Art. 1.136

European Review for Medical and Pharmacological Sciences
2008; 12(Suppl 1): 103-110 Novel treatments of GERD: focus on
the lower esophageal sphincter

Bioscience, AstraZeneca R&D, Mölndal (Sweden) Abstract. – Up to 50% of patients with
gastroesophageal reflux disease (GERD) still
suffer from GERD symptoms despite proton

Gastroesophageal reflux disease (GERD) is a pump inhibitor (PPI) therapy, indicating a need
common disorder that affects up to 20% of the for new treatments. The lower esophageal
population worldwide1,2. The classic symptoms of sphincter (LES) plays a crucial role in main-
taining the mechanical barrier necessary for

GERD, which include heartburn and acid regurgi- prevention of gastric reflux. Transient LES re-
tation, are troublesome and have a substantial neg- laxation (TLESR) is an important factor behind
ative impact on patients' health-related quality of the occurrence of reflux, and preclinical stud-
life3,4. Consequently, effective treatment to provide ies have identified a number of targets for
enduring control of GERD symptoms is necessary.
pharmacologic modification of TLESR. Howev-
Acid-suppressive therapy currently forms the er, only γ-aminobutyric acid (GABA) type B re-
ceptor (GABA ) agonists and metabotropic

mainstay of treatment for GERD and proton glutamate receptor 5 (mGluR5) modulators
pump inhibitors (PPIs) are the treatment-of- have shown positive proof of concept in the
choice in this regard5. However, GERD symp- clinical setting. The mGluR5 negative allosteric
toms often persist despite PPI therapy in a con- modulator ADX10059 improved symptoms in
siderable number of patients2,6. Recent survey da- GERD patients, but was associated with cen-
ta, for example, indicate that approximately 50% tral side effects such as dizziness. Baclofen, a
of patients diagnosed with GERD continued to receptor agonist, reduces the inci-
dence of TLESR and improves GERD symp-
experience symptoms despite PPI treatment7, and toms in both adult and pediatric GERD pa-
around one-quarter (22%) of PPI users report tients. However, the utility of baclofen is simi-
taking additional over-the-counter (OTC) medi- larly limited by poor tolerability and recent re-
cines to control their symptoms8.
search has focused on the development of
Possible reasons for a lack of effect with PPI GABA receptor agonists with improved tolera-
therapy include inadequate dosing and/or poor bility. XP19986, a prodrug of R-baclofen, re-
duced the number of reflux episodes in a dose-

compliance (possibly resulting from lack of effi- ranging study and was similarly tolerated to
cacy), pharmacokinetic characteristics (such as placebo. AZD3355 and AZD9343 are GABA re-
poor oral bioavailability or rapid metabolism due ceptor agonists with limited central nervous
to genetic polymorphisms or cytochrome P450 system activity that have been shown in pre-
induction), and incorrect diagnosis6,9,10.
clinical studies to reduce the incidence of
Esophageal hypersensitivity and weakly acidic or TLESR and decrease esophageal acid expo-
weakly alkaline reflux may also contribute to sure; data from clinical studies of these agents
in GERD patients are awaited with interest.

symptoms, outlining a need for new treatments Agents that target TLESR activity may there-
for GERD in addition to PPIs. The aim of this ar- fore offer a promising new add-on treatment
ticle is to discuss emerging novel treatments for for patients who suffer from GERD symptoms
GERD, with a focus on the lower esophageal despite PPI therapy.
sphincter (LES) as the therapeutic target.
Key Words: Reflux Mechanisms Gastroesophageal reflux disease, Lower esophageal The LES, along with the crural diaphragm sphincter, Novel treatments.
(CD), forms a mechanical barrier that prevents Corresponding Author: Anders Lehmann, Ph.D; e-mail: [email protected]

reflux at the gastroesophageal junction11. The More recently, transient LES relaxation LES is a 3-4 cm region of circular smooth mus- (TLESR) has been identified as an important fac- cle that is maintained at high resting basal pres- tor in the pathophysiology of GERD (Figure 1)17.
sure (>10 mm Hg) via neural, myogenic and hor- TLESR is characterized by rapid LES relaxation monal input12. Transport of esophageal contents in the absence of swallowing or esophageal peri- into the stomach occurs with neurally mediated stalsis18-20. Neural control of TLESR is via a va- relaxation of the LES, and concurrent partial in- go-vagal reflex initiated in response to gastric hibition of CD activity; the CD usually contracts distension by activation of mechanosensitive va- with respiration. The retrograde flow of gastric gal afferent neurons that terminate in the dorsal contents is prevented by LES contraction11. Basal vagal complex of the brainstem12,19. Efferent va- LES pressure of at least 3 mm Hg is required to gal nerve signals stimulate the release of nitric prevent gastric reflux13.
oxide, pituitary adenylate cyclase activating pep- Low tonic basal LES pressure was previously tide, and vasoactive intestinal peptide from en- a favored mechanism to explain the pathogenesis teric neurons, resulting in smooth muscle relax- of GERD14. However, this theory was largely ation12,17. The efferent neural pathway in TLESR based on flawed measurements of LES function, is thought to be the same as that for swallow-in- and it is now established that reflux episodes can duced LES relaxation, only more intense and occur in patients with normal LES pressure.
prolonged; TLESR are of greater magnitude and Moreover, the poor clinical performance of duration than the LES relaxation occurring dur- agents supposedly acting on LES pressure, such ing swallowing. Additionally, extragastric factors as the 5-HT partial receptor agonists cisapride may influence the rate and occurrence of and tegaserod, and motilides such as ery- TLESR. Increased TLESR occurs with mechani- thromycin, provides further evidence that low cal stimulation of the pharynx, hyperglycemia, tonic LES pressure is not a major mechanism in duodenal nutrient infusions, intracolonic lactose, the pathogenesis of GERD10. For example, a ran- and bronchoconstriction (in asthmatics). Con- domized, double-blind study in healthy volun- versely, TLESR is inhibited during sleep or anes- teers found no significant differences between thesia, indicating higher central nervous system tegaserod and placebo in terms of the number of (CNS) activity, and in response to supine posture, acid and weakly acidic or weakly alkaline reflux and cold stress12,17.
episodes, bolus transit time or distal esophageal TLESR is a normal physiologic response to contraction amplitude15. Similarly, Champion et postprandial gastric distension and the rate of al. reported that "standard" doses of ery- TLESR increases after meals in healthy volun- thromycin had no relevant effects on esophageal teers21,22. Some studies have shown a similar rate function or acid reflux parameters in patients and incidence of TLESR among healthy individu- with GERD16.
als and GERD patients14,18,23; however, other stud- Focal contraction of Longitudinal muscle Sustained contraction of longitudinal muscle esophageal sphincter Figure 1. Transient relaxation of the lower esophageal sphincter (TLESR) and associated motility events. Events in boldface
denote defining features of TLESR; the other changes are common but not obligatory components of a TLESR. Reproduced
with permission17.
Novel treatments of GERD: focus on the lower esophageal sphincter ies indicate an increased prevalence of TLESR hibitors, cholecystokinin receptor 1 (CCK ) an- among those with GERD24-26. In particular, tagonists, metabotropic glutamate receptor 5 GERD patients may experience more instances of (mGluR5) antagonists, and γ-aminobutyric acid TLESR in the supine position that are associated (GABA) type B receptor (GABA ) agonists with acid reflux25. Since acid secretion is un- (Table I)17. Among these, only mGluR5 receptor changed in GERD patients, possible reasons for antagonists and GABA receptor agonists have the higher likelihood of reflux during a TLESR in shown positive results in proof-of-concept stud- those with GERD include altered distribution of ies in the clinical setting, as described in the fol- gastric juices27 or a larger opening of the gastroe- lowing section.
sophageal junction during relaxation28.
The role of TLESR versus other mechanical Clinical Findings on Reflux Inhibitors factors such as low or absent tonic basal LES pressure, straining and swallowing varies between ADX10059 is an orally available small mole- endoscopy-positive and endoscopy-negative cule that acts as a negative allosteric modulator GERD patients17. Non-TLESR mechanisms may of mGluR5 receptors. In a single-blind, placebo- be equally or more important among patients with controlled, proof-of-concept study in 24 GERD endoscopy-positive GERD in the presence of hi- patients, single doses of ADX10059 reduced acid atal hernia, in which the position of the gastric re- reflux (as measured by pHmetry) and improved ceptors with the lowest threshold for initiation of GERD symptoms31. Compared with placebo, TLESR has shifted proximally29,30. However, data ADX10059 250 mg three times daily was not on- are controversial and further clarification of the ly associated with significantly lower percent- role of non-TLESR mechanisms is required.
ages of time with esophageal pH <4 over 24hours (and at night) but also fewer symptomatic Pharmacologic Targets for acid reflux episodes (Figure 2). The duration of Reflux Inhibition such episodes was also shorter with ADX10059; Theoretically, pharmacologic modification of this was a somewhat surprising finding as there is both the frequency and quality (ie, degree and no evidence or theoretical basis that TLESRs that duration) of TLESR can be achieved anywhere occur during partial pharmacological inhibition along the pathway from gastric mechanorecep- are not identical to those seen in control condi- tors to the smooth muscle cells of the LES. How- tions. The administration of ADX10059 was as- ever, observations that drugs with TLESR-modi- sociated with a very high rate of side effects, in- fying activity do not affect swallow-induced LES cluding dizziness and nausea, which indicates the relaxation suggest that these agents act on the af- need to discover new modulators of mGluR5 re- ferent, rather than efferent, pathway. A site of ac- ceptors in order to improve tolerability.
tion in the brain also seems possible in some cas-es. Targets for pharmacologic TLESR modifica- tion therapy have emerged based on preclinical Baclofen is a selective GABA receptor ago- evidence and include nitric oxide synthase in- nist with well established efficacy in the treat- Table I. Pharmacologic targets of reflux inhibition.
Drugs used to verify target
Proposed site of action
WIN55, 212-2, ∆-9-tetrahydrocannibinol (agonists) Central and/or peripheral Devazepide, loxiglumide (antagonists) Baclofen (agonist) Central and/or peripheral MPEP, MTEP (antagonists) Central and/or peripheral mGluR group III receptors L-AP4, (S)-3,4-DCPG (agonists) Central and/or peripheral Muscarinic receptor(s) Atropine (antagonist) µ opioid receptor Morphine (agonist) L-NAME, L-NMMA (inhibitors) CB = cannabinoid type 1; CCK = cholecystokinin type 1; GABA = γ-aminobutyric acid type B; mGluR5 = metabotropic glutamate receptor type 5; NO = nitric oxide.
p = 0.0028 No. of symptomatic acid reflux episodes reflux episodes (min) 0 5 10 15 20
Figure 2. Effect of the mGluR5 negative allosteric modulator, ADX10059 (250 mg three times daily), on esophageal pH and
clinical symptoms (heartburn, acid regurgitation or burping) in patients with gastroesophageal reflux disease31.
ment of spasticity. Numerous studies, in adult However, the utility of baclofen in the man- healthy volunteers and patients with GERD (in- agement of GERD is limited by the requirement cluding children), indicate that this agent reduces for frequent dosing, due to its short half-life (3-4 the number of TLESR and improves GERD hours), and poor tolerability with a high rate of symptoms (Table II)32-40. In adult healthy volun- CNS side effects such as sedation and dizziness.
teers, for example, a single dose of oral baclofen This is explained by the ability of baclofen to en- significantly decreased the incidence of TLESR ter the CNS and act on the high concentrations of (by up to 64%) and increased basal LES pressure GABA receptors in the brain17.
(by up to 40%)32,37. This effect was confirmed inadult GERD patients, in whom a single 40 mg XP19986, AZD9343 and AZD3355 dose inhibited up to 40% of instances of Efforts to overcome tolerability issues associ- TLESR34,35. Baclofen also reduced the occur- ated with baclofen have resulted in the develop- rence of acid reflux episodes and decreased acid ment of agents such as XP19986, an investiga- exposure in adult GERD patients after adminis- tional prodrug of R-baclofen. In a dose-ranging, tration of a single 40 mg dose33-35,38 or multiple placebo-controlled study in GERD patients, doses of 10-20 mg three or four times daily36. In XP19986 significantly reduced the number of re- pediatric GERD patients, a single dose of ba- flux episodes (P ≤ 0.05 vs. placebo) and showed clofen 0.5 mg/kg provided 51% inhibition of a similar rate of side effects to placebo42. Howev- TLESR40 and administration of baclofen 0.7 er, it remains to be shown that XP19986 has an mg/kg once daily for 1 week reduced acid reflux acceptable tolerability profile during long-term episodes by 39%39.
use. Indeed, while the main advantage of Add-on treatment with baclofen appears to be XP19986 is related to improved pharmacokinet- effective in patients with GERD symptoms de- ics, there is little reason to expect it to substan- spite PPI therapy. Indeed, the addition of ba- tially differ from baclofen with respect to CNS clofen 20 mg three times daily reduced the cu- side effects.
mulative severity score for 14 GERD symptoms Research has also focused on the development from 10.3 to 5.8 (P < 0.01) in patients with per- of GABA receptor agonists with primarily pe- sistent GERD symptoms while treated with ripheral, rather than central, activity. Promising omeprazole (Table II)41. This evidence suggests a preclinical results have been obtained with two potential role for add-on treatment with a such agents, AZD9343 and AZD3355.
GABA receptor agonist in patients who experi- AZD9343 showed low permeation into the CNS ence GERD symptoms despite PPI therapy.
in rats and, in dogs, it dose-dependently inhibit- Novel treatments of GERD: focus on the lower esophageal sphincter urn (day and night) and icant* reductions in nausea gastric distension related symptoms and 75%* reduction in non-acid-related All symptoms reduced, including 44%* reduction in o 78%* reduction in acid reflux- Reduced emesis in 6/8 patients % Inhibition % Inhibition Bile reflux: 48*; icant; SD = single dose; tid = three times daily; od = once daily; qid = f Increase in LES outcomes
Inhibition olunteers or GERD patients.
= not assessed; ns = not signifA 5 mg tid increasing 0.0001 vs placebo. N≤P aarden et al.
Clinical studies of baclofen in adult healthy v Lidums et al.
Ciccaglione et al.
GERD patients (including childr
Cange et al.
Zhang et al.
Ciccaglione et al.
Omari et al.
ed TLESR43. Similarly, AZD3355 has also been shown to have low CNS activity in rats and sophageal reflux symptoms and well-being in a mice44. In dogs, the latter agent demonstrated random sample of the general population of aSwedish community. Am J Gastroenterol 2006; dose-dependent inhibition of TLESR44 and re- duced esophageal acid exposure time45. The po- tentially better tolerability of these agents versus DEVAULT KR, CASTELL DO. Updated guidelines forthe diagnosis and treatment of gastroesophageal baclofen makes them promising new therapies reflux disease. Am J Gastroenterol 2005; 100: for reflux inhibition in patients who experience GERD symptoms despite PPI therapy. Results 6) FASS R, SHAPIRO M, DEKEL R, SEWELL J. Systematic from clinical studies of these agents are there- review: proton-pump inhibitor failure in gastro-oe- fore awaited with interest.
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Arava, inn-leflunomide

NOMBRE DEL MEDICAMENTO: Arava 10 mg, Arava 20 mg, Arava 100 mg comprimidos recubiertos con película COMPOSICIÓN CUALITATIVA Y CUANTITATIVA: Arava 10 mg. Cada comprimido contiene 10 mg de leflunomida. Excipiente(s) con efecto conocido: cada comprimido contiene 78 mg de lactosa monohidrato Arava 20 mg. Cada comprimido contiene 20 mg de leflunomida. Excipiente(s) con efecto conocido: cada comprimido contiene 72 mg de lactosa monohidrato. Arava 100 mg. Cada comprimido contiene 100 mg de leflunomida. Excipiente(s) con efecto conocido: cada comprimido contiene 138,42 mg de lactosa monohidrato. FORMA FARMACÉUTICA: Comprimido recubierto con película. Arava 10 mg: comprimido recubierto con película blanco o blanquecino, redondo, con la inscripción ZBN en una cara. Arava 20 mg: comprimido recubierto con película amarillento a ocre, triangulares, con la inscripción ZBO en una cara. Arava 100 mg: comprimido recubierto con película blanco o blanquecino, redondo, con la inscripción ZBP en una cara. DATOS CLÍNICOS. Indicaciones terapéuticas: La leflunomida está indicada para el tratamiento de pacientes adultos con: artritis reumatoide activa como un "fármaco antirreumático modificador de la enfermedad" (FARME), artritis psoriásica activa. El tratamiento reciente o concomitante con FARMEs hepatotóxicos o hematotóxicos (por ejemplo, metotrexato) puede producir un aumento del riesgo de aparición de reacciones adversas graves; por tanto, en estos casos, el inicio del tratamiento con leflunomida debe considerarse en función del balance beneficio/riesgo. Más aún, el sustituir la leflunomida por otro FARME sin realizar el procedimiento de lavado, puede incrementar el riesgo de aparición de reacciones adversas graves incluso durante un largo período de tiempo después del cambio. Posología y forma de administración: El tratamiento se debe iniciar y supervisar por especialistas con experiencia en el tratamiento de artritis reumatoide y artritis psoriásica. Los niveles de alanina transaminasa (ALT) o transaminasa piruvato glutamato sérico (SGPT) y un recuento hemático completo, incluyendo un recuento diferencial de leucocitos y un recuento de plaquetas, deben determinarse simultáneamente, y con la misma frecuencia en las siguientes situaciones: antes de iniciar el tratamiento con leflunomida, cada dos semanas durante los primeros seis meses de tratamiento, y posteriormente, cada ocho semanas. Posología: En artritis reumatoide: el tratamiento con leflunomida se inicia normalmente con una dosis de carga de 100 mg una vez al día durante 3 días. La omisión de la dosis de carga puede disminuir el riesgo de reacciones adversas. La dosis de mantenimiento recomendada es de 10 mg a 20 mg de leflunomida una vez al día dependiendo de la gravedad (actividad) de la enfermedad. En artritis psoriásica: el tratamiento con leflunomida se inicia con una dosis de carga de 100 mg una vez al día durante 3 días. La dosis de mantenimiento recomendada es de 20 mg de leflunomida una vez al día. El efecto terapéutico normalmente empieza después de 4 ó 6 semanas y puede mejorar posteriormente hasta los 4 ó 6 meses. No hay un ajuste de dosis recomendable en pacientes con insuficiencia renal leve. No se requiere realizar un ajuste de la dosis en los pacientes con edad superior a 65 años. Población pediátrica: No se recomienda la utilización de Arava en pacientes menores de 18 años, ya que no se ha establecido la eficacia y la seguridad en la artritis reumatoide juvenil (ARJ). Forma de administración: Los comprimidos de Arava deben ingerirse enteros con suficiente líquido. La ingesta de alimentos no modifica la absorción de la leflunomida. Contraindicaciones: Hipersensibilidad al principio activo (especialmente con historial previo de síndrome de Stevens-Johnson, necrólisis epidérmica tóxica, eritema multiforme) o a alguno de los excipientes. Pacientes con insuficiencia hepática. Pacientes con estados de inmunodeficiencia grave, por ejemplo, SIDA. Pacientes con afectación significativa de la función de la médula ósea o con anemia, leucopenia, neutropenia o trombocitopenia importante debida a causas distintas de la artritis reumatoide o psoriásica. Pacientes con infecciones graves. Pacientes con insuficiencia renal de moderada a grave, debido a que la experiencia clínica de la que se dispone en este grupo de pacientes es insuficiente. Pacientes con hipoproteinemia grave, por ejemplo en el síndrome nefrótico. Mujeres embarazadas o mujeres en edad fértil que no utilicen un método anticonceptivo eficaz durante el tratamiento con leflunomida y después de finalizar el mismo mientras los niveles plasmáticos del metabolito activo estén por encima de 0,02 mg/l. Antes de iniciar el tratamiento con leflunomida, debe descartarse el embarazo. Mujeres que se encuentren en periodo de lactancia. Advertencias y precauciones especiales de empleo: No se aconseja la administración conjunta con FARMEs hepatotóxicos o hematotóxicos (por ejemplo metotrexato). El metabolito activo de leflunomida, A771726, tiene una vida media larga, generalmente de 1 a 4 semanas. Pueden producirse efectos adversos graves (por ejemplo: hepatotoxicidad, hematotoxicidad o reacciones alérgicas, ver más abajo), aunque se haya interrumpido el tratamiento con leflunomida. Por tanto, cuando aparezcan estos efectos adversos o si por cualquier otro motivo se

Effects of substrate stiffness on cell morphology, cytoskeletal structure, and adhesion

Cell Motility and the Cytoskeleton 60:24 –34 (2005) Effects of Substrate Stiffness on Cell Morphology, Cytoskeletal Structure, Tony Yeung,1 Penelope C. Georges,1 Lisa A. Flanagan,2 Beatrice Marg,2 Miguelina Ortiz,1 Makoto Funaki,1 Nastaran Zahir,1 Wenyu Ming,1 Valerie Weaver,1 and Paul A. Janmey1,2* 1Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia