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Canadian Medical Association Journal Mar 1982
Topics: Baclofen; Canada; Health Facilities; Humans; Huntington Disease; Hydroxybutyrates; Sodium Oxybate; gamma-Aminobutyric Acid
PubMed: 6461407
DOI: No ID Found -
Molecules (Basel, Switzerland) Jun 2022γ-Aminobutyric acid (GABA) represents one of the most prolific structural units widely used in the design of modern pharmaceuticals. For example, β-substituted GABA... (Review)
Review
γ-Aminobutyric acid (GABA) represents one of the most prolific structural units widely used in the design of modern pharmaceuticals. For example, β-substituted GABA derivatives are found in numerous neurological drugs, such as baclofen, phenibut, tolibut, pregabalin, phenylpiracetam, brivaracetam, and rolipram, to mention just a few. In this review, we critically discuss the literature data reported on the preparation of substituted GABA derivatives using the Michael addition reaction as a key synthetic transformation. Special attention is paid to asymmetric methods featuring synthetically useful stereochemical outcomes and operational simplicity.
Topics: Baclofen; Pregabalin; Stereoisomerism; gamma-Aminobutyric Acid
PubMed: 35744921
DOI: 10.3390/molecules27123797 -
Journal of Psychopharmacology (Oxford,... Aug 2018Baclofen has shown promise in the treatment of alcohol dependence. However, its precise (neuro-) psychological working mechanism is still under debate. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Baclofen has shown promise in the treatment of alcohol dependence. However, its precise (neuro-) psychological working mechanism is still under debate.
AIMS
This study aimed to get a better understanding of baclofen's working mechanism by examining the effect of baclofen on cognitive biases. It was hypothesized that baclofen, compared to placebo, would lead to weaker cognitive biases. Furthermore, given a suggested anxiolytic effect of baclofen, we expected that anxiety would moderate this effect.
METHODS
From a larger randomized clinical trial (RCT) with 151 participants, a subset of 143 detoxified alcohol-dependent patients, either taking baclofen or placebo, was examined. Attentional bias for alcohol (500 and 1500 ms), alcohol approach tendencies, implicit alcohol-relaxation associations and trait anxiety were assessed before the administration of baclofen or placebo. Four weeks later, 94 patients were still abstinent (53 in the baclofen and 41 in the placebo condition) and cognitive biases were assessed again.
RESULTS
At baseline, patients showed a vigilance-avoidance pattern for the attentional bias (at 500 and 1500 ms, respectively) and alcohol-negative associations. After 4 weeks, an indication for an attentional bias away from alcohol at 500 ms was found only in the baclofen group; however, cognitive biases did not differ significantly between treatment groups. No moderating role of anxiety on cognitive biases was found.
CONCLUSIONS
Baclofen did not lead to a differential change in cognitive biases compared with placebo, and trait anxiety levels did not moderate this. A better understanding of the working mechanism of baclofen and predictors of treatment success would allow prescribing of baclofen in a more targeted manner.
Topics: Adolescent; Adult; Aged; Alcohol Drinking; Alcoholism; Anxiety; Anxiety Disorders; Attentional Bias; Baclofen; Cognition; Depression; Ethanol; Female; Humans; Male; Middle Aged; Young Adult
PubMed: 29897022
DOI: 10.1177/0269881118780010 -
World Journal of Gastroenterology Jul 2023The association between diabetes mellitus (DM) and the increased risk and progression of cholangiocarcinoma (CCA) has been reported with unclear underlying mechanisms....
BACKGROUND
The association between diabetes mellitus (DM) and the increased risk and progression of cholangiocarcinoma (CCA) has been reported with unclear underlying mechanisms. Previous studies showed that γ-aminobutyric acid (GABA) B2 receptor (GABBR2) was upregulated in CCA cells cultured in high glucose (HG) conditions. Roles of GABA receptors in CCA progression have also been studied, but their association with DM and hyperglycemia in CCA remains unclarified.
AIM
To investigate the effects of hyperglycemia on GABBR2 expression and the potential use of GABBR2 as a CCA therapeutic target.
METHODS
CCA cells, KKU-055 and KKU-213A, were cultured in Dulbecco Modified Eagle's Medium supplemented with 5.6 mmol/L (normal glucose, NG) or 25 mmol/L (HG) glucose and assigned as NG and HG cells, respectively. GABBR2 expression in NG and HG cells was investigated using real-time quantitative polymerase chain reaction and western blot. Expression and localization of GABBR2 in CCA cells were determined using immunocytofluorescence. GABBR2 expression in tumor tissues from CCA patients with and without DM was studied using immunohistochemistry, and the correlations of GABBR2 with the clinicopathological characteristics of patients were analyzed using univariate analysis. Effects of baclofen, a GABA-B receptor agonist, on CCA cell proliferation and clonogenicity were tested using the MTT and clonogenic assays. Phospho-kinases arrays were used to screen the affected signaling pathways after baclofen treatment, and the candidate signaling molecules were validated using the public transcriptomic data and western blot.
RESULTS
GABBR2 expression in CCA cells was induced by HG in a dose- and time-dependent manner. CCA tissues from patients with DM and hyperglycemia also showed a significantly higher GABBR2 expression compared with tumor tissues from those with euglycemia ( < 0.01). High GABBR2 expression was significantly associated with a poorer non-papillary histological subtype but with smaller sizes of CCA tumors ( < 0.05). HG cells of both tested CCA cell lines were more sensitive to baclofen treatment. Baclofen significantly suppressed the proliferation and clonogenicity of CCA cells in both NG and HG conditions ( < 0.05). Phospho-kinase arrays suggested glycogen synthase kinase 3 (GSK3), β-catenin, and the signal transducer and activator of transcription 3 (STAT3) as candidate signaling molecules under the regulation of GABBR2, which were verified in NG and HG cells of the individual CCA cell lines. Cyclin D1 and c-Myc, the common downstream targets of GSK3/β-catenin and STAT3 involving cell proliferation, were accordingly downregulated after baclofen treatment.
CONCLUSION
GABBR2 is upregulated by HG and holds a promising role as a therapeutic target for CCA regardless of the glucose condition.
Topics: Humans; beta Catenin; Glycogen Synthase Kinase 3; Baclofen; Cholangiocarcinoma; Diabetes Mellitus; Cell Proliferation; Hyperglycemia; Bile Ducts, Intrahepatic; Bile Duct Neoplasms; Glucose; Cell Line, Tumor
PubMed: 37576707
DOI: 10.3748/wjg.v29.i28.4416 -
The Cochrane Database of Systematic... Nov 2018Alcohol use disorder (AUD) and alcohol-related impairments belong to the most widespread psychiatric disorders leading to specific psychophysical, affective and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Alcohol use disorder (AUD) and alcohol-related impairments belong to the most widespread psychiatric disorders leading to specific psychophysical, affective and cognitive symptoms and consequences for psychosocial well-being and health. Alcohol consumption is increasingly becoming a problem in many developing regions and AUD prevalence is estimated at 4.1% worldwide, with highest prevalence in European countries (7.5%), and the North America (6.0%). Therapeutic approaches, including pharmacotherapy, play an important role in treating patients with AUD.
OBJECTIVES
To assess the efficacy and safety of baclofen for treating people with AUD, who are currently drinking, with the aim of achieving and maintaining abstinence or reducing alcohol consumption.
SEARCH METHODS
We searched the Cochrane Drugs and Alcohol Specialised Register, CENTRAL, MEDLINE, Embase, two further databases and two clinical trials registries, conference proceedings, and the reference lists of retrieved articles. The date of the most recent search was 30 January 2018.
SELECTION CRITERIA
Randomised controlled trials (RCTs) of at least four weeks' treatment duration and 12 weeks' overall study duration comparing baclofen for relapse prevention of AUD with placebo, no treatment or other treatments.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane.
MAIN RESULTS
We included 12 RCTs (1128 participants). All studies but three recruited fewer than 100 participants. Participants had a diagnosis of alcohol dependence according the Diagnostic and Statistical Manual of Mental Disorders (DSM) IV or the International Classification of Diseases (ICD)-10 criteria who were currently drinking. The mean age of participants was 48 years, and there were more men (69%), than women. All studies compared baclofen to placebo, except for one study that evaluated baclofen versus acamprosate. The included studies considered baclofen at different doses (range 10 mg a day to 150 mg a day). In all but one of the studies, participants in both the baclofen and placebo groups received psychosocial treatment or counselling of various intensity.We judged most of the studies at low risk of selection, performance, detection (subjective outcome), attrition and reporting bias.We did not find any difference between baclofen and placebo for the primary outcomes: relapse-return to any drinking (RR 0.88, 95% CI 0.74 to 1.04; 5 studies, 781 participants, moderate certainty evidence); frequency of use by percentage of days abstinent (MD 0.39, 95% CI -11.51 to 12.29; 6 studies, 465 participants, low certainty evidence) and frequency of use by percentage of heavy drinking days at the end of treatment (MD 0.25, 95% CI -1.25 to 1.76; 3 studies, 186 participants, moderate certainty evidence); number of participants with at least one adverse event (RR 1.04, 95% CI 0.99 to 1.10; 4 studies, 430 participants, high certainty evidence); the dropout rate at the end of treatment (RR 0.98, 95% CI 0.77 to 1.26, 8 studies, 977 participants, high certainty evidence) and dropout due to adverse events (RR 1.11, 95% CI 0.59 to 2.07; 7 studies, 913 participants, high certainty evidence).We found evidence that baclofen increases amount of use (drink per drinking days), (MD 1.55, 95% CI 1.32 to 1.77; 2 studies, 72 participants, low certainty evidence).Among secondary outcomes, there was no difference on craving (MD 1.38, 95% CI -1.28 to 4.03, 5 studies, 469 participants), and anxiety (SMD 0.07, 95% CI -0.14 to 0.28; 5 trials, 509 participants). We found that baclofen increased depression (SMD 0.27, 95% CI 0.05 to 0.48; 3 studies, 387 participants).Concerning the specific adverse events we found that baclofen increased: vertigo (RR 2.16, 95% CI 1.24 to 3.74; 7 studies, 858 participants), somnolence/sedation (RR 1.48, 95%CI 1.11 to 1.96; 8 studies, 946 participants), paraesthesia (RR 4.28, 95% CI 2.11 to 8.67; 4 studies, 593 participants), and muscle spasms/rigidity (RR 1.94, 95%CI 1.08 to 3.48; 3 studies, 551 participants). For all the other adverse events we did not find significant differences between baclofen and placebo.For the comparison baclofen versus acamprosate, we were only able to extract data for one outcome, craving. For this outcome, we found that baclofen increased craving compared with acamprosate (MD 14.62, 95% CI 12.72 to 16.52; 1 study, 49 participants).
AUTHORS' CONCLUSIONS
None of the primary or secondary outcomes of the review showed evidence of a difference between baclofen and placebo. The high heterogeneity among primary studies results limits the interpretation of the summary estimate, the identification of moderators and mediators of baclofen's effects on alcohol use remains a challenge for further research. Even though some results from RCTs are promising, current evidence remains uncertain regarding the use of baclofen as a first-line treatment for people with AUDs.
Topics: Acamprosate; Alcohol Deterrents; Alcohol Drinking; Alcoholism; Baclofen; Craving; Depression; Female; GABA-B Receptor Agonists; Humans; Male; Middle Aged; Patient Dropouts; Randomized Controlled Trials as Topic; Recurrence
PubMed: 30484285
DOI: 10.1002/14651858.CD012557.pub2 -
PM & R : the Journal of Injury,... Mar 2018Pharmacogenomic variability can contribute to differences in pharmacokinetics and clinical responses. Pediatric patients with cerebral palsy with genetic variations have... (Clinical Trial)
Clinical Trial
BACKGROUND
Pharmacogenomic variability can contribute to differences in pharmacokinetics and clinical responses. Pediatric patients with cerebral palsy with genetic variations have not been studied for these potential differences.
OBJECTIVE
To determine the genetic sources of variation in oral baclofen clearance and clinical responses.
DESIGN
Pharmacogenomic add-on study to determine variability in oral baclofen clearance and clinical responses.
SETTING
Multicenter study based in academic pediatric cerebral palsy clinics.
PARTICIPANTS
A total of 49 patients with cerebral palsy who had participated in an oral baclofen pharmacokinetic/pharmacodynamic study.
METHODS OR INTERVENTIONS
Of 53 participants in a pharmacokinetic/pharmacodynamic trial, 49 underwent genetic analysis of 307 key genes and 4535 single-nucleotide polymorphisms involved in drug absorption, distribution, metabolism, and excretion. Associations between genotypes and phenotypes of baclofen disposition (weight-corrected and allometrically scaled clearance) and clinical endpoints (improvement from baseline in mean hamstring Modified Tardieu Scale scores from baseline for improvement of R1 spastic catch) were determined by univariate analysis with correction for multiple testing by false discovery rate.
MAIN OUTCOME MEASUREMENTS
Primary outcome measures were the genotypic and phenotypic variability of oral baclofen in allometrically scaled clearance and change in the Modified Tardieu Scale angle compared to baseline.
RESULTS
After univariate analysis of the data, the SNP of ABCC9 (rs11046232, heterozygous AT versus the reference TT genotype) was associated with a 2-fold increase in oral baclofen clearance (mean 0.51 ± standard deviation 0.05 L/h/kg for the AT genotype versus 0.25 ± 0.07 L/h/kg for the TT genotype, adjusted P < .001). Clinical responses were associated with decreased spasticity by Modified Tardieu Scale in allelic variants with SNPs ABCC12, SLC28A1, and PPARD.
CONCLUSIONS
Genetic variation in ABCC9 affecting oral baclofen clearance highlights the need for continued studies of genetic polymorphisms to better characterize variable drug response in children with cerebral palsy. Single-nucleotide polymorphisms in ABCC12, SLC28A1, and PPARD were associated with varied responses, which warrants further investigation to determine their effect on spasticity.
LEVEL OF EVIDENCE
II.
Topics: Administration, Oral; Adolescent; Baclofen; Cerebral Palsy; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Genetic Variation; Humans; Male; Muscle Relaxants, Central; Pharmacogenetics; Polymorphism, Single Nucleotide; Prognosis; Sulfonylurea Receptors
PubMed: 28867665
DOI: 10.1016/j.pmrj.2017.08.441 -
Journal of Pharmaceutical Sciences Jul 2011Baclofen, an antispasmodic agent that acts as a GABA(B) agonist, resembles phenylalanine in structure and has been reported to be a substrate of the large amino acid...
Baclofen, an antispasmodic agent that acts as a GABA(B) agonist, resembles phenylalanine in structure and has been reported to be a substrate of the large amino acid transporter 1 (LAT-1). The objective of this study was to investigate the absorption of baclofen across the nasal mucosa both in vitro and in vivo. Baclofen transport was measured across excised bovine olfactory and respiratory mucosae to investigate site-specific uptake of baclofen, and the intranasal bioavailability of R- and S-baclofen was determined in rats. Increasing flux with increasing baclofen donor concentration and the absence of polarized transport was observed in vitro, and similar distribution profiles were observed for both enantiomers following intranasal administration in rats. The absence of stereospecificity in nasal absorption indicates limited involvement of the amino acid or other transporters in the nasal absorption of baclofen.
Topics: Absorption; Administration, Intranasal; Animals; Baclofen; Biological Availability; Biological Transport; Cattle; Cell Polarity; Electric Impedance; In Vitro Techniques; Injections, Intra-Arterial; Isomerism; Male; Models, Biological; Muscle Relaxants, Central; Nasal Mucosa; Olfactory Mucosa; Permeability; Rats; Rats, Sprague-Dawley
PubMed: 21283988
DOI: 10.1002/jps.22499 -
Alcohol and Alcoholism (Oxford,... Feb 2021The effects of alcohol on gamma-aminobutyric acid (GABA) transmission are key for the development and maintenance of alcohol use disorder (AUD). Previous research... (Review)
Review
AIMS
The effects of alcohol on gamma-aminobutyric acid (GABA) transmission are key for the development and maintenance of alcohol use disorder (AUD). Previous research consistently indicates that GABAB receptor agonists such as baclofen can attenuate addiction-related behaviors in preclinical models of AUD. More importantly, baclofen has also shown promise in clinical studies, particularly in severely alcohol-dependent patients. However, despite this promise, other clinical studies have not confirmed its efficacy and chiefly, larger clinical trials have not been conducted. Therefore, with the exception of France, baclofen is not approved for the treatment of AUD in any other country. Furthermore, it is also important to keep in mind that some patients treated with baclofen may experience important side-effects, including sedation, drowsiness and sleepiness.
METHODS
This short review will first discuss the history of baclofen for AUD treatment. We will then summarize preclinical behavioral results that have investigated the efficacy of GABAB PAMs for addiction treatment, with a special focus on our recent work that investigated the effects of ADX71441, a novel GABAB PAM, on several alcohol-related behaviors in rats that model important aspects of human AUD. Finally, in light of the recent criticism about the translational value of animal models of addiction, the specific translational potential of our work and of other preclinical studies that have unanimously reported the efficacy of GABAB PAMs to attenuate multiple alcohol-related behaviors will be discussed.
RESULTS
Positive allosteric modulators (PAMs) of the GABAB receptor offer an attractive alternative approach to baclofen and have the potential to achieve mechanistic and therapeutic effects similar to GABAB agonists, while avoiding the tolerance and toxicity issues associated with baclofen. To date, all preclinical behavioral results have invariably shown the efficacy of GABAB PAMs for addiction treatment.
CONCLUSIONS
Preclinical studies indicate that GABAB PAMs have a higher therapeutic index than orthosteric agonists, at least in terms of mitigating the sedative effects of GABAB agonism. This predicts that GABAB PAMs have a high translational potential in humans and merit being tested clinically, in particular in patients with severe AUD.
Topics: Acetamides; Alcoholism; Animals; Baclofen; Bacterial Proteins; GABA-B Receptor Agonists; Mice; Rats; Receptors, GABA-B; Recurrence; Transcription Factors; Triazines
PubMed: 33561865
DOI: 10.1093/alcalc/agab003 -
Biomolecules Feb 2023This study aims to explore the role of GABA receptors in the development of deprivation myopia (DM), lens-induced myopia (LIM) and lens-induced hyperopia (LIH). Chicks...
This study aims to explore the role of GABA receptors in the development of deprivation myopia (DM), lens-induced myopia (LIM) and lens-induced hyperopia (LIH). Chicks were intravitreally injected with 25 µg baclofen (GABAR agonist) in one eye and saline into the fellow eye. Choroidal thickness (ChT) was measured via OCT before and 2, 4, 6, 8, 24 h after injection. ChT decreased strongly at 6 and 8 h after baclofen injection and returned back to baseline level after 24 h. Moreover, chicks were monocularly treated with translucent diffusers, -7D or +7D lenses and randomly assigned to baclofen or saline treatment. DM chicks were injected daily into both eyes, while LIM and LIH chicks were monocularly injected into the lens-wearing eyes, for 4 days. Refractive error, axial length and ChT were measured before and after treatment. Dopamine and its metabolites were analyzed via HPLC. Baclofen significantly reduced the myopic shift and eye growth in DM and LIM eyes. However, it did not change ChT compared to respective saline-injected eyes. On the other hand, baclofen inhibited the hyperopic shift and choroidal thickening in LIH eyes. All the baclofen-injected eyes showed significantly lower vitreal DOPAC content. Since GABA is an inhibitory ubiquitous neurotransmitter, interfering with its signaling affects spatial retinal processing and therefore refractive error development with both diffusers and lenses.
Topics: Animals; Baclofen; Chickens; Choroid; Hyperopia; Myopia; Refractive Errors
PubMed: 36979369
DOI: 10.3390/biom13030434 -
British Journal of Pharmacology Jan 2022Activation of GIRK channels via G protein-coupled GABA receptors has been shown to attenuate nociceptive transmission. The analgesic α-conotoxin Vc1.1 activates GABA...
BACKGROUND AND PURPOSE
Activation of GIRK channels via G protein-coupled GABA receptors has been shown to attenuate nociceptive transmission. The analgesic α-conotoxin Vc1.1 activates GABA receptors resulting in inhibition of Ca 2.2 and Ca 2.3 channels in mammalian primary afferent neurons. Here, we investigated the effects of analgesic α-conotoxins on recombinant and native GIRK-mediated K currents and on neuronal excitability.
EXPERIMENTAL APPROACH
The effects of analgesic α-conotoxins, Vc1.1, RgIA, and PeIA, were investigated on inwardly-rectifying K currents in HEK293T cells recombinantly co-expressing either heteromeric human GIRK1/2 or homomeric GIRK2 subunits, with GABA receptors. The effects of α-conotoxin Vc1.1 and baclofen were studied on GIRK-mediated K currents and the passive and active electrical properties of adult mouse dorsal root ganglion neurons.
KEY RESULTS
Analgesic α-conotoxins Vc1.1, RgIA, and PeIA potentiate inwardly-rectifying K currents in HEK293T cells recombinantly expressing human GIRK1/2 channels and GABA receptors. GABA receptor-dependent GIRK channel potentiation by Vc1.1 and baclofen occurs via a pertussis toxin-sensitive G protein and is inhibited by the selective GABA receptor antagonist CGP 55845. In adult mouse dorsal root ganglion neurons, GABA receptor-dependent GIRK channel potentiation by Vc1.1 and baclofen hyperpolarizes the cell membrane potential and reduces excitability.
CONCLUSIONS AND IMPLICATIONS
This is the first report of GIRK channel potentiation via allosteric α-conotoxin Vc1.1-GABA receptor agonism, leading to decreased neuronal excitability. Such action potentially contributes to the analgesic effects of Vc1.1 and baclofen observed in vivo.
Topics: Analgesics; Animals; Baclofen; Calcium Channels, N-Type; Conotoxins; G Protein-Coupled Inwardly-Rectifying Potassium Channels; HEK293 Cells; Humans; Mice; Receptors, GABA-B
PubMed: 34599513
DOI: 10.1111/bph.15690