Efficacy and safety of oral baclofen in the management of spasticity: A rationale for intrathecal baclofen

Ertzgaard, Per; Campo, Claudia Inés; Calabrese, Alessandra

doi:10.2340/16501977-2211

Cited by 110 publications

(73 citation statements)

References 54 publications

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“…The GABA B agonist used for these preclinical studies was R -baclofen, the active enantiomer of baclofen. Racemic baclofen has been extensively used clinically for the treatment of spasticity in cerebral palsy and multiple sclerosis ( Ertzgaard et al , 2017 ; Rizzo et al , 2004 ). The well-known safety profile of the racemic mixture made R -baclofen an attractive clinical candidate for early interventions in neurodevelopmental disorders (the clinical formulation of R -baclofen is also called arbaclofen or STX209).…”

Section: Introductionmentioning

confidence: 99%

R-Baclofen Reverses Cognitive Deficits and Improves Social Interactions in Two Lines of 16p11.2 Deletion Mice

Stoppel

Kazdoba

Schaffler

et al. 2017

Neuropsychopharmacol.

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Human chromosome 16p11.2 microdeletion is among the most common gene copy number variations (CNVs) known to confer risk for intellectual disability (ID) and autism spectrum disorder (ASD) and affects an estimated 3 in 10 000 people. Caused by a single copy deletion of ~27 genes, 16p11.2 microdeletion syndrome is characterized by ID, impaired language, communication and socialization skills, and ASD. Studies in animal models where a single copy of the syntenic 16p11.2 region has been deleted have revealed morphological, behavioral, and electrophysiological abnormalities. Previous studies suggested the possibility of some overlap in the mechanisms of pathophysiology in 16p11.2 microdeletion syndrome and fragile X syndrome. Improvements in fragile X phenotypes have been observed following chronic treatment with R-baclofen, a selective agonist of GABAB receptors. We were therefore motivated to investigate the effects of chronic oral R-baclofen administration in two independently generated mouse models of 16p11.2 microdeletion syndrome. In studies performed across two independent laboratories, we found that chronic activation of GABAB receptors improved performance on a series of cognitive and social tasks known to be impaired in two different 16p11.2 deletion mouse models. Our findings suggest that R-baclofen may have clinical utility for some of the core symptoms of human 16p11.2 microdeletion syndrome.

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Section: Introductionmentioning

confidence: 99%

R-Baclofen Reverses Cognitive Deficits and Improves Social Interactions in Two Lines of 16p11.2 Deletion Mice

Stoppel

Kazdoba

Schaffler

et al. 2017

Neuropsychopharmacol.

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“… 2 3 Oral antispastics, particularly baclofen, have long been the cornerstone of treatment although they often lead to suboptimal results or cause adverse effects at therapeutic doses. 4 5 While chemodenervation with botulinum neurotoxin type A has become the treatment of choice for focal spasticity, 6 7 it may be inadequate for controlling symptoms over longer periods, particularly in severely affected patients with multifocal/segmental disabling spasticity.…”

Section: Introductionmentioning

confidence: 99%

Intrathecal baclofen therapy versus conventional medical management for severe poststroke spasticity: results from a multicentre, randomised, controlled, open-label trial (SISTERS)

Creamer

Cloud

Koßmehl

et al. 2018

J Neurol Neurosurg Psychiatry

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BackgroundIntrathecal baclofen (ITB) is a treatment option for patients with severe poststroke spasticity (PSS) who have not reached their therapy goal with other interventions.Methods’Spasticity In Stroke–Randomised Study' (SISTERS) was a randomised, controlled, open-label, multicentre phase IV study to evaluate the efficacy and safety of ITB therapy versus conventional medical management (CMM) with oral antispastic medications for treatment of PSS. Patients with chronic stroke with spasticity in ≥2 extremities and an Ashworth Scale (AS) score ≥3 in at least two affected muscle groups in the lower extremities (LE) were randomised (1:1) to ITB or CMM. Both treatment arms received physiotherapy throughout. The primary outcome was the change in the average AS score in the LE of the affected body side from baseline to month 6. Analyses were performed for all patients as randomised (primary analysis) and all randomised patients as treated (safety analysis).ResultsOf 60 patients randomised to ITB (n=31) or CMM (n=29), 48 patients (24 per arm) completed the study. The primary analysis showed a significant effect of ITB therapy over CMM (mean AS score reduction, −0.99 (ITB) vs −0.43 (CMM); Hodges-Lehmann estimate, −0.667(95.1%CI −1.0000 to −0.1667); P=0.0140). More patients reported adverse events while receiving ITB (24/25 patients, 96%; 149 events) compared with CMM (22/35, 63%; 77 events), although events were generally consistent with the known safety profile of ITB therapy.ConclusionsThese data support the use of ITB therapy as an alternative to CMM for treatment of generalised PSS in adults.Trial registration numberNCT01032239; Results.

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“…Baclofen is commonly used for treating spastic movement disease ( 49 , 50 ). However, baclofen may help to inhibit hiccups following the insertion of a stent for ESCC, according to a case report ( 51 ), and it was suggested that it may be a useful adjuvant analgesic for decreasing cancer pain ( 52 ).…”

Section: Discussionmentioning

confidence: 99%

Novel drug candidates for treating esophageal carcinoma: A study on differentially expressed genes, using connectivity mapping and molecular docking

et al. 2018

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Patients with esophageal carcinoma (ESCA) have a poor prognosis and high mortality rate. Although standard therapies have had effect, there is an urgent requirement to develop novel options, as increasing drug tolerance has been identified in clinical practice. In the present study, differentially expressed genes (DEGs) of ESCA were identified in The Cancer Genome Atlas and Genotype-Tissue Expression databases. Functional and protein-protein interaction (PPI) analyses were performed. The Connectivity Map (CMAP) was selected to predict drugs for the treatment of ESCA, and their target genes were acquired from the Search Tool for Interactions of Chemicals (STITCH) by uploading the Simplified Molecular-Input Line-Entry System structure. Additionally, significant target genes and ESCA-associated hub genes were extracted using another PPI analysis, and the corresponding drugs were added to construct a network. Furthermore, the binding affinity between predicted drug candidates and ESCA-associated hub genes was calculated using molecular docking. Finally, 827 DEGs (|log2 fold-change|≥2; q-value <0.05), which are principally involved in protein digestion and absorption (P<0.005), the plasminogen-activating cascade (P<0.01), as well as the ‘biological regulation’ of the Biological Process, ‘membrane’ of the Cellular Component and ‘protein binding’ of the Molecular Function categories, were obtained. Additionally, 11 hub genes were obtained from the PPI network (all degrees ≥30). Furthermore, the 15 first screen drugs were extracted from CMAP (score <−0.85) and the 9 second screen drugs with 70 target genes were extracted from STITCH. Furthermore, another PPI analysis extracted 51 genes, and apigenin, baclofen, Prestwick-685, menadione, butyl hydroxybenzoate, gliclazide and valproate were selected as drug candidates for ESCA. Those molecular docking results with a docking score of >5.52 indicated the significance of apigenin, Prestwick-685 and menadione. The results of the present study may lead to novel drug candidates for ESCA, among which Prestwick-685 and menadione were identified to be significant new drug candidates.

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Efficacy and safety of oral baclofen in the management of spasticity: A rationale for intrathecal baclofen

Cited by 110 publications

References 54 publications

R-Baclofen Reverses Cognitive Deficits and Improves Social Interactions in Two Lines of 16p11.2 Deletion Mice

R-Baclofen Reverses Cognitive Deficits and Improves Social Interactions in Two Lines of 16p11.2 Deletion Mice

Intrathecal baclofen therapy versus conventional medical management for severe poststroke spasticity: results from a multicentre, randomised, controlled, open-label trial (SISTERS)

Novel drug candidates for treating esophageal carcinoma: A study on differentially expressed genes, using connectivity mapping and molecular docking

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