Effect of Cimetidine on Pentagastrin-stimulated Gastric Secretion before and after Proximal Gastric Vagotomy for Duodenal Ulcer E. AADLAND, A. BERSTAD, L. S . SEMB & K. BJERKE Medical Dept. B, Aker Hospital, Surgical Dept., Diakonhjemmets Hospital, Surgical Dept., Sarpsborg Hospital, Oslo and Sarpsborg. Norway
Scand J Gastroenterol Downloaded from informahealthcare.com by Ohio State University Libraries on 11/22/14 For personal use only.
Aadland. E.. Berstad, A., Semb, L. S . & Bjerke, K. Effect of cimetidine on pentagastrinstimulated gastric secretion before and after proximal gastric vagotomy for duodenal ulcer. Scand. J. Gastroent. 1978, 13, 679-684. Nine patients with duodenal ulcer were studied before and 2-3 months after proximal gastric vagotomy (PGV). Infusion of cimetidine, 1.2 mg.kg-'h-', reduced mean gastric acid output, in response to infusion of 1.5 pg.kg 'h-' of pentagastrin, by, on an average, 79.4% before and 79.1% after vagotomy. The corresponding values for pepsin output were 66.5% before and 77.0% after the operation. The values were not statistically different. Thus, in terms of per cent inhibition, cimetidine was similarly effective before and after PGV. No correlation was found between per cent reduction of acid output by vagotomy and by cimetidine.The effect of the drug was added to that of the vagotomy. Patients with relapse ulcer after vagotomy are therefore interesting candidates for cimetidine treatment. Keywords: Acid secretion: cimetidine; pentagastrin; pepsin secretion; proximal gastric
vagotomy E. Aadland, M.D., Medical Dept. B, Aker Hospital, Oslo, Norway
Proximal gastric vagotomy (PGV) is widely used as a routine surgical method for treatment of duodenal ulcer. A certain rate of postoperative ulcer relapse after this method must be accepted (3, 4, 7, 9). So far, cimetidine, a histamine H,-receptor antagonist, has not been tried to any extent in patients with recurrent ulcer after vagotomy. These patients represent interesting candidates for cimetidine treatment. because many of them have to be reoperated upon with a more mutilating procedure. The present study was therefore performed to compare the inhibitory effect of cimetidine on pentagastrin-stimulated gastric secretion before and after PGV.
min. The substances were given in isotonic saline at a constant rate of 22 ml/min by a Harvard infusion pump. The gastric juice was collected in 15-min portions, and each portion was analysed for acid and pepsin concentration (1). The output of acid and pepsin during the last hour with pentagastrin alone and pentagastrin plus cirnetidine was taken to represent the response to pentagastrin and pentagastrin plus cimetidine, respectively. The per cent inhibition of acid and pepsin output caused by cimetidine was calculated as the response to pentagastrin plus cimetidine in per cent of the response to pentagastrin alone.
MATERIALS AND METHODS Nine patients with duodenal ulcer were studied before and 2-3 months after PGV. All but one had a negative acid response to insulin stimulation. Pentagastrin, 1.5 pg.kg-'h-', was infused intravenously for 165 min, and cimetidine, 1.2 mg.kg-'h-', was added by concomitant infusion during the last 9 0
RESULTS PGV reduced acid and pepsin output in response to pentagastrin, 1.5 pg.kg-'h-', by, on an average, 65.1%& 12.5% (S.D.) and 51.9%+ 17.3% respectively (Figs. 1 and 2). Cirnetidine, 1.2 mg.kg-'h-', inhibited acid output by, on an average, 79.4%f
Scand J Gastroenterol Downloaded from informahealthcare.com by Ohio State University Libraries on 11/22/14 For personal use only.
680
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Scand J Gastroenterol Downloaded from informahealthcare.com by Ohio State University Libraries on 11/22/14 For personal use only.
Effect of Cinzefidine after Vagofonzy
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Scand J Gastroenterol Downloaded from informahealthcare.com by Ohio State University Libraries on 11/22/14 For personal use only.
by cimetidine
40
20
0 before
after
P GV Fig. 3. Per cent inhibition ofacid output in response to pentagastrin. 1.5 1rg.kg -'h-', by cimetidine, 1.2 rng.kg-'h-'. before and after PGV. Mean and individual values. One patient had a positive insulin test (open circle).
10.3% before and 79. I % _+ 14.4% after PGV (Fig. 3). Pepsin output was inhibited by, on an average, 66.5%F 17.8% before and 77.0% +_17.0%after PGV (Fig. 4). The values before and after vagotomy are not statistically different. There was no correlation between the per cent reduction of acid output by vagotomy and that by cimetidine (Fig. 5). The results of the patient with a positive insulin test were not significantly different from those of the others.
DISCUSSION In the present study the per cent inhibition by cimetidine of pentagastrin-stimulated acid and pepsin output was the same before and after PGV. The dose of pentagastrin used (1.5 pg.kg-'h-') gives near maximal stimulation of acid output (lo), but the
degree of stimulation is probably somewhat less after than before PGV, because PGV shifts the doseresponse curve to the right ( 10). We have previously shown, however, that the effect of cimetidine is only slightly changed by wide variations in the dose of pentagastrin (non-competitive inhibition) ( 1). Accordingly, a slightly stronger stimulation by the same dose of pentagastrin before than after PGV should not influence the cimetidine-induced inhibition significantly. In this study fading of the acid and pepsin response to the prolonged intravenous infusion of pentagastrin will exaggerate the effect of cimetidine. Berstad & Petersen (2)found, by a similar technique in healthy subjects, that acid output decreased on an average 9.4% from period 15-75 min to period 105-165 min during infusion of 0.15 pg.kg-'h-' of
Scand J Gastroenterol Downloaded from informahealthcare.com by Ohio State University Libraries on 11/22/14 For personal use only.
Efleci of Cinieridine afier Vagotoniy
pentagastrin. The corresponding fall in acid output with 6.0 pg.kg-'h-' of pentagastrin was, on an average, 10.0%. Ward ( 12) found no diminution of acid output with time when infusing maximal doses of pentagastrin for three hours in duodenal ulcer patients before and after vagotomy. Therefore, fading of the acid response to pentagastrin is small, and probably not greater in duodenal ulcer patients either before or after vagotomy than in healthy subjects. The reduced acid output during infusion of pentagastrin plus cimetidine should be mainly an effect of cimetidine. The results indicate that cimetidine is a similarly effective inhibitor of pentagastrinstimulated acid secretion before and after PGV. In duodenal ulcer patients the fade of pentagastrin-stimulated pepsin secretion may be greater than that of acid secretion (1 l), but assuming that the fade of pepsin output is not greater after than before
% inhibit ion of pepsin output by cimetidine
100
683
PGV, the results show that the effect of cimetidine on pepsin output is approximately the same before and after PGV. PGV is now in many places a routine operative treatment for duodenal ulcer. The relapse rate after the operation is not finally established, but in some series it is relatively high (3, 4, 6, 7, 9). In the present study mean gastric acid output was reduced on an average by 65.1% 2-3 months after the vagotomy. Only one patient had a positive insulin test, suggesting an incomplete vagotomy. Johnston et al. ( 5 ) reported about 50% late positive insulin tests and 55% reduction of maximal acid output one year after PGV, which suggests that the effect of the vagotomy may be reduced with time. Patients with relapse ulcer after PGV might benefit from further reduction of acid secretion, especially if the vagotomy is incomplete and acid secretion not satisfactor-
-
ao-
60-
40 -
0
0
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PGV Fig. 4. Per cent inhibition of pepsin output in response to pentagastrin, 1.5 pg.kg-'h I , by cimetidine, 1.2 mg.kg-'h-', before and after PGV. Mean and individual values. One
patient had a positive insulin test (open circle).
684
E. Aadiand, A. Berstad, L . S . Senib & K . Bjerke reduction of H + output
t
,Y
Scand J Gastroenterol Downloaded from informahealthcare.com by Ohio State University Libraries on 11/22/14 For personal use only.
vagotomy
'6oi I 80
0
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20
40
60
80
100
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ily reduced (8). Since the present study showed that the effect of cimetidine on pentagastrin-stimulated acid secretion was added to that of the vagotomy, these patients must be considered interesting candiReceived 25 January 1978 Accepted 17 April 1978
dates for cimetidine treatment as an alternative to gastric resection with its unwanted side-effects. Further clinical studies with cimetidine in patients with recurrent peptic ulcer after vagotomy is therefore warranted.
REFERENCES I . Aadland. E.. Berstad. A. & Semb. L. S. Scand. J. Gastroent. 1977. 12, 501-506 2. Berstad. A. & Petersen. H. Digestion 1972. 6, 193204 3. Holst-Christensen. J.. Hansen. 0. H. & Pedersen. T. Ugeskr. Laeg. 1977. 139. 2055-2059 4. Jensen. H. E. & Amdrup. E. Ugeskr. Laeg. 1977. 139, 2052-2055 5. Johnston. D.. Wilkinson. A. R.. Humphrey. C. S.. Smith. R. B.. Goligher. J. C.. Kragelund. E. & Amdrup. E. Gastroenterology 1973. 6 4 , 1-1 1 h. Johnston. D.. Pickford. I. R. Walker. B. E. & Goligher. J. C . Brit. Med. J. 1975. I , 716-718 7. Kennedy. T.. Johnston. G. W.. Macrae. K. D. & Anne Spencer. E. F. Brit. Med. J. 1975. 2, 301-303 8. Kronborg. 0. Gut 1974. 15, 714-719 9. Liavag. I. & Roland. M. Scand. J. Gastroent. 1976. 11, Suppl. 38. 6&61 10. Roland. M.. Berstad. A. & Liavag. I. Scand. J. Gastroent. 1974. 9, 511-518 11. Thjodleifsson. B. & Wormsley. K. G. Brit. Med. J. 1974. 2, 304-306 12. Ward. A. S. Gut 1976. 17, 48-53
Scand J Gastroenterol Downloaded from informahealthcare.com by Ohio State University Libraries on 11/22/14 For personal use only.
Aadland. E.. Berstad, A., Semb, L. S . & Bjerke, K. Effect of cimetidine on pentagastrinstimulated gastric secretion before and after proximal gastric vagotomy for duodenal ulcer. Scand. J. Gastroent. 1978, 13, 679-684. Nine patients with duodenal ulcer were studied before and 2-3 months after proximal gastric vagotomy (PGV). Infusion of cimetidine, 1.2 mg.kg-'h-', reduced mean gastric acid output, in response to infusion of 1.5 pg.kg 'h-' of pentagastrin, by, on an average, 79.4% before and 79.1% after vagotomy. The corresponding values for pepsin output were 66.5% before and 77.0% after the operation. The values were not statistically different. Thus, in terms of per cent inhibition, cimetidine was similarly effective before and after PGV. No correlation was found between per cent reduction of acid output by vagotomy and by cimetidine.The effect of the drug was added to that of the vagotomy. Patients with relapse ulcer after vagotomy are therefore interesting candidates for cimetidine treatment. Keywords: Acid secretion: cimetidine; pentagastrin; pepsin secretion; proximal gastric
vagotomy E. Aadland, M.D., Medical Dept. B, Aker Hospital, Oslo, Norway
Proximal gastric vagotomy (PGV) is widely used as a routine surgical method for treatment of duodenal ulcer. A certain rate of postoperative ulcer relapse after this method must be accepted (3, 4, 7, 9). So far, cimetidine, a histamine H,-receptor antagonist, has not been tried to any extent in patients with recurrent ulcer after vagotomy. These patients represent interesting candidates for cimetidine treatment. because many of them have to be reoperated upon with a more mutilating procedure. The present study was therefore performed to compare the inhibitory effect of cimetidine on pentagastrin-stimulated gastric secretion before and after PGV.
min. The substances were given in isotonic saline at a constant rate of 22 ml/min by a Harvard infusion pump. The gastric juice was collected in 15-min portions, and each portion was analysed for acid and pepsin concentration (1). The output of acid and pepsin during the last hour with pentagastrin alone and pentagastrin plus cirnetidine was taken to represent the response to pentagastrin and pentagastrin plus cimetidine, respectively. The per cent inhibition of acid and pepsin output caused by cimetidine was calculated as the response to pentagastrin plus cimetidine in per cent of the response to pentagastrin alone.
MATERIALS AND METHODS Nine patients with duodenal ulcer were studied before and 2-3 months after PGV. All but one had a negative acid response to insulin stimulation. Pentagastrin, 1.5 pg.kg-'h-', was infused intravenously for 165 min, and cimetidine, 1.2 mg.kg-'h-', was added by concomitant infusion during the last 9 0
RESULTS PGV reduced acid and pepsin output in response to pentagastrin, 1.5 pg.kg-'h-', by, on an average, 65.1%& 12.5% (S.D.) and 51.9%+ 17.3% respectively (Figs. 1 and 2). Cirnetidine, 1.2 mg.kg-'h-', inhibited acid output by, on an average, 79.4%f
Scand J Gastroenterol Downloaded from informahealthcare.com by Ohio State University Libraries on 11/22/14 For personal use only.
680
E . Aadland, A . Berstad, L . S . Senib & K . Bjerke
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Scand J Gastroenterol Downloaded from informahealthcare.com by Ohio State University Libraries on 11/22/14 For personal use only.
Effect of Cinzefidine after Vagofonzy
L
4
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681
682
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% inhibition
100
80
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of
H+ output
0
60
0
Scand J Gastroenterol Downloaded from informahealthcare.com by Ohio State University Libraries on 11/22/14 For personal use only.
by cimetidine
40
20
0 before
after
P GV Fig. 3. Per cent inhibition ofacid output in response to pentagastrin. 1.5 1rg.kg -'h-', by cimetidine, 1.2 rng.kg-'h-'. before and after PGV. Mean and individual values. One patient had a positive insulin test (open circle).
10.3% before and 79. I % _+ 14.4% after PGV (Fig. 3). Pepsin output was inhibited by, on an average, 66.5%F 17.8% before and 77.0% +_17.0%after PGV (Fig. 4). The values before and after vagotomy are not statistically different. There was no correlation between the per cent reduction of acid output by vagotomy and that by cimetidine (Fig. 5). The results of the patient with a positive insulin test were not significantly different from those of the others.
DISCUSSION In the present study the per cent inhibition by cimetidine of pentagastrin-stimulated acid and pepsin output was the same before and after PGV. The dose of pentagastrin used (1.5 pg.kg-'h-') gives near maximal stimulation of acid output (lo), but the
degree of stimulation is probably somewhat less after than before PGV, because PGV shifts the doseresponse curve to the right ( 10). We have previously shown, however, that the effect of cimetidine is only slightly changed by wide variations in the dose of pentagastrin (non-competitive inhibition) ( 1). Accordingly, a slightly stronger stimulation by the same dose of pentagastrin before than after PGV should not influence the cimetidine-induced inhibition significantly. In this study fading of the acid and pepsin response to the prolonged intravenous infusion of pentagastrin will exaggerate the effect of cimetidine. Berstad & Petersen (2)found, by a similar technique in healthy subjects, that acid output decreased on an average 9.4% from period 15-75 min to period 105-165 min during infusion of 0.15 pg.kg-'h-' of
Scand J Gastroenterol Downloaded from informahealthcare.com by Ohio State University Libraries on 11/22/14 For personal use only.
Efleci of Cinieridine afier Vagotoniy
pentagastrin. The corresponding fall in acid output with 6.0 pg.kg-'h-' of pentagastrin was, on an average, 10.0%. Ward ( 12) found no diminution of acid output with time when infusing maximal doses of pentagastrin for three hours in duodenal ulcer patients before and after vagotomy. Therefore, fading of the acid response to pentagastrin is small, and probably not greater in duodenal ulcer patients either before or after vagotomy than in healthy subjects. The reduced acid output during infusion of pentagastrin plus cimetidine should be mainly an effect of cimetidine. The results indicate that cimetidine is a similarly effective inhibitor of pentagastrinstimulated acid secretion before and after PGV. In duodenal ulcer patients the fade of pentagastrin-stimulated pepsin secretion may be greater than that of acid secretion (1 l), but assuming that the fade of pepsin output is not greater after than before
% inhibit ion of pepsin output by cimetidine
100
683
PGV, the results show that the effect of cimetidine on pepsin output is approximately the same before and after PGV. PGV is now in many places a routine operative treatment for duodenal ulcer. The relapse rate after the operation is not finally established, but in some series it is relatively high (3, 4, 6, 7, 9). In the present study mean gastric acid output was reduced on an average by 65.1% 2-3 months after the vagotomy. Only one patient had a positive insulin test, suggesting an incomplete vagotomy. Johnston et al. ( 5 ) reported about 50% late positive insulin tests and 55% reduction of maximal acid output one year after PGV, which suggests that the effect of the vagotomy may be reduced with time. Patients with relapse ulcer after PGV might benefit from further reduction of acid secretion, especially if the vagotomy is incomplete and acid secretion not satisfactor-
-
ao-
60-
40 -
0
0
. 0 0
I
rn
0
0
0 0
20-
0before
after
PGV Fig. 4. Per cent inhibition of pepsin output in response to pentagastrin, 1.5 pg.kg-'h I , by cimetidine, 1.2 mg.kg-'h-', before and after PGV. Mean and individual values. One
patient had a positive insulin test (open circle).
684
E. Aadiand, A. Berstad, L . S . Senib & K . Bjerke reduction of H + output
t
,Y
Scand J Gastroenterol Downloaded from informahealthcare.com by Ohio State University Libraries on 11/22/14 For personal use only.
vagotomy
'6oi I 80
0
(%I
0 0 0
o m
(II 20
20
40
60
80
100
by c i m e t i d i n e Fig. 5. Correlation between per cent reduction of acid output by cirnetidine and vagotorny. The results of one patient with positive insulin test is shown by open circle.
ily reduced (8). Since the present study showed that the effect of cimetidine on pentagastrin-stimulated acid secretion was added to that of the vagotomy, these patients must be considered interesting candiReceived 25 January 1978 Accepted 17 April 1978
dates for cimetidine treatment as an alternative to gastric resection with its unwanted side-effects. Further clinical studies with cimetidine in patients with recurrent peptic ulcer after vagotomy is therefore warranted.
REFERENCES I . Aadland. E.. Berstad. A. & Semb. L. S. Scand. J. Gastroent. 1977. 12, 501-506 2. Berstad. A. & Petersen. H. Digestion 1972. 6, 193204 3. Holst-Christensen. J.. Hansen. 0. H. & Pedersen. T. Ugeskr. Laeg. 1977. 139. 2055-2059 4. Jensen. H. E. & Amdrup. E. Ugeskr. Laeg. 1977. 139, 2052-2055 5. Johnston. D.. Wilkinson. A. R.. Humphrey. C. S.. Smith. R. B.. Goligher. J. C.. Kragelund. E. & Amdrup. E. Gastroenterology 1973. 6 4 , 1-1 1 h. Johnston. D.. Pickford. I. R. Walker. B. E. & Goligher. J. C . Brit. Med. J. 1975. I , 716-718 7. Kennedy. T.. Johnston. G. W.. Macrae. K. D. & Anne Spencer. E. F. Brit. Med. J. 1975. 2, 301-303 8. Kronborg. 0. Gut 1974. 15, 714-719 9. Liavag. I. & Roland. M. Scand. J. Gastroent. 1976. 11, Suppl. 38. 6&61 10. Roland. M.. Berstad. A. & Liavag. I. Scand. J. Gastroent. 1974. 9, 511-518 11. Thjodleifsson. B. & Wormsley. K. G. Brit. Med. J. 1974. 2, 304-306 12. Ward. A. S. Gut 1976. 17, 48-53
