R-Baclofen

OBJECTIVE: To report our clinical experience using continuous intrathecal baclofen (ITB) trials prior to permanent pump implantation. DESIGN: Retrospective chart review. SETTING: An inpatient neurosurgery unit and outpatient physical medicine and rehabilitation clinics. PARTICIPANTS: Fifty-seven patients with refractory spasticity who underwent a continuous ITB trial during the years 2006-2012. METHODS: Patients underwent placement of a temporary intrathecal catheter that was connected to an external pump...

BACKGROUND: Fragile X syndrome (FXS) is the most common known inherited form of intellectual disability and the single genomic cause of autism spectrum disorders. It is caused by the absence of a fragile X mental retardation gene (Fmr1) product, FMRP, an RNA-binding translation suppressor. Elevated rates of protein synthesis in the brain and an imbalance between synaptic signaling via glutamate and γ-aminobutyric acid (GABA) are both considered important in the pathogenesis of FXS. In a mouse model of FXS (Fmr1 knockout [KO]), treatment with R-baclofen reversed some behavioral and biochemical phenotypes...

Autism spectrum disorder (ASD) is diagnosed by two core behavioral criteria, unusual reciprocal social interactions and communication, and stereotyped, repetitive behaviors with restricted interests. Excitatory/inhibitory imbalance is a prominent hypothesis for the etiology of autism. The selective GABAB receptor agonist R-baclofen previously reversed social deficits and reduced repetitive behaviors in a mouse model of Fragile X syndrome, and Arbaclofen improved some clinical symptoms in some Fragile X and ASD patients...

The GABAB receptor is a therapeutic target for CNS and neuropathic disorders; however, few preclinical studies have explored effects of chronic stimulation. This study evaluated acute and chronic baclofen treatments on GABAB-activated G-proteins and signaling protein phosphorylation as indicators of GABAB signaling capacity. Brain sections from rats acutely administered baclofen (5 mg/kg, i.p.) showed no significant differences from controls in GABAB-stimulated GTPγS binding in any brain region, but displayed significantly greater phosphorylation/activation of focal adhesion kinase (pFAK(Tyr397)) in mesocorticolimbic regions (caudate putamen, cortex, hippocampus, thalamus) and elevated phosphorylated/activated glycogen synthase kinase 3-β (pGSK3β(Tyr216)) in the prefrontal cortex, cerebral cortex, caudate putamen, nucleus accumbens, thalamus, septum, and globus pallidus...

Isovaline is a non-proteinogenic amino acid that has analgesic properties. R-isovaline is a proposed agonist of the γ-aminobutyric acid type B (GABA(B)) receptor in the thalamus and peripheral tissue. Interestingly, the responses to R-isovaline differ from those of the canonical GABA(B) receptor agonist R-baclofen, warranting further investigation. Using whole cell recording techniques we explored isovaline actions on GABA(B) receptors coupled to rectifying K+ channels in cells of recombinant and native receptor preparations...

We previously showed that isovaline is a peripheral analgesic which acts in vivo and in brain slices as an atypical metabotropic GABA(B) agonist. Peripheral inhibitory group II and III metabotropic glutamate receptors (mGluRs) belong to the same family C as GABA(B) receptors; therefore, we hypothesized that isovaline's analgesic effects could include their activation. We examined the effects of R-isovaline on mechanical allodynia produced by prostaglandin E2 in the mouse paw. Subcutaneous R-isovaline produced dose-dependent antiallodynia restricted to the injected hindlimb...

The present work reports preparative enantioseparation of (RS)-baclofen using thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC). Diastereomers were synthesized using a new monochloro-s-triazine-based chiral derivatizing reagent (CDR), namely, N-(4-chloro-6-piperidinyl-[1,3,5]-triazine-2-yl)-L-phenylalanine, under microwave irradiation. Acetonitrile-0.1% aq. triflouroacetic acid in gradient elution mode and CH3 OH-CH2 Cl2 (4:5; v/v) were successful as mobile phase in HPLC and TLC, respectively...

PURPOSE: Overdose with baclofen, a derivative of the inhibitory neurotransmitter γ-aminobutyric acid, may lead to severe respiratory and central nervous system depression and can be life-threatening. Prolonged half-lives of baclofen, of up to 34 h, have been reported in patients after overdose. Hemodialysis has proven to be a successful approach to improve clearance of baclofen, but the value of continuous venovenous hemofiltration (CVVH) is unclear. We applied CVVH in a patient with acute baclofen overdose...

The GABAB receptor agonist baclofen has been studied extensively in preclinical models of alcohol-use disorders, yet results on its efficacy have been uncertain. Racemic baclofen, which is used clinically, can be broken down into separate enantiomers of the drug. Baclofen has been shown to produce enantioselective effects in behavioral assays, including those modeling reflexive and sexual behavior. The current studies sought to characterize the enantioselective effects of baclofen in two separate models of ethanol consumption...

OBJECTIVES: To perform an analysis of oral baclofen dosage in patients with traumatic spinal cord injuries over time and to ascertain the clinical determinants of long-term baclofen dosage trends. STUDY DESIGN: Retrospective cohort study of patient records from the PM&R units at the Johns Hopkins Bayview Medical Center and the Johns Hopkins Hospital. SUBJECTS: A total of 115 PM&R patients suffering spinal cord injury due to trauma leading to either complete or incomplete paralysis...

Excitation of the renal sympathetic nervous system is important for the development of ischaemic acute kidney injury (AKI) in rats. We reported that intravenous treatment with GABA has preventive effects against ischaemia/reperfusion (I/R)-induced renal dysfunction with histological damage in rats; however, the mechanisms underlying these effects on renal injury remain unknown. Thus, the aim of the present study was to clarify how GABA mechanistically affects ischaemic AKI in rats. Ischaemic AKI was induced in rats by clamping the left renal artery and vein for 45 min and then reperfusing the kidney to produce I/R-induced injury...

Neuronal voltage-gated N-type (Cav2.2) calcium channels are expressed throughout the nervous system and regulate neurotransmitter release and hence synaptic transmission. They are predominantly modulated via G protein-coupled receptor activated pathways, and the well characterized Gβγ subunits inhibit Cav2.2 currents. Analgesic α-conotoxin Vc1.1, a peptide from predatory marine cone snail venom, inhibits Cav2.2 channels by activating pertussis toxin-sensitive Gi/o proteins via the GABAB receptor (GABA(B)R) and potently suppresses pain in rat models...

BACKGROUND: Pancreatic cancer is frequently resistant to cancer therapeutics. Smoking and alcoholism are risk factors and pancreatic cancer patients often undergo nicotine replacement therapy (NRT) and treatment for alcohol dependence. Based on our report that low dose nicotine within the range of NRT causes gemcitabine resistance in pancreatic cancer, our current study has tested the hypothesis that GABA or the selective GABA-B-R agonist baclofen used to treat alcohol dependence reverse nicotine-induced gemcitabine resistance in pancreatic cancer...

The gamma-aminobutyric acid (GABA) metabolite gamma-hydroxybutyric acid (GHB) shows a variety of behavioural effects when administered to animals and humans, including reward/addiction properties and absence seizures. At the cellular level, these actions of GHB are mediated by activation of neuronal GABA(B) receptors (GABA(B)Rs) where it acts as a weak agonist. Because astrocytes respond to endogenous and exogenously applied GABA by activation of both GABA(A) and GABA(B)Rs, here we investigated the action of GHB on astrocytes on the ventral tegmental area (VTA) and the ventrobasal (VB) thalamic nucleus, two brain areas involved in the reward and proepileptic action of GHB, respectively, and compared it with that of the potent GABA(B)R agonist baclofen...

Chemotherapy-induced peripheral neuropathy (CIPN) is a common toxicity associated with multiple chemotherapeutic agents. CIPN may have a detrimental impact on patients' quality of life and functional ability, as well as result in chemotherapy dose reductions. Although symptoms of CIPN can improve with treatment completion, symptoms may persist. Currently, the treatment options for CIPN are quite limited. Duloxetine, a serotonin-norepinephrine reuptake inhibitor, has the most evidence supporting its use in the treatment of CIPN...

OBJECTIVES: Benzodiazepines (BZDs) are the first-line drugs in alcohol-withdrawal syndrome (AWS). Baclofen, a gamma-aminobutyric acidB (GABAB) agonist, controls withdrawal symptoms without causing significant adverse effects. The objective of this study was to compare the cost-effectiveness of baclofen and chlordiazepoxide in the management of uncomplicated AWS. MATERIALS AND METHODS: This was a randomized, open label, standard controlled, parallel group study of cost-effectiveness analysis (CEA) of baclofen and chlordiazepoxide in 60 participants with uncomplicated AWS...

Intrathecal baclofen (ITB) is a reversible treatment that reduces muscle tone to ameliorate spasticity and dystonia in patients with cerebral palsy (CP). The resulting decrease in energy expenditure allows patients to gain much-needed weight, albeit temporarily. Modern techniques require sufficient abdominal musculature and subcutaneous fat to permit the implantation of an indwelling pump. In patients with extremely low muscle bulk, visceral pumps may be impractical or impossible, with increased risks of dehiscence and infection...

Muscle spasms and spasticity constitute a significant problem in patients with spinal cord injury, interfering with rehabilitation and leading to impairments in quality of life in addition to medical complications. Administration of intrathecal baclofen (ITB) is indicated when spasticity continues to produce a clinical disability despite trials of oral treatments and other alternatives in patients who have functional goals and/or pain without contractures. Severe spasticity of spinal origin has been shown to respond dramatically to long-term ITB when used in appropriate patients with spasticity...

The GABAB agonist baclofen has been widely researched clinically and preclinically as a treatment of alcohol use disorders (AUDs). However, the efficacy of baclofen remains uncertain. The clinically used racemic compound can be separated into separate enantiomers. These enantiomers have produced different profiles in behavioral assays, with the S- compound often being ineffective compared to the R- compound, or the S- compound antagonizing the effects of the R- compound. We have previously demonstrated that the R(+)-baclofen enantiomer decreases binge-like ethanol intake in the Drinking-in-the-Dark (DID) paradigm, whereas the S(-)-baclofen enantiomer increases ethanol intake...

Selective dorsal rhizotomy may have a role in the management of spinal cord injury (SCI)-induced spasticity. Spasticity and spasms are common sequelae of SCI in children. Depending on the clinical scenario, treatments may include physical and occupational therapy, oral medications, chemodenervation, and neurosurgical interventions. Selective dorsal rhizotomy (SDR) is used in the management of spasticity in selected children with cerebral palsy, but, to the authors' knowledge, its use has not been reported in children with SCI...