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.
`
`Page 1 of 5
`
`403
`
`Patent Owner Ex. 2011
`CFAD v. Pozen
`
`|PR2015-01680
`
`
`
`Page 1 of 5
`
`Patent Owner Ex. 2011
`CFAD v. Pozen
`IPR2015-01680
`
`

`
`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.
`
`Page 2 of 5
`
`Patent Owner Ex. 2011
`CFAD v. Pozen
`
`|PR2015-01680
`
`
`
`Page 2 of 5
`
`Patent Owner Ex. 2011
`CFAD v. Pozen
`IPR2015-01680
`
`

`
`MISOPROSTOL, 2.4 H ANTISECRETORY ACTION 405
`
`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.
`
`Page 3 of 5
`
`Patent Owner Ex. 2011
`CFAD v. Pozen
`
`|PR2015-01680
`
`
`
`Page 3 of 5
`
`Patent Owner Ex. 2011
`CFAD v. Pozen
`IPR2015-01680
`
`

`
`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
`Pa nt Owner Ex. 2011
`CFAD v. Pozen
`
`Page 4 of 5
`
`|PR2015-01680
`
`
`
`Page 4 of 5
`
`Patent Owner Ex. 2011
`CFAD v. Pozen
`IPR2015-01680
`
`

`
`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.
`
`REFERENCES
`
`1 Cledhill T, Howard 0 M, Buck M, Paul A,
`Hunt R H. Single nocturnal dose of an H;
`receptor antagonist for the treatment of duo-
`denal ulcer. Gut I98-3; 2.4: 904-908.
`2 Capuso L, Dal Monte P R, Mazzeo F, Men-
`ardo G, Morellini S H, Tatner G. Compari-
`son of cirneticline 800 mg once daily and
`400 mg twice daily in active duodenal ulcer-
`ation. Br Med l 1934; 2.39: 1413-20.
`Ireland A, Colin lones D G, Gear P, at at
`Comparison of ranitidine 150 mg twice a
`day with ranitidine 300 mg as a single even-
`ing dose in the treatment of duodenal ulcers.
`Lancet 1984; ii: 274-6.
`
`4 Founder R E, Williams I G, Hunt R H, at at
`The ettects of oral eimetidine on food stirnu—
`
`in the treatment of duodenal ulcers. Gastro-
`
`enterology 1986; 90: 1150.
`10 Pounder R E, Williams I C, Milton Thomp-
`son G I, at al. Ettect of cinretidine on twenty
`four hour intragastric acidity in healthy sub-
`jccts. Gut 1976; 17: I33-8 (Abstract).
`11 Eulier A R, Tytgat G, Berenger T, at at. Fait-
`ure of a cytoproteetive dose of arboprostil
`to heal acute duodenal ulcers. Results of a
`
`multiclinic trial. Gastroenterology 1987; 92:
`604-7.
`
`12
`
`Brand D L, Roufail W M, Thompson A B R,
`Tapper E]. Misoprostol, A synthetic PG]-I,
`analog in the treatment of duodenal ulcers:
`a multicenter double blind study. Dig Dis
`Sci 1985; 30: (Suppl) 1478-585.
`13 Sell A H. Review: antisecretory drugs: cell-
`ular mechanisms of action. Aliment Pharm-
`
`acol Therap 1987: 1: 77-39.
`lated gastric acid secretion and 2.4 hour intra—
`14 Etienne A, Fimmei C ], Bron B A, Loizeau E.
`gastric acidity. In: Burland W L, Sirnpkins
`Blum A L. Evaluation of pirenzepine on gas-
`M A, eds. Cimetidine. Proceedings of the
`tric acidity in healthy volunteers using
`second international
`symposium on H;
`ambulatory 24 hour intragastric monitoring.
`receptor antagonists. Amsterdam: Excerpta
`Gut I985; 2.6: 241-5.
`Medica, 1977; 193-204.
`15 Peterson W l., Barnett C, Feldrnan M,
`5 Jones D B, I-iowden C W, Burget D W, Kerr
`Richardson C T. Reduction of twenty four
`G D, Hunt R H. Acid suppression in the
`hour intragasiric acidity with combination
`healing of duodenal ulcer: a meta-analysis
`drug therapy in patients with duodenal
`to define optimal dose regimens. Gut 1987;
`ulcer. Gastroenterology 1979; 77: 1015-20.
`1120~27.
`lo Isenberg ] I, Hogan D L, Koss M A, Selling
`6 Herting R L, Nissen C H. Overview of
`IA. Human duodenal rnucosal bicarbonate
`miscoprostol clinical experience. Dig Dis Sci
`secretion. Gastroenterology
`1986:
`91:
`1986; 31: {Suppl.) 478-548.
`370-8.
`7 Savarino V, Scalabrini P, Mela G S, at at
`Evaluation of antisecretory activity of miso— 17 Sellers L A, Carroll N I H, Allen A. Mise-
`prostol in duodenal ulcer patients using long
`prostol induced increases in adherent gastric
`term intragastric pH monitoring. Dig Dis Sci
`mucus thickness and luminal mucus output.
`1988; 33: 293-7.
`Dig Dis Sci 1986: 31: (Suppl) 915-55.
`8 Merki H, Witzel 1., Harre K, at at Single dose
`18 Agrawal N. Misoprostol coadministratiorl
`treatment with H3 receptor antagonists: is
`heals aspirin induced gastric lesions in rheu-
`bedtime administration too late? Gut 1987;
`rnatoid arthritis patients. Gastroenterology
`33: 25 1—4.
`1987: 92: 1290. (Abstract.l
`9 Merki H, Wit'zel L, Hutternan W, at at. Single
`19 Cohen M M, Clark L, Armstrong L, at at.
`Reduction of aspirin induced fecal blood loss
`close treatment with H2 receptor antago-
`nists. A comparison of an early evening dose
`with low dose rnisoprostol tablets in man.
`versus bedtime administration of ranitidine
`Dig Dis Sci 1935; 30: 601-11.
`Patent Owner Ex. 2011
`CFAD v. Pozen
`
`Page 5 of 5
`
`|PR2015-01680
`
`
`
`Page 5 of 5
`
`Patent Owner Ex. 2011
`CFAD v. Pozen
`IPR2015-01680