Associate Editor: Peter Holzer

GABA
B
receptors as drug targets to treat gastroesophageal reux disease
Anders Lehmann
AstraZeneca R&D, Mlndal, Sweden
a b s t r a c t a r t i c l e i n f o
Keywords:
Gastroesophageal reux disease
GABA
B
receptor
Proton pump inhibitor
Reux inhibition
For many years, acid-suppressive therapy has been at the forefront of treating gastroesophageal reux disease
(GERD), yet despite the advent of the proton pump inhibitors (PPIs) some patients continue to experience
persistent GERD symptoms. Therapeutic (non-surgical) options for such patients are currently limited. To
tackle this clinical issue, research efforts have begun to focus on reux inhibition as a potential therapeutic
target i.e. inhibition of transient lower esophageal relaxations (TLESRs), the predominant mechanism of
gastroesophageal reux. Preclinical researchhas identied a number of drug targets through which TLESRs can
be modulated, and the -aminobutyric acid (GABA) type B (GABA
B
) receptor has emerged as one of the most
promising. Studies with baclofen, a well-known agonist of this receptor, have demonstrated that reux
inhibition is a valid concept in the clinical setting in that reducing the incidence of TLESRs improves GERD
symptoms. But baclofen is associated with signicant central nervous system (CNS) side effects, rendering it
undesirable for use as a treatment for GERD. Further development work has yielded a number of novel GABA
B
receptor agonists with reduced CNS side effect proles, and clinical trials are currently being performed with
several agents. Compounds that target TLESRs may therefore present a newadd-on treatment for patients with
persistent GERD symptoms despite PPI therapy.
2009 Elsevier Inc. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
2. The lower esophageal sphincter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240
3. The GABA
B
receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241
4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243
1. Introduction
Gastroesophageal reux disease (GERD), the cardinal symptoms
of which are heartburn and regurgitation, affects 1020% of the
Western population (Dent et al., 2005) and has a detrimental impact
on their daily lives (Wiklund, 2004, Wahlqvist et al., 2006, Wiklund
et al., 2006). It is generally accepted that such symptoms arise as a
consequence of pathologic reux of stomach contents into the
esophagus, the associated burning sensation behind the breastbone
(heartburn) being explained by prolonged exposure of the esopha-
geal mucosa to gastric acid. Consequently, acid suppression forms
the mainstay of current therapy for GERD, an approach that is
supported by numerous clinical trials in this setting (van Pinxteren
et al., 2006). As treatments for GERD have been developed, proton
pump inhibitors (PPIs) have emerged as the agents of choice as they
provide powerful acid control by suppressing gastric acid secretion
from parietal cells. However, it has become apparent that despite the
availability of potent and efcacious acid-suppressive therapies such
as PPIs, troublesome symptoms of GERD persist in 2030% of
patients (Fass et al., 2005).
Various mechanisms may contribute to the failure of PPIs to ade-
quately control GERD symptoms, many of which are related to the
reux process itself (Fass & Sifrim, 2009). For example, symptoms
may be related to weakly acidic/alkaline reuxate and mechanical
stimuli such as the volume of the reuxate (with its resulting effects
on esophageal distension and the proximal extent of esophageal
reux) (Sifrim et al., 2007). In other studies, reux episodes that
extended proximally, and having a mixed (liquidgas) composition,
Pharmacology & Therapeutics 122 (2009) 239245
Abbreviations: CNS, central nervous system; GERD, gastroesophageal reux disease;
LES, lower esophageal sphincter; TLESR, transient lower esophageal sphincter relaxation.
Research Area CVGI, AstraZeneca R&D, SE-431 83 Mlndal, Sweden. Tel.: +46 31
776 1945; fax: +46 31 776 3700.
E-mail address: anders.lehmann@astrazeneca.com.
239
240
241
244
244
244
0163-7258/$ see front matter 2009 Elsevier Inc. All rights reserved.
doi:10.1016/j.pharmthera.2009.02.008
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were signicantly associated with reux symptoms irrespective of the
pHof the reuxate (Tutuian et al., 2008). Thus, in order to help patients
with persistent and troublesome symptoms of GERD despite acid-
suppressive therapy, the focus of research has shifted away from
methods of acid suppression to the nature of the reux mechanism
itself, with particular interest being shown in the lower esophageal
sphincter (LES) and transient LES relaxations (TLESRs). Evidence
has accrued that lends weight to the concept of reux inhibition,
i.e. that modifying the behaviour of the LES and inhibiting TLESRs
can reduce the incidence of gastroesophageal reux and associated
symptoms (Lehmann, 2006). This development represents an
advance in treatment beyond acid suppression alone, which reduces
acid reux but leaves the number of reux episodes (acid + non-
acid) unchanged.
Among possible drug targets for reux inhibition, the -
aminobutyric acid type B (GABA
B
) receptor has emerged as one of
the most promising. These receptors are present in many tissues in the
humanbody, are particularly concentrated inthe brainand spinal cord,
and appear to be involved in the neural control of the LES.
The aimof this reviewis to discuss GABA
B
receptors as drug targets
for GERD, and will highlight evidence to support the emerging role of
GABA
B
receptor agonists as a new add-on treatment for patients with
persistent and troublesome GERD symptoms despite PPI therapy.
2. The lower esophageal sphincter
To grasp the concept of TLESR, the basic anatomy of the gastro-
esophageal junction (and its surrounding structures) must be under-
stood (Fig. 1). The LES is located at the gastroesophageal junction and
consists of a thickening of the muscular wall of the esophagus,
approximately 4 cm in length (Liebermann-Meffert et al., 1986). The
distal 2 cm of the LES is encircled by the crural diaphragm (CD) as it
passes through the crural hiatus (where the esophagus passes through
the diaphragm), meaning that a portion of the LES is intra-abdominal
and a portion is located in the hiatus itself (Liebermann-Meffert et al.,
1986). Research is ongoing in this area, as there is considerable debate
around whether the LES exists as an anatomical structure, or as a
physiological high pressure zone close to the gastroesophageal
junction. This is beyond the scope of this review, but is discussed more
fully by Brasseur et al. (2007).
The LES was once thought to be the main structure providing a
pressure barrier between the esophagus and the stomach. In fact, the
CD, while it contracts in parallel with the respiratory cycle, has also
been found to play an important role (Mittal and Fisher 1990; Mittal
1993; Mittal et al. 1993). Pressure at the gastroesophageal junction is
therefore governed by a dual sphincteric mechanism, comprising the
intrinsic smooth muscle of the LES and the extrinsic skeletal muscle of
the CD.
Dent (1976) greatly aided research on LES function by developing
the Dentsleeve technique, a method that allowed the pressure exerted
at the gastroesophageal junction to be accurately measured. Later
work has shown that the LES is maintained at a high resting basal
pressure (N10 mmHg) by neural, myogenic and hormonal input
(Lipan et al., 2006). During deglutition (swallowing), neurally-
mediated relaxation of the LES and weak inhibition of CD activity
allows food to enter the stomach.
2.1. Transient lower esophageal
sphincter relaxations and gastroesophageal reux
TLESRs are a normal physiological response to postprandial gastric
distension, allowing the venting of gas from the stomach into the
esophagus (belching). In healthy individuals such events occur at an
increased rate for 13 h after meals (Holloway et al., 1991). These
events are characterised by a rapid relaxation of the LES (without any
preceding deglutitive activity) where the pressure exerted at the
gastroesophageal junction decreases to a level similar to the
intragastric pressure [a basal LES pressure of at least 3 mmHg is
required to prevent gastric reux (Hunt, 1994)]. In addition to their
role in belching, TLESRs have been identied as the predominant
mechanism behind gastroesophageal reux in numerous studies
(Dent et al., 1980, Dodds et al., 1982, Mittal & McCallum, 1988,
Holloway et al., 1991, Iwakiri et al., 2005), two of the earliest of which
are highlighted below. One monitored TLESRs and reux in healthy
adults overnight (Dent et al., 1980) TLESRs either occurred in
isolation or were immediately followed by LES relaxation induced by
swallowing, and 98% of reux episodes followed TLESRs. Dodds et al.
(1982) assessed gastroesophageal reux in 10 patients with reux
esophagitis compared with healthy controls. Some 65% of reux epi-
sodes were caused by TLESRs in the patients with esophagitis, whereas
94% were caused by TLESRs in the healthy controls. It is important to
note, however, that non-TLESR mechanisms may be as important as
TLESRs as a cause of reux in some cases, particularly for patients with a
hiatal hernia (van Herwaarden et al., 2000). However, even in these
patients, TLESR is the single most important mechanism for reux.
The control mechanisms of TLESRs have been substantially
elucidated in animals and humans. For example, there is no evidence
for local reexogenic control, and spinal pathways have been excluded
(Staunton et al., 2000). Vagal blockade eliminates episodes of TLESRs
indogs, strongly suggesting that avago-vagal reex is involved(Martin
et al., 1986). Indeed, further work in animals (Blackshaw & Grundy,
1988, Zagorodnyuk et al., 2001) suggests that in response to gastric
Fig. 1. Anatomy of the lower esophageal sphincter (LES) and stomach at rest (left) and during transient LES relaxation (right). Boxed events are obligatory component of a transient
LES relaxation. Reproduced with permission (Lehmann, 2006).
240 A. Lehmann / Pharmacology & Therapeutics 122 (2009) 239245
distension (as detected primarily by intraganglionic laminar endings,
which are morphologically dened transduction sites of vagal
mechanoreceptors), nerve impulses are conducted to the nucleus of
the solitary tract (situated in the dorsal brain stem) via vagal afferent
neurons. These discharges are then conveyed to the dorsal motor
nucleus of the vagus (DMV), where vagal efferent neurons relay
inhibitory signals to the LES via inhibitory esophageal enteric neurons
(Fig. 2). Recent data indicates a more complex control mechanism in
that the CD has been found to be innervated both by afferent and
efferent vagal bers (Young et al., 2006, 2007, 2008), with electro-
physiological results suggesting that they may serve as mechanode-
tectors and motor effectors, respectively, in the control of TLESRs. In
addition, TLESRs may turn out be an inadequate term, as relaxation of
the LES seems to occur in conjunction with other gastrointestinal
motility events as part of a complex pattern. During TLESRs (in
addition to relaxation of the LES), for example:
activity of the CD is momentarily halted (Mittal & Fisher, 1990,
Martin et al., 1992)
the fundus relaxes (Zhang et al., 2001)
there is occasional contraction of the circular muscle of the
esophagus (Mittal & McCallum, 1987)
the esophagus contracts longitudinally (Shi et al., 2002, Babaei et al.,
2008).
Apart from the relaxation of the LES, however, the only events that
seem to be an essential component of TLESRs are suppression of the
CD and longitudinal esophageal contraction (Fig. 1).
2.2. Transient lower esophageal
sphincter relaxations as a therapeutic target
Previously, attempts to improve the treatment of GERDvia targeting
of the reux mechanism have focused on LES pressure, based on the
suggestionthat lowtonic LES pressure was as a contributingfactor inthe
pathogenesis of GERD. However, poor clinical efcacy of agents
supposedly acting on LES pressure, such as the 5-HT
4
partial receptor
agonist tegaserod (Tutuian et al., 2006), disputes this association.
Inhibition of TLESRs represents a more rational way inwhichreux may
be controlled, given that such events are the predominant mechanism
behind potentially pathologic gastroesophageal reux. Indeed, it would
be logical to assume that pharmacological intervention at any point in
the LES neural control pathway (Fig. 2) would alter the frequency of
TLESRs, thereby providing a newtherapeutic target for the proportionof
patients whose troublesome GERD symptoms persist despite acid-
suppressive therapy.
Taken together, this nding supports inhibition of TLESRs as a
therapeutic concept, and several drug targets have emerged from
clinical research and animal models. So far, 8 targets have been
discovered, of which7 have beenvalidated in humans (Table 1). One of
the most promising targets is the GABA
B
receptor, as described in the
following section.
3. The GABA
B
receptor
The GABA
B
receptor was originally dened pharmacologically by
its insensitivity to the GABA antagonist bicuculline and sensitivity to
Fig. 2. Schematic illustration of the pathway of nervous control of the lower esophageal sphincter. Green circles denote expression of GABA
B
receptors (and therefore potential sites
for pharmacological manipulation), as shown immunohistochemically [nodose ganglion (Smid et al., 2001), nucleus of the solitary tract (McDermott et al., 2001), and dorsal motor
nucleus of the vagus (McDermott et al., 2001)] or physiologically [vagal afferent (Page & Blackshaw, 1999) and efferent (Smid & Blackshaw, 2000) peripheral terminations). GABA
B
receptors on intraganglionic laminar endings may be the most important targets for inhibition of TLESRs.
Table 1
Pharmacological targets for inhibiting transient lower esophageal sphincter relaxations,
according to proposed site of action
a
.
Central Central and/or peripheral Peripheral
Muscarinic receptor(s) GABA
B
receptor CCK1 receptor
opioid receptor mGluR group III receptors
NO synthase mGluR5 receptor
CB1 receptor
CB1 = cannabinoid type 1; CCK
1
= cholecystokinin type 1; GABA
B
= -aminobutyric
acid type B; mGluR5 = metabolic glutamate receptor type 5; NO = nitric oxide.
a
All targets, apart from mGluR group III receptors, have been validated in humans.
241 A. Lehmann / Pharmacology & Therapeutics 122 (2009) 239245
the GABA agonist baclofen (Bowery et al., 1980). More recent studies
have shown that it consists of two subunits: GABA
B(1)
and GABA
B(2)
(Couve et al., 2000) that assemble as a heterodimer in neuronal cell
membranes (Fig. 3). The GABA
B
receptor is characterised by its large,
extracellular N-terminal ligand-binding domain and is a member of
family C of the G protein-coupled receptors. It is highly expressed in
the brain and spinal cord, but is also present in other tissues.
The GABA
B
receptor is coupled negatively to adenylyl cyclase and
voltage-gated calcium channels, and positively to inwardly rectifying
potassium channels (Billinton et al., 2001, Bowery et al., 2002, Bettler
et al., 2004). It exerts an inhibitory effect on neuronal transmission by
opening the potassium channels and closing the calcium channels,
with the former mechanism appearing to predominate in vagal
afferents (Page et al., 2006).
3.1. GABA
B
receptor agonism and reux inhibition: proof of concept
3.1.1. Preclinical
The inhibitoryeffect of GABA
B
agonismonTLESRs was rst reported
instudies involving dogs (Lehmannet al., 1999) andferrets (Blackshaw
et al., 1999) subsequently, the effect was also shown in cats (Liu et al.,
2002). These studies employed (among other compounds) baclofen as
the GABA
B
agonist, which is a well-characterised drug, having been
used as a muscle relaxant for many years. The frequency of TLESRs was
dose-dependently reduced in these studies, without affecting basal
LES tone. However, the frequency of spontaneous swallowing was also
reduced in the ferret (Blackshawet al., 1999) and dog (Lehmann et al.,
2002), suggesting a central mode of action. Agonists often lead to
tolerance (reduced efcacy after repeated dosing), but a canine study
produced no evidence of this when baclofen was administered once
daily over two weeks (Lehmann et al., 2000).
While the previous evidence suggests that GABA
B
agonists such as
baclofen may inhibit TLESRs through a central mode of action, they
mayalso have peripheral effects. Functional GABA
B
receptors are found
in the nodose ganglion of the vagus nerve in rats (Rusin & Moises,
1998) and guinea pigs (Zagorodnyuk et al. 2002), yet they are
apparently not present on central terminations of the vagal afferent
neurons in rats and ferrets (McDermott et al., 2001). This suggests that
GABA
B
receptors are transported from the nodose ganglion of the
vagus nerve to the peripheral terminals of the vagal afferent neurons.
Electrophysiological experiments in ferrets have produced evidence in
this regard in vivo (Partosoedarso et al., 2001) and in vitro (Smid et al.,
2001), but this phenomenon may be species-specic as tests in guinea
pigs (Zagorodnyuk et al. 2002) failed to show similar results.
Baclofen is approved for use in humans as a muscle relaxant, but at
therapeutic oral doses many patients experience CNS side effects such
as drowsiness, confusion or memory problems (Young and Delwaide
1981; Sandyk and Gillman 1985; Lazorthes et al. 1990). Additionally, in
patients taking baclofen on a long-term basis, the sudden withdrawal
of the drug induced seizures and hallucinations in some patients
(Terrence & Fromm, 1981). Clearly, such side effects are disadvanta-
geous in a drug destined to treat GERD, and research efforts have
focused on compounds that have a peripheral mode of action
and therefore lack the CNS side effects associated with baclofen.
Derivatives of 3-aminopropylphosphinic acid have been investigated
in this regard, one such example being AZD3355 [(R)-(3-amino-2-
uoropropyl) phosphinic acid].
AZD3355 has been shown to inhibit TLESRs in dogs, in a study
where it was compared with baclofen and GABA itself (Lehmann et al.,
2008b). The effect was dose-dependent andthe similarity betweenthe
doseresponse curves for AZD3355 andGABA(whichis a peripherally-
restrictedagonist of the GABA
B
receptor) suggests that AZD3355acts at
a peripheral site (in contrast to baclofen). This was conrmed by
further work in other animal models (Lehmann et al., 2008a), outlined
below:
Autoradiographic studies showed that AZD3355 was taken up in
regions of the rat brain lacking a blood-brain barrier, which suggested
that the compound was actively taken up by neural cells. This sug-
gestion was reinforced by observations that AZD3355 (in contrast to
baclofen) was actively taken up by rat brain slices in vitro.
AZD3355 inhibited the binding of GABA to the GABA carrier in
rat brain membranes, whereas no such effect was observed with
baclofen. This strongly suggests that AZD3355 is a substrate of the
GABA carrier.
The racemate of AZD3355 inhibited the signalling of mechanosen-
sitive vagal afferents taken from the gastric muscle wall of ferrets;
the effect was not observed in mucosal vagal afferents.
The results from this work mean that an explanation for the
favourable pharmacological prole of AZD3355 can be proposed. The
fact that AZD3355 is a substrate of the GABA carrier means that it is
actively sequestrated by neural tissue, which serves to keep extra-
cellular CNS levels low. Therefore, at lower doses, central GABA
B
receptors are not activated and the activity of AZD3355 is restricted to
Fig. 3. Structure of the GABA
B
receptor. GABA
B(1)
and GABA
B(2)
subunits form a functional heterodimer that couples negatively to Ca
2+
channels and positively to K
+
channels
through G proteins. Agonists bind to the extracellular N-terminus of GABA
B(1)
and allosteric modulators to GABA
B(2)
. The effects on ion channels are prolonged inhibition and
reduction of transmitter release. Both autoreceptors and heteroreceptors exist presynaptically. Reproduced with permission (Bowery & Smart, 2006).
242 A. Lehmann / Pharmacology & Therapeutics 122 (2009) 239245
peripheral locations. At very high doses, the uptake system is
saturated and central side effects occur. Baclofen, in contrast, is not
taken up by neural cells and extracellular CNS levels build up quickly.
As a result, AZD3355 potentially offers a wider useful dosing range and
CNS safety margin whereas the useful dosing range of baclofen is
comparatively narrow.
Inthe same study (Lehmannet al., 2008a,b), the activityandpotency
of AZD3355 and baclofen were assessed. In vitro tests using cell lines
expressing human GABA
B
receptors showed that AZD3355 was more
than 40 times more potent than baclofen. Using rat brain membranes,
AZD3355 was found to have a high selectivity for the GABA
B
compared
with the GABA
A
receptor. Preclinically, therefore, AZD3355 appears to
have a favourable pharmacological prole and is effective in inhibiting
TLESRs but does this translate into effective control of gastroesopha-
geal reux? This question was addressed in further work with dogs
(Brndn et al., 2008) where esophageal pH was monitored using a pH
catheter placed 4 cm above the LES. AZD3355 reduced acid reux
episodes by half over the 24- h monitoring period, and a similar reduc-
tion in acid exposure time was also observed.
3.1.2. Clinical
Baclofen is approved for use in humans as a muscle relaxant, so
there have been few impediments to moving forward with clinical
studies in GERD. It has been proven successful in inhibiting TLESRs in
humans, with two studies in healthy volunteers showing that single
40 mg doses reduced the incidence of TLESRs by approximately 60%
(Lidums et al. 2000; Lee et al. 2003). In addition, postprandial LES
pressure was increased (an effect not seen in animal studies), which
may provide an additional benet in patients with chronically low LES
basal tone.
Similar effects were seen when baclofen was tested in patients
with GERD (Lidums et al., 2000, van Herwaarden et al., 2002, Zhang
et al., 2002, Grossi et al., 2008) (Fig. 4), though the incidence of
TLESRs was reduced to a lesser degree than in healthy volunteer
studies. TLESR inhibition with baclofen has also been observed in a
paediatric GERD population. In a randomized, double-blind, placebo-
controlled study of 30 children (aged 2.617.4 years), a single dose
(0.5 mg/kg) of baclofenwas associatedwitha median67%reductionin
the incidence of TLESRs in the postprandial period (Omari et al., 2006).
The value of TLESR inhibition as an indicator of therapeutic benet
(i.e. reduction of GERD symptoms) has not been assessed directly, but
can be inferred to some degree from studies where the effect of
baclofen on reux variables has been measured. Interestingly, the
Omari et al. study considered the effect of baclofen on TLESRs that
occurred in conjunction with reux episodes. Some 266 episodes of
TLESR were recorded, of which 39% triggered acid reux, 38% non-acid
reux and 23% produced no evidence of reux. Baclofen reduced the
mean incidence of TLESRs associated with acid reux from 4.2 to 1.7
in the postprandial period. In another, longer-term pediatric study,
baclofen 0.7 mg/kg/day was administered to 8 neurologically
impaired children with GERD (age range 2 months to 16 years) for
7 days (Kawai et al., 2004). Esophageal pH monitoring was carried out
at baseline and on the seventh day, and the total number of acid reux
episodes was signicantly reduced by 39%. This was accompanied by a
40% reduction in esophageal acid exposure time.
Baclofen has a similar effect on reux variables in adult GERD
populations. A 12-h ambulatory pHmetry study in patients with GERD
showed that a single 40 mg dose of baclofen reduced the incidence of
acid reux and the level of esophageal exposure to acid (Cange et al.,
2002). In another study in patients with heartburn, the same dose of
baclofen signicantly reduced the median number of reux episodes
(Vela et al., 2003). This study also considered the effect of baclofen
on GERD symptoms, and the reduction in reux episodes was
accompanied by a reduction in the median number of reux-related
symptoms (heartburn, regurgitation and acid taste).
The effects of baclofen on acid reux and GERDsymptoms were also
assessed by Ciccaglione and Marzio (2003) in a two-part study. In the
rst part, the effects of baclofen (10 mg four times a day) on esophageal
acidreuxwere measuredinGERDpatients andhealthy volunteers over
24 h: the incidence of reux was reduced by 5060% in both groups. In
the second part of the study, baclofen was given to 12 patients with
GERD (at a dose of 10 mg three times a day), and placebo to 6 patients,
for 1 month. In this longer-term scenario, baclofen reduced the
incidence of acid reux and the duration of esophageal acid exposure.
In turn, all reux-related symptoms were reduced in patients taking
baclofen, with the mean consumption of antacid tablets being reduced
from8 per week (before dosing) to 2 per week. The results of this study
are important as they reinforce the point that reux inhibition is a valid
concept intreatingGERD, as the inhibitionof TLESRs appears togohand-
in-hand with a reduction in acid exposure. Furthermore, they showthat
humans do not become tolerant to the effects of baclofen when it is
taken over a longer period. Importantly, the short-term study demon-
strated that baclofen was also effective in patients with hiatal hernia,
consistent with earlier ndings (Cange et al., 2002) and contrary to
expectations from pH/manometric studies (van Herwaarden et al.,
2000). A recent study unequivocally showed that baclofen (20 mg three
times a day) is as effective in reducing non-acid reux in patients with
hiatal hernia as in those without (Beaumont & Boeckxstaens, in press).
However, since baclofenelevates basal LES pressure (Lidums et al., 2000,
Zhang et al., 2002, Lee et al., 2003), it is possible that this effect adds to
the effect on TLESRs in patients with hiatal hernia.
While baclofen usefully proves the concept of reux inhibition, its
limitations preclude its use as a treatment for GERD. Baclofen is
associated with signicant CNS side effects (as described previously)
and its short pharmacological half-life (34 h) necessitates dosing
three or more times per day. Conversely, these limitations highlight
some of the desired outcomes in the search for novel GABA
B
receptor
agonists.
Efforts to overcome these limitations have resulted in the develop-
ment of compounds such as XP19986, a pro-drug of the R-isomer of
baclofen. In a dose-ranging placebo-controlled study in GERD patients
(Castell et al., 2006), XP19986 signicantly reduced the number of
reux episodes and showed a similar rate of side effects to placebo.
However, it remains to be seen whether XP19986 offers an improved
tolerability prole over the long-term compared with baclofen itself.
Indeed, while the main advantage of XP19986 concerns improved
pharmacokinetics, there is little reason to expect that it will differ
signicantly to baclofen with respect to CNS side effects. Attaining the
Fig. 4. Effect of baclofen (40 mg single oral dose) on transient lower esophageal
sphincter relaxations (TLESRs) in patients with gastroesophageal reux disease (van
Herwaarden et al., 2002).
243 A. Lehmann / Pharmacology & Therapeutics 122 (2009) 239245
goal of GABA
B
receptor agonismwithout CNS side effects probably lies
beyond the scope of baclofen and its pro-drugs.
But how would GABA
B
receptor agonists and the concept of reux
inhibition t into the current range of treatments available for the
management of GERD? The PPIs have brought major benets to many
patients with GERD, though some still suffer from GERD symptoms
despite PPI therapy (Fass et al., 2005). This indicates that acid sup-
pressionis not enoughto relieve symptoms inthis population. It is here
that reux inhibitors, with their ability to reduce the incidence of
TLESRs and associated reux episodes, could provide added therapeu-
tic benet.
Evidence for this benet has been supplied by a study from Koek
et al. (2003), where patients with persistent GERDsymptoms (despite
PPI therapy) were given a gradually increasing dose of baclofen until a
maintenance dose of 20 mg three times a day was achieved. After
4 days onthe maintenance dose, levels of reux symptoms, esophageal
acid exposure and duodenal reux (measured by bilirubin exposure)
were assessed and compared to levels before baclofen dosing com-
menced. Patients exhibited no signicant change in acid exposure
levels over the course of the study (possibly because the exposure
levels were very low), but the incidence of duodenal reux episodes
and the severity of reux symptoms decreased.
More recent work conducted by Bajbouj et al. (2008) aimed to
evaluate the effect of combining PPI treatment with baclofen when
treating refractory pathological reux. Seven patients whose reux
acid exposure failed to respond to esomeprazole 40 mg (and sub-
sequently 80 mg) once daily had their therapy further escalated by
adding baclofen (60 mg/day) to their treatment regimen. Of these,
only 2 exhibited normalisation of their esophageal acid exposure.
Little signicance can be attached to the results of this study from the
point of viewof reux inhibition, as baclofenwas only administered to
a small number of patients.
4. Conclusions
Acid-suppressive therapy has helped to lessen the disease burden
of many patients with GERD, but there remains a segment of patients
who still suffer troublesome heartburn and regurgitation despite PPI
therapy. Researchefforts have focusedonthe pivotal role of TLESRs and
the therapeutic potential of reux inhibitors, especially GABA
B
receptor agonists such as AZD3355, for such patients. Indeed, the
preclinical and clinical studies described in this review indicate the
potential of this class of compounds to inhibit TLESRs and improve the
management of GERD symptoms as add-on therapy to PPIs. A more
complete understanding of the feasibility of the concept will only
emerge with studies demonstrating sufcient clinical efcacy paired
with good safety and tolerability of GABA
B
receptor agonists.
Acknowledgments
The author thanks David Percival and Steve Winter, from Wolters
Kluwer Health (Chester, UK), who provided medical writing support
funded by AstraZeneca.
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