RESUMEN
BACKGROUND AND PURPOSE: To assess the long-term safety and efficacy of pramipexole as a once-daily (q.d.) extended-release oral formulation in early or advanced Parkinson's disease (PD). METHODS: In two double-blind (DB) studies of early PD and one of advanced PD,active-treatment arms received pramipexole immediate release (IR) or extended release (ER), with exposure lasting up to 33 weeks. In open-label (OL) extensions that followed immediately, subjects took ER q.d. for up to 80 weeks, with dosage adjustment permitted (range 0.375-4.5 mg q.d.). RESULTS: Of 590 subjects completing an early-PD DB study, 511 entered the early-PD OL extension; 408 completed it. Reported adverse events (AEs) with incidence ≥10.0% were somnolence (15.1%), peripheral edema (11.7%) and back pain (10.6%). Of 465 subjects completing the advanced-PD DB study, 391 entered the advanced-PD OL extension; 329 completed it. Reported AEs with incidence ≥10.0%were dyskinesia (27.4%) and somnolence (13.6%). Impulse control disorders were identified by semi-structured interview in 13 subjects (1.4% of 902). In exploratory analyses, adjusted mean Unified Parkinson's Disease Rating Scale (UPDRS) PartsII + III scores (excluding ex-placebo recipients) remained substantially improved from DB baseline scores prior to pramipexole introduction, at -6.6 and -6.3 points amongst ex-DB-ER and ex-DB-IR recipients after 113 weeks of pramipexole (33 DB plus 80 OL) in early PD, and -11.5 and -9.1 after up to 113 weeks (up to 33 DB plus 80 OL) in advanced PD. CONCLUSIONS: These results support the long-term safety and efficacy of pramipexole ER in early and advanced PD. AEs were typical for dopaminergic medications, and UPDRS scores suggested sustained symptomatic benefit.
Asunto(s)
Antiparkinsonianos/uso terapéutico , Benzotiazoles/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Anciano , Trastornos de Somnolencia Excesiva/etiología , Trastornos Disruptivos, del Control de Impulso y de la Conducta/inducido químicamente , Método Doble Ciego , Esquema de Medicación , Sistemas de Liberación de Medicamentos/efectos adversos , Sistemas de Liberación de Medicamentos/métodos , Discinesia Inducida por Medicamentos/etiología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pramipexol , Índice de Severidad de la Enfermedad , Factores de TiempoRESUMEN
OBJECTIVE: Examine the correlates of Health Related Quality of Life (HRQL) in a large cohort of Parkinson's disease (PD) patients from National Parkinson Foundation (NPF) Centers of Excellence (COEs). BACKGROUND: Improving outcomes for PD will depend upon uncovering disease features impacting HRQL to identify targets for intervention and variables for risk-adjustment models. Differences in HRQL outcomes between COEs could uncover modifiable aspects of care delivery. METHODS: This cross-sectional study examined the relative contribution of demographic, social, clinical and treatment features potentially related to HRQL, as measured by the PDQ-39, in 4601 consecutive subjects from 18 COEs. Stepwise linear regression was utilized to identify correlates of HRQL. RESULTS: The variability in the PDQ-39 summary index score correlated with H&Y stage (R(2) = 22%), Timed up and Go (TUG) (17%), disease duration (11%), comorbidities (8%), cognitive status (8%), antidepressant use (6%) and center at which a patient received care (5%). Stepwise regression reordered the importance of the variables, with the H&Y first and TUG and the center becoming equal and the second most important variables determining the PDQ-39 total score. All independent variables together accounted for 44% of the variability in HRQL. CONCLUSIONS: We confirmed many but not all HRQL associations found in smaller studies. A novel observation was that the site of care was an important contributor to HRQL, suggesting that comparison of outcomes and processes among centers may identify best practices.
Asunto(s)
Afecto , Limitación de la Movilidad , Servicio Ambulatorio en Hospital , Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson/psicología , Calidad de Vida/psicología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Internacionalidad , Masculino , Persona de Mediana Edad , Servicio Ambulatorio en Hospital/normas , Enfermedad de Parkinson/diagnósticoRESUMEN
BACKGROUND AND PURPOSE: For Parkinson's disease (PD), an extended-release (ER) pramipexole formulation taken once daily, has shown efficacy, safety, and tolerability resembling those of immediate-release (IR) pramipexole taken three times daily. The present study assessed, in advanced PD, the success of an overnight switch from adjunctive IR to ER. METHODS: Levodopa users experiencing motor fluctuations were randomized to adjunctive double-blind (DB) placebo, IR, or ER. Amongst completers of ≥18 weeks, ER recipients were kept on DB ER, whilst IR recipients were switched overnight to DB ER at unchanged daily dosage. After a DB week, switch success was assessed. During the next 5 weeks, all patients underwent ER titration to optimal open-label maintenance dosage. RESULTS: One week post-switch, 86.2% of 123 IR-to-ER and 83.8% of 105 ER-to-ER patients had ≤15% (or ≤3-point, for pre-switch scores ≤20) increase on UPDRS Parts II + III, and 77.9% (of 122) and 70.2% (of 104) had ≤1-h increase in daily OFF-time. At 32 weeks, the groups showed comparable improvements from DB baseline (pramipexole inception), including, on UPDRS II + III, adjusted mean (SE) changes of -14.8 (1.5) for IR-to-ER and -13.3 (1.6) for ER-to-ER. Rates of premature discontinuation owing to adverse events were 6.5% for IR-to-ER and 4.9% for ER-to-ER. CONCLUSIONS: By OFF-time and UPDRS criteria, majorities of patients with advanced PD were successfully switched overnight from pramipexole IR to ER at unchanged daily dosage. During subsequent maintenance, pramipexole showed sustained efficacy, safety, and tolerability, regardless of formulation (IR or ER) in the preceding DB trial.
Asunto(s)
Antiparkinsonianos/administración & dosificación , Benzotiazoles/administración & dosificación , Sustitución de Medicamentos , Enfermedad de Parkinson/tratamiento farmacológico , Anciano , Método Doble Ciego , Esquema de Medicación , Sistemas de Liberación de Medicamentos , Femenino , Estudios de Seguimiento , Humanos , Levodopa/uso terapéutico , Masculino , Persona de Mediana Edad , Pramipexol , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND AND PURPOSE: In chronic diseases including Parkinson's disease (PD), complex pharmacotherapy dosing schedules are reported to reduce adherence, perhaps leading to less-effective symptom control and, in PD, more erratic stimulation of dopamine receptors. However, blinded clinical-trial designs preclude direct comparisons of adherence to various schedules. METHODS: In two double-blind (DB) studies of early PD and one of advanced PD, subjects received three-times-daily (t.i.d.) pramipexole or placebo. In open-label (OL) extensions, subjects took extended-release, once-daily (q.d.) pramipexole. At 24 or 32 OL weeks, q.d. versus t.i.d. dosing preference was surveyed by questionnaire. RESULTS: Of 590 DB-trial completers with early PD, 511 entered the OL extension. Of 374 survey respondents, 94.4% preferred q.d. dosing (72.2% of them found it 'very much more convenient' and 27.8%'more convenient'), 2.7% preferred t.i.d., and 2.9% chose 'no difference'. Of 465 DB-trial completers with advanced PD, 391 entered its OL extension. Of 334 survey respondents, 88.9% preferred q.d. dosing (59.9% of them found it 'very much more convenient' and 40.1%'more convenient'), 5.7% preferred t.i.d., and 5.4% chose 'no difference'. Results excluding DB-placebo recipients were highly similar. CONCLUSIONS: In this first direct comparison of patient preference for q.d. versus t.i.d. dopamine-agonist dosing, patients with early or advanced PD had a strong preference for q.d. rather than t.i.d. pramipexole. The high proportion of advanced-PD patients declaring this preference indicates that it does not depend on whether a patient is taking concomitant PD medications dosed more frequently than q.d.
Asunto(s)
Antiparkinsonianos/administración & dosificación , Benzotiazoles/administración & dosificación , Enfermedad de Parkinson/tratamiento farmacológico , Autoinforme , Anciano , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Cooperación Internacional , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Pramipexol , Factores de Tiempo , Resultado del TratamientoRESUMEN
AIMS: To determine the efficacy and safety of pardoprunox in levodopa-treated patients with Parkinson's disease (PD) experiencing motor fluctuations. METHODS: Patients were randomized to pardoprunox (up to 42 mg/day, n = 150) or placebo (n = 144). Pardoprunox was titrated to an optimal dose over 7 weeks, followed by a 12-week stable dose period. The primary efficacy variable was the change from baseline to study endpoint in total daily OFF time, based on patient diaries. Secondary analyses included the change in ON time without troublesome dyskinesias, UPDRS-ADL + Motor ON, UPDRS-ADL OFF and PDQ-39. Subgroup analyses explored the impact of pardoprunox on dyskinesias (UPDRS items 32 + 33), depression (Hospital Anxiety Depression Scale) and pain (Visual Analogue Scale). RESULTS: Pardoprunox significantly reduced OFF time versus placebo (-1.62 h/day versus -0.92 h/day, respectively, p = 0.0215). Compared to placebo, pardoprunox improved ON time without troublesome dyskinesias (p = 0.0386), UPDRS-ADL + Motor ON (p = 0.0003), and UPDRS-ADL OFF (p < 0.0001), while no significant difference was observed on PDQ-39. A high drop-out rate due to adverse events (AEs) (pardoprunox, 37%; placebo, 12%) suggested that the selected dose range may have been too high, and/or titration was too rapid. CONCLUSIONS: Pardoprunox decreased OFF time and increased ON time without troublesome dyskinesias in levodopa-treated PD patients. The high drop-out rate at the selected doses justifies the investigation of lower doses. The impact of pardoprunox on dyskinesias and non-motor symptoms deserves further investigation.
Asunto(s)
Benzoxazoles/uso terapéutico , Discinesia Inducida por Medicamentos/prevención & control , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/fisiopatología , Piperazinas/uso terapéutico , Adulto , Anciano , Antiparkinsonianos/efectos adversos , Método Doble Ciego , Esquema de Medicación , Discinesia Inducida por Medicamentos/etiología , Femenino , Estudios de Seguimiento , Humanos , Levodopa/efectos adversos , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: In advanced Parkinson disease (PD), immediate-release pramipexole, taken 3 times daily, improves symptoms and quality of life. A once-daily extended-release formulation may be an effective and simple alternative therapy. METHODS: For a multicenter randomized, double-blind, parallel trial of extended- and immediate-release pramipexole vs placebo, patients experiencing motor fluctuations while taking levodopa underwent flexible study drug titration and then maintenance at optimized dosage (0.375-4.5 mg/day). The primary endpoint was a change in the Unified Parkinson's Disease Rating Scale (UPDRS) part II+III score at 18 weeks, with further assessments at 33 weeks in a subset of patients. Adverse events were recorded throughout. RESULTS: Among 507 patients in the 18-week analyses, UPDRS II+III scores decreased (from baseline means of 40.0-41.7) by an adjusted mean of -11.0 for extended-release pramipexole and -12.8 for immediate-release pramipexole vs -6.1 for placebo (p = 0.0001 and p < 0.0001) and off-time decreased (from baseline means of 5.8-6.0 hours/day) by an adjusted mean of -2.1 and -2.5 vs -1.4 hours/day (p = 0.0199 and p < 0.0001). Other outcomes were largely corroborative, including a significant improvement in early morning off symptoms. Among 249 pramipexole patients completing 33 weeks, UPDRS II+III and off-time findings showed ≤10.1% change from 18-week values. Both formulations were well-tolerated. CONCLUSIONS: Extended-release pramipexole significantly improved UPDRS score and off-time compared with placebo, with similar efficacy, tolerability, and safety of immediate-release pramipexole compared with placebo. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that the extended-release form of pramipexole, taken once daily, is efficacious as an adjunct to levodopa in advanced PD.
Asunto(s)
Antiparkinsonianos/uso terapéutico , Benzotiazoles/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Adulto , Anciano , Método Doble Ciego , Esquema de Medicación , Sistemas de Liberación de Medicamentos , Femenino , Estudios de Seguimiento , Humanos , Masculino , Escala del Estado Mental , Persona de Mediana Edad , Pramipexol , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del TratamientoRESUMEN
OBJECTIVE: To assess the clinical efficacy of a novel once-daily extended-release (ER) formulation of the dopamine agonist pramipexole as monotherapy in patients with early Parkinson disease (PD) and establish its noninferiority vs standard immediate-release (IR) pramipexole. METHODS: This was a multicenter, double-blind, parallel study of patients with early PD not receiving levodopa or dopamine agonists, randomly assigned to pramipexole IR, pramipexole ER, or placebo. Seven-week flexible titration was followed by 26-week maintenance, with levodopa permitted as rescue medication. The primary analysis was to test pramipexole ER noninferiority to pramipexole IR based on a change in the Unified Parkinson's Disease Rating Scale (UPDRS) part II+III score at 33 weeks, with noninferiority predefined as a treatment group difference for which the lower bound of the 95% confidence interval (CI) did not exceed -3 points. RESULTS: Among 213 ER and 207 IR recipients, the adjusted mean 33-week UPDRS II+III change (excluding levodopa rescue effects) was -8.2 for ER and -8.7 for IR, a difference of -0.5 with a 95% CI of -2.3 to 1.3. Compared with placebo (n = 103), pramipexole ER and pramipexole IR were significantly superior on UPDRS II+III score, all key secondary outcomes, and almost all other endpoints. On the 39-item Parkinson Disease Questionnaire, superiority of pramipexole ER failed to reach statistical significance. Both formulations were equally safe and well-tolerated. CONCLUSIONS: As monotherapy for early PD, pramipexole ER was noninferior to pramipexole IR and significantly more effective than placebo. Tolerability and safety did not differ between the formulations. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that pramipexole ER is not inferior to pramipexole IR in patients with early PD.
Asunto(s)
Antiparkinsonianos/uso terapéutico , Benzotiazoles/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Anciano , Análisis de Varianza , Método Doble Ciego , Esquema de Medicación , Sistemas de Liberación de Medicamentos , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pramipexol , Índice de Severidad de la Enfermedad , Encuestas y Cuestionarios , Factores de Tiempo , Resultado del TratamientoRESUMEN
Hallucinations, delusions, and compulsive behaviors are frequent iatrogenic complications of the treatment of motor dysfunction in Parkinson's disease (PD). Although these have been studied, and the phenomenology described, there are few detailed descriptions of the various psychiatric problems our treated PD patients live with that allow physicians who do not have a great deal of experience with PD patients to appreciate the extent of their altered lives. This report is a compilation of vignettes describing these behavioral problems that the treating neurologist or psychiatrist attributed to the medications used for treating PD.
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Antiparkinsonianos/efectos adversos , Carbidopa/efectos adversos , Conducta Compulsiva/inducido químicamente , Deluciones/inducido químicamente , Alucinaciones/inducido químicamente , Levodopa/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Combinación de Medicamentos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/tratamiento farmacológico , Escalas de Valoración PsiquiátricaRESUMEN
The clinical evaluation of neural transplantation as a potential treatment for Huntington's disease (HD) was initiated in an attempt to replace lost neurons and improve patient outcomes. Two of 3 patients with HD reported here, who underwent neural transplantation containing striatal anlagen in the striatum a decade earlier, have demonstrated marginal and transient clinical benefits. Their brains were evaluated immunohistochemically and with electron microscopy for markers of projection neurons and interneurons, inflammatory cells, abnormal huntingtin protein, and host-derived connectivity. Surviving grafts were identified bilaterally in 2 of the subjects and displayed classic striatal projection neurons and interneurons. Genetic markers of HD were not expressed within the graft. Here we report in patients with HD that (i) graft survival is attenuated long-term; (ii) grafts undergo disease-like neuronal degeneration with a preferential loss of projection neurons in comparison to interneurons; (iii) immunologically unrelated cells degenerate more rapidly than the patient's neurons, particularly the projection neuron subtype; (iv) graft survival is attenuated in the caudate in comparison to the putamen in HD; (v) glutamatergic cortical neurons project to transplanted striatal neurons; and (vi) microglial inflammatory changes in the grafts specifically target the neuronal components of the grafts. These results, when combined, raise uncertainty about this potential therapeutic approach for the treatment of HD. However, these observations provide new opportunities to investigate the underlying mechanisms involved in HD, as well as to explore additional therapeutic paradigms.
Asunto(s)
Enfermedad de Huntington/cirugía , Degeneración Nerviosa , Neuronas/trasplante , Autopsia , Antígenos CD4/análisis , Antígenos CD8/análisis , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Cuerpo Estriado/ultraestructura , Femenino , Proteína Ácida Fibrilar de la Glía/análisis , Gliosis/metabolismo , Gliosis/patología , Supervivencia de Injerto , Humanos , Enfermedad de Huntington/metabolismo , Enfermedad de Huntington/patología , Inmunohistoquímica , Microscopía Electrónica , Persona de Mediana Edad , Neuronas/metabolismo , Neuronas/patología , Sinaptofisina/análisis , Ubiquitina/metabolismoRESUMEN
AIMS: To investigate the safety and tolerability of pardoprunox (SLV308), a novel partial dopamine agonist, as an adjunct to levodopa in patients with advanced Parkinson's disease, using two titration schedules. METHODS: Patients were randomized to pardoprunox (n = 51) or placebo (n = 11). Pardoprunox was titrated to the highest tolerated dose (range, 0.3-42 mg/day) over 7 weeks, using a gradual dose escalation without intermediate steps (group 1) or with intermediate steps (group 2). RESULTS: The cumulative drop-out rate was greater in group 1 (without intermediate steps, 56.0%) than in group 2 (with intermediate steps, 34.6%), or with placebo (9.1%). In group 2, doses up to 18 mg/day were well tolerated with a cumulative drop-out rate of 7.7% (2/26) and a drop-out rate due to adverse events of 4.0% (1/26). The most common adverse events reported were nausea, vomiting, headache, and dizziness. There was a trend for reduced OFF time (p = 0.054) in the combined pardoprunox group compared to placebo. CONCLUSIONS: The pardoprunox safety and tolerability profile as an adjunct to levodopa was improved using a gradual titration schedule that included intermediate dose steps. Using this titration, doses up to 18 mg/day were well tolerated.
Asunto(s)
Benzoxazoles/administración & dosificación , Benzoxazoles/efectos adversos , Agonistas de Dopamina/administración & dosificación , Agonistas de Dopamina/efectos adversos , Enfermedad de Parkinson/tratamiento farmacológico , Piperazinas/administración & dosificación , Piperazinas/efectos adversos , Anciano , Quimioterapia Adyuvante , Método Doble Ciego , Femenino , Humanos , Levodopa/administración & dosificación , Masculino , Persona de Mediana Edad , Análisis Multivariante , Resultado del TratamientoRESUMEN
OBJECTIVE: Parkinson's disease (PD) causes significant economic burden for patients and caregivers. Social Security Disability Insurance (SSDI) provides insurance to workers in the United States who have been gainfully employed, but who are no longer able to work due to a medical condition. We performed a descriptive pilot study that examined PD patients' experience with SSDI. METHODS: PD patients who were diagnosed with PD prior to age 60 and were followed at an academic movement disorders center were consecutively invited to participate in a survey concerning their employment history and experience with SSDI. RESULTS: All 68 invited patients participated in the study (mean age 58 years, mean disease duration 9.5 years). Eighty-two percent of patients felt that they were too disabled to work full time at a mean of 3.4 years after PD diagnosis. Patients applied for SSDI at a mean of 5 years after diagnosis, and two-thirds of PD patients who applied for SSDI obtained it on their first attempt. The primary debilitating symptom that subjectively contributed to work disability was fatigue (49% of patients). Patients who successfully acquired SSDI had extensive documentation of physician visits, and the aid of a disability lawyer. CONCLUSIONS: Patients felt they were too disabled to work full time at a mean of 3.4 years after diagnosis. Those who applied for SSDI did so at a mean of 5 years after diagnosis. Patients who obtained SSDI awards had extensive documentation of medical records or the help of a disability lawyer.
Asunto(s)
Seguro por Discapacidad , Enfermedad de Parkinson/economía , Seguridad Social , Personas con Discapacidad , Documentación , Fatiga/complicaciones , Femenino , Florida , Humanos , Abogados , Masculino , Registros Médicos , Persona de Mediana Edad , Proyectos PilotoRESUMEN
BACKGROUND: Essential tremor (ET) is one of the most common tremor disorders in adults and is characterized by kinetic and postural tremor. To develop this practice parameter, the authors reviewed available evidence regarding initiation of pharmacologic and surgical therapies, duration of their effect, their relative benefits and risks, and the strength of evidence supporting their use. METHODS: A literature review using MEDLINE, EMBASE, Science Citation Index, and CINAHL was performed to identify clinical trials in patients with ET published between 1966 and August 2004. Articles were classified according to a four-tiered level of evidence scheme and recommendations were based on the level of evidence. RESULTS AND CONCLUSIONS: Propranolol and primidone reduce limb tremor (Level A). Alprazolam, atenolol, gabapentin (monotherapy), sotalol, and topiramate are probably effective in reducing limb tremor (Level B). Limited studies suggest that propranolol reduces head tremor (Level B). Clonazepam, clozapine, nadolol, and nimodipine possibly reduce limb tremor (Level C). Botulinum toxin A may reduce hand tremor but is associated with dose-dependent hand weakness (Level C). Botulinum toxin A may reduce head tremor (Level C) and voice tremor (Level C), but breathiness, hoarseness, and swallowing difficulties may occur in the treatment of voice tremor. Chronic deep brain stimulation (DBS) (Level C) and thalamotomy (Level C) are highly efficacious in reducing tremor. Each procedure carries a small risk of major complications. Some adverse events from DBS may resolve with time or with adjustment of stimulator settings. There is insufficient evidence regarding the surgical treatment of head and voice tremor and the use of gamma knife thalamotomy (Level U). Additional prospective, double-blind, placebo-controlled trials are needed to better determine the efficacy and side effects of pharmacologic and surgical treatments of ET.
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Antagonistas Adrenérgicos beta/uso terapéutico , Anticonvulsivantes/uso terapéutico , Temblor Esencial/tratamiento farmacológico , Temblor Esencial/cirugía , Fármacos Neuromusculares/uso terapéutico , Procedimientos Neuroquirúrgicos/normas , Ensayos Clínicos como Asunto/estadística & datos numéricos , Estimulación Encefálica Profunda/normas , Estimulación Encefálica Profunda/estadística & datos numéricos , Temblor Esencial/fisiopatología , Humanos , Procedimientos Neuroquirúrgicos/estadística & datos numéricos , Radiocirugia/normas , Radiocirugia/estadística & datos numéricos , Tálamo/fisiopatología , Tálamo/cirugía , Resultado del TratamientoRESUMEN
OBJECTIVE: We sought to examine the prevalence of heart failure in elderly PD versus non-PD patients using a national sample of Medicare beneficiaries in the United States. SCOPE: The prevalence of heart failure in elderly PD patients was 2.27 times that of non-PD patients (19.4% versus 8.7%, 95% CI = 1.43-3.60, p 0.0005), and remained twice as high after excluding patients with stroke and possible vascular parkinsonism. CONCLUSIONS: In this cross-sectional study of a national Medicare database, heart failure occurred twice as frequently in elderly PD patients as in non-PD patients. Prospective studies are warranted to verify these findings.
Asunto(s)
Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca/etiología , Medicare/estadística & datos numéricos , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/epidemiología , Anciano , Enfermedades Cardiovasculares/complicaciones , Enfermedades Cardiovasculares/epidemiología , Comorbilidad , Estudios Transversales , Recolección de Datos , Bases de Datos Factuales , Femenino , Humanos , Masculino , Estados Unidos/epidemiologíaRESUMEN
The authors performed a double-blind, placebo-controlled, crossover study of ropinirole (0.5 to 6.0 mg/day) for restless legs syndrome (RLS). The RLS Rating Scale score improved (p < 0.001) from a mean (SD) of 25 (7) during placebo treatment to 13 (12) during ropinirole treatment. Eight of the 22 patients had complete resolution of symptoms on ropinirole. Adverse events included nausea and dizziness. Ropinirole was effective and well tolerated for treating the symptoms of RLS.
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Agonistas de Dopamina/uso terapéutico , Indoles/uso terapéutico , Síndrome de las Piernas Inquietas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Estudios Cruzados , Mareo/inducido químicamente , Agonistas de Dopamina/efectos adversos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Indoles/efectos adversos , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Resultado del TratamientoRESUMEN
Research and development of the adenosine A2A receptor selective antagonist KW6002 have focused on developing a novel nondopaminergic therapy for Parkinson's disease (PD). Salient pharmacologic features of KW6002 were investigated in several animal models of PD. In rodent and primate models, KW6002 provides symptomatic relief from parkinsonian motor deficits without provoking dyskinesia or exacerbating existing dyskinesias. The major target neurons of the A2A receptor antagonist were identified as GABAergic striatopallidal medium spiny neurons. A possible mechanism of A2A receptor antagonist action in PD has been proposed based on the involvement of striatal and pallidal presynaptic A2A receptors in the "dual" modulation of GABAergic synaptic transmission. Experiments with dopamine D2 receptor knockout mice showed that A2A receptors can function and anti-PD activities of A2A antagonists can occur independent of the dopaminergic system. Clinical studies of KW6002 in patients with advanced PD with L-dopa-related motor complications yielded promising results with regard to motor symptom relief without motor side effects. The development of KW6002 represents the first time that a concept gleaned from A2A biologic research has been applied successfully to "proof of concept" clinical studies. The selective A2A antagonist should provide a novel nondopaminergic approach to PD therapy.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Antiparkinsonianos/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Trastornos Parkinsonianos/tratamiento farmacológico , Purinas/uso terapéutico , Animales , Antiparkinsonianos/efectos adversos , Ensayos Clínicos como Asunto/estadística & datos numéricos , Cuerpo Estriado/citología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Discinesia Inducida por Medicamentos/prevención & control , Globo Pálido/citología , Globo Pálido/efectos de los fármacos , Globo Pálido/metabolismo , Humanos , Levodopa/efectos adversos , Levodopa/uso terapéutico , Ratones , Ratones Noqueados , Actividad Motora/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Oxidopamina , Trastornos Parkinsonianos/inducido químicamente , Primates , Ratas , Receptor de Adenosina A2A/metabolismo , Receptores de Dopamina D2/deficiencia , Receptores de Dopamina D2/genética , Ácido gamma-Aminobutírico/metabolismoRESUMEN
In this study, 39 patients with PD and 25 control subjects without neurologic disease completed testing in a driving simulator. PD patients had more total collisions on the driving simulator than control subjects (t = -3.7, p < 0.01). In PD patients, collisions were associated with Hoehn and Yahr stage (chi(2) = 12.4, p = 0.006) and correlated with Unified Parkinson's Disease Rating Scale score (r = 0.5, p < 0.01).
Asunto(s)
Conducción de Automóvil/psicología , Enfermedad de Parkinson/psicología , Accidentes de Tránsito/psicología , Anciano , Análisis de Varianza , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Desempeño Psicomotor/fisiología , SeguridadRESUMEN
BACKGROUND: Transplanted striatal cells have been demonstrated to survive, grow, establish afferent and efferent connections, and improve behavioral signs in animal models of Huntington's disease (HD). OBJECTIVE: To evaluate feasibility and safety and to provide preliminary information regarding the efficacy of bilateral human fetal striatal transplantation in HD. METHODS: Seven symptomatic patients with genetically confirmed HD underwent bilateral stereotactic transplantation of two to eight fetal striata per side in two staged procedures. Tissue was dissected from the lateral half of the lateral ventricular eminence of donors 8 to 9 weeks postconception. Subjects received cyclosporine for 6 months. RESULTS: Three subjects developed subdural hemorrhages (SDHs) and two required surgical drainage. One subject died 18 months after surgery from probable cardiac arrhythmia secondary to severe atherosclerotic cardiac disease. Autopsy demonstrated clearly demarcated grafts of typical developing striatal morphology, with host-derived dopaminergic fibers extending into the grafts and no evidence of immune rejection. Other adverse events were generally mild and transient. Mean Unified HD Rating Scale (UHDRS) motor scores were 32.9 plus minus 6.2 at baseline and 29.7 plus minus 7.5 12 months after surgery (p = 0.24). Post-hoc analysis, excluding one subject who experienced cognitive and motor deterioration after the development of symptomatic bilateral SDHs, found that UHDRS motor scores were 33.8 plus minus 6.2 at baseline and 27.5 plus minus 5.2 at 12 months (p = 0.03). CONCLUSIONS: Transplantation of human fetal striatal cells is feasible and survival of transplanted cells was demonstrated. Patients with moderately advanced HD are at risk for SDH after transplantation surgery.
Asunto(s)
Trasplante de Tejido Encefálico , Cuerpo Estriado/trasplante , Trasplante de Tejido Fetal , Enfermedad de Huntington/cirugía , Adulto , Animales , Cuerpo Estriado/embriología , Femenino , Trasplante de Tejido Fetal/efectos adversos , Humanos , Enfermedad de Huntington/genética , Masculino , Persona de Mediana Edad , Actividad Motora , Pruebas Neuropsicológicas , Técnicas Estereotáxicas , Tomografía Computarizada de Emisión , Resultado del TratamientoRESUMEN
Tremor is classified according to anatomic distribution among body parts, and by frequency and amplitude during rest, postural maintenance, movement, intention, and the performance of specific tasks. Key historical features include age at onset, progression over time, family history, exacerbating and remitting factors and behaviors, response to alcohol and medications, and additional neurological signs and symptoms. Accurate diagnosis is a critical factor in predicting the natural history and response to treatment.
Asunto(s)
Temblor/clasificación , Temblor/etiología , Humanos , Temblor/terapiaRESUMEN
In conclusion, proof of the principle exists that neural grafts can survive transplantation in PD and that this graft survival is related to preliminary evidence of clinical benefit and improvement on FD-PET. Two prospective, randomized, surgical placebo-controlled trials of fetal tissue transplantation for the treatment of PD will be published in the near future, as will results of a placebo-controlled xenograft trial. Lifelong survival of human fetal nigral grafts is likely. The striatum is comparatively simple to target surgically in comparison to other sites such as the subthalamic nucleus. Several new sources of dopamine cells are being developed for transplantation purposes. Long-term monitoring for toxicity, such as the development of dyskinesias, will be needed, and dose-escalation trials should be performed slowly due to the irreversible nature of transplants. There are numerous ways to improve current techniques of neural transplantation.
Asunto(s)
Trasplante de Tejido Encefálico , Trasplante de Tejido Fetal , Enfermedad de Parkinson/cirugía , HumanosRESUMEN
Medical therapy for Parkinson's disease (PD) often becomes inadequate over several years. Disability increases despite maximal medical management and many patients develop motor fluctuations and dyskinesia. In addition, medications provide good control of tremor in only 50% of cases. In appropriately selected cases, surgical therapies for PD provide benefit for medically refractory symptoms. Recent advances have provided a greater array of surgical options. Unilateral thalamotomy and thalamic stimulation are considered safe and effective procedures to treat contralateral tremor. Pallidotomy and pallidal stimulation primarily reduce contralateral dyskinesia, with lesser effects on bradykinesia and rigidity. Studies indicate that subthalamic nucleus (STN) stimulation improves "off" period function, decreases "off" time, and lessens dyskinesia. Fetal cell transplantation remains experimental, and studies are underway to evaluate the safety and efficacy of porcine fetal cell and human retinal pigment epithelial cell transplantation. This chapter reviews the history of surgical procedures for PD, describes current procedures, and offers a look into the future of neurosurgical options for PD.