N.J.V. Belt
`D. Burgef
`C.W. Howdenb
`
`J. Wilkinson1
`
`/?.//. Hunt
`
`Divisions of Gastroenterology
`McMaster University Medical
`Centre. Hamilton. Ontario.
`Canada, and
`University of South Carolina.
`Columbia. South Carolina. USA
`
`Key Words
`Reflux oesophagitis
`Gastric acid
`Pathophysiology
`Meta-analysis
`
`Digestion 1992:51(suppl I ):59—67
`
`Appropriate Acid Suppression
`for the Management of Gastro-
`Oesophageal Reflux Disease
`
`Abstract
`Gastro-ocsophageal rellux disease (GORD) results from an
`abnormally prolonged dwell time of acidic gastric contents in
`the oesophagus. Although GORD is primarily a motor disor­
`der, the injurious effects of gastric acid are central to the
`pathogenic process of oesophagitis, and the severity of disease
`correlates with the degree and duration of oesophageal acid
`exposure. In the majority of patients with mild disease, oesopha­
`geal acid exposure occurs predominantly during post-prandial
`periods. Conventional doses of PU-rcceptor antagonists cannot
`overcome the integrated stimulus to acid secretion resulting
`from a meal, and are thus relatively ineffective in preventing
`daytime, post-prandial oesophageal acid exposure. In patients
`with more severe grades of oesophagitis, there are abnormally
`high levels of nocturnal acid exposure, with the intra-oesophag-
`eal pH being less than 4.0 for 36% of the time, compared with
`5% of the time in patients with mild GORD. Control of noctur­
`nal acid secretion thus becomes increasingly important. This
`may be made worse by relative gastric acid hypersecretion in
`some patients with severe GORD. The long duration of action
`and effective inhibition of meal-stimulated acid secretion prob­
`ably explains the superiority of omeprazole in treating GORD.
`Preliminary meta-analysis shows that the healing rate of erosive
`oesophagitis at 8 weeks by antisecretory agents is directly
`related to the duration of suppression of gastric acid secretion
`achieved over a 24-hour period (r=0.87; p<0.05).
`
`R.H. Hunt.
`Divisions of Gastroenterology
`McMaster University Medical Centre
`1200 Main Street West
`Hamilton. Ontario L8N 3Z5 (Canada)
`
`© 1992
`Karger AG. Basel
`0012-2823/92/
`0517-0059 $ 2.75/0
`
`MYLAN PHARMS. INC. EXHIBIT 1015 PAGE 1
`
`

`

`In Western society, approximately 7% of
`the population suffer from gastro-oesophageal
`reflux disease (GORD) [1], Reflux of gastric
`contents into the oesophagus produces the
`symptoms of heartburn and regurgitation,
`which largely account for the widespread use of
`over-the-counter antacid medications [2].
`GORD is primarily a motor disorder, and
`dysfunction of the lower oesophageal sphincter
`(LOS) is probably the most significant abnor­
`mality [3]. Transient relaxations of the LOS
`lasting up to 35 seconds and independent of
`normal peristaltic activity, are seen in 60-83%
`of reflux episodes. Studies are needed to deter­
`mine whether the postural control of transient
`LOS relaxations that is seen normally in
`healthy subjects is impaired in patients with
`reflux disease. Studies to date indicate that
`some suppression occurs, but that this is against
`a background of a higher overall occurrence,
`so that in the supine position patients with
`reflux disease have a significantly higher rate of
`transient LOS relaxations than controls. Com­
`plete cessation of LOS tone for periods of up to
`10 minutes can account for 22% of reflux epi­
`sodes, especially in patients with the more
`severe forms of disease [4], Once reflux has
`occurred, impaired clearance of gastric con­
`tents from the oesophagus contributes to the
`prolonged dwell time of acid in the lower oeso­
`phagus.
`
`The Injurious Action of Acid
`
`Despite the spectrum of motor abnormal­
`ities described in reflux oesophagitis, gastric
`acid is central to the development of mucosal
`injury. The pH dependency of oesophageal
`mucosal injury has been demonstrated in vari­
`ous animal models [5, 6]. Goldberg et al.
`showed that perfusion of the feline oesophagus
`over a 1-hour period with hydrochloric acid
`produced oesophagitis only when solutions of
`
`pH equal to or less than 1.3 were utilized [5].
`The addition of porcine pepsin to the perfusate
`increased the severity of oesophagitis and also
`caused inflammation to occur with solutions of
`between pH 1.3 and 2.3. Pepsin solutions
`above pH 2.3 did not cause mucosal injury in
`this study, reflecting the in vitro activation of
`porcine pepsin at a pH below 2.5. Similar
`results were reported by Zaninotto et al., who
`observed mucosal erosions in rabbit oesopha­
`gus perfused with pepsin solutions at pH 1.5
`and 2.0. but not when solutions of pH 3.0 or
`4.0 were used [6]. Bile salts may also increase
`the injurious effects of acid by increasing the
`permeability of the oesophageal mucosa to
`hydrogen ions |7|. This may play a role in a
`subgroup of patients with complicated Barrett’s
`oesophagus [8].
`The sensation of pain in the oesophagus is
`also pH-dependent [0]. Smith et al. measured
`the time taken to sense pain caused by infusing
`solutions of varying pH in patients with symp­
`tomatic GORD. They found a positive correla­
`tion (r=0.77) between the time elapsed before
`pain sensation and the pH of the solution
`infused. The most significant difference was
`seen between pH 1.0 and 2.0. Between pH 2.0
`and 4.0, the time progressively increased,
`before levelling off above pH 4.0.
`A threshold of pH 4.0 was suggested by
`Johnson and DcMeester to discriminate be­
`tween aggressive and non-aggressive reflux
`during oesophageal pH monitoring [10],
`Schindlbeck et al. have evaluated this thresh­
`old formally by applying discriminant analysis
`to define optimal thresholds for evaluating
`pathological reflux [ll|. They found that a
`maximum sensitivity (93.3%) and specificity
`(92.9%) could be achieved by considering the
`percentage of time above pH 4.0 and applying
`thresholds of 10.5% of the time in the upright
`position and 6.0% of the time in the supine
`position as levels of ‘normal’ oesophageal acid
`exposure. Furthermore, although other pH
`
`60
`
`Bell/Burget/Howden/Wilkinson/
`Hunt
`
`Acid Suppression and GORD
`
`MYLAN PHARMS. INC. EXHIBIT 1015 PAGE 2
`
`

`

`thresholds could differentiate between normal
`and pathological reflux, pi I 4.0 proved optimal
`[ 12].
`Oesophageal pH monitoring has shown that
`the severity of oesophageal reflux disease is
`related to the degree of oesophageal acid expo­
`sure, there being a progressive increase in the
`percentage of time that oesophageal pH is less
`than 4.0 from mild to complicated disease and
`Barrett’s oesophagus [13-15], De Caestecker
`ct al. showed correlation coefficients of
`0.49-0.70 (all p<0.001) between oesophageal
`acid exposure in the supine, upright, total and
`post-prandial periods, anti the grade of oeso­
`phagitis [16]. The same holds true for symp­
`toms. with their severity increasing with oeso­
`phageal acid exposure, both in patients with
`erosive oesophagitis and in those with a macro-
`scopically normal oesophagus [17].
`The time taken for intra-oesophageal pH to
`return to 4.0 or above is also influenced by the
`pH of the refluxate; the lower the pH of the
`refiuxatc, the longer the clearance time. Diffu­
`sion of hydrogen ions into the unstirred, and
`presumably mucous, layer of the oesophagus is
`thought to be an important determinant of
`clearance [18]. The amount of hydrogen ions
`that diffuse is dependent firstly upon the dwell
`time of acidic gastric contents within the oeso­
`phageal lumen. In some patients with reflux
`disease, this dwell time is substantially pro­
`longed by oesophageal body dysfunction. Sec­
`ondly, the concentration of hydrogen ions in
`the refluxate influences the rate at which the
`unstirred layer is acidified. The lower the pH of
`the unstirred layer, the longer it will take for
`salivary bicarbonate to neutralize this acidity,
`and return intra-oesophageal pH to values that
`are non-injurious.
`
`Patterns of Gastro-Oesophageal Reflux
`
`It has been widely held that nocturnal reflux
`is the most important factor in the pathogenesis
`
`of reflux disease. Twenty-four-hour oesophag­
`eal pH studies have, however, shown that this
`is incorrect for the majority of patients with
`reflux disease who have mild erosive oesopha­
`gitis or no endoscopic abnormality. In these
`patients, most reflux occurs in the daytime
`post-prandial periods, and especially in the
`early evening, with relatively little reflux dur­
`ing the night 114. 16. 17, 19. 20], With more
`severe oesophagitis, there
`is progressively
`greater acid exposure, which is predominantly
`due to an increase in nocturnal reflux. In this
`situation, the aggressiveness of the gastric con­
`tents and the effectiveness of nocturnal oeso­
`phageal clearance become very important. The
`longest period of unbuffered basal gastric out­
`put occurs at night, and there is impaired clear­
`ance of acid from the oesophagus and reduced
`neutralization by salivary bicarbonate due to
`the effects of sleep on salivation and oesophag­
`eal motility. The supine position is likely to
`contribute to impairment of oesophageal acid
`clearance, but, as yet, there are no data that
`address this factor in a controlled manner. The
`increased importance of nocturnal oesophag­
`eal acid exposure has been demonstrated by
`Robertson et al., who found that patients with
`complicated oesophagitis had a mean noctur­
`nal oesophageal acid exposure time of 35.6%,
`compared with 5.2% in patients with reflux dis­
`ease who had either patchy erosions or no
`endoscopic abnormality. The corresponding
`values for the daytime period were similar in
`the two groups: 17% and 13%. respectively
`[14].
`The effects of prolonged oesophageal acid
`exposure may be compounded by gastric acid
`hypersecretion in some patients. Johansson et
`al. found pathologically high pentagastrin-
`stimulated peak acid outputs in 66% of a group
`of 100 patients referred to a surgical clinic for
`evaluation of reflux oesophagitis [21]. In
`another study from the same centre, the age-
`and body-weight-corrected maximum acid out­
`
`61
`
`MYLAN PHARMS. INC. EXHIBIT 1015 PAGE 3
`
`

`

`put was found to be above the normal range in
`76% of 4 1 patients with confirmed oesophagitis
`[22], An earlier study, however, showed no
`correlation between maximally stimulated acid
`output and oesophageal acid exposure, as
`measured by oesophageal pH monitoring [23].
`It is interesting that this latter study failed to
`show a correlation between the pH of basal
`acid secretion and oesophageal acid exposure,
`but did find that the volume of basal acid secre­
`tion correlated with the percentage of time that
`oesophageal pH was less than 4.0.
`A study from Finland showed that basal
`acid output did not vary with the severity of
`symptoms of oesophagitis, but that men with
`ulcerative oesophagitis had significantly higher
`basal and maximum acid outputs than those
`with reflux disease without endoscopic abnor­
`malities [24], A similar trend was also seen in
`female patients, but failed to reach statistical
`significance owing to the small number of
`patients studied.
`Although the data on maximally stimulated
`acid secretion by pentagastrin are confusing, it
`is possible that patients with oesophagitis may
`have an exaggerated meal-stimulated acid
`response, which would be more relevant to
`the pathophysiology of GORD. Such studies
`on meal-stimulated gastric acid secretion in
`patients with GORD have not yet been per­
`formed. Collen ct al. prospectively evaluated
`gastric acid output in a group of 23 patients
`with chronic heartburn [25]. Twelve of these
`patients remained symptomatic, despite 3
`months of standard antisecretory therapy with
`ranitidine. These patients had significantly
`higher basal acid outputs than those who
`responded to ranitidine. When compared with
`patients whose symptoms responded,
`the
`refractory patients had a significantly greater
`upright, but not supine, acid exposure time.
`Nine of the 12 patients with refractory GORD
`(39% of the total) had gastric acid hypersecre­
`tion, defined as a basal acid output of greater
`
`than 10 mmol/hour. Ten of these 12 non-
`responders had Barrett’s oesophagus, com­
`pared with only I of the 11 initial responders.
`These data need to be interpreted with cau­
`tion. as they may be substantially influenced
`by
`rebound hypersecretion secondary
`to
`IT-receptor antagonist withdrawal. This is
`because the measurements were made after a
`minimum 72 hours’ withdrawal of antisecre­
`tory therapy, a time at which rebound hyper­
`secretion is at a maximum [26-28]. Thus,
`rebound hypersecretion could have caused
`misclassification of some of these patients as
`hypersecretors.
`Patients with Zollinger-Ellison syndrome
`(ZES) also have a high incidence of reflux
`oesophagitis, which appears to be related to
`the high basal gastric acid output in such
`patients [29]. Sixty-one per cent of a group of
`122 patients with ZES were found to have
`symptomatic or endoscopic evidence of oeso­
`phagitis, and 23% had moderate to severe dis­
`ease [30].
`
`Medical Treatment of Reflux
`Oesophagitis
`
`The aims of medical therapy of GORD are
`to relieve the symptoms, to heal established
`oesophageal mucosal damage and to prevent
`the development of complications. In order to
`do this, treatment needs to either prevent the
`reflux of acidic gastric contents into the oeso­
`phagus. or to eliminate or reduce the injurious
`action of acid to a level that will allow healing
`of the oesophageal epithelium. At present,
`there are no agents that are fully effective in
`correcting motor defects that cause pathologi­
`cal oesophageal acid exposure.
`The prokinetic agents bethanecol. metoclo-
`pramide, domperidonc and cisapride have all
`been used for reflux oesophagitis, with varying
`success. Of these, only cisapride is free from
`
`62
`
`Bcli/Burget/Howden/Wilkinson/
`Hunt
`
`Acid Suppression and GORD
`
`MYLAN PHARMS. INC. EXHIBIT 1015 PAGE 4
`
`

`

`troubling side-effects [31]. It increases the LOS
`pressure and enhances oesophageal acid clear­
`ance by stimulating peristalsis via selective
`stimulation of postganglionic neurones of the
`myenteric plexus. Cisapride is significantly bet­
`ter than placebo and. in divided doses of 40 mg
`daily over a 6-12-week period, is as effective as
`ranitidine, 150 mg twice daily, or cimetidinc,
`400 mg twice or four times daily [32|. The effect
`on oesophageal acid exposure, however, is
`insufficient to produce a consistently high
`response rate in severe grades of GORD.
`Sucralfate binds to damaged epithelium and
`may act as a barrier to acid and pepsin. There is
`some evidence that it binds epidermal and
`fibroblast growth factors, and may thus pro­
`mote healing. When administered as a suspen­
`sion, sucralfate. 1 g four times daily, results in
`symptomatic relief and endoscopic improve­
`ment similar to that achieved with IL-receptor
`antagonists [32].
`The most established and effective treat­
`ment for reflux oesophagitis is to reduce the
`acidity and volume of gastric contents available
`for reflux by pharmacological gastric acid sup­
`pression. Cimetidine has been prescribed for
`GORD for 15 years, and it produces more
`rapid symptomatic relief than placebo, but has
`a lesser effect on the improvement of endo­
`scopic grading [33]. Ranitidine is effective in
`the symptomatic relief of reflux disease and
`produces improvement in endoscopic appear­
`ances in 48-88% of cases within 6-8 weeks,
`depending upon the endoscopic grading and
`severity of GORD. Complete resolution of
`oesophageal erosions or ulceration is, how­
`ever, seen less frequently, occurring in only
`27^45% of patients. Similar results have been
`obtained with the newer H2-receptor antag­
`onists famotidine and nizatidine. The proton
`pump inhibitor omeprazole is significantly
`superior to the IL-receptor antagonists, with
`complete healing of erosive oesophagitis in
`67-92% of patients at 4 weeks, and similarly
`
`high rates of symptom relief. This is especially
`true for the more severe grades of oesophagitis
`[33], Omeprazole seems to work solely by sup­
`pressing gastric acid secretion, as it has been
`shown to have no major effect on oesophageal
`motility or on the number of post-prandial
`reflux episodes [34],
`
`Tailoring Acid Suppression
`to the Disease
`
`As already described, gastro-ocsophageal
`reflux is increased in the majority of patients,
`mainly in the post-prandial and early evening
`periods. LL-receptor antagonists, however,
`cannot easily overcome the integrated stimulus
`to acid secretion produced by a meal [35, 36].
`This may explain the relative ineffectiveness of
`conventional doses of these agents in reflux dis­
`ease. Divided doses of IL-receptor antagonists
`carry no advantage over single night-time
`dosing[37,38]. Schaubet al. found that neither
`ranitidine, 150 mg twice daily, nor an increased
`dose of 300 mg twice daily, altered the 22-hour
`intra-oesophageal pH profile when compared
`with pretreatment recordings [39], Attempts to
`improve the effect of ranitidine on reducing
`evening reflux, by dosing immediately after the
`evening meal rather than at bedtime, have also
`been unsuccessful ¡40]. IL-receptor antag­
`onists arc more effective at reducing intragas-
`tric acidity when acid secretion is not otherwise
`stimulated, and this is probably the basis for
`their moderate efficacy in GORD. There is a
`modest therapeutic gain when the effects of
`cisapride on oesophageal acid clearance are
`added to the effects of ranitidine on the pH of
`the refiuxate. but it is questionable whether the
`gains arc sufficient to justify' combination ther­
`apy [41-43].
`Inhibitors of the parietal cell H+, K+-
`ATPase, the acid pump, such as omeprazole,
`effectively suppress gastric acid secretion
`
`63
`
`MYLAN PHARMS. INC. EXHIBIT 1015 PAGE 5
`
`

`

`throughout the clay, and can overcome meal-
`stimulated acid production. Targeting acid
`suppression for GORD during the day remains
`important, even for the higher grades of oeso­
`phagitis, as daytime acid exposure remains an
`important factor. In addition, though, noctur­
`nal reflux is substantially more important in
`this patient group. Thus, the most effective
`therapy is likely to be one that suppresses both
`daytime and night-time acid secretion. In a
`direct comparison with cimetidine, omepra­
`zole, 40 mg once daily, healed erosive and
`ulcerative oesophagitis in 71% of patients in 8
`weeks. 60% of whom had grades III—IV oeso­
`phagitis, compared with 23% healing on cime­
`tidine. 400 mg four times daily [44], Twenty-
`four-hour oesophageal pH-monitoring showed
`that omeprazole abolished both nocturnal and
`daytime oesophageal acid exposure in those
`patients with healed oesophagitis, whereas
`three of the five patients healing on cimetidine
`still had more than 5% daytime reflux. Those
`patients failing to heal on omeprazole had no
`change in their mean nocturnal acid exposure.
`Those patients with gastric acid hypersecre­
`tion may require higher doses of antisecretory
`drugs. Collen ct al. found that symptomatic
`relief could be obtained in their group of acid
`hypersecrctors resistant to conventional doses
`of ranitidine by increasing the dose to as much
`as 1800 mg daily [25], Basal acid output had to
`be suppressed to below 1 mmol/hour for heart­
`burn to be relieved. Combined intra-oesophag-
`eal and intragastric 24-hour pi 1-monitoring
`studies support the view that an incomplete
`response to omeprazole is primarily due to
`inadequate suppression of acid secretion in a
`small proportion of patients treated with up to
`60 mg daily [45], It would appear that in these
`patients division of dosage will lead to better
`control of the pH of refluxate throughout the
`24 hours.
`Thus, optimal treatment for reflux oesopha­
`gitis can be achieved by abolishing oesopha-
`
`Patients
`healed
`(%)
`
`Duration intragastric
`pH>4.0 (hours)
`
`Fig. 1. Relationship between the healing of erosive
`oesophagitis at 8 weeks and the duration, in hours, out
`of the 24-hour period, that the intragastric acidity is
`raised above pH 4.0.
`
`geal acid exposure throughout both the day­
`time and night-time periods. The less effective
`the LOS is in preventing reflux of gastric con­
`tents into the oesophagus, the more necessary
`it is to raise the pH of the stomach contents to
`above 4.0 throughout the 24 hours.
`We have performed a meta-analysis of
`treatment trials of reflux oesophagitis, in which
`healing was assessed endoscopically. These
`results have been correlated with 24-hour gas­
`tric acid suppression data for each drug and
`dosage regimen, obtained from a previous
`meta-analysis using patients with duodenal
`ulcer [46]. We contend that using acid suppres­
`sion data from patients with duodenal ulcer is
`more appropriate than data from normal
`volunteers, as they also have a higher incidence
`of gastric acid hypersecretors than the normal
`population, and there are limited gastric acid
`suppression data available from patients with
`GORD.
`
`64
`
`Bell/Burgct/Howclcn/Wilkinson/
`Hunt
`
`Acid Suppression and GORD
`
`MYLAN PHARMS. INC. EXHIBIT 1015 PAGE 6
`
`

`

`Patients
`healed
`(%)
`
`Duration intra-
`oesophageal
`pH<4.0
`(% total time)
`
`Duration intra-oesophageal
`pH<4.0 (% total time)
`
`Duration intragastric
`pH>4.0 (hours)
`
`Fig. 2. Relationship between the healing of erosive
`oesophagitis at 8 weeks and oesophageal aeid exposure.
`
`Fig. 3. Relationship between the duration of sup­
`pression of intragastrie acidity in hours and oesophageal
`acid exposure.
`
`Duration
`intragastric
`pH>4.()
`(hours)
`
`till Omeprazole
`□ Ranitidine
`rT7! Famotidine
`
`Fig. 4. Duration, in hours, of
`the 24-hour period that the intragas­
`tric pH is raised above 4.0 for some
`commonly prescribed drugs. 060.
`omeprazole. 60 mg once daily: 030,
`omeprazole. 30 mg once daily: 020,
`omeprazole. 20 mg once daily;
`R3N. ranitidine. 3(H) mg at bed­
`time: R150, ranitidine, 150 mg
`twice daily; F40. famotidine. 40 mg
`at bedtime; C8N, eimetidine. 800
`mg at bedtime; C40. eimetidine,
`400 mg four times daily; C4B. cime-
`tidine. 400 mg twice daily; C1G.
`eimetidine. 200 mg three times daily
`and 400 mg at bedtime: ANT. ant­
`acid. 150 mmol seven times daily.
`
`Preliminary results show a correlation co­
`efficient of 0.87 (p<0.05) between the healing
`rate of oesophagitis at 8 weeks and the dura­
`tion, in hours, that the intragastric pH is main­
`tained above 4.0 (fig. 1). A similar finding is
`
`seen with pH thresholds of 3.0 and 5.0, but the
`relationship is not so strong. Eight-week heal­
`ing of GORD follows an inverse relationship
`with oesophageal acid exposure (r=0.83;
`p<0.05) (fig.2). This finding is not surprising,
`
`65
`
`MYLAN PHARMS. INC. EXHIBIT 1015 PAGE 7
`
`

`

`given the close relationship between the dura­
`tion of suppression of intragastric acidity to
`above pH 4.0 and the inhibition of oesopha­
`geal acid exposure, as expressed as time below
`pi I 4.0 (fig.3). This is despite the variability in
`oesophageal pH studies, owing to electrode
`position or day-to-day variation in the degree
`of reflux [47. 48].
`The response to antisecretory drugs can
`therefore be predicted by the duration of sup­
`pression of intragastric acidity to above pH 4.0.
`over a 24-hour period, achieved bv each treat­
`ment regimen. Figure 4 shows some commonly
`prescribed treatments that achieve this goal.
`As can be seen, omeprazole has a clear advan­
`
`tage, and this is reflected in its ability to heal
`reflux oesophagitis.
`
`Conclusion
`
`The extent of oesophageal mucosal injury
`is determined by the degree and duration of
`oesophageal acid exposure, which, in turn, is
`related to the pH of the gastric contents. The
`effect of antisecretory therapy on GORD can
`be predicted from the duration of suppression
`of intragastric acidity to above pH 4.0 achiev­
`ed by each drug regimen, and the length of
`treatment.
`
`References
`
`1 N'ebel OT. Fornes MF. Castell DO:
`Symptomatic gastro esophageal re­
`flux: Incidence and precipitating
`factors. Am .1 Dig Dis 1976:21:
`953-956.
`2 Graham DY. Smith JL. Patterson
`KJ: Why do apparently healthy peo­
`ple use antacid tablets? Am .1 Gas­
`troenterol 1983:78:257-260.
`3 Dent .1: Recent views on the patho­
`genesis of gastro-ocsophagcal reflux
`disease, in Tylgal GNU (cd). Bail-
`litre's Clinical Gastroenterology.
`London. Baillitrc Tindall. 1987. I.
`pp 727-745.
`4 Dent .1. Holloway RU. Toouli J.
`Dodds W.I: Mechanisms of lower
`oesophageal
`sphincter
`incompe­
`tence in patients with symptomatic
`gastro-ocsophagcal
`reflux. Gut
`1988:29:120-128.
`5 Goldberg III. Dodds W.I. (tee S.
`Montgomery C, Zboralske F: Role
`of acid and pepsin in acute experi­
`mental esophagitis. Gastroenterol­
`ogy 1969:56:223-230.
`6 Zaninotto G. Coslantini M. Di-
`Mario F. el al: Oesophagitis and pH
`of the refluxale: experimental and
`clinical study. Gut 1990:31 :A602.
`
`7 Safaie-Shirazi S. DenBestcnL. Zikc
`WI.: Rffect of bile salts on the ionic
`permeability of the esophageal mu­
`cosa and their role in the production
`of esophagitis. Gastroenterology
`1975:68:728-733.
`8 Attwood SKA. DeMccster TR.
`Bremmer CG. Barlow AP. Hinder
`RA: Alkaline gastroesophageal re­
`flux: Implications in the develop­
`ment of complications in Barrett's
`columnar-lined
`lower esophagus.
`Surgery 1989:106:764-770.
`9 Smith JL. Opcrkun AR. Larkai K.
`Graham DY : Sensitivity of the eso­
`phageal mucosa to pi I in gastroeso­
`phageal reflux disease. Gastroen­
`terology 1989:96:683-689.
`10 Johnson
`I.F. DeMccster TR:
`Twenty-four hour pH monitoring of
`the distal esophagus. A quantitative
`measure of gastroesophageal re­
`flux. Am J Gastroenterol 1974:62:
`325-332.
`11 Schindlbcck NE. Heinrich C. König
`A. Dendorfer A. Pace F. Mtiller-
`Lissner SA: Optimal thresholds,
`sensitivity, and specificity of long
`term pll-mctry for the detection of
`gastroesophageal
`reflux disease.
`Gastroenterology 1987:93:85-90.
`
`12 Schindlbcck NE. Ippisch 11. Klauser
`ACi. MUller-L.issner SA: Which pi I
`threshold is best in esophageal pH
`monitoring? Am J Gastroenterol
`1991:86:1138-1141.
`13 Gillen P. Keeling P. Byrne P.I. I len-
`ncssv TPJ: Barrett's oesophagus:
`pll profile. Br J Surg 1987:74:
`774-776.
`14 Robertson D. Aldersley M. Shep­
`herd II. Smith C'L: Patterns of acid
`reflux in complicated oesophagitis.
`Gut 1987:28:1484-1488.
`15 Fiorucci S. Santucci !.. Farroni F.
`Pclli MA. Morelli A: Effect of ome­
`prazole on gastroesophageal reflux
`in Barrett's esophagus. Am J Gas­
`troenterol 1989:84:1263-1267.
`16 De Caestecker JS. Blackwell .IN.
`Prydc A. Heading RC: Daytime
`gaslro-oesophageal reflux is impor­
`tant in oesophagitis. Gut 1987:28:
`519-526.
`17 Joclsson B. Johnsson F: Heartburn:
`the
`acid
`test. Gut:
`1989:30:
`1523-1525.
`18 Shaker R. Kahrilas PJ. Dodds W.I.
`I logan WJ : Esophageal clearance of
`small amounts of acid. Gastroen­
`terology 1986:90: A 1628.
`
`66
`
`Bcll/Burget/Howden/Wilkinson/
`I litnt
`
`Acid Suppression and GORD
`
`MYLAN PHARMS. INC. EXHIBIT 1015 PAGE 8
`
`

`

`19 Gudmundsson K. Johnsson F. Joels-
`soii IS: The lime pattern of gastro­
`esophageal reflux. Scand .1 Gastro­
`enterol 1988:23:75-79.
`2d Kruse-Andersen S. Wallin L. Mad­
`sen T: Reflux patterns and related
`oesophageal motor activity in gas-
`tro-oesophageal reflux disease. Gut
`1990;31:633-638.
`21 Johansson K-F. Ask P. Boeryd B.
`Fransson S-G. Tibhling L: Oeso­
`phagitis. signs of reflux, and gastric
`acid secretion in patients with symp­
`toms of gaslro-oesophageal reflux
`disease.
`Scand
`.1 Gastroenterol
`1986;21:837-847.
`22 Johansson K-F. Tibbling L: Gastric
`secretion and reflux pattern in reflux
`oesophagitis before and during rani­
`tidine treatment. Scand .1 Gastroen­
`terol 1986:21:487-492.
`23 Boesbv S: Relationship between
`gastro-ocsophagcal sphincter pres­
`sure. and gastric acid secretion.
`Scand
`.1 Gastroenterol
`1977:12:
`547-551.
`24 Matikaincn M: Gastric acid secre­
`tion. oesophageal acid reflux, and
`oesophagitis in patients with symp­
`tomatic gastro-ocsophagcal reflux.
`Scand
`.1 Gastroenterol
`1981:16:
`1043-1048.
`25 Collen MJ. Lewis JH. Benjamin
`SB: Gastric acid hypersecretion in
`refractory gastroesophageal reflux
`disease. Gastroenterology 1990:98:
`654-661.
`26 Fullarton GM. McLauchlan G.
`Macdonald A. Crcan GP. McColl
`KEL: Rebound nocturnal hyperse­
`cretion after four weeks treatment
`with an 11; receptor antagonist. Gut
`1989:30:449-454.
`27 Prewett EJ. Hudson M. Nwokolo
`CU. Sawyerr AM. Pounder RE:
`Nocturnal intragastric acidity dur­
`ing and after a period of dosing
`with either ranitidine or omepra­
`zole. Gastroenterology 1991:100:
`873-877.
`28 Nwokolo CU. Smith JTl.. Sawyerr
`AM. Pounder RE: Rebound intra­
`gastric acidity after abrupt with­
`drawal of histamine H
`receptor
`blockade. Gut 1991:32:1455-1460.
`
`29 Hirschowitz BI: High prevalence of
`esophagitis in Zollingcr-Ellison syn­
`drome vs low prevalence in non-ZE
`DU with BAO>15 mEq/h. Gas-
`t rocnterology 1990:98: A59.
`30 Miller LS. Vinayek R. Fruclu II.
`Gardner JD. Jensen RT. Maton
`PN: Reflux esophagitis in patients
`with Zollinger-Ellison syndrome.
`Gastroenterology 1990:98:341-346.
`31 Verlinden M: Review article: A role
`for
`gastrointestinal
`prokinetic
`agents in the treatment of reflux
`esophagitis. Aliment Pharmacol
`Ther 1989:3:113-131.
`32 Tytgat GNJ. Nio CY. Schotborrgh
`R11 : Reflux esophagitis. Scand .1
`Gastroenterol I990:25(suppl 175):
`1- 12.
`33 Bell N.IV. Hunt RH: The role of
`gastric acid suppression in the treat­
`ment of gastro-oesophageal reflux
`disease. Gut 1992:33:118-124.
`34 DowntonJ. Dent .1. Heddle R .etal:
`Elevation of gastric pi I heals peptic
`oesophagitis - A role for omepra­
`zole. .1 Gastroenterol Hepatol 1987:
`2:317-324.
`35 Hannan A. Chesner I. Mann S.
`Wall R: Can I L-antagonists alone
`completely block food stimulated
`acidity? Eur J Gastroenterol I lepa-
`tol 1991;3:533-537.
`36 Merki I IS. Wilder-Smilh C. Walt R.
`Halter F: The cephalic and gastric
`phases of gastric acid secretion dur­
`ing Hi-antagonisl treatment. Gas­
`troenterology 1991:101:599-606.
`37 BoveroE.C'hcli R. Barbara L.ct al:
`Short-term
`treatment of
`reflux
`oesophagitis with ranitidine 300 mg
`node. Italian multicentre study.
`Hepatogastroentcrology
`1987:34:
`155-159.
`38 Halvorsen L. Lee FI. Wesdorp ICE.
`Johnson NJ. Mills JG. Wood JR:
`Acute treatment of reflux oesopha­
`gitis: a multicentre study to compare
`150 mg ranitidine twice daily with
`300 mg ranitidine at bedtime. Ali­
`ment Pharmacol Ther 1989:3:
`171-181.
`39 Schaub N. Mevrick Thomas J.
`MisiewiczJJ. Lovell D. Trotman IF:
`Investigation of ranitidine 150 mg
`Ixl or 300 mg bd in the treatment of
`reflux disease. Hepatogastroentcr-
`ologv 1986:33:208-213.
`
`40
`
`41
`
`42
`
`43
`
`44
`
`45
`
`46
`
`47
`
`48
`
`Johnson NJ. Laws S. Mills JG.
`Wood JR: Effect of three ranitidine
`dosage regimens in the treatment of
`reflux oesophagitis: results of a mul­
`ticentre trial. Fur J Gastroenterol
`Hepatol 1991:3:769-774.
`Wcinbcck M: Docs cisapride added
`to H.-receptor blocking treatment
`improve healing rates in patients
`with esophagitis? Digestion 1986;
`34:144.
`JP. Brandstatler G.
`Galmiche
`Evreux M. cl al: Combined therapy
`with cisapride and cimctidinc
`in
`severe reflux oesophagitis: a double-
`blind controlled trial. Gut 1988:29:
`675-681.
`Holloway RI I. Downton .1. Mitchell
`B. Dent J: Effect of cisapride on
`post prandial gastro-ocsophagcal
`reflux. Gut 1989:30:1187-1193.
`Dchn TCB. Shepherd HA. Colin-
`Jones D. Keltlewcll MGW. Carroll
`NJH: Double blind comparison of
`omeprazole (411 mgod) versus eime-
`tidine (41)11 mg qd) in the treatment
`of symptomatic erosive reflux oeso­
`phagitis. assessed endoscopieally.
`histologically and by 24 It pH moni­
`toring. Gut 1990:31:509-513.
`Klinkenberg-Knol EC. Mcuwissen
`SGM: Combined gastric and oeso­
`phageal 24-hour pi I monitoring and
`oesophageal manometry in patients
`w ith reflux disease resistant to treat­
`ment with omeprazole. Aliment
`Pharmacol Ther 1990:4:485-495.
`Burget DW. Chiverton SG. Hunt
`RII: Is there an optimal degree of
`acid suppression in healing duode­
`nal ulcer? A model of the relation­
`ship between ulcer healing and
`acid suppression. Gastroenterology
`1990:99:345-351.
`Murphy DW, Yuan Y. Castell DO:
`Docs the intraesophagea! pH probe
`accurately detect acid reflux? Simul­
`taneous recording with
`two pH
`probes in humans. Dig Dis Sci 1989;
`34:649-656.
`Johnsson F. Joelsson B: Reproduci­
`bility of ambulatory oesophageal
`pH monitoring. Gut
`1988:29:
`886-889.
`
`67
`
`MYLAN PHARMS. INC. EXHIBIT 1015 PAGE 9
`
`