RESUMEN
BACKGROUND: Treatment with levodopa-carbidopa intestinal gel (LCIG) can effectively relieve motor and non-motor symptoms in advanced Parkinson's disease (PD). However, adverse events (AEs) are frequent. OBJECTIVE: To describe AEs associated with LCIG treatment and the main reasons for treatment discontinuation. We also looked for factors that were potentially predictive of serious AEs and assessed the effectiveness of and satisfaction with LCIG. METHOD: We retrospectively analyzed data on AEs in patients treated with LCIG at a French university medical center. For patients still receiving treatment at last follow-up, effectiveness was assessed according to the Clinical Global Impression (CGI) scale and the Movement Disorders Society - Unified Parkinson's Disease Rating Scale motor score. RESULTS: Of the 63 patients treated with LCIG for a mean (range) of 19 months (8-47), 57 (90%) experienced at least one AE (340 AEs in total). Most of the AEs (in 69.8% of the patients) were related to percutaneous endoscopic gastrostomy with a jejunal tube (PEG-J) or affected the gastrointestinal tract (granuloma, leakage, or a local infection). Device-related AEs (such as PEG-J removal and device occlusion) were frequent (in 63.5% of patients). Forty-three patients (68%) required at least one additional endoscopic procedure. Dopatherapy-related AEs occurred in 30 patients (48%). Most of the AEs occurred long after treatment initiations, and only a small proportion led to discontinuation. On the CGI scale, 53 patients (84.4%) considered that their condition had improved during LCIG treatment. CONCLUSION: Despite the high frequency of AEs, patients with advanced PD gain clinical benefit from treatment with LCIG. This treatment requires a competent, multidisciplinary team on site.
Asunto(s)
Carbidopa/administración & dosificación , Carbidopa/efectos adversos , Levodopa/administración & dosificación , Levodopa/efectos adversos , Enfermedad de Parkinson/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antiparkinsonianos/administración & dosificación , Antiparkinsonianos/efectos adversos , Antiparkinsonianos/farmacocinética , Carbidopa/farmacocinética , Catéteres de Permanencia/efectos adversos , Combinación de Medicamentos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Endoscopía Gastrointestinal/efectos adversos , Endoscopía Gastrointestinal/instrumentación , Femenino , Francia/epidemiología , Gastrostomía/efectos adversos , Geles , Humanos , Bombas de Infusión/efectos adversos , Absorción Intestinal , Levodopa/farmacocinética , Masculino , Pruebas de Estado Mental y Demencia , Persona de Mediana Edad , Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
In prostate carcinogenesis, expression and/or activation of the Transient Receptor Potential Melastatin 8 channel (TRPM8) was shown to block in vitro Prostate Cancer (PCa) cell migration. Because of their localization at the plasma membrane, ion channels, such as TRPM8 and other membrane receptors, are promising pharmacological targets. The aim of this study was thus to use nanocarriers encapsulating a TRPM8 agonist to efficiently activate the channel and therefore arrest PCa cell migration. To achieve this goal, the most efficient TRPM8 agonist, WS12, was encapsulated into Lipid NanoCapsules (LNC). The effect of the nanocarriers on channel activity and cellular physiological processes, such as cell viability and migration, were evaluated in vitro and in vivo. These results provide a proof-of-concept support for using TRPM8 channel-targeting nanotechnologies based on LNC to develop more effective methods inhibiting PCa cell migration in zebrafish xenograft.
Asunto(s)
Anilidas/farmacología , Inhibición de Migración Celular/efectos de los fármacos , Mentol/análogos & derivados , Neoplasias de la Próstata/tratamiento farmacológico , Canales Catiónicos TRPM/agonistas , Anilidas/administración & dosificación , Humanos , Lípidos/química , Masculino , Mentol/administración & dosificación , Mentol/farmacología , Nanocápsulas/química , Células PC-3 , Neoplasias de la Próstata/metabolismo , Canales Catiónicos TRPM/metabolismoRESUMEN
For patients with amyotrophic lateral sclerosis (ALS), the primary therapeutic goal is to minimize morbidity. Non-invasive ventilation improves survival. We aim to assess whether Magnetic Resonance Imaging (MRI) of the cervical spinal cord predicts the progression of respiratory disorders in ALS. Brain and spinal MRI was repeatedly performed in the SOD1G86R mouse model, in 40 patients and in healthy controls. Atrophy, iron overload, white matter diffusivity and neuronal loss were assessed. In Superoxide Dismutase-1 (SOD1) mice, iron accumulation appeared in the cervical spinal cord at symptom onset but disappeared with disease progression (after the onset of atrophy). In ALS patients, the volumes of the motor cortex and the medulla oblongata were already abnormally low at the time of diagnosis. Baseline diffusivity in the internal capsule was predictive of functional handicap. The decrease in cervical spinal cord volume from diagnosis to 3 months was predictive of the change in slow vital capacity at 12 months. MRI revealed marked abnormalities at the time of ALS diagnosis. Early atrophy of the cervical spinal cord may predict the progression of respiratory disorders, and so may be of value in patient care and as a primary endpoint in pilot neuroprotection studies.
Asunto(s)
Esclerosis Amiotrófica Lateral/patología , Médula Cervical/patología , Enfermedades Respiratorias/patología , Médula Espinal/patología , Esclerosis Amiotrófica Lateral/metabolismo , Animales , Médula Cervical/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Humanos , Imagen por Resonancia Magnética/métodos , Bulbo Raquídeo/metabolismo , Bulbo Raquídeo/patología , Ratones , Corteza Motora/metabolismo , Corteza Motora/patología , Neuronas Motoras/metabolismo , Neuronas Motoras/patología , Enfermedades Respiratorias/metabolismo , Médula Espinal/metabolismo , Superóxido Dismutasa-1/metabolismo , Sustancia Blanca/metabolismo , Sustancia Blanca/patologíaRESUMEN
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal, rapidly progressive neurodegenerative disease that mainly affects the motor system. A number of potentially neuroprotective and neurorestorative disease-modifying drugs are currently in clinical development. At present, the evaluation of a drug's clinical efficacy in ALS is based on the ALS Functional Rating Scale Revised, motor tests and survival. However, these endpoints are general, variable and late-stage measures of the ALS disease process and thus require the long-term assessment of large cohorts. Hence, there is a need for more sensitive radiological biomarkers. Various sequences for magnetic resonance imaging (MRI) of the brain and spinal cord have may have value as surrogate biomarkers for use in future clinical trials. Here, we review the MRI findings in ALS, their clinical correlations, and their limitations and potential role as biomarkers. METHODS: The PubMed database was screened to identify studies using MRI in ALS. We included general MRI studies with a control group and an ALS group and longitudinal studies even if a control group was lacking. RESULTS: A total of 116 studies were analysed with MRI data and clinical correlations. The most disease-sensitive MRI patterns are in motor regions but the brain is more broadly affected. CONCLUSION: Despite the existing MRI biomarkers, there is a need for large cohorts with long term MRI and clinical follow-up. MRI assessment could be improved by standardized MRI protocols with multicentre studies.