Acid Secretory Responses and Parietal Cell Sensitivity Following Duodenal Ulcer Healing with Omeprazole, Sucralfate, and Maalox DAVID A. JOHNSTON, MB., I. N. MARKS, EL%., MB., ch.B., GERRY 0. YOUNG, W~BRANDI, SHARON BRIDGER,JOHN ZAK, M.D., CapeTown, ~outh~frica
Acid secretory responses and parietal cell sensitivity (PCS) have been studied in 21 duodenal ulcer patients before and after successful treatment with omeprazole (n = 7), sucralfate (n = 7), or Maalox (n = 7). The second study was carried out 3 days after documented healing and withdrawal of treatment in the sucralfate- and Maalox-treated groups and 14 days after documented healing and withdrawal of treatment in the omeprazole-treated patients. Acid output (mmol/hour) was measured as basal secretion, and in response to 0.1 pglkgl hour pentagastrin (low-dose) and 6.0 pg/kg/ hour pentagastrin (high-dose) stimulation. PCS was calculated as the ratio of low dose:high dose acid output (expressed as a percentage). Ulcer healing with sucralfate resulted in significant (p CO.05) decreases in low-dose acid output from 36.4% (13.2-51.0) (median [range]) to 8.4% (3.2-45.4) mmol/hour and PCS from 69.1% (44.9-91.4) to 22.0% (16.0-85.61, whereas no significant decreases in any of the measured parameters were noted following ulcer healing with Maalox. Ulcer healing with omeprazole resulted in significant (p CO.051 decreases in basal acid output from 6.3 (1.522.9) (median [range]) to 2.2 (O-6.9) mmoll hour, and low-dose acid output from 31.0 (6.058.0) to 23.0 (1.4-44.8) mmol/hour. These findings suggest that acid secretory responses following ulcer healing vary according to the therapeutic agent used.
From the Gastrointesbnal Clinic, Department of Medicine, University of Cape Town. Groote Schuur Hospital, Cape Town, South Africa. Requests for reprmts should be addressed to I. N. Marks, &SC., M.B., Ch.B., Gastrointestinal Clinic, Groote Schuur Hospital, Observatory 7925, Cape Town,
Ph.D., NEL A. TIGLER-
A
cid secretory responses (ASRs) and parietal cell sensitivity (PCS) have been shown to decrease with duodenal ulcer (DU) healing following treatment with sucralfate, but remain essentially unchanged following ulcer healing with ranitidine [l-3]. The failure of the secretory responses to decrease following DU healing with ranitidine has been construed as evidence of “acid rebound,” a possible factor in DU relapse [4,5]. The purpose of this study was to determine the effect of two further ulcer-healing agents with different mechanisms of action on ASRs.
PATIENTSAND METHODS Thirty patients with an active endoscopically proven DU were admitted to a single-blind study. These patients had received no treatment other than token antacids for a least 3 weeks, and none had undergone previous ulcer surgery. Patients were randomized to receive treatment with either omeprazole 20 mg in the morning (n = 9>, sucralfate 2 g b.i.d. (n = lo), or Maalox number 2 (aluminum hydroxide gel, 400 mg and magnesium hydroxide, 400 mg, acid neutralizing capacity of 16 mmol/ tablet) 2 tablets q.i.d. (n = 11). The uneven allocation to each treatment group was based on anticipated differences in healing rates. Patients were re-endoscoped after 4 weeks, and if unhealed, at 6 and 8 weeks. Treatment was stopped once endoscopic healing was confirmed. If healing had not occurred after 8 weeks of treatment, the patients were withdrawn from the study. An initial acid secretory study was performed within 3 days of endoscopic confirmation of the active ulcer prior to starting treatment. A second acid secretory study was performed after endoscopic confirmation of ulcer healing. In the case of Maalox and sucralfate-healed patients, this was performed 3 days after withdrawal of treatment, whereas in the omeprazole-treated patients, this was performed 14 days after withdrawal of treatment. The post-omeprazole healing study was delayed in the hope of minimizing the possibility of a prolonged inhibitory drug effect. A fasting plasma gastrin level was taken on each acid secretory study day.
August 8, 1991
The American Journal of Medicine
Volume 91 (suppl 2A)
2A-91s
SYMPOSIUM ON SUCRALFATE / JOHNSTON
ET AL
RESULTS Twenty-one patients completed the study and were eligible for analysis. Nine patients were excludedfrom analysis.Of these, six patients failed to heal despite 8 weeks of treatment (Maalox: n = 4, sucralfate: n = 2>, one omeprazole-treatedpatient had a recurrence2 weeks after withdrawal of therapy, and two patients failed to return for follow-up (sucralfate:n = 1; omeprazole:n = 1).
TABLE I Patient Characteristics Age bead Omeprazole ;$ate
46(20-67) 34(23-64) 38(28-52)
Sex
Ulcer Size (mm?
6M:lF 5M:2F 3M:4F
514-30) 4(3-7) 4(3-6)
Values represent median (+range)
TABLE II
Comparison of Treatment Groups
Acid Secretory Responses and Parietal Cell Sensitivity Before and After DU Healing with Omeprazole, Sucralfate, and Maalox
Table I showsthat the age, sex, and ulcer size in the three treatment groups were comparable.
Acid output (mmollhour) Active Basal
Om(:!yie
Sucralfate (n=7)
6$1.5-22.9)
2.9(1.4-5.6)
Influence of Treatment on Changes in Acid-Secretory Response and Parietal Cell Sensitivity on Ulcer Healing
Maalox (n=7)
1.8(0.6-4.6)
The median (+ range) of the ASRs and PCS before and after DU healing for all three treatment Low Dose groupsis listed in Table II, and the individual data are shown in Figures 1 to 4. Figure 1 shows that 8.4(3.2-45.4) 23.6(16.0-44.2) Healed 23.0(1.4-44.8) 47.2(27.4-84.8) 48.4(29.4-73.8) 51.q32.2-75.4) Hi@ Dose Active the basal acid output decreasedsignificantly in the Healed 43.8(6.6-78.0) 35.6(16.2-56.0) 48.q26.4-68.2) omeprazole-treatedgroup. Figure 2 showsthat the PCS% Active 67.1(21.9-94.3) 69.!(44.9-91.4) 48.0(36.0-87.2) responseto low-dosestimulation was significantly lower in both the omeprazole- and sucralfateHealed 57.4(21.0-71.2) 22.0(16.0-85.6) 53.8(45.2-76.2) treated groups. The responseto high-dosestimula~~o;yesent median (+range). tion tended to decrease in all three treatment groups, but significancewas not attained (Figure 3). Figure 4 shows that a significant decreasein In addition, the omeprazole-healedpatients had a PCS occurredonly in the sucralfate-treatedgroup. further endoscopyimmediately after the second No significant changein any of the measuredpaacid secretory study, and if a recurrent ulcer was rameters was noted following DU healing with present they were excluded from the study. All Maalox (Figures 1 to 4). patients were re-endoscoped6 weeks after withdrawal of therapy to assessearly relapse rates. Acid secretory studies were performed in all pa- Fasting Gastrin Levels Fasting gastrin levels beforeand after ulcer healtients following a minimum lo-hour overnight fast. ing with omeprazole,sucralfate, or Maalox can be A nasogastrictube was passedand positionedradiseen in Table III. Gastrin levels in all groups were ographically in the most dependent part of the similar regardlessof ulcer activity. stomach.Gastric acid secretionwas collectedfor six lo-minute intervals for basalacid output, and at lominute intervals in responseto a constantintrave- Early Relapse Rates Endoscopic evidence of DU relapse within 6 nous infusion of graded dosesof pentagastrin, 0.1 weeks of documentedulcer healing and withdrawal and 6.0 pgikglhour for 60 minutes each. Acid output, in mmolhour, was calculatedfor the of therapy was noted in three of the sevenMaaloxbasal hour and for the low dose and high dose of healed patients, in one of the seven sucralfatepentagastrin using the three highest consecutive healed patients, and in two of eight omeprazolelo-minute acid outputs. Parietal cell sensitivity was healedpatients. One of the latter two recurrences calculated as the ratio of low dose:highdose acid was noted just prior to the scheduledpost-healing output expressedas a percentage.Fasting serum acid study 2 weeks after documentedhealing and gastrin levels were measuredusing radioimmuno- was accordingly omitted from study. assay technique. Statistical analysis was undertaken using the signedrank test. Informed consent COMMENTS was obtained from all patients, and the study was We have previously found that ASR and PCS approvedby the Ethical Review Committee of the decrease with ulcer healing with sucralfate but remain essentiallyunchangedwith ranitidine [l-31. Faculty of Medicine. Healed Active
2A-92s
August 8,
2.210-6.9) 31;0(6.0-58.0)
1991
1.4(0-4.1) 36$13.2-51.0)
2.6(1.3-4.9) 27.4(13.2-41.0)
The American Journal of Medicine
Volume
91
(suppl 2A)
SYMPOSIUM
ON SUCRALFATE / JOHNSTON
ET AL
1
p < 0.05
301
O-1
OMEPRAZOLE
SUCRALFATE
Figure 1. Basal acid output before (closed symbols) and after ulcer healing with omeprazole, sucralfate, and Maalox.
p < 0.05 0
60-
WALOX
OMEPRAZOLE
(open symbols)
SUCRALFATE
MAALOX
I
Figure 3. High-dose acid outputs before (closed symbols) and after (open symbols) ulcer healing with omeprazole, sucralfate, and Maalox.
p < 0.05
100
2. 2 i
0 ‘O-
3
fl
0
%
0
!$*o:
O 0
n n
0 A A
+ 0 .o
l o-
0
-
OMEPfWOLE
be 8 a
%
50
.> A
l
E! 2
A :
A
b 0
0
OMEPRAZOLE SUCRALFATE
MALOX
Figure 2. Low-dose acid output before (closed symbols) and after (open symbols) ulcer healing with omeprazole, sucralfate, and Maalox.
SUCRALFATE
MAALOX
Figure 4. PCS before (closed symbols) and after (open symbols) with omeprazole, sucralfate, and Maalox.
1
ulcer healing
TABLE III
There is some evidence that ASRs decrease with ulcer healing [6], and it has been postulated that decreases in ASR and PCS following sucralfate treatment are the norm following ulcer healing by a non-acid inhibitory agent. Acid rebound has been well documented in control subjects and in patients with healed DU following treatment with histamine-2 (H&receptor blockers [7-E?], and the failure to demonstrate decreases in ASR and PCS following healing of active DU with ranitidine has been construed as further evidence of such acid rebound. Little is known regarding the effect of antacids or the proton pump blocker omeprazole on the ASR or PCS following ulcer healing. The current study was carried out to compare the changes in ASR and PCS on DU healing after sucralfate treatment with those following healing with a potent antacid or omeprazole. Sucralfatehealing was again shown to be associated with a significant decrease in the response to low-dose
Fasting Gastrin Levels Before and After Ulcer Healing with Omeprazole, Sucralfate, and Maalox Fasting Gastrin Levels (pg/mL) Active Ulcer Omeprazole Sucralfate Maalox
Healed Ulcer
33.8(19.4-48.9)
35.4(18.6-89.7)
41.0(23.6-68.1) 36.0(27.9-43.5)
38.7(30.0-49.6)
34.1(29.0-40.6)
Values represent median (+range).
stimulation and PCS. Antacid-healing, on the other hand, was unassociated with a decrease in ASR or PCS, whereas omeprazole-healing was associated with a decrease in basal and low-dose acid output but not with PCS. The finding in the Maaloxtreated group appears to be in keeping with experimental data in rats [13] and with the notion of acid rebound following antacid administration in humans [14]. The nature of acid rebound in this set-
August 8,
1991 The American Journal of Medicine
Volume
91 (suppl 2A)
2A-93s
SYMPOSlUMON SIJCRALFATE / JOHNSTONET AL
ting is unclear, but it is tempting to invoke a pH- the duration of acid inhibition and acid reboundfoldependentpositive feedbackmechanismon the pa- lowing proton pump blockaderemains unresolved. rietal cell. The findings in the omeprazole-treated REFERENCES group are even more difficult to interpret. 1. Marks IN, Young GO, Tigler-Wybrandi NA, Bridger S, Newton KA. Acid-secretory The Bertaccini concept1151of acid reboundafter response and parietal cell sensitivity in patrents with duodenal ulcer disease before treatment with a Hz-receptorblocker presupposes and after treatment with sucralfate or ranrtidine. Am J Med 1989; 86(Suppl 6A): up-regulation of Hz-receptorson the parietal cell 145-7. Johnston DA, Marks IN, Young GO, Tigler-Wybrandi NA, Bridger S. Duodenal ulcer following Hz-receptor blockade, and coincidental 2.healing and acid secretory responses to modified sham feeding and pentagastrin paradoxicalup-regulation of gastrin receptorscon- stimulation, Aliment Pharmacol Ther 1990; 4: 403-10. sequentuponthe hypergastrinemiaassociatedwith 3. Kummer AF, Johnston DA, Marks IN, Tigler-Wybrandi NA, Bridger S, Young GO. in nocturnal acid secretion on duodenal ulcer healing with ranitidine and profound acid inhibition. The latter, it may be ar- Changes sucralfate. Gut 1990; 31: A599. gued, would allow for acid reboundeven in the ab- 4. Young GO, Marks IN, Tigler-Wybrandi NA, Bridger S, Newton KA. Changes in acid senceof Hz-receptorblockadeper se. The finding of secretory response and parietal ceil sensitivrty on healing predict early relapse in a significant decreasein basalacidoutput andin the patients with duodenal ulcer. S Afr Med J 1989; 75(Suppl 3): 2. 5. Yanaka A, Muto H. Increased parietal cell responsiveness to tetragastrin in paresponseto low-dosestimulation following healing tients with current duodenal ulcer. Dig Dis Sci 1988; 33: 1459-65. with omeprazoleappearsto be at variancewith this 6. Achord JL. Gastric pepsin and acid secretion in patients with acute and healed hypothesis. duodenal ulcer. Gastroenterol 1981; 81: 15-8. It shouldbe noted, however, that the decreasein 7. Aadland E, Berstad A. Parietal and chief cell sensitivity to histamine and pentastimulation before and after cimetidine treatment in healthy subiects. Stand low-doseacid output following omeprazolehealing, Jgastrin Gastroenterol 1979; 14: 933-8. albeit significant, was more modest than that fol- 8. Frisland K, Aadland E, Berstad A. Augmented postprandial gastric acid secretion lowing sucralfate healing, and that the PCS was due to exposure to ranitidine in healthy subjects. Stand J Gastroenterol 1986; 21: essentially unaltered. The arbitrary timing of the 119-22. 9. Jones DE, Howden CW, Burget DW, Silletti C, Hunt RH. Alteration of Hsreceptor repeat acid secretory study 2 weeks after sensitivity in duodenal ulcer patients after maintenance treatment with an H,-recep omeprazolehealing also warrants consideration.It tor antagonist. Gut 1988; 29: 890-3. was consideredprudent to delay the post-healing 10. Fullarton GM, McLauchlan G, MacDonald A, Crean GP, McCall KEL. Rebound hypersecretion after four weeks treatment with an H,-receptor antagostudy for 2 weeks to minimize the effect of possible nocturnal nist. Gut 1989; 30: 449-54. variations in the duration of post-omeprazoleacid 11. Nwokolo CU, Smith JTL, Pounder RE. Rebound intragastric hyperacidlty occurs inhibition, but even this seemingly long delay may following dosing with cimetidine, nizatidine and famotidlne. Gastroenterol 1989; 96: have beeninsufficient to allow restitution of parie- A369. 12. Prewett 0, Hudson M, Nwokolo CU, Swyerr A, Pounder RE. Return of intragastal cell function in some patients. tric acidity after gastric anti-secretory drugs. Gut 1990; 31: A600. Yokota et al [16] showeda slight, albeit insignifi- 13. Mazzacca G, Cascione F, Budillon G, D’Agostino L, Cimino L, Femiano C. Parietal cant, decreasein acid secretionin a small group of cell hyperplasla induced by long-term admlnlstration of antaclds to rats. Gut 1978; healedDU patients tested 7 days after a courseof 19: 798-801. 14. Clinton Texter E. A critical look at the clinical use of antacids in acid peptic omeprazole,and Prewett et al [12] foundno signifi- disease and gastric acid rebound. Am J Gastroenterol 1989; 84: 97-108. cant changein nocturnal acidity in control subjects 15. Bertaccini A. Receptors involved in the regulation of gastric acid secretion. S Afr tested sequentially 6 to 21 days after stopping Med J 1988; 74(Suppl 2 July): 3-4, 14. treatment. Walsh et al [17], on the other hand, re- 16. Yokota H, Yanaka A, Muto H. Effect of H+, K*-dependent ATPase inhibitor on parietal cell sensitivity in duodenal ulcer patients. Gastroenterol Int ported increasedacid responsesin a group of pre- (omeprazole) 1988; I(Suppl I): A480. dominantly active DU patients tested 14days after 17. Walsh JH, Sytnik B, Maxwell V, et al. Reversibility of plasma gastrin changes omeprazoletreatment. The controversy regarding induced by omeprazole or ranitidine in man. Am J Gastroenterol 1988; 83: 1042.
2A-94s
August 8, 1991
The American Journal of Medicine
Volume 91 (suppl 2A)
Acid secretory responses and parietal cell sensitivity (PCS) have been studied in 21 duodenal ulcer patients before and after successful treatment with omeprazole (n = 7), sucralfate (n = 7), or Maalox (n = 7). The second study was carried out 3 days after documented healing and withdrawal of treatment in the sucralfate- and Maalox-treated groups and 14 days after documented healing and withdrawal of treatment in the omeprazole-treated patients. Acid output (mmol/hour) was measured as basal secretion, and in response to 0.1 pglkgl hour pentagastrin (low-dose) and 6.0 pg/kg/ hour pentagastrin (high-dose) stimulation. PCS was calculated as the ratio of low dose:high dose acid output (expressed as a percentage). Ulcer healing with sucralfate resulted in significant (p CO.05) decreases in low-dose acid output from 36.4% (13.2-51.0) (median [range]) to 8.4% (3.2-45.4) mmol/hour and PCS from 69.1% (44.9-91.4) to 22.0% (16.0-85.61, whereas no significant decreases in any of the measured parameters were noted following ulcer healing with Maalox. Ulcer healing with omeprazole resulted in significant (p CO.051 decreases in basal acid output from 6.3 (1.522.9) (median [range]) to 2.2 (O-6.9) mmoll hour, and low-dose acid output from 31.0 (6.058.0) to 23.0 (1.4-44.8) mmol/hour. These findings suggest that acid secretory responses following ulcer healing vary according to the therapeutic agent used.
From the Gastrointesbnal Clinic, Department of Medicine, University of Cape Town. Groote Schuur Hospital, Cape Town, South Africa. Requests for reprmts should be addressed to I. N. Marks, &SC., M.B., Ch.B., Gastrointestinal Clinic, Groote Schuur Hospital, Observatory 7925, Cape Town,
Ph.D., NEL A. TIGLER-
A
cid secretory responses (ASRs) and parietal cell sensitivity (PCS) have been shown to decrease with duodenal ulcer (DU) healing following treatment with sucralfate, but remain essentially unchanged following ulcer healing with ranitidine [l-3]. The failure of the secretory responses to decrease following DU healing with ranitidine has been construed as evidence of “acid rebound,” a possible factor in DU relapse [4,5]. The purpose of this study was to determine the effect of two further ulcer-healing agents with different mechanisms of action on ASRs.
PATIENTSAND METHODS Thirty patients with an active endoscopically proven DU were admitted to a single-blind study. These patients had received no treatment other than token antacids for a least 3 weeks, and none had undergone previous ulcer surgery. Patients were randomized to receive treatment with either omeprazole 20 mg in the morning (n = 9>, sucralfate 2 g b.i.d. (n = lo), or Maalox number 2 (aluminum hydroxide gel, 400 mg and magnesium hydroxide, 400 mg, acid neutralizing capacity of 16 mmol/ tablet) 2 tablets q.i.d. (n = 11). The uneven allocation to each treatment group was based on anticipated differences in healing rates. Patients were re-endoscoped after 4 weeks, and if unhealed, at 6 and 8 weeks. Treatment was stopped once endoscopic healing was confirmed. If healing had not occurred after 8 weeks of treatment, the patients were withdrawn from the study. An initial acid secretory study was performed within 3 days of endoscopic confirmation of the active ulcer prior to starting treatment. A second acid secretory study was performed after endoscopic confirmation of ulcer healing. In the case of Maalox and sucralfate-healed patients, this was performed 3 days after withdrawal of treatment, whereas in the omeprazole-treated patients, this was performed 14 days after withdrawal of treatment. The post-omeprazole healing study was delayed in the hope of minimizing the possibility of a prolonged inhibitory drug effect. A fasting plasma gastrin level was taken on each acid secretory study day.
August 8, 1991
The American Journal of Medicine
Volume 91 (suppl 2A)
2A-91s
SYMPOSIUM ON SUCRALFATE / JOHNSTON
ET AL
RESULTS Twenty-one patients completed the study and were eligible for analysis. Nine patients were excludedfrom analysis.Of these, six patients failed to heal despite 8 weeks of treatment (Maalox: n = 4, sucralfate: n = 2>, one omeprazole-treatedpatient had a recurrence2 weeks after withdrawal of therapy, and two patients failed to return for follow-up (sucralfate:n = 1; omeprazole:n = 1).
TABLE I Patient Characteristics Age bead Omeprazole ;$ate
46(20-67) 34(23-64) 38(28-52)
Sex
Ulcer Size (mm?
6M:lF 5M:2F 3M:4F
514-30) 4(3-7) 4(3-6)
Values represent median (+range)
TABLE II
Comparison of Treatment Groups
Acid Secretory Responses and Parietal Cell Sensitivity Before and After DU Healing with Omeprazole, Sucralfate, and Maalox
Table I showsthat the age, sex, and ulcer size in the three treatment groups were comparable.
Acid output (mmollhour) Active Basal
Om(:!yie
Sucralfate (n=7)
6$1.5-22.9)
2.9(1.4-5.6)
Influence of Treatment on Changes in Acid-Secretory Response and Parietal Cell Sensitivity on Ulcer Healing
Maalox (n=7)
1.8(0.6-4.6)
The median (+ range) of the ASRs and PCS before and after DU healing for all three treatment Low Dose groupsis listed in Table II, and the individual data are shown in Figures 1 to 4. Figure 1 shows that 8.4(3.2-45.4) 23.6(16.0-44.2) Healed 23.0(1.4-44.8) 47.2(27.4-84.8) 48.4(29.4-73.8) 51.q32.2-75.4) Hi@ Dose Active the basal acid output decreasedsignificantly in the Healed 43.8(6.6-78.0) 35.6(16.2-56.0) 48.q26.4-68.2) omeprazole-treatedgroup. Figure 2 showsthat the PCS% Active 67.1(21.9-94.3) 69.!(44.9-91.4) 48.0(36.0-87.2) responseto low-dosestimulation was significantly lower in both the omeprazole- and sucralfateHealed 57.4(21.0-71.2) 22.0(16.0-85.6) 53.8(45.2-76.2) treated groups. The responseto high-dosestimula~~o;yesent median (+range). tion tended to decrease in all three treatment groups, but significancewas not attained (Figure 3). Figure 4 shows that a significant decreasein In addition, the omeprazole-healedpatients had a PCS occurredonly in the sucralfate-treatedgroup. further endoscopyimmediately after the second No significant changein any of the measuredpaacid secretory study, and if a recurrent ulcer was rameters was noted following DU healing with present they were excluded from the study. All Maalox (Figures 1 to 4). patients were re-endoscoped6 weeks after withdrawal of therapy to assessearly relapse rates. Acid secretory studies were performed in all pa- Fasting Gastrin Levels Fasting gastrin levels beforeand after ulcer healtients following a minimum lo-hour overnight fast. ing with omeprazole,sucralfate, or Maalox can be A nasogastrictube was passedand positionedradiseen in Table III. Gastrin levels in all groups were ographically in the most dependent part of the similar regardlessof ulcer activity. stomach.Gastric acid secretionwas collectedfor six lo-minute intervals for basalacid output, and at lominute intervals in responseto a constantintrave- Early Relapse Rates Endoscopic evidence of DU relapse within 6 nous infusion of graded dosesof pentagastrin, 0.1 weeks of documentedulcer healing and withdrawal and 6.0 pgikglhour for 60 minutes each. Acid output, in mmolhour, was calculatedfor the of therapy was noted in three of the sevenMaaloxbasal hour and for the low dose and high dose of healed patients, in one of the seven sucralfatepentagastrin using the three highest consecutive healed patients, and in two of eight omeprazolelo-minute acid outputs. Parietal cell sensitivity was healedpatients. One of the latter two recurrences calculated as the ratio of low dose:highdose acid was noted just prior to the scheduledpost-healing output expressedas a percentage.Fasting serum acid study 2 weeks after documentedhealing and gastrin levels were measuredusing radioimmuno- was accordingly omitted from study. assay technique. Statistical analysis was undertaken using the signedrank test. Informed consent COMMENTS was obtained from all patients, and the study was We have previously found that ASR and PCS approvedby the Ethical Review Committee of the decrease with ulcer healing with sucralfate but remain essentiallyunchangedwith ranitidine [l-31. Faculty of Medicine. Healed Active
2A-92s
August 8,
2.210-6.9) 31;0(6.0-58.0)
1991
1.4(0-4.1) 36$13.2-51.0)
2.6(1.3-4.9) 27.4(13.2-41.0)
The American Journal of Medicine
Volume
91
(suppl 2A)
SYMPOSIUM
ON SUCRALFATE / JOHNSTON
ET AL
1
p < 0.05
301
O-1
OMEPRAZOLE
SUCRALFATE
Figure 1. Basal acid output before (closed symbols) and after ulcer healing with omeprazole, sucralfate, and Maalox.
p < 0.05 0
60-
WALOX
OMEPRAZOLE
(open symbols)
SUCRALFATE
MAALOX
I
Figure 3. High-dose acid outputs before (closed symbols) and after (open symbols) ulcer healing with omeprazole, sucralfate, and Maalox.
p < 0.05
100
2. 2 i
0 ‘O-
3
fl
0
%
0
!$*o:
O 0
n n
0 A A
+ 0 .o
l o-
0
-
OMEPfWOLE
be 8 a
%
50
.> A
l
E! 2
A :
A
b 0
0
OMEPRAZOLE SUCRALFATE
MALOX
Figure 2. Low-dose acid output before (closed symbols) and after (open symbols) ulcer healing with omeprazole, sucralfate, and Maalox.
SUCRALFATE
MAALOX
Figure 4. PCS before (closed symbols) and after (open symbols) with omeprazole, sucralfate, and Maalox.
1
ulcer healing
TABLE III
There is some evidence that ASRs decrease with ulcer healing [6], and it has been postulated that decreases in ASR and PCS following sucralfate treatment are the norm following ulcer healing by a non-acid inhibitory agent. Acid rebound has been well documented in control subjects and in patients with healed DU following treatment with histamine-2 (H&receptor blockers [7-E?], and the failure to demonstrate decreases in ASR and PCS following healing of active DU with ranitidine has been construed as further evidence of such acid rebound. Little is known regarding the effect of antacids or the proton pump blocker omeprazole on the ASR or PCS following ulcer healing. The current study was carried out to compare the changes in ASR and PCS on DU healing after sucralfate treatment with those following healing with a potent antacid or omeprazole. Sucralfatehealing was again shown to be associated with a significant decrease in the response to low-dose
Fasting Gastrin Levels Before and After Ulcer Healing with Omeprazole, Sucralfate, and Maalox Fasting Gastrin Levels (pg/mL) Active Ulcer Omeprazole Sucralfate Maalox
Healed Ulcer
33.8(19.4-48.9)
35.4(18.6-89.7)
41.0(23.6-68.1) 36.0(27.9-43.5)
38.7(30.0-49.6)
34.1(29.0-40.6)
Values represent median (+range).
stimulation and PCS. Antacid-healing, on the other hand, was unassociated with a decrease in ASR or PCS, whereas omeprazole-healing was associated with a decrease in basal and low-dose acid output but not with PCS. The finding in the Maaloxtreated group appears to be in keeping with experimental data in rats [13] and with the notion of acid rebound following antacid administration in humans [14]. The nature of acid rebound in this set-
August 8,
1991 The American Journal of Medicine
Volume
91 (suppl 2A)
2A-93s
SYMPOSlUMON SIJCRALFATE / JOHNSTONET AL
ting is unclear, but it is tempting to invoke a pH- the duration of acid inhibition and acid reboundfoldependentpositive feedbackmechanismon the pa- lowing proton pump blockaderemains unresolved. rietal cell. The findings in the omeprazole-treated REFERENCES group are even more difficult to interpret. 1. Marks IN, Young GO, Tigler-Wybrandi NA, Bridger S, Newton KA. Acid-secretory The Bertaccini concept1151of acid reboundafter response and parietal cell sensitivity in patrents with duodenal ulcer disease before treatment with a Hz-receptorblocker presupposes and after treatment with sucralfate or ranrtidine. Am J Med 1989; 86(Suppl 6A): up-regulation of Hz-receptorson the parietal cell 145-7. Johnston DA, Marks IN, Young GO, Tigler-Wybrandi NA, Bridger S. Duodenal ulcer following Hz-receptor blockade, and coincidental 2.healing and acid secretory responses to modified sham feeding and pentagastrin paradoxicalup-regulation of gastrin receptorscon- stimulation, Aliment Pharmacol Ther 1990; 4: 403-10. sequentuponthe hypergastrinemiaassociatedwith 3. Kummer AF, Johnston DA, Marks IN, Tigler-Wybrandi NA, Bridger S, Young GO. in nocturnal acid secretion on duodenal ulcer healing with ranitidine and profound acid inhibition. The latter, it may be ar- Changes sucralfate. Gut 1990; 31: A599. gued, would allow for acid reboundeven in the ab- 4. Young GO, Marks IN, Tigler-Wybrandi NA, Bridger S, Newton KA. Changes in acid senceof Hz-receptorblockadeper se. The finding of secretory response and parietal ceil sensitivrty on healing predict early relapse in a significant decreasein basalacidoutput andin the patients with duodenal ulcer. S Afr Med J 1989; 75(Suppl 3): 2. 5. Yanaka A, Muto H. Increased parietal cell responsiveness to tetragastrin in paresponseto low-dosestimulation following healing tients with current duodenal ulcer. Dig Dis Sci 1988; 33: 1459-65. with omeprazoleappearsto be at variancewith this 6. Achord JL. Gastric pepsin and acid secretion in patients with acute and healed hypothesis. duodenal ulcer. Gastroenterol 1981; 81: 15-8. It shouldbe noted, however, that the decreasein 7. Aadland E, Berstad A. Parietal and chief cell sensitivity to histamine and pentastimulation before and after cimetidine treatment in healthy subiects. Stand low-doseacid output following omeprazolehealing, Jgastrin Gastroenterol 1979; 14: 933-8. albeit significant, was more modest than that fol- 8. Frisland K, Aadland E, Berstad A. Augmented postprandial gastric acid secretion lowing sucralfate healing, and that the PCS was due to exposure to ranitidine in healthy subjects. Stand J Gastroenterol 1986; 21: essentially unaltered. The arbitrary timing of the 119-22. 9. Jones DE, Howden CW, Burget DW, Silletti C, Hunt RH. Alteration of Hsreceptor repeat acid secretory study 2 weeks after sensitivity in duodenal ulcer patients after maintenance treatment with an H,-recep omeprazolehealing also warrants consideration.It tor antagonist. Gut 1988; 29: 890-3. was consideredprudent to delay the post-healing 10. Fullarton GM, McLauchlan G, MacDonald A, Crean GP, McCall KEL. Rebound hypersecretion after four weeks treatment with an H,-receptor antagostudy for 2 weeks to minimize the effect of possible nocturnal nist. Gut 1989; 30: 449-54. variations in the duration of post-omeprazoleacid 11. Nwokolo CU, Smith JTL, Pounder RE. Rebound intragastric hyperacidlty occurs inhibition, but even this seemingly long delay may following dosing with cimetidine, nizatidine and famotidlne. Gastroenterol 1989; 96: have beeninsufficient to allow restitution of parie- A369. 12. Prewett 0, Hudson M, Nwokolo CU, Swyerr A, Pounder RE. Return of intragastal cell function in some patients. tric acidity after gastric anti-secretory drugs. Gut 1990; 31: A600. Yokota et al [16] showeda slight, albeit insignifi- 13. Mazzacca G, Cascione F, Budillon G, D’Agostino L, Cimino L, Femiano C. Parietal cant, decreasein acid secretionin a small group of cell hyperplasla induced by long-term admlnlstration of antaclds to rats. Gut 1978; healedDU patients tested 7 days after a courseof 19: 798-801. 14. Clinton Texter E. A critical look at the clinical use of antacids in acid peptic omeprazole,and Prewett et al [12] foundno signifi- disease and gastric acid rebound. Am J Gastroenterol 1989; 84: 97-108. cant changein nocturnal acidity in control subjects 15. Bertaccini A. Receptors involved in the regulation of gastric acid secretion. S Afr tested sequentially 6 to 21 days after stopping Med J 1988; 74(Suppl 2 July): 3-4, 14. treatment. Walsh et al [17], on the other hand, re- 16. Yokota H, Yanaka A, Muto H. Effect of H+, K*-dependent ATPase inhibitor on parietal cell sensitivity in duodenal ulcer patients. Gastroenterol Int ported increasedacid responsesin a group of pre- (omeprazole) 1988; I(Suppl I): A480. dominantly active DU patients tested 14days after 17. Walsh JH, Sytnik B, Maxwell V, et al. Reversibility of plasma gastrin changes omeprazoletreatment. The controversy regarding induced by omeprazole or ranitidine in man. Am J Gastroenterol 1988; 83: 1042.
2A-94s
August 8, 1991
The American Journal of Medicine
Volume 91 (suppl 2A)
