Journal of Pharmaceutical Research & Clinical Practice, Oct-Dec 2013; 3(4):11-21

Review Article New Pharmacological Therapies for Treatment of Gastroesophageal Reflux Disease

*Rahul Saini1, Shanmukhananda M. P.2, Sunaina3

1. Department of Pharmacology, PGIMS, Rohtak, India. 2. Novartis, Hyderabad, India. 3. Department of Radiology, PGIMS, Rohtak, India.

ABSTRACT Gastroesophageal reflux disease (GERD) is a chronic, relapsing disorder characterized by recurrent symptoms of acid reflux with esophageal injury. It rarely resolves spontaneously, and it is associated with frequent recurrences. It has adverse impact on quality of life. A variety of medications have been used in GERD treatment, and acid suppression therapy is the mainstay of treatment for GERD. Although proton pump inhibitor is the most potent acid suppressant and provides good efficacy in esophagitis healing and symptom relief, about one-third of patients with GERD still have persistent symptoms with poor response to standard dose proton pump inhibitors (PPI). These are generally well tolerated but there are associated with minor side effects such as headache, diarrhea, and abdominal pain. Newer formulations of PPI which have faster and longer duration of action and potassium-competitive acid blocker, a newer acid suppressant, are also in developing stages. Transient lower oesophageal sphincter relaxation (TLESR) is an important factor behind the occurrence of reflux, and preclinical studies have identified gamma aminobutyric acid (GABA) type B receptor (GABAB) agonists and metabotropic glutamate receptor 5 (mG1uR5) modulators as candidate drugs for modifying TLESR. Another novel therapeutic agent has focused on the underlying mechanisms of GERD, such as motility disorder, mucosal protection, and esophageal hypersensitivity are also under clinical trials.

Keywords: GERD, PPI, gastric acid, esophagitis

Received 12 Sept 2013 Received in revised form 09 Oct 2013 Accepted 13 Oct 2013

*Author for Correspondence: Dr. Rahul Saini Senior Resident, Department of Pharmacology, PGIMS, Rohtak, India, E-mail: [email protected]

INTRODUCTION Gastroesophageal reflux disease (GERD) is increased two- to six fold in the last 20 defined as “a condition which develops years [3]. when the reflux of gastric contents into the The normal antireflux mechanisms consist esophagus causes troublesome symptoms of the lower esophageal sphincter (LES), the (i.e., at least two heartburn episodes/week) crural diaphragm, and the anatomical and/or complications”[1].GERD is the most location of the gastroesophageal junction common digestive disease in the Western below the diaphragmatic hiatus. Reflux world, with an estimated prevalence of 10 – occurs only when the gradient of pressure 20% [2].With respect to the esophagus, the between the LES and the stomach is lost. It spectrum of injury includes esophagitis, can be caused by a sustained or transient stricture, Barrett's esophagus, and decrease in LES tone. A sustained adenocarcinoma. There were about 8,000 hypotension of the LES may be due to incident cases of esophageal muscle weakness that is often without adenocarcinoma in the United States in apparent cause. Secondary causes of 2010 (half of all esophageal cancers); it is sustained LES incompetence include estimated that this disease burden has scleroderma-like diseases, myopathy

Rahul Saini et.al, JPRCP 2013; 3(4) 11 Journal of Pharmaceutical Research & Clinical Practice, Oct-Dec 2013; 3(4):11-21 associated with chronic intestinal pseudo- transverse the cell membrane, imparting obstruction, pregnancy, smoking, severe cellular injury in a weakly acidic anticholinergic drugs, smooth muscle environment, and has also been invoked as relaxants (β- adrenergic agents, a cofactor in the pathogenesis of Barrett's aminophylline, nitrates, calcium channel metaplasia and adenocarcinoma. Hence, the blockers, and phosphodiesterase causticity of gastric refluxate extends inhibitors), surgical damage to the LES, and beyond hydrochloric acid. esophagitis [3]. Reflux mainly occurs during Management prolonged relaxations of the lower The goals of treatment are to provide esophageal sphincter (LES) not related to symptom relief, heal erosive esophagitis, swallowing, now referred to as transient and prevent complications. Treatment lower esophageal sphincter relaxations approach is according to the level of (TLESRs) [4]. Such relaxations are a vago- severity (Table 1). The options include vagal reflex mediated motor pattern lifestyle modifications, medical and non- generated in the brain stem and triggered medical (Antireflux surgery) management. by distension of the stomach with free air or Lifestyle modifications include reducing ingestion of a meal [5]. Increased episodes weight, sleeping with the head of the bed of TLESRs are associated with GERD. Apart elevated by about 4–6 inches with blocks, from incompetent barriers, gastric contents and elimination of factors that increase are most likely to reflux when gastric abdominal pressure. Patients should not volume is increased (after meals, in pyloric smoke and should avoid consuming fatty obstruction, in gastric stasis, during acid foods, coffee, chocolate, alcohol, mint, hypersecretion states), when gastric orange juice, and certain medications (such contents are near the gastroesophageal as anticholinergic drugs, calcium channel junction (in recumbency, bending down, blockers, and other smooth-muscle hiatal hernia), and when gastric pressure is relaxants). They should also avoid ingesting increased (obesity, pregnancy, ascites, tight large quantities of fluids with meals. clothes). Incompetence of the Medical need for new drugs for GERD diaphragmatic crural muscle, which Due to high prevalence of GERD the medical surrounds the esophageal hiatus in the costs involved seems to be enormous. The diaphragm and functions as an external LES, prevalence of both typical and atypical also predisposes to GERD. Obesity is a risk GERD has significantly risen over the last factor for GERD. Acid refluxed into the decade, increasing the demand for adequate esophagus is neutralized by saliva. Thus, GERD treatment. Though proton pump impaired salivary secretion also increases inhibitors have been extremely effective for esophageal exposure time. If the refluxed both healing of erosive esophagitis as well material extends to the cervical esophagus as controlling heartburn symptoms for the and crosses the upper sphincter, it can enter majority of GERD patients, there is still a the pharynx, larynx, and trachea. Though substantial subclass of patients (up to 40%) the refluxed gastric juice is harmful to the who do not completely respond esophageal epithelium, gastric acid symptomatically to a standard dose of PPIs. hypersecretion is usually not a dominant Refractory gastro-esophageal reflux disease factor in the development of esophagitis. An (GERD), defined as persistent symptoms obvious exception is with Zollinger-Ellison despite proton pump inhibitor (PPI) syndrome, which is associated with severe therapy, is an increasingly prevalent esophagitis in about 50% of patients. condition and is becoming a major Pepsin, bile, and pancreatic enzymes within challenge for the clinician. The specific gastric secretions can also injure the explanation for PPI treatment failure is not esophageal epithelium, but their noxious clearly known. Possible pathophysiologic properties are either lessened in an acidic mechanisms include: transient lower environment or dependent on acidity for esophageal sphincter relaxations (TLESRs), activation. Bile is more dangerous because sensitivity to weakly acidic and/or alkaline it persists in refluxate despite acid- reflux, large volume of reflux, and suppressing medications. Bile can esophageal hypersensitivity [6].

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Table 1: Therapeutic approach in GERD patients according to the level of severity as follows [7].

Stage Criteria Medical management I Sporadic uncomplicated heartburn, often in setting Lifestyle modifications of known precipitating factor. Antacids and/or H2 receptor Often not the chief complaint. antagonists as needed Less than 2-3 episodes per week. No additional symptoms. II Frequent symptoms with or without esophagitis. Proton pump inhibitors more Greater than 2-3 episodes per week. effective than H2 receptor antagonists III Chronic unrelenting symptoms; immediate relapse Proton pump inhibitors either off therapy. once or twice daily Esophageal complications (eg: stricture, Barret’s metaplasia).

Erosive esophagitis healing is one as partial or non-responders and require important trial endpoint, and a substantial further or alternative treatment, especially proportion of patients do not heal after in non-erosive reflux disease (NERD) standard doses of PPIs for 8 weeks. patients. Recent studies emphasize that Nonresponse of erosive esophagitis non-acidic reflux may also contribute to increases with severity of erosive symptom generation [12]. There may also be esophagitis grading. An intragastric pH of at a ceiling effect for the use of PPI therapy. least 4.0 maintained for 16 h is generally Thus there is a continuous need for new considered the target to promote healing of drugs for the better management of GERD erosive esophagitis with antisecretory patients. New inhibitors of the proton pump drugs [8]. Most patients will experience with a longer half-life, acting faster and reflux after midnight, when the supine time longer, have been developed, including is associated with more reflux events [9]. potassium-competitive acid blockers. There About 60% to 80% of patients have is also a need for new therapeutic strategies persistent gastric acidity at night despite reducing not only acid but also non-acidic twice-daily PPIs. PPIs only change the reflux. Newer drugs under this class are chemical composition of the refluxate. known as ‘reflux inhibitors.’ Other newer Number of reflux events remains drugs are being developed with the aim of unchanged as they do not have any effect on reducing increased esophageal perception. LES tone. With their prolonged use, there is This review aims at reviewing the upcoming an increased risk of gynaecomastia, agents under both acid suppressing and atrophic gastritis, vitamin B12 deficiency, non-acid suppressing strategies for the enteric infections and hip fracture [10]. In pharmacological management of GERD. clinical practice, low compliance or failure Recent advances in acid suppression to properly time intake of medication (30 strategy min before the meal) certainly contribute to With respect to acid suppression, PPIs are PPI failure. This implies that good superior to H2RA or antacids in reducing instruction and education of the patient is gastric acid secretion, esophageal acid indeed important and should be the first exposure and associated symptoms and in approach in these cases. In patients healing of mucosal damage. Currently optimally taking their medication, doubling available PPIs like , of the standard dose or switching to , , another PPI, or even addition of a H2 and , are equally effective, receptor antagonist before the night may with some slight superiority for increase healing (by 6%) or symptom esomeprazole in patients with severe improvement (by 22 – 26%) [11]. In spite of esophagitis [13]. Based on the assumption this, a large proportion of patients remains that better reduction in acid secretion leads

Rahul Saini et.al, JPRCP 2013; 3(4) 13 Journal of Pharmaceutical Research & Clinical Practice, Oct-Dec 2013; 3(4):11-21 to better clinical outcome, several efforts for lansoprazole (not statistically have been made to develop newer drugs or significant). But the therapeutic gain formulations, which are intended to provide (difference in healing rate) was small, that faster, better and more prolonged is, 5-7%. Similarly, post-hoc analysis suppression of acid secretion. revealed better healing of moderate-to- Newer acid suppressing agents can be severe esophagitis (LA grade C or D), but studied under three headings even there the therapeutic gain was only 1. New formulations of existing PPIs 7%. When symptom improvement is 2. New PPIs considered, the median percentage of 24-h 3. Drugs with novel mechanism of acid heartburn free days was comparable for the suppression: potassium-competitive acid different treatments varying between 78 blockers (P-CABs) and 84%. The safety profile was also New formulations of existing PPIs comparable. This study showed that By optimizing the PPI pharmacokinetics and MR is highly effective in extending the period of exposure to healing erosive esophagitis and offers effective concentrations, improved acid benefits over lansoprazole, particularly in suppression can be obtained. New moderate-to-severe disease. In a formulations with prolonged delivery of the subsequent Phase III trial, patients with drug include dual relayed release (DDR) erosive esophagitis (n = 445) healed on formulations (eg: dexlansoprazole MR).The dexlansoprazole MR were randomized to 6 DDR formulation consists of two different months of treatment with dexlansoprazole types of granules, each with a different pH- (30 or 60 mg) or placebo [16]. The dependent dissolution profile. One type of cumulative rate of maintaining mucosal granules releases the drug in the duodenum healing (intention to treat) was 75 and 82% and yields a fast peak, whereas the rest of for dexlansoprazole MR (30 and 60 mg, the drug is released in the distal part of the respectively) compared to 27% for placebo. small intestine by the other type of Although not statistically significant (low granules. The latter is responsible for a later number of patients), the higher dose had but more sustained peak prolonging the better maintenance rates (85 versus 63%) half-life to 6 h instead of 3 h for the in the patients with more severe esophagitis conventional preparation. (LA grade C and D). Symptom control was Dexlansoprazole MR also impressive with median percentage of Dexlansoprazole MR is a novel modified 24-h heartburn symptom free days of 91 – release formulation of dexlansoprazole, an 96%. Nocturnal symptoms were efficiently enantiomer of lansoprazole [14]. This controlled; median percentage of nights formulation results in a biphasic without heartburn of 96 – 99. Both doses pharmacokinetic profile with prolonged were well tolerated. Thus, Dexlansoprazole drug exposure compared to lansoprazole. MR effectively maintained healing erosive This drug combines an enantiomer of esophagitis and symptom relief. The most lansoprazole with a Dual Delayed Release commonly reported treatment-emergent (DDR) formulation designed to provide two adverse reactions (≥2%): diarrhea, separate releases of abdominal pain, nausea, upper respiratory medication.Dexlansoprazole MR 60 and 90 tract infection, vomiting, and flatulence. mg/day leads to a higher percentage of Dexlansoprazole MR was approved by the intragastric pH > 4 compared to U.S. Food and Drug Administration (FDA) lansoprazole 30 mg. On the basis of these on January 30, 2009. Taken once-daily, this findings, two large identical Phase III trials drug is approved for the healing of all were conducted including > 400 patients grades of erosive esophagitis (EE) for up to with erosive esophagitis [15]. Treatment eight weeks, maintaining healing of EE for with dexlansoprazole MR 60 or 90 mg/day up to six months, and treating heartburn during 8 weeks was compared with associated with symptomatic non-erosive lansoprazole 30 mg/day. At week 8, healing gastroesophageal reflux disease (GERD) for rates were 92-95% of patients for four weeks. dexlansoprazole MR compared to 86 – 92%

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New proton pump inhibitors (PPIs) Potassium-Competitive Acid Blockers (P- Tenatoprazole CABs) Tenatoprazole new PPI with an increased P-CABs are a new class of acid suppressive half-life. Chemically it is an imidazo- agents with a fast and prolonged effect. pyridine. The rate of activation of this Drugs of this class block acid pumping by compound to the active intermediates is K+ competitive inhibition, so this class is slower than those of omeprazole, called either acid pump antagonists or lansoprazole, and rabeprazole. Slow potassium-competitive acid blockers (P- activation of tenatoprazole enables CABs).The first core structure of a P-CAB tenatoprazole binding to Cys822, which is developed in 1980 s was an imidazo- located in the membrane domain, giving pyridine. A typical structure of this class truly irreversible inhibition [17]. having excellent inhibitory activity is Tenatoprazole has a much slower SCH28080. Later, many P-CABs were metabolism than omeprazole, lansoprazole, developed. Gastric H+,K+-ATPase requires and rabeprazole, giving a plasma half-life of K+ in exchange for H+ to allow acid about 6 h. The longer plasma half-life of secretion in the canaliculus. Therefore tenatoprazole, combined with its ability to drugs interacting with the binding of K+ bind to Cys822, provides longer inhibition ions to the proton pump will potently of gastric acid secretion. In healthy inhibit acid secretion. This principle has volunteers, tenatoprazole 40 mg provides a been the rationale to develop potassium- more profound acid suppression than 40 competitive acid blockers or P-CABs. P- mg esomeprazole; the mean percentage of CABs block gastric H+,K+-ATPase by time pH > 4 on tenatoprazole and the mean reversible and K+-competitive ionic binding pH during the night are significantly higher [21]. These agents are lipophilic weak bases with tenatoprazole.[18,19]. Clinical trials with a high pKa and are stable at low pH. As evaluating its therapeutic effect in GERD a consequence, P-CABs are rapidly absorbed patients or comparative clinical studies (peak serum concentrations between 0.5 with esomeprazole have, however, not been and 1.5 h after oral administration) and will published so far. theoretically concentrate 100,000-fold in Alevium (AGN201904-Z) the canaliculus of the parietal cell compared AGN 201904-Z is an acid stable pro-drug of to plasma levels. In this acidic environment, omeprazole. It is slowly absorbed P-CABs are instantly protonated and throughout the small intestine and not just subsequently bind ionically and reversibly in the duodenum and rapidly converted to to the proton pump. Potassium-competitive omeprazole in the systemic circulation. acid blockers most likely bind to a different These properties translate in a prolonged binding site than K+, and act by docking the residence time. Because one of the enzyme in a fixed conformation preventing benzimidazolenitrogens is substituted, the the translocation of H+ ions into the compound is acid-stable, unlike any other canaliculus [22]. Because P-CABs inhibit the PPI, and therefore does not require enteric acid pump enzyme by K+ competition, P- coating. Furthermore, it is neutral pH- CABs do not require acid-activation. stable, thus not requiring alkaline solutions Therefore, the inhibition by P-CABs is for stability in intravenous formulation, expected to be fast and effective. Rapid distribution, or administration. In a onset and efficacy to inhibit gastric acid comparative study with esomeprazole, AGN secretion of P-CABs can also be attributed 201904-Z produced a significantly greater to their rapid absorption, their ability to and more prolonged (including nocturnal) concentrate extremely in the canaliculus, acid suppression than esomeprazole. With and their unique mechanism of action. once-daily Alevium (AGN201904-Z), the pH Examples of P-CABs are AZD0865 is stably maintained at greater than 4.0. (linaprazan), YH-1885 () and PF- Averaging pH values over 24 h or at night 03716556. So far, data on the clinical shows the remarkable advantage of efficacy in GERD patients have only been Alevium, not only at night, but also during reported for AZD0865. Two large the day [20]. randomized comparative trials have been

Rahul Saini et.al, JPRCP 2013; 3(4) 15 Journal of Pharmaceutical Research & Clinical Practice, Oct-Dec 2013; 3(4):11-21 conducted in patients with erosive that about 20% of patients continue to esophagitis [23] and non-erosive reflux experience symptoms even with twice-daily disease [24]. In the first study, 1,521 patients administration of any PPI. This finding is with LA grades A – D and heartburn of largely the result of de novo pump synthesis moderate–to-severe intensity were occurring after the drug has dropped below randomized to AZD0865 25, 50 or 75 mg or threshold in the blood, about 90 min after esomeprazole 40 mg/day for 4 – 8 weeks. administration. A P-CAB with a long half-life Despite the preclinical data indicating fast would still be present and more effective and almost complete acid inhibition by than a PPI [26]. AZD0865, there were no significant Recent advances in reflux inhibition differences in healing rates among strategy AZD0865 doses or between AZD0865 and Previously, treatments for GERD have esomeprazole at 2, 4 or 8 weeks. Similarly, focused on reducing heartburn, leading to the onset of sustained absence of heartburn the advent of various acid-suppressive and was comparable with that of esomeprazole. mucosal-protective agents. In contrast, Second study was a randomized regurgitation has received relatively little comparative clinical trial in which 1,469 attention, based on the assumption that by NERD patients showed somewhat similar rendering the refluxate nonacidic, patients results. Patients with troublesome would no longer be symptomatic. To a large heartburn were randomized to receive extent, this belief has held true, because AZD0865 or esomeprazole 20 mg/day for 4 potent acid suppression, particularly by the weeks. Interestingly, although the powerful proton pump inhibitors, leads to percentage of time that intragastric pH > 4 resolution of symptoms in the vast majority was significantly greater for AZD0865 75 of patients. However, it has become mg compared to esomeprazole (75 versus increasingly recognized that a small but 60%), there were no significant differences significant subgroup of patients experience among treatment groups in the cumulative persistent reflux-type symptoms despite incidence of sustained absence of strong acid suppression, which may be heartburn. The median time to sustained result from weakly or nonacidic reflux. absence of heartburn did also not differ These patients are refractory to current between AZD0865 and esomeprazole. standard therapies and incur a significant There was also a reversible raise in healthcare burden as a result of multiple transaminases in 21 patients treated with medical consultations and unnecessary AZD0865. The clinical development of this investigations. Given the success of the drug is terminated. proton pump inhibitors in suppressing Studies conducted using a P-CAB, AZD0865, gastric acid output, it is generally believed raise important questions as to whether that any further acid suppression would be improvement in acid suppression indeed both difficult to achieve and unlikely to offer translates into better clinical efficacy. One additional therapeutic benefit. Clearly there possible explanation for an increase in acid is a demonstrated need for GERD therapies suppression (pH > 4) above the 50 -- 70% beyond the PPIs. Although these threshold not translating into additional medications have provided a significant clinical benefit is that gastric acid benefit, there remains an unmet clinical suppression is perhaps an imprecise need for other medical therapies for surrogate for what is more directly patients with GERD -- in particular to those contributory to the healing process: who may not achieve satisfactory results diminished esophageal acid exposure. In while taking PPIs. Thus there is a need for this regard, factors such as the rate of new for new therapeutic strategies reducing epithelial cell turnover and mucosal not only acid but also non-acidic reflux. inflammation are important [25]. However, More recently, research efforts have increasing the frequency of administration focused on alternative therapeutic targets, of AZD0865 to twice daily would be such as transient lower esophageal expected to outperform currently approved sphincter relaxations (TLESR). PPIs. Of particular relevance is the finding

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Transient Lower Esophageal Sphincter D-aspartate (NMDA) antagonists [39] and Relaxations (TLESRs) cannabinoid receptor agonist [40,41]. Together with the crural diaphragm, the However, only γ-aminobutyric type B lower esophageal sphincter (LES) is the (GABAB) agonists [42] and metabotropic most important contributor to the barrier glutamate receptor (mGluR) antagonists that protects against gastro-esophageal have shown any promise as therapeutic reflux.5A defective LES pressure may be the agents [43]. major cause of reflux in a subgroup of GABAB receptor agonists patients and increasing the LES pressure GABAB agonists are probably the most might therefore be a potential target. promising emerging target for the In 1980, it became clear that reflux mainly treatment of GERD. GABA is an important occurs during prolonged relaxations of the inhibitory neurotransmitter in the CNS. It is lower esophageal sphincter (LES) not abundantly present in the medullary related to swallowing [27]. These are now centres controlling swallowing, esophageal referred to as transient lower esophageal motility and respiration. In particular, sphincter relaxations (TLESRs) [28]. GABAB receptors are expressed in two Transient LES relaxations are prolonged important nuclei in the control of TLESRs, LES relaxations which are not associated namely LES-projecting neurons of the with swallowing that occur as a normal motor nucleus of the vagal nerve, and the physiological response to gastric distention, subnucleuscentralis of the nucleus tractus allowing venting of gas from the stomach. solitaries [43]. Activation of peripheral Transient LES relaxations are mediated GABAB receptors inhibits gastric vagal through a vago-vagal reflex pathway [29]. mechanoreceptors and impairs vagal motor The major stimulus is distension of the outflow, contributing to the inhibitory effect proximal stomach, particularly the gastric on the triggering of TLESRs.Baclofen, the cardia. The afferent signals are integrated in prototypical GABAB agonist, was the first to what is thought to be a pattern generator in be investigated for its potential therapeutic the vagal nuclei. A stereotyped output from use in GERD. It was shown to reduce both this generator leads to a complex response TLESR and reflux episodes in healthy that includes relaxation of the lower volunteers [44,45] and in patients with GERD esophageal sphincter (LES), inhibition of [46,47]. In addition, baclofen increases the the crural diaphragm, and esophageal basal LES tone, an additional effect which shortening [30]. TLESRs are found to be the might be beneficial in patients with a low main mechanism of both acid and non- tonic LES pressure. These studies reported acidic reflux in events both in healthy that degree of inhibition of TLESRs in man volunteers and patients, particularly in varies between 40 and 60% as against 80% those with non-erosive reflux disease in dogs [48]. The lower degree of inhibition (NERD). Hence, pharmacological reduction in man is most likely due to the fact that of TLESRs could be a potential interesting dosing is limited by the occurrence of side target for treatment of GERD. Several drug effects at higher dosages. targets have emerged from preclinical Arbaclofenplacarbil research of which a number of which have Arbaclofenplacarbil (XP19986) is a prodrug been tested in humans. The identification of for the pharmacologically active R-isomer of pharmacologic receptors on the neural baclofen. This drug was designed pathways mediating TLESR has opened the potentially to treat GERD symptoms such as opportunity for the development of drugs heartburn, spasticity and acute back that inhibit them and thereby symptoms with fewer side effects than gastroesophageal reflux. Several agents baclofen. It has shown improved have been identified to reduce the absorption, distribution, metabolism, and triggering of TLESR, including CCK-A elimination properties compared with R- antagonists [31,32], anticholinergic agents baclofen [49]. A multicenter, randomized, [33,34], nitric oxide synthase inhibitors [35], double-blind, crossover study comparing serotonin type 3 (5HT3) antagonists[36], single doses of Arbaclofenplacarbil(AP) morphine [37], somatostatin [38], N-methyl with placebo, was conducted to assess its

Rahul Saini et.al, JPRCP 2013; 3(4) 17 Journal of Pharmaceutical Research & Clinical Practice, Oct-Dec 2013; 3(4):11-21 efficacy and safety for decreasing meal- desirable side-effect profile of induced reflux episodes in patients with is most likely attributed to GABAB gastroesophageal reflux disease (GERD). transporters carrying very low levels of Different patients were enrolled at each of lesogaberan into the CNS [53]. In a four escalating AP doses: 10, 20, 40, and 60 randomized, double-blind, placebo- mg. Enrolled patients had GERD symptoms controlled, crossover study, the effects of at least three times a week and 20 reflux lesogaberan was assessed on reflux and episodes on impedance/pH monitoring over lower esophageal sphincter (LES) function a period of 2 h. During study visits when used as add-on treatment in patients separated by periods of 3-7 days, patients with reflux symptoms despite proton pump received single doses of AP or placebo, inhibitor (PPI) treatment. In this study followed by high-fat meals 2 and 6 h after lesogaberan reduced the mean number of treatment. The primary end point was the reflux events by approximately 35% number of reflux episodes over 12 h after compared with placebo. It also reduced treatment. A total of 50 patients were number of TLESRs by 25% and increased treated; efficacy analysis included 44 LES pressure by 28% compared with patients who received both AP and placebo placebo. The most common adverse events and had technically satisfactory were headache (placebo: 11/27 patients; impedance/pH data. For the combined data lesogaberan: 8/25 patients) and paresthesia from all dose cohorts, there was a (transient; placebo: 3/27 patients; statistically significant (P=0.01) decrease in lesogaberan: 5/25 patients) [54]. As a group, reflux episodes over 12 h after treatment the GABAB agonists are the most extensively with AP compared with placebo. The mean investigated and show the greatest promise (s.d.) number of reflux episodes over 12 h as non-acid inhibiting anti-reflux agents. after AP treatment was 50.5 (27.2), with a The biggest challenge for this group of mean reduction of 10.4 (23.9) episodes drugs to be adopted into clinical use is to (17%) compared with placebo, for which a overcome side effects, particularly those mean (s.d.) number of 60.9 (35.3) episodes that affect the CNS. was observed. Heartburn events associated Scope of reflux inhibitors in GERD with reflux were reduced during treatment management with AP compared with placebo. AP seemed Reflux inhibitors are a new class of drugs to be the most efficacious in the 60-mg dose reducing both acid and non-acid reflux by group, and was well tolerated at all dose interacting with the main mechanism levels. The study concluded that AP underlying reflux, that is, TLESRs. The decreased reflux and associated symptoms possible uses of reflux inhibitor drugs will with good tolerability in patients with GERD be strongly influenced by the magnitude of [50]. In a recently concluded randomized, their antireflux effect. The more that a double-blind, placebo-controlled study, the reflux inhibitor drug can approach the level efficacy and safety of AP was evaluated over of reflux inhibition of anti-reflux surgery, 4 weeks in subjects with symptomatic the more compelling will be the case for GERD. Though AP was well tolerated in this reflux inhibitor drugs to become a study it was observed that AP was not mainstream therapy in all types of reflux superior to placebo in reducing the number disease. Two classes of reflux inhibitors, of weekly heartburn events over 4 weeks. It that is, GABAB agonists and mGluR5 was also observed that response to PPI antagonists, are currently under treatment before the study was associated development. The GABAB receptor agonists with a response to AP treatment [51]. are the most promising new medications Lesogaberan undergoing clinical trials because of their Lesogaberan (AZD3355) shares the same potential to decrease the frequency of target as baclofen but with a more desired TLESRs and their potentially low side-effect side effect profile. As opposed to baclofen, profile. These drugs may be effective as sole AZD3355 has been shown to reduce TLESR therapy but more probably will have most peripherally, which is an ideal mode of clinical use and value for additive therapy action to reduce side effects [52].The more for PPI partial responders. The favourable

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