`
`Effects of single and repeated doses of omeprazole on
`gastric acid and pepsin secretion in man
`
`C W HOWDEN, J A H FORREST, AND J L REID
`
`From the University Department of Materia Medica and Gastroenterology Unit, Stobhill General Hospital,
`Glasgow
`
`SUMMARY The effects of omeprazole, a substituted benzimidazole, on gastric acid and pepsin
`secretion have been studied in twelve healthy subjects. From six to eight hours after a single oral
`dose of 30 mg, there was a 66% reduction in basal acid output, and a 71-2% reduction in
`pentagastrin stimulated acid output. A single dose of 60 mg produced a 91-7% reduction in basal
`acid output and a 95-3% reduction in pentagastrin stimulated acid output. After seven days
`treatment with 30 or 60 mg daily,
`there was almost 100% inhibition of both basal and
`pentagastrin stimulated acid output. Omeprazole did not significantly affect pepsin secretion
`which is in keeping with its proposed mode of action, as an inhibitor of the H+/K+-ATPase
`enzyme on the secretory membrane of the parietal cell. There were no side effects after
`omeprazole either with single or repeated dosing.
`
`The substituted benzimidazolcs are new agents
`which are potent inhibitors of gastric acid secretion.
`They act by selective, non-competitive inhibition of
`the H+IK+-ATPase enzyme in the parietal cell.1
`This enzyme is the active transport mechanism for
`hydrogen ion secretion in the stomach. Although
`one of these agents, omeprazole, has been shown to
`suppress basal and pentagastrin stimulated acid
`secretion after a single dose,2 little is known about
`its effects after
`repeated dosing.
`In addition,
`previous studies have used a buffered suspension of
`the drug2 as it is partially inactivated by gastric acid, _
`or have looked at its acid inhibitory effect 24 hours
`after a dose.3
`We have studied the effects of two different doses
`
`of omeprazole on basal and pentagastrin stimulated
`acid and pepsin secretion after a single dose and
`after seven days of treatment. Capsules of enteric~
`coated omeprazole granules were used, and the
`effects studied around the time of expected
`maximum acid inhibition.
`
`Methods
`
`SUBJECTS
`
`Twelve healthy male subjects, mean age 25.2 years
`
`Address for correspondence: Dr C W Howden. Department of Materia
`Medica. Stobhill General Hospital. Glasgow GZl 3UW. Scotland.
`Received for publication 29 July 1983
`
`(range 19—34 years) were studied. None had any
`past medical history of note or was on any
`medication. All subjects gave informed written
`consent to the study which was approved by the
`research and ethical committee of
`the Greater
`Glasgow Health Board, Northern District.
`Subjects were randomly allocated to one of two
`groups. Each received one dose of placebo followed
`after three to five days by either 30 mg or 60 mg of
`omeprazole orally as a single daily dose for seven
`days. Subjects attended the Clinical Pharmacology
`Research Laboratory on three occasions during the
`study: day 0 (placebo); day one (first dose omepra-
`zole) and day seven (seventh dose omeprazole). The
`study design was
`identical on each occasion.
`Subjects arrived fasted at around 0830 hours and
`were given capsules containing enteric-coated
`omeprazole granules or placebo. A standard light
`breakfast was given 15 minutes after drug admini-
`stration and the subject remained fasted for the
`remainder of the study day. At around 1415 hours
`(or 5% hours postdose) a size 16 FG vented naso-
`gastric tube was passed and its position checked by
`means of a water recovery technique.4 From 1430
`until 1530 hours — that is, from six to seven hours
`postdose — gastric juice was aspirated continuously
`and collected as
`four
`15 minute samples for
`measurement of basal acid output. During the next
`hour, each subject received an intravenous infusion
`of pentagastrin (1-2 ug/kg/h), and gastric juice was
`707
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`708
`
`Howden, Forrest, and Reid
`
`continuously aspirated and collected as four 15
`minute samples for determination of plateau acid
`output.
`the acid
`Basal acid output was defined as
`produced in the second half of the basal hour
`multiplied by a factor of two,5 and plateau acid
`output as the acid produced in the two consecutive
`highest 15 minute periods of
`the second hour
`multiplied by a factor of two. An intravenous
`infusion of pentagastrin was used to give a constant
`rate of stimulation, and the dose selected was
`designed to give a near maximal stimulus without
`producing systemic side effects.6 Acid output was
`determined by titration to pH 7-0 with 0-1M sodium
`hydroxide. A small aliquot of gastric juice was taken
`from each sample for estimation of pepsin secretion
`by the method of Berstad.7 Results are expressed as
`mean i standard deviation. Statistical comparisons
`were made using the Mann-Whitney U test.
`
`Results
`
`Basal and pentagastrin stimulated acid output after
`placebo were similar in the two groups. A single
`dose of 30 mg produced a 66% reduction in basal
`acid output, and a 71-2% reduction in plateau acid
`output (p<0-01). The volume of gastric juice was
`reduced by 30-8% in the basal hour (p<0-05) and by
`47-1% in response to pentagastrin (p<0-01). Basal
`pepsin secretion was not
`significantly altered
`although there was an apparently significant
`'(p<0-05) rise in pepsin secretion in the pentagastrin
`stimulated hour. After seven days of omeprazole 30
`mg daily, basal acid output was reduced by 99-8%
`(p<0-05) and plateau acid output by 98-4%
`(p<0-01) when compared with values following
`placebo. Five of the six subjects produced no acid in
`the basal hour and three remained achlorhydric in
`reponse to pentagastrin. The volume of gastric juice
`
`at the end of the seven day course was reduced by
`549% (p<0-01) and 79-2% (p<0-01) in the basal
`and pentagastrin stimulated hours
`respectively.
`There were no significant changes
`in pepsin
`secretion either basally or after pentagastrin (Table
`1).
`A single 60 mg dose of omeprazole had a much
`greater effect on acid output reducing basal acid
`output and plateau acid output by 91-7% (p<0-05)
`and 95-3% (p<0-01)
`respectively. Volumes of
`gastric juice secretal in the basal and pentagastrin
`stimulated hours were reduced by 59-2% (p<0-01)
`and 79-5% (p<0-01) respectively. There was no
`significant change in pepsin secretion. After seven
`days treatment with omeprazole 60 mg daily, basal
`acid output was reduced by 99-1% (p<0-01) and
`plateau acid output by 990% (p<0-01). Volumes of
`gastric juice were reduced by 62-31% (p<0-01) in the
`basal hour and by 83-8% (p<0-01) in the penta-
`gastrin stimulated hours. Pepsin secretion did not
`significantly change (Table 2).
`No side effects were encountered with
`omeprazole. Each subject kept a diary for
`the
`duration of the study in which they were asked to
`note any adverse events and none was recorded.
`Subjects were also specifically asked about side
`effects on each of the three study days and, again,
`none was
`reported. Standard biochemical and
`haematological
`indices were measured before
`inclusion in the study, and were repeated within five
`days of completion of the study. No drug related
`abnormalities were found.
`
`Discussion
`
`These data show that omeprazole, in doses of 30 or
`60 mg daily,
`is a potent inhibitor of gastric acid
`secretion, when this is assessed around the time of
`expected maximum effect. It has no significant effect
`
`Table 1 Acid and pepsin output and volume ofgastric juice after placebo, first dose of30 mg.omeprazole and seventh dose
`of 30 mg omeprazole. (n=6; mean i SD)——___—————
`Stimulated
` Basal
`
`Peprin
`Acid
`Pepsin
`Acid
`Volume
`output
`output
`Volume
`output
`output
`(ml)
`(mg/h)
`(mmal/h)
`(ml)
`(mg/h)
`(mmol/h)
`___—___—_____.—_—__—_—_————
`Placebo
`4-30
`22-2
`99-7
`35-41
`54
`302-0
`til-37
`116-4
`:34-3
`: 5-45
`: 29
`t 42-7
`1-53
`17-8
`69-0
`10-24
`368
`159-7
`t1-91
`:12-2
`i22-6'
`i10-06t
`i46-1‘
`i 66-8’r
`0-01
`5-2
`45-0
`0-58
`18-3
`62-7
`Seventh dose
`iO-OZ‘
`i 4-1
`:12-01‘
`i 0-991“
`i18-8
`1 19-31
`——_—___———————-——
`
`First dose
`
`‘ p<0-05.
`
`+ p<0-01
`
`Page 2 Dr. Reddy's Exh. 1055
`Page 2
`
`
`
`Effects of single and repeated doses of omeprazole on gastric acid and pepsin secretion in man
`
`709
`
`Table 2 Acid and pepsin output and volume ofgastric juice after placebo, first dose of 60 mg omeprazole and seventh dose
`of 60 mg omeprazole. (n=6; mean i SD)
`Basal
`Stimulated
`
`Placebo
`
`Pepsin
`Acid
`Pepsin
`Acid
`Volume
`output
`output
`Volume
`output
`output
`(ml)
`(mg/h)
`(mmol/h)
`(m1)
`(mg/h)
`(mmol/h)
`297-3
`5-5
`37-11
`96-3
`11-8
`4-56
`i 62-5
`i 62
`$10-64
`:25-6
`i 75
`t3-19
`61-0
`35-2
`1-74
`39-3
`13-1
`0-38
`t 25-21L
`i18-8
`i 2-281‘
`i14-0t
`il7-l
`:0-49‘
`48-3
`24-6
`0-37
`36-3
`6-0
`0-04
`Seventh dose
`
`
`
`
`
`i O-ZOT i186i 8-41'i 5-2i0-09'l‘ i 1021'
`
`First dose
`
`* p<0-05.
`
`t p<0-01
`
`on pepsin secretion. This is consistent with the
`proposed mechanism and site of action of the drug.
`Sixty milligrams of omeprazole produced a
`greater inhibitory effect than 30 mg after a single
`dose. This is in agreement with previous work which
`has shown a prolonged inhibition of gastric acid
`secretion which is dose-dependent.2 After seven
`days of treatment, there was no difference between
`the two dose levels with the majority of our subjects
`being achlorhydric — that is, pH of gastric juice
`>70,
`in the basal hour, and the response to
`pentagastrin being inhibited by around 99%. This
`would be consistent with an increasing response with
`time as a consequence of accumulation of the effect
`of omeprazole, which for a single dose normally
`exceeds 24 hours.
`The reduction in the volume of gastric juice
`secreted after omeprazole was not of the same
`magnitude as the reduction in acid output. There
`was no concomitant reduction in pepsin secretion.
`These observations suggest that other components
`of the gastric secretion are relatively unaltered by
`omeprazole, and give further evidence for the drug’s
`highly specific site and mode of action. The lack of
`reduction in pepsin secretion is unlikely to be of
`clinical importance as pepsin would be biologically
`inactive in the absence of intragastric acid.
`It is of considerable interest that the drug had no
`observed haematological, biochemical, or subjective
`side effects, despite its extremely powerful action on
`gastric acid secretion. Omeprazole has now been
`given to patients with the Zollinger-Ellison
`syndrome8
`with good therapeutic effect and
`without side effects. Clearly, a degree of caution is
`necessary with any new agent, but clinical trials in
`patients with active peptic ulceration seem
`indicated. The optimum dose for ulcer healing
`remains to be found but our studies indicate that
`even 30 mg omeprazole daily produces a degree of
`
`inhibition of acid secretion in excess of that seen
`
`with H2 receptor antagonists“) “ The H2 receptor
`antagonists do not have an increasing effect with
`time.
`
`Although most of our subjects had basal
`achlorhydria after seven days treatment, we were
`assessing basal secretion around the time of the
`drug’s maximal inhibitory effect. Other workers3
`have found degrees of acid inhibition of the order of
`30% 24 hours after a single dose, and have
`commented that the acid inhibitory effect reached a
`peak after five days treatment. It seems unlikely,
`therefore, that prolonged periods of achlorhydria
`would occur on long term treatment.
`Omeprazole is a powerful inhibitor of gastric acid
`secretion in man, and a potentially useful agent in
`peptic ulcer.
`
`This work has been presented in part to the Medical
`Research Society in January 1983 (Clin Sci 1983; 64:
`74p) and to the British Society of Gastroenterology
`in April 1983 (Gut 1983; 24: A498).
`
`Capsules of omeprazole and placebo were supplied
`by Astra Pharmaceuticals.
`
`References
`
`1 Fellenius E, Berglindh T, Sachs G et al. Substituted
`benzimidazoles inhibit gastric secretion by blocking
`(H++ K+) ATPase. Nature 1981; 290: 159—61.
`2 Lind T, Cederberg C, Ekenved G et al. Effect of
`omeprazole — a gastric proton pump inhibitor — on
`pentagastrin stimulated acid secretion in man. Gut
`1983; 24: 270—6.
`3 Muller P, Dammann HG, Seitz H et al. Effect of
`
`Page 3 Dr. Reddy's Exh. 1055
`Page 3
`
`
`
`710
`
`Howden, Forrest, and Reid
`
`repeated once daily, oral omeprazole on gastric
`secretion. Lancet 1983; 1: 66
`i
`4 Hassan M, Hobsley M. Positioning of subject and of
`nasogastric tube. during a gastric secretion study. Br
`Med] 1970; 1: 458—60.
`5 Faber RG, Hobsley M. Basal gastric secretion: repro-
`ducibility and relationship with duodenal ulceration.
`Gut 1977; 18: 57—63.
`6 Mason MC, Giles GR, Clark CG. Continuous intra-
`venous pentagastrin as a stimulant of maximal gastric
`acid secretion. Gut 1969; 10: 34—8.
`7 Berstad A. A modified haemaglobin substrate method
`for the estimation of pepsin in gastric juice. Scand J
`Gastroenterol 1970; 5: 343—8.
`
`8 Blanchi A, Delchier JC, Soule JC et a1. Control of
`acute Zollinger-Ellison syndrome with intravenous
`omeprazole. Lancet 1982; 2: 1223—4.
`9 Oberg K, Lindstrom H. Reduction of gastric hyper-
`secretion in Zollinger-Ellison syndrome with
`omeprazole. Lancet 1983; 1: 66—7.
`10 Burland WL, Duncan WAM, Hesselbo T et al.
`Pharmacological evaluation of cimetidine,
`a new
`histamine‘Hz-receptor antagonist, in healthy man. Br J
`Clin Pharmacol 1975; 2: 481—6.
`11 Peden NR, Saunders JHB, Wormsley KG. Inhibition
`of pentagastrin-stimulated and nocturnal gastric
`secretion by ranitidine, a new HZ—receptor antagonist.
`Lancet 1979; 1: 690—2.
`
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