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Acid Suppression Therapy: Where Do We Go from Here?

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 Review Article
Dig Dis 2006;24:11-46
DOI: 10.1159/000091298
Acid Suppression Therapy:
Where Do We Go from Here?
Carmelo Scarpignato a Iva Pelosini a Francesco Di Mario b
a
Laboratory of Clinical Pharmacology, Department of Anatomy, Pharmacology and Forensic Sciences, and
b
Department of Clinical Sciences, Section of Gastroenterology, School of Medicine and Dentistry,
University of Parma, Parma, Italy
Key Words
Gastric acid secretion
Acid inhibition
Antisecretory
drugs
H2-receptor antagonists
Ebrotidine

Lafutidine
Proton pump inhibitors
Ilaprazole-
Tenatoprazole
Potassium-competitive acid blockers

CCK2-receptor antagonists
Antigastrin vaccine
Abstract
The dramatic success of pharmacological acid suppres-
sion in healing peptic ulcers and managing patients with
gastroesophageal reflux disease (GERD) has been re-
flected in the virtual abolition of elective surgery for ulcer
disease, a reduction in nonsteroidal anti-inflammatory
drug (NSAID)-associated gastropathy and the decision
by most patients with reflux symptoms to continue med-
ical therapy rather than undergo surgical intervention.
However, a number of challenges remain in the manage-
ment of acid-related disorders. These include manage-
ment of patients with gastroesophageal symptoms who
do not respond adequately to proton pump inhibitor
(PPI) therapy, treatment of patients with nonvariceal up-
per gastrointestinal bleeding, prevention of stress-relat-
ed mucosal bleeding, optimal treatment and prevention
of NSAID-related gastrointestinal injury, and optimal
combination of antisecretory and antibiotic therapy for
the eradication of Helicobacter pylori infection. A num-
ber of new drugs are currently being investigated to pro-
vide a significant advance on current treatments. Some
© 2006 S. Karger AG, Basel
0257–2753/06/0242–0011$23.50/0
Fax +41 61 306 12 34
E-Mail karger@karger.ch Accessible online at:
www.karger.com www.karger.com/ddi
DDI923.indd 11
of them (namely potassium-competitive acid blockers
(P-CABs) and CCK2-receptor antagonists) have already
reached clinical testing while some others (like the anti-
gastrin vaccine, H3-receptor ligands or gastrin-releasing
peptide receptor antagonists) are still in preclinical de-
velopment and need the proof of concept in human be-
ings. Of the current approaches to reduce acid secretion,
P-CABs and CCK2-receptor antagonists hold the greatest
promise, with several compounds already in clinical tri-
als. Although the quick onset of action of P-CABs (i.e. a
full effect from the first dose) is appealing, the results of
phase II studies with one such agent (namely AZD0865)
did not show any advantages over esomeprazole. Thanks
to their limited efficacy and the development of tolerance
it is unlikely that CCK2 antagonists will be used alone as
antisecretory compounds but, rather, their combination
with PPIs will be attempted with the aim of reducing the
long-term consequences of hypergastrinemia. While H2-
receptor antagonists (especially soluble or over-the-
counter formulations) will become the ‘antacids of the
third millennium’ and will be particularly useful for on-
demand symptom relief, clinicians will continue to rely
on PPIs to control acid secretion in GERD and other acid-
related diseases. In this connection, several new PPI for-
mulations have been developed and two novel drugs
(namely ilaprazole and tenatoprazole) are being studied
in humans. The recently introduced immediate-release
(IR) omeprazole formulation (currently available only in
the USA) quickly increases intragastric pH and, given at
Prof. Carmelo Scarpignato, MD, DSc, PharmD, FRCP, FCP, FACG
Laboratory of Clinical Pharmacology
School of Medicine and Dentistry, University of Parma
Via Volturno, 39, IT–43100 Parma (Italy)
Tel. +39 0521 903 863, Fax +1 603 843 5621, E-Mail scarpi@tin.it
02.05.2006 16:23:33
bedtime, seems to achieve a better control of nocturnal
acidity. IR formulations of other PPIs (including the in-
vestigational ones) will probably be available in the fu-
ture and will enlarge our therapeutic armamentarium.
Amongst the novel PPIs, tenatoprazole appears to be a
true advance in the acid suppression therapy. Its long
half-life (the longest among the available compounds)
and longer duration of antisecretory action, with no dif-
ference between day and night, will allow the drug to go
beyond the intrinsic limitations of currently available
PPIs. Thanks to its favorable pharmacokinetics, the so-
dium salt of S-tenatoprazole is being developed and the
preliminary results indicate that this drug has the poten-
tial to address unmet clinical needs. Although some de-
cades have elapsed since the introduction of effective
and safe antisecretory drugs in clinical practice and their
use has stood the test of time, the ongoing research will
further provide the clinician with more effective means
of controlling acid secretion.
Copyright © 2006 S. Karger AG, Basel
Introduction
Gastric acid secretion is under nervous and hormonal
influence [1]. This physiologic process is controlled by a
number of redundant second messenger pathways acti-
vated as a result of the binding of gastrin, acetylcholine,
histamine, and prostaglandins to the specific receptors on
the basolateral surface of parietal cells. The stimulatory
effect of acetylcholine and gastrin is mediated by an in-
crease in cytosolic calcium, whereas that of histamine is
mediated by activation of adenylate cyclase and genera-
tion of cyclic AMP (cAMP). Strong potentiation between
histamine and either gastrin or acetylcholine reflects post-
receptor interaction between the distinct pathways as well
as the ability of acetylcholine and gastrin to release hista-
mine from mucosal enterochromaffin-like (ECL) cells [1].
Indeed, gastrin, the major circulating stimulus of acid se-
cretion, probably does not stimulate the parietal cells di-
rectly but acts to mobilize histamine from the ECL cells
in the oxyntic mucosa [2]. The gastrin-ECL cell pathway
has been investigated extensively in situ (gastric submu-
cosal microdialysis), in vitro (isolated ECL cells) and in
vivo (intact animals). Gastrin acts on CCK2 receptors to
control the synthesis of ECL cell histamine, accelerating
the expression of the histamine-forming enzyme, histi-
dine decarboxylase (HDC), at both the transcription and
the translation/posttranslation levels [3]. The ultimate
factor in acid secretion, however, is the stimulation of the
12 Dig Dis 2006;24:11–46
Fig. 1. Chemical structure of currently used PPIs.
proton pump (H+,K+-ATPase) to secrete hydrogen ions
into the gastric lumen in exchange for potassium ions [1].
The recognition that H+,K+-ATPase was the final step of
acid secretion culminated in the development of a class
of drugs, the proton pump inhibitors (PPIs), which are
targeted at inhibiting this enzyme [2]. They represent one
of the most commonly prescribed classes of drugs in both
gastroenterological and primary care settings and are con-
sidered a major advance in the treatment of acid-related
diseases.
After sufficient acid secretion has occurred, a feedback
system terminates gastric acid secretion. A decrease of
intragastric pH stimulates somatostatin (SST) release
from antral D cells. This peptide not only inhibits acid
secretion but also blunts gastrin release and its stimula-
tory effect on CCK2 receptors located on parietal and
ECL cells [1, 4]. Furthermore, acidification of the duode-
num triggers secretin release, which also inhibits gastric
acid secretion [5]. The inhibitory effects of SST and en-
dogenous prostaglandins (EPs) on acid secretion are me-
diated by receptors (SST2 and EP3, respectively) coupled
by guanine nucleotide-binding proteins to inhibition of
adenylate cyclase activity. All the pathways (both stimu-
latory and inhibitory) converge on and modulate the ac-
tivity of the luminal enzyme (i.e. H+,K+-ATPase) [1, 2].
In 1973, pyridylmethyl benzimidazole sulfides were
originally discovered to be active PPIs: they were then
modified to the corresponding sulfoxide timoprazole, pi-
coprazole and omeprazole in 1979. Omeprazole, the first
clinically available PPI, has been used in some countries
for more than two decades [6]. More recently, other mem-
Scarpignato /Pelosini /Di Mario
 Chiral
R3 R3
R4 R2 sulfoxide R4 R2

N N+
−
S + SOH
HN O H N NH
N

Canalicular
Pro-drug Sulfenic acid Diffusion
lumen
Parietal
R1 R1 Concentration
−H2O cell
Cytosol Conversion
R3 R3 Inhibition
R4 R2 R4 R2
Secretory
Achiral, membrane
N+ N+ optically
S S E S inactive
N NH E SH N N

R1 R1
Inactivated enzyme, Cyclic sulfenamide
fairly stable

Fig. 2. Chemical activation of PPIs within the parietal cell (modified from Kromer [9]).

bers of the PPI family including lansoprazole, pantopra-
zole rabeprazole and esomeprazole have been developed
and launched.
Inhibition of Acid Secretion: Where Are We?
Chemistry and Pharmacology of PPIs
Chemically, all the available PPIs [7, 8] consist of a
benzimidazole ring and a pyridine ring, but vary in the
specific side ring substitution (fig. 1). They are all weak
protonatable pyridines, with a pKa of about 4.0 for
omeprazole and lansoprazole, about 3.9 for pantoprazole,
and about 5.0 for rabeprazole. As a result, they accumu-
late specifically and selectively in the secretory canalicu-
lus, the highly acidic space of the parietal cell [8, 9]. With-
in that space, PPIs undergo an acid-catalyzed conversion
to a reactive species, the thiophilic sulfenamides, which
are permanent cations (fig. 2). The rate of conversion var-
ies among the compounds and is inversely proportional
to their pKa: rabeprazole (4.71) 1 omeprazole (4.09) 1
lansoprazole (3.92) 1 pantoprazole (3.89). The reactive
species interacts with the external surface of the H+,K+-
ATPase that faces the lumen of the secretory space of the
parietal cell, resulting in disulfide bond formation with
one or more key cysteines located within the
-subunit of
the enzyme; this is the residue that is intimately involved
in hydrogen ion transport. This covalent inhibition of the
enzyme by the thiophilic sulfenamide results in a specific
and long-lasting impairment of gastric acid secretion. The
selectivity of PPIs for the parietal cell proton pump stems
from the fact that H+,K+-ATPase is the only pump in the
body that generates a sufficiently steep proton gradient of
more than 1:1,000,000, corresponding to pH 0.8–1.0 in-
side the canaliculus of a secreting parietal cell [10].
PPIs are the most potent inhibitors of gastric acid se-
cretion available [8, 10]. They are most effective when
the parietal cell is stimulated to secrete acid postprandi-
ally, a relationship that has important clinical implica-
tions for timing of administration. Because the amount
of H+,K+-ATPase present in the parietal cell is greatest
after a prolonged fast, PPIs should be administered before
the first meal of the day. In most individuals, once-daily
dosing is sufficient to produce the desired level of acid

Update on Acid Suppression Therapy Dig Dis 2006;24:11–46 13

DDI923.indd 13 02.05.2
 inhibition, and a second dose, which is occasionally nec-
essary, should be administered before the evening meal
[11].
During meals, neither all parietal cells nor all proton
pumps are active. Since PPIs inhibit only activated en-
zyme present in the canalicular membrane, the reduction
of gastric acid secretion after an initial dose will probably
be suboptimal. As inactive enzyme is recruited into the
secretory canaliculus, acid secretion will resume, albeit at
a reduced level. After the second dose is given on the next
day, more H+,K+-ATPase will have been recruited and
subsequently inhibited, and after the third dose, addi-
tional recruitment and further acid inhibition will prob-
ably occur [8, 11].
Once-daily PPI dosing inhibits maximal acid output
by about 66% after 5 days. Thus, the occasional use of a
PPI taken on an ‘as needed’ basis would not be expected
to reliably provide adequate acid inhibition and would
be unlikely to produce a consistent or satisfactory clinical
response (in contrast to the H2-antagonists, which have a
more rapid onset of action) [8, 11]. Because of the delay
in optimal acid inhibition, the initial use of twice-daily
dosing (for the first 2–3 days) may be helpful in achieving
more rapid inhibition of gastric acid secretion. In addi-
tion to their delay in onset, and because PPI-derived sulf-
enamides bind covalently to H+,K+-ATPase, the restora-
tion of acid secretion will likewise be delayed, depending
upon enzyme turnover and the biological reversibility of
the disulfide bond. Maximal acid secretory capacity may
not be restored for 24–48 h after discontinuing PPIs [8,
11].
Clinical Applications of PPIs
PPIs are effective for treatment of all acid-related dis-
orders, i.e. peptic ulcer (PU) and eradication of Helico-
bacter pylori, Zollinger-Ellison syndrome (ZES), gastro-
esophageal reflux disease (GERD) and its complications,
nonsteroidal anti-inflammatory drugs (NSAID)-associ-
ated gastroduodenal ulcers as well as PU bleeding.
In a landmark study, Burget et al. [12] found a highly
significant correlation between healing and the degree of
acid suppression, the duration of acid suppression, and
the length of therapy. The shape of the contour expression
of these relationships showed that healing rate increases
as the duration of suppression increases and as gastric pH
increases. Being more potent and longer lasting than H2-
RAs, PPIs are therefore more effective in healing both
gastric and duodenal ulcers. And indeed, several meta-
analyses [13, 14] did show that these drugs are able to heal
gastroduodenal ulcer more rapidly than H2-RAs.
14 Dig Dis 2006;24:11–46
DDI923.indd 14
Raising intragastric pH with PPIs improves antimi-
crobial efficacy of chemotherapeutic agents towards H.
pylori through several mechanisms [15], thus increasing
their bactericidal effectiveness. As a consequence, the
combination of a PPI and two antimicrobials (mainly
clarithromycin and amoxicillin or metronidazole) is now
a well-established first-line regimen [16, 17], whenever
eradication of the microorganism is indicated [18, 19].
Since Warren and Marshall first described the infectious
etiology of PU disease in 1984 [20, 21], a great deal of
evidence has accumulated to suggest that H. pylori erad-
ication therapy cures PU disease [22–24] and can be ben-
eficial also to other H. pylori-related diseases [25]. A re-
cent meta-analysis [26] clearly showed that prolonging
therapy with PPIs after a PPI-based triple therapy for 7
days is not necessary to induce ulcer healing.
Both oral and intravenous PPIs have allowed for the
first time a complete control over the marked acid hyper-
secretion often seen in patients with ZES [27, 28] and are
indeed the drugs of choice in the long-term management
of ZES patients. PPIs are effective even in patients un-
responsive to H2-RAs [29] and do not show tachyphy-
laxis.
In patients with reflux esophagitis the degree of muco-
sal healing is directly related to the proportion of time
during the 24-hour period for which the intragastric pH
is maintained above 4 [30, 31]. As a consequence, numer-
ous studies have documented the marked efficacy of PPIs
in controlling symptoms of GERD and healing esophagi-
tis and a large meta-analysis [32] clearly showed a distinct
advantage – either in terms of healing and symptom re-
lief – of PPIs over H2-RAs, a finding confirmed in a re-
cent Cochrane Review [33].
Gastroduodenal mucosa possesses an array of defen-
sive mechanisms and NSAIDs have a deleterious effect
on most of them. This results in a mucosa less able to cope
with even a reduced acid load. The presence of acid ap-
pears to be a conditio sine qua non for NSAID injury,
which is in fact pH-dependent. There is therefore a strong
rationale for PPI use in both treatment and prevention of
NSAID-associated gastroduodenal ulcers [34]. Unlike
H2-blockers, PPIs protect from NSAID injury not only
the duodenum, but also the stomach, where the majority
of mucosal lesions are usually located [35–38].
The goal of medical therapy for bleeding ulcers has
been traditionally to sustain intragastric pH 16, in order
to promote platelet aggregation, clot formation and stabil-
ity [39, 40]. H2-RAs show little benefit in patients with
PU bleeding [41–43], which reflects their inadequate pH
control and the rapid onset of tolerance (see below). Sev-
Scarpignato /Pelosini /Di Mario
02.05.2006 16:24:52
 eral meta-analyses [41, 42, 44–46] have shown that treat-
ment with a PPI reduces the risk of re-bleeding and the
requirement for surgery after ulcer bleeding but has no
benefit on overall mortality, an effect seen only with in-
travenous administration of high doses to high-risk pa-
tients [47, 48]. One of these systematic reviews [48] actu-
ally suggested a significant benefit only for patients having
endoscopic high-risk stigmata for re-bleeding.
PPI therapy for ulcer bleeding has been more effica-
cious in Asia than elsewhere [49]. This may be because of
an enhanced pharmacodynamic effect of PPIs in Asian
patients [50, 51]. Combination of endotherapy with acid
suppression is superior to monotherapy in reducing bleed-
ing and surgery and superior to endotherapy alone in
minimizing re-bleeding but not surgery [52].
Treatment of H. pylori infection is more effective than
antisecretory noneradicating therapy (with or without
long-term maintenance antisecretory therapy) in prevent-
ing recurrent bleeding from PU [53]. Recurrence of infec-
tion seems to be responsible for recurrence of bleeding.
Consequently, all patients with PU bleeding should be
tested for H. pylori infection, and eradication therapy be
prescribed to H. pylori-positive patients.
Why Are PPIs Better Antisecretory Agents than
H2-RAs?
H2-RAs have a relatively short duration of action and,
depending on the individual agent and whether the pa-
tient is in a fed or fasting state, suppress acid for approx-
imately 4–8 h [54]. Consequently, multiple daily doses of
these agents are likely to be required. Furthermore, H2-
RAs produce incomplete inhibition of postprandial gas-
tric acid secretion. Overall, these agents inhibit acid se-
cretion by up to 70% over a 24-hour period [54, 55].
A further shortcoming is that tolerance to standard
H2-RAs generally develops within 2 weeks of repeated
administration, resulting in a decline in acid suppression
[56]. This can be explained by a gastrin-induced increase
in ECL-derived histamine concentrations at the H2-re-
ceptor on the parietal cell [57] and up-regulation of both
gastrin and H2-receptors [58]. In contrast, PPIs control
both basal and food-stimulated acid secretion and pro-
duce more complete and longer lasting acid suppression
than H2-blockers [8, 11]. Such acid inhibition virtually
abolishes the damaging peptic activity of gastric juice. In
addition, tolerance to PPIs has not been observed, an ad-
vantage presumably attributable to the fact that they act
at the final step of acid production, thereby blocking the
effects of any compensatory mechanisms promoting acid
secretion [11, 57].
Update on Acid Suppression Therapy
DDI923.indd 15
Despite all the above limitations, there is still a place
for H2-RAs in the era of PPIs [55]. Besides the treatment
of functional dyspepsia, where they are superior to pla-
cebo [59], H2-RAs are useful for heartburn relief in pa-
tients with mild forms of GERD [60], being better and
faster than antacids [61]. OTC (low-dose) formulations
are not only able to decrease gastric and esophageal acid-
ity but actually potentiate the antacid effect in relieving
meal-induced heartburn [62].
The appreciation that even twice-daily PPIs may not
adequately control intragastric acidity during the night
and that in a significant proportion of both healthy sub-
jects and GERD patients a ‘nocturnal acid breakthrough’
(NAB) does occur [63] has suggested the use of a bedtime
dose of H2-RAs to improve acid control [64]. However,
long-term use of these agents led to development of toler-
ance so that their effect on NAB lessened with prolonged
therapy [65]. In addition, it must be emphasized that no
study in patients with GERD has yet demonstrated that
addition of H2-RAs to twice-daily PPI therapy provides
any further benefit above that derived from PPIs alone
[66, 67]. However, a paper presented at a recent DDW in
Orlando [68] showed that, besides reducing NAB [64],
ranitidine, given at bedtime even at low doses, signifi-
cantly improves nocturnal heartburn in GERD patients
on PPI therapy, already on the first day of therapy. Al-
though the benefit lasted only a few days, these data sug-
gest that short-term or intermittent therapy with H2-RAs
might have a significant impact also on GERD-related
symptoms.
Up to 79% of patients with GERD experience noctur-
nal symptoms associated with their condition. Improve-
ment in nocturnal symptoms associated with reduction
in gastric acidity by PPIs is well documented [69]. The
clinical importance of specifically reducing NAB, how-
ever, is controversial. In patients with GERD, recovery
of nocturnal gastric acid secretion is of little importance,
if it is not accompanied by exposure of the esophagus to
acid. Nevertheless, patients with severe forms of chronic
GERD, especially those with Barrett’s esophagus, are
more likely to have acid reflux during NAB [70]. A recent
report [71] has shown 170% of patients had improved
nighttime symptoms after addition of an H2-RA to a
twice-daily PPI regimen, thus emphasizing the clinical
impact of controlling NAB.
All the above findings suggest that a hierarchy of over-
night pH control does exist [72], beginning with a PPI
given in the morning, adding an H2-RA at bedtime, pro-
gressing to PPI therapy twice daily and then again adding
an H2-RA at bedtime (table 1).
Dig Dis 2006;24:11–46 15
02.05.2006 16:24:52
 Table 1. Relative efficacy of antisecretory regimens (from Katz and
Tutuian [72])
Efficacy Therapeutic regimens
Highest PPIs twice daily with H2-RAs at bedtime
PPIs twice daily
d
Lowest
PPIs in the morning with H2-RAs at bedtime
PPIs once daily
High-dose H2-RAs
Over-the-counter H2-RAs
PPIs should always be given before a meal.
The administration of current DR PPIs is recommended 0.5–
1.0 h prior to a meal in order to ensure that proton pumps are ac-
tivated in the parietal cell at a time when drugs are available in
plasma. Since PPIs all have similar plasma half-lives of 1–2 h, any
proton pump synthesized after drug levels fall will not be blocked
from secreting acid. This kind of administration therefore allows
the maximal antisecretory effect of the PPI dose and also mini-
mizes any possibility of interaction with food.
Are Currently Available PPIs All the Same?
Although there are differences among PPIs concerning
their pharmacokinetics, pharmacodynamics, influence
by food and antacids as well as potential for drug interac-
tions [7, 73], it is not always evident whether these often
subtle differences are clinically relevant. Several compre-
hensive analyses of the available clinical trials concluded
that – when used at equivalent doses in the treatment of
various acid-related disorders – all the available agents
are similarly effective [7, 74, 75]. These conclusions con-
cerning ‘clinical’ efficacy of PPIs are backed by similar
results obtained in comparative ‘pharmacological’ analy-
sis [76].
Guidance from the National Institute for Clinical Ex-
cellence (NICE) does not differentiate between PPIs ex-
cept on the grounds of price and accepted indications
[77]. The physician’s choice of one PPI over another must
therefore rest with her/his interpretation of the clinical
importance of the generally small differences among
PPIs, their approval for treatment of specific clinical in-
dications within the physician’s practice jurisdiction, and
the strength of the evidence based on the quantity and
quality of the supporting clinical trials [74].
Is There Any Acid Peptic Disease That Is Refractory
to PPIs?
Nonhealing and/or delayed healing during acid inhibi-
tion treatment depend on the extent to which acid and
‘non-acid’ factors are causative in the particular acid pep-
16 Dig Dis 2006;24:11–46
DDI923.indd 16
tic disease, and on the effectiveness and duration of acid
suppression. Refractoriness occurs less often with PPIs
than with H2-RAs as the former decrease acid more ef-
fectively [78]. H2-RA refractory disease usually responds
to treatment with PPIs. However, although rare, refrac-
toriness to PPIs does exist [79–81], amounting to 5–10%
in GERD and 2–8% in PU [78, 81].
Potential reasons for this less than optimal response
can be found when carefully examining the intragastric
pH profiles of patients with PPI-resistant PU [82] or
GERD [83, 84]. In both cases, tracings will frequently
show that PPIs fail to adequately control intragastric acid-
ity, especially during the night, although other pathophys-
iological features should be taken into account. Increasing
the PPI dose will often offset this ‘relative’ resistance. If
NAB occurs in GERD patients with predominantly night-
time symptoms, administering an H2-RA at bedtime
would be worthwhile [70, 71], although the benefit of this
combination may be short-lasting [65]. In any event, the
reported failure of PPIs to effectively control either intra-
gastric (and intraesophageal) pH and symptoms clearly
unmask some limitations of currently available agents.
It should be mentioned, however, that there is a small
group of patients who are ‘true’ omeprazole-resistant (de-
fined as gastric pH !4 for 50% of 24 h), for whom an ab-
normality of the proton pump, due to mutations of cys-
teine 813 and 822, has been suggested [85]. Whether re-
sistance to other PPIs exists has not been currently
studied. In addition, although successful treatment with
PPIs in H2-RA-resistant GERD patients is the rule, few
patients who showed therapeutic response to high-dose
H2-RAs after failure of high-dose omeprazole to control
gastric acidity and gastroesophageal reflux have been re-
ported [86].
Shortcomings and Limitations of Current PPIs
Although effective and safe, currently available PPIs
are still far from the ideal antisecretory compound. An
ideal drug should allow full acid control around the clock
and dose-dependent and predictable pharmacokinetic
and pharmacodynamic properties. These properties and
the consequent clinical effects should also be reproduc-
ible in a wide range of patient populations [87]. Finally,
an ideal agent will display high oral bioavailability, a rap-
id onset of action and few, if any, clinically relevant in-
teractions with food or concomitantly administered drugs
[88].
The so-called first-generation PPIs (omeprazole, pan-
toprazole and lansoprazole) have notable limitations.
These drugs exhibit substantial interpatient variability in
Scarpignato /Pelosini /Di Mario
02.05.2006 16:24:52
 pharmacokinetics or may have significant interactions
with other drugs. The time of dosing and ingestion of
meals may also influence the pharmacokinetics of these
agents as well as their ability to suppress gastric acid se-
cretion. First-generation PPIs also have a relatively slow
onset of pharmacological action and may require several
doses to achieve maximum acid suppression and symp-
tom relief, possibly limiting their usefulness in on-de-
mand GERD therapy. First-generation PPIs may also fail
to provide 24-hour suppression of gastric acid, and NAB
can occur even with twice-daily dosing [88].
Taking all the above considerations into account, it is
clear that there is room for improvement and a new gen-
eration of PPIs might be able to overcome the limitations
of first-generation compounds [89]. To obtain an ideal
PPI capable of achieving full inhibition of acid control
with the first dose, different avenues can be pursued. One
way is to develop a compound whose favorable metabo-
lism would allow an enhanced delivery of the active form
to the proton pump with consequent better inhibition of
acid secretion. Exploiting the stereospecific catabolism of
enantiomers follows that way.
The extension of plasma half-life is a critical factor in
improving the onset of action of PPIs and thus com-
pounds with a half-life longer than that of current PPIs
may be expected to display first-day efficacy. Such an av-
enue can be pursued through the synthesis of new chem-
ical entities with a molecular structure different from the
current (i.e. substituted benzimidazole) one or designing
a prodrug that will release the PPI in the bloodstream
[90]. Tenatoprazole, consisting of one imidazopyridine
ring connected to a pyridine ring by a sulfinylmethyl
chain [91], represents an example of a new chemical en-
tity with an extended half-life (about 8 h compared to
1.0–1.5 h), whereas compound D [90] is an investiga-
tional pro-PPI for very stable intravenous formulation
that displays a longer duration of action in comparison
with omeprazole. Some prodrugs synthesized recently hy-
drolyze under physiological conditions (pH = 7.4) to pro-
vide PPIs with a half-life largely exceeding the 2 h and
are capable of providing sustained plasma concentration
of the released PPI for a time longer than the currently
used compounds [92].
The development of potassium-competitive acid
blockers (P-CABs, previously called acid pump antago-
nists, APAs) is another active area of research in control-
ling intragastric pH. P-CABs such as the imidazopyri-
dines have thus far shown fast first-day onset as well as
improved control of day- and nighttime intragastric pH
with twice-daily dosing when compared to a once-daily
Update on Acid Suppression Therapy
DDI923.indd 17
PPI [93]. Although these drugs also target H+,K+-ATPase,
they act via a distinct mechanism: they bind the extracy-
toplasmatic surface and act as reversible K+-competitive
antagonists [93, 94].
From Omeprazole to Esomeprazole:
Why a Chiral Switch?
Rationalization within the pharmaceutical industry to
combat escalating costs has included the close examina-
tion of research portfolios. Gastroenterology has been one
of the casualties of this exercise and few companies cur-
rently retain a specific gastrointestinal research program
[95]. AstraZeneca, who discovered the first PPI more
than 20 years ago, synthesized and started the develop-
ment of esomeprazole (the magnesium salt of the S-iso-
mer of omeprazole) in 1990, making it available for clin-
ical practice worldwide at the beginning of the third mil-
lennium.
Taking into account that omeprazole comprises a ra-
cemic mixture of its two optical isomers, S-omeprazole
and R-omeprazole, and that S-omeprazole is optically
stable in humans with negligible inversion to the other
isomer [96], the R&D team decided to follow the first of
the avenues outlined above in order to obtain a PPI with
improved acid control. By following the methodology
(the so-called ‘Sharpless Epoxidation’) discovered by
K. Barry Sharpless, one of the three scientists who re-
ceived the 2001 Nobel Prize in Chemistry [97], they set
up the stereoselective synthesis of esomeprazole [98] and
were able to produce the isomer on a large scale.
Since all the currently available PPIs are racemic mix-
tures, the stereoisomers of other molecules (namely lan-
soprazole, pantoprazole, rabeprazole and the new non-
benzyimidazole compound, tenatoprazole) have been
isolated [99] and are being extensively investigated.
The Importance of Chirality in Pharmacology
Chiral molecules were one of the great discoveries of
Louis Pasteur, who observed in the mid-1800s that two
distinct crystal forms of tartaric acid would rotate polar-
ized light in opposite directions. Pasteur correctly postu-
lated that the two crystal forms were enantiomers, or
right- and left-handed mirror images of each other. The
Greek name kheir means ‘hand’. So, chirality indeed
means ‘handedness’. Enantiomers can be thought of as
left and right hands: although they are also mirror images
of each other, a left hand, for example, does not fit into a
right-handed glove. Following Louis Pasteur’s discover-
ies, the name was coined by the Irish physicist William
Thomson, alias Lord Kelvin.
Dig Dis 2006;24:11–46 17
02.05.2006 16:24:53

Structural isomers
(different bonding and structure)
Optical isomers or enantiomers
(not superimposable – mirror images)
S-isomer
Fig. 3. Different types of chemical iso-
mers.
Chirality is central to life, as many of the important
molecules come in two mirror-image forms that have very
different properties [100]. The fundamental molecules of
life, namely DNA and proteins, are, in fact, composed
respectively of right- and left-handed subunits only. Na-
ture often discriminates between chiral forms of small
molecules, too, and what is a medicine on the one hand
can be a poison on the other. One example of this is tha-
lidomide. Thalidomide, which was given to pregnant
women as a sedative and antinausea drug in the 1950s in
Europe, turned out to produce debilitating birth defects
(i.e. missing limbs or phocomelia) [101]. But, in fact, only
one enantiomer (i.e. the S-isomer) of the molecule is re-
sponsible for these effects [102].
Stereoisomers are molecules that are identical in atom-
ic constitution and bonding, but differ in the three-di-
mensional arrangement of the atoms. The stereoisomeric
pairs of greatest interest are those with one or more asym-
metric (chiral) centers whose enantiomers (individual ste-
reoisomers) are mirror images. According to an absolute
convention, known as the Sequence Rule notation, when
the peripheral groups are dimensionally arranged clock-
wise around the chiral center, the R (rectus) configuration
is assigned to the molecule. On the contrary, if they are
arranged counterclockwise around the chiral center, the S
(sinister) configuration is allocated.
Optical isomers have essentially identical physical (ex-
cept for optical rotatory) and chemical (except in a chiral
environment) properties. Such stereoisomers usually re-
quire specialized chiral techniques for their correct iden-
tification, characterization, separation and measurement.
They are often readily distinguished by biological sys-
tems, however, and may have different pharmacokinetic
properties (absorption, distribution, biotransformation
18 Dig Dis 2006;24:11–46
DDI923.indd 18
Isomers
Stereoisomers
(structurally the same but
different 3-dimensional arrangement)
Diastereoisomers
and geometric isomers
R-isomer
and excretion) and quantitatively or qualitatively differ-
ent pharmacologic or toxicologic effects [103–105]. Ste-
reoisomers include not only the mirror-image enantio-
mers, but also geometric (cis/trans) isomers and diaste-
reoisomers (isomers of drugs with more than one chiral
center that are not mirror images of one another, fig. 3).
Diastereoisomers and geometric isomers are both chem-
ically distinct and pharmacologically different (unless
they are interconverted in vivo) and are generally readily
separated without chiral techniques. Geometric isomers
and diastereoisomers therefore should, with the rare ex-
ception of cases where in vivo interconversion occurs, be
treated as separate drugs and developed accordingly
[100].
When stereoisomers are biologically distinguishable,
they might seem to be different drugs [103–105], yet it
has been past practice to develop racemates (i.e., com-
pounds with 50:50 proportion of enantiomers). The prop-
erties of the individual enantiomers have – in the past –
not generally been well studied or characterized. Wheth-
er separated enantiomers should be developed was
largely an academic question because commercial separa-
tion of racemates was difficult. Now that technological
advances (large-scale chiral separation procedures or
asymmetric syntheses) permit production of many single
enantiomers on a commercial scale, it is appropriate to
consider the development of the single enantiomer char-
acterized by the most favorable profile of activity (euto-
mer) [104, 105]. Any decision to develop a drug as a sin-
gle enantiomer, however, should be made only after care-
ful evaluation of the cost-benefit ratio, i.e. when the
advantages of the eutomer in terms of efficacy and toler-
ability outweigh the associated increase in production
and development costs with respect to the racemic drug
Scarpignato /Pelosini /Di Mario
02.05.2006 16:24:53
 [106]. Development of racemates raises issues of accept-
able manufacturing control of synthesis and impurities,
adequate pharmacologic and toxicologic assessment,
proper characterization of metabolism and distribution,
and appropriate clinical evaluation [107].
From a theoretical standpoint, some stereochemical
aspects of drug therapy should be taken into account [108,
109]. For chiral drugs, one of the entantiomers can:
• be inactive (e.g. S-loxiglumide) or less active (e.g.
R-warfarin),
• display a quantitatively different pharmacological ef-
fect. The presence of the inactive or less active isomer
is often responsible for the greater variability observed
with racemates,
• have a different metabolic pattern,
• have an antagonistic effect,
• or be, actually, toxic.
Since no drug is completely devoid of adverse effects,
recent interest has focused on the role of the different
properties of individual drug enantiomers in causing drug
toxicity [110]. Several examples of stereoselective toxic-
ity are available in the literature. Vomiting, for instance,
is caused merely by the R-isomer of levamisole [111].
Myasthenia gravis symptoms were no longer observed
when the R-isomer was removed from the racemic mix-
ture of carnitine [112]. Only the S-isomer has been linked
to the teratogenic effects of thalidomide [102].
Development of Esomeprazole
In accordance with results of clinical trials in acid-re-
lated diseases [7, 74], where often different but somewhat
equipotent doses of the different PPIs have been used,
data from experimental pharmacological studies clearly
show that – on a milligram basis – the available com-
pounds display the same potency and efficacy [76]. Since
both R- and S-isomer of omeprazole are able to inhibit
acid secretion in isolated gastric glands to the same degree
[113], there should be no pharmacodynamic benefit in
using one stereoisomer instead of the racemate. Both en-
antiomers (which are chiral sulfoxides) will give rise –
within the secretory canaliculus – to the same reactive
species, sulfenamide, which is achiral (fig. 2). There is
therefore no pharmacodynamic reason why the racemate
or any of its enantiomers should differentially interact
with the proton pump [9].
Although the use of a PPI enantiomer does not confer
any direct advantage in vitro, the pharmacokinetic (and
pharmacodynamic) consequences of stereoselective drug
metabolism might anyway affect drug activity in vivo
[114, 115]. The metabolism of substituted benzimid-
Update on Acid Suppression Therapy
DDI923.indd 19
azoles is to a larger or lesser extent (e.g. for rabeprazole)
dependent on hepatic cytochrome P450 (CYP) isoforms,
CYP3A4 and CYP2C19 [7, 73, 116]. These heme-con-
taining enzymes are abundantly expressed in hepato-
cytes, where they exist in the smooth endoplasmic reticu-
lum in association with a number of accessory proteins.
There, the cytochromes P450 catalyze the multistep oxida-
tion reactions that inactivate xenobiotics by the intro-
duction or exposure of a functional group on their sub-
strate. The dependence of most PPIs on metabolism by
CYP2C19 makes them susceptible to alterations in bio-
availability due to genetic polymorphisms affecting the
activity of this enzyme [73, 117]. In particular, omepra-
zole is transformed into three pharmacologically inactive
metabolites, i.e. omeprazole sulfone and 5-hydroxy- plus
5-O-desmethyl-omeprazole, respectively. Studies per-
formed in healthy volunteers [118], human liver micro-
somes and cDNA-expressed enzymes [119] have shown
a significant stereoselectivity in the metabolism of
omeprazole enantiomers. The R-isomer is almost exclu-
sively metabolized (98%) via CYP2C19, 94% transform-
ing to the 5-hydroxy metabolite, and 4% to the 5-O-des-
methyl metabolite. Only 2% of the metabolism is via the
CYP3A4 isoform. The S-isomer (esomeprazole) is me-
tabolized primarily (73%) via the CYP2C19 isoform
(46% going to the 5-O-desmethyl metabolite, 27% go-
ing to the 5-hydroxy metabolite), and by 27% via the
CYP3A4 isoform to the sulfone metabolite. The intrin-
sic clearance (CL) of S-omeprazole is approximately one
third of that of R-omeprazole, because of the considerably
lower CL for formation of the 5-hydroxy metabolite (15
vs. 43 l
min/mg protein) via CYP2C19 [120]. This im-
plies that the total metabolic clearance for S-omeprazole
is lower than that for R-omeprazole, resulting in higher
plasma levels of the S-isomer in vivo (fig. 4). These data
suggest that, in vivo, S-omeprazole should undergo a low-
er first-pass effect thus leading to higher plasma levels and
consequent better availability. Since the area under time-
concentration curve correlates with secretory inhibition
[121], the S-isomer should be capable of achieving a bet-
ter acid control compared with the racemic mixture (i.e.
omeprazole). The available in vivo pharmacokinetic,
pharmacodynamic and clinical data all show that this is
the case [122–125].
The stereoselective metabolism of lansoprazole [126–
128], pantoprazole [129, 130] and rabeprazole [131] has
also been studied and consistently revealed significant
quantitative differences between isomers. The stereoiso-
mers of some of these PPIs are being extensively studied.
In particular a new modified release formulation of the
Dig Dis 2006;24:11–46 19
02.05.2006 16:24:53

1,600
1,400
Concentration (nmol/l)
1,200
1,000
800
600
400
200
0 racemates more commercially attractive than the high
0 2
Time (h)
Fig. 4. Plasma concentration vs. time at steady state (day 7) of
omeprazole, S-omeprazole and R-omeprazole in four extensive
metabolizers after intake of 15 mg of each compound (from Ander-
sson et al. [120]).
R-isomer of lansoprazole (compound marked TAK-
390MR) is now in phase III development [132] and 7
clinical trials in GERD (registered at www.clinicaltrials.
gov) are ongoing in the USA [133]. Actually, the Food
and Drug Administration (FDA) granted the permission
to move directly to phase III without going through phase
II based on the results of the phase I studies. This R-
isomer was selected either because of its higher plasma
concentrations [126] and lower clearance [127] and be-
cause – besides being the most potent inhibitor of
CYP2C19 enzyme – S-lansoprazole also inhibits CY2C9
and CYP2D6 activities [134]. These properties make the
S-isomer an unsuitable drug for the treatment of acid-re-
lated diseases for its large drug interaction potential. By
the way, NSAIDs – amongst other drugs – represent one
of the most important substrates of CYP2C9 [135]. Being
NSAID-associated symptoms and mucosal lesions are
one of the clinical indications of PPIs, the use of S-lanso-
prazole concomitantly with NSAIDs would need great
caution or be actually contraindicated.
While chirality with the elegance of its underlying con-
cepts is certainly fascinating, the demonstration that chi-
ral switching provides superior clinical benefits (either in
terms of efficacy, safety or economy) is difficult. Although
esomeprazole is considered by some [124, 125, 136] a true
therapeutic advantage and a cost-effective treatment for
acid-related diseases [137], others [138–140] have ques-
tioned its superiority over other PPIs, including omepra-
zole.
20 Dig Dis 2006;24:11–46
DDI923.indd 20
Chiral switching is a rational but undesirable response
of manufacturers to patent expiration. When patents on
Omeprazole commercially successful drugs approach their expiry
dates, the development of a stereoisomer enables compa-
S-omeprazole
R-omeprazole
nies to maintain market share and high prices despite
generic competition. Indeed, the zealously guarded pat-
ent monopoly system provides the same exclusivity and
market protection to an enantiomer of an existing prod-
uct as it does to a new chemical entity. This makes the
development and marketing of stereoisomers of existing
4 6 costs, uncertainties and risks of developing genuine in-
novative compounds [141]. It would be desirable and in
some ways ethical to explore from the very beginning the
pharmacokinetics and pharmacodynamics of enantio-
mers and start the development of the more attractive
isomer (eutomer) right away.
Inhibition of Acid Secretion:
Where Are We Going?
Unmet Needs in Acid Suppression
The dramatic success of pharmacological acid sup-
pression in healing ulcers and managing patients with
GERD has been reflected in the virtual abolition of elec-
tive surgery for ulcer disease [142], a reduction in NSAID-
associated gastropathy [143], and the decision by most
patients with reflux symptoms to continue medical ther-
apy rather than undergo surgical intervention.
However, a number of challenges remain in the man-
agement of acid-related disorders. These include manage-
ment of patients with gastroesophageal symptoms who do
not respond adequately to PPI therapy, treatment of pa-
tients with nonvariceal upper gastrointestinal (GI) bleed-
ing, prevention of stress-related mucosal bleeding, opti-
mal treatment and prevention of NSAID-related GI in-
jury, and optimal combination of antisecretory and
antibiotic therapy for the eradication of H. pylori infec-
tion [144, 145].
As outlined before, PPIs have a number of shortcom-
ings, which stem from their pharmacology. However,
there is increasing evidence of both inappropriate pre-
scribing and inappropriate use of these drugs. An expand-
ing proportion of patients have indeed poor indication to
acid suppression. Not uncommonly, empiric therapy in
nonexplored and functional dyspepsia is based upon PPI
therapy, standard or high dose for 2–4 weeks. If symptom
resolution is limited and patient dissatisfaction contin-
ues, often the dose is doubled. Upon sudden arrest of such
Scarpignato /Pelosini /Di Mario
02.05.2006 16:24:54
 therapy because of insufficient symptom relief, rebound
acid secretion may reactivate GERD-like/dyspeptic
symptoms leading to a vicious circle [144]. There is a stag-
gering lack of clear instructions in practice concerning
empirical therapy. That PPIs are often taken inappropri-
ately is revealed by a US survey [146] showing that only
27% of GERD patients dosed their PPI correctly (i.e. up
to 60 min before any meal of the day) and only 9.7% dosed
it optimally (i.e. 15–60 min before the first meal of the
day). Furthermore, in a study of 1,046 primary care phy-
sicians across the USA [147], only 36% of them did give
their patients advice on when and how to take their med-
ication.
Although a proper education can improve PPI use and
effectiveness, currently available drugs have their own
shortcomings. To overcome these limitations, novel for-
mulations of currently available PPIs [92, 148] and nov-
el PPIs [149] are being developed. In addition, new ave-
nues (i.e., competitive blockade of proton pump at K+
exchange sites [93] or blockade of CCK2, e.g. gastrin re-
ceptors on the parietal and ECL cells [150]) are being ex-
plored.
In this section, the new PPI formulations currently
under development or recently introduced in clinical
practice as well as the novel acid-lowering drugs, which
have already reached clinical testing, will be discussed.
New PPI Formulations
Some interesting new PPI formulations have recently
been patented by AstraZeneca [92]. An enteric-coated,
extended-release dosage form of a PPI provided an ex-
tended plasma concentration profile of the drug for a pe-
riod of up to 12 h. This pharmacokinetic profile is ob-
tained with a formulation comprising a core material of
a hydrophilic or hydrophobic matrix containing the PPI
protected by enteric coating. An additional patent de-
scribes a multilayered tablet capable of releasing the PPI
in discrete pulses, separated in time (2 pulses of drug re-
lease at least 0.5 h apart). The dosage form, which has one
fraction with instant release of the drug and at least an-
other fraction with a pulsed delayed release, is intended
for once-daily administration [92]. The bioavailability
and pharmacokinetic profile of these formulations have
not yet been studied in humans and it is presently un-
known whether they will assure a better and longer lasting
control of intragastric pH compared with the currently
available PPI formulations.
A Micropump™ technology, which permits either ex-
tended or both delayed and extended delivery of drugs to
the small intestine, has been developed by Flamel Tech-
Update on Acid Suppression Therapy
DDI923.indd 21
nologies (Vénissieux, France) and applied in cooperation
with TAP Pharmaceutical Products Inc. (Lake Forest, Ill.,
USA) (a joint venture between two global pharmaceutical
leaders, Abbott and Takeda Pharmaceutical Co. Ltd) to
lansoprazole [151]. This technology consists of a multi-
ple-dose system containing 5,000–10,000 microparticles
per capsule or tablet. The 200- to 500-m diameter-sized
microparticles are released in the stomach and then pass
into the small intestine, where each microparticle, operat-
ing as a miniature delivery system, releases the compound
by osmotic pressure at an adjustable rate and over an ex-
tended period of time. The design of the Micropump™
microparticles allows an extended transit time in the
small intestine with a plasma mean residence time ex-
tended up to 24 h. Thanks to the microparticles’ size,
these formulations are easy to swallow, well tolerated and
taste masking.
Another proprietary controlled-release formulation
(the so-called ChroNAB delivery technology) has been
developed by AGI Therapeutics Ltd (Dublin, Ireland)
and applied to currently available PPIs in order to mod-
ify their pharmacokinetics allowing for a better acid con-
trol, especially during the night when the NAB occurs
[152]. One such formulation, namely AGI 010, is cur-
rently undergoing clinical testing.
Currently available PPIs are orally administered as
gastroprotected preparations. The different enteric coat-
ings, which are necessary to protect the acid-labile PPI
from acid degradation within the stomach, have the po-
tential disadvantage of delaying PPI absorption and, as a
consequence, the available PPI formulations are consid-
ered delayed-release (DR) preparations.
DR oral dosage forms are supplied as enteric-coated
granules encapsulated in a gelatine shell (e.g. omeprazole
capsules and lansoprazole capsules) or as enteric-coated
tablets (e.g. pantoprazole tablets, rabeprazole tablets and
omeprazole multiple-unit pellet system [MUPS]). An al-
ternative oral formulation of lansoprazole – the lansopra-
zole orally disintegrating tablet (ODT) – has recently been
developed and introduced into clinical practice. It is easy
to swallow and can be taken orally with or without water.
This feature greatly improves compliance when patients
are away from home (and water is not readily available)
and in those patients with odynophagia or dysphagia as
well as swallowing disorders. In addition, when this for-
mulation is dispersed in water, it provides a less expen-
sive alternative to intravenous PPIs for patients with na-
sogastric or gastric tubes in ICU or long-term care settings
[153]. Some studies (reviewed by Horn and Howden
[154]) have evaluated PPI absorption from intact nonen-
Dig Dis 2006;24:11–46 21
02.05.2006 16:24:54

7 much smaller microgranules than lansoprazole capsules
4
3
1 in lansoprazole capsules, which have a core, a lanso-
2
5
6 lansoprazole ODT microgranule comprises seven layers
Fig. 5. Structure/composition of enteric-coated microgranules used
to make LFDT (thickness of each layer is not to scale). 1 = Inert
core; 2 = lansoprazole layer; 3 = undercoating layer – improves sta-
bility in high humidity; 4 = first enteric-coating layer – improves
stability of lansoprazole; 5 = second enteric-coating layer – prevents
breakage of the enteric coats during tablet compression; 6 = third
enteric-coating layer – neutralizes taste of microgranule; 7 = over-
coating layer – improves tablet hardness (from Baldi and Malfert-
heiner [156]).
capsulated omeprazole or lansoprazole as well as their
suspension in sodium bicarbonate (8.4%) solution. Al-
though, with exception of the so-called simplified omepra-
zole suspension (SOS) whose bioavailability was im-
paired, the other ‘extemporary’ formulations allowed a
proper PPI absorption, predisintegrated lansoprazole
ODT would represent the most appropriate choice for
administration via nasogastric or gastrostomy tube.
Most PPI tablets (e.g. rabeprazole) are formulated as
an enteric-coated, single-unit system, that is, a tablet with
a gastric acid-resistant layer only on its outer surface.
There is a risk that the enteric coat of such tablets can
become damaged during gastric emptying. As PPIs are
acid-labile, a small crack or damage to a single-unit sys-
tem may, therefore, affect the entire dose. Multiple-unit
systems have been developed to overcome this problem
[155]. Common formulations of multiple-unit systems in-
clude both capsules and tables containing enteric-coated
granules. The very small size and multiple coatings of
these granules mean that they are less likely to be dam-
aged during gastric emptying, and absorption issues are
therefore minimized. If a granule is damaged and a crack
develops on the surface, only a small portion of active
substance is likely to be affected. The lansoprazole cap-
sule and omeprazole MUPS are examples of multiple-
unit systems. While enteric coating of oral formulations
is beneficial for ensuring that PPI agents are effectively
delivered, it does mean that the individual dose admin-
22 Dig Dis 2006;24:11–46
DDI923.indd 22
istration unit, be it a tablet or a granule-containing cap-
sule, is relatively large. The lansoprazole ODT contains
(330 vs. 1,100 g). The tablet disintegrates rapidly (with-
in 30 s) in the mouth without water. Unlike the granules
prazole layer and a gastroresistant enteric coating, each
(fig. 5). The active lansoprazole layer surrounds an inert
core, followed by an inert under the coating layer that
improves stability in high humidity. Three enteric-coat-
ing layers prevent dissolution in the stomach, improve
stability, reduce damage during compression and neutral-
ize the taste of the microgranule. An outer layer increases
the hardness of the tablet [156, 157]. When lansoprazole
ODT disintegrates in the mouth the microgranules are
swallowed with the patient’s saliva. The enteric-coated
microgranules dissolve in the neutral condition of the
small intestine and lansoprazole is absorbed into the
bloodstream. However, absorption kinetics still depends
on the enteric coating; the oral pharmacokinetics of lan-
soprazole after dosing with the ODT is essentially identi-
cal to that observed after dosing with capsules of enteric-
coated granules [158]. The bioequivalence between these
two formulations will translate into a similar pharmaco-
dynamics and clinical efficacy. And indeed, despite that
the formulation was preferred by a higher proportion of
patients, no significant difference in symptom relief be-
tween lansoprazole ODT and other PPIs (namely esome-
prazole) was found in NERD [159].
Conversely from lansoprazole ODT, the recently
FDA-approved immediate-release (IR) omeprazole for-
mulation displays a different pharmacokinetics and phar-
macodynamics compared with the standard, DR prepa-
ration [148]. This formulation consists of pure, nonen-
teric-coated omeprazole powder (40 or 20 mg per unit
dose) along with 1,680 mg of sodium bicarbonate (con-
taining 460 mg of sodium). It is flavored with peach and
peppermint and is designed be constituted with water to
be drunk.
Besides sachets, capsules containing 40 or 20 mg of
omeprazole are also available, while a chewable tablet
formulation has been developed and an NDA (new
drug application) already submitted to FDA [160]. It is
important to distinguish IR omeprazole (IR-OME) for-
mulation from the SOS (see above). While IR-OME has
no form of enteric coating, SOS is prepared by opening
standard capsules of DR omeprazole (DR-OME), drop-
ping the granular contents into 8.4% sodium bicarbonate
solution and agitating the mixture until the enteric coat-
Scarpignato /Pelosini /Di Mario
02.05.2006 16:24:54
 900 8 IR-OME 40 mg
Omeprazole concentration (ng/ml)

IR-OME (n = 7)
800 DR-OME (n = 10) Pantoprazole 40 mg
7
700 Median pH 4.7 ✽
6
600

Gastric pH
5
500
400 4

300 3
Median pH 2.0
200 2
100 1
0
0
0 1 2 3 4 5 6
23:00 24:00 02:00 04:00 06:00
a Time post-dose (h)
Time (24-hour clock)

Dose Meal

8 Day 7 Fig. 7. Eight-hour nighttime period gastric pH on day 6 demon-

7
Baseline strated that once-daily dosing with IR-OME produced significantly
better nocturnal gastric acid control than once-daily DR pantopra-
6 zole in a crossover study in 32 GERD patients. * p ! 0.001 IR-OME
vs. pantoprazole (from Castell et al. [164]).
Gastric pH

2
1
0 tion caused an immediate increase in pH. From 4 to 6 h
0 3 6 9 12
b Time (h)
Fig. 6. Pharmacokinetics and pharmacodynamics of IR-OME in
healthy volunteers. a Mean plasma concentration from fasting sub-
jects with IR-OME (40 mg, n = 7) and DR capsules (40 mg, n = 10)
(from Hepburn and Goldlust [161]). b Effect of 7 days of once-
daily dosing with the IR formulation (40 mg, n = 24) on 24-hour
intragastric pH (from Howden [162]).
ing of the granules disintegrates and a suspension formed.
Due to the impaired absorption of omeprazole from this
extemporary preparation [154], a lower than expected an-
tisecretory effect can be predicted.
The pharmacokinetics of IR-OME has been studied in
healthy volunteers given 40 mg of both formulations in a
crossover fashion [161]. While the AUC was not signifi-
cantly different, the Cmax was higher and the Tmax shorter
with the IR formulation (fig. 6). As with the DR capsules,
both Cmax and AUC but not Tmax increased between 1
and 7 days of once-daily dosing with IR-OME, indicating
an increase of bioavailability over time.
In a crossover trial, the effect of both formulations on
intragastric acidity was investigated in healthy volun-
teers. Within the first 30 min, DR-OME had no measur-
able activity on intragastric pH, whereas the IR formula-
15 18 21 24
after ingestion, there was a 27% reduction from baseline
in intragastric activity with DR-OME and 65% decrease
with the IR formulation (fig. 6) [162]. Therefore, the an-
tisecretory effect of IR-OME was quicker than that ob-
served with the classical DR formulation while the dura-
tion of the acid-lowering activity was similar. The early
increase in intragastric pH is likely due to the neutralizing
capacity of sodium bicarbonate, which also accelerates
and enhances absorption of omeprazole whose increased
bioavailability translates into a more profound acid sup-
pression.
As already discussed, NAB is a common physiological
event, observed in approximately 70% of both healthy
subjects and GERD patients treated with up to twice-
daily administration of DR PPIs, regardless of whether
the PPI is administered in the morning, prior to dinner,
or at bedtime [163]. Bedtime dosing with 40 mg of IR-
OME suspension provides better control of nocturnal
gastric acidity than once-daily dosing with all DR PPIs
(fig. 7) [164, 165] and also decreases NAB more effec-
tively than with dosing of DR-OME 20 mg b.d. and lan-
soprazole 30 mg b.d. or pantoprazole 40 mg b.d. Night-
time control of gastric acidity with IR-OME suspension
is comparable with that achieved by twice-daily dosing of
DR esomeprazole 20 mg [164, 165].

Update on Acid Suppression Therapy Dig Dis 2006;24:11–46 23

DDI923.indd 23 02.05.2006 16:24:54

 N NH CH3 H3CO NH CH3
OCH3 N OCH3
N S N S

a O N b O N
CH3

Ilaprazole (IY-81149) Tenatoprazole (TU-199)

2-(RS)[4-methoxy-3-methyl)-2-pyridinyl]methyl- (RS)-5-methoxy-2-[[(4-methoxy-3,5-dimethylpyrid-2-yl)
sulfinyl]-5-(1H-pyrol-1-yl)-1H-benzimidazole methyl]sulfinyl]-1H-imidazo[4,5b]pyridine
[CAS Registry No. 172152-36-2] [CAS Registry No. 113712-98-4]

Fig. 8. Chemical structure of ilaprazole (a) and tenatoprazole (b), two novel PPIs, currently under active develop-
ment. Note that ilaprazole belongs – like the other PPIs – to benzimidazole compounds whereas tenatoprazole
represents a different chemical entity.

Being easy to administer through a nasogastric tube, Novel PPIs

IR-OME was also studied for its ability to control intra-
gastric pH in critically ill patients [166, 167]. A random-
ized, double-blind trial [168] found this formulation more
effective than intravenous cimetidine (the only FDA-ap-
proved drug for this indication) in maintaining gastric pH
14 and similarly effective in preventing upper GI bleed-
ing without increasing the incidence of pneumonia.
Several studies [162] have shown that antacids do not
have a major effect on the absorption or disposition of
DR PPIs. On the contrary, addition of sodium bicarbon-
ate to uncoated omeprazole clearly affects its pharmaco-
kinetics and pharmacodynamics. The putative mecha-
nism of action to explain these observations is as follows
[162]. Following ingestion of IR-OME as an oral suspen-
sion, the sodium bicarbonate causes a prompt rise in in-
tragastric pH. While this serves the primary function of
protecting the uncoated omeprazole from acid degrada-
tion within the stomach, it may also provide a temporary
stimulus to gastrin release from antral G cells. Sodium
bicarbonate solution has previously been shown to raise
circulating gastrin levels within 30 min of oral ingestion
[169, 170]. The rise in circulating gastrin may stimulate
the parietal cell mass and promote the insertion of func-
tioning molecules of H+,K+-ATPase into the secretory
canaliculi. Since the peak plasma concentration of
omeprazole occurs around 30 min after ingestion of IR-
OME, this allows for the rapid uptake of circulating
omeprazole by activated parietal cells leading to irrevers-
ible inhibition of a large proportion of available proton
pumps. This sequence of events may explain both the ra-
pidity of onset of the antisecretory effect and its pro-
longed duration.
Several new PPIs have been synthesized since the dis-
covery of omeprazole. The majority of them are still in
preclinical development or have been abandoned. This is
for instance the case of leminoprazole [171], whose de-
velopment has been interrupted despite the interesting
pharmacological profile showing also a peculiar mucosal-
protective activity of the drug [172, 173]. Only two drugs
are actively being studied in humans, namely ilaprazole
and tenatoprazole, and will be reviewed in detail.
Ilaprazole (compound marked IY-81149, fig. 8) is a
benzimidazole compound synthesized at Il-Yang (South
Korea) and presently developed by TAP Pharmaceutical
Products Inc. (Lake Forest, Ill., USA). Although the drug
is already on the market in South Korea, phase II clinical
trials will start soon in the USA.
Studies performed on rabbit isolated parietal cells
[174] have shown that ilaprazole irreversibly inhibits
H+,K+-ATPase and aminopyrine accumulation in a dose-
dependent manner with a potency comparable to that of
omeprazole. In vivo investigations [174–176] evaluated
the antisecretory activity of the compound, which proved
to be 2–3 times stronger than that of omeprazole. In a
model of experimentally-induced esophagitis in the rat
[176], both ilaprazole and omeprazole prevented the de-
velopment of esophagitis and reduced gastric acid secre-
tion in a dose-dependent manner. The antisecretory ac-
tivity of this novel PPI was confirmed in GERD patients
where the drug, at 10 and 20 mg daily, provided a great-
er and prolonged suppression of acid secretion compared
to omeprazole [177]. Since a half-life of 3.6 h (i.e. longer
than that of omeprazole) has been reported in healthy
volunteers [178], the improved pharmacodynamic activ-

24 Dig Dis 2006;24:11–46 Scarpignato /Pelosini /Di Mario

DDI923.indd 24 02.05.2006 16:24:55

 ity could reflect the improved pharmacokinetics of the
drug. It should be pointed out, however, that ilaprazole
displays an inhibitory effect on cytochrome P450 enzymes,
as revealed by its dose-dependent ability to prolong hexo-
barbital-induced sleeping time in mice [175].
Tenatoprazole (compound also marked TU-199) has
been developed by Mitsubishi Pharma in Japan [91] and
is now under active development by Negma-Gild (France).
Conversely from all the other PPIs, this compound is not
a benzimidazole derivative, consisting of one imidazo-
pyridine ring connected to a pyridine ring by a sulfinyl-
methyl chain (fig. 8). It represents therefore a new chem-
ical entity. In vitro studies, performed in hog and dog
gastric microsomes, have shown that tenatoprazole dis-
plays an inhibitory action on proton pump comparable
to that of omeprazole and lansoprazole [179]. The inhib-
itory activity of this novel compound on gastric H+,K+-
ATPase has been thoroughly characterized by George
Sachs’ team [180, 181]. Like the other PPIs, tenatoprazole
is a prodrug (pKa = 4.04), which is converted to the ac-
tive sulfenamide or sulfenic acid by acid in the secretory
canaliculus of the stimulated parietal cell of the stomach.
This active species binds to luminally accessible cysteines
of the gastric H+,K+-ATPase resulting in disulfide forma-
tion and acid secretion inhibition. Tenatoprazole binds
at the catalytic subunit of the gastric acid pump with a
stoichiometry of 2.6 nmol/mg of the enzyme in vitro. In
vivo, maximum binding of tenatoprazole was 2.9 nmol/
mg of the enzyme at 2 h after intravenous administration.
The binding sites of tenatoprazole were at cysteine 813
and cysteine 822 as shown by tryptic and thermolysin
digestion of the ATPase labeled by tenatoprazole. Both
of these sites are located in the proton transport pathway,
though cysteine 822 is found deeper in the TM5/6 mem-
brane domain than cysteine 813. Decay of tenatoprazole
binding on the gastric enzyme consisted of two compo-
nents. One was relatively fast, with a half-life 3.9 h due
to reversal of binding at cysteine 813 and the other was a
plateau phase corresponding to ATPase turnover reflect-
ing binding at cysteine 822 that also results in sustained
inhibition in the presence of reducing agents in vitro
(fig. 9).
The in vivo antisecretory potency of tenatoprazole,
evaluated in different animal models (Shay rat prep-
aration, acute fistula rats and Heidenhain pouch dogs),
proved to be 2–4 times higher than that observed with
omeprazole. As a consequence, the healing activity of the
compound on experimentally-induced gastric and duode-
nal ulcers appeared similarly higher [179]. Conversely
from omeprazole, which delays gastric emptying [182],
Update on Acid Suppression Therapy
DDI923.indd 25
4.00
3.50
TPZ bound (nmol/mg)
3.00
2.50
2.00
1.50
1.00
0.50
0
0 4 8 12 16 20 24
Time (h)
Fig. 9. Time course of loss of 14C-tenatoprazole binding to the
H+,K+-ATPase. Radioactive tenatoprazole was administered intra-
venously at 0.1 mCi/kg of animal with a dosage of 20 mol/kg
through the tail vein. The rats were sacrificed at 1, 2, 6, 12 and
24 h. Each point refers to the mean (8SD) of the values obtained
from 4 to 6 animals. After maximum binding of tenatoprazole, te-
natoprazole binding up to 24 h post-dose in vivo could be described
by a first exponential equation: C(TPZ) = 1.824e–0.176t + 1.141. This
first component is mainly from a fast decay with a half-life 3.9 h
and the plateau of 1.141 at 24 h post-dose is related to binding that
decays with a half-life corresponding to enzyme turnover (
54 h)
(from Shin et al. [180]).
tenatoprazole was unable to affect emptying rate [183].
In addition, experiments carried out in dogs with gastric
fistula revealed an elevation of intragastric pH lasting lon-
ger (by 20%) than that observed with omeprazole or lan-
soprazole [184].
Pharmacokinetic studies, performed in Japanese sub-
jects, showed a 7-fold longer half-life (7.6 and 13.7 h after
single and repeated administration of 20 mg, respective-
ly), compared to the other PPIs. As a consequence, the
area under the concentration-time curves, that reflect tis-
sue exposure, was about 20-fold higher after single oral
administration of 20 and 40 mg of the drug (24.50 and
67.76 mg
h/ml, respectively) [185]. These pharmacoki-
netic properties translated into a long-lasting antisecre-
tory action. Indeed, inhibition of basal and tetragastrin-
stimulated acid output in healthy volunteers was still sig-
nificant 2 days after tenatoprazole administration.
Intragastric pH recordings, performed after repeated ad-
ministration of a dose as low as 10 mg of the drug, did
show that the time spent above pH 3 and pH 4 reached
96.7 and 88.0%, respectively. The most interesting find-
ing was the prolonged effect of tenatoprazole during
nighttime, since the % of pH holding time above 3 and 4
was almost identical during this period compared to day-
Dig Dis 2006;24:11–46 25
02.05.2006 16:24:55

12,000
10,000
Cmax (ng/ml)
Fig. 10. Pharmacokinetics of tenatoprazole
after repeated (7 days) oral administration
in healthy volunteers. Both Cmax and AUC
show a linear correlation with the dose ad-
ministered. Each point refers to the mean
(8SEM) of the values obtained from 8 sub-
jects (drawn from data in Domagala and
Ficheux [188]).
Table 2. Comparison between pharmacokinetic parameters ob-
tained in Japanese or European healthy volunteers after single oral
administration of 20 mg tenatoprazole (from data in the Investiga-
tor’s Brochure [185] and Domagala and Ficheux [188])
Pharmacokinetic Japanese subjects Caucasian subjects
parameter (n = 6) (n = 8)
Cmax, g/ml 4.2=0.6 2.980.8
tmax, h 2.580.2 2.581.0
t½, h 13.783.0 7.882.0
AUC, g
h/ml 59.2813.0 31.0813.0
Each value represents the mean (8SD) of the values obtained
in 6–9 subjects.
time (94.7 vs. 98.3% and 86.3 vs. 89.3%, respectively)
[185].
The compound was originally discovered by Mitsubi-
shi Pharma and was therefore first studied in Japanese
subjects. Pharmacokinetic (and consequently pharmaco-
dynamic) differences between East Asians and Cauca-
sians are well known, being mainly due to genetic poly-
morphism of several phase I enzymes such as CYP2D6
and the CYP2C subfamily [186]. Since the pharmacoki-
netics and pharmacodynamics of PPIs depend on
CYP2C19 genotype status, CYP2C19 genotype-depen-
dent differences in pharmacokinetics and pharmacody-
namics of PPIs influence the cure rates for the GERD and
H. pylori infection by PPI-based therapies [187]. Phar-
macokinetics of tenatoprazole was thus re-investigated in
H. pylori-negative healthy Caucasian subjects in a ran-
domized, double-blind, dose-ranging study (10–80 mg,
26 Dig Dis 2006;24:11–46
DDI923.indd 26
14,000 y = –191.17 + 149.01x 300,000 y = –2.5215e+4 + 2953.7x
r2 = 0.998 r2 = 0.983
250,000
AUC (ng
h/ml)
200,000
8,000
150,000
6,000
100,000
4,000
2,000 50,000
0 0
0 20 40 60 80 100 0 20 40 60 80 100
Dose (mg) Dose (mg)
either single and repeated administration). A linear cor-
relation between tenatoprazole dose and AUC was found,
thus showing a linear pharmacokinetic pattern (fig. 10).
The long half-life of tenatoprazole was confirmed for ev-
ery dose, reaching 8.7 8 2.6 h for repeated administra-
tion of 40 mg [188]. A comparison of pharmacokinetic
parameters between Asian and European subjects is
shown in table 2.
Pharmacodynamic studies on the same subjects
showed an increase of intragastric pH with tenatoprazole
40 mg daily for 7 days significantly higher (p ! 0.05) than
that observed with the same regimen of esomeprazole, the
median pH being 4.6 8 0.9 and 4.2 8 0.8, respectively
[189]. In addition, the time spent above pH 4 during
nighttime after tenatoprazole administration was signifi-
cantly longer than that observed with esomeprazole (table
3). The intragastric pH during the night was similarly
higher (4.7 8 1.1 units with tenatoprazole and 3.6 8 1.4
units with esomeprazole, p ! 0.01) [189]. The better con-
trol of intragastric acidity achieved with tenatoprazole
during the night was already evident from the first 24 h
of dosing [190].
A recent pharmacodynamic and pharmacokinetic in-
vestigation [191] confirmed and extended previous data
showing the prolonged duration of acid suppression with
tenatoprazole (fig. 11). The proportion of healthy volun-
teers spending at least 16 h above pH 4 in the 24-hour
period was remarkably higher with tenatoprazole than
with esomeprazole (81.5 vs. 34.5%, p ! 0.001), while the
proportion of subjects with NAB was lower (73.1 vs.
93.1%, p = 0.06), although the difference fell short of sta-
tistical significance. Even 3 days after treatment was dis-
continued, mean 24 h pH, and percentage of time at pH
13 and pH 14 were significantly higher with tenatopra-
Scarpignato /Pelosini /Di Mario
02.05.2006 16:24:56
 pH
8

7 Tenatoprazole 40 mg Esomeprazole 40 mg
6

1 pH = 4

0
8 10 12 14 16 18 20 22 24 2 4 6 8
Time (h)

Fig. 11. Mean 24-hour intragastric pH profiles (on day 7) in 30 H. pylori-negative healthy volunteers giving te-
natoprazole (40 mg) or esomeprazole (40 mg) orally once a day. It is evident that the mean duration of NAB is
shorter on tenatoprazole than on esomeprazole (4.3 vs. 6.5 h, p ! 0.0001) (from Hunt et al. [191]).

Table 3. Intragastric acidity in healthy

volunteers given esomeprazole or Esomeprazole Tenatoprazole Tenatoprazole
tenatoprazole once daily for 7 days. 40 mg 20 mg 40 mg
Percentage of time spent above pH 4
on day 7. Each value refers to the mean 24 h (08:00–08:00 h) 56.2816.5 50.9811.1 63.3817.8*
(8SEM) of the values obtained from Daytime (08:00–20:00 h) 65.6817.7*** 47.2812.0 62.2818.5*
18 H. pylori-negative subjects (from Nighttime (20:00–08:00 h) 46.8819.7 54.6814.0 64.3821.7**
Galmiche et al. [189])
Tenatoprazole 40 mg vs. tenatoprazole 20 mg: * p < 0.01.
Tenatoprazole 40 mg vs. esomeprazole 40 mg: ** p < 0.01.
Esomeprazole 40 mg vs. tenatoprazole 20 mg: *** p < 0.01.

zole, indicating a sustained control of intragastric acidity
with this novel PPI compared to esomeprazole. After 7
days of repeated dosing the maximal plasma concentra-
tion of tenatoprazole was almost 6 times higher than that
of esomeprazole, while AUC was 32 times higher. A sig-
nificant correlation between AUC and percentage of time
intragastric pH 14 was observed with tenatoprazole not
only during but also after stopping treatment [191].
All these data clearly show that – compared to the ex-
isting PPIs – tenatoprazole has a longer half-life and a
longer duration of the antisecretory action, in agreement
with the current knowledge according to which the anti-
secretory effect is proportional to the AUC [121, 192].
Although these properties should theoretically translate
into a better therapeutic efficacy, no randomized clinical
trials in acid-related diseases are available as yet. It is
worth mentioning, however, that a preliminary analysis
of a phase II dose-ranging (10, 20 and 40 mg daily) Ca-
nadian study, performed in patients with reflux esopha-
gitis (grade A–C according to Los Angeles classification),
demonstrated that this novel PPI effectively heals muco-
sal lesions regardless of the dose [Alan B. Thomson, pers.
commun.]. After 4 weeks of treatment with whatever dose
of tenatoprazole, the healing rate was larger than that re-
ported with esomeprazole (40 mg daily) in published clin-
ical trials.
Like the other PPIs, tenatoprazole is a racemic mixture
of two stereoisomers which derive from the chiral nature
of the sulfur atom of the sulfinyl group [193]. As a conse-
quence, in order to exploit the features of stereoselective
catabolism, the S-isomer was selected for further develop-
ment [194]. As expected, the in vitro binding of both S-
and R-tenatoprazole to hog gastric H+,K+-ATPase was
virtually the same and overlapped that observed with the

Update on Acid Suppression Therapy Dig Dis 2006;24:11–46 27

DDI923.indd 27 02.05.2006 16:24:56

 200,000
Plasma concentration of TU-199
180,000 (–)TU-199 Na
160,000
140,000
120,000
(ng/ml)
100,000
80,000
60,000
40,000
20,000
0 Parietal
0 1 2 3 4 5 6 7
Time (h)
Fig. 12. Plasma levels of S-tenatoprazole (TU-199) after oral
administration in dogs. Either the sodium salt or the free from
(100 mg/kg) were administered using a gelatine capsule containing
the crystallized powder of each compound. Each point represents
the mean of the values obtained from 3 to 4 animals (from Shin et
al. [180]). (–)TU-199 = S-tenatoprazole-free form; (–)TU-199 Na =
S-tenatoprazole sodium salt hydrate.
racemate [181]. Similarly, there was no difference in
binding reversibility kinetics amongst the different forms
of this PPI [181]. Preliminary experiments in laboratory
animals did confirm the antisecretory and ulcer healing
activity of S-tenatoprazole and did point out that this iso-
mer is more effective than R-tenatoprazole [Ficheux et
al., unpubl. observations].
A careful pharmacokinetic and structural study by
George Sachs’ team [181] showed that the oral bioavail-
ability of S-tenatoprazole sodium salt hydrate is almost
twice that of S-tenatoprazole-free form (fig. 12). The dif-
ference in bioavailability can be explained by the better
solubility of the sodium salt due to its peculiar crystal
structure. The crystal form of S-tenatoprazole sodium salt
hydrate is indeed quite different from that of S-tenato-
prazole-free form. In the crystal of S-tenatoprazole sodi-
um salt hydrate there is a loose packing structure of mol-
ecules, which results in rapid water access and hence
greater solubility. The pharmacokinetics of S-tenatopra-
zole sodium was then studied in healthy volunteers and
proved to be linear with a dose-related increase in both
Cmax and AUC [Ficheux et al., unpubl. observations]. The
antisecretory effect of this stereoisomer (80 mg orally
once a day over 1 week) was investigated in H. pylori-
negative healthy subjects. On day 7, intragastric pH was
28 Dig Dis 2006;24:11–46
DDI923.indd 28
(–)TU-199 Parietal
cell canaliculus
K+ Cl –
H+
8 9 cell cytoplasm
K+
Na + K+ Cl –
K+ HCO 3–
Na + K+
Fig. 13. A simplified model for the secretion of gastric acid by the
parietal cell. The H+,K+-ATPase located on the apical membrane
of the parietal cell exchanges H+ for K+. K+ is recycled from the
canaliculus into the cytoplasm by K+ channels in the apical mem-
brane. The combined actions of K+ channels and enzymes on the
basolateral membrane regulate cytoplasmic K+ levels. Cl– enters the
cell cytoplasm via a Cl–/HCO3– exchanger and moves from the cy-
toplasm into the canaliculus via a Cl– channel (most likely ClC-2)
(from Geibel [94]).
markedly increased and remained over 5 or above
throughout most of the 24-hour recording period, both
during day- and nighttime [Galmiche, pers. commun.].
Some pharmacodynamic and healing studies with S-te-
natoprazole sodium have already been planned and will
start in the near future.
In summary, the available studies point out both phar-
macokinetic and pharmacodynamic advantages of te-
natoprazole over esomeprazole. Since this last compound
provides – amongst the members of the class – the most
effective control of intragastric pH whatever the param-
eter considered [195], it is conceivable that tenatoprazole
could similarly be better than the other existing PPIs. Te-
natoprazole (as well as its S-isomer) then appears a prom-
Scarpignato /Pelosini /Di Mario
02.05.2006 16:24:57
 Table 4. P-CABs already studied in clinical trials

P-CAB Chemical class Clinical Company

development phase

AZD0865* Imidazopyridine Phase II AstraZeneca

CS526 (R105266)* Pyrrolopyridazine Phase I Sankyo and Ube/Novartis
Revaprazan (YH1885, Revanex) Pyrimidine Phase III Yuhan
Soraprazan (BY359) Imidazonaphthyridine Phase II Altana

* Discontinued in July 2005.

ising PPI for the treatment of acid-related diseases, where
it has the potential to address unmet clinical needs.
Potassium-Competitive Acid Blockers
The next generation of drugs which suppress gastric
acidity will most likely be P-CABs which are K+-com-
petitive inhibitors of the ATPase [93]. While the PPIs
have a unique mechanism of action based on their chem-
istry, P-CABs have a structural specificity for their target,
the K+-binding region of the H+,K+-ATPase.
Although it can also be activated by NH4+ in vitro, the
proton pump is highly selective for K+ [196]. In common
with many other cells, the level of K+ in the parietal cell
is higher than that in the plasma. The higher intracellular
K+ level is dependent on H+,K+-ATPase. This enzyme,
located on the basolateral membrane of the cell, ex-
changes intracellular H+ for extracellular K+ [10]. The
level of K+ within the cell is also regulated by K+ chan-
nels, which allow ion movement across the basolateral
membrane (fig. 13). These channels have a particularly
important role in generating negative cell membrane po-
tential. Given the importance of the cation for enzyme
function, agents that compete with the binding of K+
have the potential to block acid secretion. P-CABs in-
hibit H+,K+-ATPase by binding ionically to the enzyme
and thus prevent its activation by the K+ cation. Since
these molecules are larger than K+, it is likely that they
compete by preventing the access of the cation to its
binding site rather than occupying the ion-binding site
directly.
P-CABs, despite sharing the same mechanism of ac-
tion, represent a heterogeneous class of drugs. Indeed,
they belong to four different chemical classes, namely
imidazopyridines, pyrimidines, imidazonaphthyridines
and quinolones [93, 94].
The prototype P-CAB, SCH28080, was developed by
Schering-Plough more than 20 years ago. In a study pub-
lished in 1982, this compound was shown to inhibit gas-
tric acid secretion in humans [197], although its mecha-
nism of action was not fully understood at the time. Sub-
sequently, SCH28080 was shown to block gastric
H+,K+-ATPase by competing with K+ [198]. The develop-
ment of SCH28080 was discontinued because of hepatic
toxicity. Since then, several other compounds with this
peculiar mechanism of action have been synthesized and
studied, but only few did reach clinical development.
Four representative members of the P-CAB class have
been studied in humans with the aim of finding a suitable
drug for the treatment of acid-related diseases (table 4,
fig. 14). Despite a number of papers presented at the re-
cent DDW (Chicago 2005) and UEGW (Copenhagen
2005) and two clinical trials on GERD (registered at
www.clinicaltrials.gov) that were successfully completed,
AZD0865 was discontinued [199]. The same holds true
for CS526. However, a follow-up compound of sorapra-
zan is currently in phase I [200]. Therefore, there are still
three molecules under active development.
P-CABs are lipophilic, weak bases that have high pKa
values and are stable at low pH. This combination of
properties allows them to concentrate in acidic environ-
ments. For example, the concentration of a P-CAB with
a pKa of 6.0 would theoretically be expected to be 100,000-
fold higher in the parietal cell canaliculus (pH = 1) than
in the plasma (pH = 7.4). The concentration of P-CABs
in the gastric mucosa is demonstrated by in vitro and in
vivo studies with AZD0865 and revaprazan [201, 202].
On entering an acidic environment, P-CABs are instant-
ly protonated and it is in this form that it is thought to
bind to and inhibit the enzyme. The protonated form of
a P-CAB inhibits H+,K+-ATPase by binding ionically to
it, as illustrated by the recovery of enzymatic activity af-
ter washout of AZD0865 and revaprazan [201, 202]. This
family of compounds binds to the outward-facing confor-
mation of the pump on the luminal side and do not re-

Update on Acid Suppression Therapy Dig Dis 2006;24:11–46 29

DDI923.indd 29 02.05.2006 16:24:57

 Fig. 14. Chemical structures of P-CABs under clinical investigation.
quire its activation. This would suggest that these agents
will produce more rapid acid inhibition and will be able
to elevate gastric pH to a higher level than PPIs.
Both animal and human studies have shown that P-
CABs achieve rapidly peak plasma concentrations after
oral administration. This is partly due to their stability at
low pH allowing their administration as IR formulations.
All the compounds studied to date exhibit a linear phar-
macokinetic pattern [93]. The rapid absorption of P-
CABs is mirrored by a fast onset of acid inhibition. In
healthy volunteers, a single oral dose of pumaprazole (an
imidazopyridine compound marked BY841) [203] or re-
vaprazan [204] increased intragastric pH to about 6 with-
in 30–60 min, whereas high doses of AZD0865 resulted
in over 95% inhibition of acid secretion within 1 h after
oral dosing [205]. Both the degree [206] and the duration
[205] of the antisecretory action are dose-dependent. As
30 Dig Dis 2006;24:11–46
DDI923.indd 30
for PPIs [207], the pH-rising effect of P-CABs seems to
be increased in the presence of H. pylori infection [208].
Animal studies have shown a close correlation be-
tween maximum inhibition of acid output and the loga-
rithm of Cmax [93], thus suggesting that the duration of
action of P-CABs will depend on their half-life. One draw-
back of these agents is the need for twice-daily dosing
since they inhibit the pump only for the duration of their
presence in the blood; however, since these compounds
are acid-stable, their plasma half-life may be readily pro-
longed with extended-release formulations [92]. The
main differences between P-CABs and PPIs are summa-
rized in table 5. It is evident that P-CABs offer a more
rapid elevation in intragastric pH than a PPI (and similar
to that achieved by an H2-RA) while maintaining the
same degree of antisecretory action, whose duration is
dependent on half-life and can easily be prolonged by ap-
Scarpignato /Pelosini /Di Mario
02.05.2006 16:24:58
 Fig. 15. Chemical structure of the novel H2-receptor antagonists ebrotidine and lafutidine. Besides S- and R-iso-
mers, cis- and trans-isomers of lafutidine have also been isolated.

Table 5. P-CABs and PPIs: main

differences in the mechanism of action P-CABs PPIs

Acts directly on the H+,K+-ATPase enzyme
Super-concentrates in parietal cell acid space
(100,000-fold higher than in plasma)
P-CABs binds competitively to the potassium
binding site of H+,K+-ATPase
Duration of effect related to half-life
of drug in plasma
Full effect from first dose
Requires transformation to the active form
Concentrate in parietal cell acid space
(1,000-fold higher than in plasma)
Sulfenamide binds covalently
to H+,K+-ATPase
Duration of effect related to half-life
of the sulfenamide-enzyme complex
Full effect after repeated doses

propriate formulations. Whether these favorable phar-
macodynamic properties will translate into clinical ben-
efits is unknown. Results of phase III clinical trials with
one of such compound (namely revaprazan) are eagerly
awaited.
New H2-Receptor Antagonists
As already discussed, despite all the intrinsic limita-
tions, there is still a place for H2-RAs in the era of PPIs.
A recent survey of Castell’s team [71] found that the ma-
jority of GERD patients report a persistent improvement
of nighttime symptoms from bedtime H2-RA use and sug-
gested that a possible clinically important tolerance does
occur in a small number of patients. In this connection a
fast-dissolving oral tablet containing a fixed dose combi-
nation of a PPI and an H2-RA (product marked OX 17)
has been developed by Orexo AB (Uppsala, Sweden) and
phase II clinical trials with this formulation are presently
on the way in Europe [209]. A combination of H2-RA
with the novel PPI tenatoprazole has also been patented
[210].
Although the last decade has been dominated by the
growing use of PPIs, several new H2-RAs have been syn-
thesized. While the majority of them have been discon-
tinued, few molecules reached clinical development and
two (namely ebrotidine and lafutidine, fig. 15) have actu-
ally been marketed. These drugs belong to a new genera-
tion of H2-RAs which combine the antisecretory effect
with a mucosal-protective activity.
Ebrotidine has been developed by the Ferrer group in
Spain [211]. The drug is able to displace 3H-thiotidine-
specific binding to H2-receptors with an affinity (Ki
127.5 nmol/l) significantly (p ! 0.05) higher than that
of ranitidine (Ki 190.0 nmol/l) and cimetidine (Ki
246.1 nmol/l) [212]. Its antisecretory efficacy is similar to
that of ranitidine and 10 times higher than that of cimeti-

Update on Acid Suppression Therapy Dig Dis 2006;24:11–46 31

DDI923.indd 31 02.05.2006 16:24:58


100
pH holding time (%)
80
✽✽
✽✽ ✽✽ ✽✽
60 ✽✽
40
20
0
1 2 3 3.5 4 5
pH
Fig. 16. Time spent above a given pH in the postprandial period
after administration of a single dose of lafutidine (10 mg) or rabe-
prazole (20 mg) in healthy volunteers. Each point refers to the mean
(8SD) of the values obtained from 10 subjects. ** Significant (p !
0.01) difference between means (from Inamori et al. [226]).
dine [211]. The mucosal-protective properties of ebroti-
dine, possibly due to enhanced mucosal synthesis of both
endogenous prostaglandins (PGs) and nitric oxide (NO)
[213, 214], stem from its ability to improve the physico-
chemical characteristics of mucus gel (i.e. increase in mu-
cus gel dimension, viscosity, hydrophobicity and hydrogen
ion retardation capacity). Improvements in mucus gel-pro-
tective qualities with ebrotidine are directly related to the
ability of the drug to enhance the synthesis and secretion
of sulfo- and sialomucins and phospholipids of gastric mu-
cus and to promote mucin macromolecular assembly
[215]. This drug also exhibits an inhibitory activity against
H. pylori that is synergistic with a number of antibacterial
agents; it inhibits the urease enzyme and the proteolytic
and mucolytic activities of H. pylori, and counteracts the
inhibitory effects of H. pylori lipopolysaccharide.
Although ebrotidine proved to be as effective as ra-
nitidine for the treatment of patients with PU or erosive
reflux esophagitis [211], it achieved a significantly better
ulcer healing rate (94 vs. 86%, p ! 0.05) than ranitidine
treatment in smokers [216]. Unfortunately, the drug was
prematurely withdrawn from the Spanish market because
of serious hepatotoxicity [217–219].
Another peculiar H2-RA endowed with both antisecre-
tory and mucosal-protective activities is lafutidine. This
drug, originally developed by Fujirebio Inc. [220], is cur-
rently marketed by UCB and Taiho Pharmaceutical in
Japan. This compound showed a potent and long-lasting
32 Dig Dis 2006;24:11–46
DDI923.indd 32
inhibition of tiotidine binding and histamine-induced cy-
clic-3,5-adenosine monophosphate production in Chi-
Lafutidine 10 mg nese hamster ovary cells expressing human H2-receptors
Rabeprazole 20 mg
[221]. Animal experiments [222] have pointed out that
lafutidine has a potent and long-lasting antisecretory ef-
fect, a finding confirmed by human investigations [223]
✽✽ showing that this drug inhibits acid secretion more
✽✽
strongly than conventional H2-RAs. Conversely from ra-
nitidine and famotidine, lafutidine increases both day-
and nighttime intragastric pH in H. pylori-negative sub-
jects [224], and conversely from omeprazole (and other
6 7 8
PPIs) its efficacy is not influenced by the CYP2C19 gen-
otype status [223]. When used in combination with anti-
biotics (namely clarithromycin and amoxicillin) it
achieves an eradication rate which is comparable to that
of the same PPI-based triple therapy [225]. A recent cross-
over study [226] in healthy volunteers did show that a
single dose (10 mg) of this novel H2-RA is able to increase
intragastric pH more quickly than a single dose (20 mg)
of rabeprazole, the fastest amongst the available PPIs
[227]. Both in fasting conditions and in the postprandial
state, the duration of the antisecretory action was longer
than that of the PPI since the drug maintained the pH
over a given threshold for a sustained period of time (fig.
16). Its terminal half-life (3.30 8 0.39 and 3.79 8 1.02
h in fasting and fed conditions, respectively [228]) is lon-
ger than that of cimetidine, ranitidine and nizatidine [55,
229] and shorter than that of roxatidine, but not dissimi-
lar from that of famotidine [55].
Conversely from other H2-RAs [230], lafutidine does
increase SST release, which may contribute to its antise-
cretory effect [231]. Similarly, the observed rise in calci-
tonin gene-related peptide (CGRP) levels after drug ad-
ministration could account for both its acid-lowering and
cytoprotective activities [232].
Lafutidine displays mucosal protection against a vari-
ety of noxious agents, and structure-activity relationships
revealed that the presence of furfurylsulfinyl, pyridyl and
amide moiety (fig. 15) are chemically important for the
gastroprotective activity. The mucosal-protective effect
of lafutidine is attenuated by pretreatment with the an-
tagonist of CGRP (CGRP8-37) and the blocker of NO
production (NG-nitro-L-arginine), as well as chemical ab-
lation of capsaicin-sensitive sensory neurons, suggesting
that this action appears through capsaicin-sensitive affer-
ent neurons and is mediated by CGRP and NO [233].
Interestingly enough, lafutidine also exhibits a protective
activity against the experimentally-induced mucosal le-
sions in digestive tissues other than the stomach, i.e. acid-
induced reflux esophagitis [234], indomethacin-induced
Scarpignato /Pelosini /Di Mario
02.05.2006 16:248
 small intestinal lesions [235] and colonic inflammation
induced by dextran sulfate sodium [236]. Finally, this H2-
RA inhibits H. pylori-induced IL-8 release from gastric
epithelial cells and impairs cellular adhesion of the mi-
croorganism, protecting in this way against the mucosal
inflammation associated with the infection [238].
Provided lafutidine is available worldwide, it will rep-
resent a quick and strong means of inhibiting acid secre-
tion which is particularly suitable for on-demand use in
PUD and GERD, where it could also be useful to control
NAB. It could also be particularly effective in the preven-
tion and treatment of NSAID-associated GI lesions. In
this setting, its marked and long-lasting antisecretory ac-
tivity, coupled with the mucosal-protective properties,
will probably allow the drug to go beyond the intrinsic
limitations of conventional H2-RAs, which only protects
the duodenum [35, 37]. In this connection, the use of la-
futidine and its isomers [238] in the prevention or treat-
ment of inflammatory enteropathy has recently been pat-
ented [239].
According to R&D Focus, some other H2-receptor an-
tagonists are being developed. Among them, CP-66,948
developed by Pfizer Inc. (Groton, Conn., USA), a com-
pound [2-(N-pentyl-N-guanidino)-4-(2-methylimidazol-
4-yl)thiazole] possessing both antisecretory and mucosa-
protective properties [240] entered phase I trials. Prelim-
inary results have shown that a single oral bedtime dose
(50 mg) of CP-66,948 produced the same inhibition of
acid secretion achieved by 150 mg of ranitidine. However,
no further development is currently reported. A similar
compound (TRM 115 by Terumo Co., Tokyo, Japan) was
recently discontinued after completing phase I studies.
Gastrin (CCK2) Antagonists
Gastrin is a major endocrine regulator of gastric acid
secretion and its release stimulates an estimated mean of
90% of postprandial secretion [1]. This hormonal peptide
is produced by the antral G cells in response to food pro-
teins and their digestion by-products as well as upon stim-
ulation by gastrin-releasing peptides from postganglionic
fibers of the vagus nerve [241]. Besides its central role in
the regulation of acid secretion, gastrin also affects GI
motility [242] and stimulates epithelial cell proliferation
throughout the GI tract [243].
Gastrin displays a structural similarity with cholecys-
tokinin (CCK), another GI peptide released by lipids
from the upper small bowel I cells [244]. Both peptides
share indeed the same C-terminal pentapeptide amide
sequence although they differ in sulfation at the sixth
(gastrin) and seventh (CCK) tyrosyl residues [241, 244].
Update on Acid Suppression Therapy
DDI923.indd 33
As a consequence, they both bind to the same receptors
located on parietal cells, and CCK also stimulates acid
secretion both in vitro and in vivo. CCK however stimu-
lates fundic D cells to produce SST, which in turn inhib-
its both gastrin release and acid secretion [244].
Receptors for CCK are a family of G protein-coupled
receptors, which were first characterized on pancreatic
acinar cells and identified as CCK type A receptors (now
called CCK1), with the subsequent discovery in the same
year of a second receptor with a different pharmacology
in the brain, i.e. CCK type B receptors (now CCK2)1 [244,
245]. These two types of CCK receptors could be phar-
macologically distinguished on the basis of their affinity
for the agonists CCK and gastrin and by recently devel-
oped subtype-specific antagonists. CCK1 receptors are
highly selective (500- to 1,000-fold) for sulfated analogs
of CCK, whereas CCK2 receptors have similarly high af-
finity for both sulfated and nonsulfated peptide analogs
of CCK and gastrin peptides [245, 246]. However, al-
though binding the same receptors, gastrin is mainly a
peripheral ligand, while CCK is considered a brain-gut
peptide thanks to its effects on the CNS. Formerly, the
gastrin receptor mediating acid secretion in the stomach
was thought to constitute a third type of high-affinity re-
ceptor on the basis of its location, small differences in
affinity for CCK and gastrin-like peptides, and the rever-
sal in relative affinity for receptor subtype-selective an-
tagonists in canine gastric glands. Subsequent cloning of
gastrin receptors from canine stomach and CCK2 recep-
tors from canine brain revealed their molecular identity,
leading to the classification of gastrin receptors as CCK2
receptors [245]. These receptor subtypes have been found
not only on parietal cells [246] but also on ECL cells [247],
fundic D cells [248] and the vagus nerve [246].
The known targets for gastrin-mediated acid secretion
are histamine-releasing ECL cells and acid-secreting pa-
rietal cells, which both possess a CCK2 receptor [249].
The current concept of gastrin regulation of acid secretion
involves a complex but incompletely delineated mecha-
nism. The feedback loop is constituted by at least three
key elements: the G cell, the ECL cell, and the parietal
1
The initial nomenclature of the receptors as CCK-A (A for alimentary)
and CCK-B (B for brain) receptors is generally accepted by pharmacologists
and molecular biologists. Based on the guidelines defined by the International
Union of Pharmacology (IUPHAR) Committee on Receptor Nomenclature
and Drug Classification, receptors should be named after their endogenous
ligands and identified by a numerical subscript corresponding to the chrono-
logical order of the formal demonstration of their existence by cloning and se-
quencing. Because the CCK-A receptor was the first to be cloned, it should be
renamed CCK1, and the CCK-B receptor should become CCK2.
Dig Dis 2006;24:11–46 33
02.05.2006 16:24:59
 Fig. 17. Chemical structure of CCK2 antagonists under clinical investigation.
cell, and their products gastrin, histamine and hydrochlo-
ric acid, respectively. Gastrin has a direct secretory effect
on both parietal cells and ECL cells, although the latter
effect is probably far more significant. The peptide medi-
ates histamine release from ECL cells via activation of its
CCK2 receptors. The initial signal transduction events in-
volve a transient rise in intracellular calcium, followed by
histamine granule exocytosis [249]. This process occurs
maximally within 5 min. Thereafter, extracellular calcium
influx and histidine decarboxylase (HDC) activation are
34 Dig Dis 2006;24:11–46
DDI923.indd 34
presumed to play a role in subsequent histamine release
[249]. The released histamine is a potent stimulant of acid
secretion, exerting a direct stimulatory effect on the H2-
receptor of the parietal cell. The parietal cell secretory
product, hydrochloric acid, causes antral inhibition of gas-
trin release from the G cell, probably via a SST-regulated
mechanism. It also seems probable that SST by a direct
action on ECL cells is able to inhibit histamine release,
since the direct effect of paracrine peptide on parietal cells
is not pronounced in vitro [4]. Indeed, ECL cells have been
Scarpignato /Pelosini /Di Mario
02.05.2006 16:24:59
 20,000
15,000
AUC (ng/ml
h)
10,000
Fig. 18. Pharmacokinetics and pharmaco-
dynamics of itriglumide after single admin-
5,000
istration in healthy volunteers. a Plot of
AUC vs. dose, showing a linear pharmaco-
kinetic pattern. b Dose-dependent inhibi-
tion of G-17 (32 pmol/kg
h) induced acid
secretion (drawn from data in Beglinger et a Single dose (by oral route) (mg)
al. [264]).
reported to express SST receptors, suggesting a dual regu-
lation of the ECL cell by both gastrin and SST [250].
Whilst gastrin appears to be a major stimulant for hista-
mine release, there is also significant evidence for the role
of other gut neurotransmitters, namely acetylcholine, va-
soactive intestinal peptide, PYY and corticotropin gene-
related peptide (CGRP) in this process [251].
Given the important physiological role of gastrin in
the stimulation of gastric acid secretion, selective CCK2-
receptor antagonists offer a potential approach to regulate
acid production. High-affinity nonpeptide antagonists for
both types of CCK receptors were synthesized more than
15 years ago. Their availability has stimulated a broad
array of investigations into the physiologic actions of
CCK-like peptides [252], including gastrin [253].
At least 12 chemical classes of CCK-receptor antago-
nists have been described [254]. Amongst them, several
ligands with high affinity for CCK2 receptors have been
identified and characterized by binding and pharmaco-
dynamic studies [246]. However, only few have been test-
ed in humans for their effect on acid secretion or their
anxiolytic activity2. The 5 compounds, whose antisecre-
tory effect was studied in clinical trials, will be reviewed
in detail. They belong to amino acid (i.e. spiroglumide
and itriglumide) or benzodiazepine (i.e. L-365,260, YF-
476 and Z-360) derivatives (fig. 17).
2
The involvement of CCK in human anxiety is well documented. Exog-
enous administration of CCK2-receptor agonists, such as cholecystokinin-tet-
rapeptide and pentagastrin, provoke panic attacks in man. Patients with panic
disorder are hypersensitive to CCK2-receptor stimulation compared to healthy
volunteers and patients with other anxiety disorders, and they differ from
healthy subjects in CCK metabolism and genetic characteristics of the CCK2-
receptor system. As a consequence, some CCK2 antagonists (e.g. L-365,260 or
CI-988) are being developed as anxiolytics [254, 255].
Update on Acid Suppression Therapy
DDI923.indd 35
y = –1609.9 + 24.956x 70 y = 15.471 + 7.1376e2x
r2 = 0.945 60 r2 = 1.000
Acid inhibition (%)
50
40
30
20
10
0 0
0 100 200 300 400 500 600 700 0 100 200 300 400 500 600 700
b Single dose (by oral route) (mg)
Amongst the amino acid derivatives, proglumide,
which has long been used as an antiulcer drug [256], was
considered the prototype CCK antagonist [257]. Its low
potency and specificity (the compound binds to both
types of receptors) stimulated the synthesis of glutaramic
acid derivatives, the most interesting ones being lorglu-
mide and loxiglumide (as selective CCK1-receptor antag-
onists) and spiroglumide and itriglumide (as CCK2-re-
ceptor antagonists). These compounds (developed at Rot-
ta Research Laboratorium, Milan, Italy) are active after
oral administration and able to antagonize the effects of
both endogenous and exogenous peptides (i.e. CCK and
gastrin) [258, 259].
Animal studies [260, 261] have shown that spiroglu-
mide (compound marked CR-2194) is a selective CCK2
antagonist, capable of inhibiting dose-dependently penta-
gastrin- but not carbachol- or histamine-stimulated acid
secretion. Studies performed on healthy volunteers [262]
confirmed the inhibitory activity against gastrin-induced
acid secretion and also showed its ability to inhibit post-
prandial gastric secretion. Despite these promising re-
sults, the development of spiroglumide was ended because
more potent and selective derivatives became available.
Itriglumide (compound marked CR-2945) is a follow-
up selective antagonist endowed with a good oral bio-
availability [263]. After intraduodenal administration,
the drug proved to be more potent as an antisecretory
compound than either ranitidine or omeprazole [263]. Its
healing activity of experimentally-induced gastric and
duodenal ulcer was comparable to that of ranitidine. The
pharmacodynamics and pharmacokinetics of itriglumide
were recently studied in humans, where the compound
inhibited gastrin-stimulated acid secretion in a dose-de-
pendent manner (fig. 18). The pharmacokinetics proved
to be linear in the dose range of 30–600 mg and drug was
Dig Dis 2006;24:11–46 35
02.05.2006 16:24:59
 well tolerated at any dose level [264]. Itriglumide there-
fore appears to be a promising CCK2 antagonist that de-
serves further clinical investigations in acid- and gastrin-
related disorders.
The other major chemical class of CCK2 antagonists
has exploited a benzodiazepine template present in
asperlicin, which was initially discovered in a natural
product screen for CCK receptor antagonists. The struc-
turally related benzodiazepines L-365,260 and YF-476
are selective antagonists of the CCK2 receptor subtype.
Their in vitro pharmacological profiles have been charac-
terized using the human CCK2 receptor expressed in Chi-
nese hamster ovary cells. Conversely from other benzodi-
azepine derivatives (L-740,093 and YM022), which dis-
play an insurmountable antagonism, L-365,260 (devel-
oped at Merck Research Laboratories, West Point, Pa.,
USA) behaves as a competitive antagonist [265]. Animal
experiments [266–270] have shown that this compound
inhibits pentagastrin-stimulated acid secretion and that
higher doses also affect basal gastric secretion as well as
the response to other secretagogues. Thanks to its antise-
cretory activity, the drug proved to be capable of prevent-
ing aspirin-associated gastric damage and cysteamine-in-
duced duodenal ulcer. In humans, L-325,260 confirmed
its selectivity towards CCK2 receptors being able to in-
hibit pentagastrin-stimulated acid secretion [271] but not
fat-induced gallbladder emptying [272]. The drug does
not inhibit – at the clinically tested doses – basal acid se-
cretion and has poor bioavailability. Its development as
an antisecretory compound is therefore unlikely. Never-
theless, since L-325,260 crosses the blood-brain barrier
[273], reaching and binding central CCK2 receptors, it
represents a useful tool to assess the physiology and patho-
physiology of CCK in the CNS. A placebo-controlled tri-
al in patients with panic disorders [274] gave however
disappointing results. A back-up compound (L-368,935)
with more water solubility [275] and less CNS penetra-
tion [276] and thus more suitable for peripheral receptor
blockade has entered phase I in the USA.
YF-476 is a potent and orally active CCK2 antagonist
synthesized at Ferring Research Institute (Southampton,
UK) [277] and co-developed with Yamanouchi Pharma-
ceutical Co. (Tsukuba, Japan). In vitro and vivo experi-
ments [278, 279] have confirmed its high selectivity by
showing that its affinity for the rat brain CCK2 receptors
is 4,100 times higher than that for rat pancreatic CCK1
receptors and that the drug is able to inhibit pentagastrin-
but not histamine-stimulated acid secretion in rats and
dogs. In dogs with gastric fistula its antisecretory activity
was found to be 7 and 40 times more potent than that of
36 Dig Dis 2006;24:11–46
02.05.2006
DDI923.indd
16:25:00
36
famotidine and omeprazole, respectively [279]. The po-
tent and long-lasting antisecretory effect of YF-476 was
confirmed in human studies after single administration
of the drug [280], which also found a linear pharmacoki-
netics with a half-life of 7.1 h after oral administration of
100 mg. However, the effect of repeated (7 days) doses of
this compound on intragastric pH was disappointing,
with the 200-mg daily dose giving a significant inhibition
of acid secretion only in the postprandial period [281].
The adaptation of the antisecretory effect of YF-476 after
short-term administration is unlikely to be due to endog-
enous gastrin increase [282] and might reflect up-regula-
tion of gastrin (CCK2) and/or histamine receptors.
According to R&D Focus, a third benzodiazepine de-
rivative, presently in a phase I study in UK, is the com-
pound marked Z-360, developed at Zeria Pharmaceutical
Co., Japan. Preclinical studies [283] have shown a very
high (615-fold) selectivity toward human CCK2 receptors
compared to CCK1 ones. The drug dose-dependently in-
hibited pentagastrin- but not histamine- or carbachol-
stimulated acid secretion with a potency 50 times higher
than that of L-365,260. In Pavlov pouch dogs, postpran-
dial acid secretion was inhibited by 70% by Z-360 while
other CCK2 antagonists (namely L-365,260 and YM 022)
proved to be ineffective [284].
Being CCK2 receptors expressed in the regenerative
mucosa adjacent to the ulcer margin they can mediate the
gastrin-enhanced cell proliferation underlying ulcer heal-
ing [285]. Therefore, despite their acid-lowering activity,
CCK2 antagonists might delay mucosal healing. Because
of this concern and because of the development of toler-
ance (see above), it is unlikely that these compounds will
be used as antiulcer drugs. Similarly, it is difficult to imag-
ine these agents as an alternative to PPIs in GERD. On
the contrary, their use together with long-term acid sup-
pression would prevent the consequences of PPI-induced
hypergastrinemia (e.g. ECL cell hyperplasia or gastrin-
driven GI malignancies) [286–289]. As a matter of fact,
a preclinical study using the benzodiazepine CCK2-recep-
tor antagonist Z-360 seems to confirm this hypothesis.
Rats were given repeated doses of Z-360, omeprazole or
a combination of the two compounds for 4 weeks. Al-
though both drugs caused hypergastrinemia, omeprazole
but not Z-360 caused ECL hyperplasia. In addition, Z-
360 significantly reduced omeprazole-induced hyper-
plasia [283], thus suggesting that CCK2-receptor block-
ade could prevent ECL cell proliferation stimulated by
long-term treatment with PPIs. In this connection, sev-
eral patents concerning this particular application of
CCK2 antagonists have been granted to the James Black
Scarpignato /Pelosini /Di Mario
 Foundation [290]. An additional logic use of this class of
drugs is the treatment of GI and pancreatic cancer. In-
deed, it is becoming increasingly apparent that gastrin
and gastrin (CCK2) receptors are expressed in a number
of tumor sites (GI and non-GI) throughout the body
[291]. It is noteworthy that in these neoplastic cells post-
translational processing of gastrin is not as well developed
as in endocrine cells and other less completely processed
forms of gastrin, such as glycine-extended gastrin, may
also have a role [292]. Despite being attractive from a
theoretical point of view, targeting CCK2 receptors in
cancer however has not provided optimal beneficial ef-
fects, as yet [293].
Antigastrin Vaccine
G-17DT is an immunoconjugate of the amino-termi-
nal sequence of gastrin 17 (G-17) linked by means of a
spacer peptide to diphtheria toxoid (fig. 19) [294]. It has
been developed by Aphton Corp. (Miami, Fla., USA),
originally labeled as Gastrimmune™ and later known as
Insegia™. Given as an intramuscular vaccination, it has
been shown to induce the formation of antibodies that
can neutralize not only G-17 but also its precursor gly-
cine-extended G-17, which also stimulates the growth of
human gastric and possibly other GI cancers [295]. These
antigastrin antibodies can inhibit the proliferation of
pancreatic cancer cell lines. In a phase II study of 30 pa-
tients with pancreatic cancer, 67% of them were shown
to mount an immune response to the vaccine. Eighty-two
percent of patients given the highest dose of the vaccine
(250 g) achieved a response. There was indeed a signif-
icant difference between the median survival times noted
for patients who produced an immune response and for
those who did not [296]. While preliminary, these results
are promising and three phase III clinical trials (registered
at www.clinicaltrials.gov) with G-17DT, alone or in com-
bination with chemotherapy, are ongoing [297].
In addition to the treatment of GI and pancreatic can-
cer, the use of G-17DT has been proposed for the manage-
ment of GERD. Indeed, besides stimulating acid secretion,
G-17 also affects lower esophageal sphincter function. In-
deed, continuous intravenous infusion of this peptide to
healthy volunteers significantly increases gastroesophageal
reflux and the number of transient lower esophageal sphinc-
ter relaxations associated with reflux [298]. Active immu-
nization against G-17 should not only neutralize its acid-
stimulating properties but also reduce postprandial gastro-
esophageal reflux. Animal studies [299–301] have indeed
shown that this antigastrin vaccine strongly inhibits gastric
acid secretion. Therefore, G-17DT would represent a reli-
Update on Acid Suppression Therapy
DDI923.indd 37
G-17DT immunogen
Synthesized Peptide N-terminal
gastrin peptide spacer end
DT
Diphtheria toxoid (DT)
Fig. 19. Antigastrin immunogen. G-17DT consists of: (a) A syn-
thetic peptide which is similar to a portion of the targeted hormone
gastrin 17. (b) A ‘carrier’, diphtheria toxoid (DT), to which a num-
ber of these synthetic gastrin peptides are chemically bound. DT,
which is recognized as foreign, provokes the body into initiating an
immune response. Since the body normally will not mount an im-
mune response against ‘self’ proteins and molecules, the coupling
of DT to the synthetic peptide is critical for provoking an immune
response against the synthetic peptide. Since the peptides resemble
a portion of the targeted hormone, the antibodies produced also
bind and neutralize natural gastrin 17. (c) A proprietary, slow-re-
lease emulsion which contains (a) and (b).
able mean of achieving acid suppression while avoiding
hypergastrinemia. A phase II clinical trial in GERD has
been started although not currently recruiting patients
[302]. Aphton has also patented the use of G-17DT to-
gether with antisecretory agents for the treatment of
GERD [303]. Combination therapy is claimed to be a
more effective method of controlling gastric acid secretion
since two independent mechanisms will operate. In addi-
tion, the gastrin immunogen will block PPI-induced hyper-
gastrinemia, thus reducing mucosal hyperplasia [290].
Conclusions and Perspectives for the Future
The discovery of gastrin by John Edkins [304] initi-
ated the scientific examination of the regulation of gastric
acid secretion and led to elucidation of the pathogenic
basis of PU and its subsequent cure. During the course of
the century after this breakthrough, the identification of
the cellular regulators of acid secretion culminated in the
development of novel pharmacotherapeutic agents,
namely H2-RAs and PPIs, which allowed the effective
Dig Dis 2006;24:11–46 37
02.05.2006
02.05.2006 16:25:00
16:25:00
 and safe treatment not only of PU but also of GERD and
other acid-related disorders. Although antisecretory ther-
apy has advanced dramatically since the introduction of
cimetidine in the mid-1970s, there are several identifiable
unmet needs especially in the management of GERD,
where an antisecretory therapy with rapid onset of action
and sustained antisecretory effect would be desirable.
This is also true in the management and prevention of
nonvariceal upper GI bleeding and may be increasingly
important in patients taking NSAIDs.
A number of new drugs are currently being investigated
to provide a significant advance on current treatments.
Some of them (namely P-CABs and CCK2-receptor an-
tagonists) have already reached clinical testing while some
others (like the antigastrin vaccine, H3-receptor ligands or
gastrin-releasing peptide (GRP) receptor antagonists) are
still in preclinical development and need the proof of con-
cept in human beings. An increasing body of evidence sug-
gests that H3-receptors are involved in the regulation of
acid secretion as well as mucosal protection [for review,
see 150] and several potent and selective H3-receptor ago-
nists and antagonists have been synthesized [305]. None
of these compounds has however been tested in humans,
as yet. Similarly, although endogenous GRP is involved in
the regulation of acid secretion, GRP antagonists (like, for
instance, BIM-26226 or BW2258U89) have been used in
men only as a pharmacological tool to gain new insights
into the physiological role of the peptide rather than as an-
tisecretory drugs [150]. However, the potential therapeutic
applications of these antagonists would be limited by the
fact that blockade of GRP receptors also affects other GI
functions, such as pancreatic secretion, gallbladder con-
traction and gastric as well as intestinal motility [306].
Of the current approaches to reduce acid secretion, P-
CABs and CCK2-receptor antagonists hold the greatest
promise, with several compounds already in clinical tri-
als. Although the quick onset of action of P-CABs (i.e. a
full effect from the first dose) is appealing, the results of
phase II studies with one such agent (namely AZD0865)
did not show any advantages over esomeprazole (Sohtell
et al., pers. commun.). Furthermore, the development of
this class of drugs, which started in the early of 1990s, has
been very slow, with many compounds abandoned over
the years for lack of efficacy or safety reasons. The results
of clinical trials with soraprazan are therefore eagerly
awaited to understand whether such agents will have a
role in the future management of acid-related disorders.
Thanks to their limited efficacy and the development of
tolerance, it is unlikely that CCK2 antagonists will be used
alone as antisecretory compounds but, rather, their com-
38 Dig Dis 2006;24:11–46
DDI923.indd 38
bination with PPIs will be attempted with the aim of re-
ducing the long-term consequences of hypergastrinemia
[288, 289]. This combination would be particularly useful
in patients with ZES, where the elevated gastrin levels
[307] may also be associated with reduced absorption of
sodium and water in the gut as well as with the increased
occurrence of carcinoids [308].
While H2-receptor antagonists (especially soluble or
OTC formulations) will become the ‘antacids of the third
millennium’ and will be particularly useful for on-de-
mand symptom relief, clinicians will continue to rely on
PPIs to control acid secretion in GERD and other acid-
related diseases. In this connection, new formulations,
novel compounds and better acid-suppressing regimens
are welcome.
The recently introduced IR-OME formulation (cur-
rently available only in the USA) quickly increases intra-
gastric pH and, given at bedtime, seems to achieve a bet-
ter control of nocturnal acidity. IR formulations of other
PPIs (including the investigational ones) will probably be
available in the future and will enlarge our therapeutic
armamentarium.
As far as the novel PPIs are concerned, tenatoprazole
appears to be a true advance in the acid suppression ther-
apy. Its long half-life (the longest among the available
compounds) and long duration of antisecretory action,
with no difference between day and night, will allow the
drug to go beyond the intrinsic limitations of currently
available compounds. Thanks to its favorable pharmaco-
kinetics, the sodium salt of S-tenatoprazole is being de-
veloped and the preliminary results indicate that this
drug has the potential to address unmet clinical needs.
Although some decades have elapsed from the intro-
duction of an effective and safe antisecretory drug in the
clinical practice and the therapeutic use of acid suppres-
sion has stood the test of time, a large number of basic
and clinical publications on the topic appear every year
in the medical literature. All this ongoing research clearly
shows that the final chapter on the pharmacological treat-
ment of acid-related diseases has not yet been written.
Acknowledgements
We are indebted to Prof. Marcello Tonini (Chairman, Depart-
ment of Physiological and Pharmacological Sciences, University of
Pavia, Italy) for the critical reading of the manuscript and his use-
ful suggestions. We would also like to thank Dr. Elena Losi (Depart-
ment of Pharmaceutical Chemistry, University of Parma) for the
invaluable help with the molecular structures of investigational new
drugs.
Scarpignato /Pelosini /Di Mario
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