RESUMEN
INTRODUCTION: This study explores the interaction between cytokines, cell-mediated immunity (T cells, B cells, and NK cells), and prolonged morphine administration in chronic neuropathic pain patients without cancer-related issues. Despite evidence of opioid immunomodulation, few studies have compared these interactions. METHODS: In a cross-sectional and comparative study, 50 patients with chronic low back radicular pain ("Failed Back Surgery Syndrome") were categorized into intrathecal morphine infusion (IT group, n = 18), oral morphine (PO group, n = 17), and non-opioid treatment (NO group, n = 15). Various parameters, including plasma and cerebrospinal fluid (CSF) cytokine concentrations, lymphocyte immunophenotyping, opioid escalation indices, cumulative morphine dose, and treatment duration, were assessed. RESULTS: CSF IL-8 and IL-1ß concentrations exceeded plasma levels in all patients. No differences in T, B, and NK lymphocyte numbers were observed between morphine-treated and non-treated patients. Higher plasma IL-5 and GM-CSF concentrations were noted in IT and PO groups compared to NO. CSF IFNγ concentrations were higher in PO and NO than IT. Positive correlations included CD4 concentrations with opioid escalation indices, and negative correlations involved NK cell concentrations, CSF TNFα concentrations, and opioid escalation indices. Positive correlations were identified between certain cytokines and pain intensity in IT patients, and between NK cells and cumulative morphine dose. Negative correlations were observed between CSF IL-5 concentrations and pain intensity in IT and PO, and between opioid escalation indices and CSF cytokine concentrations in PO and IT. CONCLUSION: Associations between cytokines, cellular immunity, and prolonged morphine treatment, administered orally and intrathecally were identified.
Asunto(s)
Analgésicos Opioides , Citocinas , Inyecciones Espinales , Laminectomía , Morfina , Humanos , Analgésicos Opioides/administración & dosificación , Citocinas/sangre , Citocinas/líquido cefalorraquídeo , Masculino , Persona de Mediana Edad , Femenino , Estudios Transversales , Morfina/administración & dosificación , Administración Oral , Laminectomía/métodos , Anciano , Adulto , Dolor Postoperatorio/tratamiento farmacológico , Neuralgia/tratamiento farmacológico , Síndrome de Fracaso de la Cirugía Espinal Lumbar/tratamiento farmacológicoRESUMEN
BACKGROUND: Based on previous in vivo studies and human trials, intrathecal cell delivery is a safe and relevant therapeutic tool for improving patient's quality of life with neurological conditions. We aimed to characterise the safety profile of intrathecally delivered Mesenchymal stem cells (MSCs). METHODS: Ovid MEDLINE, Embase, Scopus, Cochrane Library, KCI-Korean Journal Database, and Web of Science. Databases were searched from their inception until April 13, 2023. Randomised Controlled Trials (RCTs) that compared intrathecal delivery of MSCs to controls in adult populations were included. Adverse events (AEs) were pooled and meta-analysed using DerSimonian-Laird random effects models with a correction factor 0.5 added to studies with zero count cells. Pooled AEs were described using Risk ratio (RR) and 95% confidence intervals (95% CI). Then, a random-effects meta-regress model on study-level summary data was performed to explore the relationship between the occurrence of AEs and covariates thought to modify the overall effect estimate. Finally, publication bias was assessed. RESULTS: 303 records were reviewed, and nine RCTs met the inclusion criteria and were included in the quantitative synthesis (n = 540 patients). MSCs delivered intrathecally, as compared to controls, were associated with an increased probability of AEs of musculoskeletal and connective tissue disorders (categorised by Common Terminology Criteria for Adverse Events-CTCAE version 5.0) (RR: 1.61, 95% CI 1.19-2.19, I2 = 0%). The random-effects meta-regress model suggested that fresh MSCs increased the probability of occurrence of AEs compared to cryopreserved MSCs (RR: 1.554; p-value = 0.048; 95% CI 1.004-2.404), and the multiple-dose, decreased the probability of AEs by 36% compared to single doses (RR: 0.644; p-value = 0.048; 95% CI 0.416-0.996); however, univariate random effects meta-regression models revealed a not significant association between the occurrence of AEs from MSCs intrathecal delivery and each covariate. CONCLUSIONS: Intrathecal delivery of MSCs was associated with a slight increase in AEs associated with musculoskeletal and connective tissue disorders, albeit without serious AEs. We conclude that intrathecal MSCs delivery is safe for patients with neurological conditions. However, further high-quality, large-scale RCTs are needed to confirm these findings.
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Inyecciones Espinales , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Enfermedades del Sistema Nervioso , Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Trasplante de Células Madre Mesenquimatosas/efectos adversos , Trasplante de Células Madre Mesenquimatosas/métodos , Enfermedades del Sistema Nervioso/terapia , Células Madre Mesenquimatosas/citologíaRESUMEN
ABSTRACT Introduction: Intrathecal chemotherapy is a mainstay component of acute lymphoblastic leukemia treatment. In Mexico, there is a considerable practice variability in aspects, such as the manner of preparation and the administration technique. Objective: Our objective was to describe the different techniques used for the application of ITC and review the existing recommendations in the literature. Method: A cross-sectional, nationwide survey study was conducted by an electronic questionnaire sent to hematologists and oncologists in Mexico. We collected demographic data, personal experience, intrathecal chemotherapy techniques, drug preparation and postprocedural conduct. Results: We received 173 responses. Twenty percent had an anesthesiologist administering sedation and pain management. The platelet count considered safe was 50 × 109/L in 48% of the participants. In 77% (n = 133) of the cases, the conventional needle with stylet used was, 49% did not receive any added diluent in the intrathecal chemotherapy and only 42% were recommended to rest in a horizontal position for more than 30 min. Conclusion: We identified a considerable variation in the administration of intrathecal chemotherapy across the hematologists in Mexico. We discuss the implications and opportunities in reducing the variation in our setting, highlighting the unmet need to establish guidelines that should be evaluated by the Mexican professional society to produce a position paper regarding practice standardization.
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Humanos , Inyecciones Espinales , Leucemia , QuimioterapiaRESUMEN
Introducción: Se describe la evolución de un paciente que recibe morfina intratecal mediante una bomba de infusión, que le fuera implantada hace 14 años para tratamiento de su dolor lumbar crónico post-laminectomía. Material y método: Requería la administración de 60 mg/día de morfina subcutánea que le provocaban efectos secundarios que no toleraba, y múltiples internaciones para control del dolor. Se le implantó una bomba de infusión continua (Isomed) conectada a un catéter subaracnoideo, que libera 1 ml/día, y requiere ser llenada cada 60 días. Resultados: Se observó una disminución del dolor promedio de 50% al año, y de 75% a los 6 y 14 años. Requirió un aumento progresivo de las dosis de llenado, que pasaron de 30 mg de morfina (0.5 mg/día) al inicio, a 40 mg de morfina (0.66 mg /día) al año, a 70 mg de morfina (1.16 mg/día) a los 6 años, a 140 mg (2.33 mg/día) a los 14 años. No se registraron complicaciones médicas graves. Mantuvo constipación y sudoración durante todo el período, e instaló un hipogonadismo secundario con trastornos de la libido y de la erección que fueron corregidos con la administración de testosterona. No requirió más internaciones por dolor. No se observaron complicaciones relacionadas con el funcionamiento o llenado de la bomba, ni vinculadas al catéter. El paciente manifestó estar satisfecho con el implante. Discusión: A pesar del aumento de las dosis de llenado, expresión del desarrollo de tolerancia, las dosis de morfina/día requeridas son francamente inferiores al límite recomendado. Conclusiones: El balance del riesgo-beneficio del implante resultó positivo, considerando el mejor control del dolor logrado, las menores dosis de morfina utilizadas, así como la ausencia de complicaciones graves y de internaciones para control del dolor.
Introduction: The evolution of a patient receiving intrathecal morphine through an infusion pump that was implanted 14 years ago for the treatment of chronic post-laminectomy low back pain is described. Material and method: It required the administration of 60 mg / day of subcutaneous morphine that caused side effects that did not tolerate, and multiple hospitalizations for pain control. He was implanted with a continuous infusion pump (Isomed) connected to a subarachnoid catheter, which releases 1 ml / day, and needs to be filled every 60 days. Results: An average pain decrease of 50% per year, and 75% at 6 and 12 years was observed. It required a progressive increase in filling doses, which went from 30 mg of morphine (0.5 mg / day) at the beginning, to 40 mg of morphine (0.66 mg / day at the first year, to 70 mg of morphine (1.16 mg / day) at the sixth year, at 140 mg (2.33 mg / day) at the fourteen year. No serious medical complications were recorded, he maintained constipation and sweating throughout the period, and installed secondary hypogonadism with libido and erection disorders, that were corrected with the administration of testosterone. No further hospitalizations were required due to pain. No complications were observed related to the operation or filling of the pump or linked to the catheter. The patient stated that he was satisfied with the implant. Discussion: Despite the increase in filling doses, expression of tolerance development, the required morphine / day doses are frankly below the recommended limit. Conclusions: The risk-benefit balance of the implant was positive, considering the best pain control, the lowest doses used, the absence of serious complications, and the lack of hospitalizations for pain control.
Introdução: Descreve-se a evolução de um paciente que recebeu morfina intratecal através de uma bomba de infusão, implantada há 14 anos para o tratamento de lombalgia crônica pós-laminectomia. Material e método: Necessitou de administração de 60 mg/dia de morfina por via subcutânea, que provocou efeitos colaterais intolerantes, e múltiplas internações para controle da dor. Foi implantada uma bomba de infusão contínua (Isomed) conectada a um cateter subaracnóideo, que libera 1 ml/dia, necessitando de reenchimento a cada 60 dias. Resultados: Observou-se redução média da dor de 50% em um ano e 75% em 6 e 14 anos. Foi necessário um aumento progressivo das doses de enchimento, que passaram de 30 mg de morfina (0,5 mg/dia) no início, para 40 mg de morfina (0,66 mg/dia) por ano, para 70 mg de morfina (1,16 mg/dia) dia) aos 6 anos, para 140 mg (2,33 mg/dia) aos 14 anos. Não foram registradas complicações médicas graves. Manteve constipação e sudorese durante todo o período e desenvolveu hipogonadismo secundário com distúrbios de libido e ereção que foram corrigidos com administração de testosterona. Ele não necessitou de mais hospitalizações por dor. Não foram observadas complicações relacionadas à operação ou enchimento da bomba, ou relacionadas ao cateter. O paciente afirmou estar satisfeito com o implante. Discussão: Apesar do aumento das doses de enchimento, expressão do desenvolvimento da tolerância, as doses necessárias de morfina/dia são francamente inferiores ao limite recomendado. Conclusões: A relação risco-benefício do implante foi positiva, considerando o melhor controle da dor alcançado, as menores doses de morfina utilizadas, bem como a ausência de complicações graves e internações para controle da dor.
Asunto(s)
Humanos , Masculino , Anciano , Bombas de Infusión Implantables , Dolor de la Región Lumbar/tratamiento farmacológico , Analgésicos Opioides/administración & dosificación , Morfina/administración & dosificación , Dimensión del Dolor , Inyecciones Espinales , Resultado del Tratamiento , Medición de Riesgo , Catéteres , Dolor Crónico/tratamiento farmacológico , Analgésicos Opioides/efectos adversos , Morfina/efectos adversosRESUMEN
The Cesarean section is the most frequently performed surgical intervention in most countries, in Chile there are approximately 80,000 cases per year. In the postoperative period, effective analgesia is essential since patients define the absence of intra- and post-cesarean pain as priorities. On the other hand, entities such as cronical pain and postpartum depression have been associated with persistent postoperative pain and difficulty in mother-child interaction. Intrathecal morphine (ITM) was first described in obstetric analgesia in the 1980s and has since become widely used for post-cesarean section analgesia due to its prolonged analgesic action. In this review we will focus on the most relevant aspects that may lead to the incorporation of MIT in the Analgesia protocols for Cesarean section in our country.
La Operación Cesárea es la intervención quirúrgica más frecuentemente realizada en la mayoría de los países, en Chile son aproximadamente 80.000 casos por año. En su posoperatorio la analgesia eficaz es fundamental, dado que las pacientes definen la ausencia de dolor intra y poscesárea como prioritarios. Por otra parte, entidades como dolor cónico y depresión posparto han sido asociados con dolor posoperatorio persistente y dificultad en la interacción madre-hijo. La morfina intratecal (MIT) se describió por primera vez en analgesia obstétrica en la década de 1980 y desde entonces se ha vuelto ampliamente utilizada para la analgesia poscesárea debido a su prolongada acción analgésica. En esta revisión nos centraremos en los aspectos más relevantes que puedan conducir a la incorporación de MIT en los protocolos de Analgesia para Cesárea en nuestro país.
Asunto(s)
Humanos , Femenino , Embarazo , Cesárea/métodos , Analgésicos Opioides/administración & dosificación , Morfina/administración & dosificación , Dolor Postoperatorio/prevención & control , Inyecciones Espinales , Analgesia Obstétrica , Analgésicos Opioides/efectos adversos , Morfina/efectos adversosRESUMEN
BACKGROUND: General anesthesia (GA) was the usual anesthetic technique used for laparoscopic interventions, however regional anesthesia in the laparoscopic field started to gain familiarity. Shoulder pain is a major intraoperative problem that might hinder facilitation of laparoscopic interventions under spinal anesthesia. AIM OF THE STUDY: Evaluate the effect of intrathecal addition of dexamethasone versus fentanyl on incidence and severity of intraoperative shoulder tip pain during gynecological laparoscopic asurgeries. Methods: 120 patients, were randomly assigned into three groups. Group D: 40 patients received 15 mg bupivacaine and 8 mg dexamethasone intrathecally. Group F: 40 patients received 15 mg bupivacaine and 25 pg fentanyle intrathecally. Group C: 40 patients received 15 mg bupivacaine and normal saline intrathecally. RESULTS: Number of patients who experienced intraoperative shoulder pain was significantly lower in Group F (17) and Group D (19) than Group C (31); P = 0.008. with no ststistical difference detected between Group D and C (p value 1). Only 2 patients in Group D and F suffered moderate pain intensity in comparison to 9 patients in Group C; P =0.02. Incidence of postspinal shivering was lower in Group D and F in comparison to Group C; P 0.02. CONCLUSION: Intrathecal dexamethasone is as effective as intrathecal fentanyle in reducing incidence and severity of shoulder tip pain during laparoscopic ovarian cystectomy under spinal anesthesia.
INTRODUCCIÓN: La anestesia general (AG) era la técnica anestésica habitual utilizada para las intervenciones laparoscópicas, sin embargo, la anestesia regional en el campo laparoscópico comenzó a ganar familiaridad. El dolor de hombro es un problema intraoperatorio importante que podría dificultar la facilitación de las intervenciones laparoscópicas bajo anestesia espinal. OBJETIVO DEL ESTUDIO: Evaluar el efecto de la adición intratecal de dexametasona versus fentanilo sobre la incidencia y severidad del dolor intraoperatorio en la punta del hombro durante cirugías laparoscópicas ginecológicas. MÉTODOS: 120 pacientes, fueron asignados aleatoriamente en tres grupos. Grupo D: 40 pacientes recibieron 15 mg de bupivacaína y 8 mg de dexametasona por vía intratecal. Grupo F: 40 pacientes recibieron 15 mg de bupivacaína y 25 pg de fentanilo por vía intratecal. Grupo C: 40 pacientes recibieron 15 mg de bupivacaína y solución salina normal por vía intratecal. RESULTADOS: El número de pacientes que experimentaron dolor de hombro intraoperatorio fue significativamente menor en el Grupo F (17) y el Grupo D (19) que en el Grupo C (31); P = 0,008. sin diferencia estadística detectada entre el Grupo D y C (valor de p 1). Solo 2 pacientes del Grupo D y F sufrieron dolor de intensidad moderada en comparación con 9 pacientes del Grupo C; P = 0,02. La incidencia de escalofríos posespinales fue menor en el Grupo D y F en comparación con el Grupo C; P 0,02. CONCLUSIÓN: La dexametasona intratecal es tan eficaz como el fentanilo intratecal para reducir la incidencia y la gravedad del dolor en la punta del hombro durante la cistectomía ovárica laparoscópica bajo anestesia espinal.
Asunto(s)
Humanos , Femenino , Adulto , Dexametasona/administración & dosificación , Fentanilo/administración & dosificación , Laparoscopía/métodos , Dolor de Hombro/prevención & control , Complicaciones Intraoperatorias/prevención & control , Inyecciones Espinales , Cistectomía , Dolor de Hombro/epidemiologíaRESUMEN
The route used in the transplantation of mesenchymal stem cells (MSCs) can directly affect the treatment success. The transplantation of MSCs via the intrathecal (IT) route can be an important therapeutic strategy for neurological disorders. The objective of this study was to evaluate the safety and feasibility of the IT transplantation of autologous (Auto-MSCs) and allogeneic (Allo-MSCs) bone marrow mesenchymal stem cells (BM-MSCs) in healthy dogs. Based on neurodisability score, cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI), no significant differences from the control group were observed on day 1 or day 5 after IT Auto- or Allo-MSCs transplantation (P > 0.05). In addition, analysis of matrix metalloproteinase (MMP)-2 and MMP-9 expression in the CSF revealed no significant differences (P > 0.05) at 5 days after IT transplantation in the Auto- or Allo-MSCs group when compared to the control. Intrathecal transplantation of BM-MSCs in dogs provides a safe, easy and minimally invasive route for the use of cell-based therapeutics in central nervous system diseases.
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Médula Ósea/metabolismo , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Inyecciones Espinales/métodos , Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/metabolismo , Trasplante Autólogo/métodos , Trasplante Homólogo/métodos , Animales , PerrosRESUMEN
Resumen: Se realiza una revisión descriptiva sobre la inyección de ácido tranexámico en el espacio subaracnoideo. Se destaca que un error puede tener consecuencias catastróficas sobre el paciente, con un alto porcentaje de mortalidad. Se analizan las posibles causas que pueden llevar a la inyección errónea. Se advierte sobre la existencia de preparaciones de ácido tranexámico de similar apariencia a las de la bupivacaína de uso intratecal. Se describe el cuadro clínico de la complicación, el mecanismo de toxicidad, los tratamientos utilizados, y la evolución de los casos relatados en las referencias encontradas. Se discuten estrategias para evitar la complicación, señalando que la seguridad no debe basarse en la perfección humana, sino en medidas que dificulten cometer errores.
Summary: A descriptive review of tranexamic acid injection in the subarachnoid space is performed. A point is made that this error may have catastrophic consequences on the patient with a high percentage of mortality. Possible causes that can lead to an erroneous injection are analyzed. A warning is made about tranexamic acid preparations being similar in appearance to those of bupivacaine for intrathecal use. The study describes the clinical manifestation of this complication, the toxicity mechanism, treatments used, and the evolution of the cases reported in the references found. Strategies to avoid complications are discussed, pointing out that safety should not be based on human perfection, but on measures that make it difficult for humans to make mistakes.
Resumo: Faz-se uma revisão descritiva sobre a injeção de ácido tranexâmico no espaço subaracnóideo. Ressalta-se que é um erro que pode ter consequências catastróficas para o paciente com um elevado percentual de mortalidade. Faz-se uma análise das possíveis causas que podem levar ao uso equivocado de ácido tranexâmico devido a existência de preparações semelhantes em aparência às da bupivacaína para uso intratecal. Descreve-se o quadro clínico da complicação, o mecanismo de toxicidade, os tratamentos utilizados e a evolução dos casos relatados nas referências encontradas. Discute-se estratégias para evitar complicações, ressaltando que a segurança não deve ser baseada na perfeição humana, mas em medidas que dificultem o erro do ser humano.
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Ácido Tranexámico , Inyecciones Espinales/efectos adversos , Errores Médicos , Espacio SubaracnoideoRESUMEN
Abstract Introduction Classically, the local anesthetic (LA) has been combined with one lipophilic and another hydrophilic opioid for neuraxial anesthesia in cesarean section. In Colombia, the practice has been the use of morphine hydrochloride with fentanyl, but the occasional shortage of the former triggered an interest in new options. In response to the shortage of morphine in 2017-2018, a contingency plan was developed at the SES Hospital in Caldas, prefilling syringes at the hospital compounding central, with: bupivacaine, morphine and fentanyl (BMF); bupivacaine, fentanyl and hydromorphone (BFH); and bupivacaine and hydromorphone (BH). Hydromorphone has a rapid onset of action, long-lasting effect and is indicated for spinal administration in the safety data sheet; therefore, the advantages of adding fentanyl to this mix are questionable. Objective To compare the clinical analgesic efficacy at the time of the incision and during the first 12 hours after surgery. Methods An observational, analytical study was conducted, using the mixtures BMF, BFH and BH in patients receiving subarachnoid anesthesia for cesarean section. Pain was assessed at the time of the incision, as well as any adverse effects and the pain visual analogue scale over the following 12 hours. Results Of the 71 patients participating in the study, 40.9 % received BMF; 22.5 %, BFH; and 36.6 %, BH. None of the patients experienced pain at the time of the incision. There was no difference in terms of adverse effects among the three groups. The mean difference in the visual analogue scale (VAS) for postoperative pain at 3, 6 and 12 hours was lower in the groups in which hydromorphone was used. Conclusion BFH and BH combinations are comparable to the original preparation in terms of adverse effects, with the advantage of being more effective in controlling postoperative pain.
Resumen Introducción Para anestesia neuroaxial en cesárea, se ha combinado clásicamente el anestésico local (AL) con un opioide lipofílico y otro hidrofílico. En Colombia se ha usado clorhidrato de morfina con fentanilo, pero el ocasional desabastecimiento del primero despertó el interés por nuevas alternativas. En SES Hospital de Caldas se generó un plan de contingencia frente a la escasez de morfina en 2017-2018, pre llenando jeringas en su central de mezclas con: bupivacaína, morfina y fentanilo (BMF); bupivacaína, fentanilo e hidromorfona (BHF); y bupivacaína e hidromorfona (BH). La hidromorfona tiene inicio rápido de acción, efecto prolongado e indicación en ficha técnica por vía espinal, por lo tanto, las ventajas que pudiera generar la adición del fentanilo a esta mezcla son cuestionables. Objetivo Comparar la eficacia analgésica clínica al momento de la incisión y en las primeras 12 horas postoperatorias. Métodos Se realizó un estudio observacional analítico, empleando las mezclas BMF, BHF y BH en pacientes que recibieron anestesia subaracnoidea para cesárea. Se evaluó el dolor a la incisión, los efectos adversos y la escala visual análoga de dolor en las 12 horas siguientes. Resultados De las 71 pacientes del estudio, 40,9 % recibieron BMF; 22,5 %, BHF; y 36,6 %, BH. En ninguna paciente se observó dolor a la incisión. No hubo diferencia en efectos adversos entre los 3 grupos. La diferencia de medias de la escala visual analógica (EVA) para dolor postoperatorio a las 3, 6 y 12 horas, fue menor en los grupos en los que se usó hidromorfona. Conclusiones Las mezclas BHF y BH son equiparables a la preparación tradicional en cuanto a efectos adversos, con la ventaja de ser más efectivas para el control del dolor postoperatorio.
Asunto(s)
Humanos , Femenino , Embarazo , Espacio Subaracnoideo , Cesárea , Analgésicos Opioides , Inyecciones Espinales , Analgésicos , Anestesia EpiduralRESUMEN
Complete spinal cord lesions interrupt the connection of all axonal projections with their neuronal targets below and above the lesion site. In particular, the interruption of connections with the neurons at lumbar segments after thoracic injuries impairs voluntary body control below the injury. The failure of spontaneous regrowth of transected axons across the lesion prevents the reconnection and reinnervation of the neuronal targets. At present, the only treatment in humans that has proven to promote some degree of locomotor recovery is physical therapy. The success of these strategies, however, depends greatly on the type of lesion and the level of preservation of neural tissue in the spinal cord after injury. That is the reason it is key to design strategies to promote axonal regrowth and neuronal reconnection. Here, we test the use of a developmental axon guidance molecule as a biological agent to promote axonal regrowth, axonal reconnection, and recovery of locomotor activity after spinal cord injury (SCI). This molecule, netrin-1, guides the growth of the corticospinal tract (CST) during the development of the central nervous system. To assess the potential of this molecule, we used a model of complete spinal cord transection in rats, at thoracic level 10-11. We show that in situ delivery of netrin-1 at the epicenter of the lesion: (1) promotes regrowth of CST through the lesion and prevents CST dieback, (2) promotes synaptic reconnection of regenerated motor and sensory axons, and (3) preserves the polymerization of the neurofilaments in the sciatic nerve axons. These anatomical findings correlate with a significant recovery of locomotor function. Our work identifies netrin-1 as a biological agent with the capacity to promote the functional repair and recovery of locomotor function after SCI. These findings support the use of netrin-1 as a therapeutic intervention to be tested in humans.
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Locomoción/fisiología , Netrina-1/administración & dosificación , Traumatismos de la Médula Espinal/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Inyecciones Espinales , Masculino , Tractos Piramidales , Ratas , Ratas Endogámicas WKY , Proteínas Recombinantes , Recuperación de la Función , Traumatismos de la Médula Espinal/fisiopatología , Vértebras TorácicasRESUMEN
BackgroundSpinal muscular atrophy type 1 (SMA1) is a motor neuron disease associated with progressive muscle weakness, ventilatory failure, and reduced survival.Objective:To report the evaluation of the nusinersen, an antisense oligonucleotide, on the motor function of SMA1.MethodsThis was a longitudinal and observational study to assess the outcomes of nusinersen therapy in SMA1 patients using the HINE-2 and CHOP-INTEND scales.ResultsTwenty-one SMA1 patients (52.4% males) were included; the mean age at first symptoms was 2.7 months (SDâ=±1.5), and the mean disease duration at first dose was 34.1 (SDâ=±36.0) months. During posttreatment, the mean gain on the CHOP-INTEND was 4.9, 5.9, 6.6, and 14 points after 6, 12, 18, and 24 months, respectively. Starting medication with a disease duration of less than 12 months and/or without invasive ventilation were predictors of response on CHOP-INTEND. Of the patients, 28.6% acquired a motor milestone or gained at least three points on the HINE-2. The daily time for ventilatory support was reduced after treatment in most of the patients with noninvasive ventilation at baseline. No change in the daytime use of ventilation was observed in most of the patients using invasive ventilation at baseline.ConclusionsNusinersen produces improvements in motor and respiratory functions, even in long-term SMA1 patients. However, patients under invasive ventilation at the beginning of the treatment experience little benefit.
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Oligonucleótidos/uso terapéutico , Atrofias Musculares Espinales de la Infancia/tratamiento farmacológico , Brasil , Preescolar , Femenino , Humanos , Lactante , Inyecciones Espinales , Estudios Longitudinales , Masculino , Destreza Motora/efectos de los fármacos , Respiración/efectos de los fármacos , Resultado del TratamientoRESUMEN
PKC and PKA phosphorylation inhibit TREK-1 channels downstream of Gs protein-coupled receptor activation in vitro. However, the role of phosphorylation of TREK-1 in neuropathic pain is unknown. The purpose of this study was to investigate whether altered TREK-1 channel function by PKA and PKC modulators contributes to antiallodynia in neuropathic rats. Furthermore, we investigated if the in vitro described sites for PKC and PKA phosphorylation (S300 and S333, respectively) participate in the modulation of TREK-1 in naïve and neuropathic rats. L5/L6 spinal nerve ligation (SNL) induced tactile allodynia. Intrathecal injection of BL-1249 (TREK-1 activator) reversed nerve injury-induced tactile allodynia, whereas spadin (TREK-1 blocker) produced tactile allodynia in naïve rats and reversed the antiallodynic effect induced by BL-1249 in neuropathic rats. Intrathecal administration of rottlerin or Rp-cAMPs (PKC and PKA inhibitors, respectively) enhanced the antiallodynia observed with BL-1249 in neuropathic rats. In contrast, pretreatment with PdBu or forskolin (PKC and PKA activators, respectively) reduced the BL-1249-induced antiallodynia. Intrathecal injection of two high-activity TREK-1 recombinant channels, using a in vivo transfection method with lipofectamine, with mutations at PKC/PKA phosphosites (S300A and S333A) reversed tactile allodynia in neuropathic rats, with no effect in naïve rats. In contrast, transfection of two low-activity TREK-1 recombinant channels with phosphomimetic mutations at those sites (S300D and S333D) produced tactile allodynia in naïve rats and interfered with antiallodynic effects of rottlerin/BL-1249 or Rp-cAMPs/BL-1249. Data suggest that TREK-1 channel activity can be dynamically tuned in vivo by PKC/PKA to provoke allodynia and modulate its antiallodynic role in neuropathic pain.
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Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Neuralgia/metabolismo , Canales de Potasio de Dominio Poro en Tándem/metabolismo , Proteína Quinasa C/metabolismo , Animales , Femenino , Inyecciones Espinales , Ratones , Neuralgia/tratamiento farmacológico , Dimensión del Dolor/métodos , Péptidos/administración & dosificación , Fosforilación/efectos de los fármacos , Fosforilación/fisiología , Canales de Potasio de Dominio Poro en Tándem/agonistas , Canales de Potasio de Dominio Poro en Tándem/antagonistas & inhibidores , Ratas , Ratas Wistar , Tetrahidronaftalenos/administración & dosificación , Tetrazoles/administración & dosificaciónRESUMEN
Extrasynaptic α5 -subunit containing GABAA (α5 -GABAA ) receptors participate in chronic pain. Previously, we reported a sex difference in the action of α5 -GABAA receptors in dysfunctional pain. However, the underlying mechanisms remain unknown. The aim of this study was to examine this sexual dimorphism in neuropathic rodents and the mechanisms involved. Female and male Wistar rats or ICR mice were subjected to nerve injury followed by α5 -GABAA receptor inverse agonist intrathecal administration, L-655,708. The drug produced an antiallodynic effect in nerve-injured female rats and mice, and a lower effect in males. We hypothesized that changes in α5 -GABAA receptor, probably influenced by hormonal and epigenetic status, might underlie this sex difference. Thus, we performed qPCR and western blot. Nerve injury increased α5 -GABAA mRNA and protein in female dorsal root ganglia (DRG) and decreased them in DRG and spinal cord of males. To investigate the hormonal influence over α5 -GABAA receptor actions, we performed nerve injury to ovariectomized rats and reconstituted them with 17ß-estradiol (E2). Ovariectomy abrogated L-655,708 antiallodynic effect and E2 restored it. Ovariectomy decreased α5 -GABAA receptor and estrogen receptor α protein in DRG of neuropathic female rats, while E2 enhanced them. Since DNA methylation might contribute to α5 -GABAA receptor down-regulation in males, we examined CpG island DNA methylation of α5 -GABAA receptor coding gene through pyrosequencing. Nerve injury increased methylation in male, but not female rats. Pharmacological inhibition of DNA methyltransferases increased α5 -GABAA receptor and enabled L-655,708 antinociceptive effect in male rats. These results suggest that α5 -GABAA receptor is a suitable target to treat chronic pain in females.
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Epigénesis Genética/genética , Nocicepción/fisiología , Enfermedades del Sistema Nervioso Periférico/genética , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Receptores de GABA-A/genética , Receptores de GABA-A/fisiología , Animales , Metilación de ADN/genética , Estradiol/farmacología , Femenino , Agonistas del GABA/administración & dosificación , Agonistas del GABA/farmacología , Ganglios Espinales/metabolismo , Imidazoles/farmacología , Inyecciones Espinales , Masculino , Ratones , Ratones Endogámicos ICR , Ovariectomía , Dimensión del Dolor , Ratas , Ratas Wistar , Caracteres SexualesRESUMEN
Intraocular retinoblastoma treatment has changed radically over the last decade, leading to a notable improvement in ocular survival. However, eyes that relapse remain difficult to treat, as few alternative active drugs are available. More challenging is the scenario of central nervous system (CNS) metastasis, in which almost no advancements have been made. Both clinical scenarios represent an urgent need for new drugs. Using an integrated multidisciplinary approach, we developed a decision process for prioritizing drug selection for local (intravitreal [IVi], intrathecal/intraventricular [IT/IVt]), systemic, or intra-arterial chemotherapy (IAC) treatment by means of high-throughput pharmacological screening of primary cells from two patients with intraocular tumor and CNS metastasis and a thorough database search to identify clinical and biopharmaceutical data. This process identified 169 compounds to be cytotoxic; only 8 are FDA-approved, lack serious toxicities and available for IVi administration. Four of these agents could also be delivered by IT/IVt. Twelve FDA-approved drugs were identified for systemic delivery as they are able to cross the blood-brain barrier and lack serious adverse events; four drugs are of oral usage and six compounds that lack vesicant or neurotoxicity could be delivered by IAC. We also identified promising compounds in preliminary phases of drug development including inhibitors of survivin, antiapoptotic Bcl-2 family proteins, methyltransferase, and kinesin proteins. This systematic approach may be applied more broadly to prioritize drugs to be repurposed or to identify novel hits for use in retinoblastoma treatment.
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Descubrimiento de Drogas/organización & administración , Neoplasias de la Retina/tratamiento farmacológico , Retinoblastoma/tratamiento farmacológico , Línea Celular Tumoral , Descubrimiento de Drogas/métodos , Ensayos Analíticos de Alto Rendimiento/métodos , Humanos , Infusiones Intraventriculares , Inyecciones Espinales , Inyecciones Intravítreas , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia , Neoplasias de la Retina/patología , Retinoblastoma/patologíaRESUMEN
We present a series of four patients diagnosed with Spinal Muscular Atrophy (SMA), 2 type II, 2 type III, for placement of spinal nusinersen/Spinraza under general anesthesia with propofol. This new treatment can improve the quality of life of these patients. Its management represents a challenge for anesthesiologists as they try to provide not only adequate general anesthesia but containment to adolescent or young patients. In particular, patients that need to enter into the operating room several times a year.
Presentamos una serie de 4 pacientes con diagnóstico de atrofia muscular espinal (AME) 2 tipo II y 2 tipo III, para colocación de nusinersen/Spinraza raquídeo bajo anestesia general con propofol. Este nuevo tratamiento puede mejorar la calidad de vida de los pacientes. Su manejo representa un desafío para los anestesiólogos que intentamos brindar no solo una adecuada anestesia general sino contención a pacientes adolescentes o jóvenes que necesitan ingresar al quirófano varias veces al año.
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Humanos , Masculino , Adolescente , Adulto , Oligonucleótidos/administración & dosificación , Atrofia Muscular Espinal/tratamiento farmacológico , Anestesia General , Inyecciones EspinalesRESUMEN
Angiogenesis is considered to mediate the beneficial effects of mesenchymal cell therapy in spinal cord injury. After a moderate balloon-compression injury in rats, injections of either human adipose tissue-derived stromal/stem cells (hADSCs) or their conditioned culture media (CM-hADSC) elicited angiogenesis around the lesion site. Both therapies increased vascular density, but the presence of hADSCs in the tissue was required for the full maturation of new blood vessels. Only animals that received hADSC significantly improved their open field locomotion, assessed by the BBB score. Animals that received CM-hADSC only, presented haemorrhagic areas and lack pericytes. Proteomic analyses of human angiogenesis-related factors produced by hADSCs showed that both pro- and anti-angiogenic factors were produced by hADSCs in vitro, but only those related to vessel maturation were detectable in vivo. hADSCs produced PDGF-AA only after insertion into the injured spinal cord. hADSCs attracted resident pericytes expressing NG2, α-SMA, PDGF-Rß and nestin to the lesion, potentially contributing to blood vessel maturation. We conclude that the presence of hADSCs in the injured spinal cord is essential for tissue repair.
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Medios de Cultivo Condicionados/farmacología , Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/citología , Pericitos/citología , Traumatismos de la Médula Espinal/terapia , Animales , Vasos Sanguíneos/efectos de los fármacos , Vasos Sanguíneos/fisiología , Barrera Hematoencefálica , Movimiento Celular , Medios de Cultivo Condicionados/química , Endotelio Vascular/citología , Femenino , Hemorragia/sangre , Hemorragia/terapia , Humanos , Inyecciones Espinales , Neovascularización Fisiológica/genética , Nestina/metabolismo , Ratas Sprague-Dawley , Traumatismos de la Médula Espinal/patologíaRESUMEN
Neurotoxicity from intrathecally administered chemotherapeutic drugs is frequent, particularly with some agents like methotrexate, which are more prone to developing adverse effects. Myelopathy ranks among the most frequently reported neurological entities; with the diagnosis being straightforward, after ruling out infectious, metabolic, autoimmune or paraneoplastic causes. Scarcity of cases precludes evidence-based recommendations for the management of these complications. The most common therapeutic approach consists of the suspension of chemotherapy, exclusion of infectious and neoplastic causes, with prompt administration of high-dose steroids. We report a 21-year-old patient with acute lymphoblastic leukaemia, who developed acute transverse myelitis and bilateral sensorineural hearing loss, after five rounds of intrathecal methotrexate and cytarabine. Although neurotoxicity from both agents has been documented, this combination has not been previously reported.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Pérdida Auditiva Bilateral/inducido químicamente , Pérdida Auditiva Sensorineural/inducido químicamente , Mielitis Transversa/inducido químicamente , Neuromielitis Óptica/inducido químicamente , Diagnóstico Diferencial , Humanos , Inyecciones Espinales , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Adulto JovenRESUMEN
Malignant brain tumors are among the most aggressive cancers with poor prognosis and no effective treatment. Recently, we reported the oncolytic potential of Zika virus infecting and destroying the human central nervous system (CNS) tumors in vitro and in immunodeficient mice model. However, translating this approach to humans requires pre-clinical trials in another immunocompetent animal model. Here, we analyzed the safety of Brazilian Zika virus (ZIKVBR) intrathecal injections in three dogs bearing spontaneous CNS tumors aiming an anti-tumoral therapy. We further assessed some aspects of the innate immune and inflammatory response that triggers the anti-tumoral response observed during the ZIKVBR administration in vivo and in vitro. For the first time, we showed that there were no negative clinical side effects following ZIKVBR CNS injections in dogs, confirming the safety of the procedure. Furthermore, the intrathecal ZIKVBR injections reduced tumor size in immunocompetent dogs bearing spontaneous intracranial tumors, improved their neurological clinical symptoms significantly, and extended their survival by inducing the destruction specifically of tumor cells, sparing normal neurons, and activating an immune response. These results open new perspectives for upcoming virotherapy using ZIKV to destroy and induce an anti-tumoral immune response in CNS tumors for which there are currently no effective treatments.
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Neoplasias Encefálicas/complicaciones , Neoplasias Encefálicas/terapia , Viroterapia Oncolítica/métodos , Seguridad del Paciente , Carga Tumoral , Infección por el Virus Zika/complicaciones , Virus Zika/inmunología , Animales , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Técnicas de Cocultivo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Perros , Inmunidad , Inyecciones Espinales , Masculino , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/virología , Monocitos/inmunología , Monocitos/virología , Neuronas/metabolismo , Neuronas/virología , Resultado del TratamientoRESUMEN
Low doses of histamine or H1R agonist 2-pyridylethylamine (2-PEA) into the knee-joint were found to decrease formalin-induced articular nociception in rats. In this study, we evaluated the participation of spinal NPY in the antinociceptive effect produced by 2-PEA. Injection of formalin (1.5%) into one of the knee-joints causes the limping of the respective limb due to nociception, which was registered each 5 min over 60 min. Neuropeptide Y1 receptor (Y1R) content in the spinal cord was evaluated by western-blotting. Intrathecal (i.t.) injection of Y1R agonist Leu31, Pro34-NPY (0.7-7 µmol) decreased nociception, while injection of the antagonist BIBO 3304 (4 µmol), increased nociception. Antinociception produced by 2-PEA was reversed by a sub-effective i.t. dose of the Y1R antagonist. Similarly, this antinociceptive effect was prevented by i.t. pretreatment with the neurotoxin NPY-saporin (750 ng), which also reduced immunoblotting for Y1R in spinal cord homogenates. These data support the idea that antinociception induced by H1R agonists in the knee-joint of rats may be mediated by the spinal release of NPY, and this peptide seems to be acting via Y1R.