Aliment. Pharmacol. Themp. (1989) 3, 403—407.
`
`Does misoprostvl given as a single large dose
`improve its emtisecretory effect?
`
`5. G. CHIVERTON, D. W. BURGET, B. SALENA 8: R. H. HUNT
`
`Division of Gastroenterology, McMaster Llniversity Medical Centre, Canada
`
`Accepted for publication 6 April 1989
`
`SUMMARY
`
`H,-receptor antagonists have been shown to be effective in the
`suppression of nocturnal acidity. This double-blind, randomized,
`Crossover Latin-square study of 2.4-h intragastric pH in 12 normal
`volunteers investigated the effect of large single-dose administration of
`misoprostol on intragastric acidity. Etficacyot 800 pg misoprostol h.s.,
`600 pg h.s., 400 fig h.s. and 800 ,ug after supper was compared to
`placebo and 200 ,ug misoprostol q.d.s. Twenty-four hour mean pH : s.d.
`was placebo 2.1 i 0.3, misoprostol 200 pg q.d.s. Twenty—four hour mean
`pH i s.d. was placebo 2.1 i 0.3, rnisoprostol 200 pg q.d.s. 2.2 i 0.3,
`800 pg p.m. 2..6i 1.1, 400 pg h.s. 2.6iO.7, 600 gag h.s. 2.6iO.4,
`800 pg h.s. 2.6 i 0.5. The effect of misoprostol on gastric acidity was
`short and limited to the nocturnal period. Only misoprostol 800 pg and
`600 pg reduced 24-h acidity compared to placebo (P < 0.04).
`
`INTRODUCTION
`
`The importance of suppression of nocturnal gastric acidity in the healing of
`duodenal ulcer has been well established for
`the Hz-receptor antagonists.”
`Currently available short—acting H2-receptor antagonists are more effective in the
`suppression of nocturnal
`than daytime acidity.‘ The clinical efficacy of the
`
`Correspondence to: Professor R. H. Hunt, Rm 4W6, MUMC, 1200 Main Street West, Hamilton,
`Ontario, LBN 3Z5, Canada.
`
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`404
`
`S. G. CHIVERTON at al.
`
`H2-receptor antagonists has been borne out by the demonstration of a clear
`relationship between duodenal ulcer healing and the suppression of nocturnal
`acidity.5 Misoprostol is a prostaglandin E1 analogue, currently prescribed as a q.d.s.
`dose regimen for the treatment of duodenal ulcer. It is believed that this agent acts
`primarily through its antisecretory activity rather than its cytoprotective effect.°
`However, there is only a very weak antisecrctory effect over 2.4 h when studied by
`datalogger and pH probe.’ Thus with the increased appreciation of the importance
`of suppression of nocturnal acidity,
`it was considered important
`to study the
`efficacy of 800 pig given as a single dose in the control of nocturnal intragastric
`acidity in comparison with 200 pg q.d.s.
`Early evening dosing after supper with ranitidine has been claimed to have a
`pharmacological and therapeutic advantage over nocturnal dosing with ranitidine,
`with a significantly greater decrease in median 2.4—h acidity and a longer period of
`suppression of nocturnal acidity.” This advantage has been confirmed by an early
`clinical healing trial." We therefore also studied an early evening dose together
`with a dose—response profile, to determine whether a lower overall dose might be
`of clinical benefit.
`
`MATERIALS AND METHODS
`
`The study was designed as a double-blind, placebo controlled, randomized, cross-
`over, Latin-square experiment,
`in 12 healthy male volunteers; mean age 23.7
`(20-30 years). All were non-smokers with no history of peptic ulcer disease. Each
`regimen was administered for 4 days and on the fourth day of each treatment a 24-h
`gastric acidity study was performed. There was a 5-day wash-out period between
`each treatment period and each subject underwent six individual 24-hour study
`periods. Written informed consent was obtained from each subject together with
`McMaster University Medical Center ethical committee approval. During the
`study period subjects were asked to adhere to the meal pattern of the study Schedule
`(08.00, 12.00, 18.00 hours). Standardized meals were eaten and no snacks allowed
`on each study day (breakfast: 563 l<Cal, 12% protein, 25 % fat, 65% CHO; lunch:
`733 l<Cal, 21% protein, 38% fat, 43% CHO; supper: 909 l<Cal, 2.9 % protein, 34%
`fat, 37 % CHO). Subjects reported to the investigational laboratory at 06.30 hours
`on the study day and a 14F nasogastric tube (Salem Sump, Sherwood Medical, St
`Louis, USA) was placed in the stomach so that its tip lay in the most dependent
`position of the stomach, as indicated by the water recovery test.” At 07.00 hours,
`a 5-ml sample of gastric juice was aspirated and subsequent 5»~ml samples aspirated
`at hourly intervals and the pH determined to the nearest 0.01 pH unit using a glass
`electrode (Corning 150, Medtield) and digital pH meter (Corning 150 Medfield).
`The electrode was calibrated with standard buffers (pH 7.0, 4.0 and 2.0) before
`during and after each batch of samples.
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`MISOPROSTOL, 2.4 H ANTISECRETORY ACTION 405
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`Data analysis
`
`The data were analysed as mean and median over each of the following time
`periods: total (complete 24 hours study), night (22.00 hours to 07.00 hours),
`morning (07.00 hours to 11.00 hours), afternoon (12.00 hours to 16.00 hours) and
`evening (17.00 hours to 2.1.00 hours). The Krusl<all—Wallis test was applied to
`determine any overall statistical significance. Multiple comparisons with placebo
`were tested with the Wilcoxon test. The P value was adjusted according to the
`number of groups compared.
`
`RESULTS
`
`Statistical analysis was only performed on the pH data, because examination of
`means and medians of H+ activity indicated that further statistical analysis would
`only duplicate that already performed.
`The data are represented in Table 1 graphically as notched box-whisker plots
`compared to placebo and in Fig. 1 and Fig. 2. A short duration of antisecretory
`action for 3.5 h was seen after each dose, and this study confirms that misoprostol
`is a weak, short—acting antisecretory drug, the ettects being limited, with all doses,
`to the nocturnal period.
`
`E %$$$:
`
`400
`h.s.
`
`800
`p.rn.
`
`200
`q.d.s.
`
`.
`
`
`800
`600
`PL;’—‘AC
`h.s.
`h_s_
`
`Misoproslol
`
`Figure 1. Box whisker plot total 24 h pl-1. Annotation: horizontal line inside the box indicates the
`median, the box the interquartile range, the notch on the box the 95 % confidence limits for the
`median and the whiskers indicate the range ot the data.
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`406
`
`S. G. CHIVERTON et al.
`
`7
`
`6 i
`
`ll..tfla
`
`1
`
`__
`
`I
`
`I
`
`I
`
`400
`
`h.s.
`
`800
`
`pm.
`
`200
`
`q.d.s_
`
`800
`
`h.s.
`
`600
`
`11.5.
`
`PLAC
`
`Misoprostol
`
`Figure 2. Box whisker plot of the night-time pH.
`
`Table 1. Mean pH with standard deviation for each drug regime and time period
`
`Nocturnal
`(22.00—
`07.00 hours)
`
`Morning
`i07.00—
`11.00 hours]
`
`Afternoon
`t12..00—
`10.00 hours)
`
`Evening
`(17.00-
`21.00 hours)
`
`2.5 i 1.0
`2.3 i 1.5
`1.3i0.6
`2.8 i 0.9
`2.7 i 0.9
`1.0 1 0.2
`
`3.2 i 1.1
`2.9 i 1.2
`2..9i0.7
`3.1 i 0.3
`.3. 1 i 0.7
`2.7 i 0.9
`
`2.3 i 0.6
`2.3 i 0.9
`2.2 i0.2
`2.1 i‘ 0.3
`2.3 i 0.6
`2.2 i 0.4
`
`2.5 i 0.7
`3.0i 0.9
`2.2i0.2.
`2.2 i 0.5
`2.3 i 0.5
`2.2 i 0.4
`
`Total
`(24 bl
`
`2.6 jj 0.7
`2.0i 1.1
`2.2 i0.3
`2.6 _‘l: 0.4
`2.6 _‘l: 0.5
`2.1 35 0.3
`
`400 l'l.S.
`300 p.m.
`2.00 q.d.s.
`300 l1.s.
`600 l‘u.S.
`Placebo
`
`D I S C U 5 S10 N
`
`the placebo mean 24-h pH was high which may have made the
`in this study,
`antisecretory action of the drug appear comparatively weaker. The short duration
`of action of the drug is best indicated by the limited efficacy of the 800 pg early
`evening dose on nocturnal acid secretion compared to the bedtime doses. Overall,
`only the 800 pg and 000 pg h.s. doses were significantly different from placebo
`and these were of equal efficacy in this study.
`From this study, a trial of nocturnal therapy in duodenal ulcer healing would be
`justified with a dose of 600-800 pg of misoprostol. Despite a better understanding
`of the mechanism of the antisecretory action of the prostaglandins on the parietal
`cell,” the weak antisecretory action of misoprostol, seen here, raises the question of
`whether the positive effects on mucosal defense, induced by prostaélandins, might
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`MISOPROSTOL, 24 H ANTISECRETORY ACTION 407
`
`be more important for duodenal ulcer healing than has been hitherto thought.
`However, other drugs, also thought to act primarily by the inhibition of gastric
`secretion, have a weak antisecretory ettect on 24-h intragastric acidity.” 15 Stimu-
`lation of duodenal bicarbonate secretion,“ and an increase in thickness of the mucus
`gel layer” could perhaps be of greater importance in the prophylaxis and treatment
`of NSAID—induced injury,"’* “’ where antisecretory efficacy is less well understood.
`
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`
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