CLINICAL THERAPEUTICSVVOL. 22, NO.

3, 2000

The Proton-Pump Inhibitors: Similarities and Differences

John Horn, PharmD

University of Washington School of Pharmacy, Seattle, Washington

ABSTRACT

Objective: This paper examines the clinical pharmacology of the proton-pump in-
hibitors (PPIs) and briefly reviews some comparative studies of these agents.
Background: PPIs have emerged as the treatment of choice for acid-related diseases, in-
cluding gastroesophageal reflux disease (GERD) and peptic ulcer disease. Although these
drugs+meprazole, lansoprazole, pantoprazole, and rabeprazole-share a common struc-
ture (all are substituted benzimidazoles) and mode of action (inhibition of H’,K+-adeno-
sine triphosphatase [ATPase]), each differs somewhat in its clinical pharmacology.
Results: In comparative clinical trials found in MEDLINE@, PPIs administered once
daily produced endoscopic evidence of healing in >90% of patients with duodenal ulcer
after 4 weeks of treatment, in >90% of those with gastric ulcer after 6 weeks of treatment,
and in ~90% of those with ulcerative or erosive GERD after 8 weeks of treatment. Main-
tenance therapy with daily doses of a PPI has been shown to be an effective means of
preventing GERD relapse. PPIs also inhibit the growth of Helicobacter pylori, now rec-
ognized as an important factor in peptic ulcer disease, and, when administered in combi-
nation with antibiotics, provide the best treatment for eradication of the bacterium.
Rabeprazole has a more rapid onset of H+,K+-ATPase inhibition than the other PPIs and,
compared with omeprazole, a greater effect on intragastric pH after the first dose. Omepra-
zole and lansoprazole have a greater potential for drug-drug interactions than do panto-
prazole and rabeprazole.
Conclusion: Although the individual PPIs have similar efficacy in many cases, differ-
ences between them should be considered when choosing a treatment regimen.
Key words: acid-related disease, gastroesophageal reflux disease, peptic ulcer disease,
proton-pump inhibitors. (Clin Ther: 2000;22:266-280)

Accepted for publication February 2, 2000.

Printed in the USA. Reproduction in whole or part is not permitted.

266 0149.2918/00/$19.00
J. HORN

INTRODUCTION

Proton-pump inhibitors (PPIs) have emerged

as the drug class of choice for treating
patients with acid-related diseases, in-
cluding gastroesophageal reflux disease A
(GERD), duodenal ulcer, and gastric ul- Pantoprazole
cer. PPIs are also effective in treating
patients with Barrett’s esophagus and
Zollinger-Ellison syndrome. CHz CH,
These agents inhibit gastric acid secre-
tion by targeting the gastric acid pump,
H+,K+-adenosine triphosphatase (ATPase),
ti
in the canalicular membrane of the parietal
Omeprazole
cell.‘12The regulation of acid secretion is a
complex process involving many cell
types, hormones, and mediators, but these
processes converge in a final common step
involving H+,K+-ATPase.1As a result, PPIs
effectively inhibit acid secretion in a man-
ner independent of the processes that stim- ii
ulate the parietal cell.’ Lansoprazole
Each member of the PPI class-
omeprazole, lansoprazole, pantoprazole,
Na
and rabeprazole-has been shown to be
effective and well tolerated in random-
ized, controlled clinical trials. This paper
p&fH;~-cT;H*-&cH~
examines the clinical pharmacology of the
N-
PPIs and briefly reviews some compara-
tive PPI studies found in MEDLINE@. Rabeprazole

Figure 1. Chemical structures of the

MECHANISM OF ACTION proton-pump inhibitors.

PPIs are substituted 2-pyridyl methyl-

sulfinyl benzimidazoles that share a simi-
lar core structure (Figure 1). These agents
are protonatable weak bases with pKa (neg-
ative logarithm of the acid-ionization con-
stant) values of -4, with the exception of
rabeprazole, which has a pK, value of 5.t**
PPIs therefore accumulate selectively in
acidic spaces with a pH of <4, which are
found primarily in the secretory canalicu-
lus of the gastric parietal cell. In this acidic
environment, protonation of the pyridine
and benzimidazole nitrogens results in for-
mation of a tetracyclic sulfenamide, which
represents the active form of the drug.
The sulfenamide binds to exposed cys-
teine residues in the alpha subunit of
H+,K+-ATPase to form covalent disulfide
bonds, which inhibit the activity of the
pump. Because PPIs bind covalently, the
duration of action of these drugs extends

267

beyond their plasma half-life of -1 to 2
hours.’ Gastric acid secretion is restored
by translocation of new H+,K+-ATPase to
the secretory canaliculus membrane.
However, some enzyme activity may be
restored, depending on whether glu-
tathione can reverse the disulfide bond.3
Although all PPIs have the same gen-
eral mechanism of action, the nature of the
pyridine and benzimidazole substituents
may confer physical and chemical differ-
ences. Because of its higher pK,, rabepra-
zole is activated over a wider pH range
than omeprazole, lansoprazole, or panto-
prazole, and it converts to its sulfenamide
faster than the other 3.4 This profile might
explain why rabeprazole has a faster onset
of inhibitory action with respect to H+,K+-
ATPase and acid secretion.
In a study by Besancon et al” in porcine
gastric vesicles, rabeprazole fully inhibited
H+,K+-ATPase within 5 minutes, whereas
omeprazole and lansoprazole required 30
minutes to do so, and pantoprazole had
reached only 50% inhibition at 4.5 minutes.
Inhibition of acid secretion correlated with
rabeprazole’s ability to bind to a cysteine
residue (either cysteine-8 13 or cysteine-
822) in the fifth to sixth transmembrane
segment of the alpha domain of H+,K+-
ATPase. Even after full inhibition of acid
secretion had occurred, rabeprazole con-
tinued to bind to other exposed cysteines
in the enzyme: cysteine-892 in the seventh
to eighth transmembrane segment and cys-
teine-321 in the third transmembrane seg-
ment. In comparison, although other PPIs
also interacted initially with 1 of the 2 cys-
teines in the fifth to sixth transmembrane
segment to inhibit acid secretion, panto-
prazole did not bind to other exposed cys-
teines, whereas omeprazole also interacted
with cysteine-892 and lansoprazole with
cysteine-32 1. The pharmacologic signifi-
268
CLINICAL THERAPEUTICS@
cance of these distinct patterns of binding
remains to be determined, but they may
help explain the subtle pharmacologic dif-
ferences between PPIs.
INHIBITION OF GASTRIC ACID
SECRETION
Gastric acid is a critical factor in general
gastrointestinal health. Although the exact
nature of its role varies in GERD, gastric
ulcer, duodenal ulcer, Zollinger-Ellison
syndrome, and Barrett’s esophagus, all are
acid-related disorders. Evidence of the im-
portant role of gastric acid in these condi-
tions is provided by the success of antise-
cretory therapy in many patients6
Gastric acid activates pepsinogens to
digest proteins. Maximum peptic activity
occurs at a pH of 1.5 to 2. Increasing the
pH thus decreases the activity of pepsin,
which, because pepsin is a major compo-
nent of the refluxate in GERD, subse-
quently decreases esophageal erosion.’
GERD symptoms such as heartburn are
also associated with more acidic reflux-
ate. Patients with duodenal ulcer gener-
ally secrete more gastric acid than healthy
subjects, but there is much interpatient
variability. Ulcer pain seems to correlate
with acid secretion in most patients. Pa-
tients with gastric ulcer usually have nor-
mal or low levels of acid secretion, but
gastric acid can contribute to gastric ul-
cers because it disrupts mucosal integrity.6
The presence of Helicobacter pylori is
now thought to cause 270% of gastric ul-
cers and 90% of duodenal ulcers. Pres-
ence of this microorganism increases the
secretion of gastric acid and also affects
the antisecretory activity of PPIs. There-
fore, achieving adequate acid suppression
to produce ulcer healing is pharmacolog-
ically complex. The relationship of gas-
J. HORN
tric acid suppression to gastric ulcer heal-
ing is particularly complex, with healing
usually requiring a longer period of sup-
pression in patients with gastric ulcer than
in those with duodenal ulcer.6
Proton-Pump Inhibitors and Gastric
Acid Secretion
As a class, PPIs are more effective than
histamine, (HJ-receptor antagonists in el-
evating 24-hour intragastric pH, but indi-
vidual agents differ in time to onset of acid
control. In a placebo-controlled, crossover
study, Williams et al8 measured 24-hour
intragastric acidity after 1 and 8 days of
once-daily treatment with rabeprazole 20
mg or omeprazole 20 mg in a group of 24
healthy men. After the first dose, the me-
dian 24-hour intragastric pH and percent-
age of time during which intragastric pH
was ~3 and >4 were significantly greater
5 n Rabeprazole 20 mg
n Omeprazole 20 mg
Day 1
Figure 2. Median 24-hour intragastric pH after 1 and 8 days of rabeprazole 20 mg,
omeprazole 20 mg, or placebo in healthy volunteers.8 *P < 0.001 versus placebo;
'P < 0.001 versus omeprazole.
with rabeprazole than omeprazole (P <
0.001) (Figure 2). After 8 days, rabepra-
zole continued to produce an intragastric
pH ~3 and >4 for a greater percentage of
time. Although median 24-hour intragas-
tric pH did not differ significantly between
treatments, rabeprazole provided a signif-
icantly greater decrease in acidity during
the afternoon and nighttime periods. This
study demonstrated that rabeprazole 20
mg had a significantly faster onset of acid
control than did omeprazole 20 mg.
The results of other studies9*‘0 suggest
that pantoprazole and lansoprazole may
be more effective than omeprazole in el-
evating 24-hour intragastric pH after 7
days of treatment. However, these differ-
ences may reflect the doses compared.
For example, pantoprazole 40 mg and
lansoprazole 30 mg were more effective
in inhibiting acid secretion in healthy
volunteers than omeprazole 20 mg, but
--
Day 8
269

were equally as effective as omeprazole
40 mg.9g10
As mentioned, the presence of H pylori
appears to affect the antisecretory activity
of PPIs. In studies of omeprazole and pan-
toprazole treatment, intragastric pH was
significantly higher in subjects with Hpy-
lori infection than in other subjects (P <
0.01). In the omeprazole study, for exam-
ple, the median daytime pH in the corpus
was 5.4 in H pylori-positive subjects and
2.9 in H pylori-negative ones.” H py-
lori-related differences in intragastric pH
were evident at both low and high doses
of pantoprazole.t2
In a study in ulcer patientsI intragastric
pH following administration of omeprazole
was higher before eradication of H pylori
than after eradication. However, in the ab-
sence of omeprazole, intragastric pH did not
differ before or after eradication of H py-
lon’. Possible explanations for the apparent
greater effect of PPIs in H pylori-positive
subjects are that the bacterium produces acid-
neutralizing substances such as ammonia
that may also interfere with H+,K+-ATPase,
and that the gastritis associated with the in-
fection promotes release of acid-inhibiting
cytokines.14 In any case, PPI doses may
need to be higher in patients who do not
harbor H pylori than in those who do.
CLINICAL INDICATIONS FOR
PROTON-PUMP INHIBITORS
Gastroesophageal Rejlux Disease
GERD, which is characterized by pro-
longed and repeated exposure of the
esophageal mucosa to acidic gastric con-
tents, is often accompanied by erosive or
ulcerative damage to the esophagus. In a
meta-analysis of numerous clinical trials,
Bell et alI5 found that esophageal healing in
270
CLINICAL THERAPEUTICY
GERD is related to the duration of acid sup-
pression within a 24-hour period. Robinson
et alI6 found that administration of rabepra-
zole 20 or 40 mg once daily for 7 days in
patients with GERD increased mean 24-
hour intragastric pH to 4.2 and 4.7, respec-
tively. These increases in intragastric pH
were accompanied by reductions in the per-
centage of time that esophageal pH was ~4,
as well as in the overall number of reflux
episodes and prolonged reflux episodes.
In the majority of patients, healing oc-
curs after 4 weeks of once-daily treatment
with a PPI, compared with 8 weeks of
treatment several times daily with an H,-
receptor antagonist.’ Comparative clinical
trials show PPIs to be at least as effective
as Hz-receptor antagonists, if not more so,
and they are equally well tolerated. In a
multicenter study involving 202 patients
with erosive or ulcerative GERD, Dekkers
et alI7 found that the healing rates for
rabeprazole 20 mg and omeprazole 20 mg
were equivalent in patients with GERD:
8 1% after 4 weeks of treatment and >90%
after 8 weeks of treatment (Figure 3). Both
PPIs also provided similar relief of heart-
burn, as measured by frequency and sever-
ity of symptoms. In another multicenter
study, Mijssner et alI8 found that the
length of time required for symptom re-
lief was similar for pantoprazole 40 mg
and omeprazole 20 mg. The 2 treatments
provided similar healing rates of 74% and
78%, respectively, after 4 weeks of treat-
ment, and 90% and 94% after 8 weeks.
GERD healing is maintained and symp-
toms are prevented in the majority of pa-
tients who undergo long-term treatment
with PPIs. In patients who received 1 year
of daily treatment for GERD and had en-
doscopic evidence of healing, the relapse
rate was significantly lower with lansopra-
zole or omeprazole than with placebo or ra-
J. HORN

W Rabeprazole 20 mg
q Omeprazole 20 mg

GERD Gastric Ulcer Duodenal Ulcer

98

O-
4 8 3 2 4
Time (wky

Figure 3. Comparison of healing rates after once-daily treatment with rabeprazole 20 mg

and omeprazole 20 mg in 202 patients with ulcerative or erosive gastro-
esophageal reflux disease (GERD), I7 227 patients with active gastric ulcer,22
and 205 patients with active duodenal ulcer.2s

nitidine.‘O Rabeprazole has also been shown
to be highly effective in long-term preven-
tion of esophagitis and GERD symptoms.‘”
In various comparative triaI~,‘~ the relapse
rates for once-daily lansoprazole 30 mg and
omeprazole 20 mg were similar, and those
for lansoprazole were significantly lower
than those for twice-daily ranitidine 300
mg (P < 0.01). These studies demonstrate
the effectiveness of PPI therapy in main-
taining GERD healing.
Gastric Ulcer
In a meta-analysis of studies involving
a variety of antisecretory drug regimens,
Howden and Hunt20 found a significant
correlation between suppression of 24-
hour intragastric acidity and the rate of
gastric ulcer healing after 2 (P = O.Ol), 4
(P < O.Ol), and 8 weeks (P < 0.01) of
treatment. The pharmacologic agents
studied, which included omeprazole, var-
ious H2-receptor antagonists, and enpros-
til, suppressed 24-hour intragastric acidity
by 34% to 98%. This acid suppression
was associated with ulcer healing rates of
21% to 44% at 2 weeks, 50% to 80% at 4
weeks, and 82% to 96% at 8 weeks. Thus,
the rate of ulcer healing was related to the
duration of treatment.
PPIs provide more rapid healing and
higher ulcer healing rates than H,-recep-
tor antagonists. Studies have demon-

271

strated that once-daily treatment with
omeprazole, lansoprazole, or pantopra-
zole is superior to twice-daily treatment
with ranitidine, famotidine, or cimeti-
dine.21 In most comparative studies in pa-
tients with active gastric ulcer, individual
PPIs have exhibited similar rates of ulcer
healing. For example, in a randomized,
double-blind, multicenter study involving
227 patients with active gastric ulcers,
Dekkers et alz2 found that once-daily treat-
ment with either rabeprazole 20 mg or
omeprazole 20 mg produced equivalent
endoscopic healing rates after 3 weeks
(58% vs 61%) and 6 weeks (91% each)
(see Figure 3). However, rabeprazole pro-
vided more consistent, and in some cases
statistically superior, improvement in
symptoms compared with omeprazole at
both time points. Approximately half of
the patients in this study had antibodies
against H pylori.
Duodenal Ulcer
Treatment of patients with duodenal ul-
cer requires eradication of H pylori to re-
duce the risk of relapse. However, the ma-
jority of comparative clinical trials have
not addressed the role of H pylori. One
meta-analysis of a large number of clini-
cal studies23 found that elevation of intra-
gastric pH to >3 for 218 hours each day
was optimal for duodenal ulcer healing.
However, as will be described, eradica-
tion of H pylori with combination antibi-
otic therapy may require elevation of in-
tragastric pH to ~5.’
Duodenal ulcer healing is achieved af-
ter 2 to 4 weeks of treatment with once-
daily PPI therapy, compared with 4 to 8
weeks of treatment with H,-receptor an-
tagonists.’ Moreover, symptom relief oc-
curs more rapidly with PPI therapy. In
272
CLINICAL THERAPEUTICS@
clinical studies, once-daily rabeprazole 20
mg was more effective than twice-daily
ranitidine 150 mg in patients with duode-
nal ulcer.24 After 2 and 4 weeks of treat-
ment, once-daily pantoprazole 40 mg was
more effective than once-daily ranitidine
300 mg in producing duodenal ulcer heal-
ing, and many (but not all) studies showed
greater pain relief with pantoprazole.’
Moreover, 8 weeks of PPI treatment pro-
duces ulcer healing in the majority of pa-
tients who are refractory to treatment with
H,-receptor antagonists. lo
In a randomized, double-blind, multi-
center study, Dekkers et a12” compared
rabeprazole 20 mg and omeprazole 20 mg
in 205 patients with active duodenal ulcer,
82% of whom had H pylori infection. Re-
spective ulcer healing rates at 2 and 4
weeks were 69% and 98% with rabepra-
zole and 61% and 93% with omeprazole
(see Figure 3). By the end of the study, pa-
tients treated with rabeprazole had a sig-
nificantly greater improvement in daytime
pain compared with those given omepra-
zole (P = 0.04). In studies comparing pan-
toprazole 40 mg and omeprazole 20 mg,
the 2 PPIs provided similar rates of ulcer
healing and symptom relief.9
Zollinger-Ellison Syndrome
Sustained release of gastrin from gas-
trinomas in the pancreas or duodenum is
central to the pathogenesis of Zollinger-
Ellison syndrome. Gastrin increases basal
acid secretion, causing hypertrophy of the
gastric mucosa, which in turn causes an
increase in the number of parietal cells
and therefore increased maximum acid
output. Unregulated hypersecretion of
acid and pepsin leads to severe peptic ul-
cer disease, esophagitis, and diarrhea. Be-
cause gastrinomas tend to grow slowly,
J. HORN
the early morbidity and mortality of this
syndrome are attributable to acid hyper-
secretion and ulcer complications.26-28
Treatment goals are twofold: control of
acid hypersecretion, and location and pos-
sible removal of the gastrinoma.27 How-
ever, the 5-year cure rate can be <30% af-
ter gastrinoma resection, even among
patients who have no metastases.26There-
fore, control of acid to achieve symptom
relief and ulcer healing is central to the
management of this disease. Acid secre-
tion must be reduced to ~10 mmol/h to
prevent complications.28 Although the in-
troduction of Hz-receptor antagonists was
a major treatment advance, the necessary
level of acid suppression was difficult to
achieve, even with dosing 4 times daily.
Oral Hz-receptor antagonists are no longer
used to treat patients with Zollinger-Ellison
syndrome, because PPIs are better able to
suppress acid secretion and have a longer
duration of action. With PPIs, it is gener-
ally possible to reduce basal acid secre-
tion to 12 mrr~ol/h.~~
Long-term treatment with omeprazole,
lansoprazole, or rabeprazole is effective in
the management of this disease. The results
of several studies involving 210 patients
with Zollinger-Ellison syndrome showed
omeprazole to be effective in 99% of pa-
tients over a period ranging from 0.5 to 54
montbs.29 In these studies, omeprazole was
administered at median daily doses of 60 to
100 mg, with 20% to 60% of patients re-
ceiving treatment in divided daily doses.
In another study, 3olansoprazole was ad-
ministered for a median of 28 months to
26 patients with Zollinger-Ellison syn-
drome and peptic ulcer disease. The ini-
tial daily dose of 60 mg was individual-
ized to achieve a basal acid output of <5
mmol/h in patients with intact stomachs,
and ~1 mmol/h in patients who had had a
previous gastrectomy or esophagitis. Lan-
soprazole produced ulcer healing and
symptom resolution, usually within sev-
eral weeks of beginning treatment. No-
tably, patients with Zollinger-Ellison syn-
drome who had undergone gastrectomy
were more likely to experience ulcer re-
currence, even with strict acid control.
Rabeprazole was administered to 10 pa-
tients with Zollinger-Ellison syndrome or
idiopathic gastric acid hypersecretion at
an initial dose of 60 mg daily (or 40 mg
twice daily in patients who had had pre-
vious gastric surgery).3’ The dose was in-
creased as necessary to maintain acid se-
cretion at Cl0 mmol/h (or <5 mmol/h) for
up to 12 months. Only 2 patients required
a daily dose >60 mg, and no patients had
a recurrence of peptic acid disease over
the course of the study.
Barrett’s Esophagus
Barrett’s esophagus is characterized by
the presence of columnar epithelium in
the lower esophagus instead of the normal
squamous lining. The condition is associ-
ated with gastroesophageal reflux and an
increased risk of esophageal cancer. The
disorder cannot be distinguished from
GERD based on symptoms alone; en-
doscopy and biopsy are needed to con-
firm the diagnosis. Nevertheless, the treat-
ment of acid reflux is the same in either
case, with PPIs being more effective than
H,-receptor antagonists administered
alone or in combination with cisapride.
PPIs are also effective in many patients in
whom the condition has been refractory
to treatment with Hz-receptor antagonists.
Symptoms disappear with treatment in
most patients but may recur within days
of discontinuing therapy. Therefore, long-
term use of PPIs may be required.32,33
273

Although there is some recent evidence
that continuous PPI therapy for several
years can cause partial regression of Bar-
rett’s esophagus,34,35 this effect seems to
be modest, with the overall length of the
columnar epithelium not changing dra-
matically. Surgery, an alternative treat-
ment approach, is the same as for GERD
unless severe dysplasia occurs, in which
case esophagectomy may be indicated.
Overall, surgical treatment might provide
better results than long-term medical treat-
ment with antisecretory agents in terms of
controlling disease activity, esophagitis,
and acid reflux.“”
ERADICATION OF
HELICOBACTER PYLORI
H pylori is strongly associated with peptic
ulcer disease and appears to play a signif-
icant role in its pathogenesis. Eradication
of this organism is strongly recommended
in the management of gastric or duodenal
ulcer, whether initial or recurrent.36,37 An-
tibiotic monotherapy, however, provides
poor eradication rates, despite strong in
vitro activity against H pylori, and con-
comitant administration of multiple antibi-
otics causes unacceptable side effects.33,38
Coadministration of antibiotics with a PPI,
discussed later, appears to have a syner-
gistic effect and yields high Hpylori erad-
ication rates.
Antibacterial Effects
PPIs inhibit the growth of H pylori at
concentrations similar to those that inhibit
gastric H+,K+-ATPase. Against a panel of
58 clinical isolates of H pylori, lansopra-
zole inhibited 90% of organisms at a min-
imum concentration of 6.25 p,g/mL, and
was 4 and 16 times more active than
274
CLINICAL THERAPEUTICS@
omeprazole and pantoprazole, respec-
tively.“* In a smaller study,39 rabeprazole
was 2 times more active than lansopra-
zole and 4 times more active than omepra-
zole. The growth-inhibitory effect of PPIs
may be sufficient to enable eradication of
H pylori by coadministered antibiotics.
PPIs may inhibit H pylori growth by
several mechanisms. H pylori produces a
urease that catalyzes the hydrolysis of urea
to ammonia, which is believed to protect
the bacterium against acid and allow it to
colonize the gastric mucosa. PPIs potently
inhibit H pylori urease activity, presum-
ably by binding to the active site of the
enzyme. Rabeprazole, with an IC,, (con-
centration required to produce 50% inhi-
bition of urease) of 0.29 pmol/L, was - 10
times more potent than omeprazole and
lansoprazole in inhibiting urease at pH 5
in both cellular and cell-free systems in
vitro.40 However, omeprazole was also
shown to inhibit H p-ylori via a urease-
independent mechanism, with inhibition
of growth seen at a low pH both in the ab-
sence of urea and in a urease-deficient
strain of H pylori.4’
A second target of PPIs in H pylori may
be a membrane-bound H+,K+-ATPase,
similar to that found in human parietal
cells, that may help the bacterium main-
tain a large proton gradient in an acidic
environment. PPIs have been found to
strongly inhibit this ATPase at a pH of 4,
although they were essentially inactive at
a neutral pH.42
Proton-Pump Inhibitor-Based
Combination Therapy
Eradication of H pylori with PPI-based
dual-, triple-, and quadruple-drug regi-
mens has been evaluated in many ran-
domized clinical studies. The results of
J. HORN
several recent studies43-49are summarized
in the table. According to the Maastricht
Consensus Report,37 the recommended
regimen for H pylori eradication is PPI-
based triple-drug therapy for 7 days, con-
sisting of a PPI plus 2 of the following
antibiotics: clarithromycin, amoxicillin,
or a nitroimidazole (ie, metronidazole or
tinidazole).
Stack et a143 evaluated rabeprazole-
based dual- and triple-drug therapy in 75
H pylori-infected patients with chronic
gastritis. Patients were randomized to 7
days of twice-daily treatment with 1 of 4
antibiotic regimens consisting of rabepra-
zole 20 mg plus: (1) clarithromycin 500
mg (RC); (2) amoxicillin 1 g and clarith-
romycin 500 mg (RAC); (3) amoxicillin
1 g and metronidazole 400 mg (RAM); or
(4) clarithromycin 500 mg and metronida-
zole 400 mg (RCM). Intent-to-treat analy-
sis showed eradication rates of 100% with
RCM, 95% with RAC, and 90% with
RAM. The dual-drug treatment, RC, was
less effective (63%), and resistance to cla-
rithromycin developed in the majority of
patients in whom this treatment failed. The
patients for whom RAM failed were in-
fected with metronidazole-resistant strains
at the inception of treatment. Thus, rabepra-
zole-based triple-drug therapy for 7 days
was effective in eradicating H pylori.
In a number of recent studies,43-50triple-
drug therapy with other PPIs has been
more effective in eradicating Hpylori than
dual-drug therapy. In general, such ther-
apy produced eradication rates of 279%,
whereas dual-drug regimens produced
eradication rates of 53% to 77% (see
table). However, it is difficult to compare
the various PPI-based regimens, because
these studies differed in several important
ways. The duration of treatment ranged
from 7 to 14 days, but PPI therapy was
continued for several additional weeks in
some of the studies of ulcer healing.46,48
Antibiotic therapy differed in terms of
drugs used, dose, number of times admin-
istered daily, and duration of treatment.
In a review of 275 treatment arms in-
volving omeprazole-based therapy,“O
triple-drug therapy produced median erad-
ication rates of 86%, and dual-drug ther-
apy produced median eradication rates of
58%. Quadruple-drug therapy was no
more effective than triple-drug therapy.
Median eradication rates were similar
with treatment for 1 and 2 weeks; were
slightly higher with a daily dose of 40 mg
compared with 20 mg; and were compa-
rable with regimens including 2 of the fol-
lowing: clarithromycin, amoxicillin, and
metronidazole (or tinidazole). Taken to-
gether, these results are consistent with
those in the Maastricht Consensus Re-
port37: PPI-based triple-drug therapy for 7
days is effective in eradicating H pylori.
DRUG INTERACTIONS
Drug-drug interactions vary among the
PPIs. Omeprazole has been shown to in-
teract with diazepam, phenytoin, and war-
farin, but not with theophylline. Lansopra-
zole causesa small decrease in theophylline
concentration and may decrease the effi-
cacy of oral contraceptives. Pantoprazole
and rabeprazole appear to be free of these
interactions. The clinical significance of
these interactions is not yet known, but
careful monitoring is recommended.51,52
DISCUSSION AND CONCLUSIONS
The various PPIs have much in common,
notably their superiority to Hz-receptor an-
tagonists in the treatment of acid-related
diseases. In GERD and peptic ulcer dis-
275
Table. Recent studies of proton-pump inhibitor (PPI)-based antibiotic therapy for the eradication of Helicobacter pylori (intent-
to-treat analysis).

Antibiotic
Duration Eradication
PPI Regimen Regimen (4 Rate (%) Reference

Rabeprazole 20 mg BID C 500 mg BID + M 400 mg BID 7 100 Stack et al43

A 1 g BID + C 500 mg BID 7 95
A 1 g BID + M 400 mg BID 7 90
C 500 mg BID 7 63
Omeprazole 20 mg BID C 500 mg BID + M 400 mg BID 7 92 Chu et a144
A 1 g BID 14 74
Lansoprazole 30 mg QD* B 120 mg QID + M 400 mg BID +
TC 500 mg QID 7 90 Korman et a149
Lansoprazole 30 mg BID A 1 g BID + C 500 mg BID 14 94 Schwartz et a145
C 500 mg BID 14 57
C 500 mg TID 14 7.5
IA I gTID 14 53
Lansoprazole 30 mg TID A I g TID 14 77 Schwartz et al45
P
None 14 2 P
Pantoprazole 40 mg BID A 1 g BID + C 500 mg BID 14 91 Louw et al47 E
A I g BID + C 500 mg BID 7 79 c
Pantoprazole 40 mg BID C 500 mg TID + M 500 mg TID 7 95 Adamek et a146 2
C 500 mg TID 14 60 6
Pantoprazole 40 mg QD C 250 mg BID + T 500 mg BID 7 86 Pazzi et a14X %
2
C = clarithromycin; M = metronidazole; A = amoxicillin; B = bismuth subcitrate; TC = tetracycline; T = tinidazole.
*Lansoprazole was administered for IO days, beginning 3 days before antibiotics were started.
J. HORN
ease, once-daily administration of PPIs is
faster and more effective than treatment
with Hz-receptor antagonists several times
daily. In clinical trials, PPIs administered
once daily produced endoscopic evidence
of healing in >90% of patients with duo-
denal ulcer after 4 weeks of treatment,
>90% of those with gastric ulcer after 6
weeks of treatment, and >90% of those
with ulcerative or erosive GERD after 8
weeks of treatment. Maintenance therapy
with daily PPIs is effective in preventing
GERD relapse. Comparative clinical tri-
als indicate that individual PPIs produce
equivalent ulcer healing, but it is impor-
tant to recognize that these studies were
designed to demonstrate equivalence.
Although they share a common struc-
ture and mode of action, the PPIs differ
in their clinical pharmacology. Rabepra-
zole is a more rapid and potent inhibitor
of H+,K+-ATPase than omeprazole, pos-
sibly because of its faster activation in
the parietal cell canaliculus. After the first
dose, rabeprazole produces greater inhi-
bition of acid secretion than omeprazole,
as reflected in a higher 24-hour intragas-
tric pH and longer periods in which pH is
>3 and ~4.~ This more rapid onset of acid
control may be particularly relevant in
PPI-based triple-drug therapy for H py-
lori eradication when a short 7-day treat-
ment course is recommended. One such
regimen, rabeprazole plus clarithromycin
and metronidazole, was found to eradi-
cate H pylori in all patients treated.4”
Clinical trials comparing rabeprazole-
based triple-drug therapy with other PPI-
based triple-drug therapies are needed to
ascertain whether rabeprazole’s more
rapid onset of acid control actually does
provide a higher Hpylori eradication rate,
and to define the general clinical rele-
vance of this more rapid onset.
The in vitro potency and binding patterns
of lansoprazole are similar to those of
omeprazole. Like the other PPIs, lansopra-
zole is effective in treating GERD and pep-
tic ulcer. Both lansoprazole and omeprazole
have been shown to be effective in the long-
term treatment of Zollinger-Ellison syn-
drome. In vitro studies indicate that lanso-
prazole is more active against H pylon’ than
omeprazole and pantoprazole, although not
as active as rabeprazole.
In GERD and peptic ulcer, pantopra-
zole appears to provide symptom relief
and healing similar to those produced by
omeprazole. The in vitro activity of pan-
toprazole is unusual, given its slower cys-
teine-binding pattern, but additional stud-
ies are needed to ascertain the significance
of this characteristic.
Omeprazole is the best-established and
therefore most-studied drug in the PPI class.
Its effectiveness in the treatment of all acid-
related diseases is well documented. Ide-
ally, the differences between omeprazole
and other PPIs should be used to provide
the most advantageous treatment in indi-
vidual cases, but further study of their phar-
macologic differences is required before
such optimal use can be realized.
ACKNOWLEDGMENT
The author is a member of the speakers’bu-
reau of Eisai-Janssen,Teaneck, New Jersey,
and has served as a consultant to Janssen
Pharmaceutics, Titusville, New Jersey.
Address correspondence to: John Horn,
PharmD, Department of Pharmacy,
University of Washington School of
Pharmacy, Health Sciences Building,
Room T-341, 1959 NE Pacific Street,
Seattle. WA 98 185.
277

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