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1.
Handb Clin Neurol ; 184: 167-184, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35034732

RESUMO

l-Dopa-induced dyskinesias (LIDs) are a frequent complication in l-dopa-treated patients affected by Parkinson's disease (PD). In the last years, several progresses in the knowledge of LIDs mechanisms have led to the identification of several molecular and electrophysiologic events. A complex cascade of intracellular events underlies the pathophysiology of LIDs, and, among these, aberrant plasticity in the cortico-basal ganglia system, at striatal and cortical level, plays a key role. Furthermore, several recent studies have investigated genetic susceptibility and epigenetic modifications in LIDs pathophysiology that might have future relevance in clinical practice and pharmacologic research. These progresses might lead to the development of specific strategies not only to treat, but also to prevent or delay the development of LIDs in PD.


Assuntos
Discinesias , Doença de Parkinson , Antiparkinsonianos/efeitos adversos , Corpo Estriado , Epigênese Genética , Humanos , Levodopa/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/genética
2.
BMC Neurol ; 22(1): 25, 2022 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-35026993

RESUMO

BACKGROUND: Reducing percutaneous endoscopic gastrostomies with jejunal extension tubes (PEG-J) related complications is vital to the long-term preservation of duodenal levodopa infusion (DLI) in advanced Parkinson's disease (APD). Here, we provide data on the frequency of complications for both the standard "pull" and the non-endoscopic, radiologic assisted, "push" replacement PEG-J techniques in APD. METHODS: We retrospectively identified all patients treated with DLI from October 2009 to January 2020 at the Movement Disorders Center. Patients features and demographics, PEG-J procedures, causes for any discontinuation, reported complications and mortality were collected. In this cohort, PEG-J replacements were performed using the standard "pull" procedure or the radiologic assisted "push" method. Descriptive statistical analysis, t-test and paired t-test with False Discovery Rate correction was performed. RESULTS: This retrospective study included 30 APD patients [median age 72 ± 5.6 years; mean disease duration 17.2 + 5.7 years]. Mean treatment duration was 35.6 (30.6) months. Overall, 156 PEG-J procedures were performed, and Nineteen patients (63.3%) had a total of 185 reported complications, 85 of which were peristomal complications. 17 (56.6%) underwent 100 replacement procedures due to complications. The most commonly reported complication for replacement was J-tube dislocation (36%). One patient discontinued treatment after 6 months, due to peripheral neuropathy. Six patients died for causes not related to DLI. PEG-J replacements performed with the "push" method had a higher turnover (5.6 vs. 7.6 mo.), but fewer reported complications (67 vs. 75%). CONCLUSION: The overall rate of complications was lower for "push" technique. This result might have been due to a higher replacement turnover that acted as a protective factor.


Assuntos
Levodopa , Doença de Parkinson , Idoso , Gastrostomia , Humanos , Levodopa/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Estudos Retrospectivos
3.
Clin Neuropharmacol ; 44(6): 201-204, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34654015

RESUMO

OBJECTIVES: The aim of this study was to report a case of levodopa-induced ocular dyskinesia in an early-onset Parkinson disease patient and to investigate the pathogenic gene. METHODS: We report the case of a 49-year-old male patient with a 13-year history of Parkinson disease. Involuntary eye movements were noticed after treatment with amantadine for limb dyskinesias. Levodopa-induced ocular dyskinesias involving repetitive, transient, and stereotyped rightward deviations of gaze appeared after intake of an antiparkinsonian drug. Limb dyskinesias also occurred simultaneously. We used a next-generation sequencing targeted gene panel and found a heterozygous missense mutation (p.R535H) in GBA. Direct Sanger sequencing verified the missense mutation. CONCLUSIONS: We report the case of an uncommon early-onset PD patient carrying a GBA mutation presenting ocular dyskinesia. Genetic screening may provide a better mechanistic insight into dyskinesias.


Assuntos
Discinesias , Doença de Parkinson , Antiparkinsonianos/efeitos adversos , Humanos , Levodopa/efeitos adversos , Masculino , Pessoa de Meia-Idade , Mutação , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/genética
4.
J Vis Exp ; (176)2021 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-34661577

RESUMO

L-DOPA-induced dyskinesias (LIDs) refer to motor complications that arise from prolonged L-DOPA administration to patients with Parkinson's disease (PD). The most common pattern observed in the clinic is the peak-dose dyskinesia which consists of clinical manifestations of choreiform, dystonic, and ballistic movements. The 6-hydroxydopamine (6-OHDA) rat model of PD mimics several characteristics of LIDs. After repeated L-DOPA administration, 6-OHDA-lesioned rats exhibit dyskinetic-like movements (e.g., abnormal involuntary movements, AIMs). This protocol demonstrates how to induce and analyze AIMs in 6-OHDA-lesioned rats with 90%-95% dopaminergic depletion in the nigrostriatal pathway. Repeated administration (3 weeks) of L-DOPA (5 mg/kg, combined with 12.5 mg/kg of benserazide) can induce the development of AIMs. The time course analysis reveals a significant increase in AIMs at 30-90 min (peak-dose dyskinesia). Rodent models of LIDs are an important preclinical tool to identify effective antidyskinetic interventions.


Assuntos
Discinesia Induzida por Medicamentos , Doença de Parkinson , Animais , Dopamina , Discinesia Induzida por Medicamentos/etiologia , Levodopa/efeitos adversos , Oxidopamina , Doença de Parkinson/tratamento farmacológico , Ratos
5.
Molecules ; 26(19)2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34641332

RESUMO

L-DOPA therapy in Parkinson's disease (PD) is limited due to emerging L-DOPA-induced dyskinesia. Research has identified abnormal dopamine release from serotonergic (5-HT) terminals contributing to this dyskinesia. Selective serotonin reuptake inhibitors (SSRIs) or 5-HT receptor (5-HTr) agonists can regulate 5-HT activity and attenuate dyskinesia, but they often also produce a loss of the antiparkinsonian efficacy of L-DOPA. We investigated vilazodone, a novel multimodal 5-HT agent with SSRI and 5-HTr1A partial agonist properties, for its potential to reduce dyskinesia without interfering with the prokinetic effects of L-DOPA, and underlying mechanisms. We assessed vilazodone effects on L-DOPA-induced dyskinesia (abnormal involuntary movements, AIMs) and aberrant responsiveness to corticostriatal drive in striatal medium spiny neurons (MSNs) measured with in vivo single-unit extracellular recordings, in the 6-OHDA rat model of PD. Vilazodone (10 mg/kg) suppressed all subtypes (axial, limb, orolingual) of AIMs induced by L-DOPA (5 mg/kg) and the increase in MSN responsiveness to cortical stimulation (shorter spike onset latency). Both the antidyskinetic effects and reversal in MSN excitability by vilazodone were inhibited by the 5-HTr1A antagonist WAY-100635, demonstrating a critical role for 5-HTr1A in these vilazodone actions. Our results indicate that vilazodone may serve as an adjunct therapeutic for reducing dyskinesia in patients with PD.


Assuntos
Discinesia Induzida por Medicamentos/prevenção & controle , Levodopa/administração & dosagem , Oxidopamina/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Receptor 5-HT1A de Serotonina/metabolismo , Cloridrato de Vilazodona/administração & dosagem , Animais , Corpo Estriado/efeitos dos fármacos , Modelos Animais de Doenças , Discinesia Induzida por Medicamentos/metabolismo , Regulação da Expressão Gênica , Levodopa/efeitos adversos , Masculino , Doença de Parkinson/etiologia , Doença de Parkinson/metabolismo , Ratos , Ratos Sprague-Dawley , Cloridrato de Vilazodona/farmacologia
7.
Neurol Sci ; 42(10): 4085-4094, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34346015

RESUMO

BACKGROUND AND PURPOSE: Polymorphisms of the catechol-O-methyl transferase (COMT) or monoamine oxidase B (MAO-B) genes may affect the occurrence of dyskinesia in Parkinson's disease (PD) patients. However, the findings are inconsistent. Thus, we performed a meta-analysis to assess whether COMT and MAO-B genetic variants are associated with an increased incidence of levodopa-induced dyskinesia (LID) in PD patients. METHODS: A literature search of PubMed, Embase, and Cochrane Library was conducted to identify relevant studies published up to January 2021. The strength of the association between the polymorphisms and LID susceptibility was estimated by odds ratio (OR) and associated 95% confidence interval (CI). The pooled ORs were assessed in different genetic models. RESULTS: Ten studies involving 2385 PD patients were included in the meta-analysis. Analysis of pooled ORs and 95% CIs suggested that the AA genotype of COMT(rs4680) was associated with LID (OR = 1.39, 95%CI: 1.02-1.89, P = 0.039) in the recessive model, and this correlation was more obvious in Brazilian samples in the analysis stratified by ethnicity. For the AG genotype of MAO-B(rs1799836), the pooled OR was 1.66 (95% CI: 1.04-2.65, P = 0.03) in patients with LID versus those without LID in the heterozygote model. CONCLUSIONS: Our meta-analysis implicates the AA genotype of the COMT rs4680 polymorphism as potentially increasing the risk of LID in a recessive genetic model for PD patients. Furthermore, the AG genotype of the MAO-B rs1799836 polymorphism may influence the prevalence of LID in PD patients in the heterozygote model. However, further well-designed studies with larger PD patient cohorts are required to validate these results after adjusting for confounding factors.


Assuntos
Discinesias , Doença de Parkinson , Catecol O-Metiltransferase/genética , Humanos , Levodopa/efeitos adversos , Monoaminoxidase/genética , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/genética
8.
Artigo em Russo | MEDLINE | ID: mdl-34460155

RESUMO

OBJECTIVE: To assess the dynamics of cognitive impairments (CI) in patients with Parkinson's disease (PD) during L-dopa therapy. MATERIAL AND METHODS: The randomized clinical study included 41 patients with a refined diagnosis of PD 2.5-3.5 stages by Hoehn-Yahr scale, mainly with akinetic-rigid and mixed forms, and with CI associated with PD. All patients were on levodopa therapy. The average duration of the disease was 5 years. The study participants were randomized into two groups according to the design. To assess the dynamics of CI, a neuropsychological study was carried out twice with an interval of 6 months: in group I - at the «peak and outcome¼ of L-DOPA therapy, and in group II - at the «outcome and peak¼ of levodopa therapy, respectively. Assessment of cognitive functions (CF) was carried out using Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Frontal Assessment Battery (FAB), Scales for Outcomes in Parkinson's Disease-Cognition (SCOPA-Cog), Geriatric Depression Scale (GDS). RESULTS: The statistically significant improvement of CF at the «peak¼ of levodopa drugs and the deterioration at the «outcome¼ of L-DOPA therapy in the form of an increase in CI (p<0.05) was revealed. CONCLUSION: CI in PD, in a certain extent, may be dependent on L-DOPA therapy as well as motor manifestations. The most dependent on L-DOPA therapy CF were attention, speech, executive and visual-spatial functions.


Assuntos
Disfunção Cognitiva , Doença de Parkinson , Idoso , Antiparkinsonianos/efeitos adversos , Cognição , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Humanos , Levodopa/efeitos adversos , Testes de Estado Mental e Demência , Doença de Parkinson/tratamento farmacológico
9.
Front Immunol ; 12: 683577, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34248967

RESUMO

Dyskinesia is a serious complication of Parkinson's disease during levodopa (L-DOPA) treatment. The pathophysiology of L-DOPA-induced dyskinesia (LID) is complex and not fully illuminated. At present, treatment of dyskinesia is quite limited. Recent studies demonstrated neuroinflammation plays an important role in development of LID. Thus, inhibition of neuroinflammation might open a new avenue for LID treatment. Resveratrol (RES) is the most well-known polyphenolic stilbenoid and verified to possess a large variety of biological activities. DA neurotoxicity was assessed via behavior test and DA neuronal quantification. The movement disorders of dyskinesia were detected by the abnormal involuntary movements scores analysis. Effects of RES on glial cells-elicited neuroinflammation were also explored. Data showed that RES attenuated dyskinesia induced by L-DOPA without affecting L-DOPA's anti-parkinsonian effects. Furthermore, RES generated neuroprotection against long term treatment of L-DOPA-induced DA neuronal damage. Meanwhile, RES reduced protein expression of dyskinesia molecular markers, ΔFOS B and ERK, in the striatum. Also, there was a strong negative correlation between DA system damage and ΔFOS B level in the striatum. In addition, RES inhibited microglia and astroglia activation in substantia nigra and subsequent inflammatory responses in the striatum during L-DOPA treatment. RES alleviates dyskinesia induced by L-DOPA and these beneficial effects are closely associated with protection against DA neuronal damage and inhibition of glial cells-mediated neuroinflammatory reactions.


Assuntos
Discinesias/etiologia , Discinesias/fisiopatologia , Levodopa/efeitos adversos , Resveratrol/farmacologia , Animais , Biomarcadores , Modelos Animais de Doenças , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Discinesias/tratamento farmacológico , Discinesias/metabolismo , Masculino , Oxidopamina/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/etiologia , Doença de Parkinson/fisiopatologia , Ratos , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Substância Negra/fisiopatologia
10.
Int J Mol Sci ; 22(13)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34281267

RESUMO

BACKGROUND: Parkinson's disease (PD) is the second most frequent neurodegenerative disease, which creates a significant public health burden. There is a challenge for the optimization of therapies since patients not only respond differently to current treatment options but also develop different side effects to the treatment. Genetic variability in the human genome can serve as a biomarker for the metabolism, availability of drugs and stratification of patients for suitable therapies. The goal of this systematic review is to assess the current evidence for the clinical translation of pharmacogenomics in the personalization of treatment for Parkinson's disease. METHODS: We performed a systematic search of Medline database for publications covering the topic of pharmacogenomics and genotype specific mutations in Parkinson's disease treatment, along with a manual search, and finally included a total of 116 publications in the review. RESULTS: We analyzed 75 studies and 41 reviews published up to December of 2020. Most research is focused on levodopa pharmacogenomic properties and catechol-O-methyltransferase (COMT) enzymatic pathway polymorphisms, which have potential for clinical implementation due to changes in treatment response and side-effects. Likewise, there is some consistent evidence in the heritability of impulse control disorder via Opioid Receptor Kappa 1 (OPRK1), 5-Hydroxytryptamine Receptor 2A (HTR2a) and Dopa decarboxylase (DDC) genotypes, and hyperhomocysteinemia via the Methylenetetrahydrofolate reductase (MTHFR) gene. On the other hand, many available studies vary in design and methodology and lack in sample size, leading to inconsistent findings. CONCLUSIONS: This systematic review demonstrated that the evidence for implementation of pharmacogenomics in clinical practice is still lacking and that further research needs to be done to enable a more personalized approach to therapy for each patient.


Assuntos
Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/genética , Antiparkinsonianos/efeitos adversos , Antiparkinsonianos/metabolismo , Antiparkinsonianos/farmacologia , Catecol O-Metiltransferase/genética , Catecol O-Metiltransferase/metabolismo , Inibidores de Catecol O-Metiltransferase/metabolismo , Inibidores de Catecol O-Metiltransferase/farmacologia , Agonistas de Dopamina/metabolismo , Agonistas de Dopamina/farmacologia , Genótipo , Humanos , Levodopa/efeitos adversos , Levodopa/metabolismo , Levodopa/farmacologia , Inibidores da Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Doença de Parkinson/metabolismo , Farmacogenética/métodos , Farmacogenética/tendências , Variantes Farmacogenômicos
11.
Rev Esp Enferm Dig ; 113(10): 727-728, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34281347

RESUMO

We read with interest the article by Garrido Durán C, et al. in which endoscopic aspects of duodenal levodopa/carbidopa therapy in the treatment of advanced Parkinson's disease were analyzed. In this article, buried bumper syndrome (BBS) is documented in 5.4 % of cases. Normally, the initial treatment of BBS is endoscopic therapy, although sometimes surgery may be necessary. Thus, 4 cases of BBS treated with surgery are presented.


Assuntos
Carbidopa , Doença de Parkinson , Antiparkinsonianos/efeitos adversos , Carbidopa/efeitos adversos , Combinação de Medicamentos , Nutrição Enteral , Gastrostomia , Humanos , Levodopa/efeitos adversos , Doença de Parkinson/tratamento farmacológico
12.
BMC Neurol ; 21(1): 242, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34172002

RESUMO

BACKGROUND: Levodopa-carbidopa intestinal gel (LCIG) treatment, a unique drug delivery system for patients with advanced Parkinson's disease (PD), is covered by health insurance in Japan since September 2016. Various LCIG procedure/device-associated adverse events (AEs) have been reported; however, reports on their treatment have been limited. This is the first multicenter study to clarify the frequency and timing of device-related AEs. METHODS: Between September 2016 and December 2018, 104 patients introduced to the LCIG treatment for advanced PD in 11 hospitals were included. The patients' characteristics, AEs incidence, AEs time, and tube exchange time were investigated. RESULTS: The median follow-up period was 21.5 months. Minor AE cases were 29.4%, whereas major AE cases were 43.1%. Majority of major AEs (n = 55, 94.8%) were managed with endoscopic treatment, such as tube exchange. Few severe AEs required surgical treatment (n =3, 5.2%). The mean (range) exposure to percutaneous endoscopic gastrojejunostomy (PEG-J) was 14.7 (0-33) months. One year after the LCIG treatment introduction, 55 patients (54.0%) retained the original PEG-J tube. The mean PEG-J tube exchange time was 10.8 ± 7.0 months in all patients, 11.6 ± 4.7 and 10.5 ± 7.7 months in patients with scheduled exchange and who underwent exchange due to AEs, respectively. CONCLUSIONS: Some device-related AEs occurred during the LCIG treatment; however, only few were serious, most of which could be treated with simple procedures or tube replacement with endoscopy. Therefore, the LCIG treatment is feasible and safe and is a unique treatment option for PD, requiring endoscopists' understanding and cooperation.


Assuntos
Antiparkinsonianos , Carbidopa , Derivação Gástrica , Géis , Levodopa , Doença de Parkinson/tratamento farmacológico , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/efeitos adversos , Antiparkinsonianos/uso terapêutico , Carbidopa/administração & dosagem , Carbidopa/efeitos adversos , Carbidopa/uso terapêutico , Combinação de Medicamentos , Derivação Gástrica/efeitos adversos , Derivação Gástrica/métodos , Géis/administração & dosagem , Géis/efeitos adversos , Géis/uso terapêutico , Humanos , Levodopa/administração & dosagem , Levodopa/efeitos adversos , Levodopa/uso terapêutico , Estudos Retrospectivos
13.
Rev Neurol (Paris) ; 177(8): 919-923, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34154827

RESUMO

BACKGROUND: Levodopa-carbidopa intestinal gel (LCIG) is an advanced therapy for patients with Parkinson Disease (PD). Weight loss has been pointed out as an adverse event of LCIG infusion. AIMS OF THE STUDY: To compare weight changes between three groups of PD patients: patients treated with LCIG, patients within the first year of subthalamic deep brain stimulation (STN-DBS) and patients treated exclusively with oral treatment during 1 year of follow up. METHODS: Patients treated with LCIG were retrospectively matched by age, gender, disease duration and Hoehn and Yahr to patients undergoing STN-DBS and to patients both receiving the standard of care treatment and unwilling advanced therapies (SOC). Clinical features and weight were collected at baseline, and 12 months after introducing the treatment (LCIG and STN-DBS groups) or for one year of treatment (SOC). RESULTS: Eighteen patients were included in each group. They had no differences in clinical and demographic features, except for cognitive impairment. There was a mean weight (-5.8kg ±6.8) and BMI (-2.1kg/m2±2.6) reduction in the LCIG group after 12 months, while there was a slight weight loss in the SOC (-1.4kg ±3.1) and a weight increase in the STN-DBS group (5.4kg ±4.7). Differences of weight were statistically different between, LCIG and STN-DBS (P<0.001), LCIG and SOC (P=0.002) and STN-DBS and SOC (P<0.001). CONCLUSIONS: The study shows a significant weight reduction after starting LCIG infusion compared to the other groups. Weight loss should be closely monitored in patients treated with LCIG.


Assuntos
Estimulação Encefálica Profunda , Doença de Parkinson , Núcleo Subtalâmico , Antiparkinsonianos , Índice de Massa Corporal , Carbidopa , Estudos de Casos e Controles , Combinação de Medicamentos , Géis , Humanos , Levodopa/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Estudos Retrospectivos , Padrão de Cuidado
14.
Rev Assoc Med Bras (1992) ; 67(1): 125-130, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34161485

RESUMO

OBJECTIVES: To assess the effect of withdrawal of the antiparkinsonian drug regimen administration on patients with PD and its relation to pain. METHODS: The sample included 22 men and 12 women who were candidates for neurosurgery to control motor signs and symptoms treated with L-dopa as a drug, alone or in combination with others (Cholinergic Antagonists; Dopamine Agents). All of them were examined at two different moments, with and without medication, and analyzed for painful symptoms. The Hoehn and Yahr scale was used for functional staging of the disease. Pain intensity was assessed by using the numerical verbal scale. RESULTS: The mean pain intensity among those on medication {2.17±0.39 (SE)} was significantly lower than in the abstinence group {4.2±0.59 (SE), p=0.006, Wilcoxon}, which corresponded to the increase in the total functional staging score from 93 to 111, respectively. CONCLUSION: The interruption of the administration of specific medications in patients with Parkinson's disease caused, or increased the intensity of, painful discomfort correlated with the intensity of functional impairment. This effect was also observed in women, but it was statistically relevant only for men. The results suggest that pain may be a "red flag" that points to the need for a therapeutic drug review when its presence or worsening is detected.


Assuntos
Doença de Parkinson , Antiparkinsonianos/efeitos adversos , Feminino , Humanos , Levodopa/efeitos adversos , Masculino , Dor/tratamento farmacológico , Dor/etiologia , Doença de Parkinson/tratamento farmacológico
15.
J Neurosci ; 41(30): 6388-6414, 2021 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-34131032

RESUMO

The striatum is the main structure of the basal ganglia. The striatum receives inputs from various cortical areas, and its subregions play distinct roles in motor and emotional functions. Recently, striatal maps based on corticostriatal connectivity and striosome-matrix compartmentalization were developed, and we were able to subdivide the striatum into seven subregions. Dopaminergic modulation of the excitability of medium spiny neurons (MSNs) is critical for striatal function. In this study, we investigated the functional properties of dopamine signaling in seven subregions of the striatum from male mice. By monitoring the phosphorylation of PKA substrates including DARPP-32 in mouse striatal slices, we identified two subregions with low D1 receptor signaling: the dorsolateral portion of the intermediate/rostral part (DL-IR) and the intermediate/caudal part (IC). Low D1 receptor signaling in the two subregions was maintained by phosphodiesterase (PDE)10A and muscarinic M4 receptors. In an animal model of 6-hydroxydopamine (6-OHDA)-induced hemi-parkinsonism, D1 receptor signaling was upregulated in almost all subregions including the DL-IR, but not in the IC. When L-DOPA-induced dyskinesia (LID) was developed, D1 receptor signaling in the IC was upregulated and correlated with the severity of LID. Our results suggest that the function of the striatum is maintained through the subregion-specific regulation of dopamine D1 receptor signaling and that the aberrant activation of D1 receptor signaling in the IC is involved in LID. Future studies focusing on D1 receptor signaling in the IC of the striatum will facilitate the development of novel therapeutics for LID.SIGNIFICANCE STATEMENT Recent progress in striatal mapping based on corticostriatal connectivity and striosome-matrix compartmentalization allowed us to subdivide the striatum into seven subregions. Analyses of D1 receptor signaling in the seven subregions identified two unique subregions with low D1 receptor signaling: the dorsolateral portion of the intermediate/rostral part (DL-IR) and the intermediate/caudal part (IC). Aberrant activation of D1 receptor signaling in the IC is involved in L-DOPA-induced dyskinesia (LID). Previous studies of LID have mainly focused on the DL-IR, but not on the IC of the striatum. Future studies to clarify aberrant D1 receptor signaling in the IC are required to develop novel therapeutics for LID.


Assuntos
Corpo Estriado/metabolismo , Discinesia Induzida por Medicamentos/metabolismo , Levodopa/efeitos adversos , Transtornos Parkinsonianos/metabolismo , Receptores de Dopamina D1/metabolismo , Animais , Antiparkinsonianos/efeitos adversos , Corpo Estriado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/fisiologia
16.
Neurol Sci ; 42(8): 3135-3143, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34014397

RESUMO

BACKGROUND: Mavoglurant (AFQ056), a selective metabotropic glutamate receptor 5 (mGluR5) inhibitor, was tested for t levodopa-induced dyskinesia (LID) in patients with Parkinson's Disease (PD). However, clinical trials showed inconsistent results regarding the efficacy of mavoglurant in treating LID in patients with Parkinson's disease (PD). METHODS: A computer literature search of PubMed, Scopus, Web of science, and Cochrane CENTRAL was conducted until March 2021. We selected relevant randomized controlled trials comparing mavoglurant to placebo. Study data were extracted and pooled as mean difference (MD) in the meta-analysis model. RESULTS: Six RCTs were included in this meta-analysis with a total of 485 patients. Mavoglurant was not significantly superior to placebo in terms of the "off-time" (MD -0.27 h, 95% CI -0.65 to 0.11), "on time" (MD 0.29 h, 95% CI -0.09 to 0.66), Lang-Fahn activities of daily living dyskinesia scale (MD -0.95, 95% CI -1.98 to 0.07), UPDRS-III (MD -0.51, 95% CI -1.66 to 0.65), or UPDRS-IV (MD -0.41, 95% CI -0.85 to 0.03). However, the pooled modified abnormal involuntary movement scale favored the mavoglurant group than the placebo group (MD -2.53, 95% CI -4.23 to -0.82). CONCLUSIONS: This meta-analysis provides level one evidence that mavoglurant is not effective in treating the LID in patients with PD.


Assuntos
Discinesias , Doença de Parkinson , Atividades Cotidianas , Antiparkinsonianos/efeitos adversos , Humanos , Indóis , Levodopa/efeitos adversos , Doença de Parkinson/tratamento farmacológico
17.
Intern Med ; 60(20): 3317-3320, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-33867393

RESUMO

Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel (LCIG) is an established device-aided therapy for advanced Parkinson's disease (PD). Phytobezoar associated with LCIG is a rare device-related complication and presents with exacerbations of gastrointestinal and PD symptoms. We herein report the case of a phytobezoar that was formed at a knot on the pigtail-shaped J-tube and developed only in association with postprandial abdominal pain, similar to a feeling of a tube being pulled in without an exacerbation of PD symptoms. Such abdominal pain may be a warning sign of phytobezoar in LCIG-treated patients. Despite device-related complications, high-pressure alarms are not always present, and PD symptoms are not always exacerbated.


Assuntos
Bezoares , Doença de Parkinson , Antiparkinsonianos/efeitos adversos , Bezoares/induzido quimicamente , Carbidopa/efeitos adversos , Humanos , Levodopa/efeitos adversos , Doença de Parkinson/tratamento farmacológico
18.
Artigo em Russo | MEDLINE | ID: mdl-33834727

RESUMO

Progressive supranuclear palsy (PNP) is a neurodegenerative disease characterized by a combination of progressive akinetic-rigid syndrome, postural instability with frequent falls, supranuclear ophthalmoplegia, pseudobulbar syndrome and frontal dementia. The disease usually develops after the sixth decade of life, and has a progressive course. An own description of the clinical case of progressive supranuclear palsy in a 79-year-old patient with oromandibular hyperkinesis while taking levodopa is presented.


Assuntos
Discinesias , Transtornos dos Movimentos , Doenças Neurodegenerativas , Paralisia Supranuclear Progressiva , Idoso , Humanos , Levodopa/efeitos adversos , Paralisia Supranuclear Progressiva/induzido quimicamente , Paralisia Supranuclear Progressiva/tratamento farmacológico
19.
Mov Disord ; 36(8): 1759-1771, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33899262

RESUMO

Advanced Parkinson's disease is inconsistently defined, and evidence is lacking in relation to device-aided therapies. To update existing reviews of intrajejunal infusion of levodopa/carbidopa (LCIG), we performed a literature search for relevant articles (to November 3, 2020) using PubMed supplemented by hand searching. Retrieved articles were categorized by relevance to identified research questions, including motor complications and symptoms; nonmotor symptoms; functioning, quality of life, and caregiver burden; optimal timing of treatment initiation and administration duration; discontinuation; and complications. Most eligible studies (n = 56) were open-label, observational studies including relatively small patient numbers. LCIG consistently reduces OFF time and increased ON time without troublesome dyskinesia with varying effects regarding ON time with troublesome dyskinesia and the possibility of diphasic dyskinesia. More recent evidence provides some increased support for the benefits of LCIG in relation to nonmotor symptoms, quality of life, activities of daily living, and reduced caregiver burden. Patient age does not appear to significantly impact the effectiveness of LCIG. Discontinuation rates with LCIG (~17%-26%) commonly relate to device-related issues, although the ability to easily discontinue LCIG may represent a potential benefit. LCIG may be a favorable option for patients with advanced Parkinson's disease who show predominant nonmotor symptoms and vulnerability to complications of other advanced therapy modalities. Larger, well-controlled studies, including precise investigation of cost effectiveness, would further assist treatment selection. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Assuntos
Carbidopa , Doença de Parkinson , Atividades Cotidianas , Antiparkinsonianos , Combinação de Medicamentos , Géis , Humanos , Levodopa/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Qualidade de Vida
20.
Brain ; 144(4): 1127-1137, 2021 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-33895825

RESUMO

Dipeptidyl peptidase 4 (DPP4) inhibitors are widely used hypoglycaemic agents and improve glucose metabolism by enhancing the bioavailability of active glucagon-like peptide-1. In this study, we hypothesized that treatment with DPP4 inhibitors may have beneficial effects on nigrostriatal dopamine and longitudinal motor performance in diabetic patients with Parkinson's disease. We classified 697 drug naive patients with de novo Parkinson's disease who had undergone dopamine transporter imaging into three groups according to a prior diagnosis of diabetes and use of DPP4 inhibitors: diabetic patients with Parkinson's disease being treated with (n = 54) or without DPP4 inhibitors (n = 85), and non-diabetic patients with Parkinson's disease (n = 558). Diabetic patients with Parkinson's disease being treated with DPP4 inhibitors had a higher baseline dopamine transporter availability in the anterior (2.56 ± 0.74 versus 2.10 ± 0.50; P = 0.016), posterior (1.83 ± 0.69 versus 1.40 ± 0.50; P < 0.001), and ventral putamina (1.72 ± 0.58 versus 1.35 ± 0.37; P = 0.001) than that in diabetic patients with Parkinson's disease without DPP4 inhibitors. Additionally, diabetic patients with Parkinson's disease being treated with DPP4 inhibitors had higher dopamine transporter availability in the posterior putamen than that in non-diabetic patients with Parkinson's disease (1.83 ± 0.69 versus 1.43 ± 0.59; P < 0.001). After adjusting for age, sex, disease duration, and vascular risk factors, linear regression models showed that a prior treatment of DPP4 inhibitors remained independently and significantly associated with dopamine transporter availability in the anterior (ß = -0.186, P = 0.012; ß = -0.207, P = 0.003), posterior (ß = -0.336, P < 0.001; ß = -0.286, P < 0.001), and ventral putamina (ß = -0.204, P = 0.005; ß = -0.250, P < 0.001). A linear mixed model revealed that the diabetic group with Parkinson's disease being treated with DPP4 inhibitors had a slower longitudinal increase in levodopa-equivalent dose than the other groups (P = 0.003). Survival analyses showed that the rate of levodopa-induced dyskinesia was significantly lower in the diabetic group with a prior treatment with DPP4 inhibitors than the diabetic group without DPP4 inhibitors (hazard ratio = 0.194, P = 0.037). These findings suggest that DPP4 inhibitors may confer beneficial effects on the baseline nigrostriatal dopamine degeneration and long-term motor outcomes in diabetic patients with Parkinson's disease and may extend its role into non-diabetic patients with Parkinson's disease.


Assuntos
Encéfalo/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hipoglicemiantes/uso terapêutico , Doença de Parkinson , Idoso , Antiparkinsonianos/efeitos adversos , Encéfalo/metabolismo , Diabetes Mellitus Tipo 2/complicações , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Discinesia Induzida por Medicamentos/epidemiologia , Feminino , Humanos , Levodopa/efeitos adversos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/complicações , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/patologia , Estudos Retrospectivos
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