Intoxicaciones agudas por baclofeno consultadas al Centro Nacional de Toxicología en cinco años / Acute intoxications by baclofen consulted to Toxicology National Center in five years

Introducción: el baclofeno se indica como relajante muscular para el alivio de espasticidad grave y ejerce sus efectos como agonista selectivo del receptor GABA-B. Objetivo: caracterizar las intoxicaciones por baclofeno según reportes al Servicio de Información de Urgencia del Cenatox entre 2011 y 2015. Métodos: se realizó un estudio observacional retrospectivo con un universo de 16 notificaciones, en las que se estudiaron: el centro de salud que asistió al paciente, provincia de procedencia por año de estudio, grupo de edad, sexo, circunstancias del evento, manifestaciones clínicas y severidad de la intoxicación. Resultados: el año 2014 aportó la mayor cantidad de reportes y los niños las mayores frecuencias absolutas, no hubo diferencias en relación al sexo, aunque entre los hombres predominó la causa accidental y entre las féminas las intencionales suicidas. Todas las notificaciones procedieron de atención secundaria, aunque cinco de los pacientes habían sido previamente asistidos en áreas de salud. Todos los afectados presentaron manifestaciones neurológicas, la mayoría fueron reportados de grave y la mitad de los casos presentaron alteraciones cardiorrespiratorias con inestabilidad hemodinámica que llevó a la asistencia ventilatoria. La recuperación fue completa en todos los pacientes y no se reportaron fallecidos por esta causa durante el período de estudio. Conclusiones: la sobredosis de baclofeno es más común en niños y cursa con manifestaciones de neurotoxicidad e inestabilidad hemodinámica(AU)

Introduction: Baclofen is indicated as a muscle relaxant for the relief of severe spasticity and exerts its effects as a selective agonist of the GABA-B receptor. Objective: To characterize baclofen poisonings according to reports to the Cenatox emergency information service between 2011 and 2015. Methods: A retrospective observational study with a universe of 16 notifications, in which the health center that attended the patient and province of origin was studied by year of study, age group, gender, circumstances, clinical manifestations and severity of intoxication. Results: The bigger number of reports and the highest absolute frequencies occurred in the year 2014, there were no differences with regard to sex, although among the men, the accidental cause was predominant, and among women the suicides attemps were predominant. All reports came from secondary care, although five of the patients had previously been assisted in health care areas; all affected had neurological manifestations, most were reported as severe and half of the cases presented cardiorespiratory alterations with hemodynamic instability leading to ventilatory assistance. Recovery was complete in all patients and no deaths were reported for this cause during the study period. Conclusions: Baclofen overdose was more common in children and was characterized by neurotoxicity and hemodynamic instability(AU)

Participação de receptores GABA B na modulação do consumo etílico em ratos Wistar / Involvement of GABA B receptor on ethylic consumption modulation in Wistar rats

Introdução: o baclofeno, uma droga agonista seletivo de GABA B, tem sido apontado como uma nova opção de tratamento do etilismo. Neste estudo avaliou-se o efeito do baclofeno no consumo etílico em ratos Wistar. Materiais e Métodos: o experimento ocorreu em quatro fases: exposição, abstinência, reexposição e tratamento. Os animais foram alocados em grupos: 1, 2, 3 e 4 (n=5 por grupo), expostos à água pura, solução hidroalcoólica (SHA) 5% e SHA 10%; grupo 5 (subdividido em A, B e C N =5 por subgrupo) e grupo 6 (n=5), ambos expostos a apenas água pura. A administração de baclofeno via intraperitoneal destinou aos grupos 1, 2, 3 e 5 em diferentes doses. Nos demais grupos, administrou-se placebo. Aferiu-se o consumo das soluções em todas as fases, para fins comparativos. Resultados: o baclofeno, na dose de 1mg/Kg, reduziu o consumo de SHA 10% no grupo 1, que apresentou maior consumo etílico durante o experimento. Os demais grupos apresentaram menor consumo das SHA ofertadas, sem redução da ingesta etílica após administração da droga nas doses de 2 e 3mg/Kg. Conclusão: baclofeno reduziu etilismo apenas em animais com maior consumo etílico prévio à sua administração. O peso dos animais não foi fator determinante na resposta à droga. A dose efetiva no tratamento dos efeitos da privação alcoólica foi a de menor concentração (1mg/kg).

Introduction: Baclofen, a GABA B agonist, has been pointed as a new drug on the alcohol consumption treatment. This study has evaluated baclofen ́s effect on ethanol consumption in Wistar rats. Materials and Methods: four phases protocol: exposure, abstinence, re-exposure and treatment. Animals were allocated into groups: 1, 2, 3 and 4 (n=5 per group), exposed to pure water, 5% ethanol solution and 10% ethanol solution. Group 5 (subdivided into A, B and C, n=5 by subgroup) and group 6 (n=5), exposed to pure water. Baclofen intraperitoneal administration was destined to groups 1, 2, 3 and 5 (A, B and C) in different doses. The remaining groups received saline solution as control. Solutions consumption was assessed in all phases for comparative purposes. Results: Baclofen at 1mg/Kg reduced the 10% (vv) water-alcohol consumption in animals from Group 1, which also presented greater ethanol consumption during the experiment. The other groups showed a lower water - alcohol consumption and did not show an ethanol intake reduction after the drug administration in both 2 and 3mg/Kg doses. Conclusion: Baclofen only reduces alcoholism in animals with higher ethanol consumption. Animals weight is not a determining factor in ethanol consumption or in baclofen response. The effective baclofen dose in treating the deprivation alcohol effects was observed in the lowest concentration, corresponding to 1mg/Kg dose.

Pharmacology of Intracisternal or Intrathecal Glycine, Muscimol, and Baclofen in Strychnine-induced Thermal Hyperalgesia of Mice

Glycine and gamma-aminobutyric acid (GABA) are localized and released by the same interneurons in the spinal cord. Although the effects of glycine and GABA on analgesia are well known, little is known about the effect of GABA in strychnine-induced hyperalgesia. To investigate the effect of GABA and the role of the glycine receptor in thermal hyperalgesia, we designed an experiment involving the injection of muscimol (a GABAA receptor agonist), baclofen (a GABAB receptor agonist) or glycine with strychnine (strychnine sensitive glycine receptor antagonist). Glycine, muscimol, or baclofen with strychnine was injected into the cisterna magna or lumbar subarachnoidal spaces of mice. The effects of treatment on strychnine-induced heat hyperalgesia were observed using the pain threshold index via the hot plate test. The dosages of experimental drugs and strychnine we chose had no effects on motor behavior in conscious mice. Intracisternal or intrathecal administration of strychnine produced thermal hyperalgesia in mice. Glycine antagonize the effects of strychnine, whereas, muscimol or baclofen does not. Our results indicate that glycine has anti-thermal hyperalgesic properties in vivo; and GABA receptor agonists may lack the binding abilities of glycine receptor antagonists with their sites in the central nervous system.

Pharmacologic interventions for reducing spasticity in cerebral palsy.

Motor function abnormalities are a key feature of cerebral palsy. Spasticity is one of the main motor abnormalities seen in children with cerebral palsy. Spasticity is a velocity dependent increased resistance to movement. While in some children, spasticity may adversely impact the motor abilities, in others, it may help maintain posture and ability to ambulate. Thus, treatment to reduce spasticity requires careful consideration of various factors. Non-pharmacologic interventions used to reduce spasticity include physiotherapy, occupational therapy, use of adaptive equipment, various orthopedic surgical procedures and neurosurgical procedures. Pharmacologic interventions used for reducing spasticity in children with cerebral palsy reviewed in this article include oral administration of baclofen, diazepam, dantrolene and tizanidine, intrathecal baclofen, and local injections of botulinum toxin, phenol, and alcohol.

Manejo de la espasticidad en pacientes con lesión medular con infusión de baclofeno intratecal mediante bomba implantable / Treating spasticity in medullar lesion patients with intrathecal baclofen

Presentamos 3 casos con lesión medular traumática alta, secuelados con tetraplejia y espasticidad de difícil manejo, en los que se evalúa la seguridad y eficacia del uso de baclofeno intratecal. Para evaluar la respuesta a baclofeno intratecal, previo a la implantación de la bomba, los pacientes fueron sometidos a una prueba terapéutica con bolos de baclofeno en dosis de 25, 50, 75 y 100 gamas, administradas por punción lumbar, con lo que se obtuvo una significativa disminución de la rigidez y espasticidad por más de 8 horas en todos los casos, evaluados con las escalas de Ashworth y de espasmos de Penn. A estos 3 pacientes se les implantó una bomba programable con un catéter intratecal para infusión de baclofeno a nivel dorsal. Los pacientes se controlaron neurológicamente cada 3 meses. Se logró mantener una respuesta clínicamente satisfactoria, debiéndose ajustar progresivamente dosis de baclofeno. No se han observado complicaciones significativas

Effect of continuous infusion of GABA and baclofen on gastric secretion in anaesthetised rats.

Continuous infusion of gamma- aminobutyric acid (GABA) and baclofen (BAC) on gastric acid and pepsin secretion in perfused rat stomach showed that GABA (25-100 mg/kg/hr, i.v.) and BAC (1 mg/kg/hr, i.v.) increased the acid output which was blocked by bicuculline (Bicc, 1 mg/kg, i.v.) when given 30 min before their infusion. However, lower dose of GABA (5 mg/kg/hr) and hig her doses of BAC (5 or 10 mg/kg/hr) did not show any significant effect on acid secretion. GABA (5 and 25 mg/kg/hr) inhibited peptic output and again Bicc in the above dose inhibited the inhibitory effect of 25 mg/kg/hr of GABA on peptic output. The result indicate dichotomy on the effects of GABA on acid and pepsin secretion. As both the effects were blocked by Bicc, involvement of GABAA receptor may be a possibility. The antiulcer effect of GABA and BAC could not be due to their effect on gastric acid secretion, but may be due to inhibition of pepsin secretion by GABA or effects of GABA or BAC on mucosal defensive factors.

Effect of manipulation of the GABA system on dopamine-related behaviors

The interaction between GABAergic and dopaminergic system within the central nervous system was investigated in rats using the open-field apparatus and apomorphine-induced stereotypy, and in mice using haloperidol-induced catalepsy. The single intraperitoneal adminsitration of baclofen 3.0 mg/kg, 4,5,6,7-tetrahydroisoxasolo-(5,4-c) piridin-3-ol (THIP) 10.0 mg/kg and picrotoxin 2.0 mg/kg decreased both ambulation and rearing frequencies of the rats in the open-field; only the GABA agonists increased the duration of animal immobility. THIP (10.0 mg/kg) increased the duration of haloperidol-induced catalepsy. For apomorphine-induced stereotypy, baclofen 3.0 mg/kg and picrotoxin 1.0 mg/kg induced a significant leftward displacement of the control dose-response curve constructed for apomorphine (0.1-10 mg/kg) in relation to the control. In addition, baclofen, THIP, picrotoxin and 3-mercaptopropionic acid (3-MPA) 10.0 mg/kg decreased both rearing and sniffing behaviors elicited by apomorphine and increased licking and/ or gnawing. Different mechanisms seem to be involved in the similar effects induced by GABA agonists and antagonists. Picrotoxin induced stereotyped movements per se with a dose-dependent effect, but baclofen and THIP did not. The present data suggest that GABA manipulation facilitates the progressive activation of the different dopaminergic pathways involved in stereotyped behaviors, thus increasing those stereotyped components (gnawing and licking) that appear after a high level of activation of dopaminergic pathways

Baclofen intrarraquiano no tratamento da espasticidade grave e do espasmo muscular / Intraspinal blacofen in the treatment of severe spaticity and spasm

Säo relatados 9 casos de pacientes portadores de lesöes neurológicas diversas que apresentaram, em suas manifestaçöes clínicas, espasticidade grave e/ou espasmos musculares intensos e que foram submetidos a tratamento com o baclofen intrarraquiano. Todos os pacientes foram avaliados longitudinalmente segundo protocolo pré-estabelecido. Para ser incluído no estduo, era necessário que o paciente fosse portador de lesäo estabilizada do sistema nervoso central, que apresenta-se espasticidade grave, e/ou espasmos musculares näo controlados por baclofen e/ou diazepan oral. Todos os pacientes foram submetidos a avaliaçäo neurológica completa, caracterizando-se o grau da espasticidade pela escala de Aschworth, os espasmos pela escala de Penn e a espasticidade funcional pela escala de Frankel. Em todos os casos houve melhora da espasticidade e/ou espasmos; assim, na avaliaçäo prévia, a espasticidade apresentava a média de 4,7 na escala de Aschworth que foi reduzida para 1,2 e os espasmos, de 3,3 para 0,2 na Escala de Penn. Como efeitos colaterais, tivemos apenas 3 casos, bradicardia e hipotensäo transitórias e, em 1, discreta sonolência. um caso apresentou infecçäo pós-operatória, tendo sido retirado o sistema, tratada a infecçäo e colocado um novo conjunto

Rizotomía con radiofrecuencia para el tratamiento de la espasticidad / Rhizotomy with radiofrequency for the spasticity treatment

Se presentan siete operados por una espasticidad invalidante, refractaria al tratamiento farmacológico, con paraplejia irreductible en flexión en seis y plejia crural dolorosa en flexión en uno. Cuatro eran hombres, con un rango de edad entre 13 y 66 años. En tres casos la espasticidad era secundaria a un tumor intramedular, en dos a un traumatismo raquimedular cervical, en uno a un infarto paracentral y en uno a una aracnoiditis. El procedimento quirúrgico consistió en una rizotomía posterior con radiofrecuencia, desde D12 hasta L5, bilateral en seis y unilateral en uno. En los siete pacientes hubo una disminución importante de la espasticidad, sin morbilidad. En dos pacientes se repitió el procedimiento con un buen resultado. En un caso, al recurrir la espasticidad, se instaló un dispositivo para administración intermitente de baclofeno intratecal, con un buen resultado mientras se administraba el fármaco. Posteriormente se le efectuó una mielotomía. La rizotomía con RF es un tratamiento efectivo para la mayoría de los casos de espasticidad, especialmente en los casos secundarios a una lesión medular, seguro, fácil de efectuar, con escasas recurrencias y que es posible repetir sin aumentar la morbilidad

Tratamento da doença de Meige com droga agonista de receptores GABA / Treatment of Meige disease with GABA receptors agonist

A doença de Meige é distúrbio de movimento que consiste no aparecimento espontâneo de blefarospamo associado a movimentos dispônicos de musculatura orofacial. Associadamente podem ser encontrados torcicolo espasmódico disfonia espática e distonia de extremidades. Várias hipóteses foram formuladas para explicar esse distúrbio, tendo em vista a resposta a drogas com açäo conhecida nos sitemas de neurotransmissores do cérebro. Algumas evidências apontam para um estado de preponderância dopaminérgica e, nesse sentido, justifica-se a estimulaçäo da atividade GABA, sabendo-se que esse neurotransmissor age sobre uma da alças de controle da produçäo de dopamina na substância negra. Por essa razäo investigamos a açäo de um agonista GABA, o baclofen, sobre a doença de Meige. Foram incluídos no protocolo 5 pacientes, 4 mulheres e um homem, com idade variando entre 50 e 63 anos e duraçäo da doença variando entre 4 meses e 18 anos. Todos apresentavam blefarospasmo-distonia orofacial e, além disso três apresentavam disfonia espástica e um distonia de extremidades. A droga era iniciada em dose de 20mg/dia, aumentada em 10mg a cada três ser obtida resposta ou sugirem efeitos colaterais. Um dos pacientes apresentou melhora marcada do blefarospasmo-distonia orofacial e outro melhora moderada dos mesmos sintomas em avaliaçäo 30 dias após establilizaçäo da dose. Näo houve melhora da distonia espástica e ocorreu melhora a moderada da distonia de extremidades. Näo podemos afirmar que a melhora observada ao fim de um mês se mantenha, ou mesmo que melhora mais significativa fosse observada em avaliaçäo feita mais tardiamente. Concluimos que o baclofen pode ser útil, pelo menos por algum tempo, na doença de Meige