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Effects of Eight Weeks' Continuous Treatment with Oral Ranitidine and Cimetidine on Gastric Acid Secretion, Pepsin Secretion, and Fasting Serum Gastrin

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Effects of Eight Weeks' Continuous Treatment with Oral Ranitidine and Cimetidine on Gastric Acid Secretion, Pepsin Secretion, and Fasting Serum Gastrin 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 cimetidine on gastric acid secretion, pepsin secretion, and fasting serum gastrin 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 Gastric acid 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. Pentagastrin 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<O-Ol) after 800 mg and 1600 mg cimetidine respectively and to 65% (p<0-005) with ranitidine after one week's treatment. Pepsin secretion remained at this reduced level in both cimetidine 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 histamine H2-receptor antagonist, have been are well known.1 2 Ranitidine hydrochloride is a reported to produce parietal cell 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 stomach, 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 metiamide, 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 antibody 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 cholecystokinin-pancreozymin and no cross- mean ± SEM. Results combinedfor group I (800 mg reactivity with other gastrointestinal peptides. 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.
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