Arbaclofen Research Articles

Screening Targets and Therapeutic Drugs for Alzheimer's Disease Based on Deep Learning Model and Molecular Docking.

Alzheimer's disease (AD) is a neurodegenerative disorder caused by a complex interplay of various factors. However, a satisfactory cure for AD remains elusive. Pharmacological interventions based on drug targets are considered the most cost-effective therapeutic strategy. Therefore, it is paramount to search potential drug targets and drugs for AD. We aimed to provide novel targets and drugs for the treatment of AD employing transcriptomic data of AD and normal control brain tissues from a new perspective. Our study combined the use of a multi-layer perceptron (MLP) with differential expression analysis, variance assessment and molecular docking to screen targets and drugs for AD. We identified the seven differentially expressed genes (DEGs) with the most significant variation (ANKRD39, CPLX1, FABP3, GABBR2, GNG3, PPM1E, and WDR49) in transcriptomic data from AD brain. A newly built MLP was used to confirm the association between the seven DEGs and AD, establishing these DEGs as potential drug targets. Drug databases and molecular docking results indicated that arbaclofen, baclofen, clozapine, arbaclofen placarbil, BML-259, BRD-K72883421, and YC-1 had high affinity for GABBR2, and FABP3 bound with oleic, palmitic, and stearic acids. Arbaclofen and YC-1 activated GABAB receptor through PI3K/AKT and PKA/CREB pathways, respectively, thereby promoting neuronal anti-apoptotic effect and inhibiting p-tau and Aβ formation. This study provided a new strategy for the identification of targets and drugs for the treatment of AD using deep learning. Seven therapeutic targets and ten drugs were selected by using this method, providing new insight for AD treatment.

Is Arbaclofen an Effective Treatment for Autism

Autism spectrum disorder (ASD) frequently occurs in fragile X syndrome, which is associated with increased glutamate-pathway activity in animals (NEJM

Randomised clinical trial: arbaclofen placarbil in gastro‐oesophageal reflux disease – insights into study design for transient lower sphincter relaxation inhibitors

Arbaclofen placarbil is a pro-drug of the gamma-aminobutyric acid-B agonist R-baclofen that has been shown to reduce reflux episodes in patients with gastro-oesophageal reflux disease (GERD). To evaluate the efficacy and safety of arbaclofen placarbil vs. placebo as adjunctive therapy in subjects with troublesome GERD symptoms despite therapy with once-daily doses of a proton pump inhibitor (PPI) and to identify the characteristics of patients who were responders. Patients (n = 460) with symptomatic GERD experiencing troublesome symptoms on once-daily PPI therapy were enrolled in this phase II, randomised, multicentre, double-blind, placebo-controlled, dose-ranging study. Patients were randomised to receive placebo or arbaclofen placarbil (20 or 40 mg once daily, 20 or 30 mg twice daily) with their current PPI for 6 weeks. Patients recorded heartburn and other GERD symptoms in a daily diary and rated severity of each event. The primary endpoint was percent change from baseline in heartburn events per week. In the primary analysis, there was no significant difference between arbaclofen placarbil and placebo. Post hoc analyses removing mild and very mild heartburn events resulted in greater percent reductions for all arbaclofen placarbil doses with nominal P values <0.05 for each dose compared with placebo. There was a dose-related increase for the most common adverse events. Arbaclofen placarbil was not superior to placebo in the primary analysis. Post hoc analyses suggest that subjects with more clinically relevant moderate or severe symptoms are more likely to respond to arbaclofen placarbil (clinicaltrials.gov NCT00978016).

An Ongoing Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of Arbaclofen Placarbil in Subjects with Spasticity Due to Multiple Sclerosis (P03.267)

An Ongoing Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of Arbaclofen Placarbil in Subjects with Spasticity Due to Multiple Sclerosis (P03.267)

1153 A Dose-Response Efficacy and Safety Study of Arbaclofen Placarbil as Adjunctive Therapy in GERD Patients Who Incompletely Responded to PPI Therapy

1153 A Dose-Response Efficacy and Safety Study of Arbaclofen Placarbil as Adjunctive Therapy in GERD Patients Who Incompletely Responded to PPI Therapy

A New Approach May Help Patients with Fragile X Autism

In preclinical research on the pathways affected by the fragile X mutation (>200 CGG repeats on FMR1 ), researchers found increased glutamate activity at the mGlu5 receptor (JW Psychiatry Feb 25 2008). Now, investigators have examined the effect of inhibiting excessive glutamate production by increasing gamma-aminobutyric acid (GABA) B activity with arbaclofen, the …

Revisiting Baclofen for the Treatment of Severe Chronic Tinnitus

Revisiting Baclofen for the Treatment of Severe Chronic Tinnitus

Efficacy and safety study of arbaclofen placarbil in patients with spasticity due to spinal cord injury

Randomized, double-blind, placebo-controlled, two-period crossover. To evaluate the efficacy and safety of arbaclofen placarbil (AP) in patients with spasticity secondary to spinal cord injury (SCI). United States and Canada. Patients received extended-release AP tablets 10, 20 or 30 mg every 12 h in one of two AP/placebo sequences, with 26 days of each treatment. The primary analysis compared Ashworth scale assessments of muscle tone between AP and placebo for the muscle group with maximum baseline Ashworth score. Secondary endpoints included a patient-rated Severity of Spasticity Scale. In the primary analysis, AP significantly improved Ashworth scores compared with placebo over the dosing interval: least-squares mean reduction versus placebo was 0.60 for AP 20 mg (P=0.0059) and 0.88 for AP 30 mg (P=0.0007). The difference was significant for the pre-morning dose time point, 12 h after the prior evening dose, indicating that efficacy was maintained throughout the dosing interval. Treatment differences for AP 10 mg versus placebo were not significant. Severity of Spasticity ratings were significantly reduced for the combined 20/30-mg group versus placebo (P=0.018). No statistically significant differences between AP and placebo were observed for muscle strength. AP-related AEs were generally mild to moderate in intensity, and none led to early withdrawal or were serious. AP was well tolerated at all investigated dosages and, when administered at doses of 20 or 30 mg twice daily, was efficacious in reducing spasticity due to SCI.

Arbaclofen Placarbil in GERD: A Randomized, Double-Blind, Placebo-Controlled Study

It has been shown that arbaclofen placarbil (AP) inhibits reflux in gastroesophageal reflux disease (GERD) following single oral dosing. This study evaluated the efficacy and safety of AP over 4 weeks in subjects with symptomatic GERD. One hundred fifty-six subjects with heartburn and/or regurgitation ≥3 days/week and either no history of taking proton pump inhibitors (PPIs naive, n=58) or at least partial symptom response to PPI therapy (PPI responsive, n=98) were enrolled in this randomized, double-blind, placebo-controlled trial. All GERD therapies including PPIs were discontinued 2 weeks before randomization to AP 20, 40, or 60 mg daily, 30 mg twice daily, or placebo for 4 weeks. Randomization was stratified by prior PPI use. In the primary analysis, change from baseline in weekly heartburn events between AP and placebo for the entire study group was not statistically significant. However, a significant interaction was observed between prior PPI use and response to AP treatment. In pre-planned secondary analyses of the PPI-responsive subgroup, percent reductions from baseline in weekly heartburn events were greater for each AP dose vs. placebo (P<0.05) and the percentage of subjects who reported complete resolution of heartburn during week 4 was higher in each AP treatment group (21, 28, 30, and 50% for AP 20, 40, 60 mg daily, and 30 mg twice daily, respectively) compared with placebo (6%) (P<0.05 for 30 mg twice daily). Corresponding analyses of the PPI-naive subgroup showed no significant differences. AP was well tolerated; withdrawals due to adverse events were infrequent. AP was not superior to placebo in reducing the number of weekly heartburn events over 4 weeks in the primary analysis of the entire study population. Exploratory subgroup analyses suggest that response to PPI treatment before the study was associated with a response to AP treatment.

Arbaclofen Placarbil Decreases Reflux With Good Tolerability in Patients With Gastroesophageal Reflux Disease (Am J Gastroenterol 2010;105:1266-1275)

Arbaclofen placarbil (AP), previously designated as XP19986, is a novel transported prodrug of the active R-isomer of baclofen, which overcomes the pharmacokinetic limitations of racemic baclofen.1 AP is efficiently absorbed by high-capacity active transport pathways expressed throughout the gastrointestinal (GI) tract, and rapidly metabolized to release R-baclofen after the absorption. This multicenter, randomized, double-blind, crossover study comparing single doses of AP with placebo was conducted to assess the efficacy and safety of AP for decreasing meal-induced reflux episodes in patients with gastroesophageal reflux disease (GERD).2 Different patients were enrolled at each of 4 escalating AP doses: 10, 20, 40 and 60 mg. A total of 50 patients were treated and the efficacy analysis included 44 patients who completed the protocol and had technically satisfactory impedance/pH data. There was a statistically significant decrease in reflux episodes over 12 hours after treatment with AP compared with placebo (p = 0.01). The mean ± SD number of reflux episodes over 12 hours after AP treatment was 50.5 ± 27.2, with a mean reduction of 10.4 ± 23.9 episodes (17%) compared with placebo (60.9 ± 35.3). Only acid reflux episodes were statistically decreased after treatment with AP. Heartburn events associated with reflux were reduced during treatment with AP compared with placebo (12.9 ± 11.9 vs 16.7 ± 18.2, p = 0.03). AP seemed to be the most efficacious in the 60 mg dose group, and was well tolerated at all dose levels.

A Clinical Pharmacokinetic Drug-Drug Interaction Study of Arbaclofen Placarbil, a Novel Reflux Inhibitor, With Esomeprazole

Purpose: Arbaclofen placarbil (AP), a novel reflux inhibitor, is an actively transported prodrug of the R isomer of baclofen (RB). AP is currently under investigation as an adjunct to proton pump inhibitors (PPI) for the treatment of gastroesophageal reflux disease (GERD) in patients who remain symptomatic on PPIs. The purpose of this study was to assess the potential for pharmacokinetic (PK) drug-drug interaction between AP and esomeprazole. Methods: In this open-label, 2-treatment, 2-period, sequential design study, 15 healthy adult subjects were treated with sustained-release AP 60 mg qd for 5 days, followed by AP 60 mg + esomeprazole 40 mg qd for 5 days. There was a 3-day titration period and a 5-day tapering period for AP. Steady-state AP and RB concentrations were determined on days 8 and 13, using LC/MS/MS methods. PK parameters were estimated using noncompartmental analysis and compared for AP and AP + esomaprazole (days 8 and 13) using ANOVA. Results: Fifteen subjects completed the study. AP was well absorbed and rapidly converted to RB. Mean RB Css,max and AUCss,24 values were 144 ng/mL and 1480 ng*h/mL, respectively, for AP alone, and were 124 ng/mL and 1270 ng*h/mL, respectively, when AP was dosed with esomeprazole. Mean Css,max and AUCss,24 of RB were each decreased by approximately 14% when AP was coadministered with esomeprazole. Statistical analysis showed no significant treatment effect on the PK parameters at level α=0.05. The 90% confidence intervals of ratio of means included 1. Levels of the intact prodrug were low and transient for both treatments (Mean of % [AP AUClast to RB AUClast] of ≤ 10). There was no effect on AP exposure when AP was coadministered with esomeprazole. Both AP and AP+ esomaprazole treatments were generally safe and well tolerated. There were no clinically significant changes in laboratory values, vital signs, or ECG parameters. Conclusion: There was no clinically relevant or statistically significant drug-drug interaction when AP was administered with esomeprazole. The results of this study suggest that no AP dose adjustment is needed with coadministration of PPIs. Disclosure: All authors are employees of XenoPort, Inc. The study was funded by XenoPort, Inc.

Evolving drugs in gastroesophageal reflux disease: pharmacologic treatment beyond proton pump inhibitors

Importance of the field: Despite the clinical success of proton pump inhibitors to treat gastroesophageal reflux disease (GERD), for the majority of patients in both gastroenterology and primary care clinics there is still a substantial group of patients (up to 40% in some studies) who do not completely respond symptomatically to a standard dose of proton pump inhibitors (PPIs). Specific explanations for these PPI noncomplete responders included transient lower esophageal sphincter relaxations (TLESRs), sensitivity to weakly acidic and/or alkaline reflux, large volume of reflux and esophageal hypersensitivity. There is a clear need for GERD therapies beyond the PPIs.Areas covered in this review: These drug classes include the GABAB receptor agonists (including lesogaberan and arbaclofen placarbil), mGluR5 receptor antagonists, P-CABs, cholecystokinin2 antagonists and add-on therapies to PPIs including mosapride and rikkunshito.What the reader will gain: Both physicians and patients are eagerly awaiting the development and FDA approval of a new class of anti-GERD medications targeting distinct mechanisms. This article provides information on pharmacologic strategies, clinical trials and side-effect profiles on several of the most promising and heavily researched compounds being developed today for the treatment of GERD symptoms and inflammation. Hopefully, this important research will help a large group of PPI noncomplete responding patients receive symptomatic relief and reduce esophageal inflammation through a unique pharmacologic mechanism in the near future.Take home message: The treatment of GERD has greatly improved with the PPI class of therapy. Despite excellent success, there is a sizeable population of patients who do not have adequate response to therapies directed only at acid suppression. Emerging new pharmacologic treatment options show promise in further advancing the treatment success of GERD.

W1102 Arbaclofen Placarbil, a Novel Reflux Inhibitor, is Well Tolerated at Efficacious Doses in Subjects With Gastroesophageal Reflux Disease

W1102 Arbaclofen Placarbil, a Novel Reflux Inhibitor, is Well Tolerated at Efficacious Doses in Subjects With Gastroesophageal Reflux Disease

W1105 Clinical Pharmacokinetics and Pharmacodynamics of Arbaclofen Placarbil, a Novel Reflux Inhibitor, in Subjects With GERD

W1105 Clinical Pharmacokinetics and Pharmacodynamics of Arbaclofen Placarbil, a Novel Reflux Inhibitor, in Subjects With GERD

Arbaclofen Placarbil Decreases Postprandial Reflux in Patients With Gastroesophageal Reflux Disease

Arbaclofen placarbil (AP), previously designated as XP19986, is an investigational prodrug of the active R-isomer of baclofen, a gamma-aminobutyric acid agonist reflux inhibitor. The aim of this study was to assess the efficacy and safety of AP for decreasing meal-induced reflux episodes in patients with gastroesophageal reflux disease (GERD). We conducted a multicenter, randomized, double-blind, crossover study comparing single doses of AP with placebo. Different patients were enrolled at each of four escalating AP doses: 10, 20, 40, and 60 mg. Enrolled patients had GERD symptoms at least three times a week and 20 reflux episodes on impedance/pH monitoring over a period of 2 h. During study visits separated by periods of 3-7 days, patients received single doses of AP or placebo, followed by high-fat meals 2 and 6 h after treatment. The primary end point was the number of reflux episodes over 12 h after treatment. A total of 50 patients were treated; efficacy analysis included 44 patients who received both AP and placebo and had technically satisfactory impedance/pH data. For the combined data from all dose cohorts, there was a statistically significant (P=0.01) decrease in reflux episodes over 12 h after treatment with AP compared with placebo. The mean (s.d.) number of reflux episodes over 12 h after AP treatment was 50.5 (27.2), with a mean reduction of 10.4 (23.9) episodes (17%) compared with placebo, for which a mean (s.d.) number of 60.9 (35.3) episodes was observed. Heartburn events associated with reflux were reduced during treatment with AP compared with placebo. AP seemed to be the most efficacious in the 60-mg dose group, and was well tolerated at all dose levels. AP decreased reflux and associated symptoms with good tolerability in patients with GERD.

Evaluation of the Effect of Arbaclofen Placarbil, a Novel Transported Prodrug of R-Baclofen, on Cardiac Repolarization in a Thorough QT Study in Healthy Subjects

Purpose: Arbaclofen Placarbil (AP) is a novel Transported Prodrug of the reflux inhibitor R-baclofen, and is under investigation for the treatment of symptomatic gastroesophageal reflux disease (GERD) in patients who remain symptomatic on proton pump inhibitors. The purpose of this study was to assess the effect of steady-state oral dosing of AP on cardiac repolarization (QTcF interval duration) in healthy subjects. Methods: In this randomized, double-blind, double-dummy, placebo- and active-controlled parallel group study, 199 subjects were randomized to receive sustained-release AP treatment, moxifloxacin (active control) treatment or placebo treatments. Subjects randomized to AP treatment were titrated in escalating doses over 19 days and steady-state levels of AP/R-baclofen were reached on Days 7, 13 and 19 at doses of 30 mg BID, 60 mg BID and 90 mg BID, respectively. Subjects randomized to the moxifloxacin treatment arm received a single 400-mg dose of moxifloxacin on Days 7, 13 and 19. Continuous Holter electrocardiograms (ECG) were collected at baseline (Day -1) and on Days 7, 13 and 19. Steady-state AP/R-baclofen and single-dose moxifloxacin concentrations were determined using LC/MS/MS methods. The primary analysis was on baseline-adjusted QTcF interval using a repeated measures ANCOVA model. Assay sensitivity using moxifloxacin was analyzed on prospectively specified time points using a hierarchical stepwise testing procedure. Results: The baseline-adjusted LS mean change in QTcF (ddQTcF) between AP and placebo treatment from 0.5 to 21 hours post morning dose ranged from 0.5 to 3.8 msec at 30 mg BID, 0.7 to 3.4 msec at 60 mg BID and 0.2 to 3.5 msec at 90 mg BID. The largest one-sided 95% CI upper bound for mean ddQTcF was 7.0 at 30 mg BID and 6.9 msec at 60 mg BID and 90 mg BID, all within 10 msec. No subject had a QTcF >480 msec or changes in QTcF from baseline >60 msec. No relationship was detected between ddQTcF and AP/R-baclofen concentrations. Assay sensitivity was established by demonstrating the moxifloxacin QT prolongation effect. No dose of AP investigated was associated with cardiac dysrhythmia, morphology changes, cardiogenic syncope or seizures. AP was well absorbed and rapidly converted to R-baclofen. R-baclofen exposures were proportional to AP dose over the dose range studied. Steady-state levels of intact prodrug in blood were low. The most commonly reported treatment-emergent adverse events were dizziness, nausea, headache, insomnia, somnolence and vomiting, and were of mild or moderate intensity. No clinically significant changes in vital signs, safety ECG or laboratory values associated with AP treatment were observed. Conclusion: AP does not have an effect on cardiac repolarization at doses up to 90 mg BID. Disclosure: All authors are employees of XenoPort, Inc. This research was supported by an industry grant from XenoPort, Inc.

Arbaclofen Placarbil Monotherapy Improves Sleep Quality in Patients Who Have Previously Responded to a PPI

Arbaclofen Placarbil Monotherapy Improves Sleep Quality in Patients Who Have Previously Responded to a PPI

Arbaclofen Placarbil, a Novel R-Baclofen Prodrug: Improved Absorption, Distribution, Metabolism, and Elimination Properties Compared with R-Baclofen

Baclofen is a racemic GABA(B) receptor agonist that has a number of significant pharmacokinetic limitations, including a narrow window of absorption in the upper small intestine and rapid clearance from the blood. Arbaclofen placarbil is a novel transported prodrug of the pharmacologically active R-isomer of baclofen designed to be absorbed throughout the intestine by both passive and active mechanisms via the monocarboxylate type 1 transporter. Arbaclofen placarbil is rapidly converted to R-baclofen in human and animal tissues in vitro. This conversion seems to be primarily catalyzed in human tissues by human carboxylesterase-2, a major carboxylesterase expressed at high levels in various tissues including human intestinal cells. Arbaclofen placarbil was efficiently absorbed and rapidly converted to R-baclofen after oral dosing in rats, dogs, and monkeys. Exposure to R-baclofen was proportional to arbaclofen placarbil dose, whereas exposure to intact prodrug was low. Arbaclofen placarbil demonstrated enhanced colonic absorption, i.e., 5-fold higher R-baclofen exposure in rats and 12-fold higher in monkeys compared with intracolonic administration of R-baclofen. Sustained release formulations of arbaclofen placarbil demonstrated sustained R-baclofen exposure in dogs with bioavailability up to 68%. In clinical use, arbaclofen placarbil may improve the treatment of patients with gastroesophageal reflux disease, spasticity, and numerous other conditions by prolonging exposure and decreasing the fluctuations in plasma levels of R-baclofen.

490 Arbaclofen Placarbil Monotherapy Decreases GERD Symptoms in Subjects with Previous PPI Therapy

490 Arbaclofen Placarbil Monotherapy Decreases GERD Symptoms in Subjects with Previous PPI Therapy