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Scarpignato 2006
Scarpignato 2006
© 2006 S. Karger AG, Basel Prof. Carmelo Scarpignato, MD, DSc, PharmD, FRCP, FCP, FACG
University of Edinburgh
E-Mail karger@karger.ch Accessible online at: Via Volturno, 39, IT–43100 Parma (Italy)
www.karger.com www.karger.com/ddi Tel. +39 0521 903 863, Fax +1 603 843 5621, E-Mail scarpi@tin.it
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 Fig. 1. Chemical structure of currently used PPIs.
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 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
Introduction acid secretion culminated in the development of a class
of drugs, the proton pump inhibitors (PPIs), which are
Gastric acid secretion is under nervous and hormonal targeted at inhibiting this enzyme [2]. They represent one
influence [1]. This physiologic process is controlled by a of the most commonly prescribed classes of drugs in both
number of redundant second messenger pathways acti- gastroenterological and primary care settings and are con-
vated as a result of the binding of gastrin, acetylcholine, sidered a major advance in the treatment of acid-related
histamine, and prostaglandins to the specific receptors on diseases.
the basolateral surface of parietal cells. The stimulatory After sufficient acid secretion has occurred, a feedback
effect of acetylcholine and gastrin is mediated by an in- system terminates gastric acid secretion. A decrease of
crease in cytosolic calcium, whereas that of histamine is intragastric pH stimulates somatostatin (SST) release
mediated by activation of adenylate cyclase and genera- from antral D cells. This peptide not only inhibits acid
tion of cyclic AMP (cAMP). Strong potentiation between secretion but also blunts gastrin release and its stimula-
histamine and either gastrin or acetylcholine reflects post- tory effect on CCK2 receptors located on parietal and
receptor interaction between the distinct pathways as well ECL cells [1, 4]. Furthermore, acidification of the duode-
as the ability of acetylcholine and gastrin to release hista- num triggers secretin release, which also inhibits gastric
mine from mucosal enterochromaffin-like (ECL) cells [1]. acid secretion [5]. The inhibitory effects of SST and en-
Indeed, gastrin, the major circulating stimulus of acid se- dogenous prostaglandins (EPs) on acid secretion are me-
cretion, probably does not stimulate the parietal cells di- diated by receptors (SST2 and EP3, respectively) coupled
rectly but acts to mobilize histamine from the ECL cells by guanine nucleotide-binding proteins to inhibition of
in the oxyntic mucosa [2]. The gastrin-ECL cell pathway adenylate cyclase activity. All the pathways (both stimu-
has been investigated extensively in situ (gastric submu- latory and inhibitory) converge on and modulate the ac-
cosal microdialysis), in vitro (isolated ECL cells) and in tivity of the luminal enzyme (i.e. H+,K+-ATPase) [1, 2].
vivo (intact animals). Gastrin acts on CCK2 receptors to In 1973, pyridylmethyl benzimidazole sulfides were
control the synthesis of ECL cell histamine, accelerating originally discovered to be active PPIs: they were then
the expression of the histamine-forming enzyme, histi- modified to the corresponding sulfoxide timoprazole, pi-
dine decarboxylase (HDC), at both the transcription and coprazole and omeprazole in 1979. Omeprazole, the first
the translation/posttranslation levels [3]. The ultimate clinically available PPI, has been used in some countries
factor in acid secretion, however, is the stimulation of the for more than two decades [6]. More recently, other mem-
129.215.17.188 - 7/13/2013 8:28:07 PM
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- species interacts with the external surface of the H+,K+-
zole rabeprazole and esomeprazole have been developed ATPase that faces the lumen of the secretory space of the
and launched. 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
Inhibition of Acid Secretion: Where Are We? in hydrogen ion transport. This covalent inhibition of the
enzyme by the thiophilic sulfenamide results in a specific
Chemistry and Pharmacology of PPIs and long-lasting impairment of gastric acid secretion. The
Chemically, all the available PPIs [7, 8] consist of a selectivity of PPIs for the parietal cell proton pump stems
benzimidazole ring and a pyridine ring, but vary in the from the fact that H+,K+-ATPase is the only pump in the
specific side ring substitution (fig. 1). They are all weak body that generates a sufficiently steep proton gradient of
protonatable pyridines, with a pKa of about 4.0 for more than 1:1,000,000, corresponding to pH 0.8–1.0 in-
omeprazole and lansoprazole, about 3.9 for pantoprazole, side the canaliculus of a secreting parietal cell [10].
and about 5.0 for rabeprazole. As a result, they accumu- PPIs are the most potent inhibitors of gastric acid se-
late specifically and selectively in the secretory canalicu- cretion available [8, 10]. They are most effective when
lus, the highly acidic space of the parietal cell [8, 9]. With- the parietal cell is stimulated to secrete acid postprandi-
in that space, PPIs undergo an acid-catalyzed conversion ally, a relationship that has important clinical implica-
to a reactive species, the thiophilic sulfenamides, which tions for timing of administration. Because the amount
are permanent cations (fig. 2). The rate of conversion var- of H+,K+-ATPase present in the parietal cell is greatest
ies among the compounds and is inversely proportional after a prolonged fast, PPIs should be administered before
to their pKa: rabeprazole (4.71) 1 omeprazole (4.09) 1 the first meal of the day. In most individuals, once-daily
lansoprazole (3.92) 1 pantoprazole (3.89). The reactive dosing is sufficient to produce the desired level of acid
129.215.17.188 - 7/13/2013 8:28:07 PM
d
Lowest
PPIs in the morning with H2-RAs at bedtime
PPIs once daily
High-dose H2-RAs
Over-the-counter H2-RAs
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
PPIs should always be given before a meal. GERD [83, 84]. In both cases, tracings will frequently
The administration of current DR PPIs is recommended 0.5– show that PPIs fail to adequately control intragastric acid-
1.0 h prior to a meal in order to ensure that proton pumps are ac-
ity, especially during the night, although other pathophys-
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 iological features should be taken into account. Increasing
proton pump synthesized after drug levels fall will not be blocked the PPI dose will often offset this ‘relative’ resistance. If
from secreting acid. This kind of administration therefore allows NAB occurs in GERD patients with predominantly night-
the maximal antisecretory effect of the PPI dose and also mini- time symptoms, administering an H2-RA at bedtime
mizes any possibility of interaction with food.
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
Are Currently Available PPIs All the Same? unmask some limitations of currently available agents.
Although there are differences among PPIs concerning It should be mentioned, however, that there is a small
their pharmacokinetics, pharmacodynamics, influence group of patients who are ‘true’ omeprazole-resistant (de-
by food and antacids as well as potential for drug interac- fined as gastric pH !4 for 50% of 24 h), for whom an ab-
tions [7, 73], it is not always evident whether these often normality of the proton pump, due to mutations of cys-
subtle differences are clinically relevant. Several compre- teine 813 and 822, has been suggested [85]. Whether re-
hensive analyses of the available clinical trials concluded sistance to other PPIs exists has not been currently
that – when used at equivalent doses in the treatment of studied. In addition, although successful treatment with
various acid-related disorders – all the available agents PPIs in H2-RA-resistant GERD patients is the rule, few
are similarly effective [7, 74, 75]. These conclusions con- patients who showed therapeutic response to high-dose
cerning ‘clinical’ efficacy of PPIs are backed by similar H2-RAs after failure of high-dose omeprazole to control
results obtained in comparative ‘pharmacological’ analy- gastric acidity and gastroesophageal reflux have been re-
sis [76]. ported [86].
Guidance from the National Institute for Clinical Ex-
cellence (NICE) does not differentiate between PPIs ex- Shortcomings and Limitations of Current PPIs
cept on the grounds of price and accepted indications Although effective and safe, currently available PPIs
[77]. The physician’s choice of one PPI over another must are still far from the ideal antisecretory compound. An
therefore rest with her/his interpretation of the clinical ideal drug should allow full acid control around the clock
importance of the generally small differences among and dose-dependent and predictable pharmacokinetic
PPIs, their approval for treatment of specific clinical in- and pharmacodynamic properties. These properties and
dications within the physician’s practice jurisdiction, and the consequent clinical effects should also be reproduc-
the strength of the evidence based on the quantity and ible in a wide range of patient populations [87]. Finally,
quality of the supporting clinical trials [74]. an ideal agent will display high oral bioavailability, a rap-
id onset of action and few, if any, clinically relevant in-
Is There Any Acid Peptic Disease That Is Refractory teractions with food or concomitantly administered drugs
to PPIs? [88].
Nonhealing and/or delayed healing during acid inhibi- The so-called first-generation PPIs (omeprazole, pan-
tion treatment depend on the extent to which acid and toprazole and lansoprazole) have notable limitations.
‘non-acid’ factors are causative in the particular acid pep- These drugs exhibit substantial interpatient variability in
129.215.17.188 - 7/13/2013 8:28:07 PM
S-isomer R-isomer
Fig. 3. Different types of chemical iso-
mers.
Chirality is central to life, as many of the important and excretion) and quantitatively or qualitatively differ-
molecules come in two mirror-image forms that have very ent pharmacologic or toxicologic effects [103–105]. Ste-
different properties [100]. The fundamental molecules of reoisomers include not only the mirror-image enantio-
life, namely DNA and proteins, are, in fact, composed mers, but also geometric (cis/trans) isomers and diaste-
respectively of right- and left-handed subunits only. Na- reoisomers (isomers of drugs with more than one chiral
ture often discriminates between chiral forms of small center that are not mirror images of one another, fig. 3).
molecules, too, and what is a medicine on the one hand Diastereoisomers and geometric isomers are both chem-
can be a poison on the other. One example of this is tha- ically distinct and pharmacologically different (unless
lidomide. Thalidomide, which was given to pregnant they are interconverted in vivo) and are generally readily
women as a sedative and antinausea drug in the 1950s in separated without chiral techniques. Geometric isomers
Europe, turned out to produce debilitating birth defects and diastereoisomers therefore should, with the rare ex-
(i.e. missing limbs or phocomelia) [101]. But, in fact, only ception of cases where in vivo interconversion occurs, be
one enantiomer (i.e. the S-isomer) of the molecule is re- treated as separate drugs and developed accordingly
sponsible for these effects [102]. [100].
Stereoisomers are molecules that are identical in atom- When stereoisomers are biologically distinguishable,
ic constitution and bonding, but differ in the three-di- they might seem to be different drugs [103–105], yet it
mensional arrangement of the atoms. The stereoisomeric has been past practice to develop racemates (i.e., com-
pairs of greatest interest are those with one or more asym- pounds with 50:50 proportion of enantiomers). The prop-
metric (chiral) centers whose enantiomers (individual ste- erties of the individual enantiomers have – in the past –
reoisomers) are mirror images. According to an absolute not generally been well studied or characterized. Wheth-
convention, known as the Sequence Rule notation, when er separated enantiomers should be developed was
the peripheral groups are dimensionally arranged clock- largely an academic question because commercial separa-
wise around the chiral center, the R (rectus) configuration tion of racemates was difficult. Now that technological
is assigned to the molecule. On the contrary, if they are advances (large-scale chiral separation procedures or
arranged counterclockwise around the chiral center, the S asymmetric syntheses) permit production of many single
(sinister) configuration is allocated. enantiomers on a commercial scale, it is appropriate to
Optical isomers have essentially identical physical (ex- consider the development of the single enantiomer char-
cept for optical rotatory) and chemical (except in a chiral acterized by the most favorable profile of activity (euto-
environment) properties. Such stereoisomers usually re- mer) [104, 105]. Any decision to develop a drug as a sin-
quire specialized chiral techniques for their correct iden- gle enantiomer, however, should be made only after care-
tification, characterization, separation and measurement. ful evaluation of the cost-benefit ratio, i.e. when the
They are often readily distinguished by biological sys- advantages of the eutomer in terms of efficacy and toler-
tems, however, and may have different pharmacokinetic ability outweigh the associated increase in production
properties (absorption, distribution, biotransformation and development costs with respect to the racemic drug
129.215.17.188 - 7/13/2013 8:28:07 PM
S-omeprazole
1,200
R-omeprazole
nies to maintain market share and high prices despite
1,000
generic competition. Indeed, the zealously guarded pat-
800
ent monopoly system provides the same exclusivity and
600
market protection to an enantiomer of an existing prod-
400 uct as it does to a new chemical entity. This makes the
200 development and marketing of stereoisomers of existing
0 racemates more commercially attractive than the high
0 2 4 6 costs, uncertainties and risks of developing genuine in-
Time (h)
novative compounds [141]. It would be desirable and in
some ways ethical to explore from the very beginning the
Fig. 4. Plasma concentration vs. time at steady state (day 7) of
pharmacokinetics and pharmacodynamics of enantio-
omeprazole, S-omeprazole and R-omeprazole in four extensive mers and start the development of the more attractive
metabolizers after intake of 15 mg of each compound (from Ander- isomer (eutomer) right away.
sson et al. [120]).
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
2
teers. Within the first 30 min, DR-OME had no measur-
1
able activity on intragastric pH, whereas the IR formula-
0 tion caused an immediate increase in pH. From 4 to 6 h
0 3 6 9 12 15 18 21 24
b Time (h) 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-
Fig. 6. Pharmacokinetics and pharmacodynamics of IR-OME in tisecretory effect of IR-OME was quicker than that ob-
healthy volunteers. a Mean plasma concentration from fasting sub- served with the classical DR formulation while the dura-
jects with IR-OME (40 mg, n = 7) and DR capsules (40 mg, n = 10)
tion of the acid-lowering activity was similar. The early
(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 increase in intragastric pH is likely due to the neutralizing
intragastric pH (from Howden [162]). capacity of sodium bicarbonate, which also accelerates
and enhances absorption of omeprazole whose increased
bioavailability translates into a more profound acid sup-
pression.
ing of the granules disintegrates and a suspension formed. As already discussed, NAB is a common physiological
Due to the impaired absorption of omeprazole from this event, observed in approximately 70% of both healthy
extemporary preparation [154], a lower than expected an- subjects and GERD patients treated with up to twice-
tisecretory effect can be predicted. daily administration of DR PPIs, regardless of whether
The pharmacokinetics of IR-OME has been studied in the PPI is administered in the morning, prior to dinner,
healthy volunteers given 40 mg of both formulations in a or at bedtime [163]. Bedtime dosing with 40 mg of IR-
crossover fashion [161]. While the AUC was not signifi- OME suspension provides better control of nocturnal
cantly different, the Cmax was higher and the Tmax shorter gastric acidity than once-daily dosing with all DR PPIs
with the IR formulation (fig. 6). As with the DR capsules, (fig. 7) [164, 165] and also decreases NAB more effec-
both Cmax and AUC but not Tmax increased between 1 tively than with dosing of DR-OME 20 mg b.d. and lan-
and 7 days of once-daily dosing with IR-OME, indicating soprazole 30 mg b.d. or pantoprazole 40 mg b.d. Night-
an increase of bioavailability over time. time control of gastric acidity with IR-OME suspension
In a crossover trial, the effect of both formulations on is comparable with that achieved by twice-daily dosing of
intragastric acidity was investigated in healthy volun- DR esomeprazole 20 mg [164, 165].
129.215.17.188 - 7/13/2013 8:28:07 PM
a O N b O N
CH3
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.
Conversely from all the other PPIs, this compound is not 0.50
Cmax (ng/ml)
200,000
8,000
150,000
6,000
Fig. 10. Pharmacokinetics of tenatoprazole 100,000
after repeated (7 days) oral administration 4,000
in healthy volunteers. Both Cmax and AUC 2,000 50,000
show a linear correlation with the dose ad-
0 0
ministered. Each point refers to the mean 0 20 40 60 80 100 0 20 40 60 80 100
(8SEM) of the values obtained from 8 sub- Dose (mg) Dose (mg)
jects (drawn from data in Domagala and
Ficheux [188]).
Table 2. Comparison between pharmacokinetic parameters ob- either single and repeated administration). A linear cor-
tained in Japanese or European healthy volunteers after single oral relation between tenatoprazole dose and AUC was found,
administration of 20 mg tenatoprazole (from data in the Investiga-
thus showing a linear pharmacokinetic pattern (fig. 10).
tor’s Brochure [185] and Domagala and Ficheux [188])
The long half-life of tenatoprazole was confirmed for ev-
Pharmacokinetic Japanese subjects Caucasian subjects ery dose, reaching 8.7 8 2.6 h for repeated administra-
parameter (n = 6) (n = 8) tion of 40 mg [188]. A comparison of pharmacokinetic
parameters between Asian and European subjects is
Cmax, g/ml 4.2=0.6 2.980.8
shown in table 2.
tmax, h 2.580.2 2.581.0
t½, h 13.783.0 7.882.0 Pharmacodynamic studies on the same subjects
AUC, g h/ml 59.2813.0 31.0813.0 showed an increase of intragastric pH with tenatoprazole
40 mg daily for 7 days significantly higher (p ! 0.05) than
Each value represents the mean (8SD) of the values obtained that observed with the same regimen of esomeprazole, the
in 6–9 subjects.
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
time (94.7 vs. 98.3% and 86.3 vs. 89.3%, respectively) higher (4.7 8 1.1 units with tenatoprazole and 3.6 8 1.4
[185]. units with esomeprazole, p ! 0.01) [189]. The better con-
The compound was originally discovered by Mitsubi- trol of intragastric acidity achieved with tenatoprazole
shi Pharma and was therefore first studied in Japanese during the night was already evident from the first 24 h
subjects. Pharmacokinetic (and consequently pharmaco- of dosing [190].
dynamic) differences between East Asians and Cauca- A recent pharmacodynamic and pharmacokinetic in-
sians are well known, being mainly due to genetic poly- vestigation [191] confirmed and extended previous data
morphism of several phase I enzymes such as CYP2D6 showing the prolonged duration of acid suppression with
and the CYP2C subfamily [186]. Since the pharmacoki- tenatoprazole (fig. 11). The proportion of healthy volun-
netics and pharmacodynamics of PPIs depend on teers spending at least 16 h above pH 4 in the 24-hour
CYP2C19 genotype status, CYP2C19 genotype-depen- period was remarkably higher with tenatoprazole than
dent differences in pharmacokinetics and pharmacody- with esomeprazole (81.5 vs. 34.5%, p ! 0.001), while the
namics of PPIs influence the cure rates for the GERD and proportion of subjects with NAB was lower (73.1 vs.
H. pylori infection by PPI-based therapies [187]. Phar- 93.1%, p = 0.06), although the difference fell short of sta-
macokinetics of tenatoprazole was thus re-investigated in tistical significance. Even 3 days after treatment was dis-
H. pylori-negative healthy Caucasian subjects in a ran- continued, mean 24 h pH, and percentage of time at pH
domized, double-blind, dose-ranging study (10–80 mg, 13 and pH 14 were significantly higher with tenatopra-
129.215.17.188 - 7/13/2013 8:28:07 PM
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]).
zole, indicating a sustained control of intragastric acidity of a phase II dose-ranging (10, 20 and 40 mg daily) Ca-
with this novel PPI compared to esomeprazole. After 7 nadian study, performed in patients with reflux esopha-
days of repeated dosing the maximal plasma concentra- gitis (grade A–C according to Los Angeles classification),
tion of tenatoprazole was almost 6 times higher than that demonstrated that this novel PPI effectively heals muco-
of esomeprazole, while AUC was 32 times higher. A sig- sal lesions regardless of the dose [Alan B. Thomson, pers.
nificant correlation between AUC and percentage of time commun.]. After 4 weeks of treatment with whatever dose
intragastric pH 14 was observed with tenatoprazole not of tenatoprazole, the healing rate was larger than that re-
only during but also after stopping treatment [191]. ported with esomeprazole (40 mg daily) in published clin-
All these data clearly show that – compared to the ex- ical trials.
isting PPIs – tenatoprazole has a longer half-life and a Like the other PPIs, tenatoprazole is a racemic mixture
longer duration of the antisecretory action, in agreement of two stereoisomers which derive from the chiral nature
with the current knowledge according to which the anti- of the sulfur atom of the sulfinyl group [193]. As a conse-
secretory effect is proportional to the AUC [121, 192]. quence, in order to exploit the features of stereoselective
Although these properties should theoretically translate catabolism, the S-isomer was selected for further develop-
into a better therapeutic efficacy, no randomized clinical ment [194]. As expected, the in vitro binding of both S-
trials in acid-related diseases are available as yet. It is and R-tenatoprazole to hog gastric H+,K+-ATPase was
worth mentioning, however, that a preliminary analysis virtually the same and overlapped that observed with the
129.215.17.188 - 7/13/2013 8:28:07 PM
100,000
80,000 H+
60,000
40,000
20,000
0 Parietal
0 1 2 3 4 5 6 7 8 9 cell cytoplasm
Time (h)
K+
Na + K+ Cl –
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 = K+ HCO 3–
S-tenatoprazole sodium salt hydrate. Na + K+
racemate [181]. Similarly, there was no difference in Fig. 13. A simplified model for the secretion of gastric acid by the
binding reversibility kinetics amongst the different forms parietal cell. The H+,K+-ATPase located on the apical membrane
of the parietal cell exchanges H+ for K+. K+ is recycled from the
of this PPI [181]. Preliminary experiments in laboratory
canaliculus into the cytoplasm by K+ channels in the apical mem-
animals did confirm the antisecretory and ulcer healing brane. The combined actions of K+ channels and enzymes on the
activity of S-tenatoprazole and did point out that this iso- basolateral membrane regulate cytoplasmic K+ levels. Cl– enters the
mer is more effective than R-tenatoprazole [Ficheux et cell cytoplasm via a Cl–/HCO3– exchanger and moves from the cy-
al., unpubl. observations]. toplasm into the canaliculus via a Cl– channel (most likely ClC-2)
(from Geibel [94]).
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 markedly increased and remained over 5 or above
solubility of the sodium salt due to its peculiar crystal throughout most of the 24-hour recording period, both
structure. The crystal form of S-tenatoprazole sodium salt during day- and nighttime [Galmiche, pers. commun.].
hydrate is indeed quite different from that of S-tenato- Some pharmacodynamic and healing studies with S-te-
prazole-free form. In the crystal of S-tenatoprazole sodi- natoprazole sodium have already been planned and will
um salt hydrate there is a loose packing structure of mol- start in the near future.
ecules, which results in rapid water access and hence In summary, the available studies point out both phar-
greater solubility. The pharmacokinetics of S-tenatopra- macokinetic and pharmacodynamic advantages of te-
zole sodium was then studied in healthy volunteers and natoprazole over esomeprazole. Since this last compound
proved to be linear with a dose-related increase in both provides – amongst the members of the class – the most
Cmax and AUC [Ficheux et al., unpubl. observations]. The effective control of intragastric pH whatever the param-
antisecretory effect of this stereoisomer (80 mg orally eter considered [195], it is conceivable that tenatoprazole
once a day over 1 week) was investigated in H. pylori- could similarly be better than the other existing PPIs. Te-
negative healthy subjects. On day 7, intragastric pH was natoprazole (as well as its S-isomer) then appears a prom-
129.215.17.188 - 7/13/2013 8:28:07 PM
ising PPI for the treatment of acid-related diseases, where lished in 1982, this compound was shown to inhibit gas-
it has the potential to address unmet clinical needs. tric acid secretion in humans [197], although its mecha-
nism of action was not fully understood at the time. Sub-
Potassium-Competitive Acid Blockers sequently, SCH28080 was shown to block gastric
The next generation of drugs which suppress gastric H+,K+-ATPase by competing with K+ [198]. The develop-
acidity will most likely be P-CABs which are K+-com- ment of SCH28080 was discontinued because of hepatic
petitive inhibitors of the ATPase [93]. While the PPIs toxicity. Since then, several other compounds with this
have a unique mechanism of action based on their chem- peculiar mechanism of action have been synthesized and
istry, P-CABs have a structural specificity for their target, studied, but only few did reach clinical development.
the K+-binding region of the H+,K+-ATPase. Four representative members of the P-CAB class have
Although it can also be activated by NH4+ in vitro, the been studied in humans with the aim of finding a suitable
proton pump is highly selective for K+ [196]. In common drug for the treatment of acid-related diseases (table 4,
with many other cells, the level of K+ in the parietal cell fig. 14). Despite a number of papers presented at the re-
is higher than that in the plasma. The higher intracellular cent DDW (Chicago 2005) and UEGW (Copenhagen
K+ level is dependent on H+,K+-ATPase. This enzyme, 2005) and two clinical trials on GERD (registered at
located on the basolateral membrane of the cell, ex- www.clinicaltrials.gov) that were successfully completed,
changes intracellular H+ for extracellular K+ [10]. The AZD0865 was discontinued [199]. The same holds true
level of K+ within the cell is also regulated by K+ chan- for CS526. However, a follow-up compound of sorapra-
nels, which allow ion movement across the basolateral zan is currently in phase I [200]. Therefore, there are still
membrane (fig. 13). These channels have a particularly three molecules under active development.
important role in generating negative cell membrane po- P-CABs are lipophilic, weak bases that have high pKa
tential. Given the importance of the cation for enzyme values and are stable at low pH. This combination of
function, agents that compete with the binding of K+ properties allows them to concentrate in acidic environ-
have the potential to block acid secretion. P-CABs in- ments. For example, the concentration of a P-CAB with
hibit H+,K+-ATPase by binding ionically to the enzyme a pKa of 6.0 would theoretically be expected to be 100,000-
and thus prevent its activation by the K+ cation. Since fold higher in the parietal cell canaliculus (pH = 1) than
these molecules are larger than K+, it is likely that they in the plasma (pH = 7.4). The concentration of P-CABs
compete by preventing the access of the cation to its in the gastric mucosa is demonstrated by in vitro and in
binding site rather than occupying the ion-binding site vivo studies with AZD0865 and revaprazan [201, 202].
directly. On entering an acidic environment, P-CABs are instant-
P-CABs, despite sharing the same mechanism of ac- ly protonated and it is in this form that it is thought to
tion, represent a heterogeneous class of drugs. Indeed, bind to and inhibit the enzyme. The protonated form of
they belong to four different chemical classes, namely a P-CAB inhibits H+,K+-ATPase by binding ionically to
imidazopyridines, pyrimidines, imidazonaphthyridines it, as illustrated by the recovery of enzymatic activity af-
and quinolones [93, 94]. ter washout of AZD0865 and revaprazan [201, 202]. This
The prototype P-CAB, SCH28080, was developed by family of compounds binds to the outward-facing confor-
Schering-Plough more than 20 years ago. In a study pub- mation of the pump on the luminal side and do not re-
129.215.17.188 - 7/13/2013 8:28:07 PM
quire its activation. This would suggest that these agents for PPIs [207], the pH-rising effect of P-CABs seems to
will produce more rapid acid inhibition and will be able be increased in the presence of H. pylori infection [208].
to elevate gastric pH to a higher level than PPIs. Animal studies have shown a close correlation be-
Both animal and human studies have shown that P- tween maximum inhibition of acid output and the loga-
CABs achieve rapidly peak plasma concentrations after rithm of Cmax [93], thus suggesting that the duration of
oral administration. This is partly due to their stability at action of P-CABs will depend on their half-life. One draw-
low pH allowing their administration as IR formulations. back of these agents is the need for twice-daily dosing
All the compounds studied to date exhibit a linear phar- since they inhibit the pump only for the duration of their
macokinetic pattern [93]. The rapid absorption of P- presence in the blood; however, since these compounds
CABs is mirrored by a fast onset of acid inhibition. In are acid-stable, their plasma half-life may be readily pro-
healthy volunteers, a single oral dose of pumaprazole (an longed with extended-release formulations [92]. The
imidazopyridine compound marked BY841) [203] or re- main differences between P-CABs and PPIs are summa-
vaprazan [204] increased intragastric pH to about 6 with- rized in table 5. It is evident that P-CABs offer a more
in 30–60 min, whereas high doses of AZD0865 resulted rapid elevation in intragastric pH than a PPI (and similar
in over 95% inhibition of acid secretion within 1 h after to that achieved by an H2-RA) while maintaining the
oral dosing [205]. Both the degree [206] and the duration same degree of antisecretory action, whose duration is
[205] of the antisecretory action are dose-dependent. As dependent on half-life and can easily be prolonged by ap-
129.215.17.188 - 7/13/2013 8:28:07 PM
Acts directly on the H+,K+-ATPase enzyme Requires transformation to the active form
Super-concentrates in parietal cell acid space Concentrate in parietal cell acid space
(100,000-fold higher than in plasma) (1,000-fold higher than in plasma)
P-CABs binds competitively to the potassium Sulfenamide binds covalently
binding site of H+,K+-ATPase to H+,K+-ATPase
Duration of effect related to half-life Duration of effect related to half-life
of drug in plasma of the sulfenamide-enzyme complex
Full effect from first dose Full effect after repeated doses
propriate formulations. Whether these favorable phar- on the way in Europe [209]. A combination of H2-RA
macodynamic properties will translate into clinical ben- with the novel PPI tenatoprazole has also been patented
efits is unknown. Results of phase III clinical trials with [210].
one of such compound (namely revaprazan) are eagerly Although the last decade has been dominated by the
awaited. growing use of PPIs, several new H2-RAs have been syn-
thesized. While the majority of them have been discon-
New H2-Receptor Antagonists tinued, few molecules reached clinical development and
As already discussed, despite all the intrinsic limita- two (namely ebrotidine and lafutidine, fig. 15) have actu-
tions, there is still a place for H2-RAs in the era of PPIs. ally been marketed. These drugs belong to a new genera-
A recent survey of Castell’s team [71] found that the ma- tion of H2-RAs which combine the antisecretory effect
jority of GERD patients report a persistent improvement with a mucosal-protective activity.
of nighttime symptoms from bedtime H2-RA use and sug- Ebrotidine has been developed by the Ferrer group in
gested that a possible clinically important tolerance does Spain [211]. The drug is able to displace 3H-thiotidine-
occur in a small number of patients. In this connection a specific binding to H2-receptors with an affinity (Ki
fast-dissolving oral tablet containing a fixed dose combi- 127.5 nmol/l) significantly (p ! 0.05) higher than that
nation of a PPI and an H2-RA (product marked OX 17) of ranitidine (Ki 190.0 nmol/l) and cimetidine (Ki
has been developed by Orexo AB (Uppsala, Sweden) and 246.1 nmol/l) [212]. Its antisecretory efficacy is similar to
phase II clinical trials with this formulation are presently that of ranitidine and 10 times higher than that of cimeti-
129.215.17.188 - 7/13/2013 8:28:07 PM
80
✽✽
lafutidine has a potent and long-lasting antisecretory ef-
✽✽ ✽✽ ✽✽
fect, a finding confirmed by human investigations [223]
60 ✽✽
✽✽ showing that this drug inhibits acid secretion more
40 ✽✽
strongly than conventional H2-RAs. Conversely from ra-
20 nitidine and famotidine, lafutidine increases both day-
0
and nighttime intragastric pH in H. pylori-negative sub-
jects [224], and conversely from omeprazole (and other
1 2 3 3.5 4 5 6 7 8
PPIs) its efficacy is not influenced by the CYP2C19 gen-
pH 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-
Fig. 16. Time spent above a given pH in the postprandial period
over study [226] in healthy volunteers did show that a
after administration of a single dose of lafutidine (10 mg) or rabe-
prazole (20 mg) in healthy volunteers. Each point refers to the mean single dose (10 mg) of this novel H2-RA is able to increase
(8SD) of the values obtained from 10 subjects. ** Significant (p ! intragastric pH more quickly than a single dose (20 mg)
0.01) difference between means (from Inamori et al. [226]). 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
dine [211]. The mucosal-protective properties of ebroti- than that of the PPI since the drug maintained the pH
dine, possibly due to enhanced mucosal synthesis of both over a given threshold for a sustained period of time (fig.
endogenous prostaglandins (PGs) and nitric oxide (NO) 16). Its terminal half-life (3.30 8 0.39 and 3.79 8 1.02
[213, 214], stem from its ability to improve the physico- h in fasting and fed conditions, respectively [228]) is lon-
chemical characteristics of mucus gel (i.e. increase in mu- ger than that of cimetidine, ranitidine and nizatidine [55,
cus gel dimension, viscosity, hydrophobicity and hydrogen 229] and shorter than that of roxatidine, but not dissimi-
ion retardation capacity). Improvements in mucus gel-pro- lar from that of famotidine [55].
tective qualities with ebrotidine are directly related to the Conversely from other H2-RAs [230], lafutidine does
ability of the drug to enhance the synthesis and secretion increase SST release, which may contribute to its antise-
of sulfo- and sialomucins and phospholipids of gastric mu- cretory effect [231]. Similarly, the observed rise in calci-
cus and to promote mucin macromolecular assembly tonin gene-related peptide (CGRP) levels after drug ad-
[215]. This drug also exhibits an inhibitory activity against ministration could account for both its acid-lowering and
H. pylori that is synergistic with a number of antibacterial cytoprotective activities [232].
agents; it inhibits the urease enzyme and the proteolytic Lafutidine displays mucosal protection against a vari-
and mucolytic activities of H. pylori, and counteracts the ety of noxious agents, and structure-activity relationships
inhibitory effects of H. pylori lipopolysaccharide. revealed that the presence of furfurylsulfinyl, pyridyl and
Although ebrotidine proved to be as effective as ra- amide moiety (fig. 15) are chemically important for the
nitidine for the treatment of patients with PU or erosive gastroprotective activity. The mucosal-protective effect
reflux esophagitis [211], it achieved a significantly better of lafutidine is attenuated by pretreatment with the an-
ulcer healing rate (94 vs. 86%, p ! 0.05) than ranitidine tagonist of CGRP (CGRP8-37) and the blocker of NO
treatment in smokers [216]. Unfortunately, the drug was production (NG-nitro-L-arginine), as well as chemical ab-
prematurely withdrawn from the Spanish market because lation of capsaicin-sensitive sensory neurons, suggesting
of serious hepatotoxicity [217–219]. that this action appears through capsaicin-sensitive affer-
Another peculiar H2-RA endowed with both antisecre- ent neurons and is mediated by CGRP and NO [233].
tory and mucosal-protective activities is lafutidine. This Interestingly enough, lafutidine also exhibits a protective
drug, originally developed by Fujirebio Inc. [220], is cur- activity against the experimentally-induced mucosal le-
rently marketed by UCB and Taiho Pharmaceutical in sions in digestive tissues other than the stomach, i.e. acid-
Japan. This compound showed a potent and long-lasting induced reflux esophagitis [234], indomethacin-induced
129.215.17.188 - 7/13/2013 8:28:07 PM
cell, and their products gastrin, histamine and hydrochlo- presumed to play a role in subsequent histamine release
ric acid, respectively. Gastrin has a direct secretory effect [249]. The released histamine is a potent stimulant of acid
on both parietal cells and ECL cells, although the latter secretion, exerting a direct stimulatory effect on the H2-
effect is probably far more significant. The peptide medi- receptor of the parietal cell. The parietal cell secretory
ates histamine release from ECL cells via activation of its product, hydrochloric acid, causes antral inhibition of gas-
CCK2 receptors. The initial signal transduction events in- trin release from the G cell, probably via a SST-regulated
volve a transient rise in intracellular calcium, followed by mechanism. It also seems probable that SST by a direct
histamine granule exocytosis [249]. This process occurs action on ECL cells is able to inhibit histamine release,
maximally within 5 min. Thereafter, extracellular calcium since the direct effect of paracrine peptide on parietal cells
influx and histidine decarboxylase (HDC) activation are is not pronounced in vitro [4]. Indeed, ECL cells have been
129.215.17.188 - 7/13/2013 8:28:07 PM
AUC (ng/ml h)
50
40
10,000
Fig. 18. Pharmacokinetics and pharmaco- 30
dynamics of itriglumide after single admin- 20
5,000
istration in healthy volunteers. a Plot of
10
AUC vs. dose, showing a linear pharmaco-
kinetic pattern. b Dose-dependent inhibi- 0 0
tion of G-17 (32 pmol/kg h) induced acid 0 100 200 300 400 500 600 700 0 100 200 300 400 500 600 700
secretion (drawn from data in Beglinger et a Single dose (by oral route) (mg) b Single dose (by oral route) (mg)
al. [264]).
reported to express SST receptors, suggesting a dual regu- Amongst the amino acid derivatives, proglumide,
lation of the ECL cell by both gastrin and SST [250]. which has long been used as an antiulcer drug [256], was
Whilst gastrin appears to be a major stimulant for hista- considered the prototype CCK antagonist [257]. Its low
mine release, there is also significant evidence for the role potency and specificity (the compound binds to both
of other gut neurotransmitters, namely acetylcholine, va- types of receptors) stimulated the synthesis of glutaramic
soactive intestinal peptide, PYY and corticotropin gene- acid derivatives, the most interesting ones being lorglu-
related peptide (CGRP) in this process [251]. mide and loxiglumide (as selective CCK1-receptor antag-
Given the important physiological role of gastrin in onists) and spiroglumide and itriglumide (as CCK2-re-
the stimulation of gastric acid secretion, selective CCK2- ceptor antagonists). These compounds (developed at Rot-
receptor antagonists offer a potential approach to regulate ta Research Laboratorium, Milan, Italy) are active after
acid production. High-affinity nonpeptide antagonists for oral administration and able to antagonize the effects of
both types of CCK receptors were synthesized more than both endogenous and exogenous peptides (i.e. CCK and
15 years ago. Their availability has stimulated a broad gastrin) [258, 259].
array of investigations into the physiologic actions of Animal studies [260, 261] have shown that spiroglu-
CCK-like peptides [252], including gastrin [253]. mide (compound marked CR-2194) is a selective CCK2
At least 12 chemical classes of CCK-receptor antago- antagonist, capable of inhibiting dose-dependently penta-
nists have been described [254]. Amongst them, several gastrin- but not carbachol- or histamine-stimulated acid
ligands with high affinity for CCK2 receptors have been secretion. Studies performed on healthy volunteers [262]
identified and characterized by binding and pharmaco- confirmed the inhibitory activity against gastrin-induced
dynamic studies [246]. However, only few have been test- acid secretion and also showed its ability to inhibit post-
ed in humans for their effect on acid secretion or their prandial gastric secretion. Despite these promising re-
anxiolytic activity2. The 5 compounds, whose antisecre- sults, the development of spiroglumide was ended because
tory effect was studied in clinical trials, will be reviewed more potent and selective derivatives became available.
in detail. They belong to amino acid (i.e. spiroglumide Itriglumide (compound marked CR-2945) is a follow-
and itriglumide) or benzodiazepine (i.e. L-365,260, YF- up selective antagonist endowed with a good oral bio-
476 and Z-360) derivatives (fig. 17). 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
2
The involvement of CCK in human anxiety is well documented. Exog- duodenal ulcer was comparable to that of ranitidine. The
enous administration of CCK2-receptor agonists, such as cholecystokinin-tet-
rapeptide and pentagastrin, provoke panic attacks in man. Patients with panic
pharmacodynamics and pharmacokinetics of itriglumide
disorder are hypersensitive to CCK2-receptor stimulation compared to healthy were recently studied in humans, where the compound
volunteers and patients with other anxiety disorders, and they differ from inhibited gastrin-stimulated acid secretion in a dose-de-
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 pendent manner (fig. 18). The pharmacokinetics proved
CI-988) are being developed as anxiolytics [254, 255]. to be linear in the dose range of 30–600 mg and drug was
129.215.17.188 - 7/13/2013 8:28:07 PM
Antigastrin Vaccine
G-17DT is an immunoconjugate of the amino-termi- Fig. 19. Antigastrin immunogen. G-17DT consists of: (a) A syn-
nal sequence of gastrin 17 (G-17) linked by means of a thetic peptide which is similar to a portion of the targeted hormone
spacer peptide to diphtheria toxoid (fig. 19) [294]. It has gastrin 17. (b) A ‘carrier’, diphtheria toxoid (DT), to which a num-
ber of these synthetic gastrin peptides are chemically bound. DT,
been developed by Aphton Corp. (Miami, Fla., USA),
which is recognized as foreign, provokes the body into initiating an
originally labeled as Gastrimmune™ and later known as immune response. Since the body normally will not mount an im-
Insegia™. Given as an intramuscular vaccination, it has mune response against ‘self’ proteins and molecules, the coupling
been shown to induce the formation of antibodies that of DT to the synthetic peptide is critical for provoking an immune
can neutralize not only G-17 but also its precursor gly- response against the synthetic peptide. Since the peptides resemble
a portion of the targeted hormone, the antibodies produced also
cine-extended G-17, which also stimulates the growth of
bind and neutralize natural gastrin 17. (c) A proprietary, slow-re-
human gastric and possibly other GI cancers [295]. These lease emulsion which contains (a) and (b).
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 able mean of achieving acid suppression while avoiding
percent of patients given the highest dose of the vaccine hypergastrinemia. A phase II clinical trial in GERD has
(250 g) achieved a response. There was indeed a signif- been started although not currently recruiting patients
icant difference between the median survival times noted [302]. Aphton has also patented the use of G-17DT to-
for patients who produced an immune response and for gether with antisecretory agents for the treatment of
those who did not [296]. While preliminary, these results GERD [303]. Combination therapy is claimed to be a
are promising and three phase III clinical trials (registered more effective method of controlling gastric acid secretion
at www.clinicaltrials.gov) with G-17DT, alone or in com- since two independent mechanisms will operate. In addi-
bination with chemotherapy, are ongoing [297]. tion, the gastrin immunogen will block PPI-induced hyper-
In addition to the treatment of GI and pancreatic can- gastrinemia, thus reducing mucosal hyperplasia [290].
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- Conclusions and Perspectives for the Future
deed, continuous intravenous infusion of this peptide to
healthy volunteers significantly increases gastroesophageal The discovery of gastrin by John Edkins [304] initi-
reflux and the number of transient lower esophageal sphinc- ated the scientific examination of the regulation of gastric
ter relaxations associated with reflux [298]. Active immu- acid secretion and led to elucidation of the pathogenic
nization against G-17 should not only neutralize its acid- basis of PU and its subsequent cure. During the course of
stimulating properties but also reduce postprandial gastro- the century after this breakthrough, the identification of
esophageal reflux. Animal studies [299–301] have indeed the cellular regulators of acid secretion culminated in the
shown that this antigastrin vaccine strongly inhibits gastric development of novel pharmacotherapeutic agents,
acid secretion. Therefore, G-17DT would represent a reli- namely H2-RAs and PPIs, which allowed the effective
129.215.17.188 - 7/13/2013 8:28:07 PM
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