The long-acting dopamine receptor agonist cabergoline in early Parkinson's disease: final results of a 5-year, double-blind, levodopa-controlled study.

OBJECTIVES: Cabergoline is an ergoline derivative with a very long half-life that allows once-daily administration and the potential for more continuous stimulation of dopaminergic receptors than is possible with other dopamine receptor agonists (DAs). The aim of this study was to evaluate whether the possible advantage resulting from a more sustained dopaminergic effect of cabergoline would translate into delayed onset of motor complications, compared with levodopa, in patients with newly diagnosed Parkinson's disease. STUDY DESIGN AND METHODS: This study was a double-blind, multicentre trial that compared cabergoline and levodopa as initial therapy for Parkinson's disease. A total of 419 levodopa-, DA- and selegiline-naive patients with newly diagnosed Parkinson's disease were randomised to receive either cabergoline (n = 211) or levodopa (n = 209). Treatment was titrated to an optimal dose over a period of up to 24 weeks and then continued at this dose until the study endpoint (confirmed motor complications) or up to a maximum of 5 years. At years 1-5, the cabergoline group was receiving cabergoline at average daily doses ranging from 2.8-2.9 mg, with added levodopa at mean daily doses ranging from 322 mg at year 1 to 431 mg at year 5; over the same period, the levodopa group was receiving daily levodopa doses of 784 mg. Thus, patients in the cabergoline group received <50% levodopa than patients in the levodopa group. RESULTS: Motor complications were significantly delayed (p = 0.0175) and occurred less frequently in cabergoline-treated patients than in levodopa-treated patients (22.3% vs 33.7%). Cox model proportional hazards regression analysis showed that the relative risk of developing such complications was >50% lower (0.46; p < 0.001) in the cabergoline group compared with the levodopa group. In particular, development of dyskinesias was markedly delayed in the cabergoline group and occurred in 9.5% of patients compared with 21.2% in the levodopa group (p < 0.001). Among patients not requiring supplemental levodopa, the frequency of motor complications was three times higher with levodopa (15.5% of 110 patients) than with cabergoline (5.3% of 76 patients). Among patients who did need supplemental levodopa, motor complications were more frequent in the levodopa arm (54.1% of 98 patients) than in the cabergoline arm (31.9% of 135 patients). Consistent improvements relative to baseline in average Unified Parkinson's Disease Rating Scale (UPDRS) daily living activities and motor function sections, and in Clinical Global Impression severity of illness and physician- and patient- rated global improvement scores, were seen in both treatment groups, with maximal effects occurring within 2 years. However, levodopa treatment was associated with a significantly (p < 0.001) greater improvement in motor disability (as measured by the UPDRS motor score) over time, with mean values of 13.8 versus 12.9 in the cabergoline versus levodopa arm recorded at 1 year, 18.6 versus 17.2 at 3 years and 19.2 versus 16.3 at 5 years, respectively. While the overall frequency of adverse events was similar in the two groups, the cabergoline-treated group experienced marginally, but not significantly, higher frequencies of nausea, vomiting, dyspepsia and gastritis (37.4% vs 32.2% in the levodopa group) and of dizziness and postural hypotension (31.3% vs 24% in the levodopa group). Cabergoline-treated patients also experienced a significantly higher frequency of peripheral oedema (16.1% vs 3.4%, respectively; p < 0.0001). The cabergoline and levodopa groups had similar rates of sleepiness (17.5% vs 18.3%, respectively) and hallucinations (4.8% vs 4.4%, respectively); in an elderly population subset, hallucinations were reported in 7.1% and 6.5% of patients taking cabergoline and levodopa, respectively. Adverse events generally occurred more frequently in female patients (with the exception of dyskinesias, hyperkinesias and hallucinations, which occurred more frequently in men) and in the elderly. CONCLUSION: This study showed that, compared with levodopa, initial therapy with cabergoline in patients with Parkinson's disease is associated with a lower risk of response fluctuations at the cost of a marginally reduced symptomatic improvement and some tolerability disadvantages that are mostly limited to a significantly higher frequency of peripheral oedema.

Asociación de inhibidores de la catecol-o-metil-transferasa: (COMT), su significado y ubicación en la evolución de la terapéutica de la enfermedad de Parkinson / Association of COMT inhibitor and its meaning and place in the evolution of therapeutics of Parkinson's disease

Se revisa la util;idad de los inhibidores de la catecol-o-metiltransferasa, especialmente tolcapona, en el tratamiento de la enfermedad de Parkinson y en el síndrome a largo plazo de la levodopaterapia.

Enfermedad de Parkinson y senilidad / Parkinson's disease and senility

La enfermedad de Parkinson puede ser interpretada como una forma particular del envejecimiento precoz. Cuanto menor es la edad de comienzo el trastorno metabólico es más específico, los signos parkinsonianos son más puros, la respuesta a la L-dopa es mayor y las complicaciones del tratamiento son más precoces y frecuentes. En el parkinsonismo senil los signos son de grado moderado, simétricos, con predominio de la aquinesia y de la rigidez; los trastornos posturales y la hipotensión ortostática son de mayor relevancia, es frecuente la asociación de deterioro intelectual y de signos frontales, la evolución es benigna y la respuesta a la L-dopa es menor. El perfil de la desintegración cognitiva es similar en los parkinsonianos y en los seniles (afectación del dominio espacial, de las memorias visual y visuoespacial y de la praxia constructiva), pero en los primeros el promedio de edad es significativamente menor, lo cual sugiere un proceso de envejecimiento precoz. El estudio de la desintegración motora del anciano reveló que el parkinsonismo es la manifestación más precoz y frecuente, ubicándose en segundo término los signos frontales y piramidales. A pesar de la exclusión de los seniles con antecedentes o signos de vasulopatía, la tomografía computada mostró infartos lacunares en 23 por ciento de los casos, señalando la importancia del factor vascular en la encefalopatía senil

Prevención y tratamiento de los síndromes extrapiramidales farmacológicos / Prevention and treatment of pharmacologic extrapyramidal syndromes

Los síndromes extrapiramidales farmacológicos son una complicación frecuente de la terapéutica con neurolépticos y sustancias afines. El parkinsonismo farmacológico es el más conocido, se presenta con aquinesia y rigidez predominantes, estando en el otro extremo del espectro las disquinesias tardías y las hiperquinesias (acatisia y tasiquinesia). Las disquinesias tardías potencialmente irreversibles e invalidantes pueden ser muy proteiformes imitando todos los movimientos anormales observados en la neurología clásica pero su forma más frecuente es la disquinesia buco-linguo-facial. Se destaca la particular predisposición del anciano para desarrollar parkinsonismo y disquinesia tardía. El tratamiento puede plantear dificultades sobre todo con la disquinesia tardía, para lo que no existe terapéutica farmacológica universalmente aceptada. Debe destacarse entonces la prevención con un correcto diagnóstico e indicación precisa de la medicación, un conocimiento adecuado de los fármacos y de sus propiedades iatrogénicas. Existem medicamentos que contienen neurolépticos como antieméticos, antivertiginosos y sustancias de acción similar y de extendido uso como la flunarizina y la cinarizina. El parkinsonismo farmacólogico cede generalmente con la suspensión del neuroléptico o la asociación de anticolinérgicos. Las disquinesias tardías deben ser tratadas precozmente para evitar el riesgo de irreversibilidad y como medida terapéutica fundamental aconsejamos la desintoxicación a largo plazo