A method is described for the evaluation of the effect of oral therapy on gastric acid secretion. Metiamide, a histamine H2-receptor antagonist, produced a 51% inhibition of pentagastrin-stimulated gastric acid secretion during the third hour after a standard 200-mg oral dose in man.S. Afr. Med. J., 48, 2018 (1974)

Bank, S

Barbezat, GO

Clain, J

Marks, IN

Novis, B

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2018 S.A. MEDICAL JOURNAL 5 October 1974Oral Metiamide as an Effective Inhibitor ofGastric Acid Secretion in ManG. O. BARBEZAT, S. BANK, J. CLAIN, B. NOVIS, I. N. MARKSSUMMARYA method is described for the evaluation of the effect oforal therapy on gastric acid secretion. Metiamide, a hista-mine H2-receptor antagonist, produced a 51 % inhibition ofpentagastrin-stimulated gastric acid secretion during thethird hour after a standard 200-mg oral dose in man.S. Afr. Med. J., 48, 2018 (1974).Histamine H,-receptor antagonists' have evoked intenseinterest as inhibitors of gastric acid secretion. Burimamide,and its derivative metiamide, have been shown to inhibitgastric acid secretion stimulated by histamine, pentagastrin,insulin hypoglycaemia, food and cholinergic stimuli.Studies have been performed in rats,'" dogs."" cats: pigs,'and man.'" The potential of this drug as a therapeuticagent in the treatment of duodenal ulcer is presently beinginvestigated. Metiamide is available in tablet form, andtwo recent studies have demonstrated its effect on over-night fasting gastric acid secretion:"· In this article wehave investigated the effect of oral metiamide on gastricacid secretion stimulated by maximal doses of penta-gastrin in man.PATIENTS AND METHODSStudies were performed on 9 patients with endoscopicallyproved duodenal ulcers. Their mean age was 31,1 years(range 20 - 53 years). None had any complicating factors.After an overnight fast, a nasogastric tube was position-ed in the dependant part of the stomach, and its positionchecked fluoroscopically. Fasting gastric juice was aspiratedand discarded. Basal secretions were collected for two 15-minute periods. An intravenous infusion of pentagastrin(6 p.gj kg - h) was then given into a forearm vein by meansof a Braun Vnita I pump (B. Braun, Melsungen, WestGermany) for I hour. Gastric secretions were aspiratedby continuous mechanical suction for I hour. The tubewas frequently cleared with a syringe. Samples weredivided into four I5-minute collections. At the end of thehour, O,I5M NaCl was infused intravenously, instead ofGastro-intestinal Clinic and Department of Medicine, GrooteSchuur Hospital and University of Cape TownG. O. BARBEZAT, l\'f.B. CH.B., M.D., F.C.P. (S.A.), SenioTSpecialistS. BANK. M.B. CH.B., F.B.C.P., Associate ProfessorJ. CLAIN, M.B. CH.B., F.C.P. (S.A.) Senior Regi.strarB. NOVIS, M.B. CH.B., M.R.C.P., Senior Specialist -1. N. MARKS, B.SC-, M.B. CH.B., F.R.C.P., SeniOT SpecialistDale received: 25 June 1974.the pentagastrin. Nasogastric aspiration was stopped.Metiamide tablets (200 mg) were crushed, suspended in100 ml 0,03M HCl solution and injected into the stomachvia the nasogastric tube. The metiamide suspension con-tained a radioactive marker (14C-polyethylene glycol (PEG)in I patient and tritiated metiamide in 8), and a 2-m1aliq uot was retained for isotope counting. After I t hours,gastric aspiration was recommended. The first 15-minutesample was discarded and the second retained as 'basal'collection. The intravenous infusion of pentagastrin (6 p.gjkg - h) was restarted and four 15-minute samples of gastricsecretion collected. Each patient therefore acted as hisown control, the first study without metiamide and thesecond after metiamide. Aliquots of gastric aspirate fromall samples collected after giving metiamide were examinedfor radioactivity, by using a Beckman LS-250 liquidscintillation system. This enabled calculation of how muchmetiamide had been retained in the stomach and how muchwithdrawn during subsequent gastric aspiration. Acid con-centration in the gastric aspirate was titrated against 0,1 MNaOH using a Metrohm Automatic Titrator (MetrohmLtd, Herisau, Switzerland). Basal volume and acid outputfor the first half of the study represent 30-minute col-lections multiplied by 2, and for the second half of thestudy I5-minute collections multiplied by 4. Maximal acidoutput (MAO) represents the total acid output during thehour of pentagastrin stimulation. Peak acid output (PAO)represents the highest stimulated acid output in a 3D-minuteperiod multiplied by 2. Results are compared by means ofa paired Student's Hest.. RESULTSThere was a significant reduction in basal and pentagastrin-stimulated volume output and acid concentration (TableI, Figs I and 2). Maximal acid output and PAO werereduced by 51,8% (range 33,2 -72,5%) and 51,% (range19,0 -71,7%) respectively, which represents a highly signi-ficant inhibition of gastric acid secretion (P< 0,00 I andP<0,005 respectively) (Table I, Figs 3 and 4).Only 4,1 % of the radioactive marker introduced into thestomach with the metiamide was recovered during thesecond half of the study, the remainder having presumablypassed into the duodenum. The one patient who receivedPEG as a marker had 18,7% of the ingested dose aspiratedfrom his stomach, while the remainder, who receivedtritiated metiamide, had a mean recovery of 2,3 %. Thetest was repeated in this patient by using tritiated metia-mide, and the label recovered from the stomach It hourslater was again high (16,2 %). This patient, therefore, hadslow gastric emptying.5 Oktober 1974 S.-A. MEDIESE TVDSKRIFTABLE J. GASTRIC SECRETION BEFORE AND AFTER METIAMIDE2019Before metiamide After metiamide Mean(mean -+- SEM) (mean -+- SEM) % reduction PVolume (ml/h)Basal 156 -+- 17,2 91 -+- 20,7 41,7 <0,02MAO ... 343 -+- 30,4 206 -+- 19,2 39,9 <0,001Acid concentration (mEq/litre)Basal ... 45,4 -+- 5,8 24,1 -+- 10,7 46,9 <0,025MAO ... 100,3 -+- 5,6 76,9 -+- 6,7 23,3 <0,005Acid output (mEq/h)Basal 6,9 -+- 1,1 3,3 -+- 2,2 52,2 NSMAO 35,5 -+- 4,4 17,1 -+- 2,9 51,8 <0,001PAO 44,1 -+- 5,9 21,6 -+- 3,1 51,0 <0,005MAO = maximal (stimulated) acid output; PAO = peak acid output; P = probability value; NS not significant.iPENTAGASTRIN 6~gjkg-hrl 12 iPENTAGASTRIN 6.ugjkg-hrl~ y~ ~-------.100 /. 10 /././.8°1.~. 8§/ ~-_oerEwE 66°1.w .....I/O~~ / 0/:::lQ..:::l::1• BEFORE ..... 4 • BEFORE0 ~./ :::lo AFTER 0 o AFTER> ~o :c2 ___./00--0,°B 3 5 B 3 515 min PERIODS 15 min PERIODSFig. 1. Volume output before and after metiamide.Fig. 3. Acid output before and after metiamide.3,PENTAGASTRIN 6Vg/kg-hrl... .----------. .~100 I~ 0/°-"F~/!~ 4°1 0-0/0;; 20:;:o ,B• BEFOREoAFTER5BAO5040erw 30E.....:::lQ.......:1:::l0+J:r1h° ...B AMAOB APAOiIT-n-::..::: ~B A15 min PERIODSFig. 2. Acid concentration before and after metiamide.aFig. 4. Mean basal, stimulated and peak acid output beforeand after metiamide.S.A. MEDICAL JOURNALI-I-~­fIIIII·1I2020DISCUSSIONThe results of the present study show that metiamide ishighly effective in reducing pentagastrin-stimulated gastricacid secretion when taken orally. A standard 200 - mg doseproduced ~a 51 o~ reduction in acid output, both volumeoutput and acid concentration being inhibited. This re-duction represents the effect of the drug 2 - 3 hours afterentering the stomach. The dose of pentagastrin given byintravenous infusion in this study (6 p.g/ kg - h) is some-what supramaximal, since most patients reach theirmaximal output with doses of 2 p.g / kg - h. This is there-fore a more strenuous test of drug efficacy. The relativelysmall drop in mean basal acid secretion in the second testwas probably due to one patient who increased his basalacid output after metiamide. Excluding this patient re-sulted in a highly significant inhibition of basal acidsecretion with metiamide (P<0,005), as has been foundin previous studies."'· It is unlikely that this was a legacyof the previous pentagastrin infusion.Metiamide is well absorbed from the gastro-intestinaltract. A study in 2 patients has shown that it producessimilar inhibition when perfused into the duodenum aswhen given intravenously.lO A 51 % reduction in acid out-put is only slightly less than that achieved with vagotomy,a procedure associated with a high incidence of healingduodenal ulcers."'''' Anticholinergics may also producesignificant inhibition of gastric acid secretion," but dosesrequired to achieve this are often associated with un-pleasant side-effects. In contrast, there have been no sub-jective side-effects with the 200 - mg dose of metiamide.5 October 1974The safety of long-term administration of this drug ispresently being evaluated. Initial impressions in an openpilot study on 10 patients are that it affords rapid sympto-matic relief of duodenal ulcer pain. Seven of the patientsshowed complete and 3 partial endoscopic healing of theirulcers in 4 - 6 weeks. H A randomised double-blind trial ofmetiamide in the treatment of duodenal ulcer is needed toassess its value as a therapeutic agent.We wish to thank Mrs S. Bridger and Mrs M. Daniel fortechnical help; Dr B. Shepstone for providing facilities forthe isotope counting; and Smith, Kline & French LaboratoriesLld for the metiamide.Financial support was provided by the South AfricanMedical Research Council and the University of Cape TownStaff Research Fund.REFERENCES1. Black, J. W., Duncan, W. A. M., Durani, C. J., Granellin, C. R.and Parsons, E. M. (1972): Nature (Lond.), 236, 385.2. Ridley, P. T., Groves, W. G., Schlosser, J. H. and Massenberg, J. S.in Wood, C. J. and Simkins, M. A., eds (1973): International Sym-posium 011 Histamine H':!.-ReceptOr AnTagonists. London, J - 2 Octo-ber 1973, p. 259. Welwyn Garden City: Research and DevelopmeniDivision, Smith, Kline & French Laboratories.3. Grossman, M. 1. and Konturek, S. J. (1973): Ibid., p. 297.4. Hirschowitz, B. 1. and Gibson, R. (1973): Ibid., p. 273.5. Konturek, S. J., Demitrescu, T., Radecki, T. and Dembinski, A.(1973): Ibid., p. 247.6. Barbezat, G. 0., Waterworth, M. W. and Bank, S. (1973): Ibid., p.291.7. Wyllie, J. H. and Hesselbo, T. (1973): Ibid., p. 371.8. Wyllie, J. H., Hesselbo, T. and Black, J. W. (1972): Lancet, 2, lll7.9. Milton-Thompson, G. J .. Williams, J. G .. Jenkins, D. J. A. andMisiewicz, J. J. (1974): Ibid., I, 693.10. Thjodleifsson, B. and Wormsley, K. G. (1974): Brit. Med. J., 2, 304.11. Bank, S., Marks, 1. N. and Louw, J. H. (1967): Gut, 8. 36.12. Gillespie, 1. E. and Kay, A. W. (1961): Brit. Med. J., I, 1557.13. Schrumpf, E., Roland, M. and Liavag, 1. (1974): Seand. J. Gaslroent.,9, ll5~14. Bank. S~. Barbezat, G. 0., 'ovis, B., Cia in, J. and Marks, 1. N.(1974): Unpublished data.

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Oral metiamide as an effective inhibitor of gastric acid secretion in man

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Oral metiamide as an effective inhibitor of gastric acid secretion in man

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