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2.
BMC Urol ; 21(1): 139, 2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34607587

RESUMO

BACKGROUND: Baclofen, a clinically available GABAB receptor agonist, produces non-opioid analgesia in multiple models of pain but has not been tested for effects on bladder nociception. METHODS: A series of experiments examined the effects of systemic and spinally administered baclofen on bladder nociception in female anesthetized rats. Models of bladder nociception included those which employed neonatal and adult bladder inflammation to produce bladder hypersensitivity. RESULTS: Cumulative intraperitoneal dosing (1-8 mg/kg IP) and cumulative intrathecal dosing (10-160 ng IT) of baclofen led to dose-dependent inhibition of visceromotor responses (VMRs) to urinary bladder distension (UBD) in all tested models. There were no differences in the magnitude of the analgesic effects of baclofen as a function of inflammation versus no inflammation treatments. Hemodynamic (pressor) responses to UBD were similarly inhibited by IT baclofen as well as UBD-evoked excitatory responses of spinal dorsal horn neurons. The GABAB receptor antagonist, CGP 35,348, antagonized the antinociceptive effects of IT baclofen on VMRs in all tested models but did not affect the magnitude of the VMRs by itself suggesting no tonic GABAB activity was present in this preparation. Tolerance to a seven day continuous IT infusion of baclofen was not observed. CONCLUSIONS: These data provide support for a clinical trial of baclofen as a non-opioid treatment of human bladder pain.


Assuntos
Baclofeno/farmacologia , Agonistas dos Receptores de GABA-B/farmacologia , Nociceptividade/efeitos dos fármacos , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/fisiologia , Animais , Baclofeno/administração & dosagem , Feminino , Agonistas dos Receptores de GABA-B/administração & dosagem , Injeções Espinhais , Ratos , Ratos Sprague-Dawley
3.
Drug Des Devel Ther ; 15: 4383-4402, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34690500

RESUMO

PURPOSE: This study aimed to formulate an orally disintegrating tablet (ODT) containing both baclofen and meloxicam together for treating osteoarthritis. METHODS: Direct compression method was used to prepare ODTs using three types of co-processed excipients (Prosolv ODT G2®, F-melt®, and Pharmaburst®500). ODTs were evaluated according to weight variation, thickness, friability, hardness, drug content, wetting time, in-vitro disintegration time, in-vitro dissolution test, and palatability. To enhance the in-vitro dissolution of meloxicam and palatability of ODT, a six sigma methodology was used, and an improvement phase was established where ODTs were prepared using lyophilization and levigation techniques. Finally, a pharmacokinetic study of the improved ODT was accomplished in comparison to the conventional oral tablet. RESULTS: Pharmaburst-based formula (F4) showed the shortest wetting time and, consequently, the shortest disintegration time and the highest percentage of drug dissolved within 3 min compared to the other formulae. All the improved ODTs had a bitterness taste score vary from (0) palatable and (+1) tasteless. The current sigma level was 3.628 σ and 3.33 σ for palatability and solubility of ODT, respectively, which indicated the process was successfully improved compared with the previous sigma level of 2.342 σ of both processes. Pharmacokinetic study of the improved ODTs showed a significant decrease of Tmax to 120 and 30 min instead of 180 and 120 min for meloxicam and baclofen, respectively. CONCLUSION: ODTs were successfully improved using the six sigma methodology, the pharmacokinetic parameters of both drugs were enhanced due to rapid absorption through the oral mucosa.


Assuntos
Baclofeno/administração & dosagem , Excipientes/química , Meloxicam/administração & dosagem , Relaxantes Musculares Centrais/administração & dosagem , Administração Oral , Adulto , Baclofeno/química , Baclofeno/farmacocinética , Composição de Medicamentos , Liberação Controlada de Fármacos , Feminino , Liofilização , Humanos , Masculino , Meloxicam/química , Meloxicam/farmacocinética , Relaxantes Musculares Centrais/química , Relaxantes Musculares Centrais/farmacocinética , Solubilidade , Comprimidos , Paladar , Gestão da Qualidade Total
4.
Sci Rep ; 11(1): 19296, 2021 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-34588513

RESUMO

Previous studies suggest that signaling by the gamma-aminobutyric acid (GABA) type B receptor (GABABR) is involved in the regulation of binge eating, a disorder which might contribute to the development of obesity. Here, we show that intermittent access to a high fat diet (HFD) induced binge-like eating behavior with activation of dopamine receptor d1 (drd1)-expressing neurons in the caudate putamen (CPu) and nucleus accumbens (NAc) in wild-type (WT) mice. The activation of drd1-expressing neurons during binge-like eating was substantially increased in the CPu, but not in the NAc, in corticostriatal neuron-specific GABABR-deficient knockout (KO) mice compared to WT mice. Treatment with the GABABR agonist, baclofen, suppressed binge-like eating behavior in WT mice, but not in KO mice, as reported previously. Baclofen also suppressed the activation of drd1-expressing neurons in the CPu, but not in the NAc, during binge-like eating in WT mice. Thus, our data suggest that GABABR signaling in CPu neurons expressing drd1 suppresses binge-like consumption during a HFD in mice.


Assuntos
Bulimia/fisiopatologia , Obesidade/fisiopatologia , Putamen/fisiopatologia , Receptores de GABA-B/metabolismo , Animais , Baclofeno/administração & dosagem , Bulimia/tratamento farmacológico , Bulimia/genética , Bulimia/patologia , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Feminino , Agonistas dos Receptores de GABA-B/administração & dosagem , Humanos , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Núcleo Accumbens/citologia , Núcleo Accumbens/metabolismo , Núcleo Accumbens/patologia , Obesidade/etiologia , Obesidade/prevenção & controle , Putamen/citologia , Putamen/metabolismo , Putamen/patologia , Receptores de Dopamina D1/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores de GABA-B/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
5.
BMC Neurol ; 21(1): 276, 2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34253183

RESUMO

BACKGROUND: Spasticity is present in more than 80% of the population with cerebral palsy (CP). The aim of this study was to describe and compare the use of three spasticity reducing methods; Botulinum toxin-A therapy (BTX-A), Selective dorsal rhizotomy (SDR) and Intrathecal baclofen therapy (ITB) among children and adolescents with CP in six northern European countries. METHODS: This registry-based study included population-based data in children and adolescents with CP born 2002 to 2017 and recorded in the follow-up programs for CP in Sweden, Norway, Denmark, Iceland and Scotland, and a defined cohort in Finland. RESULTS: A total of 8,817 individuals were included. The proportion of individuals treated with SDR and ITB was significantly different between the countries. SDR treatment ranged from 0% ( Finland and Iceland) to 3.4% (Scotland) and ITB treatment from 2.2% (Sweden) to 3.7% (Denmark and Scotland). BTX-A treatment in the lower extremities reported 2017-2018 ranged from 8.6% in Denmark to 20% in Norway (p < 0.01). Mean age for undergoing SDR ranged from 4.5 years in Norway to 7.3 years in Denmark (p < 0.01). Mean age at ITB surgery ranged from 6.3 years in Norway to 10.1 years in Finland (p < 0.01). Mean age for BTX-A treatment ranged from 7.1 years in Denmark to 10.3 years in Iceland (p < 0.01). Treatment with SDR was most common in Gross Motor Function Classification System (GMFCS) level III, ITB in level V, and BTX-A in level I. The most common muscle treated with BTX-A was the calf muscle, with the highest proportion in GMFCS level I. BTX-A treatment of hamstring and hip muscles was most common in GMFCS levels IV-V in all countries. CONCLUSION: There were statistically significant differences between countries regarding the proportion of children and adolescents with CP treated with the three spasticity reducing methods, mean age for treatment and treatment related to GMFCS level. This is likely due to differences in the availability of these treatment methods and/or differences in preferences of treatment methods among professionals and possibly patients across countries.


Assuntos
Baclofeno/administração & dosagem , Toxinas Botulínicas Tipo A/administração & dosagem , Paralisia Cerebral/terapia , Espasticidade Muscular/terapia , Sistema de Registros , Rizotomia/métodos , Adolescente , Paralisia Cerebral/diagnóstico , Paralisia Cerebral/epidemiologia , Criança , Pré-Escolar , Estudos de Coortes , Europa (Continente)/epidemiologia , Humanos , Injeções Espinhais/métodos , Masculino , Relaxantes Musculares Centrais/administração & dosagem , Espasticidade Muscular/diagnóstico , Espasticidade Muscular/epidemiologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia
6.
Toxicol In Vitro ; 76: 105223, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34293430

RESUMO

Physiologically-based kinetic (PBK) models can simulate concentrations of chemicals in tissues over time without animal experiments. Nevertheless, in vivo data are often used to parameterise PBK models. This study aims to illustrate that a combination of kinetic and dynamic readouts from in vitro assays can be used to parameterise PBK models simulating neurologically-active concentrations of xenobiotics. Baclofen, an intrathecally administered drug to treat spasticity, was used as a proof-of-principle xenobiotic. An in vitro blood-brain barrier (BBB) model was used to determine the BBB permeability of baclofen needed to simulate plasma and cerebrospinal concentrations. Simulated baclofen concentrations in individuals and populations of adults and children generally fall within 2-fold of measured clinical study concentrations. Further, in vitro micro-electrode array recordings were used to determine the effect of baclofen on neuronal activity (cell signalling). Using quantitative in vitro-in vivo extrapolations (QIVIVE) corresponding doses of baclofen were estimated. QIVIVE showed that up to 4600 times lower intrathecal doses than oral and intravenous doses induce comparable neurological effects. Most simulated doses were in the range of administered doses. This show that PBK models predict concentrations in the central nervous system for various routes of administration accurately without the need for additional in vivo data.


Assuntos
Baclofeno/administração & dosagem , Agonistas dos Receptores de GABA-B/administração & dosagem , Modelos Biológicos , Relaxantes Musculares Centrais/administração & dosagem , Adulto , Animais , Baclofeno/líquido cefalorraquidiano , Baclofeno/farmacocinética , Bioensaio , Barreira Hematoencefálica/metabolismo , Bovinos , Criança , Técnicas de Cocultura , Simulação por Computador , Eletrodos , Células Endoteliais/metabolismo , Feminino , Agonistas dos Receptores de GABA-B/líquido cefalorraquidiano , Agonistas dos Receptores de GABA-B/farmacocinética , Humanos , Cinética , Masculino , Relaxantes Musculares Centrais/líquido cefalorraquidiano , Relaxantes Musculares Centrais/farmacocinética , Pericitos/metabolismo
7.
Pediatr Neurol ; 122: 106-109, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34330615

RESUMO

OBJECTIVE: We studied physicians' opinions and experiences concerning clinical concerns, perceived severity, occurrence, and management of baclofen withdrawal due to abrupt discontinuation. METHODS: A nationwide 26-question electronic survey was distributed via e-mail to physicians (N = 952) representing varying specialties who manage spasticity with baclofen. A total of 110 physicians provided responses to the survey (response rate = 11.6%). Results were evaluated using descriptive statistics. RESULTS: Withdrawal from both oral and intrathecal (IT) baclofen was recognized as a significant concern and was observed by most respondents. However, approximately 75% and 35% of respondents or their clinic sites lack established management protocols for managing anticipated interruption of oral or IT baclofen, respectively. CONCLUSIONS: These findings highlight the need for further research on and the development of guidelines for the prevention and treatment of baclofen withdrawal. The results of this survey, along with a systematic literature review and multidisciplinary stakeholder input, may be helpful in establishing guidelines for the treatment and prevention of baclofen withdrawal.


Assuntos
Atitude do Pessoal de Saúde , Baclofeno/administração & dosagem , Relaxantes Musculares Centrais/administração & dosagem , Espasticidade Muscular/tratamento farmacológico , Guias de Prática Clínica como Assunto/normas , Síndrome de Abstinência a Substâncias/etiologia , Baclofeno/efeitos adversos , Pesquisas sobre Atenção à Saúde , Humanos , Relaxantes Musculares Centrais/efeitos adversos , Médicos , Síndrome de Abstinência a Substâncias/prevenção & controle
8.
J Rehabil Med ; 53(7): jrm00215, 2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34160624

RESUMO

OBJECTIVE: To evaluate the effectiveness and safety of intrathecal baclofen treatment of spasticity, administered via a cervical catheter tip. DESIGN: A review of PubMed and the Cochrane Library up to September 2020. No restriction in study design. Two reviewers independently evaluated eligibility, extracted data and evaluated risk of bias. Studies were included in which patients were treated with intrathecal baclofen for spasticity, with the catheter tip at or above the first thoracic level, independent of diagnosis and age. RESULTS: Thirteen studies were eligible, with a moderate to critical risk of bias. Improvement in spasticity was seen only in the upper extremity in 6% of subjects, only in the lower extremity in 2%, in both upper and lower extremities in 50% and without specification of location in 41%. Upper extremity function improved in 88% of cases. Neither drug-related (1%) nor technical (21%) complications occurred more often than in lower placement of the tip. Effects on respiratory function and sleep apnoea were not investigated. CONCLUSION: Cervically administered intrathecal baclofen seems to improve upper extremity spasticity and function, without causing more complications than thoracolumbar intrathecal baclofen. However, the mainly drug-related complications have not been thoroughly investigated and the available literature is of poor methodological quality. Further research is needed to confirm the efficacy and safety of this procedure.


Assuntos
Baclofeno/administração & dosagem , Relaxantes Musculares Centrais/administração & dosagem , Espasticidade Muscular/tratamento farmacológico , Adulto , Braço/fisiopatologia , Baclofeno/efeitos adversos , Baclofeno/uso terapêutico , Cateterismo/efeitos adversos , Humanos , Infusão Espinal/efeitos adversos , Infusão Espinal/instrumentação , Perna (Membro)/fisiopatologia , Masculino , Pessoa de Meia-Idade , Relaxantes Musculares Centrais/efeitos adversos , Relaxantes Musculares Centrais/uso terapêutico
9.
NeuroRehabilitation ; 48(4): 481-491, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33967066

RESUMO

BACKGROUND: Patients with cerebral palsy and other static encephalopathies (CP) are known to be at increased risk of sleep-related breathing disorders (SRBD). Few studies have reviewed whether intrathecal baclofen (ITB) can contribute to SRBD. OBJECTIVE: To assess the prevalence of SRBD in patients with CP receiving ITB by using nocturnal polysomnography (NPSG). METHODS: We performed a retrospective chart review of patients receiving ITB who had NPSG at Children's Hospital Colorado (CHCO) and Seattle Children's Hospital (SCH) from 1995 to 2019. The Gross Motor Function Classification System (GMFCS) measured the severity of motor disability. Screening sleep questionnaires collected subjective data and NPSG provided objective data of SRBD. RESULTS: All patients except one were GMFCS 4 or 5 with median age at ITB pump placement of 9.7 years. The screening questionnaire for SRBD detected one or more nighttime symptoms in > 82% of all patient groups. Pre-ITB criteria for a SRBD was met in 83% of patients at CHCO and 91% at SCH. Post-ITB prevalence remained similarly high. CONCLUSIONS: NPSG identified a high prevalence of SRBD in these cohorts from CHCO and SCH. Our study showed neither improvement nor worsening of SRBD in patients receiving ITB.


Assuntos
Baclofeno/efeitos adversos , Paralisia Cerebral/tratamento farmacológico , Relaxantes Musculares Centrais/efeitos adversos , Síndromes da Apneia do Sono/etiologia , Baclofeno/administração & dosagem , Baclofeno/uso terapêutico , Criança , Pré-Escolar , Humanos , Injeções Espinhais , Masculino , Relaxantes Musculares Centrais/administração & dosagem , Relaxantes Musculares Centrais/uso terapêutico , Síndromes da Apneia do Sono/epidemiologia
10.
Arch Dis Child ; 106(12): 1202-1206, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-33853760

RESUMO

BACKGROUND: Intrathecal baclofen (ITB) is a useful treatment for hypertonia where non-invasive treatments have been ineffective or poorly tolerated. There is an absence of national guidance on selection criteria and a lack of literature regarding patient characteristics and treatment details for children and young people (CYP) receiving ITB therapy in the UK and Ireland. We aimed to gather patient and treatment characteristics for CYP receiving ITB in the UK and Ireland. METHODS: An electronic survey was sent to all paediatric ITB centres in the UK and Ireland. Anonymised data were returned between December 2019 and April 2020. CYP >16 years and those awaiting ITB pump removal were excluded from the dataset. RESULTS: 176 CYP were identified as receiving ITB therapy across the UK and Ireland. The majority of CYP with ITB pumps were non-ambulant (93%) with a diagnosis of cerebral palsy (79%). Median age of ITB insertion was 9 years; median current age was 14 years. 79% of CYP had significant spasticity, 55% had significant dystonia. The most commonly used ITB dosing modes were continuous (73%) and flexible (23%). CONCLUSIONS: ITB pumps were most frequently used for non-ambulant CYP with cerebral palsy and existence of spasticity and/or dystonia in the UK and Ireland. Most CYP were receiving a continuous dose of ITB. There is significant variation in the number of paediatric ITB pumps across UK and Ireland. There is a need for development of nationally accepted paediatric referral criteria and clinical standards for ITB use.


Assuntos
Baclofeno/administração & dosagem , Hipertonia Muscular/tratamento farmacológico , Relaxantes Musculares Centrais/administração & dosagem , Espasticidade Muscular/tratamento farmacológico , Adolescente , Baclofeno/uso terapêutico , Paralisia Cerebral/diagnóstico , Paralisia Cerebral/tratamento farmacológico , Criança , Pré-Escolar , Estudos Transversais , Humanos , Injeções Espinhais , Irlanda , Masculino , Relaxantes Musculares Centrais/uso terapêutico , Inquéritos e Questionários , Resultado do Tratamento , Reino Unido
12.
Dev Med Child Neurol ; 63(9): 1038-1050, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33772789

RESUMO

AIM: To update a systematic review of evidence published up to December 2015 for pharmacological/neurosurgical interventions among individuals with cerebral palsy (CP) and dystonia. METHOD: Searches were updated (January 2016 to May 2020) for oral baclofen, trihexyphenidyl, benzodiazepines, clonidine, gabapentin, levodopa, botulinum neurotoxin (BoNT), intrathecal baclofen (ITB), and deep brain stimulation (DBS), and from database inception for medical cannabis. Eligible studies included at least five individuals with CP and dystonia and reported on dystonia, goal achievement, motor function, pain/comfort, ease of caregiving, quality of life (QoL), or adverse events. Evidence certainty was evaluated using GRADE. RESULTS: Nineteen new studies met inclusion criteria (two trihexyphenidyl, one clonidine, two BoNT, nine ITB, six DBS), giving a total of 46 studies (four randomized, 42 non-randomized) comprising 915 participants when combined with those from the original systematic review. Very low certainty evidence supported improved dystonia (clonidine, ITB, DBS) and goal achievement (clonidine, BoNT, ITB, DBS). Low to very low certainty evidence supported improved motor function (DBS), pain/comfort (clonidine, BoNT, ITB, DBS), ease of caregiving (clonidine, BoNT, ITB), and QoL (ITB, DBS). Trihexyphenidyl, clonidine, BoNT, ITB, and DBS may increase adverse events. No studies were identified for benzodiazepines, gabapentin, oral baclofen, and medical cannabis. INTERPRETATION: Evidence evaluating the use of pharmacological and neurosurgical management options for individuals with CP and dystonia is limited to between low and very low certainty. What this paper adds Meta-analysis suggests that intrathecal baclofen (ITB) and deep brain stimulation (DBS) may improve dystonia and pain. Meta-analysis suggests that DBS may improve motor function. Clonidine, botulinum neurotoxin, ITB, and DBS may improve achievement of individualized goals. ITB and DBS may improve quality of life. No direct evidence is available for oral baclofen, benzodiazepines, gabapentin, or medical cannabis.


Assuntos
Paralisia Cerebral/terapia , Distonia/terapia , Procedimentos Neurocirúrgicos , Baclofeno/administração & dosagem , Baclofeno/uso terapêutico , Toxinas Botulínicas/efeitos adversos , Toxinas Botulínicas/uso terapêutico , Paralisia Cerebral/tratamento farmacológico , Paralisia Cerebral/cirurgia , Clonidina/efeitos adversos , Clonidina/uso terapêutico , Estimulação Encefálica Profunda/efeitos adversos , Distonia/tratamento farmacológico , Distonia/cirurgia , Humanos , Injeções Espinhais/efeitos adversos , Levodopa/uso terapêutico , Triexifenidil/efeitos adversos , Triexifenidil/uso terapêutico
13.
Rev. esp. anestesiol. reanim ; 68(3): 153-155, Mar. 2021. ilus
Artigo em Espanhol | IBECS | ID: ibc-231010

RESUMO

La esclerosis múltiple es una enfermedad neurológica con clínica variada, que en algunos casos es progresiva y muy invalidante, y que requiere tratamientos invasivos para el dolor y la espasticidad. El uso de perfusiones de baclofeno intratecal es una alternativa eficaz y segura para pacientes con espasticidad refractaria y severa, y logra mejorar la calidad de vida, pero es preciso disponer de una unidad del dolor con personal entrenado para emplear estas terapias invasivas y conocer las indicaciones, farmacología y posibles riesgos tanto del implante como del uso del baclofeno. Se tiene que individualizar el tratamiento y hacer seguimientos periódicos.(AU)


Multiple sclerosis is a neurological disease that presents with various symptoms; in some cases it is progressive and highly disabling, requiring invasive techniques to treat pain and spasticity. The use of intrathecal baclofen infusions is an effective and safe alternative for patients with severe and refractory spasticity. The therapy can improve quality of life, but must be performed in a pain unit by medical staff trained in the technique, its indications, pharmacology, and the potential risks of both the implant and the drug. The treatment can be individualized and patients must be followed up periodically.(AU)


Assuntos
Humanos , Feminino , Adulto , Esclerose Múltipla/tratamento farmacológico , Baclofeno/administração & dosagem , Qualidade de Vida , Relaxantes Musculares Centrais , Espasticidade Muscular/terapia , Pacientes Internados , Exame Físico , Anestesiologia , Analgesia
14.
Pediatr. aten. prim ; 23(89): 71-74, ene.-mar. 2021.
Artigo em Espanhol | IBECS | ID: ibc-202616

RESUMO

El síndrome neuroléptico maligno es una urgencia pediátrica con una elevada morbimortalidad, relacionada con alteración de sistema de neurotransmisión dopaminérgico. Se caracteriza por hipertermia junto con hipertonía muscular, alteración autonómica y de los niveles de conciencia. Un diagnóstico precoz es imprescindible para prevenir complicaciones comunes como la broncoaspiración, desgaste, escaras, procesos infecciosos y cambios neuropsiquiátricos. El tratamiento debe incluir en medidas generales de soporte y terapéutica farmacológica sintomática. Pese a que la mayoría de los casos descritos corresponden a población adulta, también se ha descrito en niños y adolescentes. Presentamos un caso de síndrome neuroléptico maligno en un adolescente de 12 años con encefalopatía y tetraparesia espática secundario al cese de la administración de baclofeno


Neuroleptic malignant syndrome is a pediatric emergency with high morbidity and mortality, related to an alteration of the dopaminergic neurotransmission system. It is characterized by hyperthermia along with muscular hypertonia, dysautonomia, and altered level of consciousness. An early diagnosis is essential to prevent common complications such as bronchoaspiration, wear, bedsores, infectious processes, and neuropsychiatric changes. Treatment should include general support measures and symptomatic pharmacological therapy. Although most of the cases described correspond to the adulthood, it has also been described in children and adolescents. We present a case of neuroleptic malignant syndrome in a 12-year-old adolescent with encephalopathy and spastic tetraparesis secondary to the cessation of baclofen administration


Assuntos
Humanos , Masculino , Criança , Síndrome Maligna Neuroléptica/diagnóstico por imagem , Síndrome Maligna Neuroléptica/terapia , Quadriplegia/complicações , Hidratação/métodos , Medicina de Emergência Pediátrica/métodos , Diagnóstico Precoce , Encefalopatias , Gastrostomia/métodos , Leucocitose/complicações , Unidades de Terapia Intensiva Pediátrica , Hipertonia Muscular/tratamento farmacológico , Combinação Amoxicilina e Clavulanato de Potássio/uso terapêutico , Baclofeno/administração & dosagem
15.
JAMA ; 325(8): 732-741, 2021 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-33620407

RESUMO

Importance: Unhealthy alcohol use can lead to agitation in the intensive care unit (ICU). Objective: To assess whether high-dose baclofen reduces agitation-related events compared with placebo in patients with unhealthy alcohol use receiving mechanical ventilation. Design, Settings, and Participants: This phase 3, double-blind, placebo-controlled, randomized clinical trial conducted in 18 ICUs in France recruited adults receiving mechanical ventilation who met criteria for unhealthy alcohol use. Patients were enrolled from June 2016 to February 2018; the last follow-up was in May 2019. Interventions: Baclofen (n = 159), adjusted from 50 to 150 mg per day based on estimated glomerular filtration rate, or placebo (n = 155) during mechanical ventilation up to a maximum of 15 days before gradual dose reduction over 3 to 6 days. Main Outcomes and Measures: The primary end point was the percentage of patients with at least 1 agitation-related event over the treatment period. Secondary outcomes included duration of mechanical ventilation, length of ICU stay, and 28-day mortality. Results: Among 314 patients who were randomized (mean age, 57 years; 60 [17.2%] women), 313 (99.7%) completed the trial. There was a statistically significant decrease in the percentage of patients who experienced at least 1 agitation-related event in the baclofen group vs the placebo group (31 [19.7%] vs 46 [29.7%]; difference, -9.93% [95% CI, -19.45% to -0.42%]; adjusted odds ratio, 0.59 [95% CI, 0.35-0.99]). Of 18 prespecified secondary end points, 14 were not significantly different. Compared with the placebo group, the baclofen group had a significantly longer median length of mechanical ventilation (9 vs 8 days; difference, 2.00 [95% CI, 0.00-3.00]; hazard ratio [HR] for extubation, 0.76 [95% CI, 0.60-0.97]) and stay in the ICU (14 vs 11 days; difference, 2.00 [95% CI, 0.00-4.00]; HR for discharge, 0.70 [95% CI, 0.54-0.90]). At 28 days, there was no significant difference in mortality in the baclofen vs placebo group (25.3% vs 21.6%; adjusted odds ratio, 1.24 [95% CI, 0.72-2.13]). Delayed awakening (no eye opening at 72 hours after cessation of sedatives and analgesics) occurred in 14 patients (8.9%) in the baclofen group vs 3 (1.9%) in the placebo group. Conclusions and Relevance: Among patients with unhealthy alcohol use receiving mechanical ventilation, treatment with high-dose baclofen, compared with placebo, resulted in a statistically significant reduction in agitation-related events. However, considering the modest effect and the totality of findings for the secondary end points and adverse events, further research is needed to determine the possible role of baclofen in this setting and to potentially optimize dosing. Trial Registration: ClinicalTrials.gov Identifier: NCT02723383.


Assuntos
Transtornos Induzidos por Álcool/tratamento farmacológico , Alcoolismo/tratamento farmacológico , Baclofeno/administração & dosagem , Agonistas dos Receptores de GABA-B/administração & dosagem , Agitação Psicomotora/tratamento farmacológico , Respiração Artificial , Adulto , Idoso , Alcoolismo/complicações , Baclofeno/efeitos adversos , Método Duplo-Cego , Feminino , Agonistas dos Receptores de GABA-B/efeitos adversos , Humanos , Unidades de Terapia Intensiva , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Razão de Chances , Agitação Psicomotora/etiologia
16.
Addict Biol ; 26(2): e12892, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32146727

RESUMO

For several decades, studies conducted to evaluate the efficacy of RS(±)-Baclofen in the treatment of alcohol dependence yielded contrasting results. Human and animal studies recently questioned the use of the racemic drug in patients since a potential important role of the different enantiomers has been revealed with an efficacy thought to reside with the active R(+)-enantiomer. Here we conducted experiments in the postdependent rat model of alcohol dependence to compare the efficacy of R(+)-Baclofen or S(-)-Baclofen to that of RS(±)-Baclofen on ethanol intake, seeking, and relapse. R(+)-Baclofen was more effective than RS(±)-Baclofen in reducing ethanol intake and seeking during acute withdrawal and during relapse after abstinence. We also used an original population approach in order to identify drug responders. We found a significant proportion of responders to S(-)-Baclofen and RS(±)-Baclofen, displaying an increase in ethanol intake, and this increasing effect on alcohol intake was not seen in the R(+)-Baclofen group. At an intermediate dose of R(+)-Baclofen, devoid of any motor side effects, we identified a very large proportion of responders (75%) with a large decrease in ethanol intake (90% decrease). Finally, the response to RS(±)-Baclofen on ethanol intake was correlated to plasma level of Baclofen. R(+)-Baclofen and RS(±)-Baclofen were effective in reducing sucrose intake. Our study has important clinical implication since it suggests that the wide variability in the therapeutic responses of patients to RS(±)-Baclofen may come from the sensitivity to the R(+)-Baclofen but also to the one of the S(-)-Baclofen that can promote an increase in ethanol intake.


Assuntos
Alcoolismo/tratamento farmacológico , Baclofeno/química , Baclofeno/uso terapêutico , Agonistas dos Receptores de GABA-B/química , Agonistas dos Receptores de GABA-B/uso terapêutico , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Animais , Baclofeno/administração & dosagem , Baclofeno/efeitos adversos , Relação Dose-Resposta a Droga , Agonistas dos Receptores de GABA-B/administração & dosagem , Agonistas dos Receptores de GABA-B/efeitos adversos , Masculino , Ratos , Ratos Long-Evans , Recidiva , Síndrome de Abstinência a Substâncias/tratamento farmacológico
17.
J Surg Res ; 259: 431-441, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33069391

RESUMO

BACKGROUND: Ivermectin (IVM) was first used as an antiparasitic agent; however, the role of this drug evolved into a broad spectrum. Many mechanisms have been proposed, including interaction with the GABAergic system. Considering the presence of GABA receptor in the skin tissue and its role in ischemia-reperfusion I/R injury, we aimed to evaluate the effect of IVM through GABA receptors on random-pattern skin flap survival. METHODS: Sixty Wistar male rats were used. Multiple doses of IVM (0.01, 0.05, 0.2, and 0.5 mg/kg) were injected intraperitoneally before the surgery. Baclofen (selective GABAB agonist) and bicuculline (selective GABAA antagonist) were administered in combination with IVM to assess the role of the GABAergic system. Histopathological evaluations, immunohistochemical staining, quantitative assessment of IL-1ß and TNFα, and the expression of GABAA α1 subunit and GABAB R1 receptors were evaluated in the skin tissue. RESULTS: IVM 0.05 mg/kg could significantly increase flap survival compared with the control group (P < 0.001). Subeffective dose of baclofen (0.1 mg/kg) had synergistic effect with the subeffective dose of IVM (0.01 mg/kg) (P < 0.001), whereas bicuculline 1 mg/kg reversed the effect of IVM (0.05 mg/kg) (P < 0.001). IVM 0.05 mg/kg could also decrease the IL-1ß and TNFα levels and increase the expression of GABAA α1 subunit and GABAB R1 receptors in the flap tissue compared with the control group. CONCLUSIONS: IVM could improve skin flap survival, probably mediated by the GABAergic pathway. Both GABAA and GABAB receptors are involved in this process. This finding may repurpose the use of old drug, "Ivermectin."


Assuntos
Sobrevivência de Enxerto/efeitos dos fármacos , Ivermectina/administração & dosagem , Retalhos Cirúrgicos/transplante , Ácido gama-Aminobutírico/metabolismo , Animais , Baclofeno/administração & dosagem , Bicuculina/administração & dosagem , Reposicionamento de Medicamentos , Antagonistas GABAérgicos/administração & dosagem , Antagonistas de Receptores de GABA-A/administração & dosagem , Humanos , Masculino , Modelos Animais , Ratos , Receptores de GABA-A/metabolismo , Receptores de GABA-B/metabolismo , Pele/efeitos dos fármacos , Pele/metabolismo , Retalhos Cirúrgicos/efeitos adversos
18.
Medicine (Baltimore) ; 99(50): e23607, 2020 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-33327330

RESUMO

RATIONALE: Stiff-person syndrome (SPS) is an uncommon neurological disorder with autoimmune features. Here, we report a 60-year-old man with SPS associated with critical illness polyneuropathy (CIP). CIP was diagnosed during an episode of acute respiratory failure secondary to muscular rigidity and spasms, which has rarely been reported in this condition. The overlapping of CIP and SPS complicated the case. PATIENT CONCERNS: A 60-year-old man presented with gradual onset of cramps, stiffness, and rigidity in his lower limbs 1 year before admission, which eventually led to inability to stand and walk. The persistent nature of his symptoms progressed to frequent acute episodes of dyspnea and he was admitted to intensive care unit (ICU). DIAGNOSIS: SPS had been diagnosed after 2 tests of electromyography (EMG) and the detection of an elevated anti-GAD65 antibody titer. During the first EMG, low or absent compound muscle action potentials (CMAP), and sensory nerve action potentials (SNAP) were shown. Therefore, the diagnosis of SPS coexisting with CIP was made. INTERVENTIONS: Symptomatic treatment was initiated with oral clonazepam (0.5 mg Bid) and baclofen (5 mg Bid). Intravenous immunoglobulin (IVIG) (0.4 g/kg/d) was administered for the patient for 5 days after admission. We observed a significant clinical improvement during the administration period, and the patient became ambulatory. OUTCOMES: On follow-up, the patient reported complete relief of his pain and rigidity. LESSONS: We report this special case to address the varied clinical features of SPS. Electrophysiological testing is an important diagnostic approach. Accurate recognition of the disease ensures that the patients can be given appropriate treatment without delay.


Assuntos
Polineuropatias/diagnóstico , Insuficiência Respiratória/etiologia , Rigidez Muscular Espasmódica/diagnóstico , Baclofeno/administração & dosagem , Baclofeno/uso terapêutico , Clonazepam/administração & dosagem , Clonazepam/uso terapêutico , Diagnóstico Diferencial , Eletromiografia , Humanos , Imunoglobulinas Intravenosas/administração & dosagem , Imunoglobulinas Intravenosas/uso terapêutico , Masculino , Pessoa de Meia-Idade , Relaxantes Musculares Centrais/administração & dosagem , Relaxantes Musculares Centrais/uso terapêutico , Polineuropatias/complicações , Rigidez Muscular Espasmódica/complicações
20.
J Pediatr Rehabil Med ; 13(3): 379-384, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33164962

RESUMO

The COVID-19 pandemic has been a challenge to healthcare systems around the world. Within pediatric rehabilitation medicine, management of intrathecal baclofen has been particularly challenging. This editorial reviews how programs in the US and Canada coped with the quickly changing healthcare environment and how we can learn from this pandemic to be prepared for future crises.


Assuntos
Baclofeno/administração & dosagem , COVID-19/epidemiologia , Espasticidade Muscular/tratamento farmacológico , Pandemias , Criança , Comorbidade , Humanos , Injeções Espinhais , Relaxantes Musculares Centrais/administração & dosagem , Espasticidade Muscular/epidemiologia , SARS-CoV-2 , Resultado do Tratamento
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