Effect of Duodenal Ulcer Healing Induced by Omeprazole and Ranitidine on the Generation of Gastroduodenal Eicosanoids, Platelet-Activating Factor, Pepsinogen 9 A, and Gastrin in Duodenal Ulcer Patients J. LYSY, F. KARMELI, D. WENGROWER & D. RACHMILEWITZ and Hebrew University Hadassah
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Lysy J , Karmeli F, Wengrower D, Rachmilewitz D . Effect of duodenal ulcer healing induced by omeprazole and ranitidine on the generation of gastroduodenal eicosanoids, platelet-activating factor, pepsinogen A, and gastrin in duodenal ulcer patients. Scand J Gastroenterol 1992, 27, 13-19 G h e effect of duodenal ulcer healing induced by omeprazole on gastroduodenal generation of eicosanoids, platelet-activating factor (PAF), pepsinogen A, and gastrin was evaluated. Sixty patients with endoscopically proven duodenal ulcer were randomized to receive 20 mg omperazole once daily or 300 mg ranitidine at bedtime for 2 weeks. Patients whose ulcers did not heal were treated for an additional 2 weeks. Endoscopic biopsy specimens and serum samples were obtained before and after treatment. There was no significant difference in the healing rate between the two treatment modalities. At 2 weeks healing rates were 60% and 56% in the omperazole and ranitidine groups, respectively, whereas at 4 weeks the respective healing rates were 96% and 86%. Ulcer healing induced by omeprazole and ranitidine was' not accompanied by significant changes in mucosal leukotriene B, or C, generation. Mucosal PAF significantly decreased in patients treated with omeprazole for 4 weeks. In omperazoletreated patients there was a trend towards increase in mucosal prostaglandin Ez generation which was significant in the fundus after 4 weeks of treatment. After 2 weeks of omeprazole treatment, serum gastrin and pepsinogen A levels almost doubled when compared with their pretreatment levels. In conclusion, duodenal ulcer healing with 20 mg omeprazole daily is not superior to healing rates with 300 rng ranitidine at bedtime after both 2 and 4 weeks of treatment. In omeprazole-treated subjects ulcer healing was accompanied by a significant decrease in mucosal PAF generation and increased levels of serum gastrin and pepsinogen A
J
Key words: Duodenal ulcer; gastrin; leukotrienes; omeprazole; pepsinogen A; platelet-activating factor; prostaglandin E,; ranitidine Daniel Rachmilewitz, M . D . , Dept. of Medicine, Hadassah University Hospital, Mount Scopus, P . 0. Box 240.75, Jerusalem 91240, Israel
Gastroduodenal generation of the mediators of inflammation-platelet-activating factor (PAF) and leukotrienes (LT) B4 and C,-was shown to be increased in patients with active duodenal ulcer. Moreover, after induction of ulcer healing with cimetidine, their generation was shown to decrease, suggesting that they may have a role in the pathogenesis of peptic ulcer (1). On the other hand, in patients with duodenal ulcer gastric prostanoid generation was shown to b e decreased and to resume normal control levels after healing induced by cimetidine and ranitidine (2,3), thus suggesting that the induction of endogenous prostanoids by H2 blockers may contribute to their therapeutic effect. The aim of the present study was to assess the effect of omeprazole on gastroduodenal generation of eicosanoids and platelet-activating factor in duodenal ulcer patients. Omeprazole was reported to increase serum gastrin levels (4,5),
which may be involved in the pathogenesis of enterochromaffin-like cell hyperplasia in rats (5,7). Omeprazole effects on pepsinogen generation are not well defined. In the present study the effect of treatment with omeprazole on serum gastrin and pepsinogen A levels and on their gastric generation was also evaluated. MATERIALS AND METHODS
Patients Endoscopic antral fundic and duodenal biopsy specimens and serum were obtained from patients with endoscopically proven duodenal ulcer. All patients were examined on the day the diagnosis was established, before treatment was started, and also after 2 or 4 weeks of therapy, in a clinical trial designed to compare the efficacy of 20 mg omeprazole
14
J. Lysy et al.
Table I. Patients’ characteristics
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No. Sex, male to female ratio Age (years) Range Mean Smokers, no.
Omeprazole
Ranitidine
30 2317
30 26:4
1 %74 36.3 2 2.6 12
19-69 42.3 ? 2.1 14
once daily in the morning versus 300mg ranitidine at bedtime. The trial was double-blind. Patients recruited were men or women, 18-75 years old with at least one ulcer with a diameter of 5 mm or larger. Patients were excluded if they were pregnant or breast-feeding, if they had been treated with anti-ulcer drugs for more than 3 days during the 14 days preceding endoscopy, or if they had pyloric stenosis or concurrent gastric or prepyloric ulcer. Other exclusion criteria were previous gastric surgery, continuous treatment with non-steroidal anti-inflammatory drugs and chronic alcoholism. The double-dummy technique was used, and each patient received either omeprazole with placebo ranitidine or ranitidine with placebo omeprazole. Patients were endoscoped after 2 weeks of treatment, and those in whom the ulcer had not healed received medication for another 2 weeks, when endoscopy was repeated. The nature of the specific therapy the patients were receiving was not known until the trial was completed. The investigators were made aware of the medication the patients were receiving only after all the experiments and study were completed. All 60 patients recruited concluded the trial satisfactorily, with 30 patients in each of the treatment groups. Sex and age distribution were similar in the groups (Table I). In 41 subjects 2 mucosal specimens were obtained during each endoscopy from the stomach antrum and fundus and also from the duodenal bulb from an area opposite the ulcer site. In most patients specimens were obtained during both endoscopies, but in several only during one of the procedures. The last medication was taken 10 h before the second or third endoscopy in those patients whose ulcers did not heal after 2 weeks of treatment. In all subjects endoscopy was performed with the Olympus GIFQ or OES endoscope after a 10-h fast. Diazepam was given intravenously as premedication. Biopsy specimens were obtained with the biopsy forceps 12 BK (Olympus), washed i n 0.15 M NaC1, weighed (average weight, 9 mg wet wt), and cultured within 10 min of excision. The study was approved by the Helsinki Committee of the Hadassah University Hospital.
Organ culture Non-proliferative organ culture was performed as previously described by us in detail (8). The culture medium
used was RPMI 1640 (Bio Lab., Israel) containing penicillin (100 U/ml) and streptomycin (100 pglml). The culture was carried out for 2 h . A t the end of each culture the medium was kept at -20°C for eicosanoid determination. The tissue was homogenized in 1.0 ml ice-cold 50 mM Tris HCI buffer, pH 7.0, containing 0.02 M ethylenediaminetetraacetic acid (EDTA) and 1.0ml ether, and the aqueous phase was assayed for its eicosanoid content.
Measurement of LTB, LTB, immunoreactivity was determined with a radioimmunoassay (RIA) kit (Amersham, TRK 940). The assay combines the use of a high specific activity leukotriene B4 tracer, an antiserum specific for LTB, (cross-reactivity, loo%), and a leukotriene standard (range, 1.6-200 pg/tube). The specific binding of tracer is 42.5% ; non-specific binding, 2.4%. Fifty per cent B/Bo displacement is obtained with 15 pg/tube, and 90% B/Bo displacement with 2.2 pgftube of LTB,. Measurement of LTC, LTC, immunoreactivity was determined with a RIA kit (Amersham, TRK 905). The assay combined the use of a high specific activity LTC4 tritiated tracer with a monoclonal antibody specific for LTC, and LTC, standard. The standard curve covers the range 8 to 500pg/tube. The assay uses highly specific LTC, antiserum (cross-reactivity , 100%) and has low cross-reactivity with LTD, (< 5%). The specific binding of tracer is 40.2%; non-specific binding, 3%. Fifty per cent B/Bo displacement is obtained with 34pg/tube, and 80% B/Bo displacement with 9.5 pg/tube of LTC,. Measurement of PGE2 Prostaglandin E2 was determined with R I A as previously described (9). Measurement of gastrin and pepsinogen levels Gastrin level in the serum and culture medium was determined with a R I A (International CIS, St. Quentin, Yvelines, France). Pepsinogen A level in the serum and the culture medium was determined with a R I A (International CIS). PAF determination Organ culture. Fundic, antral, and duodenal biopsy specimens were organ-cultured for 2 h at 37°C in a humidified atmosphere containing 5% C 0 2 in 0.5ml of modified Tyrode’s buffer containing 1 mm C a + + , 0.1 mM Mg++$and 0.5% fatty acid-free bovine albumin ( p H 7.4) (TBSA), to which 0.2 pM calcium ionophore A23187 was added. After 2 h of incubation cultured specimens and medium were transferred t o separate tubes and kept at -20°C until extraction of PAF activity. Twenty-four hours before performance of the aggregation assay 0.5 ml ethanol (80%) was added to the gastric mucosa to extract P A F from the tissue.
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Effect of Omeprazole on Duodenal Ulcer
Plateletpreparation. Fifty milliliters of rabbit venous blood were collected into Falcon tubes, mixed with 1 ml 0.2 M EDTA and centrifuged for 20 min at 1600 rpm. Plasma was transferred to another Falcon tube and centrifuged for 15 min at 3000 rpm. The platelet pellet was reconstituted with a washing buffer (pH 6.5) containing 2.6 mM KCI, 1 m M MgCI2, 137mM NaCI, 12mM NaHC03, 0.2mM ethyleneglycol-bis(beta-amino-ethylether)-&', "-tetraacetic acid, 5.5 mM glucose, and 0.25% gelatine and centrifuged for 15 min at 3000 rpm. The platelet pellet was resuspended in the above buffer and treated with 0.1 mM aspirin for 15 min at room temperature, followed by another centrifugation for 15min at 3000rpm. Platelets were resuspended in washing buffer at appropriate concentrations for the measurement of platelet aggregation (25). Aggregation assay. PAF activity was measured by platelet aggregation using a Chrono-Log Corp. aggregometer. Platelets were stirred in 400 pl of buffer containing 2.6 mM KCI, 1mM MgC12, 137mM NaCl, 12mM NaHC03, 1.3mM CaClz, 5.5 mM glucose, 0.25% gelatin, 1 mM creatine phosphate, and 10 U/ml creatine phosphokinase (pH 7.4). Samples of 1Oyl of the 80% ethanol extract or from the medium were added and aggregation recorded. Ten microliters of ethanol or calcium ionophore, 0.2 pM, did not induce aggregation. In some experiments the inhibitory effect of the PAF antagonist WEB 2086 was tested by adding 10 p1 1 min before adding the aggregating agent. WEB 2086 BS inhibited dose-dependently (0.17-17 pM) the PAF-induced platelet aggregation ( r = 0.891; y = 140-8.8X). The effect of WEB 2086 was tested both on synthetic PAF and PAF extracted from specimens. Materials Aspirin was obtained from Aspegic, Lab Egic, Amilly, France; EDTA, ethylene glycol-bis-(beta-aminoethy1ether)N,N'-tetraacetic acid, calcium ionophore A23187, creatine phosphate, creatine phosphokinase, phosphatidylcholine, lysophosphatidylcholine, sphingomyelin, fatty acid-free bovine serum albumin, and horse serum from Sigma Laboratories, Israel; gelatin, precoated silica gel 60 F 254 plates, and Norit-activated charcoal from E. Merck, Darmstadt,
Table 11. Duodenal ulcer healing 2 weeks Treatment Orneprazole All patients Smokers Ranitidine All patients Smokers
4 weeks
No.
96
No.
%
18/30 4/12
60.0 33.3
29/30 11/12
96.6 91.6
17/30 9/16
56.5 56.2
26/30 14/16
86.6 87.5
15
Germany; PAF (C18) 1-0-octadecyl-2-0-acetyl-sn glycero3 phosphorylcholine from Bachem, Switzerland; RPMI 1640 from Biolab, Israel; leukotriene B4 [3H]assay system, leukotriene C4 [3H] from Amersham, England; 3-[4-(2-chlorphenyl)-9-methyl-6H-thieno-(3,2-f)-( 1,2,4)], triazolo-[ ( 4 3 a)(1,4)-diazepin-2-yl]-l-(4-morpholinyl)l-propanon, and WEB 2086 BS were donated by Boehringer Ingelheim KG, Germany; and dextran T-70 was purchased from Pharmacia, Uppsala, Sweden. Statistical methods Statistical differences between the various groups were evaluated with Student's t test for unpaired and paired data and by the non-parametric Mann-Whitney test. P values less than 0.05 were considered significant. Results are expressed as the mean 4 standard error (mean & SE).
RESULTS There was no statistically significant difference in healing rates between the omeprazole and ranitidine treatment modalities at 2 and 4 weeks. At 2 weeks the healing rate was 60% and 56% in the omeprazole- and ranitidine-treated groups, respectively, whereas at 4 weeks the respective healing rates were 96% and 86% (Table 11). Smoking adversely affected healing only after 2 weeks of treatment with omeprazole. Ulcer healing induced by both omeprazole and ranitidine was not accompanied by significant changes in gastric or duodenal LTB4 or LTC4 generation. Ulcer healing induced by both drugs was accompanied by a trend towards a decrease in the mucosal generation of LTB4 at 4 weeks, although it did not reach statistical significance (Tables 111 and IV). The generation of mucosal PAF, LTB4, and LTC4 in the four patients whose ulcers did not heal during 4 weeks on ranitidine did not differ at the end of the treatment from the respective generation in the other patients whose ulcers healed (Tables 111-V). In these four patients pretreatment generation of PAF, LTB4, and LTC4 was also similar to the pretreatment generation in the other patients (results not shown). In the omeprazole-treated patients gastric and duodenal PAF significantly decreased in those patients who were treated for 4 weeks. After 2 weeks of omeprazole treatment only fundal PAF generation was significantly decreased. In the ranitidine-treated patients significant decrease in mucosal PAF was observed only in the duodenum after 2 weeks of treatment (Table V). There was a trend towards an increase in mucosal PGEz generation in the omeprazoletreated subjects, although it reached statistical significance only in the fundus after 4 weeks of treatment (Table VI). Serum gastrin levels were significantly increased 2 weeks after treatment with omeprazole, whereas ranitidine treatment did not affect serum gastrin levels. Antral and duodenal
16
J. Lysy
el
al.
Table 111. Gastroduodenal leukotriene B, (LTB,) generation in duodenal ulcer patients No.
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Rani tidine Before treatment Healed 2 weeks Healed 4 weeks Not healed Omeprazole Before treatment Healed 2 weeks Healed 4 weeks
*
*
4
15.6 3.3 15.7 2 6.0 10.0 k 2.0 30.0 14.5
*
19.0 _t 5.0 9.5 t 2.8 16.7 7.7 32.0 t 14.0
*
29.0 7.0 28.5 t 10.0 19.5 _t 6.0 22.0 +- 3.0
15 10 6
15.4 2 2.5 24.2 ? 3.9 20.6 2 6.7
23.2 t 5.0 18.0 ‘-c 4.9 22.4 t 7.0
19.0 t 3.0 23.0 3.0 24.0 5 6.4
23 14
5
*
Endoscopic biopsy specimens were obtained from gastric and duodenal mucosa of patients with active duodenal ulcers before treatment and also after 2 or 4 weeks’ treatment with 300 mg ranitidine at bedtime or 20 mg omeprazole. The tissue was cultured for 2 h, and LTB4 relcased into the medium and its tissue content at the end of the culture were determined by radioimmunoassay. Results are mean t SE.
Table 1V. Gastroduodenal leukotriene C4 (12TC4)generation in duodenal ulcer patients
Ranitidine Before treatment Healed 2 weeks Healed 4 weeks Not healed Omeprazole Before treatment Healed 2 weeks Healed 4 weeks
22 14
4
142 t 21 I24 t 26 159 2 30 274 t 56
97 t_ 17 6 9 t 11 83 5 19 75 t 21
181 2 30 182 ? 34 308 5 58 230 t 93
17 10 7
183 t 33 1 3 8 t 14 188 38
9 6 5 13 86 ? 18 78 t 17
230 f 40 228 5 38 230 t 56
5
*
Endoscopic biopsy specimens were obtained from gastric and duodenal mucosa of patients with active duodenal ulcers before treatment and also after 2 or 4 weeks’ treatment with 300mg ranitidine at bedtime or 20 mg omeprazole. The tissue was cultured for 2 h , and LTC, release into the medium and its tissue contcnt at the cnd of the culture were determined by radioimmunoassay. Results are mean SE.
*
gastrin generation were not significantly affected by either omeprazole or ranitidine (Table VII). Significant increase in the serum pepsinogen A level was observed after 2 and 4 weeks of treatment with omeprazole. Fundic pepsinogen A was not stimulated by omeprazole. and ranitidine also did not affect its serum level or fundic generation (Table VlII).
DISCUSSION
In the present study duodenal ulcer healing induced by omeprazole administered for 2 weeks in a dose of 20mg/ day was found to be similar to that induced by ranitidine, 300mg/day. At 4 weeks, too, there was no statistically significant difference between the two treatment modalities, although in absolute terms, healing rates with omeprazole were higher. The relatively high healing rate with ranitidine reported here may be due to the fact that in Israel healing rates of duodenal ulcers are generally higher than those reported elsewhere, irrespective of the treatment modalityranitidine or even placebo (10, 11). The reason for this has never been properly defined.
The generation of gastric and duodenal PAF, LTB4, and LTC4in patients with duodenal ulcers enrolled in the present study is in the range previously reported by us and higher than their respective generation in normal healthy subjects (1). We have previously shown that, after ulcer healing induced by 4 weeks’ treatment with cimetidine, the enhanced generation of these inflammatory mediators decreases and tends to resume normal control levels (1). In the present study ulcer healing induced by ranitidine was not accompanied by a significant decrease in the generation of these inflammatory mediators, and this may be because there were relatively few patients in this treatment group. O n the other hand, ulcer healing induced by omeprazole was accompanied by a significant decrease in P A F generation, confirming that P A F may be involved in the pathogenesis of peptic ulcer disease. Gastric, antral, and fundal PGEz generation are also reduced in duodenal ulcer patients when compared with their generation by normal healthy subjects, previously reported by us (3). Induction of ulcer healing with omeprazole was accompanied by increase in PGE2 generation but reached statistical significance only in the fundus. We have previously
Effect of Omeprazole on Duodenal Ulcer
17
Table V. Gastroduodenal platelet-activating factor (PAF) generation in duodenal ulcer patients before and after treatment Fundus
Antrum (pg/l0 mg wet wt)
106 t 16 87 t 14 74 t 14 37 2 6
82 & 12 61 2 10 61 15 61 t 11
*
126 _t 19 102 t 17* 74 2 11 I19 2 46
80 t 9 6 6 5 11 53 2 10*
9 6 2 14 89 2 20 50 +- 10*
No.
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Ranitidine Before treatment Healed 2 weeks Healed 4 weeks Not healed Omeprazole Before treatment Healed 2 weeks Healed 4 weeks
22 13 5 4 16
83 2 11 68 t 13* 51 -+ 13*
10
4
Duodenum
Endoscopic biopsy specimens were obtained from gastric and duodenal mucosa of patients with active duodenal ulcers before treatment and also after 2 or 4 weeks’ treatment with 300 mg ranitidine at bedtime or 20 mg omeprazole. The tissue was cultured 2 h, and PAF generation following extraction was determined as described in Materials and Methods. Results are mean 2 SE. * Significantly different from level before treatment. Each subject was compared with himself ( p < 0.05; f test for paired data).
Table VI. Gastroduodenal prostaglandin E2 (PGEJ generation in duodenal ulcer patients
~~
Ranitidine Before treatment Healed 2 weeks Healed 4 weeks Not healed Omeprazole Before treatment Healed 2 weeks Healed 4 weeks
23 14 5 4
180 t 20 197 ? 30 188 t 41 189 t 15
190 t 22 189 2 32 333 115 239 2 55
*
284 2 39 313 t 51 213 5 44 182? 23
15 11 7
167 ? 28 263 2 52 424 t 82*
154 k 21 137 t 22 237 t 55
248 2 43 265 k 54 350 & 67
Endoscopic biopsy specimens were obtained from gastric and duodenal mucosa of patients with active duodenal ulcers before treatment and also after 2 or 4 weeks’ treatment with 300 mg ranitidine at bedtime or 20 mg omeprazole. The tissue was cultured for 2 h, and PGE, released into the medium and its tissue content at the end of the culture were determined by radioimmunoassay. Results are mcan 2 SE. * Significantly different from before treatment ( p < 0.05; t test for unpaired data and Mann-Whitney test).
Table VII. Serum gastrin and gastrin generation by the stomach antrum and duodenum in duodenal ulcer patients
Ranitidine Before treatment Healed 2 weeks Healed 4 weeks Not healed Omeprazole Before treatment Healed 2 weeks Healed 4 weeks
1s 12 5 4
39.9 -+ 3.9 47.2 rt 4.4 35.4 k 6.6 43.5 rt 9.5
1132 8 127 2 11 140 t 24 207 2 40
88 k 14 75 2 1s 63 t 14 162 2 41
17 10 7
39.6 k 4.2 83.7 2 20.0* 48.9 k 5.7
124 t 14 110 f 11 135 ? 13
103 _t 22 98 IT 33 65 t 10
Serum and endoscopic biopsy specimens were obtained from the gastric antrum and duodenum of patients with active duodenal ulcers before treatment and after 2 or 4 weeks’ treatment with 300 mg ranitidine at bedtime or 20 mg omeprazole. The tissue was cuitured 2 h, and gastrin levels determined by radioimmunoassay. Results are mean t SE. * Significantly different from before treatment ( p < 0.05; t test for paired data).
shown that ulcer healing induced by Hz blockers is accompanied by a n increase in mucosal PGE2 generation, suggesting that this may be one of the mechanisms to explain
their therapeutic effects (2,3). There are no data available on the effect of 2 weeks’ treatment on mucosal PGEz with any drug, and in the present study, in five subjects 4 weeks’
18
J . Lysy et al.
Table VIII. Serum pepsinogen A and gastric pepsinogen A generation in duodenal ulcer patients Serum (ng/ml)
Fundus (ng/mg wet wt/2 h)
3
108 t 14 115 t 1 I 119+31 79 12
*
219 ? 19 252 24 233 ? 30 33s t 63
17 10 7
107 k 10 257 62* 279? 29*
249 41 244 2 49 322 t 43
No.
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Ranitidine Before treatment Healed 2 weeks Healed 4 weeks Not healed Omeprazole Before treatment Healed 2 weeks ilealed 4 weeks
15 15
5
*
*
Serum and endoscopic biopsy specimcns were obtained from the gastric antrum and duodenum of patients with active duodenal ulcers bcfore treatment and after 2 or 4 weeks' treatment with 300 mg ranitidine at bedtime or 20 mg omeprazole. The tissue was cultured 2 h, and gastrin levels determined by radioimniunoassay. Results arc mean ? SE. * Significantly different from before treatment ( p < 0.05; t test for paired data).
with the respective pretreatment generation. Previous reports demonstrated that oral administration of omeprazole concomitantly increased fasting gastrin and pepsinogen A levels (17, 18). A possible mechanism to explain the effect of omeprazole on serum pepsinogen A is back-diffusion of its increased gastric gland concentration. The latter is probably not due to enhanced secretion of pepsinogen A but to diminished dilution of the proteins in the reduced gastric secretion during omeprazole treatment, as ex vivo studies in rabbits (19) and guinea pigs (20) did not show an effect of omeprazole on pepsinogen A secretion. The increase in serum pepsinogen A may also be due t o omeprazole-induced stimulation of the pepsinogen-producing gastric cells (18). The results presented here showing increased serum levels o f pepsinogen A after omeprazole treatment without parallel enhanced generation of pepsinogen A by the gastric fundic mucosa support the first hypothesis.
REFERENCES
treatment with ranitidine was not accompanied by significant increase in mucosal PGE2, probably because of the small number of subjects. There is an inverse relationship between intragastric acidity and plasma gastrin concentration. All generally available anti-secretory drugs induce release of gastrin into the circulation (12). The more potent the gastric anti-secretory drug, the greater the rise of plasma gastrin concentration. In the present study we found a recovery of the pretreatment plasma gastrin concentration after the last dose of 300mg ranitidine after 2 or 4 weeks of treatment. Other investigators found longer-lasting elevated plasma gastrin concentrations after ranitidine treatment (13). The plasma gastrin concentration in the present study was almost doubled after 2 weeks of treatment when determined 24 h after the last dose of omeprazole when compared with its pretreatment level. Thcse results may indicate a possible advantage of ranitidine in terms of safety, since recent studies have demonstrated a significantly positive relationship between druginduced hypergastrinemia and the development of enterochromaffin-like cell hyperplasia and carcinoids in rats (6.7). On the other hand, gastrin is a trophic hormone stimulating the growth of epithelial cells in the alimentary tract (14, 15). The rate of peptic ulcer healing is usually related to the anti-secretory potency of a drug (16), and that is, in turn, related to drug-induced hypergastrinemia. It is, t h u s , possible that in addition to the anti-secretory properties, induction of hypergastrinemia may be another contributory mechanism to ulcer healing. After 2 weeks of omeprazole treatment, serum pepsinogen A levels increased significantly compared with their pretreatment levels. At the same time, fundic mucosal generation of pepsinogen A was not different when compared
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Effect of Omeprazole on Duodenal Ulcer
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with oral ranitidine and cimetidine on gastric acid secretion, pepsin secretion and fasting serum gastrin. Gut 1983,24,61-66 13. Lanzon-Miller S , Pounder RE, Chronos NAF, Raymond SF, Hamilton HR, Dalgleish D. 24 hour intragastric acidity and plasma gastrin concentration in healthy volunteers taking nizatidine 150 mg, nizatidine 300 mg, ranitidine 300 mg or placebo at 2215 h. Gut 1988, 29, 1364-1369 14. Majumadar A, Johnson LR. Mucosal cell proliferation during development in rats and effects of pentagastrin. Am J Physiol 1982, 242, G135-Gl39 15. Solomon TE. Trophic effects of pentagastrin on the gastrointestinal tract in fed and fasted rats. Gastroenterology 1986, 91, 1OG-116 16. Chiverton SG, Burget DW, Hunt RH. Response surface methodology predicts dudoenal ulcer healing from acid suppression data. Gut 1988, 29, A711 Received 17 April 1991 Accepted 15 July 1991
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17. Biemond I, Crobach LFSJ, Jansen JBMJ, Lamers CBHW. Effect of short-term omeprazole administration on serum pepsinogens in relation to fasting serum gastrin and gastric acid secretion. Eur J Clin Pharmacol 1989, 37, 345-349 18. Jansen JMBJ, Klinkenberg-Knol EC, Meuwissen SGM, et al. Effect of long-term treatment with omeprazole on serum gastrin and serum group A and C pepsinogens in patients with reflux esophagitis. Gastroenterology 1990, 99, 621-628 19. Fryklund J, Wallmark B , Larsson H, Helander HF. Effect of omeprazole on gastric secretion on H + , K+-ATPase and in pepsinogen-rich cell fractions from rabbit gastric mucosa. Biochem Pharmacol 1984, 33, 273-280 20. Basson MD, Adrian TE, Modlin IM. Dissociation of pepsinogen and acid secretion in the guinea pig. Gastroenterology 1988,95, 321-326
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Lysy J , Karmeli F, Wengrower D, Rachmilewitz D . Effect of duodenal ulcer healing induced by omeprazole and ranitidine on the generation of gastroduodenal eicosanoids, platelet-activating factor, pepsinogen A, and gastrin in duodenal ulcer patients. Scand J Gastroenterol 1992, 27, 13-19 G h e effect of duodenal ulcer healing induced by omeprazole on gastroduodenal generation of eicosanoids, platelet-activating factor (PAF), pepsinogen A, and gastrin was evaluated. Sixty patients with endoscopically proven duodenal ulcer were randomized to receive 20 mg omperazole once daily or 300 mg ranitidine at bedtime for 2 weeks. Patients whose ulcers did not heal were treated for an additional 2 weeks. Endoscopic biopsy specimens and serum samples were obtained before and after treatment. There was no significant difference in the healing rate between the two treatment modalities. At 2 weeks healing rates were 60% and 56% in the omperazole and ranitidine groups, respectively, whereas at 4 weeks the respective healing rates were 96% and 86%. Ulcer healing induced by omeprazole and ranitidine was' not accompanied by significant changes in mucosal leukotriene B, or C, generation. Mucosal PAF significantly decreased in patients treated with omeprazole for 4 weeks. In omperazoletreated patients there was a trend towards increase in mucosal prostaglandin Ez generation which was significant in the fundus after 4 weeks of treatment. After 2 weeks of omeprazole treatment, serum gastrin and pepsinogen A levels almost doubled when compared with their pretreatment levels. In conclusion, duodenal ulcer healing with 20 mg omeprazole daily is not superior to healing rates with 300 rng ranitidine at bedtime after both 2 and 4 weeks of treatment. In omeprazole-treated subjects ulcer healing was accompanied by a significant decrease in mucosal PAF generation and increased levels of serum gastrin and pepsinogen A
J
Key words: Duodenal ulcer; gastrin; leukotrienes; omeprazole; pepsinogen A; platelet-activating factor; prostaglandin E,; ranitidine Daniel Rachmilewitz, M . D . , Dept. of Medicine, Hadassah University Hospital, Mount Scopus, P . 0. Box 240.75, Jerusalem 91240, Israel
Gastroduodenal generation of the mediators of inflammation-platelet-activating factor (PAF) and leukotrienes (LT) B4 and C,-was shown to be increased in patients with active duodenal ulcer. Moreover, after induction of ulcer healing with cimetidine, their generation was shown to decrease, suggesting that they may have a role in the pathogenesis of peptic ulcer (1). On the other hand, in patients with duodenal ulcer gastric prostanoid generation was shown to b e decreased and to resume normal control levels after healing induced by cimetidine and ranitidine (2,3), thus suggesting that the induction of endogenous prostanoids by H2 blockers may contribute to their therapeutic effect. The aim of the present study was to assess the effect of omeprazole on gastroduodenal generation of eicosanoids and platelet-activating factor in duodenal ulcer patients. Omeprazole was reported to increase serum gastrin levels (4,5),
which may be involved in the pathogenesis of enterochromaffin-like cell hyperplasia in rats (5,7). Omeprazole effects on pepsinogen generation are not well defined. In the present study the effect of treatment with omeprazole on serum gastrin and pepsinogen A levels and on their gastric generation was also evaluated. MATERIALS AND METHODS
Patients Endoscopic antral fundic and duodenal biopsy specimens and serum were obtained from patients with endoscopically proven duodenal ulcer. All patients were examined on the day the diagnosis was established, before treatment was started, and also after 2 or 4 weeks of therapy, in a clinical trial designed to compare the efficacy of 20 mg omeprazole
14
J. Lysy et al.
Table I. Patients’ characteristics
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No. Sex, male to female ratio Age (years) Range Mean Smokers, no.
Omeprazole
Ranitidine
30 2317
30 26:4
1 %74 36.3 2 2.6 12
19-69 42.3 ? 2.1 14
once daily in the morning versus 300mg ranitidine at bedtime. The trial was double-blind. Patients recruited were men or women, 18-75 years old with at least one ulcer with a diameter of 5 mm or larger. Patients were excluded if they were pregnant or breast-feeding, if they had been treated with anti-ulcer drugs for more than 3 days during the 14 days preceding endoscopy, or if they had pyloric stenosis or concurrent gastric or prepyloric ulcer. Other exclusion criteria were previous gastric surgery, continuous treatment with non-steroidal anti-inflammatory drugs and chronic alcoholism. The double-dummy technique was used, and each patient received either omeprazole with placebo ranitidine or ranitidine with placebo omeprazole. Patients were endoscoped after 2 weeks of treatment, and those in whom the ulcer had not healed received medication for another 2 weeks, when endoscopy was repeated. The nature of the specific therapy the patients were receiving was not known until the trial was completed. The investigators were made aware of the medication the patients were receiving only after all the experiments and study were completed. All 60 patients recruited concluded the trial satisfactorily, with 30 patients in each of the treatment groups. Sex and age distribution were similar in the groups (Table I). In 41 subjects 2 mucosal specimens were obtained during each endoscopy from the stomach antrum and fundus and also from the duodenal bulb from an area opposite the ulcer site. In most patients specimens were obtained during both endoscopies, but in several only during one of the procedures. The last medication was taken 10 h before the second or third endoscopy in those patients whose ulcers did not heal after 2 weeks of treatment. In all subjects endoscopy was performed with the Olympus GIFQ or OES endoscope after a 10-h fast. Diazepam was given intravenously as premedication. Biopsy specimens were obtained with the biopsy forceps 12 BK (Olympus), washed i n 0.15 M NaC1, weighed (average weight, 9 mg wet wt), and cultured within 10 min of excision. The study was approved by the Helsinki Committee of the Hadassah University Hospital.
Organ culture Non-proliferative organ culture was performed as previously described by us in detail (8). The culture medium
used was RPMI 1640 (Bio Lab., Israel) containing penicillin (100 U/ml) and streptomycin (100 pglml). The culture was carried out for 2 h . A t the end of each culture the medium was kept at -20°C for eicosanoid determination. The tissue was homogenized in 1.0 ml ice-cold 50 mM Tris HCI buffer, pH 7.0, containing 0.02 M ethylenediaminetetraacetic acid (EDTA) and 1.0ml ether, and the aqueous phase was assayed for its eicosanoid content.
Measurement of LTB, LTB, immunoreactivity was determined with a radioimmunoassay (RIA) kit (Amersham, TRK 940). The assay combines the use of a high specific activity leukotriene B4 tracer, an antiserum specific for LTB, (cross-reactivity, loo%), and a leukotriene standard (range, 1.6-200 pg/tube). The specific binding of tracer is 42.5% ; non-specific binding, 2.4%. Fifty per cent B/Bo displacement is obtained with 15 pg/tube, and 90% B/Bo displacement with 2.2 pgftube of LTB,. Measurement of LTC, LTC, immunoreactivity was determined with a RIA kit (Amersham, TRK 905). The assay combined the use of a high specific activity LTC4 tritiated tracer with a monoclonal antibody specific for LTC, and LTC, standard. The standard curve covers the range 8 to 500pg/tube. The assay uses highly specific LTC, antiserum (cross-reactivity , 100%) and has low cross-reactivity with LTD, (< 5%). The specific binding of tracer is 40.2%; non-specific binding, 3%. Fifty per cent B/Bo displacement is obtained with 34pg/tube, and 80% B/Bo displacement with 9.5 pg/tube of LTC,. Measurement of PGE2 Prostaglandin E2 was determined with R I A as previously described (9). Measurement of gastrin and pepsinogen levels Gastrin level in the serum and culture medium was determined with a R I A (International CIS, St. Quentin, Yvelines, France). Pepsinogen A level in the serum and the culture medium was determined with a R I A (International CIS). PAF determination Organ culture. Fundic, antral, and duodenal biopsy specimens were organ-cultured for 2 h at 37°C in a humidified atmosphere containing 5% C 0 2 in 0.5ml of modified Tyrode’s buffer containing 1 mm C a + + , 0.1 mM Mg++$and 0.5% fatty acid-free bovine albumin ( p H 7.4) (TBSA), to which 0.2 pM calcium ionophore A23187 was added. After 2 h of incubation cultured specimens and medium were transferred t o separate tubes and kept at -20°C until extraction of PAF activity. Twenty-four hours before performance of the aggregation assay 0.5 ml ethanol (80%) was added to the gastric mucosa to extract P A F from the tissue.
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Effect of Omeprazole on Duodenal Ulcer
Plateletpreparation. Fifty milliliters of rabbit venous blood were collected into Falcon tubes, mixed with 1 ml 0.2 M EDTA and centrifuged for 20 min at 1600 rpm. Plasma was transferred to another Falcon tube and centrifuged for 15 min at 3000 rpm. The platelet pellet was reconstituted with a washing buffer (pH 6.5) containing 2.6 mM KCI, 1 m M MgCI2, 137mM NaCI, 12mM NaHC03, 0.2mM ethyleneglycol-bis(beta-amino-ethylether)-&', "-tetraacetic acid, 5.5 mM glucose, and 0.25% gelatine and centrifuged for 15 min at 3000 rpm. The platelet pellet was resuspended in the above buffer and treated with 0.1 mM aspirin for 15 min at room temperature, followed by another centrifugation for 15min at 3000rpm. Platelets were resuspended in washing buffer at appropriate concentrations for the measurement of platelet aggregation (25). Aggregation assay. PAF activity was measured by platelet aggregation using a Chrono-Log Corp. aggregometer. Platelets were stirred in 400 pl of buffer containing 2.6 mM KCI, 1mM MgC12, 137mM NaCl, 12mM NaHC03, 1.3mM CaClz, 5.5 mM glucose, 0.25% gelatin, 1 mM creatine phosphate, and 10 U/ml creatine phosphokinase (pH 7.4). Samples of 1Oyl of the 80% ethanol extract or from the medium were added and aggregation recorded. Ten microliters of ethanol or calcium ionophore, 0.2 pM, did not induce aggregation. In some experiments the inhibitory effect of the PAF antagonist WEB 2086 was tested by adding 10 p1 1 min before adding the aggregating agent. WEB 2086 BS inhibited dose-dependently (0.17-17 pM) the PAF-induced platelet aggregation ( r = 0.891; y = 140-8.8X). The effect of WEB 2086 was tested both on synthetic PAF and PAF extracted from specimens. Materials Aspirin was obtained from Aspegic, Lab Egic, Amilly, France; EDTA, ethylene glycol-bis-(beta-aminoethy1ether)N,N'-tetraacetic acid, calcium ionophore A23187, creatine phosphate, creatine phosphokinase, phosphatidylcholine, lysophosphatidylcholine, sphingomyelin, fatty acid-free bovine serum albumin, and horse serum from Sigma Laboratories, Israel; gelatin, precoated silica gel 60 F 254 plates, and Norit-activated charcoal from E. Merck, Darmstadt,
Table 11. Duodenal ulcer healing 2 weeks Treatment Orneprazole All patients Smokers Ranitidine All patients Smokers
4 weeks
No.
96
No.
%
18/30 4/12
60.0 33.3
29/30 11/12
96.6 91.6
17/30 9/16
56.5 56.2
26/30 14/16
86.6 87.5
15
Germany; PAF (C18) 1-0-octadecyl-2-0-acetyl-sn glycero3 phosphorylcholine from Bachem, Switzerland; RPMI 1640 from Biolab, Israel; leukotriene B4 [3H]assay system, leukotriene C4 [3H] from Amersham, England; 3-[4-(2-chlorphenyl)-9-methyl-6H-thieno-(3,2-f)-( 1,2,4)], triazolo-[ ( 4 3 a)(1,4)-diazepin-2-yl]-l-(4-morpholinyl)l-propanon, and WEB 2086 BS were donated by Boehringer Ingelheim KG, Germany; and dextran T-70 was purchased from Pharmacia, Uppsala, Sweden. Statistical methods Statistical differences between the various groups were evaluated with Student's t test for unpaired and paired data and by the non-parametric Mann-Whitney test. P values less than 0.05 were considered significant. Results are expressed as the mean 4 standard error (mean & SE).
RESULTS There was no statistically significant difference in healing rates between the omeprazole and ranitidine treatment modalities at 2 and 4 weeks. At 2 weeks the healing rate was 60% and 56% in the omeprazole- and ranitidine-treated groups, respectively, whereas at 4 weeks the respective healing rates were 96% and 86% (Table 11). Smoking adversely affected healing only after 2 weeks of treatment with omeprazole. Ulcer healing induced by both omeprazole and ranitidine was not accompanied by significant changes in gastric or duodenal LTB4 or LTC4 generation. Ulcer healing induced by both drugs was accompanied by a trend towards a decrease in the mucosal generation of LTB4 at 4 weeks, although it did not reach statistical significance (Tables 111 and IV). The generation of mucosal PAF, LTB4, and LTC4 in the four patients whose ulcers did not heal during 4 weeks on ranitidine did not differ at the end of the treatment from the respective generation in the other patients whose ulcers healed (Tables 111-V). In these four patients pretreatment generation of PAF, LTB4, and LTC4 was also similar to the pretreatment generation in the other patients (results not shown). In the omeprazole-treated patients gastric and duodenal PAF significantly decreased in those patients who were treated for 4 weeks. After 2 weeks of omeprazole treatment only fundal PAF generation was significantly decreased. In the ranitidine-treated patients significant decrease in mucosal PAF was observed only in the duodenum after 2 weeks of treatment (Table V). There was a trend towards an increase in mucosal PGEz generation in the omeprazoletreated subjects, although it reached statistical significance only in the fundus after 4 weeks of treatment (Table VI). Serum gastrin levels were significantly increased 2 weeks after treatment with omeprazole, whereas ranitidine treatment did not affect serum gastrin levels. Antral and duodenal
16
J. Lysy
el
al.
Table 111. Gastroduodenal leukotriene B, (LTB,) generation in duodenal ulcer patients No.
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Rani tidine Before treatment Healed 2 weeks Healed 4 weeks Not healed Omeprazole Before treatment Healed 2 weeks Healed 4 weeks
*
*
4
15.6 3.3 15.7 2 6.0 10.0 k 2.0 30.0 14.5
*
19.0 _t 5.0 9.5 t 2.8 16.7 7.7 32.0 t 14.0
*
29.0 7.0 28.5 t 10.0 19.5 _t 6.0 22.0 +- 3.0
15 10 6
15.4 2 2.5 24.2 ? 3.9 20.6 2 6.7
23.2 t 5.0 18.0 ‘-c 4.9 22.4 t 7.0
19.0 t 3.0 23.0 3.0 24.0 5 6.4
23 14
5
*
Endoscopic biopsy specimens were obtained from gastric and duodenal mucosa of patients with active duodenal ulcers before treatment and also after 2 or 4 weeks’ treatment with 300 mg ranitidine at bedtime or 20 mg omeprazole. The tissue was cultured for 2 h, and LTB4 relcased into the medium and its tissue content at the end of the culture were determined by radioimmunoassay. Results are mean t SE.
Table 1V. Gastroduodenal leukotriene C4 (12TC4)generation in duodenal ulcer patients
Ranitidine Before treatment Healed 2 weeks Healed 4 weeks Not healed Omeprazole Before treatment Healed 2 weeks Healed 4 weeks
22 14
4
142 t 21 I24 t 26 159 2 30 274 t 56
97 t_ 17 6 9 t 11 83 5 19 75 t 21
181 2 30 182 ? 34 308 5 58 230 t 93
17 10 7
183 t 33 1 3 8 t 14 188 38
9 6 5 13 86 ? 18 78 t 17
230 f 40 228 5 38 230 t 56
5
*
Endoscopic biopsy specimens were obtained from gastric and duodenal mucosa of patients with active duodenal ulcers before treatment and also after 2 or 4 weeks’ treatment with 300mg ranitidine at bedtime or 20 mg omeprazole. The tissue was cultured for 2 h , and LTC, release into the medium and its tissue contcnt at the cnd of the culture were determined by radioimmunoassay. Results are mean SE.
*
gastrin generation were not significantly affected by either omeprazole or ranitidine (Table VII). Significant increase in the serum pepsinogen A level was observed after 2 and 4 weeks of treatment with omeprazole. Fundic pepsinogen A was not stimulated by omeprazole. and ranitidine also did not affect its serum level or fundic generation (Table VlII).
DISCUSSION
In the present study duodenal ulcer healing induced by omeprazole administered for 2 weeks in a dose of 20mg/ day was found to be similar to that induced by ranitidine, 300mg/day. At 4 weeks, too, there was no statistically significant difference between the two treatment modalities, although in absolute terms, healing rates with omeprazole were higher. The relatively high healing rate with ranitidine reported here may be due to the fact that in Israel healing rates of duodenal ulcers are generally higher than those reported elsewhere, irrespective of the treatment modalityranitidine or even placebo (10, 11). The reason for this has never been properly defined.
The generation of gastric and duodenal PAF, LTB4, and LTC4in patients with duodenal ulcers enrolled in the present study is in the range previously reported by us and higher than their respective generation in normal healthy subjects (1). We have previously shown that, after ulcer healing induced by 4 weeks’ treatment with cimetidine, the enhanced generation of these inflammatory mediators decreases and tends to resume normal control levels (1). In the present study ulcer healing induced by ranitidine was not accompanied by a significant decrease in the generation of these inflammatory mediators, and this may be because there were relatively few patients in this treatment group. O n the other hand, ulcer healing induced by omeprazole was accompanied by a significant decrease in P A F generation, confirming that P A F may be involved in the pathogenesis of peptic ulcer disease. Gastric, antral, and fundal PGEz generation are also reduced in duodenal ulcer patients when compared with their generation by normal healthy subjects, previously reported by us (3). Induction of ulcer healing with omeprazole was accompanied by increase in PGE2 generation but reached statistical significance only in the fundus. We have previously
Effect of Omeprazole on Duodenal Ulcer
17
Table V. Gastroduodenal platelet-activating factor (PAF) generation in duodenal ulcer patients before and after treatment Fundus
Antrum (pg/l0 mg wet wt)
106 t 16 87 t 14 74 t 14 37 2 6
82 & 12 61 2 10 61 15 61 t 11
*
126 _t 19 102 t 17* 74 2 11 I19 2 46
80 t 9 6 6 5 11 53 2 10*
9 6 2 14 89 2 20 50 +- 10*
No.
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Ranitidine Before treatment Healed 2 weeks Healed 4 weeks Not healed Omeprazole Before treatment Healed 2 weeks Healed 4 weeks
22 13 5 4 16
83 2 11 68 t 13* 51 -+ 13*
10
4
Duodenum
Endoscopic biopsy specimens were obtained from gastric and duodenal mucosa of patients with active duodenal ulcers before treatment and also after 2 or 4 weeks’ treatment with 300 mg ranitidine at bedtime or 20 mg omeprazole. The tissue was cultured 2 h, and PAF generation following extraction was determined as described in Materials and Methods. Results are mean 2 SE. * Significantly different from level before treatment. Each subject was compared with himself ( p < 0.05; f test for paired data).
Table VI. Gastroduodenal prostaglandin E2 (PGEJ generation in duodenal ulcer patients
~~
Ranitidine Before treatment Healed 2 weeks Healed 4 weeks Not healed Omeprazole Before treatment Healed 2 weeks Healed 4 weeks
23 14 5 4
180 t 20 197 ? 30 188 t 41 189 t 15
190 t 22 189 2 32 333 115 239 2 55
*
284 2 39 313 t 51 213 5 44 182? 23
15 11 7
167 ? 28 263 2 52 424 t 82*
154 k 21 137 t 22 237 t 55
248 2 43 265 k 54 350 & 67
Endoscopic biopsy specimens were obtained from gastric and duodenal mucosa of patients with active duodenal ulcers before treatment and also after 2 or 4 weeks’ treatment with 300 mg ranitidine at bedtime or 20 mg omeprazole. The tissue was cultured for 2 h, and PGE, released into the medium and its tissue content at the end of the culture were determined by radioimmunoassay. Results are mcan 2 SE. * Significantly different from before treatment ( p < 0.05; t test for unpaired data and Mann-Whitney test).
Table VII. Serum gastrin and gastrin generation by the stomach antrum and duodenum in duodenal ulcer patients
Ranitidine Before treatment Healed 2 weeks Healed 4 weeks Not healed Omeprazole Before treatment Healed 2 weeks Healed 4 weeks
1s 12 5 4
39.9 -+ 3.9 47.2 rt 4.4 35.4 k 6.6 43.5 rt 9.5
1132 8 127 2 11 140 t 24 207 2 40
88 k 14 75 2 1s 63 t 14 162 2 41
17 10 7
39.6 k 4.2 83.7 2 20.0* 48.9 k 5.7
124 t 14 110 f 11 135 ? 13
103 _t 22 98 IT 33 65 t 10
Serum and endoscopic biopsy specimens were obtained from the gastric antrum and duodenum of patients with active duodenal ulcers before treatment and after 2 or 4 weeks’ treatment with 300 mg ranitidine at bedtime or 20 mg omeprazole. The tissue was cuitured 2 h, and gastrin levels determined by radioimmunoassay. Results are mean t SE. * Significantly different from before treatment ( p < 0.05; t test for paired data).
shown that ulcer healing induced by Hz blockers is accompanied by a n increase in mucosal PGE2 generation, suggesting that this may be one of the mechanisms to explain
their therapeutic effects (2,3). There are no data available on the effect of 2 weeks’ treatment on mucosal PGEz with any drug, and in the present study, in five subjects 4 weeks’
18
J . Lysy et al.
Table VIII. Serum pepsinogen A and gastric pepsinogen A generation in duodenal ulcer patients Serum (ng/ml)
Fundus (ng/mg wet wt/2 h)
3
108 t 14 115 t 1 I 119+31 79 12
*
219 ? 19 252 24 233 ? 30 33s t 63
17 10 7
107 k 10 257 62* 279? 29*
249 41 244 2 49 322 t 43
No.
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Ranitidine Before treatment Healed 2 weeks Healed 4 weeks Not healed Omeprazole Before treatment Healed 2 weeks ilealed 4 weeks
15 15
5
*
*
Serum and endoscopic biopsy specimcns were obtained from the gastric antrum and duodenum of patients with active duodenal ulcers bcfore treatment and after 2 or 4 weeks' treatment with 300 mg ranitidine at bedtime or 20 mg omeprazole. The tissue was cultured 2 h, and gastrin levels determined by radioimniunoassay. Results arc mean ? SE. * Significantly different from before treatment ( p < 0.05; t test for paired data).
with the respective pretreatment generation. Previous reports demonstrated that oral administration of omeprazole concomitantly increased fasting gastrin and pepsinogen A levels (17, 18). A possible mechanism to explain the effect of omeprazole on serum pepsinogen A is back-diffusion of its increased gastric gland concentration. The latter is probably not due to enhanced secretion of pepsinogen A but to diminished dilution of the proteins in the reduced gastric secretion during omeprazole treatment, as ex vivo studies in rabbits (19) and guinea pigs (20) did not show an effect of omeprazole on pepsinogen A secretion. The increase in serum pepsinogen A may also be due t o omeprazole-induced stimulation of the pepsinogen-producing gastric cells (18). The results presented here showing increased serum levels o f pepsinogen A after omeprazole treatment without parallel enhanced generation of pepsinogen A by the gastric fundic mucosa support the first hypothesis.
REFERENCES
treatment with ranitidine was not accompanied by significant increase in mucosal PGE2, probably because of the small number of subjects. There is an inverse relationship between intragastric acidity and plasma gastrin concentration. All generally available anti-secretory drugs induce release of gastrin into the circulation (12). The more potent the gastric anti-secretory drug, the greater the rise of plasma gastrin concentration. In the present study we found a recovery of the pretreatment plasma gastrin concentration after the last dose of 300mg ranitidine after 2 or 4 weeks of treatment. Other investigators found longer-lasting elevated plasma gastrin concentrations after ranitidine treatment (13). The plasma gastrin concentration in the present study was almost doubled after 2 weeks of treatment when determined 24 h after the last dose of omeprazole when compared with its pretreatment level. Thcse results may indicate a possible advantage of ranitidine in terms of safety, since recent studies have demonstrated a significantly positive relationship between druginduced hypergastrinemia and the development of enterochromaffin-like cell hyperplasia and carcinoids in rats (6.7). On the other hand, gastrin is a trophic hormone stimulating the growth of epithelial cells in the alimentary tract (14, 15). The rate of peptic ulcer healing is usually related to the anti-secretory potency of a drug (16), and that is, in turn, related to drug-induced hypergastrinemia. It is, t h u s , possible that in addition to the anti-secretory properties, induction of hypergastrinemia may be another contributory mechanism to ulcer healing. After 2 weeks of omeprazole treatment, serum pepsinogen A levels increased significantly compared with their pretreatment levels. At the same time, fundic mucosal generation of pepsinogen A was not different when compared
1. Ackerman Z, Karmeli F, Ligumsky M, Rachmilcwitz D. Enhanced gastric and duodenal platelet activating factor and leukotriene generation in duodenal ulcer patients. Scand J Gastroenterol 1990, 25, 925-234 2. Branski D Sharon P , Karmeli F, Rachmilewitz D . Effect of cimctidine on human gastric and duodenal prostanoid synthesis. Scand J Gastroentcroi 1YX4, 19, 457-460 . 3. Rachmilcwitz D , Ligumsky M, Fich A , Goldin E , Eliakim A , Karmcli F. Role of endogenous gastric prostanoids in the pathogenesis and therapy of duodenal ulcer. Gastroenterology 1986. 90, 963-969 4. Fcsten H P M , Tuynman H A R E , Dcfizc J , et al. Effect of single and repeated doses of oral orneprazole on gastric acid and pcpsin secretion, and fasting serum gastrin and scrum pepsinogen I levels. Dig Dis Sci 1986, 31, 561-566 5 . Festen H P M , Thijs JC, Lamers CBHW, et al. Effect of oral omeprazole o n serum gastrin and scrum pepsinogen I levels. Gastrocnterology 1984, 87. 103G1034 6 . Larsson H , Calsson E , Hattsson H,et al. Plasma gastrin and gastric enterochromaffin-like cell activation and proliferation studics with omeprazole and ranitidine in intact and anterectomized rats. Gastrocnterology 1986, 30, 391-399 7. Havu N. Entcrochromaffin-like carcinoids of gabtric mucosa in rats after life-long inhibition of gastricsecretion. Digestion 1986, 35 SUPPI1, 42-45 8. Sharon P, Cohen F. Zifroni A , Karmcli F, Ligumsky M, Rachinilewitz D . Prostanoid synthesis by cultured gastric and duodenal mucosa: possiblc role in the pathogenesis of duodenal ulcer. Scand J Gastroenterol 1983, 18, 1045-1049 9. Ligumsky M, Karmeli F , Sharon P, Zor U , Cohen F, Rachmilewitz D . Enhanced thromboxane A2 and prostacyclin production by cultured rectal mucosa in ulcerative colitis and its inhibition by steroids and sulfasalazine. Gastroenterology 1981. 81, 444449 10 Goldin E, Fich A , Eliakim R , Zimmerman J . Ligumsky M , Rachmilewitz D. Comparison of misoprostol and ranitidine in the treatment of duodenal ulcer. Isr J Med Sci 1990, 24, 282285 I I Wcngrowcr D , Fich A , Goldin E, Eliakim R , Ligumsky M , Rachmilewitz D . Cytoprotcctive doses of arhacet with minimal antisecretory properties are not effective in duodenal ulcer healing. Dig Dis Sci 1987, 32, 857-860 12 Mohammed R , Holden RJ, Hearns JB, Meckihbeii BM, Buchanan K D , Crcan GP. Effect of 8 weeks continuous trcatment
Effect of Omeprazole on Duodenal Ulcer
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with oral ranitidine and cimetidine on gastric acid secretion, pepsin secretion and fasting serum gastrin. Gut 1983,24,61-66 13. Lanzon-Miller S , Pounder RE, Chronos NAF, Raymond SF, Hamilton HR, Dalgleish D. 24 hour intragastric acidity and plasma gastrin concentration in healthy volunteers taking nizatidine 150 mg, nizatidine 300 mg, ranitidine 300 mg or placebo at 2215 h. Gut 1988, 29, 1364-1369 14. Majumadar A, Johnson LR. Mucosal cell proliferation during development in rats and effects of pentagastrin. Am J Physiol 1982, 242, G135-Gl39 15. Solomon TE. Trophic effects of pentagastrin on the gastrointestinal tract in fed and fasted rats. Gastroenterology 1986, 91, 1OG-116 16. Chiverton SG, Burget DW, Hunt RH. Response surface methodology predicts dudoenal ulcer healing from acid suppression data. Gut 1988, 29, A711 Received 17 April 1991 Accepted 15 July 1991
19
17. Biemond I, Crobach LFSJ, Jansen JBMJ, Lamers CBHW. Effect of short-term omeprazole administration on serum pepsinogens in relation to fasting serum gastrin and gastric acid secretion. Eur J Clin Pharmacol 1989, 37, 345-349 18. Jansen JMBJ, Klinkenberg-Knol EC, Meuwissen SGM, et al. Effect of long-term treatment with omeprazole on serum gastrin and serum group A and C pepsinogens in patients with reflux esophagitis. Gastroenterology 1990, 99, 621-628 19. Fryklund J, Wallmark B , Larsson H, Helander HF. Effect of omeprazole on gastric secretion on H + , K+-ATPase and in pepsinogen-rich cell fractions from rabbit gastric mucosa. Biochem Pharmacol 1984, 33, 273-280 20. Basson MD, Adrian TE, Modlin IM. Dissociation of pepsinogen and acid secretion in the guinea pig. Gastroenterology 1988,95, 321-326
