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Effect of one-month treatment with cimetidine on gastric secretion and serum gastrin and pepsinogen levels
00165085/78/7402-0376$02.00/O GAETROENTEROLOGY 74:376-379, 1978 Copyright 0 1978 by the American Gastroanterological Association
Vol. 74,No. 2,Part2 Printed in USA.
EFFECT OF ONE-MONTH TREATMENT WITH CIMETIDINE ON GASTRIC SECRETION AND SERUM GASTRIN AND PEPSINOGEN LEVELS K. F. SEWING, M.D., LINDA HAGIE, A. F. IPPOLITI, M.D., J. I. ISENBERG, M.D., I. M. SAMLOFF, M.D.,
AND R. A. L. STURDEVANT, M.D.
Medical and Research Services, Veterans Administration Wadsworth Hospital Center, and the Department of Medicine, UCLA, Los Angeles, California
The inhibitory effects of cimetidine on gastric acid and pepsin secretion were studied before and after 1 month of treatment with 300 mg of cimetidine four times a day in 15 male duodenal ulcer patients. Cimetidine inhibited both pentagastrin- and peptone meal-stimulated acid secretion significantly better before, than after, 1 month of treatment. Similarly cimetidine inhibited pentagastrin-stimulated pepsin secretion significantly better before treatment. Meal-stimulated serum gastrin concentrations were significantly higher after treatment. The mechanism(s) of these effects was not apparent. Some observations suggest that Hz-receptor blocking drugs might lose efficacy during a course of treatment.‘+ Therefore, a study was designed to evaluate the effects of cimetidine on meal- and pentagastrinstimulated gastric acid and pepsin secretion, and gastrin release in response to a meal, before and after 1 month of treatment with cimetidine. Materials and Methods Patients. Fifteen male patients (53.5 + 3.2 years; mean f were studied. They each had previous endoscopic or radiographic evidence of duodenal ulcer, and had pain suggesting recurrent ulcer on accession into this study. On 2 consecutive days the patients had acid secretory tests, with pentagastrin and with peptone meal stimulation, in random order. They were then treated with 300 mg of cimetidine four times a day for 30 days. Both tests were then repeated. Patients were allowed antacid as needed for pain. Pentagastrin tests. A radioopaque nasogastric tube was fluoroscopically positioned in the stomach. Gastric acid secretion was collected for 4 hr in 15-min intervals. The volume was read to the nearest 0.1 ml. Acid was automatically titrated (Autoburet, Radiometer, Copenhagen, Denmark) against 0.2 N NaOH topH 7. Pepsin was determined according to the method of Samloff and Dadufalza.5 After a 1-hr basal secretion collection, 6 pg kg-’ hr-’ of pentagastrin were infused intravenously for 3 hr. After the 1st hr of pentagastrin, 300 mg of cimetidine were injected intravenously over 60 sec. Blood samples were drawn before and at intervals after cimetidine injection for determination of cimetidine; however, SEM)
Address requests for reprints to: J. I. Isenberg, M.D., Gastroenterology Section, Veterans Administration Wadsworth Hospital Center, Los Angeles, California 90073. This study was supported in part by a research grant from Smith Kline & French Laboratories, by the Veterans Administration, and by Grant AM 17328 from the National Institute of Arthritis, Metabolism and Digestive Diseases to CURE (Center for Ulcer Research and Education). K. F. S. is grateful to the Paul-Martini-Foundation for a personal grant.
some of these samples were unsatisfactory for technical reasons and the data are not discussed here. Peptone meal-stimulated acid secretion. After fluoroscopitally placing a double lumen nasogastric tube in the stomach, basal secretion was collected for 1 hr in 15-min periods. Then 500 ml of a 10% peptone meal, adjusted to pH 5.5 with 0.5 N HCl, were instilled into the stomach. Acid secreted in response to that meal was titrated intragastrically topH 5.5 with 0.5 N NaOH for 1 hr.” The gastric contents were then aspirated, and 300 mg of cimetidine were given orally. After 30 min (to permit drug absorption) a second peptone meal, identical to the first one, was instilled into the stomach. Intragastric titration was carried out until the test meal had emptied into the duodenum (usually 60 to 120 min). Gastric juice then was aspirated by continuous suction until 3 hr after instillation of the second test meal. The following determinations were made: serum gastrin concentrations at 0, 60, 120, 150, 180, 210, 250, and 300 min after the start of the secretory test, and blood cimetidine determinations at 0, 30, 60, 90, 120, 150, 360, and 600 min after cimetidine administration. After 1 month of cimetidine therapy, the two secretory tests were repeated on 2 consecutive days beginning about 12 hr after the last dose. Serum gastrin and group I pepsinogen concentrations were determined by radioimmunoassay.‘, 8 Blood cimetidine was measured by high pressure liquid chromatography after extraction into octanol (W. C. Randolph et al., unpublished data). Student’s t-test (paired) was used in the statistical analysis of the data. Results are expressed as mean * 1 SE.
Results Basal secretion. The mean basal secretion from the two secretory tests (pentagastrin and intragastric titration) was significantly reduced (P < 0.05) from 6.4 k 1.4 to 3.7 2 1.0 r&q per hr (42%) after 1 month of cimetidine treatment (figs. 1 and 4). Pentagastrin-stimulated secretion. One month of cimetidine therapy reduced pentagastrin-stimulated acid secretion significantly (P < 0.01) from 46 to 4.5 to
376
February 1978
CIMETIDINE
AND
GASTRIC
32.4 k 3 mEq per hr (fig. 1). Rapid intravenous injection of 300 mg of cimetidine inhibited acid secretion before and after treatment to the same absolute mean value (before, 6.6 + 0.8; after, 6.5 k 1 mEq per hr). After 1 month of treatment the percentage of inhibition was smaller because of lower acid secretion before cimetidine injection. During the 2nd hr after injection of cimetidine the acid response to pentagastrin was significantly (P < 0.05) higher after the 30-day cimetidine treatment (fig. 1). Pepsin secretion. The response to pentagastrin alone was unaltered by 1 month of cimetidine treatment (fig. 2). However, during the 2nd hr after the 300-mg dose of cimetidine, given intravenously, pepsin secretion was significantly (P < 0.01) higher after treatment than before (fig. 2). Meal-stimulated acid secretion. The acid response to the first peptone meal was 26.6 k 3.8 mEq per hr before and 23.9 +- 3.9 mEq per hr after 1 month of cimetidine treatment (fig. 3). The difference was not significant. Before treatment, 300 mg of cimetidine,
377
SECRETION BASAL
PEPTONE
MEALS
CIMETK)INE TREATMENT N .15 ?? . P’
2
1
0
3
. 6 ~g~k~-’
hr-’
,
4
5
(
6
1
FIG. 3. Effect of an oral dose of 300 mg of cimetidine on gastric acid secretion in response to a peptone meal (intragastric titration) in 15 duodenal ulcer patients before (0) and after (0) 30 days of treatment with 300 mg of cimetidine four times daily. Values are mean? ssM. MEALS
PENTAGASTRIN 4
300
CIMETIDINE
r
,
TIME ( hrs
PEPTONE BASAL
0025
300 mg
I
lo
lo ClMETlDlNE TREATMENT
ClMETlDlNE 300
v.
.
mg PO
N-15
CIMETIOINE
?? *
TREATMENT
/\
”
N.
15
.
D<
PC005 P~OOI
200 005
P < 0.01
z g 100
1
0
3
2
TIME (hr:)
FIG. 1. Effect of 300 pentagastrin-stimulated patients before (0) and of cimetidine four times
mg of cimetidine,
given intravenously, on gastric acid secretion in 15 duodenal ulcer after (0) 30 days of treatment with 300 mg daily. Values are mean k SEM.
6 yo
BASAL
ICQ-’ hr-’
c 31
1
2
3
4
5 TIME Ch:s)
FIG. 4. Serum gastrin in response to two consecutive peptone meals (intragastric titration) and an acute oral dose of 300 mg of cimetidine before the second meal in 15 duodenal ulcer patients before (0) and after (0) 30 days of treatment with 300 mg of cimetidine four times daily. Values are mean t SEM.
PENTAGASTRIN 4
CIMETIDINE TREATMENT N - 15 .
p < 0.01
I
0
1
2
3 TIME (I&:
FIG. 2. Effect of 300 mg of cimetidine, given intravenously, on pentagastrin-stimulated gastric pepsin secretion in 15 duodenal ulcer patients before (0) and after (0) 30 days of treatment with 300 mg of cimetidine four times daily. Values are mean t SEM.
orally, significantly (P < 0.005) reduced the peptonestimulated acid response during the 1st hr. In contrast, after treatment, acid secretion was not significantly inhibited in the corresponding hour. Acid secretion in the 2nd hr was inhibited in both instances (fig. 3,4 hr). However, the total acid response in the first 2 hr after the second meal was significantly greater (P < 0.05) after than before 1 month of treatment with cimetidine (fig. 3,3 and 4 hr). Serum gastrin. Mean basal serum gastrin concentrations were higher after 1 month of treatment with cimetidine (50 k 9 versus 83 + 22 pg per ml, 0.05 < P < 0.1) (fig. 4). The gastrin responses to both meals were significantly greater after 1 month of treatment than before (fig. 4). Serum pepsinogen. Fasting serum group I pepsinogen concentrations were 130.1 2 10.2 ng per ml before
378
Vol. 74, No. 2, Part 2
DISCUSSION
> 0
2
4
6
8
10
TIME (hrs)
FIG. 5. Concentration of cimetidine in blood after an oral dose of 300 mg of cimetidine before (0) and after (0) 30 days of treatment with 300 mg of cimetidine four times daily in 10 duodenal ulcer patients. Values are mean 2 sz~.
treatment, and 146.3 + 13.2 ng per ml after treatment. The difference was not statistically significant. Cimetidine blood concentrations. Before treatment, a maximum concentration of 0.53 + 0.06 pg per ml was reached 2 hr after oral administration of cimetidine (fig. 5). After treatment, peak concentration occurred 3 hr after administration and was significantly higher than at the corresponding time before treatment (0.69 & 0.1 versus 0.47 -e 0.1 pg per ml, P C 0.025). The blood levels remained significantly higher until 10 hr after drug administration. Fourteen of the 15 patients had measurable cimetidine blood concentrations during basal acid secretion collection after treatment. The concentrations ranged from 0 to 0.33 pg per ml, with a median of 0.05 pg per ml. The presence of cimetidine had no clear relationship to the lowered basal and pentagastrin-stimulated acid secretion after treatment, as blood cimetidine concentration was not significantly correlated with basal acid output (r = 0.39), change in basal acid output from pretreatment (r = 0.07), pentagastrin-stimulated acid output (r = -0.211, or change in pentagastrin-stimulated acid output from pretreatment (r = 0.40). Discussion One month of cimetidine therapy in 15 male duodenal ulcer patients resulted in increased meal-stimulated
serum gastrin concentrations and decreased inhibition by cimetidine of pentagastrin- and meal-stimulated acid secretion, and pentagastrin-stimulated pepsin secretion. The mechanism of these effects was not apparent. Two previous studies have found no consistent effect of cimetidine therapy on postprandial serum gastrin concentrationsg* *OThe reason for the differences between our data and previous work is not known. In one of these studies, patients with relatively large posttherapy reductions in basal intragastric pH and histamine-stimulated acid secretion did have increases in basal and meal-stimulated serum gastrin concentrations.‘O Further work is necessary to improve understanding of the effects of chronic cimetidine therapy upon gastric secretion and of the mechanism of observed effects. Detailed studies of cimetidine pharmacokinetics after chronic therapy are in order. REFERENCES 1. Bontils S, Bernier JJ, Mignon M, et al: Syndrome de ZollingerEllison traitemedicalement par un inhibiteur des recepteurs H, a l’histamine. Nouv Presse Med 4:2377-2381, 1975 2. Richardson CT, Walsh JH: The value of a histamine H,-receptor antagonist in the management of patients with the ZollingerEllison syndrome. N Engl J Med 294:133-1351976 3. Blair EL, Grund ER, Miller IT, et al: Metiamide in the ZollingerEllison syndrome. Am J Dig Dis 20:1123-1130,1975 4. Saunders JHB, Wormsley KG: Long-term effects and aftereffects of treatment of duodenal ulcer with metiamide. Lancet 1:765-767, 1977 5. Samloff IM, Dadufalza V: Biochemical studies of human group I and group II pepsins (abstr). Gastroenterology 70:963, 1976 6. Fordtran JS, Walsh JH: Gastric acid secretion rate and buffer content of the stomach after eating: results in normal subjects and in patients with duodenal ulcer. J Clin Invest 57:645-651, 1973 Yalow RS, Berson SA: Radioimmunoassay of gastrin. Gastroenterology 58:1-14, 1970 Samloff IM, Liebman WM: Radioimmunoassay of group I pepsinogens in serum. Gastroenterology 66494-502, 1974 Bank S, Barbezat GO, Vinik AI, et al: Cimetidine and gastrin levels in man. In Cimetidine: Proceedings of the Second International Symposium on Histamine HP-Receptor Antagonists. Edited by WL Burland, MA Simkins. Amsterdam-Oxford, Excerpta Medica, 1977, p 155-162 10. Spence RW, Celestin LR, McCormick DA, et al: The effect of 3 months’ treatment with cimetidine on basal and ‘Oxo’-stimulated serum gastrin. In Cimetidine: Proceedings of the Second International Symposium on Histamine Hz-Receptor Antagonists. Edited by WL Burland, MA Simkins. Amsterdam-Oxford, Excerpta Medica, 1977, p 163-174
DISCUSSION OF PAPER PRESENTED BY DRS. SEWING ET AL. DR. FORDTRAN:Was serum gastrin concentration higher
with cimetidine, even when you keep the pH constant by in vivo titration? DR. SEWING: That is correct. DR. FORDTRAN: This is new, then, and different from what Dr. Richardson was saying. DR. SEWING:That is right. DR. G. M. GRAY (Stanford): You inferred increased
absorption of cimetidine in the second part of the study from the concentrations of the drug in serum. Is that correct? DR. SEWING:That is correct, yes. DR. GRAY:Did you do any studies of the metabolism of the drug after it was absorbed to see whether or not it might have been metabolized differently in the second study, or that it might have been ex-
February 1978
DISCUSSION
creted differently. It seems to me more likely that body metabolism may have been altered, rather than that absorption from the gut changed. DR. SEWING:No, we did not do those kinds of studies. DR. H. T. DEBAS(Vancouver, B. C.): It seems to me that the degree of inhibition you got, with 300 mg of cimetidine, with peptone-stimulated acid secretion, was much less impressive than the inhibition that was shown to us by Dr. Richardson. Could you comment? DR. SEWING:Yes, I think that this has to be related to the absorption of the drug. It may well be that, at the time when cimetidine has reached an effective blood level, most of the peptone meal had been emptied from the stomach, so we do not have a meal stimulus any more; under these conditions we have to work very hard to show the inhibition. DR. F. KERN, JR. (Denver): What is known about the mechanism of absorption from the intestine? DR. SEWING:There are only animal data available, and these animal data indicate that the highest rate of absorption occurs in the ileum, medium absorption in the duodenum, and very low absorption in the jejunum. The physical chemical properties of the drug are such that it is very poorly absorbed in highly acidic environment, such as in the stomach. This is the only thing that I can say so far. Whether active transport is involved, that is something we do not know. DR. G. 0. BARBEZAT(Cape Town, South Africa): We have looked at the effect on acid secretion before and after 6 weeks of treatment in 20 patients with duodenal ulcer and have shown no significant reduction in effect after the g-week treatment. Basal gastrins were also unaffected after the 6-weeks of continuous treatment. Dr. Sewing, you have shown in your graphs a significant reduction after 4 weeks in stimulated acid secretion, which is significant, and a nonsig-
379
nificant reduction in your placebo patients. Have you compared the percentage changed in the placebo versus the percentage changed in the treated patients? I suggest that these would not be significant. DR. SEWING:No, we have not done that. DR. W. J. SNAPE,JR. (Philadelphia): With the elevated serum gastrin levels that you have shown over the 1 month of cimetidine, have you seen any increase in the gastric secretory mucosa in these patients? DR. SEWING:Peak acid secretion was not increased at the end of the treatment period with cimetidine. Therefore, I doubt that there was an increase in the parietal cell population. DR. D. M. MCCARTHY(Bethesda): I personally am not at all convinced that anybody has shown serious changes in basal acid output related to cimetidine therapy. I think that most of the so-called tachyphylactic episodes could be explained on the basis of inherent variation in the measurement of basal acid secretion. DR. SEWING:This is probably so. And I really did not put very much emphasis on the basal acid output data, so I would entirely agree with that. DR. J. J. MISIEWICZ(London): Correct me if I am wrong. Did not your repeat study after the 30-day treatment show a basal level of cimetidine of 0.2 pg per ml before you started your measurements, and could that have affected the data that you have presented? DR. SEWING:Yes. Just to make that point clear: it was not 0.2 pg per ml; it was 0.1 pg per ml on the graph. But, nevertheless, the point that you made is valid, and we have to take that into consideration. But that was part of the design of the study. Of course, if we had known that at that time we would still have some cimetidine levels in the blood, we would have waited a little longer before we started the second test.
Vol. 74,No. 2,Part2 Printed in USA.
EFFECT OF ONE-MONTH TREATMENT WITH CIMETIDINE ON GASTRIC SECRETION AND SERUM GASTRIN AND PEPSINOGEN LEVELS K. F. SEWING, M.D., LINDA HAGIE, A. F. IPPOLITI, M.D., J. I. ISENBERG, M.D., I. M. SAMLOFF, M.D.,
AND R. A. L. STURDEVANT, M.D.
Medical and Research Services, Veterans Administration Wadsworth Hospital Center, and the Department of Medicine, UCLA, Los Angeles, California
The inhibitory effects of cimetidine on gastric acid and pepsin secretion were studied before and after 1 month of treatment with 300 mg of cimetidine four times a day in 15 male duodenal ulcer patients. Cimetidine inhibited both pentagastrin- and peptone meal-stimulated acid secretion significantly better before, than after, 1 month of treatment. Similarly cimetidine inhibited pentagastrin-stimulated pepsin secretion significantly better before treatment. Meal-stimulated serum gastrin concentrations were significantly higher after treatment. The mechanism(s) of these effects was not apparent. Some observations suggest that Hz-receptor blocking drugs might lose efficacy during a course of treatment.‘+ Therefore, a study was designed to evaluate the effects of cimetidine on meal- and pentagastrinstimulated gastric acid and pepsin secretion, and gastrin release in response to a meal, before and after 1 month of treatment with cimetidine. Materials and Methods Patients. Fifteen male patients (53.5 + 3.2 years; mean f were studied. They each had previous endoscopic or radiographic evidence of duodenal ulcer, and had pain suggesting recurrent ulcer on accession into this study. On 2 consecutive days the patients had acid secretory tests, with pentagastrin and with peptone meal stimulation, in random order. They were then treated with 300 mg of cimetidine four times a day for 30 days. Both tests were then repeated. Patients were allowed antacid as needed for pain. Pentagastrin tests. A radioopaque nasogastric tube was fluoroscopically positioned in the stomach. Gastric acid secretion was collected for 4 hr in 15-min intervals. The volume was read to the nearest 0.1 ml. Acid was automatically titrated (Autoburet, Radiometer, Copenhagen, Denmark) against 0.2 N NaOH topH 7. Pepsin was determined according to the method of Samloff and Dadufalza.5 After a 1-hr basal secretion collection, 6 pg kg-’ hr-’ of pentagastrin were infused intravenously for 3 hr. After the 1st hr of pentagastrin, 300 mg of cimetidine were injected intravenously over 60 sec. Blood samples were drawn before and at intervals after cimetidine injection for determination of cimetidine; however, SEM)
Address requests for reprints to: J. I. Isenberg, M.D., Gastroenterology Section, Veterans Administration Wadsworth Hospital Center, Los Angeles, California 90073. This study was supported in part by a research grant from Smith Kline & French Laboratories, by the Veterans Administration, and by Grant AM 17328 from the National Institute of Arthritis, Metabolism and Digestive Diseases to CURE (Center for Ulcer Research and Education). K. F. S. is grateful to the Paul-Martini-Foundation for a personal grant.
some of these samples were unsatisfactory for technical reasons and the data are not discussed here. Peptone meal-stimulated acid secretion. After fluoroscopitally placing a double lumen nasogastric tube in the stomach, basal secretion was collected for 1 hr in 15-min periods. Then 500 ml of a 10% peptone meal, adjusted to pH 5.5 with 0.5 N HCl, were instilled into the stomach. Acid secreted in response to that meal was titrated intragastrically topH 5.5 with 0.5 N NaOH for 1 hr.” The gastric contents were then aspirated, and 300 mg of cimetidine were given orally. After 30 min (to permit drug absorption) a second peptone meal, identical to the first one, was instilled into the stomach. Intragastric titration was carried out until the test meal had emptied into the duodenum (usually 60 to 120 min). Gastric juice then was aspirated by continuous suction until 3 hr after instillation of the second test meal. The following determinations were made: serum gastrin concentrations at 0, 60, 120, 150, 180, 210, 250, and 300 min after the start of the secretory test, and blood cimetidine determinations at 0, 30, 60, 90, 120, 150, 360, and 600 min after cimetidine administration. After 1 month of cimetidine therapy, the two secretory tests were repeated on 2 consecutive days beginning about 12 hr after the last dose. Serum gastrin and group I pepsinogen concentrations were determined by radioimmunoassay.‘, 8 Blood cimetidine was measured by high pressure liquid chromatography after extraction into octanol (W. C. Randolph et al., unpublished data). Student’s t-test (paired) was used in the statistical analysis of the data. Results are expressed as mean * 1 SE.
Results Basal secretion. The mean basal secretion from the two secretory tests (pentagastrin and intragastric titration) was significantly reduced (P < 0.05) from 6.4 k 1.4 to 3.7 2 1.0 r&q per hr (42%) after 1 month of cimetidine treatment (figs. 1 and 4). Pentagastrin-stimulated secretion. One month of cimetidine therapy reduced pentagastrin-stimulated acid secretion significantly (P < 0.01) from 46 to 4.5 to
376
February 1978
CIMETIDINE
AND
GASTRIC
32.4 k 3 mEq per hr (fig. 1). Rapid intravenous injection of 300 mg of cimetidine inhibited acid secretion before and after treatment to the same absolute mean value (before, 6.6 + 0.8; after, 6.5 k 1 mEq per hr). After 1 month of treatment the percentage of inhibition was smaller because of lower acid secretion before cimetidine injection. During the 2nd hr after injection of cimetidine the acid response to pentagastrin was significantly (P < 0.05) higher after the 30-day cimetidine treatment (fig. 1). Pepsin secretion. The response to pentagastrin alone was unaltered by 1 month of cimetidine treatment (fig. 2). However, during the 2nd hr after the 300-mg dose of cimetidine, given intravenously, pepsin secretion was significantly (P < 0.01) higher after treatment than before (fig. 2). Meal-stimulated acid secretion. The acid response to the first peptone meal was 26.6 k 3.8 mEq per hr before and 23.9 +- 3.9 mEq per hr after 1 month of cimetidine treatment (fig. 3). The difference was not significant. Before treatment, 300 mg of cimetidine,
377
SECRETION BASAL
PEPTONE
MEALS
CIMETK)INE TREATMENT N .15 ?? . P’
2
1
0
3
. 6 ~g~k~-’
hr-’
,
4
5
(
6
1
FIG. 3. Effect of an oral dose of 300 mg of cimetidine on gastric acid secretion in response to a peptone meal (intragastric titration) in 15 duodenal ulcer patients before (0) and after (0) 30 days of treatment with 300 mg of cimetidine four times daily. Values are mean? ssM. MEALS
PENTAGASTRIN 4
300
CIMETIDINE
r
,
TIME ( hrs
PEPTONE BASAL
0025
300 mg
I
lo
lo ClMETlDlNE TREATMENT
ClMETlDlNE 300
v.
.
mg PO
N-15
CIMETIOINE
?? *
TREATMENT
/\
”
N.
15
.
D<
PC005 P~OOI
200 005
P < 0.01
z g 100
1
0
3
2
TIME (hr:)
FIG. 1. Effect of 300 pentagastrin-stimulated patients before (0) and of cimetidine four times
mg of cimetidine,
given intravenously, on gastric acid secretion in 15 duodenal ulcer after (0) 30 days of treatment with 300 mg daily. Values are mean k SEM.
6 yo
BASAL
ICQ-’ hr-’
c 31
1
2
3
4
5 TIME Ch:s)
FIG. 4. Serum gastrin in response to two consecutive peptone meals (intragastric titration) and an acute oral dose of 300 mg of cimetidine before the second meal in 15 duodenal ulcer patients before (0) and after (0) 30 days of treatment with 300 mg of cimetidine four times daily. Values are mean t SEM.
PENTAGASTRIN 4
CIMETIDINE TREATMENT N - 15 .
p < 0.01
I
0
1
2
3 TIME (I&:
FIG. 2. Effect of 300 mg of cimetidine, given intravenously, on pentagastrin-stimulated gastric pepsin secretion in 15 duodenal ulcer patients before (0) and after (0) 30 days of treatment with 300 mg of cimetidine four times daily. Values are mean t SEM.
orally, significantly (P < 0.005) reduced the peptonestimulated acid response during the 1st hr. In contrast, after treatment, acid secretion was not significantly inhibited in the corresponding hour. Acid secretion in the 2nd hr was inhibited in both instances (fig. 3,4 hr). However, the total acid response in the first 2 hr after the second meal was significantly greater (P < 0.05) after than before 1 month of treatment with cimetidine (fig. 3,3 and 4 hr). Serum gastrin. Mean basal serum gastrin concentrations were higher after 1 month of treatment with cimetidine (50 k 9 versus 83 + 22 pg per ml, 0.05 < P < 0.1) (fig. 4). The gastrin responses to both meals were significantly greater after 1 month of treatment than before (fig. 4). Serum pepsinogen. Fasting serum group I pepsinogen concentrations were 130.1 2 10.2 ng per ml before
378
Vol. 74, No. 2, Part 2
DISCUSSION
> 0
2
4
6
8
10
TIME (hrs)
FIG. 5. Concentration of cimetidine in blood after an oral dose of 300 mg of cimetidine before (0) and after (0) 30 days of treatment with 300 mg of cimetidine four times daily in 10 duodenal ulcer patients. Values are mean 2 sz~.
treatment, and 146.3 + 13.2 ng per ml after treatment. The difference was not statistically significant. Cimetidine blood concentrations. Before treatment, a maximum concentration of 0.53 + 0.06 pg per ml was reached 2 hr after oral administration of cimetidine (fig. 5). After treatment, peak concentration occurred 3 hr after administration and was significantly higher than at the corresponding time before treatment (0.69 & 0.1 versus 0.47 -e 0.1 pg per ml, P C 0.025). The blood levels remained significantly higher until 10 hr after drug administration. Fourteen of the 15 patients had measurable cimetidine blood concentrations during basal acid secretion collection after treatment. The concentrations ranged from 0 to 0.33 pg per ml, with a median of 0.05 pg per ml. The presence of cimetidine had no clear relationship to the lowered basal and pentagastrin-stimulated acid secretion after treatment, as blood cimetidine concentration was not significantly correlated with basal acid output (r = 0.39), change in basal acid output from pretreatment (r = 0.07), pentagastrin-stimulated acid output (r = -0.211, or change in pentagastrin-stimulated acid output from pretreatment (r = 0.40). Discussion One month of cimetidine therapy in 15 male duodenal ulcer patients resulted in increased meal-stimulated
serum gastrin concentrations and decreased inhibition by cimetidine of pentagastrin- and meal-stimulated acid secretion, and pentagastrin-stimulated pepsin secretion. The mechanism of these effects was not apparent. Two previous studies have found no consistent effect of cimetidine therapy on postprandial serum gastrin concentrationsg* *OThe reason for the differences between our data and previous work is not known. In one of these studies, patients with relatively large posttherapy reductions in basal intragastric pH and histamine-stimulated acid secretion did have increases in basal and meal-stimulated serum gastrin concentrations.‘O Further work is necessary to improve understanding of the effects of chronic cimetidine therapy upon gastric secretion and of the mechanism of observed effects. Detailed studies of cimetidine pharmacokinetics after chronic therapy are in order. REFERENCES 1. Bontils S, Bernier JJ, Mignon M, et al: Syndrome de ZollingerEllison traitemedicalement par un inhibiteur des recepteurs H, a l’histamine. Nouv Presse Med 4:2377-2381, 1975 2. Richardson CT, Walsh JH: The value of a histamine H,-receptor antagonist in the management of patients with the ZollingerEllison syndrome. N Engl J Med 294:133-1351976 3. Blair EL, Grund ER, Miller IT, et al: Metiamide in the ZollingerEllison syndrome. Am J Dig Dis 20:1123-1130,1975 4. Saunders JHB, Wormsley KG: Long-term effects and aftereffects of treatment of duodenal ulcer with metiamide. Lancet 1:765-767, 1977 5. Samloff IM, Dadufalza V: Biochemical studies of human group I and group II pepsins (abstr). Gastroenterology 70:963, 1976 6. Fordtran JS, Walsh JH: Gastric acid secretion rate and buffer content of the stomach after eating: results in normal subjects and in patients with duodenal ulcer. J Clin Invest 57:645-651, 1973 Yalow RS, Berson SA: Radioimmunoassay of gastrin. Gastroenterology 58:1-14, 1970 Samloff IM, Liebman WM: Radioimmunoassay of group I pepsinogens in serum. Gastroenterology 66494-502, 1974 Bank S, Barbezat GO, Vinik AI, et al: Cimetidine and gastrin levels in man. In Cimetidine: Proceedings of the Second International Symposium on Histamine HP-Receptor Antagonists. Edited by WL Burland, MA Simkins. Amsterdam-Oxford, Excerpta Medica, 1977, p 155-162 10. Spence RW, Celestin LR, McCormick DA, et al: The effect of 3 months’ treatment with cimetidine on basal and ‘Oxo’-stimulated serum gastrin. In Cimetidine: Proceedings of the Second International Symposium on Histamine Hz-Receptor Antagonists. Edited by WL Burland, MA Simkins. Amsterdam-Oxford, Excerpta Medica, 1977, p 163-174
DISCUSSION OF PAPER PRESENTED BY DRS. SEWING ET AL. DR. FORDTRAN:Was serum gastrin concentration higher
with cimetidine, even when you keep the pH constant by in vivo titration? DR. SEWING: That is correct. DR. FORDTRAN: This is new, then, and different from what Dr. Richardson was saying. DR. SEWING:That is right. DR. G. M. GRAY (Stanford): You inferred increased
absorption of cimetidine in the second part of the study from the concentrations of the drug in serum. Is that correct? DR. SEWING:That is correct, yes. DR. GRAY:Did you do any studies of the metabolism of the drug after it was absorbed to see whether or not it might have been metabolized differently in the second study, or that it might have been ex-
February 1978
DISCUSSION
creted differently. It seems to me more likely that body metabolism may have been altered, rather than that absorption from the gut changed. DR. SEWING:No, we did not do those kinds of studies. DR. H. T. DEBAS(Vancouver, B. C.): It seems to me that the degree of inhibition you got, with 300 mg of cimetidine, with peptone-stimulated acid secretion, was much less impressive than the inhibition that was shown to us by Dr. Richardson. Could you comment? DR. SEWING:Yes, I think that this has to be related to the absorption of the drug. It may well be that, at the time when cimetidine has reached an effective blood level, most of the peptone meal had been emptied from the stomach, so we do not have a meal stimulus any more; under these conditions we have to work very hard to show the inhibition. DR. F. KERN, JR. (Denver): What is known about the mechanism of absorption from the intestine? DR. SEWING:There are only animal data available, and these animal data indicate that the highest rate of absorption occurs in the ileum, medium absorption in the duodenum, and very low absorption in the jejunum. The physical chemical properties of the drug are such that it is very poorly absorbed in highly acidic environment, such as in the stomach. This is the only thing that I can say so far. Whether active transport is involved, that is something we do not know. DR. G. 0. BARBEZAT(Cape Town, South Africa): We have looked at the effect on acid secretion before and after 6 weeks of treatment in 20 patients with duodenal ulcer and have shown no significant reduction in effect after the g-week treatment. Basal gastrins were also unaffected after the 6-weeks of continuous treatment. Dr. Sewing, you have shown in your graphs a significant reduction after 4 weeks in stimulated acid secretion, which is significant, and a nonsig-
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nificant reduction in your placebo patients. Have you compared the percentage changed in the placebo versus the percentage changed in the treated patients? I suggest that these would not be significant. DR. SEWING:No, we have not done that. DR. W. J. SNAPE,JR. (Philadelphia): With the elevated serum gastrin levels that you have shown over the 1 month of cimetidine, have you seen any increase in the gastric secretory mucosa in these patients? DR. SEWING:Peak acid secretion was not increased at the end of the treatment period with cimetidine. Therefore, I doubt that there was an increase in the parietal cell population. DR. D. M. MCCARTHY(Bethesda): I personally am not at all convinced that anybody has shown serious changes in basal acid output related to cimetidine therapy. I think that most of the so-called tachyphylactic episodes could be explained on the basis of inherent variation in the measurement of basal acid secretion. DR. SEWING:This is probably so. And I really did not put very much emphasis on the basal acid output data, so I would entirely agree with that. DR. J. J. MISIEWICZ(London): Correct me if I am wrong. Did not your repeat study after the 30-day treatment show a basal level of cimetidine of 0.2 pg per ml before you started your measurements, and could that have affected the data that you have presented? DR. SEWING:Yes. Just to make that point clear: it was not 0.2 pg per ml; it was 0.1 pg per ml on the graph. But, nevertheless, the point that you made is valid, and we have to take that into consideration. But that was part of the design of the study. Of course, if we had known that at that time we would still have some cimetidine levels in the blood, we would have waited a little longer before we started the second test.