Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 554
Filtrar
1.
Clin Pharmacol Ther ; 116(1): 225-234, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38666589

RESUMO

Amantadine, despite being on the market for 55 years, has several unknown aspects of its pharmacokinetics especially related to the influence of covariates such as age, disease, or interactions linked to amantadine's renal elimination. As amantadine is used in Parkinson's disease and is considered a potential candidate in COVID treatment and other diseases, there is an unmet need for thorough understanding of its pharmacokinetic in special populations, such as the elderly. We aimed to mechanistically describe amantadine pharmacokinetics in healthy subjects and shed some light on the differences in drug behavior between healthy volunteers (18-65 years) and an elderly/geriatric population (65-98 years) using PBPK modeling and simulation. The middle-out PBPK model includes mechanistic description of drug renal elimination, specifically an organic cation transporter (OCT)2-mediated electrogenic bidirectional transport (basolateral) and multidrug and toxic compound extrusion (MATE)1-mediated efflux (apical). The model performance was verified against plasma and urine data reported after single and multiple dose administration in healthy volunteers and elderly patients from 18 independent studies. The ratios of predicted vs. observed maximal plasma concentration and area under the concentration-time curve values were within 1.25-fold. The model illustrates that renal transporter activity is expected to decrease in healthy elderly compared to healthy volunteers, which is in line with literature proteomic data for OCT2. The model was applied to assess the potential of reaching toxicity-related plasma concentrations in different age groups of geriatric subjects.


Assuntos
Amantadina , Modelos Biológicos , Humanos , Idoso , Amantadina/farmacocinética , Amantadina/administração & dosagem , Adulto , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Masculino , Adulto Jovem , Adolescente , Feminino , Transportador 2 de Cátion Orgânico/metabolismo , Eliminação Renal , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Tratamento Farmacológico da COVID-19 , Fatores Etários , Voluntários Saudáveis , Simulação por Computador
2.
Parkinsonism Relat Disord ; 122: 106088, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38461688

RESUMO

INTRODUCTION: Dystonia is a painful OFF-related complication in Parkinson's disease (PD) with limited treatment options. METHODS: Post-hoc analysis using pooled data from two extended-release amantadine pivotal trials and follow-on open-label extension. Dystonia was assessed using the Unified Dyskinesia Rating Scale (UDysRS) Part 2 and the Movement Disorder Society-Unified PD Rating Scale (MDS-UPDRS) item 4.6. RESULTS: Of 196 participants, 119 (60.7%) reported OFF-related dystonia at baseline per UDysRS. Twelve-week treatment with extended-release amantadine improved OFF dystonia (treatment differences vs placebo: UDysRS Part 2, -1.0 [-1.9,-0.1]; p = 0.03 and MDS-UPDRS Item 4.6, -0.3 [-0.6,-0.05]; p = 0.02). There was no correlation between changes in OFF time and changes in OFF dystonia. Double-blind improvements in OFF dystonia were sustained throughout the 2-year follow-up. CONCLUSIONS: Extended-release amantadine yielded a sustained reduction in OFF-related dystonia in PD patients that was independent from a reduction in OFF time. A randomized controlled trial is warranted to confirm these findings.


Assuntos
Amantadina , Antiparkinsonianos , Preparações de Ação Retardada , Distonia , Doença de Parkinson , Humanos , Amantadina/administração & dosagem , Doença de Parkinson/complicações , Doença de Parkinson/tratamento farmacológico , Masculino , Feminino , Distonia/tratamento farmacológico , Distonia/etiologia , Idoso , Pessoa de Meia-Idade , Antiparkinsonianos/administração & dosagem , Método Duplo-Cego
3.
CNS Drugs ; 35(11): 1141-1152, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34648150

RESUMO

The best practice for the initiation of symptomatic motor treatment for Parkinson's disease is an ongoing topic of debate. Fueled by interpretation of the results of the LEAP and MED Parkinson's disease studies, many practitioners opt for early initiation of levodopa formulations, avoiding dopamine agonists to circumvent potential deleterious side effects, namely impulse control disorder. Compared with levodopa, monoamine oxidase inhibitors may lack necessary potency. Ignored in this academic debate is another therapeutic option for patients with Parkinson's disease requiring treatment initiation: amantadine. Amantadine was first reported effective in the treatment of Parkinson's disease in 1969 and several studies were published in the 1970s supporting its efficacy. Currently, amantadine is mainly utilized as an add-on therapy to mitigate levodopa-related dyskinesia and, more recently, new long-acting amantadine formulations have been developed, with new indications to treat motor fluctuations. Amantadine has not been reported to cause dyskinesia and is rarely implicated in impulse control disorder.


Assuntos
Amantadina/administração & dosagem , Antiparkinsonianos/administração & dosagem , Discinesia Induzida por Medicamentos/tratamento farmacológico , Doença de Parkinson/tratamento farmacológico , Amantadina/efeitos adversos , Amantadina/farmacocinética , Animais , Antiparkinsonianos/efeitos adversos , Antiparkinsonianos/farmacocinética , Confusão/induzido quimicamente , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/efeitos adversos , Preparações de Ação Retardada/farmacocinética , Dopamina/metabolismo , Quimioterapia Combinada , Discinesia Induzida por Medicamentos/metabolismo , Humanos , Levodopa/efeitos adversos , Náusea/induzido quimicamente , Doença de Parkinson/metabolismo
4.
Behav Brain Res ; 413: 113443, 2021 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-34216648

RESUMO

The present study investigated the pharmacological mechanisms of the antidepressant-like effects of amantadine in mice and their influence on hippocampal neurogenesis. To improve the translational validity of preclinical results, reproducibility across laboratories and replication in other animal models and species are crucial. Single amantadine administration at doses of 50 and 75 mg/kg resulted in antidepressant-like effects in mice in the tail suspension test (TST), reflected by an increase in immobility time. The effects of amantadine were seen at doses that did not alter locomotor activity. The tyrosine hydroxylase inhibitor α-methyl-ρ-tyrosine did not influence the anti-immobility effect of amantadine in the TST. Pretreatment with the α1 adrenergic receptor antagonist prazosin, ß adrenergic receptor antagonist propranolol, α2 adrenergic receptor antagonist yohimbine, and α2 adrenergic receptor agonist clonidine did not alter the antidepressant-like effect of amantadine. However, amantadine's effect was blocked by the dopamine D2 receptor antagonist haloperidol and glutamate receptor agonist N-methyl-D-aspartate (NMDA). Repeated amantadine administration (50 mg/kg) also exerted an antidepressant-like effect, paralleled by an increase in hippocampal neurogenesis. The present results demonstrate that the antidepressant-like effects of amantadine may be mediated by its actions on D2 and NMDA receptors and likely involve hippocampal neurogenesis.


Assuntos
Agonistas Adrenérgicos/farmacologia , Antagonistas Adrenérgicos/farmacologia , Amantadina/farmacologia , Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Agonistas de Aminoácidos Excitatórios/farmacologia , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Amantadina/administração & dosagem , Animais , Antidepressivos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Hipocampo/efeitos dos fármacos , Masculino , Camundongos , Neurogênese/efeitos dos fármacos , alfa-Metiltirosina/farmacologia
5.
Lancet Neurol ; 20(1): 38-48, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33242419

RESUMO

BACKGROUND: Methylphenidate, modafinil, and amantadine are commonly prescribed medications for alleviating fatigue in multiple sclerosis; however, the evidence supporting their efficacy is sparse and conflicting. Our goal was to compare the efficacy of these three medications with each other and placebo in patients with multiple sclerosis fatigue. METHODS: In this randomised, placebo-controlled, four-sequence, four-period, crossover, double-blind trial, patients with multiple sclerosis who reported fatigue and had a Modified Fatigue Impact Scale (MFIS) score of more than 33 were recruited at two academic multiple sclerosis centres in the USA. Participants received oral amantadine (up to 100 mg twice daily), modafinil (up to 100 mg twice daily), methylphenidate (up to 10 mg twice daily), or placebo, each given for up to 6 weeks. All patients were intended to receive all four study medications, in turn, in one of four different sequences with 2-week washout periods between medications. A biostatistician prepared a concealed allocation schedule, stratified by site, randomly assigning a sequence of medications in approximately a 1:1:1:1 ratio, in blocks of eight, to a consecutive series of numbers. The statistician and pharmacists had no role in assessing the participants or collecting data, and the participants, caregivers, and assessors were masked to allocation. The primary outcome measure was the MFIS measured while taking the highest tolerated dose at week 5 of each medication period, analysed by use of a linear mixed-effect regression model. This trial is registered with ClinicalTrials.gov, NCT03185065 and is closed. FINDINGS: Between Oct 4, 2017, and Feb 27, 2019, of 169 patients screened, 141 patients were enrolled and randomly assigned to one of four medication administration sequences: 35 (25%) patients to the amantadine, placebo, modafinil, and methylphenidate sequence; 34 (24%) patients to the placebo, methylphenidate, amantadine, and modafinil sequence; 35 (25%) patients to the modafinil, amantadine, methylphenidate, and placebo sequence; and 37 (26%) patients to the methylphenidate, modafinil, placebo, and amantadine sequence. Data from 136 participants were available for the intention-to-treat analysis of the primary outcome. The estimated mean values of MFIS total scores at baseline and the maximal tolerated dose were as follows: 51·3 (95% CI 49·0-53·6) at baseline, 40·6 (38·2-43·1) with placebo, 41·3 (38·8-43·7) with amantadine, 39·0 (36·6-41·4) with modafinil, and 38·6 (36·2-41·0) with methylphenidate (p=0·20 for the overall medication effect in the linear mixed-effect regression model). As compared with placebo (38 [31%] of 124 patients), higher proportions of participants reported adverse events while taking amantadine (49 [39%] of 127 patients), modafinil (50 [40%] of 125 patients), and methylphenidate (51 [40%] of 129 patients). Three serious adverse events occurred during the study (pulmonary embolism and myocarditis while taking amantadine, and a multiple sclerosis exacerbation requiring hospital admission while taking modafinil). INTERPRETATION: Amantadine, modafinil, and methylphenidate were not superior to placebo in improving multiple sclerosis fatigue and caused more frequent adverse events. The results of this study do not support an indiscriminate use of amantadine, modafinil, or methylphenidate for the treatment of fatigue in multiple sclerosis. FUNDING: Patient-Centered Outcomes Research Institute.


Assuntos
Amantadina/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Fadiga/tratamento farmacológico , Fadiga/etiologia , Metilfenidato/farmacologia , Modafinila/farmacologia , Esclerose Múltipla/complicações , Avaliação de Resultados em Cuidados de Saúde , Adulto , Amantadina/administração & dosagem , Amantadina/efeitos adversos , Estimulantes do Sistema Nervoso Central/administração & dosagem , Estimulantes do Sistema Nervoso Central/efeitos adversos , Estudos Cross-Over , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Masculino , Metilfenidato/administração & dosagem , Metilfenidato/efeitos adversos , Pessoa de Meia-Idade , Modafinila/administração & dosagem , Modafinila/efeitos adversos , Índice de Gravidade de Doença
6.
Acta Med Port ; 33(9): 604-609, 2020 Sep 01.
Artigo em Português | MEDLINE | ID: mdl-32893777

RESUMO

The use of amantadine in clinical practice still seems limited, despite its increasing evidence in the emergence of vegetative state after traumatic brain injury. We describe the case of an adolescent with severe traumatic brain injury after being run over by a car. After four months of hospitalization in a Central Hospital where he remained in a vegetative state, he was transferred to a Rehabilitation Center. He underwent a comprehensive rehabilitation program with physiotherapy, occupational therapy and speech therapy, including multisensory stimulation and intervention in the surrounding environment. He started amantadine, 50 mg/day, titrated up to 200 mg/day, with significant clinical and functional improvements, and emerged from vegetative state to minimally conscious state at week three and recovered consciousness at the sixth week of amantadine, maintaining progressive improvement, even after drug suspension. The case described underlines the importance of a holistic intervention and corroborates the literature in demonstrating the efficacy and safety of amantadine in the emergence from vegetative state.


A utilização da amantadina na prática clínica ainda parece pouco difundida, apesar da evidência crescente na emergência de alterações do estado de consciência após traumatismo cranioencefálico. Descrevemos o caso de um adolescente com traumatismo cranioencefálico grave por atropelamento. Após quatro meses de internamento num hospital central onde se manteve em estado vegetativo foi transferido para um centro de reabilitação. Iniciou um programa de reabilitação integral liderado por equipa médica, incluindo estimulação multissensorial e intervenção no meio envolvente. Iniciou amantadina, 50 mg/dia, titulada até 200 mg/dia, verificando-se melhoria clínica e funcional significativas, com emergência para estado de consciência mínima à terceira semana e recuperação da consciência à sexta semana de amantadina. Manteve melhoria progressiva mesmo após suspensão do fármaco. O caso descrito salienta a importância da intervenção holística e corrobora a literatura ao demonstrar a eficácia e segurança da amantadina na emergência do estado vegetativo.


Assuntos
Amantadina/administração & dosagem , Lesões Encefálicas Traumáticas/reabilitação , Estado Vegetativo Persistente , Adolescente , Lesões Encefálicas Traumáticas/tratamento farmacológico , Hospitalização , Humanos , Masculino , Resultado do Tratamento
7.
Parkinsonism Relat Disord ; 78: 151-157, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32846366

RESUMO

BACKGROUND: Long-term treatment of Parkinson's disease (PD) with l-DOPA typically leads to development of l-DOPA induced dyskinesia (LID). Amantadine, an NMDA antagonist, attenuates LID, but with limited efficacy and considerable side-effects. NLX-112 (also known as befiradol or F13640), a highly selective and efficacious 5-HT1A receptor agonist, reduced LID when tested in rodent and marmoset models of PD. METHODS: The effects of NLX-112 (0.03, 0.1 and 0.3 mg/kg PO) on established LID evoked by acute challenge with l-DOPA (27.5 ± 3.8 mg/kg PO) were assessed in MPTP-treated cynomolgus macaques. Amantadine (10 mg/kg PO) was tested as a positive control. Plasma exposure of NLX-112 (0.1 mg/kg PO) was determined. RESULTS: NLX-112 significantly and dose-dependently reduced median LID levels by up to 96% during the first hour post-administration (0.3 mg/kg). Moreover, NLX-112 reduced the duration of 'bad on-time' associated with disabling LID by up to 48% (0.3 mg/kg). In contrast, NLX-112 had negligible impact on the anti-parkinsonian benefit of l-DOPA. NLX-112 exposure peaked at ~50 ng/ml at 30 min post-administration but decreased to ~15 ng/ml at 2h. Amantadine reduced by 42% 'bad on-time' associated with l-DOPA, thereby validating the model. CONCLUSION: These data show that, in MPTP-lesioned cynomolgus macaques, NLX-112 exerts robust anti-dyskinetic effects, without reducing the anti-parkinsonian benefit of l-DOPA. These observations complement previous findings and suggest that selective and high efficacy activation of 5-HT1A receptors by NLX-112 may constitute a promising approach to combat LID in PD, providing an alternative for patients in whom amantadine is poorly tolerated or without useful effect.


Assuntos
Amantadina/farmacologia , Dopaminérgicos/farmacologia , Discinesia Induzida por Medicamentos/tratamento farmacológico , Levodopa/farmacologia , Transtornos Parkinsonianos/tratamento farmacológico , Piperidinas/farmacologia , Piridinas/farmacologia , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Amantadina/administração & dosagem , Animais , Modelos Animais de Doenças , Dopaminérgicos/efeitos adversos , Discinesia Induzida por Medicamentos/etiologia , Feminino , Levodopa/efeitos adversos , Macaca fascicularis , Piperidinas/administração & dosagem , Piperidinas/farmacocinética , Piridinas/administração & dosagem , Piridinas/farmacocinética , Agonistas do Receptor 5-HT1 de Serotonina/administração & dosagem , Agonistas do Receptor 5-HT1 de Serotonina/farmacocinética
8.
Expert Opin Emerg Drugs ; 25(2): 131-144, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32366130

RESUMO

INTRODUCTION: Prolonged treatment with L-3,4-dihydroxyphenylalanine (L-DOPA) leads to the development of uncontrolled movements (L-DOPA-induced dyskinesias (LID)) in Parkinson's disease (PD). There is currently only a single approved drug for the treatment of LID, a long-acting preparation of the NMDA antagonist, amantadine, that has variable benefits and side-effects. Therefore, new treatments for LID remain an unmet in PD. AREAS COVERED: We review the current strategies for the management of LID; the pathogenic mechanisms underlying the development of LID, which provides the rationale for clinical trials of novel targets for LID and provide a review of phase II/III trials for emerging drugs for LID, with either positive results, or ongoing studies, reported between January 2014 and December 2019. EXPERT OPINION: There are several ongoing studies for agents that showed possible benefit at phase Ib/IIa for reducing LID. However, there are no new positive phase III double-blind randomized controlled clinical trials (DBRCT) for emerging treatments for LID. Generating better preclinical models, more precise recruitment tools and better outcome measures remain a priority. The pharmacology of drugs investigated for LID may be too selective; therefore, evaluating combinations of drugs is worthy of consideration as is the repurposing of existing drugs with multiple pharmacological targets.


Assuntos
Antiparkinsonianos/efeitos adversos , Discinesia Induzida por Medicamentos/tratamento farmacológico , Levodopa/efeitos adversos , Amantadina/administração & dosagem , Amantadina/farmacologia , Animais , Antiparkinsonianos/administração & dosagem , Desenvolvimento de Medicamentos , Reposicionamento de Medicamentos , Discinesia Induzida por Medicamentos/etiologia , Discinesia Induzida por Medicamentos/fisiopatologia , Humanos , Levodopa/administração & dosagem , Doença de Parkinson/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto
10.
Pharmacol Rep ; 72(2): 443-448, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32144743

RESUMO

BACKGROUND: Dopamine replacement therapy using L-3,4-dihydroxyphenylalanine (L-DOPA) is a gold standard treatment in patients with Parkinson's disease (PD); however, chronic administration of L-DOPA causes excessive involuntary movements called L-DOPA-induced dyskinesia. Therefore, the novel pharmacological treatment is needed. METHODS: We examined the antidyskinetic effect of a phosphodiesterase 10A (PDE10A) inhibitor, MR1916 and a currently available antidyskinetic drug, amantadine in unilateral 6-OHDA lesioned rats exhibited stably dyskinesia after chronic administration of L-DOPA. We also examined the influence of MR1916 and amantadine on the improvement of forelimb akinesia induced by L-DOPA using stepping test in unilateral 6-OHDA lesioned rats. RESULTS: MR1916 (0.03‒0.3 mg/kg, po) reduced L-DOPA-induced dyskinesia in a dose-dependent manner and showed significant effects at doses of 0.1 and 0.3 mg/kg, while amantadine (40 mg/kg, sc) had no remarkable effects. Neither MR1916 (0.03‒0.3 mg/kg, po) nor amantadine (40 mg/kg, sc) affected the antiparkinsonian effects induced by L-DOPA in unilateral 6-OHDA lesioned rats. CONCLUSIONS: These results indicate that MR1916 specifically reduces L-DOPA-induced dyskinesia without affecting the antiparkinsonian effect of L-DOPA in parkinsonian rats.


Assuntos
Antiparkinsonianos/efeitos adversos , Discinesia Induzida por Medicamentos/tratamento farmacológico , Levodopa/efeitos adversos , Transtornos Parkinsonianos/tratamento farmacológico , Inibidores de Fosfodiesterase/uso terapêutico , Diester Fosfórico Hidrolases/metabolismo , Administração Oral , Amantadina/administração & dosagem , Amantadina/uso terapêutico , Animais , Antiparkinsonianos/uso terapêutico , Relação Dose-Resposta a Droga , Discinesia Induzida por Medicamentos/enzimologia , Levodopa/uso terapêutico , Masculino , Atividade Motora/efeitos dos fármacos , Oxidopamina/administração & dosagem , Inibidores de Fosfodiesterase/administração & dosagem , Ratos Sprague-Dawley
12.
J Parkinsons Dis ; 10(2): 543-558, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31929122

RESUMO

BACKGROUND: Gocovri® (amantadine) extended release capsules are approved for the treatment of dyskinesia in patients with Parkinson's disease (PD) receiving levodopa-based therapy. OBJECTIVE: To evaluate the long-term safety, tolerability, and efficacy of Gocovri in patients with PD experiencing levodopa-induced dyskinesia. METHODS: In this 2-year open-label trial, patients completing double-blind Gocovri clinical trials or excluded from prior trials because of deep-brain stimulation (DBS) received Gocovri 274 mg once daily at bedtime. The primary objective was to evaluate long-term safety and tolerability. In addition, dyskinesia and OFF time were assessed using Part IV (Motor Complications) scores on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS). RESULTS: Among 223 enrolled patients (mean PD duration, 11.7 years; mean levodopa use, 9.3 years), 75.8% completed 1 year of treatment and 57.8% completed the trial, with a median treatment duration of 1.9 years. Common adverse events were fall (32.7%), hallucination (24.2%), peripheral edema (16.1%), constipation (13.5%), and urinary tract infection (10.3%); 31 patients (13.9%) discontinued because of adverse events considered related to study drug. At baseline, MDS-UPDRS Part IV scores were lower for patients continuing Gocovri (mean, 6.5 points) than for previous placebo (9.4) or DBS groups (10.5) but were similar for all groups by week 8 (6.3, 6.2, 6.4, respectively), and remained low for the duration of the trial (at week 100: 6.9, 7.3, 7.0, respectively). CONCLUSIONS: In patients with PD, Gocovri showed long-term safety and tolerability consistent with double-blind trial findings, and durable reduction in motor complications (dyskinesia and OFF time).


Assuntos
Amantadina/farmacologia , Dopaminérgicos/farmacologia , Discinesia Induzida por Medicamentos/tratamento farmacológico , Levodopa/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Idoso , Amantadina/administração & dosagem , Amantadina/efeitos adversos , Amantadina/farmacocinética , Preparações de Ação Retardada , Dopaminérgicos/administração & dosagem , Dopaminérgicos/efeitos adversos , Dopaminérgicos/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde
13.
Behav Brain Res ; 380: 112432, 2020 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-31838141

RESUMO

Amantadine is a glutamatergic antagonist that works by inhibiting the NMDA receptor. Besides the inhibition of NMDA receptors amantadine also stabilizes the glutamatergic system and protects the neurons against the NMDA toxicity. Amantadine treatment also reduces the production of NO and metabolism of GABA. Therefore amantadine modulates glutamate, GABA and NO which are known to be implicated in the pathogenesis of anxiety and related behavior. The present study was designed to investigate the anxiolytic like effect of amantadine in mice. Nitrergic and GABAergic signaling influence in the anxiolytic like effect of amantadine was also studied. Amantadine (25, 50 and 75 mg/kg, i.p.) was administered and the anxiety related behavior was determined using light and dark box (LDB) and elevated plus maze (EPM) methods. Further, the effect of various treatments on the whole brain glutamate, nitrite and GABA levels were also determined. The results obtained demonstrated that the amantadine (50 mg/kg, i.p.) exerted anxiolytic like effect in mice and reduced the levels of glutamate, nitrite and GABA in the brain of mice as compared to control. Further, the influence of NO and GABA in the anxiolytic like effect of the amantadine was also determined. The results obtained demonstrated that NO donor counteracted while NO inhibitor potentiated the anxiolytic like effect of amantadine in mice. Also the combined treatment of amantadine (25 mg/kg, i.p.) and diazepam (1 mg/kg, i.p.) did not affect the anxiety related behavior, brain GABA and nitrite level of mice but reduced the levels the brain glutamate levels significantly as compared to amantadine (25 mg/kg, i.p.) and diazepam (1 mg/kg, i.p.) treated mice. Thus, amantadine exerted anxiolytic like effect in mice and the anxiolytic like effect of amantadine was modulated by nitrergic and GABAergic signaling pathway.


Assuntos
Amantadina/farmacologia , Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ácido Glutâmico/efeitos dos fármacos , Óxido Nítrico/metabolismo , Nitritos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ácido gama-Aminobutírico/efeitos dos fármacos , Amantadina/administração & dosagem , Animais , Ansiolíticos/administração & dosagem , Encéfalo/metabolismo , Diazepam/farmacologia , Modelos Animais de Doenças , Quimioterapia Combinada , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Moduladores GABAérgicos/administração & dosagem , Moduladores GABAérgicos/farmacologia , Masculino , Camundongos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores
14.
J Parkinsons Dis ; 10(1): 173-178, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31868682

RESUMO

BACKGROUND: A wide variety of conversion factors for a levodopa-equivalent-dose (LED) have been proposed for each Parkinson's disease (PD) medication. The currently-used set of conversion factors is based on studies that relied on subjective experience or theoretical assumptions. This set was never validated in patients receiving polytherapy. OBJECTIVES: To use real-life data to identify an optimal set of conversion factors independent of prior assumptions regarding clinical efficacy of different medications. METHODS: Retrospective analysis of data from 206 cognitively-preserved patients with advanced PD receiving polytherapy before deep brain stimulation (DBS) surgery. A nonlinear automated problem solver was used to find a set of conversion factors that, when applied, minimized the coefficient of variation of LEDs in a relatively homogenous cohort of patients. RESULTS: Independent and model-free evaluation of a wide range of possible sets of conversion factors to LED suggested a set of normalized conversion factors for immediate release levodopa (1.00), controlled release levodopa (0.88), and amantadine (1.23). A minimal clinical benefit of entacapone was observed for patients with motor fluctuations. Our analysis could not detect conversion factors for dopamine agonists and MAO-B inhibitors, possibly because their clinical contribution when added to levodopa is limited. CONCLUSIONS: Independent from previous studies and prior assumptions we show that the currently-used LED conversion factors for immediate release levodopa, controlled release levodopa and amantadine are largely correct and that dopamine agonists, MAO-B inhibitors and entacapone, given in addition to levodopa, have little additional clinical value for PD patients with motor fluctuations.


Assuntos
Amantadina/farmacologia , Antiparkinsonianos/farmacologia , Agonistas de Dopamina/farmacologia , Levodopa/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Avaliação de Resultados em Cuidados de Saúde/normas , Doença de Parkinson/tratamento farmacológico , Idoso , Amantadina/administração & dosagem , Antiparkinsonianos/administração & dosagem , Catecóis/farmacologia , Agonistas de Dopamina/administração & dosagem , Quimioterapia Combinada , Feminino , Humanos , Levodopa/administração & dosagem , Masculino , Pessoa de Meia-Idade , Inibidores da Monoaminoxidase/administração & dosagem , Nitrilas/farmacologia , Estudos Retrospectivos
15.
Isr Med Assoc J ; 21(12): 812-816, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31814345

RESUMO

BACKGROUND: The effect of repeated intravenous amantadine (IVAM) in advanced Parkinsonism has not been studied in depth. OBJECTIVES: To report the experience of our medical center with repeated IVAM infusions in patients with advanced Parkinsonism. METHODS: Thirty patients with advanced Parkinsonism of various etiologies were enrolled in an open-label retrospective study. All patients were treated with IVAM infusions in a neurological daycare center. Treatment was initiated with a loading dose of 200/400 mg per day for 5 days followed by a once-daily maintenance dose of 200/400 mg every 1 to 3 weeks. Patients and their caregivers participated in a structured interview and independently completed a clinical global impression of changes scale questionnaire on various motor and non-motor symptoms. RESULTS: Patient mean age was 73.3 ± 9.7 years, average disease duration was 6.2 ± 5.7 years, and mean Hoehn and Yahr score was 3.2 ± 0.84. Mean duration of the IVAM treatment was 15.1 ± 11.6 months. An improvement in general function was reported by 91% of the patients and 89% of the caregivers. Most of the patients reported improvement in tremor and rigidity, as well as in gait stability, freezing of gait, and reduced falls. The treatment was safe with few side effects. CONCLUSIONS: Our data suggest that repeated IVAM infusions could be an effective treatment against various motor symptoms and for improvement of mobility in patients with advanced Parkinsonism. Further randomized clinical trials with a larger sample size using objective measures are warranted to validate our results.


Assuntos
Acidentes por Quedas/prevenção & controle , Amantadina , Destreza Motora/efeitos dos fármacos , Doença de Parkinson , Recuperação de Função Fisiológica/efeitos dos fármacos , Idoso , Amantadina/administração & dosagem , Amantadina/efeitos adversos , Progressão da Doença , Dopaminérgicos/administração & dosagem , Dopaminérgicos/efeitos adversos , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/fisiopatologia , Estudos Retrospectivos , Resultado do Tratamento
16.
Artigo em Inglês | MEDLINE | ID: mdl-31656691

RESUMO

Background: Paraneoplastic chorea is typically a subacute progressive hyperkinetic movement disorder. The mainstay of treatment is managing the underlying neoplasm. However, the clinical course may be variable, and effective symptomatic management can precede the start of cancer treatment. Case report: A 63-year-old man presented with insidious onset, slowly progressive generalized chorea for 1 year, later diagnosed as anti-CV2/CRMP5 autoantibody positive paraneoplastic chorea. His chorea was markedly improved with intravenous amantadine. Discussion: In patients with anti-CV2/CRMP5 autoantibody-related chorea, sequential follow-up of brain magnetic resonance imaging reveals progression from active inflammation to atrophy. Our report highlights the efficacy of intravenous amantadine in paraneoplastic chorea.


Assuntos
Amantadina/administração & dosagem , Autoanticorpos/sangue , Proteínas de Transporte/sangue , Coreia/sangue , Coreia/tratamento farmacológico , Hidrolases/sangue , Proteínas Associadas aos Microtúbulos/sangue , Administração Intravenosa , Coreia/diagnóstico por imagem , Dopaminérgicos/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
17.
Clin Transl Sci ; 12(6): 586-590, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31436382

RESUMO

Amantadine is an antiviral drug available in oral and intravenous forms. Oral amantadine is used to treat the motor symptoms of early Parkinson's disease (PD) and to ameliorate dyskinesia in late-stage disease. However, the long-term influence of intravenous amantadine on motor symptoms and dyskinesias in PD has not been investigated. The aim of the present study was to examine the long-term effect of repeated boosts of intravenous amantadine in patients with PD with and without response fluctuations and dyskinesias. Twelve patients diagnosed with PD, six with levodopa intolerance or insufficient response to antiparkinson medications, and six with response fluctuations and dyskinesias, were treated with intravenous amantadine for 6 months: three sequential infusions over 3 days in the first month followed by five once-monthly infusions. Changes in motor function and involuntary movements were evaluated with the Unified Parkinson Disease Rating Scale (UPDRS) and Abnormal Involuntary Movement Scale (AIMS; dyskinesia group). A significant immediate improvement in motor scores was documented in both groups after amantadine infusion. However, the difference in mean UPDRS motor score from before the first infusion to after 6 months of treatment was not statistically significant. In patients with dyskinesias, there was a significant improvement in AIMS scores between the first and the last visits (6.3 ± 2.7 vs. 1.6 ± 1.3; P = 0.014). In conclusion, continuous treatment with intravenous amantadine can be useful in patients with PD for immediate relief of motor symptoms and in patients with dyskinesias for progressive reduction of involuntary movements.


Assuntos
Amantadina/administração & dosagem , Antiparkinsonianos/administração & dosagem , Discinesias/tratamento farmacológico , Doença de Parkinson/tratamento farmacológico , Idoso , Esquema de Medicação , Discinesias/diagnóstico , Discinesias/etiologia , Feminino , Humanos , Infusões Intravenosas , Masculino , Atividade Motora/efeitos dos fármacos , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico , Projetos Piloto , Índice de Gravidade de Doença , Resultado do Tratamento
18.
Neurodegener Dis Manag ; 9(4): 205-215, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31392922

RESUMO

Aim: To determine the effectiveness and safety of extended-release amantadine (ADS-5102) for levodopa-induced dyskinesias (LID) in patients with Parkinson disease (PD) by conducting a meta-analysis of relevant trials. Methods: The electronic databases were searched on or before March 1, 2019 for relevant trials. Only randomized, double-blind, parallel-group, placebo-controlled trials using ADS-5102 for LID in PD were included. Results: The ADS-5102 showed a reduction in the dyskinesia scores (mean difference: -9.56: CI: -10.05 to -9.07; p < 0.00001) and in the on time without troublesome dyskinesia (mean difference 2.50: CI 2.38 to 2.63; p < 0.00001). The adverse events identified in ADS-5102 were visual hallucinations, constipation, dry mouth and fall. Conclusion: ADS-5102 can be used as an adjunct therapy for LID.


Assuntos
Amantadina/uso terapêutico , Antiparkinsonianos/uso terapêutico , Discinesia Induzida por Medicamentos/tratamento farmacológico , Levodopa/efeitos adversos , Acidentes por Quedas , Idoso , Idoso de 80 Anos ou mais , Amantadina/administração & dosagem , Amantadina/efeitos adversos , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/efeitos adversos , Viés , Constipação Intestinal/induzido quimicamente , Preparações de Ação Retardada , Método Duplo-Cego , Quimioterapia Combinada , Discinesia Induzida por Medicamentos/etiologia , Feminino , Alucinações/induzido quimicamente , Humanos , Levodopa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença , Resultado do Tratamento , Xerostomia/induzido quimicamente
19.
CNS Drugs ; 33(8): 783-789, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31342404

RESUMO

BACKGROUND: An extended-release formulation of amantadine (Osmolex ER™, Osmotica Pharmaceutical US LLC) was approved in February 2018 to treat Parkinson's disease and drug-induced extrapyramidal reactions in adults. OBJECTIVES: To determine the pharmacokinetic profile of extended-release amantadine in subjects with varying degrees of renal impairment. METHODS: Adults with normal renal function (creatinine clearance > 89 mL/min/1.73 m2), moderate renal impairment (creatinine clearance 30-59 mL/min/1.73 m2), or severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73 m2) received a single 129-mg dose (160 mg amantadine hydrochloride) of extended-release amantadine. Blood and urine samples for pharmacokinetic analysis were taken at scheduled intervals. A two-compartment pharmacokinetic population model was employed to determine optimum extended-release amantadine dosing in subjects with renal impairment. RESULTS: Following a single oral dose of the 129-mg extended-release amantadine tablet, amantadine plasma concentration increased slowly, reaching a peak at approximately 11 h. Amantadine elimination was reduced in subjects with renal impairment. Renal clearance decreased from 10,965 to 2618 mL/h in subjects with severe renal impairment compared to those with normal renal function. Pharmacokinetic modeling and simulation methods were used to recommend the oral administration of 129-mg extended-release amantadine tablets at intervals of 24, 48, 72, 96, 120, or 168 h depending on the degree of renal function. CONCLUSIONS: Renal impairment was associated with reduced amantadine clearance. Based on pharmacokinetic modeling and simulations, dose regimens were recommended for subjects with impaired renal function to provide systemic amantadine exposure similar to subjects with normal renal function taking a once-daily extended-release amantadine tablet.


Assuntos
Amantadina/administração & dosagem , Amantadina/farmacocinética , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Insuficiência Renal/metabolismo , Comprimidos/administração & dosagem , Comprimidos/farmacocinética , Administração Oral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Amantadina/uso terapêutico , Preparações de Ação Retardada/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/tratamento farmacológico , Comprimidos/uso terapêutico , Adulto Jovem
20.
Brain Inj ; 33(9): 1137-1150, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31250669

RESUMO

Objectives: To systematically review literature on efficacy of amantadine on behavior (irritability/aggression/agitation, emotional lability, apathy, impairment of executive functioning), participation, quality-of-life (QoL), and safety, in patients with acquired brain injury (ABI). Amantadine is widely used clinically, so comprehensive information on efficacy, participation, QoL and safety is relevant. Methods: We used PRISMA Guidelines. We searched PubMed/EMBASE/CINAHL (last search 28-8-2018) Two independent reviewers performed selection and data-extraction. Quality of studies was assessed, using CONSORT and Quality Assessment Tool for Quantitative Studies (QATFQS). Results: Eleven out of 500 studies were included. Of five RCTs, two reported significant effects on irritability/aggression, and one no effect. One RCT on cognition no effect. One prospective cohort study showed a significant effect on executive functioning. One retrospective study was inconclusive. One single-case experimental design (SCED) study reported significant effect on apathy and three case-reports indicated effects on behavior. QoL and societal participation were not measured. No safety issues emerged. Conclusion: Amantadine may be efficacious on irritability and aggression after ABI. Amantadine is a safe drug in the presence of adequate creatinine clearance. Future studies should use designs, suitable for the heterogeneous ABI population, like randomized SCEDs, and should include the effect on societal participation and QoL.


Assuntos
Agressão/efeitos dos fármacos , Amantadina/uso terapêutico , Lesões Encefálicas/complicações , Disfunção Cognitiva/tratamento farmacológico , Dopaminérgicos/uso terapêutico , Função Executiva/efeitos dos fármacos , Humor Irritável/efeitos dos fármacos , Amantadina/administração & dosagem , Apatia/efeitos dos fármacos , Disfunção Cognitiva/etiologia , Dopaminérgicos/administração & dosagem , Humanos , Comportamento Problema , Qualidade de Vida , Resultado do Tratamento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...