Aliment Pharmacol Ther 1994; 8 (Suppl. 1): 65-70.
`
`Safety of proton pump inhibitors-an overview
`
`R.ARNOLD
`Department of Internal Medicine. Division of Gastroenterology and Metabolism. Philipps University. Marburg. Germany
`
`SUMMARY
`
`Drug-induced achlorhydria in experimental animals
`results in excessive hypergastrinaemia. ECL-cell
`hyperplasia and ECL-cell carcinoidosis. However. these
`events have not been observed in long-term studies in
`patients receiving proton pump inhibitors. Serum
`gastrin levels increase only modestly during acute and
`long-term treatment. It is concluded that monitoring of
`serum gastrin levels and of fundic ECL cells is of no
`clinical relevance even during long-term therapy with
`proton pump inhibitors. The clinically available proton
`pump inhibitors such as pantoprazole. omeprazole and
`lansoprazole are well tolerated. with a low incidence of
`side-effects. Minor and serious side-effects classified as
`possibly related to proton pump therapy have been
`described in up to 2.5% of patients. This is the same
`
`order of magnitude as that found in patients treated
`with H2-receptor blockers and in placebo-treated
`controls. In most cases. therefore. the observed side(cid:173)
`effects are unrelated to the intake of proton pump
`inhibitors. Minor adverse events include headache.
`diarrhoea. dizziness. pruritus and rash. Proton pump
`inhibitors are metabolized mainly in the liver via the
`cytochrome P450 system and interactions with drugs
`metabolized by the same system are possible. Evidence
`is becoming available which suggests that pantoprazole
`may have less potential to interact with the
`cytochrome P450 system than the other proton pump
`inhibitors. In the case of diazepam metabolism.
`pantoprazole had the least effect on prolongation of the
`diazepam effect. This may well be an advantage in the
`clinical use of the drug.
`
`INTRODUCTION
`
`Over the past 15 years. major advances have been made
`in the therapeutic control of acid secretion. The advent of
`H2-receptor antagonists provided an effective class of
`drugs. and their widespread use has brought relief to
`millions of patients without significant side-effects. 1
`4
`-
`Earlier in this symposium. Professor Sachs described the
`limitations of the H2-receptor antagonists and provided a
`biological basis for the therapeutic control of acid
`secretion by an entirely new class of anti secretory drugs.
`the substituted benzimidazoles. which act as inhibitors of
`gastric H+,K+-ATPase. the gastric acid pump.5 Many
`investigators have demonstrated advantages of proton
`pump inhibitors in the treatment of peptic ulcers resistant
`to high doses of H2-receptor antagonists. 6
`10
`-
`
`Correspondence to: Professor R. Arnold. Department of Internal Medicine.
`Division of Gastroenterology and Metabolism. Philipps University. Balding(cid:173)
`erstrasse. D-35033 Marburg/L .. Germany.
`
`The safety and long-term use of proton pump inhibitors
`have been discussed extensively in this symposium. This
`paper will provide an overview of the current overall
`safety data available. First of all. it is important to begin
`with the gastrin hypothesis and its relation to therapy
`with proton pump inhibitors.
`
`The gastrin hypothesis
`
`The gastrin hypothesis implies that hypergastrinaemia
`can arise. either because of the Zollinger-Ellison syn(cid:173)
`drome. or via achlorhydria. The state of achlorhydria can
`be achieved by pharmacological induction in animals or
`by atrophic gastritis. for instance. in the case of pernicious
`anaemia in humans. Achlorhydria leads to hyper(cid:173)
`gastrinaemia. which then exerts a trophic effect leading
`to enterochromaffin-like (ECL)-cell hyperplasia. ll In his
`paper. Professor Sachs also described the presence of a
`receptor on the ECL cells for progastrin5 and it follows
`
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`66 R. ARNOLD
`
`that ECL-cell hyperplasia is the physiological or patho(cid:173)
`physiological consequence of every case of hyper(cid:173)
`gastrinaemia. whether or not
`it arises from
`the
`Zollinger-Ellison syndrome. pernicious anaemia or fol(cid:173)
`lowing pharmacological induction. However. ECL-cell
`hyperplasia does not necessarily lead to the appearance
`of either ECL-cell dysplasia or ECL-cell carcinoidosis.
`There may be important cofactors involved which have
`still to be identified. For example. in humans. carcinoids
`have only been observed in patients with pernicious
`anaemia and gastrin om a patients associated with the
`Multiple Endocrine Neoplasia (MEN) I synclrome.12. 13 In
`contrast. patients with sporadic gastrinoma do not
`develop carcinoid tumours.13 This indicates that the
`presence of atrophic gastritis (pernicious anaemia) or of a
`genetic trait (MEN I syndrome) could be such cofactors.
`When rats were treated experimentally with BY308 (a
`predecessor of pantoprazole). there was a marked rise in
`serum gastrin levels paralleled by a rise in the number of
`ECL cells. compared with control values (Figure 1 ).14
`Measurement of the ECL-ceillabelling index reveals the
`extent of cells which are dividing. Figure 2 shows the
`dividing capacity of ECL cells in rats under the influence
`of BY308. It can be seen that in contrast to control
`values. the ECL-cell labelling index increased rapidly
`within 10 days of treatment after which time a plateau
`occurred through to 70 days. This corresponds with the
`linear increase in ECL cell numbers over this 70-day
`period. (Figure 2 ).14
`When the experiments were repeated with BY308 in
`rats in the presence of a specific gastrin receptor
`antagonist. it was possible to reverse the increases both
`in the number of ECL cells and in the ECL-cell labelling
`index despite persisting hypergastrinaemia. This normal(cid:173)
`ization of the ECL-ceillabelling index demonstrated that
`the ECL-cell hyperplasia observed was gastrin-medi(cid:173)
`ated. 15
`
`Types of ECL-cell hyperplasia
`
`Several types of ECL-cell hyperplasia have been identified.
`namely diffuse. linear and micronodular.16 Linear and
`diffuse ECL-cell hyperplasia is often observed in patients
`with duodenal and gastric ulcer disease in which H.
`pylori-associated gastritis ofthe antral and fundic mucosa
`is a common finding. Changes in ECL-cell morphology in
`these patients seem to be independent of the mode of
`treatment (H2-blockers. proton pump inhibitors) as simi(cid:173)
`lar events have been described even in untreated
`
`2400
`
`E 1800
`" '" .2:
`
`1200
`
`600
`
`0
`
`600
`
`400
`
`Qj
`>
`~
`
`" E
`.,
`0 '" E
`
`:::>
`0;
`(J)
`
`1:
`E
`"
`~ .,
`D
`E
`:::> " Qj
`
`o
`~ 200
`u
`w
`
`0
`
`10
`
`20
`
`30
`
`40
`
`50
`
`60
`
`70
`
`~
`
`Time (days)
`
`- --- - - - - - - - - - - - - -..
`
`Control
`
`-
`
`-
`
`- - - - -
`
`o
`
`~~ __ _L __ _L __ J_ __ L_~ __ -L __ ~
`10
`20
`30
`40
`50
`60
`70
`
`o
`
`Time (days)
`
`Figure 1. Serum gastrin levels and number of ECL-cells in rats
`treated with BY308. and untreated controls (data from Eissele et
`a/l.14
`
`5
`
`)(
`
`~
`~
`:E 4
`Q)
`u
`-.J 3
`0 w
`Q) 2
`'0
`.S:
`O'l c
`ai
`..0
`
`S 0
`
`Control
`
`0
`
`10
`
`20 30 40 50 60 70
`Time (days)
`
`Figure 2. Percentage labelling index of ECL cells in rats treated
`with BY308. and untreated controls (data from Eissele et a/).14
`
`Aliment Pharmacol Ther 1994. vo!' 8 (Supp!. 1).
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`

`SAFETY OF PROTON PUMP INHIBITORS
`
`67
`
`e------e Vagotomy
`___ Omeprazole 20 mg om
`0--0 Pre-treatment
`
`...J
`
`120
`
`"-a
`E
`E 100
`
`.s
`
`80
`
`." g 60
`o ." 10 .,
`'" E
`
`40
`
`.~
`c
`.!!
`."
`Q)
`::;:
`
`20
`
`09.00
`
`12.00
`
`15.00
`
`18.00
`
`21.00
`
`24.00
`
`03,00
`
`06.00
`
`09.00
`
`Ti me (24 - hour clock)
`
`Figure 3. 24-hour intragastric acidity in
`duodenal ulcer patients. treated with
`omeprazole during or after selective
`proximal vagotomy (data from Lind et
`al)."o
`
`19 Micronodular ECL-cell hyperplasia can also
`patients. 16
`-
`be observed in patients with atrophic gastritis due to
`pernicious anaemia. resulting from atrophy of the glands
`where parietal cells are destroyed. 12, 16 From these
`observations it has been concluded that there is a
`correlation between the grade of gastritis and the
`development of linear. diffuse and micronodular ECL-cell
`hyperplasia.
`
`Serum gastrin and EeL cells in patients treated with proton
`pump inhibitors
`
`In contrast to patients with permclOUS anaemia and
`Zollinger-Ellison syndrome. only moderate increases in
`serum gastrin levels have been observed during acute
`and long-term treatment with either the proton pump
`inhibitor. omeprazole. or with ranitidine. 17
`,19 These
`
`Table 1. Side-effects in patients receiving
`pantoprazole. ranitidine or omeprazole
`
`Description
`
`Controls
`(n=20)
`
`Zollinger(cid:173)
`Ellison
`Syndrome
`(n= 13)
`Figure 4. Median EeL-cell number in various conditions (data
`from Arnold et al.).19
`
`Pernicious
`anaemia
`(n=8)
`
`3 years
`2 year~
`Omeprazole Omeprazole
`(n=16)
`(n=8)
`
`moderate increases mirror the levels in serum gastrin
`obtained during or after selective proximal vagotomy
`(SPV) (Figure 3).20 Selective proximal vagotomy has been
`
`Pantoprazole
`
`Ranitidine
`
`Omeprazole
`
`Oedema
`Vasodilation
`Peripheral vascular disorder
`Tremor
`Taste perversion
`Sleep disorder
`Bilirubinaemia
`Arthritis
`Chills
`Exfoliative dermatitis
`Depression
`Anorexia
`Apathy
`
`0
`1
`0
`0
`0
`0
`0
`0
`0
`1
`0
`0
`0
`
`1
`0
`1
`1
`1
`1
`1
`0
`1
`0
`1
`1
`1
`
`0
`0
`0
`0
`0
`0
`
`1
`0
`0
`0
`0
`0
`
`Aliment Pharmacol Ther 1994, vol. 8 (Suppl. 1).
`
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`

`68
`
`R. ARNOLD
`
`Table 2. Frequency of adverse events (percentages in parentheses) for patients receiving pantoprazole (20, 40 or 80 mg), ranitidine
`(300 mg) or omeprazole (20 mg)
`
`Parameter
`
`Episodes
`Patients with episodes
`All episodes
`Serious episodes
`Patients treated
`
`Pantoprazole
`20mg
`
`Pantoprazole
`40mg
`
`Pantoprazole
`80mg
`
`6
`
`180
`
`23
`
`Ranitidine
`300mg
`
`114
`
`Omeprazole
`20mg
`
`20
`
`6 (7.0%)
`1 (1.2%)
`86
`
`170 (lO.6%)
`17(1.1%)
`16lO
`
`21 (15.2%)
`0(0.0%)
`138
`
`105 (12.3%)
`9 (1.1 %)
`854
`
`19 (11.0%)
`3 (1.7%)
`173
`
`proven as safe for more than 30 years. In a recent
`publication we described the EeL cell density in patients
`several years after Spy, and the results showed that there
`was a modest increase in EeL cell density. similar to that
`observed after proton pump treatment. 21
`Treatment with omeprazole for up to 6 years induces
`only a modest increase in the EeL cell density. which is
`much lower than that observed in patients with
`Zollinger-Ellison syndrome or with pernicious anaemia
`(Figure 4).17.19 A doubling of the mean argyrophil cell
`volume density was paralleled by a decrease in the
`normal endocrine cell growth pattern 17 and an increase
`in micronodular hyperplasia.17 These changes correlate
`with the severity of corpus gastritis and seem to be more
`than drug-related.17 Similarly. only modest
`disease-
`increases in serum gastrin levels are observed in humans
`with pantoprazole. increases which are not clinically
`significant.22 From the present studies it can be concluded
`that the monitoring of serum gastrin levels and of the EeL
`cell numbers in fundic biopsies in patients treated with
`proton pump inhibitors is of no clinical relevance. even
`during the longer term.
`
`Safety of proton pump inhibitors
`
`There are numerous studies on the side-effects of proton
`pump inhibitors which demonstrate that proton pump
`inhibitors are as safe as H2-receptor antagonists. Most
`studies compared the safety of omeprazole in comparison
`with the H2-blockers cimetidine and ranitidine. 23,24
`Studies involving almost 3500 patients with peptic ulcer
`and reflux oesophagitis indicated that the incidence of
`, the major side-effects in the short term. such as headache.
`diarrhoea. abdominal pain. fatigue and flatulence. was
`very similar following treatment with either drug. Ome(cid:173)
`prazole had no clinically relevant effects on laboratory
`variables
`including: haematology;
`liver
`function;
`
`electrolytes; renal function; thyroid hormones; blood
`pressure; heart rate; EeG. Available data indicate that
`pantoprazole is similarly well tolerated in humans.25-28
`There is. in addition. ample evidence that the pattern
`and frequency of adverse events following omeprazole
`therapy did not increase. even during long-term treat(cid:173)
`ment. 29,30 In this symposium. Dr Schepp has presented
`comparative data of side-effects in patients receiving
`pantoprazole. ranitidine or omeprazole and observed
`very little differences between them (Table 1).31
`Similarly. Table 2 shows percentages of all episodes. and
`of serious episodes. of adverse events in patients receiving
`pantoprazole (20. 40 or 80 mg/day). ranitidine (300
`mg/day) or omeprazole (20 mg/day) for 4-8 weeks.
`There was little difference between the three drugs in
`terms of the frequency of serious episodes.
`
`Interactions with pharmaceutical compounds
`
`Proton pump inhibitors are metabolized mainly in the
`liver via the cytochrome P450 system and it is possible
`that interactions could occur with other drugs metabol(cid:173)
`ized by the same system. Interactions of omeprazole with
`phenytoin. warfarin. diazepam. digoxin and nifedipine
`have been described. some of which could possibly
`achieve clinical significance. Pantoprazole has a much
`lower potential than omeprazole for interaction with the
`cytochrome P450 system and is likely to exhibit fewer
`interactions with any of the above-mentioned drugs. 32,33
`Indeed. it has been shown in rats that pantoprazole
`interacts less with the metabolism of diazepam and
`theophylline in comparison with either of the other two
`proton pump inhibitors or with cimetidine.32, 34 Fur(cid:173)
`thermore. clinical studies with pantoprazole have demon(cid:173)
`strated no interaction with diazepam.35
`
`Aliment Pharmacol Ther 1994, vo!' 8 (Supp!. I),
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`

`CONCLUSIONS
`
`The clinically available proton pump inhibitors. panto(cid:173)
`prazole. omeprazole and lansoprazole. are well tolerated.
`This holds true for overall safety. unwanted effects with
`drug-metabolizing enzymes and the consequences of the
`gastrin hypothesis. With proton pump inhibitors. there is
`a low incidence of side-effects. Minor and serious side(cid:173)
`effects. classified as possibly related to proton pump
`therapy. he.ve been described in up to 2.5 % of patients.
`which is the same order of magnitude as that found in
`patients treated with H2-receptor blockers and in placebo(cid:173)
`treated controls. In most cases. the observed side-effects
`are unrelated to the intake of proton pump inhibitors.
`Moreover. clinical monitoring of serum gastrin levels is
`deemed unnecessary. With this overall good safety
`profile. the proton pump inhibitors represent a very
`useful treatment for the management of peptic ulcers and
`other acid-related diseases.
`Proton pump inhibitors are metabolized mainly in the
`liver via the cytochrome P450 system. and interactions
`with drugs metabolized by the same system are possible.
`It appears that pantoprazole has considerably less po(cid:173)
`tential to interact with the cytochrome P450 system
`than the other proton pump inhibitors and. in the case of
`diazepam metabolism. pantoprazole in rats had the least
`effect on prolongation of the diazepam effect. In clinical
`use this may well be an advantage of the drug.
`
`REFERENCES
`
`1 Arcidiacono R. Benvestito V, Bonomo GM. et al. Comparison
`between ranitidine 150 mg b.d. and ranitidine 300 mg nocte
`in the treatment of duodenal ulcer. Int J Pharmacol Ther
`Toxicol1986: 24: 381-4.
`2 Alcala Santaella R, Guardia J, Pajares J, et al. A multicentre,
`randomized. double blind study comparing nocte famotidine or
`ranitidine for the treatment of active duodenal ulceration.
`Aliment Pharmacol Ther 1989: 3: 103-10.
`3 Bank S, Greenberg RE, Magier D, et al. The efficacy and
`tolerability of famotidine and ranitidine on the healing of active
`duodenal ulcer and during six-month maintenance treatment
`with special reference to NSAID aspirin-related ulcers. Clin
`Ther 1991: 13: 204-11.
`4 Lee FJ. Reed PI. Crowe JP, et al. Acute treatment of duodenal
`ulcer: a multicentre study to compare ranitidine 150 mg twice
`daily with ranitidine 300 mg once at night. Gut 1986: 27:
`1091-5.
`5 Shin J M. Besancon M, Prinz C. Simon A. Sachs G. Continuing
`development of acid pump inhibitors: site of action of pan to-
`
`Aliment Pharmacol Ther 1994. vol. 8 (Suppl. 1).
`
`SAFETY OF PROTON PUMP INHIBITORS
`
`69
`
`prazole. Aliment Pharmacol Ther 1994: 8 (Suppl. 1):
`11-23.
`6 Lundell L, Backman I. Ekstrom p, et al. Omeprazole or high-dose
`ranitidine in the treatment of patients with reflux oesophagitis
`not responding to 'standard doses' of H2-receptor antagonists.
`Aliment Pharmacol Ther 1990: 4: 145-55.
`7 Tytgat GNJ, Lamers CBHW, Hameeteman W, et al. Omeprazole
`in peptic ulcers resistant to histamine H2-receptor antagonists.
`Aliment Pharmacol Ther 1987: 1: 31-8.
`8 Brunner G, Arnold R, Hennig U, Fuchs W. An open trial of
`long-term therapy with lansoprazole in patients with peptic
`ulceration resistant to extended high-dose ranitidine treatment.
`Aliment Pharmacol Ther 1993: 7 (Suppl. 1): 51-5.
`9 Walan A, Bader JP, Classen M, et al. Effect of omeprazole and
`ranitidine on ulcer healing and relapse rates in patients with
`benign gastric ulcer. N Engl J Med 1989: 320: 69-75.
`10 Brunner G, Creutzfeldt W, Harke U, Lamberts S. Therapy with
`omeprazole in patients with peptic ulcerations resistant to
`extended high-dose ranitidine treatment. Digestion 1988: 38:
`80-90.
`11 Larsson H, Carlsson E, Hakonson R, et al. Time-course of
`development and reversal of gastric endocrine cell hyperplasia
`after inhibition of acid secretion. Gastroenterology 1988: 95:
`1477-86.
`12 Borch K, Renvall H, Kullman E, Wilander E. Gastric carcinoid
`associated with the syndrome of hypergastrinemic atrophic
`gastritis. Am J Surg Pathol 1987: 11: 435-44.
`13 Solcia E, Capella C, Fiocca R, Rindi G, Rosai J. Gastric argyrophil
`carcinoidosis in patients with Zollinger-Ellison syndrome due
`to type 1 multiple endocrine neoplasia. Am J Surg Pathol
`1990: 14: 503-13.
`14 Eissele R, Rosskopf B, Koop H, et al. Proliferation of endocrine
`cells, in the rat stomach caused by drug-induced achlorhydria.
`Gastroenterology 1991: 101: 71-6.
`15 Eissele R, Patberg H, Koop H, et al. Effect of gastrin receptor
`blockade on endocrine cells, in rats during achlorhydria.
`Gastroenterology 1992: 103: 1596-601.
`16 Solcia E, Bordi L, Creutzfeldt W, et al. Histopathological
`classification of nonantral gastric endocrine growths in man.
`Digestion 1988: 41: 185-200.
`17 Lamberts R, Creutzfeldt W, Striiben HG, et al. Long-term
`omeprazole therapy in peptic ulcer disease: gastrin, endocrine
`cell growth, and gastritis. Gastroenterology 1993; 104:
`1350-70.
`18 Solcia E, Fiocca R, Havu N, et al. Gastric endocrine cells and
`gastritis in patients receiving long-term omeprazole treatment.
`Digestion 1992; 51: 82-92.
`19 Arnold R, Frank M, Simon B, et al. Adaptation and renewal of
`the endocrine stomach. Scand J Gastroenterology 1992; 27
`(Suppl. 193): 20-7.
`20 Lind T, Cederberg L, Olausson M, Olbe L. 24 hour intragastric
`acidity and plasma gastrin after omeprazole treatment and
`after proximal gastric vagotomy in duodenal ulcer patients.
`Gastroenterology 1990; 99: 1593-8.
`21 Koop H, Frank M, Kuly S. et al. Gastric argyrophil (entero(cid:173)
`chromaffin-like), gastrin, and somatostatis cell, after proximal
`selective vagotomy in men. Dig Dis Sci 1993; 38: 295-302.
`
`Patent Owners' Ex. 2040
`IPR2018-00272
`Page 5 of 6
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`

`70 R. ARNOLD
`
`22 Miiller p, Simon B, Khalil H, Liihmann R, Leucht U, Schneider
`A. Dose-range study with the proton pump inhibitor panto(cid:173)
`prazole in acute duodenal ulcer patients. Gastroenterology
`1992; 30: 771-5.
`23 Sandmark A, Carlsson R, Fansa 0, et al. Omeprazole or
`ranitidine in the treatment of reflux esophagitis. The results of
`a double-blind, randomised, Scandinavian, multicenter study.
`Scand J Gastroenterol1988; 23: 625-32.
`24 Massooni F, Savage HIJ, Destache C, et al. Omeprazole: a
`comprehensive review. Pharmacol Ther 1993; 13: 46-59.
`25 Schepp W, Classen M. Pantoprazole vs. ranitidine in the
`treatment of acute duodenal ulcer-German Multicenter
`Study. Gastroenterology 1993; 104: A 186 (Abstract).
`26 Koelz HR, Judmaier G. Double-blind comparison of pan to(cid:173)
`prazole and ranitidine in short-term treatment of acute
`duodenal ulcer. Gastroenterology 1993; 104: A 121 (Ab(cid:173)
`stract).
`27 Miiller p, Simon B. Treatment of acute duodenal ulcer with
`pantoprazule: a dose-finding study. Gastroenterology 1993;
`104: A 151 (Abstract).
`28 Koop H, Classen M, Schepp W, Dammann HG. Comparison of
`pantoprazole and ranitidine in reflux esophagitis: German
`Multicenter Study. Gastroenterology 1993; 104: A 123
`(Abstract).
`29 Lloyd-Davis KA, Rutgersson K. Salvell L. Omeprazole in the
`
`treatment of Zollinger-Ellison syndrome: a 4 year international
`study. Aliment Pharmacol Ther 1988; 2: 13-32.
`30 Maton PM, Vinayek R, Frucht H, et al. Long-term efficacy and
`safety of omeprazole in patients with Zollinger-Ellison syn(cid:173)
`drome: a prospective study. Gastroenterology 1989: 97:
`827-36.
`31 Schepp W. Treatment of duodenal and gastric ulcers, pan to(cid:173)
`prazole vs. omeprazole. Aliment Pharmacol Ther 1994: 8
`(Supp!. 1): 53-7.
`32 Hanauer G, Graf U, Meissuer T. In vivo cytochrome P450
`interaction of the newly developed W,K+-ATPase inhibitor
`pantoprazole (BY1023jSKF96022) compared to other anti(cid:173)
`ulcer drugs. Meth Find Exp Clin Pharmacol 1991; 13: 63-7.
`33 Kromer W, Postius S, Reidel R, et al. BY1023jSKF96022 INN
`pantoprazole, a novel gastric proton pump inhibitor, potently
`inhibits acid secretion but lacks relevant cytochrome P450
`interactions. J Pharmacol Exp Ther 1990; 254: 129-35.
`34 Schulz H-U, Hartmann M, Steinijaus VW, et al. Lack of
`influence of pantoprazole on the disposition kinetics of theo(cid:173)
`phylline in man. IntI Clin Pharmacol Ther Toxicol1991 ; 29:
`369-75.
`35 Gugler R, Hartmann M, Rudi J, et al. Lack of interaction of
`pantoprazole and diazepam in man. Gastroenterology 1992:
`102: A77 (Abstract).
`
`Aliment Pharmacol Ther 1994, vo!' 8 (Supp!. 1).
`
`Patent Owners' Ex. 2040
`IPR2018-00272
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