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`JOURNAL TITLE:
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`European journal of gastroenterology & hepatology
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`USER JOURNAL TITLE: European Journal of Gastroenterology & Hepatology
`
`ARTICLE TITLE:
`
`Intragastric pH and serum gastrin during administration of different doses of pantoprazole in
`healthy subjects.
`
`ARTICLE AUTHOR:
`
`Koop, Koop
`
`VOLUME:
`
`ISSUE:
`
`MONTH:
`
`YEAR:
`
`PAGES:
`
`ISSN:
`
`OCLC #:
`
`8
`
`9
`
`9
`
`1996
`
`915-918
`
`0954-691X
`
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`JOURNAL TITLE;
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`European journal of gastroenterology & hepatology
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`
`5 European Journal of Gastroenterology & Hepatology
`European journal of gastroenterology & hepatology
`Intragastric pH and serum gastrin during administration of different doses of
`pantoprazole in healthy subjects.
`KooP: KOOD
`8
`9
`
`
`
`9
`1996
`
`PAGES:
`
`‘
`
`_
`
`915-918
`
`ISSN:
`
`om; #;
`
`0954-691X
`
`HUA OCLC #: 20609040
`
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`[TN:574208][ODYSSEY:128.6.218.9’l/RULILL] '
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`gastric pH and serum gastrin were performed on the 7th day of treatment by continuous pH
`recording and radioimmunoassay in blood samples obtained in 1—h intervals, respectively.
`Results: Pantoprazole significantly increased gastric pH above basal at all pantoprazole
`doses studied: median 24-h pH rose from 1.2 without therapy to 3.4, 3.3 and 3.6 at 40, 80
`and 120 mg daily, respectively. The corresponding integrated 24-h gastrin output was 1632,
`2338 and 2248 pg/ml><24h compared to 575 pg/ml><24h without pantoprazole. There was
`no interindividual correlation between values of 24-h median pH and 24-h gastrin output at
`any pantoprazole dose studied. However, fasting gastrin levels closely correlated with 24-h
`gastrin output (r=O.789; P< 0.0001). The acid inhibitory effect was significantly (P< 0.01)
`augmented in Helicobacter pylori positive subjects.
`
`is concluded that pantoprazole is an effective inhibitor of gastric acid secre-
`Conclusion: It
`tion. lncreasing a single pantoprazole dose above 40 mg does not lead to increased median
`pH elevation. The individual extent of acid inhibition does not predict the magnitude of
`gastrin elevation. Acid inhibition appears more efficient in Helicobacter pylori positive
`subjects.
`
`European Journal of Gastroenterology & Hepatology 1996, 82915-918
`Keywords: acid secretion, gastrin, healthy subjects, Helicobacter pylori,
`intragastric pH, pantoprazole
`
`Introduction
`
`Gastric acid exerts a constant inhibitory influence on the
`antral gastrin—produeing G-cell (‘acid brake’)
`In
`conditions with low gastric acidity or achlorhydria [2],
`gastrin levels markedly increase, often exceeding levels of
`1000 pg/ml whereas hypergastrinaemia is only of slight or
`moderate magnitude during treatment with potent antise-
`cretory drugs such as proton pump inhibitors [3—5] despite
`profound and long—lasting suppression of acid secretion at
`least in some individuals [3,4]. In the present study, the
`interrelationship between intragastric pH and changes in
`the 24-h profile of serum gastrin was investigated using
`various doses of the proton pump inhibitor pantoprazole.
`Pantoprazole is a new substituted benzimidazole with
`
`potent acid inhibitory efficacy which is devoid of interac—
`tion with the cytochrome P450 system at therapeutic
`dosages
`After activation within the acidic compart-
`ment pantoprazole binds covalently to the Ht/K*-ATPase
`of the gastric parietal cell thus inhibiting the final step of
`acid secretion [7]. In clinical studies, pantoprazole
`markedly suppressed basal and stimulated acid secretion [8]
`to an extent comparable to omeprazole [9].
`
`Methods
`
`Subjects
`In this randomized, prospective, double—blind crossover
`trial, 15 healthy subjects (5 females, 10 males; age 22-31
`
`From the Department of internal Medicine ll, Klinikum Buch, Berlin, *Division of Gastroenterology, Department of Medicine,
`Philipps—University, Marburg and *Byk Gulden, Konstanz, Germany.
`Requests for reprints to Prof. Dr Herbert Koop, Department of Internal Medicine ll, Klinikum Buch, Karower Strasse 11, D-
`13122 Berlin, Germany.
`Date received: 30 April 1996; accepted: 6 June 1996.
`
`© Rapid Science Publishers ISSN 0954-691X
`
`
`
`

`
`ment were started in an identical manner with further pH
`recordings and gastrin measurements on the seventh day
`of therapy. Treatment was with 40, 80 and 120 mg daily,
`and the different doses were studied i11 random order
`using a double-blind crossover design.
`
`pH recordings and gastrin profiles
`Continuous 24-h pH recordings were performed on an
`in—patient basis. A glass electrode (Ingold 440 M 4, Ingold,
`Urdorf, Switzerland) connected to a solid state recorder
`(Mark II; Synectics, Frankfurt, Germany) previously cali-
`brated with buffcrs ofpH 1 and 7.4 was placed transnasally
`into the proximal stomach 5cm below the cardia;
`the
`cardia was identified by a drop in pH below pH 4. After
`successful placement of the electrode, the length from the
`nasal
`tip was documented during the primary pH
`recording without therapy and identically placed in subse-
`quent recordings. The proper placement of the electrode
`during pantoprazole treatment was additionally checked
`fluoroscopically. Intragastric pH was recorded for a
`complete 24-h period in 6-s intervals. After completion of
`the recordings, data were evaluated using an established
`computer program (Esophogram, Gastrosoft). For each
`course of treatment,
`the median 24-h pH and the
`percentage of time with pH above 4 were determined;
`additionally,
`these parameters were calculated separately
`for the time frames of 7.00 am to 7.00 pm and 7.00 pm to
`7.00 am.
`
`Mann—Whitney U test. Differences at the 5% level were
`considered significant. The study was approved by the
`Ethics Committee of the Medical Faculty of the Philipps—
`University 0fMarburg.
`
`Results
`
`The pH profile under basal condition showed a typical
`circadian pattern with increases in intragastric pH in
`response to meals. Treatment with 40 mg of pantoprazole
`given for 7 days markedly increased 24-h pH from a
`median of 1.2 (basal) to 3.4 (Fig. 1, Table 1). The
`profound inhibition of acid secretion is also exemplified
`by the increase in time with pH above 4 (Table 1).
`Administration of pantoprazole doses exceeding 40 mg
`did not result in a further increase in median pH or time
`with pH above 4 (Table 1); however, subjects showing
`only moderate increases in intragastric pH with the lower
`pantoprazole dose (e.g. median pH 1.3 to 2.2 at the 40
`mg dose) exhibited further elevations of median pH
`reaching values above 2.3 in all cases and above 3.0 in 13
`out of 15 cases at the highest pantoprazole dose studied
`(Fig. 1).
`to profound suppression of acid secretion,
`Parallel
`serum gastrin levels increased in response to 40mg panto-
`7
`
`MedianpH
`
`0
`
`80 mg
`40 mg
`Daily Dose
`
`120 mg
`
`Three milllilitres of blood were obtained from an
`indwelling catheter placed in an antecubital vein at 1—h
`intervals (apart from 2—h intervals between 12.00 am and
`6.00 am). Blood samples were centrifuged and stored at
`—20°C until assayed. Gastrin concentration was deter-
`mined by means of a sensitive and specific radioi1n—
`munoassay previously described in detail [10]. Serum
`samples from all four courses were run in the same assay
`in order to reduce the influence of interassay variation. In
`addition to blood samples taken at regular intervals for
`gastrin determination, routine laboratory values were
`measured on each final day of treatment. IgG and IgA
`antibodies to Helicobacrer pylori (H.p.) were determined by
`enzyme—linked immunosorbent assay using whole cell
`lysate antigen (Pyloristat [11]; Helicobacter pylori ELISA®,
`Serva, Heidelberg, Germany). Only individuals with IgG
`
`Fig. 1. Median 24-h intragastric pH in response to increasing doses
`of pantoprazole in 15 healthy volunteers. Closed symbols and solid
`lines indicate Helicobacter pyIori—negative subjects, open symbols
`and dotted line H. pylori positive subjects.
`
`
`
`

`
`*95% confidence intervals in brackets; * P< 0.05 or less vs. Control without therapy; “P < 0.05 vs. 40 mg pantoprazole.
`
`respectively; P< 0.005) and 120 mg (5.3 versus 3.4,
`respectively; P<0.005). No differences in median 24-h
`pH without antisecretory treatment, nor in 24-h gastrin
`both without therapy and during treatment with panto-
`prazole, were detected between volunteers positive and
`negative for H. pylori antibodies.
`Pantoprazole doses up to 120mg daily were well toler-
`ated. The volunteers did not report any adverse events
`during the whole study period. There were no changes in
`any of the standard laboratory parameters at any dose of
`pantoprazole.
`
`Discussion
`
`Data from the present study confirm that pantoprazole is
`an effective and well-tolerated acid inhibitory drug
`comparable to omeprazole. This matches well with results
`from clinical trials in which pantoprazole exerted healing
`rates in acid peptic diseases also comparable to omeprazole
`[13—16]. Pantoprazole doses exceeding 40mg did not
`induce a further progressive increase in intragastric pH
`though the 24-h median pH further rose in those subjects
`responding less markedly at the lowest dose studied. It
`seems reasonable to assume that divided doses should
`result in further inhibition of acid secretion when panto-
`prazole is administered in higher amounts than 40 mg
`daily, as with other proton pump inhibitors [17]. This
`assumption is presently under investigation.
`The profound and long—lasting increase in intragastric
`pH in response to the proton pump inhibitor resulted in
`an enhanced secretory activity of the gastrin producing G-
`cell. Unlike its effect on gastric acidity, there was a dose
`relationship between the pantoprazole dose and the eleva-
`tion of gastrin secretion. The progressive increase in 24-h
`integrated gastrin output is probably due to enhanced
`antisecretory activity of higher pantoprazole doses in those
`subjects who revealed only moderate suppression of acid
`secretion at the 40 mg dose. Based upon the close correla-
`tion between a single fasting serum gastrin level obtained
`24h post dose and 24-h integrated gastrin output, the
`gastrin concentration in a fasting serum sample offers a
`
`
`
`prazole compared to gastrin levels without therapy.
`However, in contrast to pantoprazole effects on gastric
`acidity, integrated gastrin responses further increased
`during administration of 80mg and 120mg pantoprazole
`reaching the level of significance at the highest dose
`studied (Table 1).
`In the basal state without any antisecretory treatment,
`there was a significant correlation between median 24-h
`pH and integrated serum gastrin (r: 0.72; P< 0.002).
`However, no correlation was observed during pantopra-
`zole therapy at any dose: coefficients of correlation varied
`between 0.187 and 0.266 (P> 0.1). Fasting gastrin levels
`(obtained at 7.00 am prior to repeat dosing and breakfast)
`showed a highly significant correlation (r=0.798; P<
`0.0001) with 24-h integrated gastrin output (Fig. 2).
`The effect of H. pylori status on the acid inhibitory
`effect and on serum gastrin levels was studied retrospec-
`tively (Fig. 1). In three subjects positive for H. pylori IgG
`antibodies, acid inhibition was more pronounced at 40 mg
`pantoprazole (median 24-h pH 5.5; 11:3) than in those 12
`subjects negative for H. pylori antibodies (median 24-h pH
`3.2; P<0.01). Similar differences were observed at panto—
`prazole doses of 80 mg (median 24-h pH 5.0 versus 3.1,
`
`E 12
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`Basal Gastrin (pg/ml)
`
`Fig. 2. Correlation between basal gastrin levels obtained before
`dosing and 24-h integrated gastrin in the basal state and after
`1-week continuous therapy with 40-120 mg pantoprazole daily.
`All determinations available irrespective of treatment were plotted.
`r=O.798; P<0.0001.
`
`
`
`

`
`though this
`pump inhibitors and gastrin release [18—19]
`has not been observed in a preliminary study using panto-
`prazole [20]. In the present study IgG antibodies were
`used as a marker for H. pylori infection because this para-
`meter has been found to be as reliable as the urea breath
`
`test [11], which is regarded the gold standard for the diag-
`nosis of H. pylori infection. Subjects positive for IgG anti-
`bodies against H. pylorl revealed a more pronounced anti-
`secrctory effect in response to pantoprazole than those
`who were negative. These data — though obtained in a
`small number of volunteers and therefore preliminary —
`are in agreement with previous reports of higher acid
`suppressing activity of omeprazole in H. pylori positive
`subjects [18,19]. The mechanism underlying the enhanced
`acid inhibitory activity of proton pump inhibitors is spec-
`ulative at present; gastritis related phenomena and
`increased buffer production by H. pylori have been
`suggested as major factors [18].
`In conclusion, pantoprazole is an effective inhibitor of
`gastric acid secretion. Increasing a single dose above 40mg
`does not lead to increased acid secretion. The individual
`
`extent of acid secretion does not predict the magnitude of
`gastrin release; however, determination of the basal gastrin
`level 24 h post close enables a very close estimate of
`changes occurring during the 24-h period. Infection with
`H. pylori seems to augment the acid inhibitory effect of
`pantoprazole in healthy subjects.
`
`Acknowledgements
`
`This study was supported by grants from Byk Gulden,
`Konstanz, and the Deutsche Forschungsgemeinschaft,
`Bonn—Bad Godesberg, grant K0 847/2-1. The skilful
`technical assistance of Mrs E. Bothe—Sandfort is gratefully
`acknowledged, The authors are indebted to Dr Mehl and
`D02. Dr Scholz, Dept of Microbiology, Klinikum Buch,
`Berlin, for determination of antibody titres to H. pylori.
`
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`al.: Effect of curing Helicobacter pylori infection on intragastric pH
`during treatment with omeprazole. Gut1995, 36:743-748.
`Labenz J, Tillenburg B, Peitz U, Verdti E, Stolte M, Tillenburg G,
`et al.: Helicobacter pylori augments the pH-increasing effect of
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`1996,110Z725—732.
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