RESUMO
Alterations of the microbiota-gut-brain axis has been associated with intestinal and neuronal inflammation in Parkinson's disease (PD). The aim of this work was to study some mechanisms associated with the neuroprotective effect of a combination (MIX) of lactic acid bacteria (LAB) composed by Lactiplantibacillus plantarum CRL2130 (riboflavin overproducing strain), Streptococcus thermophilus CRL808 (folate producer strain), and CRL807 (immunomodulatory strain) in cell cultures and in a chronic model of parkinsonism induced with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in aged mice, and under levodopa-benserazide treatment. In vitro, N2a differentiated neurons were exposed to the neurotoxin 1-methyl-4-phenylpyridinium (MPP+) and treated with intracellular bacterial extracts or with conditioned media from BV-2 cells exposed to the bacterial extracts. In vivo, motor skills, tyrosine hydrolase (TH) in brain and cytokine concentrations in serum and in brain were evaluated. The study of the faecal microbiota and the histology of the small intestine was also performed. The results showed that the neuroprotective effect associated with LAB MIX administration did not interfere with levodopa-benserazide treatment. This effect could be associated with the antioxidant and immunomodulatory potential of the LAB selected in the MIX, and was associated with the significant improvement in the motor tests and a higher number of TH + cells in the brain. In addition, LAB MIX administration was associated with modulation of the immune response. LAB administration decreased intestinal damage with an increase in the villus length /crypt depth ratio. Finally, the administration of the LAB MIX in combination with levodopa-benserazide treatment was able to partially revert the intestinal dysbiosis observed in the model, showing greater similarity to the profiles of healthy controls, and highlighting the increase in the Lactobacillaceae family. Different mechanisms of action would be related to the protective effect of the selected LAB combination which has the potential to be evaluated as an adjuvant for conventional PD therapies.
Assuntos
Benserazida , Levodopa , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores , Transtornos Parkinsonianos , Animais , Levodopa/farmacologia , Benserazida/farmacologia , Benserazida/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Fármacos Neuroprotetores/farmacologia , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/metabolismo , Masculino , Camundongos , Combinação de Medicamentos , Microbioma Gastrointestinal/efeitos dos fármacos , Modelos Animais de Doenças , Lactobacillales , Probióticos/uso terapêutico , Antiparkinsonianos/farmacologia , Antiparkinsonianos/uso terapêutico , Streptococcus thermophilus/efeitos dos fármacosRESUMO
Monotherapy is the recommended initial treatment for early Parkinson's disease. The pharmacological options for initial treatment include dopaminergic agonists, monoamine oxidase B inhibitors, and levodopa formulations. Several factors should be considered when selecting the optimal treatment, such as disease severity, disease duration, age, activity level, and the risk of developing motor and non-motor complications. Early evidence on the potential role of levodopa formulations in the risk of dyskinesia led to levodopa aversion in the late 1990s and early 2000s, favoring the use of levodopa-sparing options like dopamine agonists. This shift resulted in an increase in behavioral adverse effects, such as impulse control disorders, leading to a subsequent dopamine agonist aversion in the mid-2000s. This review aims to provide a comprehensive evaluation of the existing literature regarding the benefits and drawbacks of levodopa versus levodopa-sparing strategies in drug-naive early-stage Parkinson's disease.
Assuntos
Antiparkinsonianos , Agonistas de Dopamina , Levodopa , Doença de Parkinson , Humanos , Levodopa/administração & dosagem , Levodopa/uso terapêutico , Levodopa/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Antiparkinsonianos/uso terapêutico , Antiparkinsonianos/farmacologia , Antiparkinsonianos/administração & dosagem , Agonistas de Dopamina/uso terapêutico , Agonistas de Dopamina/administração & dosagem , Índice de Gravidade de DoençaRESUMO
Parkinson's disease (PD) is a gradually worsening neurodegenerative disorder affecting the nervous system, marked by a slow progression and varied symptoms. It is the second most common neurodegenerative disease, affecting over six million people in the world. Its multifactorial etiology includes environmental, genomic, and epigenetic factors. Clinical symptoms consist of non-motor and motor symptoms, with motor symptoms being the classic presentation. Therapeutic approaches encompass pharmacological, non-pharmacological, and surgical interventions. Traditional pharmacological treatment consists of administering drugs (MAOIs, DA, and levodopa), while emerging evidence explores the potential of antidiabetic agents for neuroprotection and gene therapy for attenuating parkinsonian symptoms. Non-pharmacological treatments, such as exercise, a calcium-rich diet, and adequate vitamin D supplementation, aim to slow disease progression and prevent complications. For those patients who have medically induced side effects and/or refractory symptoms, surgery is a therapeutic option. Deep brain stimulation is the primary surgical option, associated with motor symptom improvement. Levodopa/carbidopa intestinal gel infusion through percutaneous endoscopic gastrojejunostomy and a portable infusion pump succeeded in reducing "off" time, where non-motor and motor symptoms occur, and increasing "on" time. This article aims to address the general aspects of PD and to provide a comparative comprehensive review of the conventional and the latest therapeutic advancements and emerging treatments for PD. Nevertheless, further studies are required to optimize treatment and provide suitable alternatives.
Assuntos
Doença de Parkinson , Humanos , Doença de Parkinson/terapia , Levodopa/uso terapêutico , Estimulação Encefálica Profunda/métodos , Antiparkinsonianos/uso terapêutico , Terapia Genética/métodos , AnimaisRESUMO
INTRODUCTION: Parkinson's disease (PD) causes gait abnormalities that may be associated with an arm swing reduction. Medication and freezing of gait (FoG) may influence gait characteristics. However, these comparisons do not consider differences in gait speed and clinical characteristics in individuals with PD. OBJECTIVE: This study aims to analyze the effect of FoG and medication on the biomechanics of the trunk and upper limbs during gait in PD, controlling for gait speed and clinical differences between groups. METHODS: Twenty-two people with a clinical diagnosis of idiopathic PD in ON and OFF medication (11 FoG), and 35 healthy participants (control) were selected from two open data sets. All participants walked on the floor on a 10-m-long walkway. The joint and linear kinematic variables of gait were compared: (1) Freezers and nonfreezers in the ON condition and control; (2) Freezers and nonfreezers in the OFF condition and control; (3) Group (freezers and nonfreezers) and medication. RESULTS: The disease affects the upper limbs more strongly but not the trunk. The medication does not significantly influence the joint characteristics but rather the linear wrist displacement. The FoG does not affect trunk movement and partially influences the upper limbs. The interaction between medications and FoG suggests that the medication causes more substantial improvement in freezers than in nonfreezers. CONCLUSION: The study shows differences in the biomechanics of the upper limbs of people with PD, FoG, and the absence of medication. The future rehabilitation protocol should consider this aspect.
Assuntos
Transtornos Neurológicos da Marcha , Marcha , Doença de Parkinson , Tronco , Extremidade Superior , Humanos , Doença de Parkinson/fisiopatologia , Doença de Parkinson/tratamento farmacológico , Fenômenos Biomecânicos , Masculino , Feminino , Idoso , Extremidade Superior/fisiopatologia , Pessoa de Meia-Idade , Tronco/fisiopatologia , Transtornos Neurológicos da Marcha/fisiopatologia , Transtornos Neurológicos da Marcha/tratamento farmacológico , Marcha/fisiologia , Dopaminérgicos , Antiparkinsonianos/uso terapêuticoRESUMO
One of the biggest problems in the treatment of idiopathic Parkinson's disease is the lack of new drugs that slow its progression. L-Dopa remains the star drug in the treatment of this disease, although it induces severe side effects. The failure of clinical studies with new drugs depends on the use of preclinical models based on neurotoxins that do not represent what happens in the disease since they induce rapid and expansive neurodegeneration. We have recently proposed a single-neuron degeneration model for idiopathic Parkinson's disease that requires years to accumulate enough lost neurons for the onset of motor symptoms. This single-neuron degeneration model is based on the excessive formation of aminochrome during neuromelanin synthesis that surpass the neuroprotective action of the enzymes DT-diaphorase and glutathione transferase M2-2, which prevent the neurotoxic effects of aminochrome. Although the neurotoxic effects of aminochrome do not have an expansive effect, a stereotaxic injection of this endogenous neurotoxin cannot be used to generate a preclinical model in an animal. Therefore, the aim of this review is to evaluate the strategies for pharmacologically increasing the expression of DT diaphorase and GSTM2-2 and molecules that induce the expression of vesicular monoamine transporter 2, such as pramipexole.
Assuntos
Doença de Parkinson , Humanos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Animais , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Degeneração Neural/tratamento farmacológico , Degeneração Neural/patologia , Glutationa Transferase/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Modelos Animais de Doenças , Antiparkinsonianos/farmacologia , Antiparkinsonianos/uso terapêuticoRESUMO
Venom-derived peptides are important sources for the development of new therapeutic molecules, especially due to their broad pharmacological activity. Previously, our research group identified a novel natural peptide, named fraternine, with promising effects for the treatment of Parkinson's disease. In the present paper, we synthesized three peptides bioinspired in fraternine: fra-10, fra-14, and fra-24. They were tested in the 6-OHDA-induced model of parkinsonism, quantifying motor coordination, levels of TH+ neurons in the substantia nigra pars compacta (SN), and inflammation mediators TNF-α, IL-6, and IL-1ß in the cortex. Peptides fra-14 and fra-10 improved the motor coordination in relation to 6-OHDA lesioned animals. However, most of the peptides were toxic in the doses applied. All three peptides reduced the intensity of the lesion induced rotations in the apomorphine test. Fra-24 higher dose increased the number of TH+ neurons in SN and reduced the concentration of TNF-α in the cortex of 6-OHDA lesioned mice. Overall, only the peptide fra-24 presented a neuroprotection effect on dopaminergic neurons of SN and a reduction of cytokine TNF-α levels, making it worthy of consideration for the treatment of PD.
Assuntos
Doença de Parkinson , Camundongos , Animais , Doença de Parkinson/tratamento farmacológico , Oxidopamina , Fator de Necrose Tumoral alfa , Substância Negra , Antiparkinsonianos/farmacologia , Antiparkinsonianos/uso terapêutico , Neurônios Dopaminérgicos , Modelos Animais de DoençasRESUMO
INTRODUCTION: The aim was to determine the time elapsed between the start of treatment with antiparkinsonian agents and the modification of the pharmacological therapy, and to establish its related factors, in a group of patients with Parkinson's disease from Colombia. PATIENTS AND METHODS: Retrospective cohort study that collected information about the treatment of patients with Parkinson's disease who started drug therapy between June, 2011 and December, 2013; a five-year follow-up was performed. Survival analyses for time to therapy modification were generated, and factors related to these changes were determined using Cox regression models. RESULTS: A total of 3,224 patients (51.8% men) with a mean age of 73.1 ± 13.5 years started treatment with antiparkinsonian agents. After five years, 2,046 patients (63.5%) had modifications in drug therapy, in a mean time of 36.4 months (95% confidence interval: 35.7-37.1). A total of 1,216 patients (37.8%) required the addition of another active principle, while 830 (25.7%) had a switch to another drug. In the multivariate analysis, male sex, age over 65 years, and the start of amantadine were identified as factors that increased the likelihood of therapy modification. The use of bromocriptine, biperiden, and monotherapy as an initial treatment were associated with a reduction in this likelihood. CONCLUSIONS: After five years of treatment, 63.5% of the patients with Parkinson's disease required modifications to their therapy, with a mean time of three years. Male sex, age over 65 years, and receiving initial therapy with amantadine affected the likelihood of switching therapy in these patients in Colombia.
TITLE: Tiempo hasta la modificación de la terapia antiparkinsoniana en un grupo de pacientes de Colombia.Introducción. Se buscó determinar el tiempo transcurrido desde el inicio del tratamiento con fármacos antiparkinsonianos hasta la modificación en la terapia y establecer sus factores relacionados en un grupo de pacientes con enfermedad de Parkinson de Colombia. Pacientes y métodos. Estudio de cohorte retrospectiva que recolectó información sobre el tratamiento de pacientes con enfermedad de Parkinson que iniciaron terapia farmacológica entre junio de 2011 y diciembre de 2013; se realizó seguimiento a cinco años. Se generaron análisis de sobrevida para el tiempo trascurrido hasta la modificación de la terapia y se determinaron los factores relacionados con estos cambios utilizando modelos de regresión de Cox. Resultados. Un total de 3.224 pacientes (51,8%, hombres), con edad media de 73,1 ± 13,5 años, iniciaron tratamiento con fármacos antiparkinsonianos. Después de cinco años, 2.046 pacientes (63,5%) tuvieron modificaciones en la terapia farmacológica, con un promedio de tiempo de 36,4 meses (intervalo de confianza al 95%: 35,7-37,1). Un total de 1.216 pacientes (37,8%) requirió adición de otro principio activo, mientras que 830 (25,7%) tuvieron un cambio por otro medicamento. En el análisis multivariado, el sexo masculino, la edad mayor de 65 años y el inicio de amantadina se identificaron como factores que aumentaron la probabilidad de modificar la terapia. El uso de bromocriptina y biperideno, y la monoterapia como tratamiento inicial redujeron dicho riesgo. Conclusión. Después de cinco años de tratamiento, el 63,5% de los pacientes con enfermedad de Parkinson requirió modificaciones de la terapia, con un tiempo promedio de tres años. El sexo masculino, la edad mayor de 65 años y recibir terapia inicial con amantadina afectaron a la probabilidad de cambio de terapia en estos pacientes en Colombia.
Assuntos
Doença de Parkinson , Humanos , Masculino , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Feminino , Doença de Parkinson/tratamento farmacológico , Estudos Retrospectivos , Colômbia , Antiparkinsonianos/uso terapêutico , Amantadina/uso terapêutico , Levodopa/uso terapêuticoRESUMO
Rotigotina e outros medicamentos antiparkinsonianos, com ênfase em agonistas dopaminérgicos (bromocriptina e pramipexol). Indicação: Tratamento da doença de Parkinson. Pergunta: Há superioridade de eficácia e segurança da rotigotina, comparado aos agonistas dopaminérgicos disponíveis atualmente no SUS para o tratamento da doença de Parkinson? Revisão rápida de evidências (overview) de revisões sistemáticas, com levantamento bibliográfico realizado na base de dados PubMed e utilizando estratégia estruturada de busca. A qualidade metodológica das revisões sistemáticas foi avaliada com AMSTAR-2 (Assessing the Methodological Quality of Systematic Reviews Version 2). Foram selecionadas três revisões sistemáticas que atendiam aos critérios de inclusão. A rotigotina não apresenta eficácia e segurança superiores ao pramipexol; não há quantidade de estudos suficientes para comparação com a bromocriptina
Rotigotine and other antiparkinsonians medicines, with emphasis on dopaminergic agonists (bromocriptine and pramipexole). Indication: Treatment of Parkinson disease. Question: Is rotigotine more effective and safer than other dopamine agonists available in the Brazilian Public Health System for the treatment of Parkinson's Disease? Rapid evidence review (overview) from systematic reviews, with a literature search in the PubMed database by employing a structured strategy. The methodological quality of systematic reviews was evaluated using AMSTAR-2 (Assessing the Methodological Quality of Systematic Reviews Version 2). Three systematic reviews that met the inclusion criteria were selected. Rotigotine has not shown superior efficacy and safety when compared to pramipexole; there are insufficient studies for comparison with bromocriptine
Assuntos
Doença de Parkinson/tratamento farmacológico , Bromocriptina/uso terapêutico , Agonistas de Dopamina , Pramipexol/uso terapêutico , Antiparkinsonianos/uso terapêuticoRESUMO
Background: Canine distemper (CD) is a highly contagious viral disease caused by the canine distemper virus (CDV). In dogs, CDV infection is characterized by the presentation of systemic and/or neurological signs with viral persistence in some organs, including the central nervous system (CNS). Neurological damages resulting from CD are a defiance for veterinarians, due to occasioned clinical sequels that influence the patient quality of life. The treatment of sequelae should seek to promote the resolution or decrease of the deleterious effects that impede the patient independence. Thus, the present report aims to describe the action of antiparkinsonian medication (levodopa associated with carbidopa) administered to 3 dogs who presented neurological sequels resulting from the canine distemper. Cases: Dog 1. A 9-month-old male mixed breed; Dog 2. A 6-month-old male Shih Tzu. Dog 3. A 8-years-old bitch mixed breed. All animals were referred for neurological care because presented neurological damages after distemper involvement. Only the Dog 2 was vaccinated to CD. Dog 1 (mixed male) had severe myoclonus, lack of proprioception, decreased of muscle tonus and paralysis in both pelvic limbs, associated with a marked thoracolumbar kyphosis. Dog 2 (a puppy Shih Tzu male) presented myoclonus in PL, proprioceptive loss in thoracic and pelvic limbs, absence of withdrawal reflex in thoracic and pelvic limbs, decrease in muscle tonus in pelvic limb and increase in thoracic limb. Dog 3 (adult unneutered bitch) presented intense myoclonus, absence of proprioception, decrease in muscle tonus and paresis of pelvic limb. All patients were treated with antiparkinsonian medication (levodopa 250 mg associated with carbidopa 25 mg) with following dosages: Dog 1 received a commercially available tablet, orally once a day for 30 days, while Dogs 2 and 3 had doses calculated by extrapolation allometric. For the Dog 2 it was prescribed 0.25 mg of levodopa and 0.025 mg of carbidopa daily for 30 days. Dog 3 was treated with 1 mg of levodopa and 0.1 mg of carbidopa patient day for the same period. Thirty days after starting the treatment, the 3 patients were evaluated again, and showed improvement of the motor signs, and the treatment was maintained. At the next return (30 days): Dog 1 showed significant improvement, however, Dog 2 started to present epileptic seizures and nystagmus that were treated with levetiracetam, while the Dog 3 not returned. As Dog 1 had a better prognosis, treatment was maintained for 1 year, with the frequency being changed from 24 h x 24 h to 48 h x 48 h after 30 days and 72x72 h after another 30 days. Unfortunately, Dog 2 had a worsening of epileptic condition and died, while Dog 3 died by road-kill. Discussion: The cases reported are uncommon, because not exist information about the use of antiparksonian to treatment of neurological damages occasioned by canine distemper. Although there are emerging therapies, such as the use of mesenchymal stem cells, that can reduce these sequels, the access is still restricted to a few professionals. Thus, the use of medications for demyelinating diseases, as antiparkinsonian, may be an alternative. In fact, the three reported patients showed recovery of the motor and sensorial damages observed, which corroborates with the possibility of a new treatment using antiparkinsonian or other drugs to demyelinating diseases.
Assuntos
Animais , Cães , Carbidopa/administração & dosagem , Levodopa/administração & dosagem , Transtornos Parkinsonianos/veterinária , Cinomose/terapia , Antiparkinsonianos/uso terapêuticoRESUMO
BACKGROUND: Parkinson's disease (PD) causes a series of movement disorders, many of them starting in the early stage. OBJECTIVE: To analyze the pulmonary function of mild-stage subjects with PD and to investigate the effects of levodopa on it. METHODS: We included 21 patients with idiopathic PD and 20 healthy control subjects. The participants were submitted to spirometry and impulse oscillometry assessments. The PD patients were evaluated during the "off" and "on" phases of their anti-PD medication, which was was converted to levodopa in an equivalent daily dose. A statistical analysis was performed with cross-sectional (PD patients "off" medication versus controls) and paired (PD patients "off" medication versus PD patients "on" medication) tests. The effect of levodopa was calculated with partial Eta-squared (η2 ρ). Significance was set at 5%. RESULTS: The PD patients presented normal values in the impulse oscillometry. Regarding spirometry, the results indicated an incipient obstructive ventilatory disorder in the PD group - confirmed by patients' flow-volume curves. The PD patients received a daily dose of 354.7 ± 148.2 mg of levodopa. The paired analyses showed a small effect of anti-PD medication on pulmonary parameters (η2 ρ = 0.197 for spirometry and η2 ρ= 0.043 for impulse oscillometry). CONCLUSION: Patients with PD in the mild stage of the disease present pulmonary compliance and resistance compatible with normal parameters. The differences regarding the spirometric results indicate an incipient obstructive ventilatory disorder in patients with PD. Levodopa had small effect on pulmonary function in the mild stage of the disease.
ANTECEDENTES: A doença de Parkinson (DP) causa uma série de distúrbios do movimento, muitos deles se desenvolvendo na fase inicial. OBJETIVO: Analisar função pulmonar de pessoas com DP em estágio leve e investigar o efeito da levodopa nesse processo. MéTODOS: Vinte e um participantes com DP idiopática e vinte controles saudáveis foram incluídos na pesquisa. Todos os sujeitos foram submetidos a avaliações de espirometria e oscilometria de impulso. Participantes com DP foram avaliados nas fases 'on' e 'off' de medicação anti-parkinsoniana. A medicação dos pacientes foi convertida em dose diária de levodopa. A análise estatística foi realizada com testes transversais (Parkinson na fase 'off' da medicação vs controles) e pareados (Parkinson nas fases 'off' vs 'on' da medicação). O efeito da levodopa foi calculado pelo eta ao quadrado parcial (η2 ρ). Significância foi estipulada em 5%. RESULTADOS: Pacientes com DP apresentaram valores normais na oscilometria de impulso. Na espirometria, os resultados indicaram uma desordem ventilatória obstrutiva incipiente no grupo DP confirmada pelas curvas fluxo-volume dos pacientes. Pacientes com DP receberam uma dose diária de 354,7 ± 148,2 miligramas de levodopa. Análises pareadas mostraram baixo impacto da medicação anti-parkinsoniana nos parâmetros pulmonares (η2 ρ = 0,197 na espirometria e η2 ρ = 0,043 na oscilometria de impulso). CONCLUSãO: Pacientes com DP na fase leve apresentam complacência e resistência pulmonares compatíveis com parâmetros normais. Diferenças espirométricas indicam distúrbio ventilatório obstrutivo incipiente em pacientes com DP. A administração de levodopa apresentou baixo efeito na função pulmonar na fase leve da doença.