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Gut: first published as 10.1136/gut.24.1.61 on 1 January 1983. Downloaded from

Gut, 1983, 24, 61-66

Effects of eight weeks' continuous treatment with oral ranitidine and on gastric secretion, pepsin secretion, and fasting serum

R MOHAMMED, R J HOLDEN, J B HEARNS, B M McKIBBEN, K D BUCHANAN, and G P CREAN From the Gastro-Intestinal Centre, Southern General Hospital, Glasgow, and University Department of Medicine, Queen's University, Belfast

SUMMARY secretion, pepsin secretion, and fasting serum gastrin levels were measured in 23 patients with duodenal ulcer disease, divided into three groups which received either cimetidine 800 mg daily, cimetidine 1600 mg daily, or ranitidine hydrochloride 300 mg daily for eight weeks. tests were carried out at intervals both before and after treatment. Each dose of cimetidine reduced acid secretion to 42% of control one week after starting therapy. Ranitidine reduced acid secretion to 33% of the pretreatment value. Acid secretion remained suppressed to these levels throughout treatment with each drug. Acid secretion returned to pretreatment levels in all patients one week after treatment and remained normal until the end of the study. Both drugs reduced pepsin, which fell to 64% and 61% (p

groups till the end of treatment. Pepsin levels fell to 50% at two weeks of therapy with ranitidine http://gut.bmj.com/ but stabilised at this level till the end of therapy. Cimetidine withdrawal was followed by a return towards pretreatment levels of pepsin secretion; but secretion remained significantly depressed (p<0.05) to the end of the study period. In the ranitidine-treated patients pepsin output returned to normal after drug withdrawal. Fasting gastrin levels rose during treatment with both drugs but failed to reach significant levels. After withdrawal of treatment fasting serum gastrin levels returned to normal in all three groups of patients. on September 30, 2021 by guest. Protected copyright.

The gastric acid inhibitory properties of cimetidine a H2-receptor antagonist, have been are well known.1 2 Ranitidine hydrochloride is a reported to produce hyperplasia and new histamine H2-receptor antagonist which is gastric hypersecretion in rats.10 Cimetidine, in very structurally different from cimetidine and is large doses (150 mg/kg-950 mg/kg) for up to two reported to be several times more potent on a molar years, appears to induce an increase in the surface basis.3 4 Although the half life of these drugs is area of the , with consequential increases in short,5 6 each is capable of reducing gastric pH to the volume (mass) of the fundic mucosa, and in the low levels for long periods over 24 hours during total parietal cell population. These effects are treatment with usual therapeutic doses.7 relatively trivial and are dissimilar to the effects Substantial suppression of acid secretion could induced by gastrin: the mechanism is unknown.11 theoretically result in sustained hypergastrinaemia The present investigation was carried out in an and subsequent acid hypersecretion. attempt to discover whether such effects could be Gastrin induces parietal cell hyperplasia in experi- identified in subjects with duodenal ulcer disease mental animals9 and very large doses of , treated for a two month period with two different doses of cimetidine and with the likely therapeutic Received for publication 26 March 1982 dose of ranitidine. 61 Gut: first published as 10.1136/gut.24.1.61 on 1 January 1983. Downloaded from

62 Mohammed, Holden, Hearns, McKibben, Buchanan, and Crean Methods Results

PATIENTS ACID SECRETION (Figs 1 and 2) Twenty-three patients with duodenal ulcer disease In all three groups there was a highly significant fall participated in the study, each giving informed in acid output after one week of treatment as consent. Six patients were treated with 800 mg compared with control values (p<0.001), the acid cimetidine daily (group 1); six were treated with falling to 42% of control in both cimetidine groups 1600 mg cimetidine daily (group 2); and 11 received and to 33% in the ranitidine group. The acid output 300 mg ranitidine daily (group 3). Cimetidine was remained suppressed at this level throughout the prescribed in doses 200 mg and 400 mg to be taken remainder of the treatment period. After drug after meals and before retiring to bed and ranitidine withdrawal acid output returned towards normal in was prescribed in a dose of 150 mg at breakfast and all three groups, the acid output reaching 83% and with the evening meal. 72% in the cimetidine groups and 93% in the After the injection of pentagastrin 6 ug/kg intra- ranitidine group. The acid output values after muscularly four 15 minute collections of gastric treatment did not differ significantly from control secretions were made (MAO). These gastric values in any group studied. secretion studies were performed before treatment began (control test) and on day 7, 14, 28, and 56 of treatment (designated treatment weeks 1, 2, 4, and 8) and on day 7, 14, and 28 after treatment with 150 1 cimetidine was stopped (post-treatment weeks 1, 2, Em and 4) and on day 7, 14, 28, and 56 after ranitidine e- was stopped (post-treatment weeks 1, 2, 4, and 8). C 100 On the days that secretion tests were performed 9 during the treatment period, the first dose of 0~ E cimetidine and ranitidine was taken 60 minutes 3 before gastric aspiration started. 'Oh 50 r-0 28 From each collection of gastric juice 5 ml were _ http://gut.bmj.com/ titrated for hydrogen ion concentration against 0.1 40 N sodium hydroxide and acid secretion expressed as the output of HCI (concn x volume) in the hour 2 after pentagastrin. A 10 ml aliquot was deep frozen 30 - _ E at -18°C for subsequent pepsin analysis by Piper's E method. 12 The results were expressed as milli- a3 grammes of sigma pepsin standard (1 mg=450 IU) 20- on September 30, 2021 by guest. Protected copyright. in the hour after pentagastrin. 30 In patients treated with ranitidine a single blood u E sample was taken 90 minutes after the ingestion of E 10 the morning dose, heparinised and stored at -20°C x for subsequent plasma ranitidine estimation. I Blood was also withdrawn for fasting serum gastrin levels on each test occasion before gastric Control l 2 4 8 1 2 4 aspiration was begun. These blood samples were Weeks on cimetidine Weeks post-cimetidine stored at -20°C until transported to Belfast for Time (weeks) gastrin estimation by radioimmunoassay. The assay Fig. 1 Serum gastrin levels (pglml) and acid output was performed using R98, which showed (mmoi/h) - ordinate. Control week, weeks during, and cross-reactivity (1:10 000) on a weight basis with weeks after therapy - abscissa. Points show the -pancreozymin and no cross- mean ± SEM. Results combinedfor group I (800 mg reactivity with other gastrointestinal . The cimetidine) and group 11(1600 mg cimetidine) daily assay has a lower limit of detection of 5 picograms (n=12). Last dose taken one hour before test. P values: the per ml.13 value at each test during the treatmentperiod was significantly lower than the control test (p<0.01). There Statistical analysis was carried out using analysis were no significant differences among the valuesfound of variance and Page's L test and differences during the treatment period, the control test compared with between weeks in the experiment assessed by the any post-treatment test, nor among any ofthe post-treatment Wilcoxon signed rank test. tests. Gut: first published as 10.1136/gut.24.1.61 on 1 January 1983. Downloaded from

Effects of eight weeks' continuous treatment with oral ranitidine and cimetidine 63

150 - output fell significantly to 65% of the control value after one week of treatment (p<0.005). There was a further significant fall to 50% of the control level at .c 100 a week 2 of treatment; the values stabilising thereafter at this level for the 0 remainder of the treatment S period. After ranitidine E withdrawal, unlike the 0 50- cimetidine-treated patients, there was a prompt rise u' i, in pepsin output to levels not significantly different from that of control.

FASTING SERUM GASTRIN (groups 1, 2, and 3) The changes in serum gastrin are shown in Figs 1 30 and 2. The values during treatment with cimetidine

E show a slight rise in both groups; these changes did not, however, attain statistical significance. Similarly, in patients given ranitidine there was a 20 rise in fasting serum gastrin levels during treatment which also failed to reach statistical significance. After withdrawal of cimetidine and ranitidine, fasting serum gastrin levels fell towards normal in all three groups. No correlation was found to exist between serum gastrin and acid secretion before, 0 during, or after therapy with either drug. Control 1 2 4 8 1 2 4 8

Weeks on ranitidine Weeks post - ranitidine Time (weeks, PLASMA DRUG LEVELS The mean ranitidine levels during the treatment Fig. 2 Serum gastrin levels (pglml) and acid output period (taken 90 minutes after the oral dose of the (mmollh) - ordinate. Control week, weeks during, and drug) were 399 ng/ml (±58), 467 ng/ml (±53), 466 weeks after therapy - abscissa. Points show the ng/ml (±61), and 287 ng/ml (±73) at weeks 1, 2, 4, http://gut.bmj.com/ mean ± SEM. Group II (300 mg ranitidine) daily (n=11). and 8 of treatment respectively. Last dose taken one hour before test. P values: the value at each test during the treatmentperiod was significantly lower than the control test (p

provides a reproducible test of the maximal on September 30, 2021 by guest. Protected copyright. secretory capacity of the stomach, which is indis- tinguishable from the response obtained with 40 PEPSIN SECRETION (Fig. 3) ,ug/kg histamine.'4 15 The simplicity and repro- In the two cimetidine-treated groups there was a ducibility of the test makes it an ideal method for significant fall in pepsin output after one week of monitoring drug effects on gastric acid secretion. treatment (p<0.01) to 64% and 61% in group 1 and Acid output of the stomach was reduced by group 2 respectively. Pepsin output remained at this approximately 60% after one week of treatment level for the rest of the treatment period, so that with 800 mg or 1600 mg cimetidine daily and by 70% none of the values obtained during treatment after one week of treatment with ranitidine. Acid differed significantly from each other, although all secretion was maintained at this reduced level values were significantly less than the control output throughout treatment, with no suggestion that acid (p

64 Mohammed, Holden, Hearns, McKibben, Buchanan, and Crean

2000 U Cimetidine 800 mg C0 Cimetidine 1600 mg 0 Ranitidine 300 mg W 1500 C 0 E4,

.CF 1000 E

500

0.

Control 1 2 4 8 1 2 4 8 Weeks on drug therapy Weeks post-drug therapy Fig. 3 Pepsin output (mglh) - ordinate. Control week, weeks during, and weeks after therapy - abscissa. Points show mean ± SEM (groups I, II, III). P values: (groups I and II). The value at each test during the treatmentperiod was significantly lower than the control testfor both groups (p

return after therapy with either drug. The results are after therapy. This was in contrast with patients on September 30, 2021 by guest. Protected copyright. in keeping with previous studies which showed no treated with ranitidine in whom there was an change from control values of basal and pentagastrin apparent hypersecretion of pepsin after drug with- stimulated secretion tested after four and eight drawal, although none of the post-treatment values weeks of treatment,'7 16 but differ from a further differed significantly from control. It has been study in which acid output was stimulated by suggested that pepsin secretion falls with duodenal histamine infusion.'8 This showed a 23% reduction ulcer healing,2 but with pepsin levels returning in stimulated acid secretion after three months' promptly to normal after ranitidine treatment this treatment with cimetidine, but acid secretion was cannot be the complete answer for the effect tested at variable intervals after treatment ended. observed in patients given cimetidine. The difference between this study and the present Fasting serum gastrin levels showed no significant results could be due to any of several factors, changes during cimetidine or ranitidine therapy in including the differences in the stimulant, the this study, which is in keeping with other studies.21 duration of treatment, the timing of tests after drug 23 In themselves, these results are not surprising withdrawal, or a combination of these factors. because, while histamine H2-receptor antagonists Rebound hypersecretion, however, has never been clearly reduce gastric acidity, mere alkalinisation of described. the stomach may not stimulate gastrin release.24 The Although pepsin output was reduced during alkaline antrum, however, may be more sensitive to treatment with cimetidine and ranitidine the effects stimulation by other factors, particularly , of pepsin secretion were much less pronounced, a which accounts for the disproportinate rise in serum feature which has been noted in previous studies. 1 19 gastrin obtained by food stimulation during Gut: first published as 10.1136/gut.24.1.61 on 1 January 1983. Downloaded from

Effects of eight weeks' continuous treatment with oral ranitidine and cimetidine 65 treatment with metiamide or cimetidine.5 26 In Simkins MA, eds. Cimetidine: proceedings of the other studies, however, no changes in the serum second international symposium on histamine H2- gastrin response to food have been obtained,18 22 receptor antagonists. Amsterdam: Excerpta Medica, differences which have probably depended upon 1977: 38-51. or antral 6 Woodings EP, Dixon GT, Harrison C, Carey P, whether not pH was controlled during the Richards DA. Ranitidine. A new H2-receptor experiment. In addition, fasting gastrin levels antagonist. Gut 1980; 21: 187-91. largely comprise high molecular weight species 7 Pounder RE, Williams JG, Milton-Thompson GJ, which have dubious biological significance, and have Misiewicz JJ. 24 Hour control of intra gastric acidity by relatively low amounts of G34 and G17, the more cimetidine in duodenal ulcer patients. Lancet 1975; 2: biologically active molecules. Response to feeding 1069-72. would have given a more exact assessment of the 8 Damman HG, Kather H, Augustin HJ, Simon B. gastrin status.28 Investigations on the length of action of ranitidine. The levels of plasma ranitidine obtained in this Dtsch Med Wochenschr 1980; 105: 603-5. study were found to be well within the 9 Crean GP, Marshall MW, Rumsey RD. Parietal cell therapeutic hyperplasia induced by the administration of penta- range27 suggesting that 300 mg oral ranitidine daily gastrin. Gastroenterology 1969; 57: 147-55. is likely to be adequate for the treatment of 10 Halter F, Witzel L. Increased acid secretion after duodenal ulceration. sustained metiamide medication in the rat. Gastro- It would appear that 300 mg ranitidine hydro- enterology 1977; 72: A6/816. chloride, in twice daily dose, has a very similar effect 11 Crean GP, Daniel D, Leslie GB, Bates C. The effects to that of 800 mg or 1600 mg cimetidine in terms of of prolonged administration of large doses of acid and pepsin secretion in patients with duodenal cimetidine on the of rats. In: Wastell C, ulcer disease without affecting gastrin levels. This Lance P, eds. Cimetidine: The Westminster Hospital suggests that the two drugs are likely to be very Symposium. Edinburgh: Churchill Livingstone, 1978: 191-205. similar in their clinical effect. 12 Piper BW. The estimation of peptic activity in gastric juice using radio-iodinated serum albumin as . We thank Dr J Bem and Dr R of Glaxo Gastroenterology 1960; 38: 616. Group Research Ltd, for the supply of drugs and 13 Ardill JES. The measurement of gastrin by radio- Mrs Mary McDougall for secretarial assistance. immunoassay. Queen's University, Belfast: Thesis, Thanks are also due to the Medical Illustration 1973. http://gut.bmj.com/ Department of Stobhill General Hospital, Glasgow, 14 Kay AW. Effect of large doses of histamine on gastric and to the Staff of the Gastro-Intestinal Centre, secretion of HCl. Br Med J 1953; 2: 77-80. Southern General Hospital, for performing the 15 Multi-centre pilot study. Pentagastrin as stimulant of maximal gastric acid response in man. Lancet 1967; 1: gastric secretion tests. 291-5. 16 Crean GP, Holden RJ, Mackenzie I, Hearns JB. The effect of six weeks administration of cimetidine on

gastric acid secretion. In: Burland WL, Simkins MA, on September 30, 2021 by guest. Protected copyright. eds. Cimetidine: proceedings ofthe second international symposium on histamine H2-receptor antagonists. References Amsterdam: Excerpta Medica, 1977: 122-3. 17 Barbezat GO, Bank S. Basal acid output response to 1 Burland WL, Duncan WAM, Hesselbo T, Mills JG, cimetidine in man. In: Burland WL, Simkins MA, eds. Sharp PC, Haggie SJ, Wyllie JH. Pharmacological Cimetidine: proceedings of the second international evaluation of cimetidine. A new histamine H2-receptor symposium on histamine H2-receptor antagonists. antagonist in healthy man. Br J Clin Pharmacol 1975; Amsterdam: Excerpta Medica, 1977: 110-9. 2: 481-6. 18 Spence RW, Celestin LR, McCormick DA. Effect on 2 Pounder RE, Williams JG, Milton-Thompson GJ, gastric acid output of prolonged treatment with Misiewicz JJ. Effect of cimetidine on 24 hour intra- cimetidine in duodenal ulcer patients. Gut 1976; 17: gastric acidity in normal subjects. Gut 1976; 17: 131-8. 831. 3 Bradshaw J, Brittain RT, Clitherow JW, Daly MJ, Jack 19 Peden NR, Saunders JHB, Wormsley KG. Inhibition D, Price BJ, Stables R. Ranitidine (AH 19065): a new of pentagastrin-stimulated and nocturnal gastric potent, selective histamine H2receptor antagonist. Br J secretion by ranitidine. Lancet 1979; 1: 690-2. Pharmacol 1979; 66: 464. 20 Elder JB, Smith IS. Gastric acid output, pepsin output 4 Domschke W, Lux S, Domschke S, Demling L. New and lean body mass in normals and duodenal ulcer H2-receptor antagonist inhibits human gastric acid subjects. Lancet 1975; 1: 1000-3. secretion more strongly than cimetidine. Gut 1979; 20: 21 Bank S, Barbezat GO, Vinik AI, Halter F, Helman A450-1. CA. Cimetidine and serum gastrin levels in man. In: 5 Griffiths R, Lee RM, Taylor BC. Kinetics of cimetidine Burland WL, Simkins MA, eds. Cimetidine: in man and experimental animals. In: Burland WL, proceedings of the second international symposium on Gut: first published as 10.1136/gut.24.1.61 on 1 January 1983. Downloaded from

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histamine H2-receptor antagonists. Amsterdam: pressure and serum gastrin. N Engl J Med 1974; 291: Excerpta Medica, 1977: 155-62. 486-90. 22 Spence RW, Celestin LR, McCormick DA, Owens CJ. 25 Barbezat GO, Grant B, Bank S, Vinik AI. The effect The effect of three months treatment with cimetidine of histamine H2-receptor blockade with metiamide on on basal and 'Oxo' stimulated serum gastrin. In: serum gastrin levels in man. Gut 1975; 16: 186-7. Burland WL, Simkins MA, eds. Cimetidine: 26 Richardson CT, Walsh JH, Hicks MI. The effect of proceedings of the second international symposium on cimetidine, a new histamine H2-receptor antagonist on histamine H2-receptor antagonists. Amsterdam: meal stimulated acid secretion, serum gastrin and Excerpta Medica, 1977: 163-74. gastric emptying in patients with duodenal ulcer. 23 Konturek SJ, Obtulowicz W, Kwiecien N, Sito E, Gastroenterology 1976; 71: 19-23. Mikos E, Oleksy J. Comparison of ranitidine and 27 Peden NR, Richards DA, Saunders JHB, Wormsley cimetidine in the inhibition of histamine, sham-feeding KG. Pharmacologically effective plasma concentrations and meal-induced gastric secretion in duodenal ulcer of ranitidine. Lancet 1979; 2: 199-200. patients. Gut 1980; 21: 181-6. 28 Dockray GJ, Taylor IL. Heptadecapeptide gastrin: 24 Higgs RH, Smyth RD, Castell DO. Gastric measurement in blood by specific radioimmunoassay. alkalinisation effect on lower oesophageal sphincter Gastroenterology 1976; 71: 971-7. http://gut.bmj.com/ on September 30, 2021 by guest. Protected copyright.