RESUMEN
Malignant catatonia (MC) is a complex, life-threatening condition characterized by motor dysregulation and autonomic instability, which requires prompt and effective treatment. There are some limitations to the current recommendations for treating MC, including barriers to receiving ECT, failure to respond to benzodiazepines, or benzodiazepine intolerance. To the authors' knowledge, there are 3 case reports in the literature describing the use of amantadine in the treatment of MC. We present the case of a 51-year-old female with a history of multiple medical and psychiatric conditions who was admitted to the hospital for altered mental status. During her admission, she developed symptoms that raised concern about MC, which was initially managed with lorazepam. However, due to concerns about severe respiratory compromise, lorazepam was discontinued, and the patient was started on liquid amantadine. She showed marked reduction in the symptoms of malignant catatonia, and the autonomic instability resolved after she was started on amantadine. The patient was eventually discharged home with outpatient follow-up scheduled. Our case report shows successful treatment of MC with liquid amantadine in a patient who was unable to tolerate escalating doses of benzodiazepines. The positive response to amantadine suggests that it may be a useful treatment option for MC. While further studies are needed, clinicians should consider the use of amantadine in the treatment of MC, especially in patients who are unable to tolerate benzodiazepines, who have failed to respond to treatment with benzodiazepines, or who are being treated in institutions where the availability of ECT is limited. Amantadine may be more readily accessible given its multiple formulations and wide availability.
Asunto(s)
Amantadina , Catatonia , Humanos , Amantadina/administración & dosificación , Amantadina/uso terapéutico , Femenino , Persona de Mediana Edad , Catatonia/tratamiento farmacológico , Catatonia/etiología , Dopaminérgicos/administración & dosificación , Lorazepam/administración & dosificación , Lorazepam/uso terapéuticoRESUMEN
BACKGROUND: Cognitive dysfunction is a non-motor manifestation of Parkinson's disease (PD). We aimed to determine the frequency and patterns of cognitive dysfunction in treated patients with PD and their predictors. RESEARCH DESIGN AND METHODS: This study included 80 patients (male = 48; female = 32) and 30 healthy individuals. They underwent neuropsychiatric evaluations. Measurements included Beck's depression inventory - II (BDI-II), mini-mental state examination (MMSE) and Montreal cognitive assessment (MoCA). RESULTS: Patients had mean age of 55.56 ± 9.06 yrs, duration of PD of 4.86 ± 2.71 yrs and Hoehn and Yahr Scoring of 2.19 ± 0.89. They were on levodopa/carbidopa therapy and adjuvant therapy with benztropine mesylate, an anticholinergic drug, (n = 51) or amantadine sulfate, a dopaminergic drug, (n = 29). Sixteen (20%) had moderate depressive symptoms. Mild and moderate cognitive impairments were reported in 38.8% and 28.8% (by MMSE) and 46.3% and 31.3% (by MoCA). Patients had lower global cognitive scoring (p = 0.0001) and scorings of different cognitive functions (naming, attention, language, abstraction, memory and orientation) than controls. Patients treated with benztropine had lower cognition than with amantadine. Correlation analyses showed that lower cognition was only associated with chronic PD and its treatment (p = 0.0001). CONCLUSIONS: Cognitive dysfunction is common with PD (77.5%) particularly with anticholinergic drugs. De-prescription of anticholinergics is recommended for patients with PD.
Asunto(s)
Antiparkinsonianos , Antagonistas Colinérgicos , Disfunción Cognitiva , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/fisiopatología , Masculino , Persona de Mediana Edad , Antagonistas Colinérgicos/administración & dosificación , Antagonistas Colinérgicos/efectos adversos , Femenino , Antiparkinsonianos/administración & dosificación , Antiparkinsonianos/farmacología , Antiparkinsonianos/efectos adversos , Estudios de Cohortes , Disfunción Cognitiva/etiología , Disfunción Cognitiva/tratamiento farmacológico , Egipto , Anciano , Estudios de Casos y Controles , Levodopa/administración & dosificación , Levodopa/farmacología , Levodopa/efectos adversos , Adulto , Amantadina/administración & dosificación , Amantadina/farmacología , Amantadina/efectos adversos , Carbidopa/administración & dosificación , Carbidopa/farmacología , Carbidopa/efectos adversos , Pruebas Neuropsicológicas , Combinación de Medicamentos , Depresión/tratamiento farmacológico , Depresión/epidemiología , Benzotropina/farmacología , Benzotropina/administración & dosificación , Benzotropina/efectos adversos , Cognición/efectos de los fármacos , Dopaminérgicos/administración & dosificación , Dopaminérgicos/farmacología , Dopaminérgicos/efectos adversosRESUMEN
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.
Asunto(s)
Amantadina , Modelos Biológicos , Humanos , Anciano , Amantadina/farmacocinética , Amantadina/administración & dosificación , Adulto , Persona de Mediana Edad , Anciano de 80 o más Años , Masculino , Adulto Joven , Adolescente , Femenino , Transportador 2 de Cátion Orgánico/metabolismo , Eliminación Renal , Proteínas de Transporte de Catión Orgánico/metabolismo , Tratamiento Farmacológico de COVID-19 , Factores de Edad , Voluntarios Sanos , Simulación por ComputadorRESUMEN
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.
Asunto(s)
Amantadina , Antiparkinsonianos , Preparaciones de Acción Retardada , Distonía , Enfermedad de Parkinson , Humanos , Amantadina/administración & dosificación , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/tratamiento farmacológico , Masculino , Femenino , Distonía/tratamiento farmacológico , Distonía/etiología , Anciano , Persona de Mediana Edad , Antiparkinsonianos/administración & dosificación , Método Doble CiegoRESUMEN
OBJECTIVE: To quantify the benefits versus harms of amantadine in the treatment of irritability and aggression following traumatic brain injury. METHODS: Secondary outcome data from a randomized controlled multisite trial of amantadine 100 mg twice daily were used to calculate number-needed-to-treat (NNT). Given prior findings of positive clinician-perceived effects and low incidence of adverse events, we hypothesized low number-needed-to-treat for benefit (NNTB; high benefit) and high number-needed-to-treat for harm (NNTH; low risk) based on the clinician ratings, supporting the use of amantadine in clinical practice. Specifically, NNTB values were calculated using number of individuals with improvement on the Clinician Global Impressions-Global Improvement scale (GI). NNTH values were computed using number of individuals with worsening on the GI and experiencing serious and any adverse events. RESULTS: Based on clinician ratings, on average for every six patients treated with amantadine rather than placebo, one extra patient would be expected to improve (NNTB = 6.4; 95% confidence interval [CI]: [3.3-76.8]). More participants in the placebo group worsened than in the amantadine group, but the result was not statistically significant (NNTH = -92.4; 95% CI: [NNTB -32.9 to infinity to NNTH -19.2]). The amantadine and placebo groups did not differ on the numbers of adverse events experienced during the trial. CONCLUSION: Clinician ratings suggest modest benefit of amantadine 100 mg twice daily with low risk to appropriately selected patients with adequate renal clearance. Thus, amantadine should be considered a treatment option for the experienced brain injury clinician. These data may support treatment decisions when a pharmaceutical agent is being considered to control irritability/aggression.
Asunto(s)
Agresión , Amantadina , Lesiones Traumáticas del Encéfalo , Genio Irritable , Humanos , Amantadina/uso terapéutico , Amantadina/administración & dosificación , Amantadina/efectos adversos , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Lesiones Traumáticas del Encéfalo/complicaciones , Agresión/efectos de los fármacos , Genio Irritable/efectos de los fármacos , Masculino , Femenino , Adulto , Medición de Riesgo , Persona de Mediana Edad , Dopaminérgicos/administración & dosificación , Dopaminérgicos/efectos adversos , Dopaminérgicos/uso terapéutico , Resultado del Tratamiento , Método Doble Ciego , Relación Dosis-Respuesta a DrogaRESUMEN
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.
Asunto(s)
Amantadina/administración & dosificación , Antiparkinsonianos/administración & dosificación , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Enfermedad de Parkinson/tratamiento farmacológico , Amantadina/efectos adversos , Amantadina/farmacocinética , Animales , Antiparkinsonianos/efectos adversos , Antiparkinsonianos/farmacocinética , Confusión/inducido químicamente , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/efectos adversos , Preparaciones de Acción Retardada/farmacocinética , Dopamina/metabolismo , Quimioterapia Combinada , Discinesia Inducida por Medicamentos/metabolismo , Humanos , Levodopa/efectos adversos , Náusea/inducido químicamente , Enfermedad de Parkinson/metabolismoRESUMEN
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.
Asunto(s)
Agonistas Adrenérgicos/farmacología , Antagonistas Adrenérgicos/farmacología , Amantadina/farmacología , Antidepresivos/farmacología , Conducta Animal/efectos de los fármacos , Agonistas de Aminoácidos Excitadores/farmacología , Receptores de Dopamina D2/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Amantadina/administración & dosificación , Animales , Antidepresivos/administración & dosificación , Inhibidores Enzimáticos/farmacología , Hipocampo/efectos de los fármacos , Masculino , Ratones , Neurogénesis/efectos de los fármacos , alfa-Metiltirosina/farmacologíaRESUMEN
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.
Asunto(s)
Amantadina/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Fatiga/tratamiento farmacológico , Fatiga/etiología , Metilfenidato/farmacología , Modafinilo/farmacología , Esclerosis Múltiple/complicaciones , Evaluación de Resultado en la Atención de Salud , Adulto , Amantadina/administración & dosificación , Amantadina/efectos adversos , Estimulantes del Sistema Nervioso Central/administración & dosificación , Estimulantes del Sistema Nervioso Central/efectos adversos , Estudios Cruzados , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Masculino , Metilfenidato/administración & dosificación , Metilfenidato/efectos adversos , Persona de Mediana Edad , Modafinilo/administración & dosificación , Modafinilo/efectos adversos , Índice de Severidad de la EnfermedadRESUMEN
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.
Asunto(s)
Amantadina/administración & dosificación , Lesiones Traumáticas del Encéfalo/rehabilitación , Estado Vegetativo Persistente , Adolescente , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Hospitalización , Humanos , Masculino , Resultado del TratamientoRESUMEN
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.
Asunto(s)
Amantadina/farmacología , Dopaminérgicos/farmacología , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Levodopa/farmacología , Trastornos Parkinsonianos/tratamiento farmacológico , Piperidinas/farmacología , Piridinas/farmacología , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Amantadina/administración & dosificación , Animales , Modelos Animales de Enfermedad , Dopaminérgicos/efectos adversos , Discinesia Inducida por Medicamentos/etiología , Femenino , Levodopa/efectos adversos , Macaca fascicularis , Piperidinas/administración & dosificación , Piperidinas/farmacocinética , Piridinas/administración & dosificación , Piridinas/farmacocinética , Agonistas del Receptor de Serotonina 5-HT1/administración & dosificación , Agonistas del Receptor de Serotonina 5-HT1/farmacocinéticaRESUMEN
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.
Asunto(s)
Antiparkinsonianos/efectos adversos , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Levodopa/efectos adversos , Amantadina/administración & dosificación , Amantadina/farmacología , Animales , Antiparkinsonianos/administración & dosificación , Desarrollo de Medicamentos , Reposicionamiento de Medicamentos , Discinesia Inducida por Medicamentos/etiología , Discinesia Inducida por Medicamentos/fisiopatología , Humanos , Levodopa/administración & dosificación , Enfermedad de Parkinson/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como AsuntoAsunto(s)
Amantadina/administración & dosificación , Síndrome de Opsoclonía-Mioclonía , Clorhidrato de Venlafaxina/administración & dosificación , Fiebre del Nilo Occidental , Anciano , Anticuerpos Antivirales/sangre , Antivirales/administración & dosificación , Femenino , Humanos , Examen Neurológico/métodos , Síndrome de Opsoclonía-Mioclonía/líquido cefalorraquídeo , Síndrome de Opsoclonía-Mioclonía/diagnóstico , Síndrome de Opsoclonía-Mioclonía/etiología , Síndrome de Opsoclonía-Mioclonía/inmunología , Pruebas Serológicas/métodos , Inhibidores de Captación de Serotonina y Norepinefrina/administración & dosificación , Resultado del Tratamiento , Fiebre del Nilo Occidental/complicaciones , Fiebre del Nilo Occidental/diagnóstico , Fiebre del Nilo Occidental/tratamiento farmacológico , Fiebre del Nilo Occidental/fisiopatología , Virus del Nilo Occidental/inmunología , Virus del Nilo Occidental/aislamiento & purificaciónAsunto(s)
Conducta Compulsiva/inducido químicamente , Trastornos Disruptivos, del Control de Impulso y de la Conducta/inducido químicamente , Agonistas de Dopamina/efectos adversos , Gonorrea/etiología , Enfermedad de Parkinson/tratamiento farmacológico , Disfunciones Sexuales Psicológicas/inducido químicamente , Amantadina/administración & dosificación , Amantadina/efectos adversos , Apomorfina/administración & dosificación , Apomorfina/efectos adversos , Conducta Compulsiva/complicaciones , Trastornos Disruptivos, del Control de Impulso y de la Conducta/complicaciones , Agonistas de Dopamina/administración & dosificación , Femenino , Humanos , Levodopa/administración & dosificación , Levodopa/efectos adversos , Persona de Mediana Edad , Enfermedad de Parkinson/complicaciones , Disfunciones Sexuales Psicológicas/complicaciones , Tetrahidronaftalenos/administración & dosificación , Tetrahidronaftalenos/efectos adversos , Tiofenos/administración & dosificación , Tiofenos/efectos adversosRESUMEN
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 (0.03â0.3 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 (0.03â0.3 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.
Asunto(s)
Antiparkinsonianos/efectos adversos , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Levodopa/efectos adversos , Trastornos Parkinsonianos/tratamiento farmacológico , Inhibidores de Fosfodiesterasa/uso terapéutico , Hidrolasas Diéster Fosfóricas/metabolismo , Administración Oral , Amantadina/administración & dosificación , Amantadina/uso terapéutico , Animales , Antiparkinsonianos/uso terapéutico , Relación Dosis-Respuesta a Droga , Discinesia Inducida por Medicamentos/enzimología , Levodopa/uso terapéutico , Masculino , Actividad Motora/efectos de los fármacos , Oxidopamina/administración & dosificación , Inhibidores de Fosfodiesterasa/administración & dosificación , Ratas Sprague-DawleyRESUMEN
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 274âmg 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).
Asunto(s)
Amantadina/farmacología , Dopaminérgicos/farmacología , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Levodopa/efectos adversos , Enfermedad de Parkinson/tratamiento farmacológico , Anciano , Amantadina/administración & dosificación , Amantadina/efectos adversos , Amantadina/farmacocinética , Preparaciones de Acción Retardada , Dopaminérgicos/administración & dosificación , Dopaminérgicos/efectos adversos , Dopaminérgicos/farmacocinética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de SaludRESUMEN
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 75â¯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 (50â¯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 (25â¯mg/kg, i.p.) and diazepam (1â¯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 (25â¯mg/kg, i.p.) and diazepam (1â¯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.
Asunto(s)
Amantadina/farmacología , Ansiolíticos/farmacología , Ansiedad/tratamiento farmacológico , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/farmacología , Ácido Glutámico/efectos de los fármacos , Óxido Nítrico/metabolismo , Nitritos/metabolismo , Transducción de Señal/efectos de los fármacos , Ácido gamma-Aminobutírico/efectos de los fármacos , Amantadina/administración & dosificación , Animales , Ansiolíticos/administración & dosificación , Encéfalo/metabolismo , Diazepam/farmacología , Modelos Animales de Enfermedad , Quimioterapia Combinada , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Moduladores del GABA/administración & dosificación , Moduladores del GABA/farmacología , Masculino , Ratones , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidoresRESUMEN
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.
Asunto(s)
Amantadina/farmacología , Antiparkinsonianos/farmacología , Agonistas de Dopamina/farmacología , Levodopa/farmacología , Inhibidores de la Monoaminooxidasa/farmacología , Evaluación de Resultado en la Atención de Salud/normas , Enfermedad de Parkinson/tratamiento farmacológico , Anciano , Amantadina/administración & dosificación , Antiparkinsonianos/administración & dosificación , Catecoles/farmacología , Agonistas de Dopamina/administración & dosificación , Quimioterapia Combinada , Femenino , Humanos , Levodopa/administración & dosificación , Masculino , Persona de Mediana Edad , Inhibidores de la Monoaminooxidasa/administración & dosificación , Nitrilos/farmacología , Estudios RetrospectivosRESUMEN
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.
Asunto(s)
Accidentes por Caídas/prevención & control , Amantadina , Destreza Motora/efectos de los fármacos , Enfermedad de Parkinson , Recuperación de la Función/efectos de los fármacos , Anciano , Amantadina/administración & dosificación , Amantadina/efectos adversos , Progresión de la Enfermedad , Dopaminérgicos/administración & dosificación , Dopaminérgicos/efectos adversos , Relación Dosis-Respuesta a Droga , Monitoreo de Drogas/métodos , Femenino , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/fisiopatología , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
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.
Asunto(s)
Amantadina/administración & dosificación , Autoanticuerpos/sangre , Proteínas Portadoras/sangre , Corea/sangre , Corea/tratamiento farmacológico , Hidrolasas/sangre , Proteínas Asociadas a Microtúbulos/sangre , Administración Intravenosa , Corea/diagnóstico por imagen , Dopaminérgicos/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
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.