RESUMEN
As a gamma amino butyric acid-ergic agonist, Baclofen is often prescribed to adults and children for the treatment of severe spasticity that originates in the brain or spinal cord. Even after reviewing the literature extensively, no one has documented a method for estimating baclofen using microwave-assisted stability-indicating spectrofluorimetric techniques, despite the abundance of options for baclofen stability, assay, and bioanalysis. Organic solvents, which are typically necessary for current procedures but may be costly and toxic, have a severe effect on aquatic life and the environment. Using green solvents and 4-chloro-7-nitrobezofuran as a fluorescent probe, this work conducted a stability-indicating spectrofluorimetric estimate of baclofen. Through the use of a design-of-experiments technique, a reliable microwave-aided spectrofluorimetric method was developed, with little solvent consumption and time for sample analysis. Prior to conducting response surface analysis and optimizing important variables and responses, a fractional factorial design was used to screen method variables and responses. A central composite design was then employed for these purposes. This flexible spectrofluorimetric technique was used to assess baclofen concentrations in forced degraded samples and marketed formulations. For baclofen determination, the suggested spectrofluorimetric approach was found to be green, quick, easy to use, economical, and user-friendly.
Asunto(s)
Baclofeno , Microondas , Espectrometría de Fluorescencia , Baclofeno/química , Baclofeno/análisis , Tecnología Química Verde , Color , Solventes/químicaRESUMEN
BACKGROUND: Tissue expansion is a well-established technique for soft tissue reconstruction in the pediatric population. We present a case series of this technique to create a safe pocket for baclofen pump insertion to minimize risk of complications including pump migration, extrusion, wound dehiscence and infection. METHODS: A case series of 3 pediatric patients undergoing tissue expansion prior to baclofen pump insertion at a single center in Melbourne. The expansion procedure was performed by senior surgeon N Low in all cases, and patients followed up 6 months after expander-pump exchange. The study was conducted over a 4-year period 2019 to 2023. RESULTS: We suffered 2 minor complications with the tissue expansion process including cellulitis and pump deflation. Neither complication precluded further tissue expansion nor led to premature removal of the expander. All patients proceeded to safely complete expander-pump exchange. One patient suffered a small (6 mL) abdominal seroma associated with pump insertion, which required no intervention. All patients have had a successful outcome 6 months after pump insertion. CONCLUSIONS: We describe a reliable and reproducible approach in creating a safe abdominal wall pocket to better accommodate baclofen pump insertion. Our series has overcome the imbalance between device size and abdominal wall pocket, now offering an alternative approach to achieve the safe delivery of intrathecal baclofen in the pediatric population.
Asunto(s)
Baclofeno , Bombas de Infusión Implantables , Relajantes Musculares Centrales , Expansión de Tejido , Humanos , Baclofeno/administración & dosificación , Expansión de Tejido/métodos , Expansión de Tejido/instrumentación , Niño , Femenino , Masculino , Relajantes Musculares Centrales/administración & dosificación , Adolescente , Parálisis Cerebral/complicaciones , Dispositivos de Expansión Tisular , PreescolarRESUMEN
OBJECTIVE: Intraventricular baclofen has been reported as an alternative to intrathecal baclofen for managing refractory spasticity and dystonia in some circumstances. In this report, we described a frame-based stereotactic approach for precisely positioning of the infusion catheter into the third ventricle. MATERIAL AND METHODS: High resolution contrast-enhanced anatomical MR sequences was acquired prior to surgery for pre-planning. Catheter trajectory was planned to pass from the lateral ventricle to the third ventricle through the Foramen of Monro. The surgical procedure was adapted from the frame-based deep brain stimulation surgery. The Touch-Loc kit (SceneRay, China) was used to temporarily secure the catheter in place during the surgery. From July 2022 to December 2022, three patients suffering from intractable spasticity and/or secondary dystonia received IVB successfully using the described technique. RESULTS: No severe adverse events, including death, intracranial hemorrhage, infection, catheter migration or fracture, were documented at the last follow-up (range: 12â24 months). Transient side effects included mild nausea following the initiation of infusion or the increase in infusion rate. All three patients responded to the IVB. CONCLUSIONS: The described frame-based stereotactic technique for IVB catheter implant is feasible and could be quickly mastered by neurosurgeons in related fields. Larger prospective cohorts with longer follow-up periods are necessary to further evaluate the long-term safety and efficacy of this procedure.
Asunto(s)
Baclofeno , Distonía , Relajantes Musculares Centrales , Espasticidad Muscular , Humanos , Baclofeno/administración & dosificación , Baclofeno/uso terapéutico , Espasticidad Muscular/tratamiento farmacológico , Espasticidad Muscular/cirugía , Espasticidad Muscular/etiología , Masculino , Relajantes Musculares Centrales/administración & dosificación , Relajantes Musculares Centrales/uso terapéutico , Femenino , Adulto , Persona de Mediana Edad , Distonía/tratamiento farmacológico , Técnicas Estereotáxicas , Resultado del Tratamiento , Infusiones IntraventricularesRESUMEN
OBJECTIVE: To study the histological changes in lung of rats, evaluate their dynamics and determine the Bax and Bcl-2 genes expression in bronchial epithelium, alveolar type 1 cells and neutrophils at different times after the administration of baclofen. MATERIAL AND METHODS: The experiment was conducted on 20 mature (at the age of 20 weeks) male Wistar rats with a mass of 290-350 g, distributed in 4 groups (5 rats in each). Animals in the control group did not receive baclofen. Rats in experimental groups received baclofen at a dose of 85 mg/kg: in the 1st group, the experiment duration was 3 hours (time to maximum observed blood drug concentration); in the 2nd group - 4.5 h (drug half-life and time to maximum observed concentration of the main drug's metabolite - beta-[p-chlorophenyl])-gamma-hydroxybutyric acid in the blood); in the 3rd group - 24 h. RESULTS: A complex of pathological reactions developed in lungs of experimental animals when baclofen muscle relaxant was administered, namely circulatory disturbances at all levels of the microvasculature (venular and capillary congestion, hemorrhages in the interalveolar septums, alveoli, sludge), emphysema, sites of which punctuated with atelectases and dystelectases. The complex of pathological changes in the lungs had a certain dynamics and reached its highest severity by the 24th hour. Bax expression was strong, while Bcl-2 expression was moderate in the immunohistochemical (IHC) study of bronchical epithelium and alveolar type 1 cells, Bax and Bcl-2 expression in neutrophils was moderate in rats of the 1st group. The expression of Bax and Bcl-2 was strong in the bronchial epithelium and alveolar type 1 cells, the expression of Bax in neutrophils was moderate, and BCL-2 - strong in animals of the 2nd group. The expression of Bax in bronchial epithelium and alveolar type 1 cells was moderate, expression of Bcl-2 in bronchial epithelium and alveolar type 1 cells - strong, expression of Bax in neutrophils - weak and expression of Bcl-2 - strong among the rats of the 3rd group. CONCLUSION: The complex of pathological changes in lungs had a certain dynamic. Data on the histological changes in lungs in combination with the results of the chemical study, can be used to diagnose the poisoning by baclofen and to establish the time since the drug was administered. The results obtained during the IHC study suggest the involvement of apoptosis in the development of lesion of bronchial epithelium and alveolar type 1 cells. In addition, the expression of Bcl-2 in epithelial cells may play a role in the process of their regeneration.
Asunto(s)
Baclofeno , Pulmón , Neutrófilos , Proteínas Proto-Oncogénicas c-bcl-2 , Ratas Wistar , Proteína X Asociada a bcl-2 , Animales , Proteína X Asociada a bcl-2/metabolismo , Ratas , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Neutrófilos/patología , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Masculino , Baclofeno/farmacología , Pulmón/patología , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Relajantes Musculares Centrales/farmacología , Alveolos Pulmonares/patología , Alveolos Pulmonares/efectos de los fármacos , Alveolos Pulmonares/metabolismoRESUMEN
INTRODUCTION: Patients managed in the Pediatric Palliative Care Integral Unit (PPCIU) have serious neurological conditions that involve significant damage at central nervous system level. The movement disorder is a very common clinical problem and for the patients where an adequate control of muscle tone is not achieved with usual techniques or drugs, intrathecal baclofen therapy (IBT) should be considered. MATERIALS AND METHODS: Descriptive retrospective study based on the review of clinical records of patients who received IBT being followed by the PPCIU of Madrid Autonomous Region in the timeframe between September 2012 and February 2021. RESULTS: IBT was implanted in 8 patients affected by infantile cerebral palsy (ICP) with a Gross Motor Function Scale (GMFCS) IV-V, 3 patients was a Pantothenate kinase deficit-associated neurodegeneration (PKAN), 2 had Acquired Brain Damage, and the remaining 3 had, respectively, 2 glutaric aciduria type I (GA-1), and poly-malformative syndrome. In all patients we observed a period of clinical stability after IBT, we call this period "honeymoon". Two patients died while in the honeymoon period, at 24.9 and 19.6 months from implantation of the pump; the median of duration of the honeymoon period in the remaining 14 was 14.4 months (IQ: 8.3-25.8). CONCLUSIONS: IBT was not only used in patients with non-progressive diseases, but also in the group of patients with neurodegenerative or progressive diseases. In all of them, after implantation of the device, we have objectified a period of clinical stability and a better control of muscle tone disorders.
Asunto(s)
Baclofeno , Distonía , Inyecciones Espinales , Relajantes Musculares Centrales , Espasticidad Muscular , Cuidados Paliativos , Humanos , Baclofeno/administración & dosificación , Baclofeno/uso terapéutico , Espasticidad Muscular/tratamiento farmacológico , Estudios Retrospectivos , Relajantes Musculares Centrales/uso terapéutico , Relajantes Musculares Centrales/administración & dosificación , Distonía/tratamiento farmacológico , Masculino , Femenino , Preescolar , Niño , Parálisis Cerebral/tratamiento farmacológico , Lactante , Adolescente , Neurodegeneración Asociada a Pantotenato Quinasa/tratamiento farmacológicoRESUMEN
Thrust manipulation is one of the most commonly used techniques for managing musculoskeletal pain in clinical practice. This involves the application of a high-velocity, low-amplitude force directed to the joints with the intent of achieving joint cavitation. This current case report describes a female in her mid-20s who presented with excessive bilateral and involuntary hand muscle contractions after bilateral thrust manipulation. Dystonia appeared both at rest and during voluntary movements but was aggravated by actions such as finger flexion or spreading and disappeared during sleep. A diagnosis of complex regional pain syndrome (CRPS) type I combined with dystonia was made. Prednisolone administered between 2 and 5 weeks after symptom onset significantly reduced CRPS symptoms, but intramuscular botulinum toxin injection 5 weeks after symptom onset was ineffective at controlling her symptoms. Seven weeks after symptom onset, the patient was administered 2 mg trihexyphenidyl oral twice a day, 2.5 mg diazepam oral twice a day and 5 mg baclofen oral three times a day for 1 month and this significantly reduced dystonia, but complete resolution was not achieved. Clinicians should be aware that dystonia is a rare complication of thrust manipulation.
Asunto(s)
Baclofeno , Distonía , Mano , Humanos , Femenino , Mano/fisiopatología , Adulto , Distonía/tratamiento farmacológico , Distonía/etiología , Distonía/diagnóstico , Distonía/fisiopatología , Baclofeno/uso terapéutico , Baclofeno/administración & dosificación , Trihexifenidilo/uso terapéutico , Diazepam/uso terapéutico , Diazepam/administración & dosificación , Prednisolona/uso terapéutico , Prednisolona/administración & dosificación , Manipulaciones Musculoesqueléticas/métodosRESUMEN
The off-label use of an intravenous dexmedetomidine infusion is an option for refractory symptoms in pediatric palliative care with a few published cases of in-home use, most limited to end-of-life care. After an intrathecal baclofen pump malfunction with meningitis and medication withdrawal, a 17-year-old adolescent with quadriparetic cerebral palsy and paroxysmal autonomic instability experienced relief of refractory pain and dystonia with an in-home intravenous dexmedetomidine infusion. His interdisciplinary care team collaborated to establish safety measures and adjust his home medication regimen to further improve quality of life well before his end of life.
Asunto(s)
Parálisis Cerebral , Dexmedetomidina , Distonía , Humanos , Dexmedetomidina/administración & dosificación , Adolescente , Masculino , Distonía/tratamiento farmacológico , Infusiones Intravenosas , Parálisis Cerebral/tratamiento farmacológico , Parálisis Cerebral/complicaciones , Baclofeno/administración & dosificación , Terapia de Infusión a Domicilio , Cuidados PaliativosRESUMEN
CASE PRESENTATION: A woman in her 70s was found unresponsive and brought to our hospital with respiratory distress, cardiomyopathy and volatile alternation between hypotension and hypertension. She was intubated and admitted to intensive care for supportive treatment of suspected baclofen overdose. She gradually recovered and was discharged 10 days after presentation. Laboratory testing confirmed baclofen overdose. CONCLUSION: This case illustrates the classic features of baclofen toxicity but also includes unusual features including ST elevations on ECG and apical ballooning on echocardiogram. Lack of immediate laboratory testing can be a significant diagnostic challenge, so a high index of suspicion is needed to definitively diagnose baclofen overdose. Furthermore, haemodynamic volatility requires careful and frequent re-evaluation of treatment, so early recognition and anticipation of complications are essential for effective management of this life-threatening condition.
Asunto(s)
Baclofeno , Sobredosis de Droga , Humanos , Baclofeno/envenenamiento , Femenino , Sobredosis de Droga/complicaciones , Anciano , Relajantes Musculares Centrales/envenenamiento , Electrocardiografía , EcocardiografíaRESUMEN
INTRODUCTION: Spinal cord injury (SCI) may bring lifelong consequences for affected patients and a high financial burden to the health care system. SOURCE OF DATA: Published peer-reviewed scientific articles identified from EMBASE, Google Scholar, PubMed and Scopus. AREAS OF AGREEMENT: Surgery and blood pressure management are the main targets in acute SCI to avoid secondary damage. AREAS OF CONTROVERSY: The management of secondary chronic SCI is challenging, with unpredictable outcomes. GROWING POINTS: Given the lack of consensus on pharmacological therapy for acute and secondary chronic SCI, the present study analyses the currently available drugs and treatment options to manage secondary chronic SCI. AREAS TIMELY FOR DEVELOPING RESEARCH: Different approaches exist for the pharmacological management of secondary chronic SCI. One of the most investigated drugs, 4-aminopyridine, improves central motor conduction and shows improvement in neurological signs. Positive results in different areas have been observed in patients receiving the anti-spastic drugs tizanidine and baclofen or Granulocyte colony-stimulating factor. Growth hormone showed only minimal or no significant effects, and the therapy of secondary chronic SCI with riluzole has been poorly researched to date.
Asunto(s)
Traumatismos de la Médula Espinal , Humanos , 4-Aminopiridina/uso terapéutico , Baclofeno/uso terapéutico , Enfermedad Crónica , Riluzol/uso terapéutico , Traumatismos de la Médula Espinal/complicaciones , Traumatismos de la Médula Espinal/tratamiento farmacológicoRESUMEN
RATIONALE: Although the mesocorticolimbic dopamine (DA) system is the main neurochemical substrate that regulates the addictive and reinforcing effects of ethanol (EtOH), other neurotransmitter systems, such as the acetylcholine (Ach) system, modulate DAergic function in the nucleus accumbens (nAcc). Previously, we reported that intra-nAcc administration of the nicotinic Ach receptor agonist cytisine increased oral EtOH self-administration. GABAB receptors in the nAcc are expressed in DAergic terminals, inhibit the regulation of DA release into the nAcc, and could modulate the effects of cytisine on oral EtOH self-administration. The present study assessed the effects of intra-nAcc administration of the GABAB receptor agonist baclofen (BCF) on the impacts of cytisine on oral EtOH self-administration. METHODS: Male Wistar rats were deprived of water for 23.30 h and then trained to press a lever to receive EtOH on an FR3 schedule until a stable response rate of 80 % was achieved. After this training, the rats received an intra-nAcc injection of the nAch receptor agonist cytisine, BCF, and cytisine or 2-hydroxysaclofen, BCF, and cytisine before they were given access to EtOH on an FR3 schedule. RESULTS: Intra-nAcc injections of cytisine increased oral EtOH self-administration; this effect was reduced by BCF, and 2-hydroxysaclofen blocked the effects of BCF. CONCLUSIONS: These findings suggest that the reinforcing effects of EtOH are modulated not only by the DA system but also by other neurotransmitter systems involved in regulating DA release from DAergic terminals.
Asunto(s)
Alcaloides , Azocinas , Baclofeno , Condicionamiento Operante , Etanol , Agonistas de Receptores GABA-B , Agonistas Nicotínicos , Núcleo Accumbens , Quinolizinas , Ratas Wistar , Autoadministración , Animales , Masculino , Baclofeno/farmacología , Baclofeno/administración & dosificación , Ratas , Alcaloides/farmacología , Alcaloides/administración & dosificación , Azocinas/farmacología , Azocinas/administración & dosificación , Quinolizinas/farmacología , Quinolizinas/administración & dosificación , Agonistas de Receptores GABA-B/farmacología , Agonistas de Receptores GABA-B/administración & dosificación , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Etanol/administración & dosificación , Etanol/farmacología , Condicionamiento Operante/efectos de los fármacos , Agonistas Nicotínicos/farmacología , Agonistas Nicotínicos/administración & dosificación , Administración Oral , Consumo de Bebidas Alcohólicas/tratamiento farmacológico , Consumo de Bebidas Alcohólicas/psicología , Alcaloides de QuinolizidinaRESUMEN
Hippocamposeptal (HS) neurons send GABAergic projections from the hippocampus to the medial septum/diagonal band of Broca (MS/DBB) as part of a reciprocal loop that is critical for memory. HS neurons are proposed to be particularly sensitive to the deleterious effects of pathological exposure to amyloid-ß (Aß), as would occur during Alzheimer's disease (AD). However, it is not known how HS GABA release in the MS/DBB is altered during the progression of AD. To target HS neurons in a mouse model of AD, we crossed SST-Cre mice to 5XFAD mice and performed stereotaxic injections of Cre-dependent AAV containing mCherry/channelrhodopsin-2 (ChR2) into the hippocampus of offspring at 4, 6, 9, and 12 months. We used optogenetics to selectively stimulate HS terminals while performing whole-cell patch-clamp recordings from MS/DBB neurons in slices. There was a transient reduction in HS-inhibitory postsynaptic current (IPSC) amplitude in female 5XFAD mice at 6 months, but no difference in males at any age, and no difference in paired-pulse ratio in either sex at any age. When bath applying the GABABR agonist, baclofen, we found a larger decrease in HS-IPSC amplitude in 5XFAD females at 9 months and 5XFAD males at 12 months. In 12-month-old 5XFAD females, response to baclofen was significantly reduced. These data suggest that there is a transient increase in responsiveness to GABABR activation in 5XFAD mice that occurs earlier in females than in males. These sex-specific changes to HS function are likely to impact the relay of information between the hippocampus and MS/DBB.
Asunto(s)
Hipocampo , Receptores de GABA-B , Animales , Ratones , Masculino , Femenino , Receptores de GABA-B/metabolismo , Receptores de GABA-B/genética , Hipocampo/metabolismo , Enfermedad de Alzheimer/metabolismo , Potenciales Postsinápticos Inhibidores , Baclofeno/farmacología , Agonistas de Receptores GABA-B/farmacología , Núcleos Septales/metabolismoRESUMEN
STUDY DESIGN: Preclinical pilot study. OBJECTIVES: To explore peripheral and central nociceptive mechanisms that contribute to muscle stretch-induced locomotor deficits following spinal cord injury. SETTING: Kentucky Spinal Cord Injury Research Center, Louisville, KY, USA. METHODS: Ten female Sprague-Dawley rats received moderate, 25 g/cm T10 contusion injuries and recovered for 4 weeks. Rats were divided into three groups: Morphine/Ibuprofen-treated, Acetaminophen/Baclofen-treated, and saline control. Each group received daily hindlimb muscle stretching during weeks 4, 5, 9, and 10 post-injury and drugs were administered with stretching during weeks 4 and 9 only. Locomotor function was assessed throughout the experiment using the BBB Open Field Locomotor Scale. Hindlimb responses including spasticity, writhing, and clonic-like vibrations during muscle stretching were classified and scored. RESULTS: Consistent with our previous studies, hindlimb muscle stretching caused significant deficits in locomotor recovery following spinal cord injury. Baclofen and Ibuprofen partially mitigated the stretching effect, but none of the drugs significantly prevented the drop in locomotor function during stretching. Interestingly, treatment with Baclofen or Ibuprofen significantly reduced hindlimb responses such as spasticity and writhing during stretching, while Morphine exacerbated clonic-like vibrations in response to stretching maneuvers. CONCLUSIONS: These findings suggest that stretching may inhibit locomotor recovery through combined mechanisms of peripheral inflammation and sensitization of nociceptive afferents. When combined with central sprouting and loss of descending controls after SCI, this results in exaggerated nociceptive input during stretching. The inability of the applied clinical drugs to mitigate the detrimental effects of stretching highlights the complexity of the stretching phenomenon and emphasizes the need for further investigation.
Asunto(s)
Modelos Animales de Enfermedad , Miembro Posterior , Ibuprofeno , Morfina , Ratas Sprague-Dawley , Traumatismos de la Médula Espinal , Animales , Femenino , Traumatismos de la Médula Espinal/fisiopatología , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/complicaciones , Miembro Posterior/fisiopatología , Miembro Posterior/efectos de los fármacos , Ibuprofeno/farmacología , Ibuprofeno/administración & dosificación , Morfina/farmacología , Morfina/administración & dosificación , Ratas , Baclofeno/farmacología , Baclofeno/administración & dosificación , Acetaminofén/farmacología , Acetaminofén/administración & dosificación , Proyectos Piloto , Ejercicios de Estiramiento Muscular , Relajantes Musculares Centrales/farmacología , Relajantes Musculares Centrales/administración & dosificación , Analgésicos Opioides/farmacología , Analgésicos Opioides/administración & dosificaciónRESUMEN
INTRODUCTION: Spasticity is one of the most common secondary complications following a spinal cord injury (SCI), which can significantly debilitate a patient irrespective of the severity of the injury. Intrathecal baclofen therapy can effectively reduce global spasticity in bilateral lower extremities at lower doses and allows precise dose titration to manage spasticity optimally. In complex patients with spasticity and multiple medical comorbidities, multidisciplinary teamwork is required to assess ITB safety and deliver timely intervention to prevent secondary complications of spasticity and improve quality of life. CASE PRESENTATION: A 61-year-old African American male with multiple comorbidities, including end-stage renal disease (ESRD) requiring dialysis sustained non-traumatic SCI due to epidural abscess resulting in paraplegia and severe debilitating spasticity. Spasticity gradually worsened and interfered with his ability to achieve independence with functional activities appropriate for his neurological level of injury. A multidisciplinary team approach in this complex case resulted in a successful ITB trial and subsequent ITB implantation, resulting in reduced spasticity and improved quality of life. To our knowledge, this is the first case report of the administration of intrathecal baclofen pump therapy in a person with SCI and end-stage renal disease (ESRD) dependent on hemodialysis. DISCUSSION: ITB therapy can be safely delivered in a person with SCI and multiple medical comorbidities, including ESRD, dependent on hemodialysis to manage spasticity. However, a careful evaluation and discussion among the multidisciplinary team managing the patient's morbidities and patient is required to assess the risks and benefits of ITB therapy to allow the patient to make an informed decision.
Asunto(s)
Baclofeno , Inyecciones Espinales , Fallo Renal Crónico , Relajantes Musculares Centrales , Espasticidad Muscular , Diálisis Renal , Traumatismos de la Médula Espinal , Humanos , Baclofeno/administración & dosificación , Espasticidad Muscular/tratamiento farmacológico , Espasticidad Muscular/etiología , Masculino , Persona de Mediana Edad , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/terapia , Traumatismos de la Médula Espinal/complicaciones , Relajantes Musculares Centrales/administración & dosificaciónRESUMEN
Previous studies from our laboratory have shown sex differences in the behavioral, molecular, and neurochemical manifestations of morphine withdrawal and they were related to an increased sensitivity to morphine effects in males. In addition, we observed an interaction between the GABAergic and opioid systems that could also be sex-dependent. Baclofen, a GABAB receptor agonist, prevented the somatic expression and the molecular and neurochemical changes induced by morphine withdrawal syndrome in mice. On the contrary, little is known about baclofen effects in the rewarding properties of morphine in male and female mice. The present study aimed to explore the effect of baclofen (1, 2 and 3 mg/kg, i.p.) pretreatment in the rewarding effects induced by morphine (7 mg/kg, s.c.) and its effect on c-Fos and brain-derived neurotrophic factor (BDNF) expression induced by the rewarding properties of morphine in prepubertal male and female mice. Baclofen (2 mg/kg) pretreatment prevented the rewarding effects of morphine only in male mice, while baclofen (3 mg/kg) reduced these effects in both sexes. Moreover, the rewarding effects of morphine were associated with a decrease of BDNF and c-Fos expression cingulate cortex, nucleus accumbens shell, cornu ammonis 1 (CA1), and cornu ammonis 3 (CA3) areas of the hippocampus only in male mice. In addition, baclofen pretreatment prevented these changes in BDNF, but not in c-Fos expression. In conclusion, our results show that GABAB receptors have a regulatory role in the rewarding effects of morphine that could be of interest for a potential future therapeutic application in opioid use disorders.
Asunto(s)
Baclofeno , Factor Neurotrófico Derivado del Encéfalo , Morfina , Proteínas Proto-Oncogénicas c-fos , Recompensa , Animales , Baclofeno/farmacología , Masculino , Femenino , Morfina/farmacología , Ratones , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Agonistas de Receptores GABA-B/farmacología , Caracteres Sexuales , Conducta Animal/efectos de los fármacos , Factores SexualesRESUMEN
BACKGROUND: Cerebral palsy (CP) is the most cause of motor dysfunction in children. Selective dorsal rhizotomy (SDR) plays a major role in long term spasticity control. However, limited data exists on the effect of SDR on postoperative spasticity treatment requirements and supraspinal effects, and the stimulation responses of dorsal nerve roots in those with CP. METHODS: The current study included the outcome for 35 individuals undergoing SDR for motor functional outcome, spasticity, baclofen dose changes, botulinum toxin injection frequency, and spasticity related orthopedic procedures. We also report on the stimulation responses in 112 individuals who underwent SDR at our institution. RESULTS: There was a significant difference in gross motor function measures (GMFM)-66 scores at last follow up that remained present when considering only ambulatory children but not with non-ambulatory children. Ashworth scores were significantly decreased for both upper and lower extremities after SDR at all follow up points. There was a significant decrease in Baclofen dose and botulinum toxin injections requirements after SDR, but no significant difference in the need for orthopedic intervention. A total of 5502 dorsal nerve roots were tested showing a decrease in stimulation intensity and increase in grade on the right side and for descending lumbosacral levels. CONCLUSIONS: SDR improves gross motor scores during short term follow up but has additional benefits in decreasing baclofen dosing and botulinum toxin injections requirements after surgery. They stimulation responses of sectioned dorsal nerve roots adds to the limited available data and our understanding of the pathological changes that occur in CP.
Asunto(s)
Parálisis Cerebral , Espasticidad Muscular , Rizotomía , Raíces Nerviosas Espinales , Parálisis Cerebral/cirugía , Humanos , Rizotomía/métodos , Masculino , Raíces Nerviosas Espinales/cirugía , Niño , Femenino , Espasticidad Muscular/cirugía , Espasticidad Muscular/tratamiento farmacológico , Resultado del Tratamiento , Adolescente , Baclofeno/administración & dosificación , Baclofeno/uso terapéutico , Preescolar , Relajantes Musculares Centrales/uso terapéutico , Relajantes Musculares Centrales/administración & dosificaciónRESUMEN
BACKGROUND: Drug addiction is a social and medical problem that must be urgently addressed. The nucleus accumbens (NAc) is closely related to addiction-related learning memory, and γ-aminobutyric acid type B receptor (GABA B R) is a potential target for the treatment of drug addiction. However, the role of GABA B R activity levels in the NAc in cocaine addiction is unclear. METHODS: In this study, we established an animal model of cocaine dependence, modulated the level of GABA B R activity, applied a conditioned place preference assay (CPP) to assess the role of the NAc in reconsolidation of addiction memory, evaluated learning and memory functions by behavioral experiments, examined the expression of GB1, GB2, cyclic adenosine monophosphate response element binding protein (CREB), p-CREB, protein kinase A (PKA), protein kinase (ERK), and Brain-derived neurotrophic factor (BDNF) in the NAc by molecular biology experiments, and screened differentially significantly expressed genes by transcriptome sequencing. RESULTS: Our study showed that the GABA B receptor agonist baclofen (BLF) had a significant effect on locomotor distance in rats, promoted an increase in GABA levels and significantly inhibited the PKA and ERK1/2/CREB/BDNF signaling pathways. Moreover, transcriptome sequencing showed that GABA B R antagonist intervention identified a total of 21 upregulated mRNAs and 21 downregulated mRNAs. The differentially expressed (DE) mRNA genes were mainly enriched in tyrosine metabolism; however, further study is needed. CONCLUSION: GABA B R activity in the NAc is involved in the regulation of cocaine addiction and may play an important role through key mRNA pathways.
Asunto(s)
Trastornos Relacionados con Cocaína , Núcleo Accumbens , ARN Mensajero , Ratas Sprague-Dawley , Receptores de GABA-B , Animales , Ratas , Núcleo Accumbens/metabolismo , Núcleo Accumbens/efectos de los fármacos , Masculino , Receptores de GABA-B/genética , ARN Mensajero/análisis , Trastornos Relacionados con Cocaína/metabolismo , Baclofeno/farmacología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismoRESUMEN
BACKGROUND: The first pump for intrathecal administration of baclofen was implanted in 1984. Over thirty years, intrathecal prolonged infusion of muscle relaxants has occupied a worthy niche among all methods for correction of non-focal drug-resistant disabling muscle spasticity. However, this method has not become routine despite high awareness of specialists in Russia and abroad, as well as undeniable advantages for restoring the daily activity, improving the walking pattern and providing care and quality of life in people with limited mobility. This is due to scrupulous analysis of adverse events and accurate attitude towards its use.The purpose of this review was to systematize data on indications, selection criteria, pump implantation technique, subsequent patient management and treatment outcomes over a 30-year history. METHOD: A review of national and foreign literature was performed. RESULTS AND CONCLUSION: Prolonged intrathecal baclofen therapy is perspective for long-term treatment of severe spasticity interfering with quality of life and self-care if oral muscle relaxants are contraindicated or ineffective. This procedure is effective for impaired articulation, chewing and spastic pain syndrome. One can reduce the incidence of side effects via correct dosage of the drug, and tolerance to therapy can be reduced by timely elimination of problems with catheter.
Asunto(s)
Baclofeno , Inyecciones Espinales , Relajantes Musculares Centrales , Espasticidad Muscular , Baclofeno/administración & dosificación , Baclofeno/uso terapéutico , Humanos , Espasticidad Muscular/tratamiento farmacológico , Inyecciones Espinales/métodos , Relajantes Musculares Centrales/administración & dosificación , Bombas de Infusión Implantables , Calidad de VidaRESUMEN
OBJECTIVE: The aim of this study was 1) to describe the rate of intrathecal baclofen (ITB)-associated complications at a large tertiary center, and 2) to evaluate the impact of patient-related factors on the likelihood of developing such complications. METHODS: A retrospective single-center study was carried out. A total of 301 eligible patients were included in the analysis. Univariate regression models were used to evaluate the impact of age, sex, diagnosis, ambulation status, modified Ashworth scale score, body mass index, diabetes status, and pain level on the likelihood of developing a device-related infection, pump malfunction, catheter malfunction, and other clinically significant complications. RESULTS: Overall, 27% of patients experienced an ITB-related complication. The most common complications included infection (6%, 18/301), pump malfunction (7.3%, 22/301), and catheter malfunction (14%, 42/301). The univariate analyses revealed that the patient's ambulatory status had a significant impact on the likelihood of developing a catheter-related malfunction. Furthermore, a trend toward significance was identified between patients' preoperative body mass index and device-related infection. Finally, the risk of suffering any ITB-related complications was statistically correlated with the number of years that had passed since the initial pump implantation. CONCLUSIONS: The authors' analysis reveals a previously underrecognized association between ambulatory status at the time of ITB pump implantation and the incidence of catheter-related complications, and confirms the impact of time since surgery on the risk of developing any ITB-related complication. The patient's age, sex, diagnosis, diabetes status, or pain level at baseline were not associated with the risk of complications. Collectively, these insights contribute novel information to the existing literature, providing practical value for physicians in guiding patient selection for ITB therapy.
Asunto(s)
Baclofeno , Bombas de Infusión Implantables , Inyecciones Espinales , Relajantes Musculares Centrales , Humanos , Baclofeno/administración & dosificación , Baclofeno/efectos adversos , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto , Factores de Riesgo , Bombas de Infusión Implantables/efectos adversos , Relajantes Musculares Centrales/administración & dosificación , Relajantes Musculares Centrales/efectos adversos , Inyecciones Espinales/efectos adversos , Anciano , Adulto Joven , Espasticidad Muscular/tratamiento farmacológico , Falla de Equipo/estadística & datos numéricos , AdolescenteRESUMEN
The evolution of neurosurgical approaches to spasticity spans centuries, marked by key milestones and innovative practitioners. Probable ancient descriptions of spasmodic conditions were first classified as spasticity in the 19th century through the interventions of Dr. William John Little on patients with cerebral palsy. The late 19th century witnessed pioneering efforts by surgeons such as Dr. Charles Loomis Dana, who explored neurotomies, and Dr. Charles Sherrington, who proposed dorsal rhizotomy to address spasticity. Dorsal rhizotomy rose to prominence under the expertise of Dr. Otfrid Foerster but saw a decline in the 1920s due to emerging alternative procedures and associated complications. The mid-20th century saw a shift toward myelotomy but the revival of dorsal rhizotomy under Dr. Claude Gros' selective approach and Dr. Marc Sindou's dorsal root entry zone (DREZ) lesioning. In the late 1970s, Dr. Victor Fasano introduced functional dorsal rhizotomy, incorporating electrophysiological evaluations. Dr. Warwick Peacock and Dr. Leila Arens further modified selective dorsal rhizotomy, focusing on approaches at the cauda equina level. Later, baclofen delivered intrathecally via an implanted programmable pump emerged as a promising alternative around the late 1980s, pioneered by Richard Penn and Jeffrey Kroin and then led by A. Leland Albright. Moreover, intraventricular baclofen has also been tried in this matter. The evolution of these neurosurgical interventions highlights the dynamic nature of medical progress, with each era building upon and refining the work of significant individuals, ultimately contributing to successful outcomes in the management of spasticity.
Asunto(s)
Espasticidad Muscular , Rizotomía , Rizotomía/historia , Rizotomía/métodos , Espasticidad Muscular/cirugía , Humanos , Historia del Siglo XX , Historia del Siglo XIX , Historia del Siglo XXI , Procedimientos Neuroquirúrgicos/historia , Procedimientos Neuroquirúrgicos/métodos , Baclofeno/uso terapéutico , Baclofeno/historia , Parálisis Cerebral/cirugía , Parálisis Cerebral/historia , Historia del Siglo XVIIIRESUMEN
OBJECTIVE: Intrathecal baclofen (ITB) pumps are commonly used in pediatric patients with cerebral palsy (CP) and medically refractory spasticity. However, catheter malfunction and associated risk factors are not well understood. The aim of this study was to examine potential risk factors for spinal catheter malfunction and characterize postoperative follow-up to understand the clinical consequences. METHODS: Patients who received ITB pump replacement or revision at Boston Children's Hospital between 2010 and 2023 were retrospectively reviewed. The spinal catheter revision cohort (SCRC) included patients whose spinal catheter was occluded requiring lumbar catheter revision. The second cohort included abdominal pump replacements only (APRC). Between-group comparisons and multivariable regression identified factors associated with catheter revision and postoperative outcomes. RESULTS: Forty-one (33.6%) patients underwent spinal catheter revision and were compared with 81 patients (66.4%) who underwent abdominal pump replacement only. Younger age at surgery and an elevated preoperative lower-extremity modified Ashworth scale grade were associated with spinal catheter revision (p < 0.05). Catheter model type, tip location, and history of spinal fusion were not associated with obstruction. Postoperatively, SCRC patients experienced a higher rate of infection (17.1%) relative to APRC patients (0%) within 30 days from their ITB pump replacement procedure (p < 0.05) and greater likelihood of subsequent ITB system removal compared with the APRC (24.4% vs 7.4%, p < 0.05). Although not differing preoperatively, SCRC patients had lower postoperative ITB doses when compared with the APRC group (median dose 143 vs 350 µg/day, p < 0.05) at hospital discharge and remained statistically different at the 6-month and 1-year follow-ups (p < 0.05). There were no postoperative differences in baclofen overdose, withdrawal, or median number of hospital readmissions within 30 days. Overall, 31.7% of spinal catheter revisions were unanticipated by the clinical team at time of surgery. CONCLUSIONS: Younger age at surgery and increased preoperative lower-extremity tone may be risk factors for catheter obstruction, resulting in a higher rate of postoperative infection and subsequent ITB pump removal compared with pump replacement alone. Spinal catheter occlusion can complicate revision or replacement procedures, especially when unanticipated. Routine clinical assessment may be inadequate for diagnosing insidious catheter malfunction. Catheter occlusion deserves further study, and routine assessment of catheter patency may be warranted to prevent suboptimal tone therapy.