Gut 1995; 37: 482-487

Eradication of Helicobacter pylori restores theinhibitory effect of cholecystokinin onpostprandial gastrin release in duodenal ulcerpatients

JW Konturek, A Gillessen, S J Konturek, W Domschke

AbstractHelicobacter pylon infection may beassociated with duodenal ulcer (DU) andaccompanied by enhanced gastrin releasebut the mechanism ofthis Hpylori relatedhypergastrinaemia in DU patients isunclear. Cholecystokinin (CCK) has beenimplicated in the feedback control ofgastrin release and gastric acid secretionin healthy subjects. This study there-fore investigated if CCK participates inthe impairment of postprandial gastrinrelease and gastric secretion in six DUpatients. Tests were undertaken withand without elimination of endogenousCCK by loxiglumide, a selective CCK-Areceptors antagonist, before and aftereradication ofHpylori with triple therapy(omeprazole, amoxicyllin, bismuth). InH pylon positive DU patients, the post-prandial decline in pH (with median pH3.5) was accompanied by a pronouncedincrement in plasma gastrin but theadministration of loxiglumide did notaffect significantly this postprandial risein plasma gastrin and gastric pH profile.After eradication ofH pylon, the plasmagastrin concentration was reduced whilethe median postprandial pH was signifi-cantly increased (median pH 4.3). Theadministration of loxiglumide resulted insignificantly greater increase in postpran-dial plasma gastrin and greater decreasein pH (median pH 3.1) in these patients.This study shows that (a) infection withH pylori is accompanied by an enhancedgastrin release and gastric acidity in DUpatients, (b) the failure of loxiglumide toaffect plasma gastrin or gastric acid secre-tion inHpylori infectedDU patients couldbe attributed, at least in part, to the fail-ure of endogenous CCK to control gastrinrelease and gastric secretion by releasingsomatostatin, and (c) the test with loxiglu-mide may be useful in the identification ofpatients with impaired feedback control ofgastrin release and gastric secretionresulting from infection with Hpylon.(Gut 1995; 37: 482-487)

Keywords: Helicobacterpylori, gastrin, CCK, CCKreceptors.

Duodenal ulcer (DU) patients, as a group,tend to secrete more acid than normal subjects

both at rest and in response to secretory stimu-lation. ' As, after ingestion of a meal, theimportant stimulant of gastric acid secretion isan increased plasma gastrin,2-4 the DUpatients have been reported to have higherplasma gastrin response to a meal and toexhibit an impaired inhibition of gastrin releaseat lower intragastric pH.5 Other studiesshowed that endogenous cholecystokinin(CCK) may be implicated in the feedbackcontrol of gastrin release and gastric acidsecretion6 7 because the administration of loxi-glumide, a highly selective antagonist of CCK-A receptors,68 greatly enhanced the plasmagastrin and gastric acid secretion in response toordinary feeding, protein meal or gastrinreleasing peptide. Moreover, DU patients werefound to exhibit the defect in the inhibitoryaction of endogenous CCK9-12 on gastricrelease and gastric acid secretion suggesting animportant role ofCCK in the feedback controlof gastric secretory functions.The role of CCK as 'enterogastrone' in the

control of gastric secretion by duodenal acid orfat has also been tested in dogs using highlyselective CCK receptor antagonists such as L-364,718.13 14 These studies confirmed thatCCK released by a peptone meal, especiallywhen combined with fat'3 or acid,'4 exerts apotent inhibitory influence on gastric acidsecretion and gastrin release through enhanc-ing the release of endogenous somatostatin.Also in DU patients the defect in the inhibitoryaction of CCK on gastric secretion'0-12has been suggested to result from the failureof CCK to activate (through the CCK-Areceptors) the D cells to release somatostatinbecause loxiglumide in these patients did notaffect significantly the plasma somatostatinconcentration. 10More recently it was found that chronic

infection ofHpylori can be found in up to 90%of DU patients and is usually accompanied bynon-specific antral gastritis.15-17 It has beensuggested that chronic H pylori infection maylead to DU disease because of an inappropriategastrin release and subsequent enhancement ingastric acid secretion. In other reports reduc-tion in postprandial gastrin responses aftereradication of H pylori in DU patients havebeen shown.1820 Furthermore, studies onasymptomatic (without DU) subjects infectedwith Hpylori showed that these subjects have asignificantly higher peptone meal inducedplasma gastrin concentration and significantlyattenuated inhibition of plasma gastrin at low

Department ofMedicine B, UniversityofMunster, Munster,GermanyJW KonturekW DomschkeA Gillessen

Institute ofPhysiology,School ofMedicine,JagiellonianUniversity, Krakow,PolandS J Konturek

Correspondence to:Dr JW Konturek,Departnent of Medicine B,University of Miunster,Albert-Schweitzer-Str 33,48129 Munster, Germany.Accepted for publication24 February 1995

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intragastric pH compared with uninfectedasymptomatic subjects.21 It was proposed thatthe impaired inhibition of gastrin release andgastric acid secretion seen previously in DUpatients5 may be related to the infection ofH pylori in these patients.

This study was designed to assess thepossible role of endogenous CCK in theimpaired control of gastrin release in DUpatients before and after eradication ofH pylori.

Methods

SubjectsStudies were approved by the Research andHuman Use Committee at the UniversityMedical School, Krakow and written consentwas obtained from each subject.

Studies included 10 male patients, their agesranged from 22 to 28 years (mean age 24). Allof them had active DU diagnosed by clinicalhistory and actual gastroduodenal endoscopy.All of them had two or more episodes ofsymptomatic relapse within one year. Nonehad symptoms of ulcer disease at the time ofstudy. All drugs were withdrawn for three daysbefore the examination.

Study protocolSubjects were studied on three separate daysbefore and after eradication ofHpylori. On oneday, Hpylori status was tested using two endo-scopic biopsy specimens obtained from thelesser curvature of the middle antrum. Onespecimen was assessed histologically and oneby the rapid urease test for evidence ofHpyloriinfection. For histological assessment, thespecimen was fixed in 10% buffer formalin,embedded in paraffin wax, and sectioned.Sections were stained with haematoxylin andeosin with Giemsa for detection of H pylon.The second specimen was used for rapidurease CLO test (Delta West Pty, Bentley,Western Australia). Only H pylori positivesubjects were included in further studies.

Gastric secretory studies with intragastric pHmonitoringOn a second day, gastric acid secretion wasstudied for one hour under basal conditionsand then for three hours after standard liquid500 kcal meal (500 ml Fresubin, Fresenius,Germany). This meal consisted of protein(3.80/o), aminoacids (0.60/o), carbohydrates(14%), fat (3.8%), minerals, vitamins, andwater with osmolarity of about 300 mOsm/land pH of about 60.Throughout the examination period, the

intragastric pH was monitored by means of anintraluminal system including the pH anti-mony electrode (Monocrystal model 9-0215,Synectics AB, Sweden) connected to theportable apparatus, which permitted the pHrecording to be sampled every four seconds(Digitrapper MKII, 6200, Synectics AB,Sweden). The antimony electrode used an

external reference on the thorax with contactjelly (Hellige 217, Fritz Hellige, Germany). Atthe beginning and at the end of each examina-tion, the pH electrode was accurately cali-brated at 21°C with pH 7.01 and pH 1-07(buffers 5001 and 5002, Synectics AB,Sweden) and a temperature correction forintragastric reading (37°C) was performed asdescribed before.22 The pH electrode waspassed through an anaesthetised nostril andwas positioned in the gastric corpus underfluoroscopic control roughly 15 cm below thelower oesophageal sphincter. The pH record-ing started at about 0800 and lasted four hoursand this included 60 minutes of basal periodand 180 minutes after digestion of liquid meal.Data from intragastric pH monitoring were

transferred to an IBM compatible computer(80386-IBM) programmed with Gastrogramversion 5.50 serial No E1024 (Gastrosoft,Irvine, TX, USA) for calculation of mean andmedian pH values for each three hour post-prandial period. Data from all six subjectstreated with placebo and loxiglumide wereanalysed with the use ofprogram STATpHACII/PHARM, version 216 D3 (Gastrosoft,Irvine, TX, USA). Gastric acidity wasexpressed as pH and values from each subjectwere transferred into 10 minute median values.The median and mean three hour intragastricpHs were pre-defined for comparison betweenstudy days using Wilcoxon's signed rank test.Box and whisker plots of median and meanintragastric pH in six patients were calculatedfor a three hour period after standard meal andcompared in medians and means with a signifi-cance value of less than 0 05.Each subject was tested twice before and

twice after eradication of H pylori using (a)standard liquid meal with oral administrationof a placebo tablet 30 minutes before meal and(b) standard meal and oral administration of aloxiglumide tablet (1200 mg) given 30 minutesbefore meal.

Eradication of H pylori was achieved withtriple therapy including amoxycillin, 500 mgthree times daily, for two weeks omeprazole(20 mg twice daily) for two weeks, and col-loidal bismuth subcitrate, 120 mg four timesdaily for four weeks. Endoscopy performedfour weeks after the ending of treatmentshowed complete ulcer healing in all examinedpatients but the second test for eradication ofHpylori including 13C urea breath test showedH pylori eradication in only six of 10 treatedpatients. A second gastric secretory examina-tion was performed five weeks after the end oftreatment and was only carried out in H pylorinegative patients.

RadioimmunoassaysVenous blood samples were obtained from aperipheral vein under basal conditions (twice)at 30 minute intervals before and after a stan-dard meal (six times) before and after eradica-tion ofHpylori in subjects receiving placebo orloxiglumide tablets. Plasma gastrin wasdetermined using gastrin antiserum 4562(kindly donated by Professor J E Rehfeld of

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Figure 1: Median intragastric pH in DUpatients before (A) and after (B) eradication ofH pylori before and after a standard meal in tests with administration ofplacebo orloxiglumide. Six tests on six patients. Box-whisker plots of three hour postprandial pHmeasurement period in tests with placebo (PL) or loxiglumide (LOX) treatment.

Copenhagen, Denmark) and used in a finaldilution of 1:140000. The antibody usedrecognises G17 and G34 equally. The sensitiv-ity of the gastrin measurement in the presentassay was 2.5 pmollml serum equivalent tohuman G-17 as described previously.23

Plasma CCK concentrations were deter-mined by a radioimmunoassay using antiserumNY 11 (kindly provided by Professor NYanaihara, Skizuoka, Japan), which recognisesthe sulphated residue of CCK-8 but has onlynegligible cross reactivity with sulphated G-1 7(</5%) and does not cross react with unrelatedgastrointestinal peptides. Plasma samples were

extracted with ethanol/acetic acid mixture,dried in a vacuum, and restituted with assaydilutent just before the assay. Syntheticsulphated human CCK-8 (gift of ProfessorN Yanaihara) was used as a standard and1251-labelled with Bolton and Hunter reagent(Amersham, UK) as a tracer.1' The detectionlimit of the assay was 0.5 pmol/ml plasmaCCK-8 standard. Intra-assay and interassaycoefficients of variation were 8% and 12%,respectively.

Plasma somatostatin was measured using a

commercially available radioimmunoassay kitpurchased from Milab, Malmo Immun-LabsAb, Malmo, Sweden as described." The anti-serum used recognises only cyclic forms ofsomatostatin-14 and somatostatin-28 equallyand did not cross react with any knowngastrointestinal peptide. Plasma somatostatinwas extracted with ethanol/acetic acid mixture,dried in a vacuum, and restituted as in the case

of CCK. The detection limit was 0.5 pmol/ml.Interassay and intra-assay variations were 8%and 12%, respectively.

StatisticsThe results of plasma hormones are expressed

as means (SEM). Statistical significance wasdetermined by both the Wilcoxon signed ranktest and the paired t test. Significance wasaccepted with a p value of less than 0.05.

ResultsOf 10 H pylon' positive patients initiallyincluded in the study, only six had negativehistological, rapid urease (CLO test), and 13Curea breath tests four weeks after the end oftriple therapy. The results presented in thisreport concern only the six subjects whoshowed negative Hpylori status and who com-pleted the intragastric pH monitoring testswith placebo and loxiglumide before and aftereradication of Hpylori.

Figure 1 shows the pH profile recordedduring one hour of basal state and during threehours after ingestion of standard liquid meal.The pH value in H pylorn positive patientsduring the basal period was about 1. 1 and wasnot significantly different between placebo andloxiglumide treated subjects. With the inges-tion of a meal, the median pH immediatelyrose to about 6 and then slowly declined withinabout 90 minutes to the pre-meal value, themedian pH for three hours of the postprandialperiod being about 3-5. In subjects treatedwith loxiglumide, the median pH also rose topH 6.0 and then declined to the pre-meal valuewithin about 60 minutes, the median pH forthe examined period (three hours) being about3*1. The difference in the median postprandialpH between placebo and loxiglumide treatedH pylori positive DU patients was not statisti-cally significant.The pH profile in DU patients with negative

H pylori status, showed similar basal pH value(pH 1-3) and similar pH peak (about pH 6)after ingestion of standard meal. The return ofintragastric pH after a meal to the pre-mealvalue occurred after about 120 minutes inplacebo treated subjects and after about 60minutes in loxiglumide treated subjects. Themedian pH for the examined period (threehours) was significantly lower in tests withloxiglumide (pH 3-1) than in tests with placebo(pH 4.2).

Basal plasma gastrin, CCK, and somato-statin in placebo treated H pylori positive DUpatients averaged 27 (3), 0-8 (0.2), and 3-8(0.3) pmolI1. Ingestion of a standard liquidmeal by those patients treated with placeboresulted in a significant increment (abovebasal) of plasma concentrations of gastrin (Fig2), plasma CCK (Fig 3), and somatostatin(Fig 4) by about 88%, 150%, and 68%,respectively. In tests with loxiglumide basalplasma hormone concentrations were notsignificantly affected compared with placebobut the postprandial increments of plasmagastrin and somatostatin were similar to thoseseen in those patients after treatment withplacebo. The increment of meal inducedplasma CCK was almost twofold higher intests with loxiglumide than with placebo.

After eradication ofH pylori in DU patients,the basal concentrations ofplasma gastrin weresignificantly reduced, while plasma CCK and

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* and t for p < acid secretion and that these effects of Hpylori

Meal infection could be caused, at least in part, byA

l the abolition of the gastric inhibitory effects ofA * < * Loxiglumide endogenous CCK.-y YPrevious studies on healthy subjects showed

that exerts a potent inhibitory influencePlacebo on gastrin release and gastric acid secretion in

I response to ordinary feeding or administrationof gastrin releasing peptide.6 7 It has beenproposed that CCK exerts a tonic inhibitoryinfluence of gastric secretory functions and

Meal t~ t* participates in the negative feedback control ofB /* Loxiglumide gastrin release and gastric secretion.'0 This

suggestion was supported by the finding thatPlace 0

the removal of the biological effects (by loxi-Placebo 2 glumide) of CCK either given exogenously or

I I I released endogenously by peptone meal or-60 0 60 120 180 infusion of gastrin releasing peptide resulted in

Time (min) a pronounced increase in plasma gastrin and2: Plasma gastrin under basal conditions and after a gastric acid secretion.rd meal in DUpatients before (A) and after (B) Our further studies with DU patientsrtion ofH pylori in tests with placebo or loxiglumide. showed that blockade of CCK-A receptorsof six tests on six patients. *Shows significante above the basal value; tshows significant change with loxiglumide failed to influence the,ed with the value obtained with placebo. enhanced basal or postprandial plasma gastrin

and gastric acid secretion in these patientstostatin values were similar to those in suggesting an impaired inhibition of gastricits before the H pylori eradication. The functions by endogenous CCK possibly causedrandial increment in plasma gastrin in by the failure of this CCK to stimulatebo treated patients was similar to that somatostatin release from the D cells.'0-12 Thein subjects before the eradication but in implication of somatostatin in the 'entero-with loxiglumide, the increment in the gastrone-like' action of CCK originates fromrandial plasma gastrin was about twice as the studies on dogs'0 13 14 in which an additionLs in tests with placebo (Fig 2). The post- to a peptone meal of fat or acid (whichlial increment in plasma CCK concentra- are known releasers of CCK) significantlyin H pylori negative DU patients treated inhibited gastrin release and gastric acid secre-placebo were significantly lower than tion. These inhibitory effects were completelyin tests with loxiglumide. Thus, the eliminated by the blockade of CCK-A recep-

nistration of loxiglumide resulted in a tors with L-364,718, a specific antagonist oficant rise in plasma CCK over that seen these receptors. As CCK is known to stimulateacebo treated subjects both before and the release of somatostatin from isolatedthe eradication of Hpylori (Fig 3). canine fundic D cells in vitro29 and thesma somatostatin concentrations showed administration of L-367,718 in vivo alsoa small increase over basal when a stan- reduced the postprandial release of somato-meal was given to placebo treated patients statin'3 14 it was proposed that the major factor

both with H pylorn positive and H pyloni nega-tive status. On the other hand, in H pylori neg-ative DU patients, the increment in plasmasomatostatin in tests with loxiglumide wassignificantly smaller than that in tests withplacebo (Fig 4).

DiscussionThis study confirms that eradication ofHpyloriin DU patients reduces plasma gastrinrelease20 24 25 and attenuates the postprandialgastric acid response in these patients.20 25-28The most important finding of this study isthat the blockade of CCK-A receptors withloxiglumide in DU patients infected withH pylori did not influence significantly thepostprandial gastrin concentrations or gastricacid secretion but after eradication ofH pylornin the same patients, loxiglumide resulted in apronounced increment in plasma gastrin con-centrations similar to that seen previously inhealthy subjects.6 7 These results could beinterpreted that the H pylori infection in DU isresponsible for the increased basal plasmagastrin concentrations and increased gastric

*andt forp<O-05Meal

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607 B

40

20

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Time (min)Figure 3: Plasma CCK concentrations under basalconditions and after a standard meal in DU patients before(A) and after (B) eradication ofH pylori in tests withplacebo or loxiglumide. Mean of six tests on six patients.*Shows significant increase above the basal value; tshowssignificant change compared with the value obtained withplacebo.

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*and t forp<O.0512 Meal

Placebo8 ~ ~ *

E 4 ALoxiglumide

0

cnCo

2

t2-B Meal

Loxiglumide

-60 0 60 120 180Time (min)

Figure 4: Plasma somatostatin concentrations under basalconditions and after a standard meal in DUpatients before(A) and after (B) eradication ofH pylon in tests withplacebo or loxiglumide. Mean of six tests on six patients.*Shows significant increase above the basal value; tshowssignificant change compared with the value obtained withplacebo.

in the mechanism of gastric acid inhibition byCCK in dogs is probably somatostatin actingpredominantly by a paracrine pathway on theG cells and oxyntic cells.The somatostatin hypothesis in the control

of gastric secretion in humans, particularly inDU patients, is attractive because the defi-ciency of somatostatin in DU patients has beensuggested previously.30 31 The reports2627 thatgastric D cells are suppressed in H pylonpositive duodenal ulcer disease offered anexplanation for the deficient inhibitory path-way and support the somatostatin link in thisdisease. Our results show that after a standardmeal in DU patients with or without H pyloninfection, there was a small but significantincrement in plasma somatostatin, which maynot be able by itself to inhibit gastrin release orgastric acid secretion but it may reflect theimportant changes in paracrine release ofsomatostatin by CCK just around the G cellsor oxyntic cells. This could explain the appar-ent discrepancy between the pronouncedincrement in the postprandial plasma gastrinby loxiglumide in H pylon negative DUpatients and the comparatively small decreasein the concentrations of circulating plasmasomatostatin. DU patients infected withH pylori may exhibit the defective inhibitoryaction of endogenous CCK on paracrinerelease of somatostatin resulting in augmentedbasal plasma gastrin release and gastric acidsecretion in response to a meal in thesepatients. After eradication of H pylon, loxi-glumide could suppress the release of somato-statin possibly by antagonising CCK-Areceptors localised to these cells. The antago-nism of CCK-A receptors and the fall insomatostatin output will remove the G cellsfrom the paracrine inhibitory influence ofsomatostatin with subsequent excessive post-prandial release of gastrin and greatlyincreased gastric acidity. This is in keepingwith our data that after the eradication of

H pylori, a significant decrease in basal plasmagastrin and gastric acid responses to the mealwas seen but the blockade ofCCK-A receptorswith loxiglumide resulted in a greatly increasedpostprandial gastrin release and enhancedgastric acid secretion, similar to those seenin healthy subjects.6 7 As no significant dif-ferences in plasma CCK and somatostatinvalues were seen before and after eradication ofH pylori, it is probable that in addition to theproposed CCK-somatostatin-gastrin link thereare other factors, such as cytokines (forexample, interleukin 1) that may impair thenormal physiological feedback loop for gastrinregulation in chronic inflammation resultingfrom infection by H pylon. Indeed, animalsstudies32 showed that interleukin 1 given intra-venously increased plasma gastrin concentra-tion while inhibiting gastric acid secretionand these effects were mediated by theprostaglandin pathway. Further studies areneeded to elucidate the relative contribution ofvarious factors in the control of gastrin releaseand gastric secretion in the H pylon infectedpatients.

It is of interest that loxiglumide resulted in aconsiderable increase in postprandial plasmaCCK concentration both in H pylori positiveand H pylori negative DU patients. Thisactually confirms previous findings6 regardinghigher postprandial concentrations of circulat-ing CCK in loxiglumide treated patients com-pared with placebo treated subjects. Higherplasma CCK concentrations in tests with loxi-glumide were reported previously in healthysubjects6 11 12 and, according to this study, thisis also true for DU patients after eradication ofHpylori.Our results show that the infection of H

pylorn not only enhanced gastrin release butalso increased postprandial gastric acid secre-tion as reported by some investigators'5 24 25but this is a controversial issue because otherreports showed that H pylori infection isaccompanied by hypergastrinaemia but not byhyperchlohydria28 33 34 or increased integrated24 hour intragastric acidity.35

1 Baron JH. The clinical use of gastric function tests. ScandJ3Gastroenterol 1970; 6 (suppl): 9-17.

2 Feldman M, Walsh JA, Wong HG, Richardson CT. Role ofgastrin heptadecapeptide in the acid secretory response toamino acids in man. Gastroenterology 1978; 61: 303-13.

3 Eysselein VE, Kovacs TOG, Kleibenker JH, Maxwell V,Reedy T, Walsh JH. Regulation of gastric acid secretionby gastrin in duodenal ulcer patients and healthy subjects.Gastroenterology 1992; 102: 1142-8.

4 Walsh JH. Gastrin. In: Walsh JH, Dockray GJ, eds. Gutpeptides. New York: Raven Press, 1974: 75-122.

5 Walsh JH, Richardson CT, Fordtran JS. pH dependence ofacid secretion and gastrin release in normal and ulcerpatients. J Clin Invest 1975; 55: 462-8.

6 Beglinger C, Hildebrand P, Meier R, Bauerfeind P,Hasslocher H, Urscheler N, et al. A physiological role forcholecystokinin as a regulator of gastrin secretion.Gastroenterology 1992; 103: 490-5.

7 KonturekJW, Maczka J, Garlicki A, Gabryelewicz A, RovatiL, Domschke W, et al. Cholecystokinin (CCK) in the con-trol of gastric secretion in man. Gut 1993; 34: 321-8.

8 Setnikar I, Christe R, Makovec F, Rovati LC, WarringtonRT. Pharmacokinetics of loxiglumide after single intra-venous or oral doses in man. Arrzneimietelforshung 1988;39: 716-20.

9 Gross RA, Isenberg JI, Hogen D, Samloff IM. Effect of faton meal-stimulated duodenal acid load, duodenal pepsinload, and serum gastrin in duodenal ulcer and normalsubjects. Gastroenterology 1978; 75: 357-62.

10 Konturek JW, Konturek SJ, Domschke W. Role of chole-cystokinin in the control of gastric acid secretion and gas-tin release in dogs and healthy and duodenal ulcersubjects. ScandJf Gastroenzterol 1993; 28: 657-60.

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11 Konturek JW, Thor P, Maczka M, Domschke W, KonturekSJ. Role of CCK in the control gastric secretory pattern inresponse to fatty meal in normal subjects and duodenalulcer patients. Scand Jf Gastroenterol 1994; 29: 583-90.

12 Konturek JW, Maczka M, Stoll R, Konturek SJ, DomschkeW. Cholecystokinin (CCK) in the inhibition of gastricacid secretion and gastrin release in response to meals oflow and high pH in healthy subjects and duodenal ulcerpatients. Gastroenterology 1994; 106: Al10.

13 Lloyd KC, Maxwell V, Kovass TO, Walsh JH.Cholecystokinin receptor antagonist MK-329 blocksintestinal fat-induced inhibition of meal-stimulated gastricacid secretion. Gastroenterology 1992; 102: 131-8.

14 Konturek SJ, Bilski J, Tasler J, Cieszkowski M. Role ofcholecystokinin in the inhibition of gastric acid secretionin dogs. Jf Physiol 1992; 451: 477-98.

15 Levi S, Beardshall K, Desa LA, Calam J. Campylobacterpylori, gastrin, acid secretion, and duodenal ulcer. Lancet1989; ii: 613.

16 Levi S, Haddad G, Ghosh P, Beardshall K, Playford R,Calam J. Campylobacter pylori and duodenal ulcer: thegastrin link. Lancet 1989; i: 1167-8.

17 Chamberlain CE, Peura DA. Campylobacter(Helicobacter) pylori - is peptic disease a bacterial infec-tion? Arch Intern Med 1990; 150: 951-5.

18 McColl KEL, Fullarton GM, El Nujumi AM, MacDonaldAM. Lowered gastrin and gastric acidity after eradicationof Campylobacter pylori in duodenal ulcer. Lancet 1989;ii: 499-500.

19 Graham DY, Opekun A, Lew GM, Evans DJ, Klein PD,Evans DG, et al. Ablation of exaggerated meal-stimulatedgastrin release in duodenal ulcer patients after clearance ofHelicobacter (Campylobacter) pylori infection. Am J7Gastroenterol 1990; 85: 394-8.

20 Konturek PCh, Konturek SJ. Role of Helicobacter pyloriinfection in gastro-duodenal secretion and pathogenesis ofpeptic ulcer and gastritis. Jf Physiol Pharmacol 1994; 45:333-50.

21 Tarnasky PR, Kovacs TOG, Sytnik B, Walsh JH.Asymptomatic H pylori infection impairs pH inhibition ofgastrin and acid secretion during second hour of peptonemeal stimulation. Dig Dis Sci 1993; 38: 1681-7.

22 Savarino V. Continuous intragastric pH monitoring, a realprogress in the assessment of antisecretory drugs. Ital JfGastroenterol 1990; 22 (suppl 2): 10-23.

23 Konturek SJ, Swierczek J, Kwiecien N, Obtulowicz W,

Dobrzanska M, Kopp B, et al. Gastric secretory andplasma hormonal responses to sham-feeding of varyingduration in patients with duodenal ulcer. Gut 1981; 22:1003-10.

24 Mullin GE, Kallo AN. Does Helicobacter pylori infectionaffect gastric acid secretion. Gastroenterology 1990; 98:A92.

25 Moss SF, Calam J. Acid secretion and sensitivity to gastrinin patient with duodenal ulcer: effect of eradication ofHelicobacter pylori. Gut 1993; 34: 888-92.

26 McHenry I, Vuyyuruu L, Schubert ML. Helicobacter pyloriand duodenal ulcer disease: the somatostatin link?Gastroenterology 1993; 104: 1573-5.

27 Kaneko H, Nakada K, Mitsuma T, Uchida K, Furusawa A,Maeda Y. H pylori infection induces a decrease inimmunoreactive somatostatin concentrations in humanstomach. Dig Dis Sci 1992; 37: 409-16.

28 Brady ECI, Hadfied TL, Hyatt JR, Utts SJ. Acid secretionand serum gastrin levels in individuals withCampylobacter pylori. Gastroenterology 1988; 94: 923-7.

29 Soll AH, Amirian DA, Park J, Elashoff JD, Yamada T.Cholecystokinin potently releases somatostatin fromcanine fundic mucosal cells in short-term culture. Am JPhysiol 1985; 248: G569-73.

30 Chayvialle JAP, Descos F, Bernard C, Martin A, Barbe C,Partensky C. Somatostatin in mucosa of stomach andduodenum in gastroduodenal disease. Gastroenterology1978; 75: 13-9.

31 Harty RF, Malco DG, McGuigan JE. Antral release ofgastrin and somatostatin in duodenal ulcer and controlsubjects. Gut 1986; 27: 652-8.

32 Seperas E, Comiinelli F, Tache Y. Potent inhibition ofgastric acid secretion by intravenous interleukin-1 betaand -alpha in rats. Peptides 1992; 13: 221-6.

33 Katelaris PH, Seow F, Lin BPC, Napoli J, Ngu MC, JonesDB. Effect of age, Helicobacter pylori infection, and gas-tritis with atrophy on serum gastrin and gastric acid secre-tion in healthy men. Gut 1993; 34: 1032-7.

34 Haruma K, Kawaguchi H, Yoshihara M, Okamoto S, SumiiK, Kishimoto S, et al. Relationship between Helicobacterpylori infection and gastric acid secretion in young healthysubjects. J7Clin Gastroenterol 1984; 19: 20-2.

35 Vagner S, Gladziwa U, Haruma K, Varrentrapp M, GabelE. Effect of Helicobacter pylori infection on 24 h intragas-tric acidity in patients with gastritis and duodenal ulcer.Gut 1992; 33: 1024-8.

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