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1.
Mov Disord ; 39(2): 350-359, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37886872

RESUMO

BACKGROUND: There remains uncertainty as to the optimal way to initiate therapy for Parkinson's disease (PD) to maximize benefit and minimize adversity. OBJECTIVES: The objective was to determine if P2B001 (a fixed, low-dose, extended-release [ER] combination of pramipexole 0.6 mg and rasagiline 0.75 mg) is superior to each of its components and compare its safety and efficacy to optimized treatment with marketed doses of pramipexole-ER. METHODS: This was a 12-week, double-blind study (NCT03329508). Total of 544 untreated patients with PD were randomized (2:2:2:1) to treatment with P2B001, its individual components (pramipexole-ER 0.6 mg or rasagiline-ER 0.75 mg), or commercial doses of pramipexole-ER titrated to optimal dose (1.5-4.5 mg). The primary endpoint was change from baseline to week 12 in Unified Parkinson's Disease Rating Scale (UPDRS) parts II and III. The key secondary endpoint was the change from baseline in the Epworth Sleepiness Scale (ESS) for P2B001 versus the titrated dose of pramipexole-ER. RESULTS: P2B001 provided superior efficacy compared to each of its components; mean (95% CI) treatment differences in UPDRS II + III scores were -2.66 (95% CI, -4.33 to -1.00) versus pramipexole-ER 0.6 mg (P = 0.0018) and - 3.30 (95% CI, -4.96 to -1.63) versus rasagiline-ER 0.75 mg (P < 0.0001). P2B001 had comparable efficacy with the titrated dose of pramipexole-ER (mean, 3.2 mg), but significantly less worsening in daytime-sleepiness (ESS treatment difference: -2.66 [95% CI, -3.50 to -1.81]; P < 0.0001). P2B001 was well-tolerated with fewer sleep-related and dopaminergic adverse events than titrated doses of pramipexole-ER including somnolence, orthostatic hypotension, and neuropsychiatric side effects. CONCLUSIONS: P2B001 had superior efficacy to its individual components and was comparable with commercially used doses of pramipexole-ER with less worsening of sleepiness and fewer dopaminergic adverse events. These findings support considering once-daily P2B001 as initial therapy for patients with early PD. © 2023 International Parkinson and Movement Disorder Society.


Assuntos
Indanos , Doença de Parkinson , Humanos , Pramipexol , Doença de Parkinson/tratamento farmacológico , Antiparkinsonianos/efeitos adversos , Sonolência , Benzotiazóis/uso terapêutico , Método Duplo-Cego
2.
Am J Case Rep ; 22: e933995, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34776506

RESUMO

BACKGROUND Multiple system atrophy cerebellar type (MSA-C) is a subtype of MSA that presents with predominant ataxia along with lesser signs of parkinsonism and autonomic dysfunction. Previous studies have shown benefits from carbidopa/levodopa therapy for the MSA parkinsonian subtype but few studies have focused on the MSA-C subtype. We present a video case of MSA-C that demonstrated significant improvement with carbidopa/levodopa therapy. CASE REPORT A right-handed 61-year-old man with a past medical history of chronic microvascular ischemia, mild lower extremity neuropathy, and lumbar and cervical stenosis status after decompression presented with progressive worsening gait changes over several months with acute deterioration before admission. The initial neurological workup demonstrated bilateral cogwheel rigidity; difficulty with movement initiation. including standing up from a seated position; slow saccadic eye movements; masked facies (hypomimia); right ankle clonus; bilateral upper and left lower limb ataxia; and hyperreflexia. A follow-up workup was negative for metabolic, infectious, and paraneoplastic causes, but magnetic resonance imaging demonstrated cerebellar atrophy along with a "hot cross bun sign" suggestive of probable MSA-C according to consensus criteria, and the patient was started on carbidopa-levodopa. He subsequently demonstrated improvement in key motor domains, including his cogwheel rigidity and gait testing, and was discharged shortly thereafter. CONCLUSIONS Through this case report, we highlight a significant response to L-dopa therapy beyond what is normally expected according to diagnostic criteria for MSA. MSA treatment responsiveness can vary significantly across patients, which warrants additional studies into appropriate treatment choices for patients with Parkinson's disease and MSA.


Assuntos
Atrofia de Múltiplos Sistemas , Doença de Parkinson , Transtornos Parkinsonianos , Cerebelo , Dopamina , Humanos , Masculino , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/diagnóstico , Atrofia de Múltiplos Sistemas/tratamento farmacológico
3.
J Parkinsons Dis ; 9(3): 591-600, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31081793

RESUMO

BACKGROUND: Parkinson's disease (PD) patients using levodopa commonly develop dyskinesia and OFF episodes that reduce quality of life. OBJECTIVE: Evaluate prevalence of troublesome dyskinesia and OFF through the day, assessed by 30-minute intervals, as well as the mean number and duration of troublesome dyskinesia and OFF episodes, transitions between PD states, and effects of Gocovri® (amantadine) extended release capsules on these episodes. METHODS: Evaluate diary data from pooled Gocovri phase 3, placebo-controlled trials-analyzed for 17 hours following wake-up-at baseline and week 12. RESULTS: Diaries were evaluable for 162 patients. At baseline, 67% of patients woke up OFF, with prevalence decreasing to 13% at 2 hours and then remaining relatively steady at ∼12% (range, 6-17%) across half-hour intervals thereafter. Troublesome dyskinesia prevalence rose steadily from 5% to 24% over the first 2 hours, then fluctuated between 20% and 44% through the rest of the waking day. At baseline, patients experienced a mean of 3.0 daily episodes of troublesome dyskinesia (average duration 2.0 hours each), and 2.2 daily episodes of OFF (average duration 1.1 hour each). At week 12, Gocovri-treated patients showed greater reductions than placebo in troublesome dyskinesia and OFF episodes per day (treatment difference: -1.0 episodes and -0.4 episodes, respectively) and average episode duration (treatment difference: -0.6 hours and -0.3 hours, respectively). Mean duration of individual episodes of ON without troublesome dyskinesia (Good ON) increased by 5.0 hours for Gocovri, compared with 2.0 hours for placebo. Patients taking Gocovri experienced 2.2 fewer transitions between states than patients taking placebo. CONCLUSIONS: Troublesome dyskinesia and OFF occurred in the morning and throughout the waking day. Gocovri-treated patients experienced fewer, shorter episodes of both troublesome dyskinesia and OFF, thereby increasing the duration of continuous Good ON episodes and reducing the frequency of transitions between motor states.


Assuntos
Amantadina/efeitos adversos , Antiparkinsonianos/efeitos adversos , Discinesia Induzida por Medicamentos/epidemiologia , Levodopa/efeitos adversos , Avaliação de Resultados em Cuidados de Saúde , Doença de Parkinson/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Preparações de Ação Retardada , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência
4.
CNS Drugs ; 32(4): 399-400, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29637528

RESUMO

An Online First version of this article was made available online at http://link.springer.com/journal/40263/onlineFirst/page/1 on 12 March 2018. An error was subsequently identified in the article, and the following correction should be noted.

5.
CNS Drugs ; 32(4): 387-398, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29532440

RESUMO

BACKGROUND: Although levodopa is considered the most effective pharmacotherapy for motor symptoms of Parkinson's disease (PD), chronic use is associated with motor complications, including fluctuating response and unpredictable, involuntary movements called dyskinesia. ADS-5102 (amantadine) extended-release (ER) capsules (GOCOVRITM) is a recent US FDA-approved treatment for dyskinesia in PD patients. ADS-5102 is a high-dose, ER formulation of amantadine, administered orally once daily at bedtime, that achieves high plasma drug concentrations throughout the day. OBJECTIVE: In this study, we present pooled results from two randomized, double-blind, placebo-controlled, phase III ADS-5102 trials. PATIENTS AND METHODS: The two studies in PD patients with dyskinesia shared design and eligibility criteria, differing only in treatment duration. Results from common assessment time points were pooled. RESULTS: At 12 weeks, the least squares (LS) mean change in total score on the Unified Dyskinesia Rating Scale among 100 patients randomized to ADS-5102 and 96 patients randomized to placebo was - 17.7 (standard error [SE] 1.3) vs. - 7.6 (1.3) points, respectively (- 10.1 points, 95% confidence interval [CI] - 13.8, - 6.5; p < 0.0001). The relative treatment difference between groups was 27.3% (p < 0.0001). At 12 weeks, the LS mean change in OFF time was - 0.59 (0.21) vs. +0.41 (0.20) h/day, a difference of - 1.00 h/day (95% CI - 1.57, - 0.44; p = 0.0006). For both efficacy measures, a significant difference from placebo was attained by two weeks, the first post-baseline assessment, and was maintained throughout 12 weeks. In the pooled ADS-5102 group, the most common adverse events were hallucination, dizziness, dry mouth, peripheral edema, constipation, falls, and orthostatic hypotension. CONCLUSIONS: These analyses provide further evidence supporting ADS-5102 as an adjunct to levodopa for treating both dyskinesia and OFF time in PD patients with dyskinesia. Clinicaltrials.gov identifier: NCT02136914 and NCT02274766.


Assuntos
Amantadina/uso terapêutico , Antiparkinsonianos/efeitos adversos , Antiparkinsonianos/uso terapêutico , Discinesia Induzida por Medicamentos/tratamento farmacológico , Doença de Parkinson/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Amantadina/efeitos adversos , Cápsulas , Preparações de Ação Retardada , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
6.
JAMA Neurol ; 74(8): 977-982, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28692723

RESUMO

Importance: Tetrabenazine is efficacious for chorea control; however, tolerability concerns exist. Deutetrabenazine, a novel molecule that reduces chorea, was well tolerated in a double-blind, placebo-controlled study. Objectives: To evaluate the safety and explore the efficacy of conversion from tetrabenazine to deutetrabenazine in patients with chorea associated with Huntington disease (HD). Design, Setting, and Participants: In this ongoing, open-label, single-arm study that started on December 21, 2013, 37 patients at 13 Huntington Study Group sites in the United States and Australia who were taking stable doses of tetrabenazine that provided a therapeutic benefit were switched overnight to deutetrabenazine therapy. After week 1, the deutetrabenazine dose was titrated on a weekly basis for optimal chorea control. Interventions: Deutetrabenazine administration at a dosage thought to provide comparable systemic exposure to the active metabolites of the prior, stable tetrabenazine regimen. Main Outcomes and Measures: Safety measures included adverse events (AEs), clinical laboratory tests, vital signs, electrocardiograms, and validated scales. Changes in the Unified Huntington's Disease Rating Scale total maximal chorea score and total motor score were efficacy end points. Results: Of the 53 patients with HD screened for the study, 37 ambulatory patients with manifest HD (mean [SD] age, 52.4 [11.5] years; 22 [59%] male and 15 [41%] female; 36 white [97.3%]) were enrolled. Deutetrabenazine was generally well tolerated, with low rates of neuropsychiatric AEs. Safety scales did not reveal subclinical toxicity with deutetrabenazine treatment. Rates of dose reduction or suspension attributable to AEs were also low. Chorea control, as measured by the total maximal chorea score, was maintained at week 1 and significantly improved at week 8 (mean [SD] change from baseline, 2.1 [3.2]; P < .001). Conclusions and Relevance: In patients with chorea, overnight conversion to deutetrabenazine therapy provided a favorable safety profile and effectively maintained chorea control.


Assuntos
Inibidores da Captação Adrenérgica/uso terapêutico , Coreia/tratamento farmacológico , Substituição de Medicamentos/métodos , Tetrabenazina/análogos & derivados , Tetrabenazina/uso terapêutico , Austrália , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do Tratamento , Estados Unidos
7.
Mov Disord ; 32(5): 783-789, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28370340

RESUMO

BACKGROUND: Rasagiline and pramipexole act to improve striatal dopaminergic transmission in PD via distinct and potentially synergistic mechanisms. We performed a placebo-controlled study to determine whether 2 doses of a novel slow-release, low-dose combination of rasagiline and pramipexole (P2B001) are effective and have a good safety profile in patients with early untreated PD. METHODS: Previously untreated patients with early PD were randomized (1:1:1) to once-daily treatment with P2B001 (0.3 mg pramipexole/0.75 mg rasagiline), P2B001 (0.6 mg pramipexole/0.75 mg rasagiline) or placebo in a 12-week multicenter double-blind, placebo-controlled trial. The primary endpoint was the change from baseline to final visit in Total-UPDRS score versus placebo. Secondary measures included responder analyses of patients achieving ≥4 UPDRS point reduction, and changes in Parkinson Disease Quality of Life Scale-39 and UPDRS activities of daily living and motor scores. RESULTS: A total of 149 participants were randomized and 136 (91.3%) completed the study. Adjusted mean change from baseline to final visit versus placebo in Total-UPDRS score was -4.67 ± 1.28 points for the P2B001 0.6/0.75 mg group (P = .0004) and -3.84 ± 1.25 points for the 0.3/0.75 mg group (P = .003). Significant benefits were also observed for both doses in the responder analysis (P = .0002 and P = .0001), Parkinson Disease Quality of Life Scale-39 scores (P = .05 and P = .01), and the UPDRS motor (P = .02 and P = .006) and activities of daily living (P = .005 and P = .0004) subscores. Adverse events of P2B001 were comparable to placebo apart from transient nausea and somnolence, which were more common with P2B001 treatment. CONCLUSIONS: P2B001 offers a promising treatment option for patients with early PD with good clinical efficacy and a low risk of adverse events. © 2017 International Parkinson and Movement Disorder Society.


Assuntos
Antiparkinsonianos/uso terapêutico , Benzotiazóis/uso terapêutico , Indanos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Idoso , Preparações de Ação Retardada , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Humanos , Israel , Masculino , Pessoa de Meia-Idade , Pramipexol , Índice de Gravidade de Doença , Trietilenomelamina , Estados Unidos
8.
Neurol Clin Pract ; 7(1): 86-93, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28243505

RESUMO

PURPOSE OF REVIEW: To help clinicians optimize the conversion of a patient's Parkinson disease pharmacotherapy from immediate-release carbidopa/levodopa (IR CD/LD) to an extended-release formulation (ER CD/LD). RECENT FINDINGS: Eleven movement disorders specialists achieved consensus positions on the modification of trial-based conversion guidelines to suit individual patients in clinical practice. SUMMARY: Because the pharmacokinetics of ER CD/LD differ from those of IR CD/LD, modification of dosage and dosing frequency are to be expected. Initial regimens may be based on doubling the patient's preconversion levodopa daily dosage and choosing a division of doses to address the patient's motor complications, e.g., wearing-off (warranting a relatively high ER CD/LD dose, possibly at a lower frequency than for IR CD/LD) or dyskinesia (warranting a relatively low dose, perhaps at an unchanged frequency). Patients should know that the main goal of conversion is a steadier levodopa clinical response, even if dosing frequency is unchanged.

9.
Clin Neuropharmacol ; 39(2): 88-93, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26882318

RESUMO

OBJECTIVES: Transdermal delivery of rotigotine maintains stable plasma concentrations for 24 hours. Three phase 3 studies of rotigotine as add-on to levodopa in advanced Parkinson's disease showed a significant reduction in "off" time from baseline to end of maintenance (EoM). However, detailed analyses over the range of a day have not yet been performed. The objective was to examine the time course of the efficacy profile of rotigotine throughout the day. METHODS: Post hoc analysis of diary data from 3 double-blind, placebo-controlled studies of rotigotine in patients with advanced Parkinson's disease inadequately controlled with levodopa, with average "off" time of ≥2.5 h/d (CLEOPATRA-PD [NCT00244387], 16-week maintenance; PREFER, 24-week maintenance; SP921 [NCT00522379], 12-week maintenance). Patients marked 30-minute intervals as "off," "on without troublesome dyskinesia," "on with troublesome dyskinesia," or "sleep." Diaries completed on the 3 days before EoM were analyzed. A 2-sample t test was performed for comparison of rotigotine + levodopa versus placebo + levodopa for mean percentage of time per status during four 6-hour periods: 12:00AM (midnight) to 6:00AM, 6:00AM to 12:00PM (noon), noon to 6:00PM, and 6:00PM to midnight. RESULTS: Data were available for 967 patients (placebo + levodopa, 260; rotigotine + levodopa, 707). During the 24-hour period at EoM, an advantage in mean percentage time spent "off" and "on without troublesome dyskinesia" was observed with rotigotine + levodopa versus placebo + levodopa during the three 6-hour periods from 6:00AM to midnight (P < 0.05; exploratory analysis). CONCLUSIONS: These exploratory analyses of patients with motor fluctuations suggest that the efficacy of rotigotine transdermal patch, as captured by diary data, in reducing "off" time and increasing "on time without troublesome dyskinesia" may cover the full waking day.


Assuntos
Agonistas de Dopamina/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/fisiopatologia , Tetra-Hidronaftalenos/uso terapêutico , Tiofenos/uso terapêutico , Vigília/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Levodopa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença
10.
J Parkinsons Dis ; 5(4): 837-45, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26444090

RESUMO

BACKGROUND: Due to the short half-life of levodopa, immediate-release carbidopa-levodopa (IR CD-LD) produces fluctuating LD concentrations, contributing to a risk of eventual motor complications. IPX066 was designed to rapidly attain therapeutic LD concentrations and maintain them to allow a dosing interval of ∼6 hours. OBJECTIVE: To extensively analyze the dosing data collected in IPX066 studies during open-label conversions from IR CD-LD alone or with entacapone (CLE) and identify patterns relevant for managing conversion in the clinical setting. METHODS: Patients had ≥2.5 hours/day of "off" time despite a stable IR or CLE regimen. Suggested initial dosing conversion tables based on prior LD daily dosage were provided. RESULTS: Of 450 patients previously treated with IR CD-LD and 110 with CLE, 87.3% and 82.7% completed conversion to IPX066, respectively. At the end of conversion, average IPX066 LD daily dosages were higher than pre-conversion dosages, with a mean conversion ratio of 2.1±0.6 for IR CD-LD and 2.8±0.8 for CLE; >90% of patients took IPX066 3 or 4 times/day, compared with a median of 5 times/day at baseline in both studies. After conversion, daily "off" time significantly decreased, with no significant increase in troublesome dyskinesia. The most common adverse event reported during conversion was nausea, with an incidence of 5.3% for conversion from IR and 7.3% from CLE. CONCLUSIONS: Among PD patients with substantial "off" time, a majority were safely converted to IPX066. The sustained LD profile from the IPX066 formulation allowed an increase in LD dose accompanied by improved motor functions, without increased troublesome dyskinesia.


Assuntos
Antiparkinsonianos/administração & dosagem , Carbidopa/administração & dosagem , Levodopa/administração & dosagem , Avaliação de Resultados em Cuidados de Saúde , Doença de Parkinson/tratamento farmacológico , Idoso , Antiparkinsonianos/efeitos adversos , Antiparkinsonianos/farmacologia , Carbidopa/efeitos adversos , Carbidopa/farmacologia , Catecóis/administração & dosagem , Catecóis/efeitos adversos , Catecóis/farmacologia , Estudos Cross-Over , Método Duplo-Cego , Esquema de Medicação , Combinação de Medicamentos , Feminino , Humanos , Levodopa/efeitos adversos , Levodopa/farmacologia , Masculino , Pessoa de Meia-Idade , Nitrilas/administração & dosagem , Nitrilas/efeitos adversos , Nitrilas/farmacologia , Resultado do Tratamento
11.
Case Rep Neurol Med ; 2015: 538523, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26106495

RESUMO

Posterior Reversible Encephalopathy Syndrome (PRES) is a clinical neuroradiological condition characterized by insidious onset of neurological symptoms associated with radiological findings indicating posterior leukoencephalopathy. PRES secondary to cerebrospinal fluid (CSF) leak leading to intracranial hypotension is not well recognized etiology of this condition. Herein, we report a case of PRES that occurred in the setting of CSF leak due to inadvertent dural puncture. Patient underwent suturing of the dural defect. Subsequently, his symptoms resolved and a repeated brain MRI showed resolution of brain lesions. The pathophysiology and mechanistic model for developing PRES in the setting of intracranial hypotension were discussed. We further highlighted the importance of tight blood pressure control in patients with CSF leak and suspected intracranial hypotension because they are more vulnerable to develop PRES with normal or slightly elevated bleed pressure values.

12.
Expert Opin Pharmacother ; 16(10): 1423-33, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25997442

RESUMO

OBJECTIVE: Investigate impact of 6-month earlier versus postponed initiation of rotigotine in patients with early Parkinson's disease (PD) with mild symptom severity. BACKGROUND: Long-term benefit of rotigotine in early-PD has been demonstrated: SP702 (NCT00594165) and SP716 (NCT00599196) were long-term, open-label extensions of double-blind, placebo-controlled studies of 6-month maintenance; rotigotine was well tolerated for up to 6 years, and demonstrated efficacy (Unified Parkinson's Disease Rating Scale [UPDRS] II + III below baseline) for ∼ 2 years (SP702) and ∼ 4 years (SP716). METHODS: Post hoc analysis of patients at Hoehn and Yahr 1-2; groups defined by treatment received in 6-month double-blind studies: 'Rotigotine-Rotigotine' received rotigotine (n = 221), 'Placebo-Rotigotine' received placebo (n = 125). RESULTS: At the start of open-label rotigotine maintenance, UPDRS II + III mean ± SD change from double-blind baseline was: -8.5 ± 10.6 'Rotigotine-Rotigotine', -7.7 ± 9.0 'Placebo-Rotigotine.' After this initial improvement scores gradually increased: It took ∼ 45 months for mean scores to cross baseline in 'Rotigotine-Rotigotine', and ∼ 21 months in 'Placebo-Rotigotine.' At the time mean UPDRS II + III had crossed baseline in 'Placebo-Rotigotine' (open-label week 84; ∼ 21 months), treatment difference (LS-mean) to 'Rotigotine-Rotigotine' change from baseline was -3.89 (95% CI -6.94, -0.84); p = 0.013. CONCLUSIONS: In this post hoc analysis, 6-month earlier initiation of rotigotine resulted in slower return to baseline mean UPDRS II + III; initiation of rotigotine in patients with minimal/no functional disability or impairment may lead to an extended benefit.


Assuntos
Agonistas de Dopamina/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Tetra-Hidronaftalenos/uso terapêutico , Tiofenos/uso terapêutico , Atividades Cotidianas , Administração Cutânea , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/fisiopatologia , Doença de Parkinson/psicologia , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento
13.
J Parkinsons Dis ; 4(3): 361-73, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24643203

RESUMO

BACKGROUND: Previous phase III studies in patients with advanced Parkinson's disease (PD) not adequately controlled on levodopa demonstrated significant reduction of 'off' time with rotigotine transdermal system up to 16 mg/24 h. However, the minimal effective dose has not been established. OBJECTIVE: This international, randomized, double-blind, placebo-controlled study (SP921; NCT00522379) investigated rotigotine dose response up to 8 mg/24 h. METHODS: Patients with advanced idiopathic PD (≥2.5 h of daily 'off' time on stable doses of levodopa) were randomized 1:1:1:1:1 to receive rotigotine 2, 4, 6, or 8 mg/24 h or placebo, titrated over 4 weeks and maintained for 12 weeks. The primary efficacy variable was change from baseline to end of maintenance in absolute time spent 'off'. RESULTS: 409/514 (80%) randomized patients completed maintenance. Mean (±SD) baseline daily 'off' times (h/day) were placebo: 6.4 (±2.5), rotigotine 2-8 mg/24 h: 6.4 (±2.6). Rotigotine 8 mg/24 h was the minimal dose to significantly reduce 'off' time versus placebo. LS mean (±SE) absolute change in daily 'off' time (h/day) from baseline was -2.4 (±0.28) with rotigotine 8 mg/24 h, and -1.5 (±0.26) with placebo; absolute change in 'off' time in the 8 mg/24 h group compared with placebo was -0.85 h/day (95% CI -1.59, -0.11; p = 0.024). There was an apparent dose-dependent trend. Adverse events (AEs) reported at a higher incidence in the rotigotine 8 mg/24 h group versus placebo included application site reactions, nausea, dry mouth, and dyskinesia; there was no worsening of insomnia, somnolence, orthostatic hypotension, confusional state or hallucinations, even in patients ≥75 years of age. CONCLUSIONS: The minimal statistically significant effective dose of rotigotine to reduce absolute 'off' time was 8 mg/24 h. The AE profile was similar to previous studies.


Assuntos
Doença de Parkinson/tratamento farmacológico , Tetra-Hidronaftalenos/administração & dosagem , Tiofenos/administração & dosagem , Administração Cutânea , Idoso , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
14.
Parkinsonism Relat Disord ; 19(11): 930-6, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23849501

RESUMO

BACKGROUND: Rasagiline was safe and effective when used as adjunct therapy with levodopa in patients with moderate-to-advanced Parkinson's disease (PD) in the phase III PRESTO and LARGO studies. OBJECTIVE: To assess clinical effects of rasagiline 1 mg/day on cardinal PD symptoms and motor fluctuations in defined patient subgroups using pooled data from PRESTO and LARGO. METHODS: Both double-blind, randomized, and placebo-controlled studies included PD patients with motor fluctuations despite optimized therapy with levodopa, with or without concomitant dopamine agonists (DA) or catechol-O-methyltransferase inhibitor (COMT-I) treatment. These post hoc analyses measured effects of rasagiline 1 mg vs placebo on individual cardinal PD symptoms during ON time and mean change from baseline in daily OFF time in subgroups of patients who at baseline were receiving only levodopa, were considered "mild fluctuators" (daily OFF time ≤ 4 h), and who were or were not receiving concomitant DA or COMT-I therapy. RESULTS: Compared with placebo, rasagiline significantly improved all cardinal PD symptoms and significantly reduced adjusted mean daily OFF time when used as first adjunct therapy in levodopa-treated patients and in patients with mild motor fluctuations. Significant improvement in motor fluctuations was reported with rasagiline regardless of concomitant DA or COMT-I use. Overall incidence of dopaminergic adverse events did not increase with concomitant DA or COMT-I use. CONCLUSION: Rasagiline was an effective first adjunct therapy in levodopa-treated patients; benefited patients with signs of early "wearing off"; improved all cardinal PD symptoms; and further improved symptoms in patients already receiving other adjunctive dopaminergic treatment.


Assuntos
Indanos/administração & dosagem , Inibidores da Monoaminoxidase/administração & dosagem , Doença de Parkinson/diagnóstico , Doença de Parkinson/tratamento farmacológico , Idoso , Antiparkinsonianos/administração & dosagem , Inibidores de Catecol O-Metiltransferase , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/epidemiologia , Resultado do Tratamento
15.
Parkinsonism Relat Disord ; 18(5): 488-93, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22326237

RESUMO

PURPOSE: This prospective, open-label extension (SP702; NCT00594165) of a 6-month double-blind, randomized study investigated the long-term safety and tolerability of rotigotine transdermal system in early Parkinson's disease (PD). METHODS: Patients with early-stage idiopathic PD received transdermal rotigotine for up to 6 years at optimal dose (up to 16 mg/24h). Adjunctive levodopa was allowed. Primary outcomes included adverse events (AEs) and extent of rotigotine exposure. Other outcomes included time to levodopa, incidence of dyskinesias, and efficacy using the Unified Parkinson's Disease Rating Scale (UPDRS) II+III total score. RESULTS: Of 217 patients entering the open-label study, 47% were still in the study upon closure; 24% withdrew because of AEs and 6% because of lack of efficacy. The median exposure to rotigotine was 1910 days (≈ 5 years, 3 months; range 1-2188 days). Most common AEs were somnolence (23% per patient-year), falls (17%), peripheral edema (14%), nausea (12%), and application site reactions (ASRs; 12%). 3% withdrew because of ASRs. 26% patients did not initiate levodopa; of those who did, fewer than half started levodopa in the first year. Dyskinesias were reported by 25% patients; the majority (83%) reported their first episode after initiating levodopa. Mean UPDRS II+III total scores remained below double-blind baseline for up to 2 years of open-label treatment. CONCLUSION: This is the longest interventional study of rotigotine conducted to date. Transdermal rotigotine was generally well tolerated for up to 6 years; AEs reported were similar to those observed in shorter studies and led to discontinuation in only 24% patients.


Assuntos
Agonistas de Dopamina/administração & dosagem , Doença de Parkinson/tratamento farmacológico , Tetra-Hidronaftalenos/administração & dosagem , Tiofenos/administração & dosagem , Administração Cutânea , Adulto , Idoso , Idoso de 80 Anos ou mais , Agonistas de Dopamina/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Tetra-Hidronaftalenos/efeitos adversos , Tiofenos/efeitos adversos , Resultado do Tratamento
16.
Pacing Clin Electrophysiol ; 34(6): 750-5, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21410722

RESUMO

BACKGROUND: The long-term efficacy of pyridostigmine, a reversible acetyl cholinesterase inhibitor, in the treatment of postural orthostatic tachycardia syndrome (POTS) patients remains unclear. We report our retrospective, single-center, long-term experience regarding the efficacy and adverse effect profile of pyridostigmine in the treatment of POTS patients. METHODS: This retrospective study included an extensive review of electronic charts and data collection in regards to patient demographics, orthostatic parameters, side-effect profile, subjective response to therapy, as well as laboratory studies recorded at each follow-up visit to our institution's Syncope and Autonomic Disorders Center. The response to pyridostigmine therapy was considered successful if patient had both symptom relief in addition to an objective response in orthostatic hemodynamic parameters (heart rate [HR] and blood pressure). Three hundred patients with POTS were screened for evaluation in this study. Of these 300, 203 patients with POTS who received pyridostigmine therapy were reviewed. Of these 203 patients, 168 were able to tolerate the medication after careful dose titration. The mean follow-up duration in this group of patients was 12 ± 3 (9-15) months. Pyridostigmine improved symptoms of orthostatic intolerance in 88 of 203 (43%) of total patients or 88 of 172 (51%) who were able to tolerate the drug. The symptoms that improved the most included fatigue (55%), palpitations (60%), presyncope (60%), and syncope (48%). Symptom reduction correlated with a statistically significant improvement in upright HR and diastolic blood pressure after treatment with pyridostigmine as compared to their baseline hemodynamic parameters (standing HR 94 ± 19 vs 82 ± 16, P < 0.003, standing diastolic blood pressure 71 ± 11 vs 74 ± 12, P < 0.02). Gastrointestinal problems were the most common adverse effects (n = 39, 19%) reported. The overall efficacy of pyridostigmine in our study was seen in 42% of total patients or 52% of patients who could tolerate taking the drug. CONCLUSION: The subgroup of POTS patients who can tolerate oral pyridostigmine may demonstrate improvement in their standing HR, standing diastolic blood pressure, and clinical symptoms of orthostatic intolerance.


Assuntos
Síndrome da Taquicardia Postural Ortostática/diagnóstico , Síndrome da Taquicardia Postural Ortostática/tratamento farmacológico , Brometo de Piridostigmina/uso terapêutico , Inibidores da Colinesterase/uso terapêutico , Feminino , Humanos , Masculino , Resultado do Tratamento , Adulto Jovem
17.
Clin Neuropharmacol ; 33(1): 5-10, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-19855267

RESUMO

OBJECTIVE: To determine whether adding orally disintegrating selegiline (ODS) while decreasing dopamine agonist (DA) dosages would reduce DA-related adverse effects (AEs) of excessive daytime sleepiness (EDS), pedal edema, hallucinations, and impulse control disorders (ICDs) without compromising efficacy in Parkinson disease (PD) patients. METHODS: This was a 12-week open-label study of 60 PD patients with motor fluctuations and DA-related AEs of EDS, pedal edema, hallucinations, and ICDs. Orally disintegrating selegiline was initiated at 1.25 mg once daily, and down titration of the DA was started with a goal of a 50% reduction by 1 week. At week 6, ODS was increased to 2.5 mg, and further reductions of the DA were allowed if the AEs were not resolved. RESULTS: The addition of ODS allowed a reduction in the mean daily dose of pramipexole from 2.3 to 0.5 mg and immediate-release ropinirole from 11.2 to 2.9 mg. Most subjects reported a reduction or resolution of DA-related AEs; 94% with EDS (n = 50), 73% with pedal edema (n = 26), 86% with hallucinations (n = 15), and 84% with ICDs (n = 25). Mean activities of daily living and motor scores from the Unified Parkinson's Disease Rating Scale as well as quality-of-life scores were significantly improved without an increase in daily "off" time. The most common AEs, most of which resolved after titration, were worsening of PD, nausea/vomiting, dyskinesia, increased off time, body aches, insomnia, orthostatic hypotension, and increased anxiety and depression. CONCLUSIONS: In most subjects, the addition of ODS with decreasing dosages of DAs substantially reduced EDS, pedal edema, hallucinations, and ICDs without compromising efficacy.


Assuntos
Agonistas de Dopamina/efeitos adversos , Agonistas de Dopamina/uso terapêutico , Inibidores da Monoaminoxidase/administração & dosagem , Doença de Parkinson/tratamento farmacológico , Selegilina/administração & dosagem , Administração Oral , Idoso , Benzotiazóis/efeitos adversos , Benzotiazóis/uso terapêutico , Transtornos Disruptivos, de Controle do Impulso e da Conduta/induzido quimicamente , Transtornos Disruptivos, de Controle do Impulso e da Conduta/prevenção & controle , Relação Dose-Resposta a Droga , Esquema de Medicação , Sistemas de Liberação de Medicamentos/métodos , Feminino , Seguimentos , Doenças do Pé/induzido quimicamente , Doenças do Pé/prevenção & controle , Alucinações/induzido quimicamente , Alucinações/prevenção & controle , Humanos , Indóis/efeitos adversos , Indóis/uso terapêutico , Masculino , Entrevista Psiquiátrica Padronizada , Pessoa de Meia-Idade , Doença de Parkinson/fisiopatologia , Pramipexol , Qualidade de Vida , Índice de Gravidade de Doença , Transtornos do Sono-Vigília/induzido quimicamente , Transtornos do Sono-Vigília/prevenção & controle , Inquéritos e Questionários , Resultado do Tratamento
18.
Eur Neurol ; 61(4): 193-205, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19176960

RESUMO

The management of early Parkinson's disease (PD) involves the treatment of motor symptoms and, increasingly, non-motor symptoms. Given the fast pace of clinical research in PD, clinicians are faced with the challenge of integrating the latest findings into the ongoing care of individual PD patients. Part 1 of this 2-part article reviews motor symptom efficacy data for the newest PD treatment options, as well as for established therapies. Safety and tolerability data are also reviewed. Part 2 of the article reviews key findings relevant to the assessment of potential neuroprotective therapies and the treatment of non-motor symptoms.


Assuntos
Antiparkinsonianos/uso terapêutico , Transtornos dos Movimentos/tratamento farmacológico , Doença de Parkinson/tratamento farmacológico , Ensaios Clínicos como Assunto , Agonistas de Dopamina/efeitos adversos , Agonistas de Dopamina/uso terapêutico , Humanos , Levodopa/uso terapêutico , Inibidores da Monoaminoxidase/uso terapêutico , Cooperação do Paciente
19.
Eur Neurol ; 61(4): 206-15, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19176961

RESUMO

The management of early Parkinson's disease (PD) involves the treatment of motor symptoms, and, increasingly, non-motor symptoms. Given the fast pace of clinical research in PD, clinicians are faced with the challenge of integrating the latest findings into the ongoing care of individual PD patients. Part 1 of this 2-part article reviews efficacy and safety data for the newest PD treatment options, as well as for established therapies. Part 2 of the article, presented here, reviews key data relevant to the assessment of potential neuroprotective therapies and the treatment of non-motor symptoms.


Assuntos
Antiparkinsonianos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Doenças do Sistema Nervoso Autônomo/tratamento farmacológico , Ensaios Clínicos como Assunto , Transtornos Cognitivos/tratamento farmacológico , Depressão/tratamento farmacológico , Transtornos Disruptivos, de Controle do Impulso e da Conduta/tratamento farmacológico , Agonistas de Dopamina/uso terapêutico , Humanos , Levodopa/uso terapêutico , Inibidores da Monoaminoxidase/uso terapêutico , Transtornos do Olfato/tratamento farmacológico , Dor/tratamento farmacológico , Transtornos Psicóticos/tratamento farmacológico , Transtornos do Sono-Vigília/tratamento farmacológico , Fatores de Tempo
20.
Expert Opin Pharmacother ; 9(16): 2759-72, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18937611

RESUMO

BACKGROUND: The role of monoamine oxidase type B inhibitors in the treatment of Parkinson's disease has expanded with the new monoamine oxidase B inhibitor rasagiline and a new formulation, selegiline oral disintegrating tablets. As primary therapy in early disease monoamine oxidase B inhibitors reduce motor disability and delay the need for levodopa. In more advanced disease requiring levodopa, adjunctive monoamine oxidase B inhibitors reduce 'off' time and may improve gait and freezing. OBJECTIVE: Rasagiline and selegiline oral disintegrating tablets may reduce the safety risks associated with the amfetamine and methamfetamine metabolites of conventional oral selegiline while retaining or improving therapeutic efficacy. METHODS: Articles were identified by searches of PubMed and searches on the Internet and reviewed. All articles and other referenced materials were retrieved using the keywords 'Parkinson's disease', 'treatment' and 'monoamine oxidase B inhibitor' and were published between 1960 and 2007, with older references selected for historical significance. Only papers published in English were reviewed. CONCLUSION: Accumulating data support the use of monoamine oxidase B inhibitors as monotherapy for early and mild Parkinson's disease and as adjunctive therapy for more advanced Parkinson's disease with levodopa-associated motor fluctuations. The recently released monoamine oxidase B inhibitor rasagiline and a new formulation, selegiline oral disintegrating tablets, have potential advantages over conventional oral selegiline.


Assuntos
Inibidores da Monoaminoxidase/uso terapêutico , Monoaminoxidase/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/enzimologia , Animais , Ensaios Clínicos como Assunto , Humanos , Indanos/uso terapêutico , Levodopa/uso terapêutico , Inibidores da Monoaminoxidase/classificação
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