Treatment of duodenal ulcer by metiamide

The Lancet · Saturday 25 October 1975

TREATMENT OF DUODENAL ULCER BY METIAMIDE A Multicentre Trial"

Summary

In a multicentre double-blind trial 68 patients with endoscopically confirmed duodenal ulceration received metiamide (36 patients) or placebo (32 patients) for four weeks. Healing of doudenal ulcers was significantly increased in patients receiving metiamide (67%) compared with those on placebo (25%). There was also an associated significant decrease in daytime pain and antacid consumption in those on metiamide. Introduction

BURIMAMIDE was the first Hj-receptor antagonist to be evaluated in man and shown to inhibit gastric-acid secretion. I 2 Metiamide succeeded burimamide and was the first histamine H 2-receptor antagonist to be evaluated clinically. It inhibits resting and stimulated gastric-acid and pepsin secretion.v !" Treatment with metiamide is reported to be associated with relief. from the pain of duodenal ulceration and a reduction in antacid consumption.!' and an open study suggested that its administration was followed by a high rate of healing in endoscopically confirmed duodenal ulcers.P To substantiate these initial findings, a multicentre endoscopically monitored double-blind trial was undertaken to assess whether its administration would increase the rate of healing when compared with that of placebo.

Patients and Methods The trial was conducted simultaneously in the hospital centres listed and coordinated by the clinical research group of Smith Kline and French Laboratories. Patients entering the trial were aged sixteen and over, with symptoms of proven duodenal ulceration, who had not responded to conventional medi'Participants: L. R. CELESTIN (FrenchayHospital,Bristol); V.HARVEY (Gloucester Royal Infirmary); J. H. B. SAUNDERS, K. G. WORMSLEY (Ninewells Hospital, Dundee); J. A. H. FORREST, R. F. A. LOGAN, D. 1. C. SHEARMAN (Royal Infirmary, Edinburgh); D. FERMONT, S. J. HAGGlE, J. H. WYLLIE (University College Hospital, London); M. ALBINus, M. H. THOMPSON, C. W. VENABLES (RoyalVictoria Infirmary, Newcastle); W. L. BURLAND, W. A. M. DUNCAN, B. W. HAWKINS, P. C. SHARPE (Smith Kline and French Laboratories, Welwyn Garden City, Hertfordshire). 7939

cal treatment, and in whom surgery was regarded as the only alternative treatment. Patients in whom evidence of renal, hepatic, allergic, cardiac, or respiratory diseases was strong and those receiving chronic medication for these or other conditions were excluded from the study. So also were pregnant or lactating patients, patients in whom surgery for peptic ulceration had been previously performed, other than the simple repair of a perforation, and patients who had significant and unexplained biochemical abnormalities on routine laboratory testing of blood and urine before entry. These included hsemoglobin concentration, red and white blood-cell indices, platelet and reticulocyte counts, plasma-electrolytes, serum-transarninases, serum-alkaline-phosphatase, plasma-ereatinine, tests of thyroid function, microscopy of urine, and tests for proteinuria and glycosuria. Those patients meeting the criteria and consenting to enter the study underwent endoscopy to confirm the presence of a duodenal ulcer within 4 days of being randomly allocated to treatment with metiamide or placebo. AU treatments other than antacid were withdrawn during the trial. Treatment in the first phase of the trial consisted of rnetiamide 200 mg (1 tablet) taken immediately after the three main meals and 400 mg (2 tablets) at bedtime, or placebo, identical in taste and appearance, containing lactose. Treatment lasted 4 weeks. In the second phase of the study the dose of rnetiamide was increased to 300 mg (2 tablets) three times a day immediately after meals and 400 mg (2 tablets) at bedtime, and the placebo therapy was increased proponionately. Random allocation of patients to metiamide or placebo treatment was continued. Each patient was given a supply of unmarked 'Rennie' antacid tablets (specially prepared by Nicholas Research Laboratories) with instructions to take these as often as necessary to relieve pain/indigestion. Each patient was asked to complete a diary card twice daily, recording his daytime and nocturnal pain and antacid consumption. Dietary advice was limited to a suggestion that foods causing discomfort should be avoided. Diary cards were returned each week and reviewed. Patients were seen, interviewed, and examined at weekly intervals. Unused test medicines and antacids were counted and the laboratory tests repeated. Endoscopy was repeated within 48 hours of completion of treatment in each case by the same operator using the same instruments and technique as used for the pre-treatment examination. The presence of ulceration and the severity and extent of duodenitis (a visual assessment of presumed inflammation of the duodenum) were recorded by a scored system. Laboratory tests were repeated a week after the completion of treatment. Results were analysed using the test to assess healing and effect on duodenitis and for pre-trial comparison of severity of pain in the treatment groups. AU other results were

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780

T HE LANCET, OCTOBE R

compared using the anal ysis of vari ance with comparison of means or individual observations using the t test.

Results Seventy -six pat ients met the criteria for entry into the trial. T went y-one received metiamide 1 g daily, seventeen received 1· 3 g daily, and th irt y-eight received placebo. Seven pat ients were withdrawn from the trial before completing 4 weeks' treatment, five had rece ived placebo, and two metiamide. Of the five pat ients receiving placebo who were withdrawn, four had worsening symptoms warranting a chan ge in treatment and one had influenza. One pat ient receiving metiamide spontaneously stopped treatment because of headaches, and one was withdrawn because of influenzal illness associated with abnormal liver-funct ion tests, subsequently attributed to biliary disease. One more patient receiving placebo completed 4 weeks' treatment but did not have a second endoscopy and was not included in the anal ysis TABL E I-

Trea tme nt

PAT IENTS COM PL ET ING THE STUDY

M

F

Metiamidel gdaily 14 Metia midel -3 g d aily 14 Placebo 25

7 I 7

Mean d uration Mean durat ion Mean age of ulcer disease of current relapse (mon ths) (yr ) (yr) 8 ·8 10·3 9·0

40·3 42·7 47-7

4·3 4·0 3·2

TABLE II- RE SUL T S Of ENDOS COP IC EXAMINATION IN ALL PATIE NTS AT 4 WEEKS

Duodenal ulcera tion T reatment Metiamide I g daily Metiamide 1·3 gdai ly Placebo

Duodenitis

Healed

Not healed

Improved

13 (62%) 11 ( 73%) 8 (2 5%)

8

10

10

I

4

8

6

1

24

7

23

2

Not improved Never pre sent

of results. The results in the sixty-eight patients satisfac torily completing the tr ial were analysed; twenty-one received metiamide 1 g daily, fifteen received metiamide 1·3 g daily; and thirty-two received placebo (table I). There were no significant differences among the three group s for age, sex, duration of peptic-ulcer disease, or the duration of the current relapse. Nor were there significant differences in the frequency and severity of daytime pa in in the week before trea tment. However, fewer patients in the placebo-treated group reported nocturnal pain during the week before tr eatm ent (1'< 0·01).

Ulcer H ealing and Duodenit is Th ere was complete healing of ulcer s in 62% of metiarnide-treated patients at the 1 g dose and in 73% at the 1·3 g dose, whilst only 25% of those on placebo therapy healed (table II ). These differences were significant (p<0·02 at 1 gdaily, 1'< 0· 01 at 1·3 gdaily). T here were also significant differences in improvement in duodenitis in rnetiamide-treated group s compared with those on placebo therap y (p< 0 .05 in both regimens). The correlation between improvement in duodenitis and the healing of an ulcer was highly significant (1' <0 ·001). Pain There was a significant increase in the number of pain-

25, 1975

TABLE III - M EAN NUMBER Of PAII'-fREE DAYS AND NIGHTS PER PAT IENT IN T HE WEEK PRE CEDING TREATMENT AND EACH Of THE 4 WEEKS Of TRE ATMEN T

Preceding Week

-

Week \

Week 2

Week 3

Week 4

Do vs: Met iamide I g daily Meri arn ide \ · 3 g dai ly Placebo

3·4

3·4

4·6

5·\

6 ·3

4· 5 5·0

5-\ 4·4

5·4 4·7

6·\ 4·9

6·4 4· 7

Nig hts : Metiamide I g d aily MCli amide 1·3gdaily Placeb o

5·0

5·3

5·8

6· \

6·2

4·6 6 ·5

5·5 5·6

6·6 5·7

6 ·9 5· 3

6·7 5· 3 ~

free days with treatment in both group s of metiamide-treated patients (p
Antacid Consumption Antacid consumption decre ased as the trial progressed in both group s of rnetiamide-trc at ed pat ients compared with placebo (table v). The decrease in amount of antacid consumed was statistically significant only in the group receiving 1 g metiamide. Untow ard Symptoms and S igns In the metiamide-treated group. constipation develTAB LE IV- MEAN NUMBER Of PAI N- FRH DAYS AND NIGHTS PER PATlFNT IN EACH Of T HE 4 WEEKS Of TR EATM ENT ACCOR DING TO EVIDENCE Of ULCER HEALI NG AT

Davs: ~iet i a mide I g da ily Meriamide 1·3 g daily Placebo

N ight s: Metiam ide \ gdaily Metiamide 1· 3 g daily Placebo

TARL E V-

WEEKS

Ulcer

Week 1

Week 2

Week 3

Week 4

Healed NOl healed Healed Not healed Healed Not healed

3· 7 2·9 5·9 3·0 4·5 4·4

4·4 5·0 5 ·4 5·3 4 ·9 4·6

5·2 4·9 6 ·2 5·8 5·3 4·8

6·4 6· 1 6·6 5·8 5 ·) 4·6

Healed Not healed Healed Not healed Healed Not healed

5· 5 4· 9 6 ·5

5·9 5·6 6 ·6 6 ·5 6 ·0 5 ·6

6· 3 5·8 6 ·9 7·0 4·8 5·5

6·2 6 ·\ 6·6 7·0 5·5 5·2

z.s 5·3 5·6

ANTACID CO NS UMPTION PER PATI E NT FO R EACH WEE K Of TR EATME NT

-

Metiamide I g daily (21) Meti arnide I · 3 g daily Placebo

4

----

(1 5) (32)

Week \

Week 2

Week 3

Week 4 _

10·3

9·0

6· \

5·4

4·8 5·9

2·6 5·5

}· 7 5 ·8

) ·5 7·0

Numbe rs of patie nts are shown in parent heses.

-

781

THE LANCET, OCTOBER 25,1975 oped in one patient, headache in one (who withdrew from treatment), vomiting in one, and one complained of sweating, one of itching without rash, two of a sore throat, and one of acne. In the placebo-treated group two patients reported headache, one constipation, two nausea, one vomiting, two drowsiness, and one diarrhoea. There were no important abnormalities in heematological indices in any patient in the trial. Plasma-ereatinine concentrations increased in twentysix patients receiving metiamide and in twelve receiving placebo. In ten patients receiving metiamide and three who received placebo, plasma-ereatinine was above the upper limit of normality for the laboratory (1· 3 or 1·4 mg/dl). The highest concentration recorded for a patient receiving metiamide was 1· 8 mg/dl after 2 weeks' treatment. In this patient and four others, two of whom received metiamide, the concentrations returned to normal before treatment was completed. In the remaining seven metiamide-treated patients plasma-ereatinine was 1· 5 mg/dl after 4 weeks' treatment. Three patients receiving placebo and nine patients receiving metiamide had abnormal serum-transaminase values during treatment. Serum-glutarnic-oxaloacetictransaminase (S.G.O.T.) concentration rose above the upper limits of normal laboratory values (20 to 35 I.v.!l) in four patients receiving metiamide, but the maximum value reached was only 36 LV.!l. Serum-glutamic-pyruvic-transaminase (s.G.P.L) also rose to 40 and 70 I.v.!1 in two of these four patients (laboratory upper limits of normal 30 I.v.!I). The highest value in four other patients treated with metiamide and with increased S.G.P.L values above normal was 65 LV.!l. One remaining patient receiving metiamide had raised S.G.P.T. values before and throughout the study (3667 I.v.!I). All these patients and four others whose transaminase values remained within normal limits demonstrated increases with duration of treatment. Three patients on placebo had marginally abnormal values for serum-alkaline-phosphatase during treatment, and one patient receiving metiamide had a persistent but only marginally abnormal value for alkaline phosphatase before and during the trial. One patient receiving placebo also had a persistently raised y-glutamyl transpeptidase value before and throughout the trial. No significant abnormalities were detected in plasmaelectrolytes, thyroid-function tests, or urinalysis.

Discussion The setiology of peptic ulcer remains obscure, but it has often been suggested that acid and pepsin secretion are involved in the maintenance and recurrence of peptic ulcer. The significant difference in the frequency of healed ulcers between the metiamide-treated groups and the placebo group in this study of previously unresponsive patients is encouraging. The results of this trial show that metiamide treatment is associated with a reduction in the frequency of pain, occurring within 2 weeks of starting treatment. Increasing the dose of metiamide to 1· 3 g daily seemed to marginally improve the frequency of healing and the number of pain-free days and antacid consumption. The lack of significant improvement in night-pain is likely to have been due to the high frequency of pain-free nights before treatment. Despite a report of reversible agranulocytosis associ-

ated with metiamide treatment,'? there were no hrematological complications of treatment, nor any clinical or laboratory signs to cause serious concern, especially when these were compared to the responses to placebo. This study shows that a histamine H 2-receptor antagonist can promote healing of duodenal ulceration and that these compounds are likely to play a major therapeutic role in the treatment of duodenal ulceration. We thank the departments of biochemistry and hsematology in the hospitals for their contributions to this study. Requests for reprints should be addressed to Dr W. L. Burland, Research Institute, Smith Kline and French Laboratories, Welwvn Garden City. Hertfordshire. . REFERENCES 1. Black, J. W., Duncan, W. A. M., Durant, C. j., Ganellin, C. R., Parsons, M. E. Nature, 1972,236,385. 2. Wyllie, J. H., Hesselbo, T.,Black, J. W. Lancet, 1972, ii, 1117. l Wyllie, J. H., Hesselbo, T. in International Symposium on Histamine H 2-Receptor Antagonists (edited by C. J. Wood and M. A. Simkins) p. 371, Smith Kline and French Laboratories, Welwyn Garden City, 1973. 4. Carter, D. C., Forrest, J. A. H., Werner, M., Heading, R. C., Park, j., Shearman, D.J. c. Br, med.J. 1974, iii, 554. 5. Konturek, S.]., Biernat, J., Olesky, J. Am.J. dig. Dis. 1974,19,609. 6. Mainardi, M., Maxwell, V., Sturdevant, R. A. L., Isenberg, J. I. New Engl. J. Med. 1974,291,373. 7. Milton-Thompson, G. J., Williams,]. G., Jenkins, D. .I. A., Misiewicz,.l- J. Lancet, 1974, i, 693. 8. Thjodleifsson, B., Worm,ley, K. G. Br. med.J. 1974, ii, 304. 9. Thjodleifsson, B., Wormsley, K. G. Gur, 1975,16, 501. 10. Richardson, C. T.,Bailey, B. A., Walsh, J. H., Fordtran, j. S.J. din. Invest. 1975,55,536. 11. Pounder, R. E., Williams, J. G., Milton-Thompson, G. J, Misiewicz, J. J. Br. med.J. 1975, ii,307. 12. Thompson, M. H., Reed, J. D., Dale, G., Venables, C. W. Am. J. dig. Dis.

(in the press).

13. Forrest, j. A. H., Shearman, D. J. C., Spence, R., Celestin, L. R. Lancet, 1975, i, 392.

OCCURRENCE OF OTHER ENDOCRINE TUMOURS IN PRIMARY HYPERPARATHYROIDISM

J. H. BOEY J. M. GILBERT

T. J. C. COOKE E. C. SWEENEY

SELWYN TAYLOR Departments of Surgery and Histopathology, Royal Postgraduate Medical School and Hammersmith Hospital, London W12 OHS

In a review of a hundred and nineteen patients with primary hyperparathyroidism an unexpectedly high number (17·5%) were found to have evidence of associated endocrine disease and were deemed to have multiple endocrine adenomatosis (M.E.A.). The clinical pattern of hypercalcemia in no way distinguished these patients from other hyperparathyroid patients. M.E.A. was most commonly found in patients with several diseased parathyroid glands.

Summary

Introduction Underdahl et a!. first described the occurrence of more than one type of endocrine tumour in the same patient in a report on eight such patients.' Wermer2 drew further attention to this disease complex in which adenoma or hyperplasia are found, often synchronously, in the parathyroids, pituitary, pancreas, and adrenals. The syndrome is familial, being transmitted as an autosomal dominant with varying penetrance, and is now