PMID- 18924449
OWN - NLM
STAT- MEDLINE
DCOM- 20081114
LR  - 20081017
IS  - 1128-3602 (Print)
IS  - 1128-3602 (Linking)
VI  - 12 Suppl 1
DP  - 2008 Aug
TI  - Novel treatments of GERD: focus on the lower esophageal sphincter.
PG  - 103-10
AB  - Up to 50% of patients with gastroesophageal reflux disease (GERD) still suffer 
      from GERD symptoms despite proton pump inhibitor (PPI) therapy, indicating a need 
      for new treatments. The lower esophageal sphincter (LES) plays a crucial role in 
      maintaining the mechanical barrier necessary for prevention of gastric reflux. 
      Transient LES relaxation (TLESR) is an important factor behind the occurrence of 
      reflux, and preclinical studies have identified a number of targets for 
      pharmacologic modification of TLESR. However, only gamma-aminobutyric acid (GABA) 
      type B receptor (GABA(B)) agonists and metabotropic glutamate receptor 5 (mGluR5) 
      modulators have shown positive proof of concept in the clinical setting. The 
      mGluR5 negative allosteric modulator ADX10059 improved symptoms in GERD patients, 
      but was associated with central side effects such as dizziness. Baclofen, a 
      GABA(B) receptor agonist, reduces the incidence of TLESR and improves GERD 
      symptoms in both adult and pediatric GERD patients. However, the utility of 
      baclofen is similarly limited by poor tolerability and recent research has 
      focused on the development of GABA(B) receptor agonists with improved 
      tolerability. XP19986, a prodrug of R-baclofen, reduced the number of reflux 
      episodes in a dose-ranging study and was similarly tolerated to placebo. AZD3355 
      and AZD9343 are GABA(B) receptor agonists with limited central nervous system 
      activity that have been shown in preclinical studies to reduce the incidence of 
      TLESR and decrease esophageal acid exposure; data from clinical studies of these 
      agents in GERD patients are awaited with interest. Agents that target TLESR 
      activity may therefore offer a promising new add-on treatment for patients who 
      suffer from GERD symptoms despite PPI therapy.
FAU - Lehmann, A
AU  - Lehmann A
AD  - Bioscience, AstraZeneca R&D, Molndal, Sweden. anders.lehmann@astrazeneca.com
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
PL  - Italy
TA  - Eur Rev Med Pharmacol Sci
JT  - European review for medical and pharmacological sciences
JID - 9717360
SB  - IM
MH  - Animals
MH  - Clinical Trials as Topic
MH  - Esophageal Sphincter, Lower/*drug effects/physiopathology
MH  - Gastroesophageal Reflux/*drug therapy/physiopathology
MH  - Humans
RF  - 45
EDAT- 2008/10/18 09:00
MHDA- 2008/11/15 09:00
CRDT- 2008/10/18 09:00
PHST- 2008/10/18 09:00 [pubmed]
PHST- 2008/11/15 09:00 [medline]
PHST- 2008/10/18 09:00 [entrez]
PST - ppublish
SO  - Eur Rev Med Pharmacol Sci. 2008 Aug;12 Suppl 1:103-10.