. acid output during maximal In retrospect, why was it generally thought infusion increased from 36&9 to 44 2 mmollhour. Gut: first published as 10.1136/gut.32.12.1455 on 1 December 1991. Downloaded from that H2 blockers do not induce hypersecretion of The antisecretory effect of intravenous raniti- acid?8 Some experiments were performed before dine given after impromidine was also enhanced the expected complete plasma elimination of the at the end of treatment. Thus, the hyper- H2 antagonist, and others were completed some secretory response could be a result of 'up weeks after withdrawal of treatment'-7 9 10; almost regulation,' whether by increased number, all the original experiments examined maximal affinity, or activity (in coupling to adenylate acid secretion, stimulated by either histamine or cyclase) ofthe H2 receptors. pentagastrin. It is now clear that measurement of Fullarton et al suggested that rebound hyper- nocturnal intragastric acidity represents the pro- acidity could be one explanation for recurrent longed observation of 'spontaneous' gastric peptic ulceration after withdrawal of H2 block- function, unaffected by meals or outside stimuli. ade." Recent experiments at the Royal Free Reliable studies ofbasal gastric acid secretion are Hospital have shown that the phenomenon of exceptionally difficult,"7 but remarkable repro- nocturnal hyperacidity exists for only six days ducibility can be achieved in studies of after 25 days of dosing with ranitidine 300 mg at nocturnal intragastric acidity.'3 This sensitivity night - from days 9-21 after dosing there is no has allowed the detection of rebound hyper- significant change in intragastric acidity, com- acidity, and similarly the detection of nocturnal pared with values before dosing.23 tolerance to H2 blockade.214 18 19 Miss Doris Elliott prepared this manuscript. The study was The mechanism of nocturnal rebound hyper- supported by grants from Glaxo Group Research Limited. acidity remains unclear. A drug induced Enthusiastic technical assistance was provided by Nurse J Sercombe and the following clinical medical students: P Peyser, decrease in intragastric acidity induces a rise in J Tuckley, J Greening, A Emmanuel, A Muir, J Ablett, L Pallis, the plasma gastrin concentration,20 and it is H Reid, H Seymour. possible that continued H2 blockade could 1 Saunders JHB, Wormsley KG. Long-term effects and after- induce proliferation of G cells or sustained effects of treatment of duodenal ulcer with . hypergastrinaemia. The present studies show Lancet 1977; i: 765-7. 2 Crean GP, Holden RJ, MacKenzie I, Hearns JR. The effects of that when the phenomenon of rebound hyper- 6 weeks' administration of cimetidine on gastric acid acidity is occurring, plasma gastrin concentra- secretion. In: Burland WL, Simkins MA, eds. Cimetidine: Proceedings of the Second International symposium on tions have returned to the values before dosing. Histamine H2-Receptor Antagonists. Amsterdam: Excerpta Hence, rebound hyperacidity is not the result of Medica, 1977: 217-23. - 3 Gillespie G, Gray GR, Smith IS, et al. Short-term and hypergastrinaemia but it could be argued that maintenance cimetidine treatment in severe duodenal the concentration of gastrin remains 'inappro- ulceration. In: Burland WL, Simkins MA, eds. Cimetidine: Proceedings of the Second International Symposium on priately' high, as it is not decreased at a time Histamine H2-Receptor Antagonists. Amsterdam: Excerpta http://gut.bmj.com/ when intragastric acidity is increased.20 It is Medica, 1977: 240-7. 4 Hetzel DJ, Hansky J, Shearman DJC, et al. Cimetidine possible therefore that part of the phenomenon treatment of duodenal ulcer: short-term clinical trial and of rebound acid hypersecretion results from a maintenance study. Gastroenterology 1978; 74 (suppl): 389- 92. persisting drug induced change in gastrin 5 Binder HJ, Cocco A, Crossley RJ, et al. Cimetidine versus release. intensive antacid therapy for duodenal ulcer: a multicentre trial. Gastroenterology 1978; 74 (suppl): 380-8. The original experiments, using pentagastrin 6 Domschke W, Domschke S, Demling L. A double-blind

or histamine tests to measure maximal acid study of cimetidine in patients with duodenal ulceration: on September 29, 2021 by guest. Protected copyright. clinical, kinetic and gastric and pancreatic secretory data. In: output,2`79 ' showed that there is no increase in Burland WL, Simkins MA, eds. Cimetidine: Proceedings of parietal cell mass after short term treatment with the Second International Symposium on Histamine H2-Receptor a that Antagonists. Amsterdam: Excerpta Medica, 1977: 217-23. an H2 blocker. It remains possibility 7 Sewing KF, Hagie L, Ippoliti AF, et al. Effect of one-month prolonged pharmacological control of gastric treatment with cimetidine on gastric secretion and serum gastrin and pepsinogen levels. Gastroenterology 1978; 74 acid secretion results in an overactivity of, or (suppl): 376-9. increased sensitivity to, vagal drive. It will be 8 Winship DH. Cimetidine in the treatment of duodenal ulcer. in man that Gastroenterology 1978; 74: 402-6. very difficult to devise experiments 9 Brown P, Ceravolo C, Zambelli A. Rebound rise in gastric acid can either prove or disprove whether rebound secretion: study of cimetidine vs trithiozine: a preliminary to report. Curr Ther Res 1978; 23: 706-8. hypersecretion is due vagal drive. 10 Bodemar G, Walan A. Maintenance treatment of recurrent An alternative mechanism to explain the peptic ulcer by cimetidine. Lancet 1978; i: 403-7. withdrawal 11 Fullarton GM, McLaughlan G, MacDonald A, Crean GP, rebound hypersecretion of acid after McColl KEL. Rebound nocturnal hypersecretion after four of an H2 antagonist is that H2 receptors become weeks treatment with an H2 receptor antagonist. Gut 1989; treat- 30: 449-54. more sensitive, or 'up regulated' during 12 Nwokolo CU, Smith JTL, Gavey C, Sawyerr A, Pounder RE. ment. Aadland and Berstad21 showed that the Tolerance during 29 days of conventional dosing with to a low dose of cimetidine, nizatidine, famotidine or ranitidine. Aliment mean acid output in response Pharmacol Therap 1990; 4 (suppl): 29-45. intravenous histamine increased from 6 7 to 10 1 13 Smith JTL, Nwokolo CU, Gavey C, Pounder RE. Tolerance and 60-84 during eight days of high-dose H2-blockade: placebo- mmol/hour, when measured before controlled studies of 24 hour acidity and gastrin. Aliment hours after stopping four weeks of treatment Pharmacol Therap 1990; 4 (suppl): 47-63. The acid 14 Nwokolo CU, Sawyerr A, Smith JTL, Pounder RE. Intra- with cimetidine 1 g/day. output venous pentagastrin can induce tolerance to H2-blockade in measured one to four weeks later had returned to man. AlimentPharmacol Therap 1990; 4 (suppl): 75-83. 15 Lanzon-Miller 5, Pounder RE, Hamilton MR, Chronos NAF, pretreatment values. This response is consistent Ball 5, Mercicca JE, et al. Twenty-four hour intragastric with augmented parietal cell sensitivity to hista- acidity and plasma gastrin concentration in healthy subjects and patients with duodenal or gastric ulcer or pernicious mine stimulation. Jones et a122 assessed the anaemia. AlimentPharmacol Therap 1987; 1: 225-37. sensitivity of the H2 receptor using impromi- 16 Bryant MG, Adrian TE. Gastrin. In: Bloom SR, Long RG, eds. Radioimmunoassay of gut regulatory peptides. London: dine, a specific H2 agonist, before and after a Saunders, 1982: 51-9. three month course ofranitidine 150mg at night. 17 Sharms B, Axelson M, Pounder RE, et al. Acid secretory capacity and plasma gastrin concentration after administra- Six duodenal ulcer patients were studied 10 tion of to normal subjects. Aliment Pharmnacol hours after the last dose of ranitidine: basal acid Therap 1987; 1: 67-76. 1460 Nwokolo, Smith, Sawyerr, Pounder

18 Wilder-Smith CH, Ernst T, Gennoni, M, Zeyen B, Varoa L, 21 Aadland E, Berstad A. Parietal and chief cell sensitivity to Roehmel 0, et al Loss of acid suppression dosing with H2- histamine and pentagastrin stimulation before and after receptor antagonists. Aliment Pharmnacol Therap 1989; 4 cimetidine treatment in healthy subjects. Scand J (suppi 1): 15-28. Gastroenterol 1979; 14: 933-8. Gut: first published as 10.1136/gut.32.12.1455 on 1 December 1991. Downloaded from 19 Rogers MJ, Primrose JN, Holmfield H, Johnston D. The 22 Jones DB, Howden CW, Burget DW, Silletti C, Hunt RH. effects of 15 days of dosing with placebo, 600 mg Alteration of H2-receptor sensitivity in duodenal ulcer noctre, or sufotidine 600 mg twice daily, on 24-hour patients after maintenance treatment with an H2-receptor intragastric acidity and 24-hour plasma gastrin. Aliment antagonist. Gut 1988; 29: 890-3. Pharmacol Therap 1990; 4 (suppl 1): 65-74. 23 Prewett EJ, Hudson M, Nwokolo CU, Sawyerr AM, Pounder 20 Pounder RE, Smith JTL. Drug-induced changes of plasma RE. Nocturnal intragastric acidity during and after a period gastrin concentration. Gastroenterology Clin North Am 1990; of dosing with either ranitidine or omeprazole. Gastro- 19: 141-53. enterology 1991; 100: 873-7. http://gut.bmj.com/ on September 29, 2021 by guest. Protected copyright.