RESUMEN
The aim of the study was to investigate the relationship between dyskinesias and motor fluctuations in patients with Parkinson's disease on l-dopa monotherapy. We identified 116 patients on l-dopa monotherapy treated between 1965 and 1992 and followed until death. Dyskinesias occurred in 102 patients. Of these, 48 only developed dyskinesias while 54 had both dyskinesias and motor fluctuations. Among patients with both complications, 49 developed dyskinesias before fluctuations, and only five had dyskinesias after the onset of fluctuations. Our findings suggest that dyskinesias predict the onset of motor fluctuations, and may share a common pathophysiological mechanism.
Asunto(s)
Antiparkinsonianos/efectos adversos , Discinesia Inducida por Medicamentos/epidemiología , Levodopa/efectos adversos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/epidemiología , Edad de Inicio , Anciano , Discinesia Inducida por Medicamentos/diagnóstico , Discinesia Inducida por Medicamentos/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neuronas Motoras/fisiología , Enfermedad de Parkinson/fisiopatología , Valor Predictivo de las Pruebas , Factores de RiesgoRESUMEN
We used cerebral microdialysis to assess the ability of the anticonvulsant drug Zonisamide (ZNS) to release striatal dopamine in 6-hydroxydopamine nigrotomized rats. Following exogeneously administered ZNS we measured dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels in striatal dialysates obtained from the ipsilateral side of the nigrotomy. ZNS administration alone had no effect on levels of DA and its metabolites or rotational behavior. Administration of carbidopa-levodopa alone led to small but insignificant increases in rotational behavior contralateral to the side of the nigrotomy but no corresponding increases in indices of striatal catecholamine release. In contrast, if animals were preloaded with carbidopa and ZNS was co-administered with levodopa 30 minutes later significant increases in contralateral rotational behavior occurred within 20 minutes of ZNS-levodopa injection that lasted for at least 90 minutes. In contrast to the uniform rotational behavioral responses observed in all our nigrotomized animals, less than half demonstrated neurochemical evidence of DA release. In these "responder" animals DOPAC levels increased 300% following carbidopa-levodopa-ZNS administration. We conclude that these results support previously reported findings and provide additional evidence that the anticonvulsant ZNS appears to possess anti-Parkinson's properties. ZNS could therefore be a novel agent for the treatment of PD that could delay the use of or reduce the amount of levodopa needed to treat patients with PD.
Asunto(s)
Antiparkinsonianos/farmacología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Isoxazoles/farmacología , Ácido 3,4-Dihidroxifenilacético/metabolismo , Adrenérgicos/farmacología , Animales , Conducta Animal/efectos de los fármacos , Carbidopa/farmacología , Modelos Animales de Enfermedad , Dopaminérgicos/farmacología , Ácido Homovanílico/metabolismo , Levodopa/farmacología , Microdiálisis , Oxidopamina/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Ratas , ZonisamidaRESUMEN
Less than a consensus exists as to whether chronic treatment with selegiline in combination with levodopa/carbidopa in patients with Parkinson's disease, is associated with more pronounced orthostatic hypotension than treatment with levodopa/carbidopa alone. To resolve this issue, we compared orthostatic tolerance and autonomic reflexes in 95 patients with Parkinson's disease treated chronically with either selegiline alone (n = 10), levodopa/carbidopa alone (n = 49) or both agents combined (n = 36). Supine heart rate and blood pressure, autonomic cardiovascular reflexes and the frequency and magnitude of orthostatic hypotension were similar in all three treatment groups.
Asunto(s)
Antiparkinsonianos/uso terapéutico , Hipotensión Ortostática/tratamiento farmacológico , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/fisiopatología , Selegilina/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Sistema Nervioso Autónomo/efectos de los fármacos , Sistema Nervioso Autónomo/fisiología , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Carbidopa/uso terapéutico , Quimioterapia Combinada , Femenino , Hemodinámica/efectos de los fármacos , Hemodinámica/fisiología , Humanos , Hipotensión Ortostática/etiología , Levodopa/uso terapéutico , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/complicaciones , Posición Supina/fisiologíaRESUMEN
A multigenerational family complex with an admixture of essential tremor (ET) and PD is presented. Medical information obtained either by historic documentation and/or examination was available for five generations and included 36 members. Of these, 11 family members had tremor of the limbs and/or head. In all these instances ET made its first appearance at an early age, usually prior to the second decade of life. In one case focal dystonia of the hand, a possible prelude to PD occurred, while in three brothers of the third generation, two of them identical twins, classical Parkinson's disease (PD) developed. They had ET develop at an early age, which persisted and in their 50s began showing evidence of PD. Two decades later the twin brothers succumbed to cancer of the colon and at autopsy typical findings of PD with cell loss in the substantia nigra and Lewy-body formation positive for alpha-synuclein by immunohistochemistry was found. Additionally, more than the usual number of senile plaques and neurofibrillatory tangles were present without clinical evidence of dementia or significant decline in cognitive function. This unusual set of clinical and pathological circumstances can hardly be attributed to chance occurrence and raise the question of a specific genetic mutation and/or clustering, which may link ET with PD.
Asunto(s)
Temblor Esencial/complicaciones , Enfermedad de Parkinson/complicaciones , Adulto , Anciano , Autopsia , Ganglios Basales/patología , Encéfalo/patología , Temblor Esencial/patología , Familia , Femenino , Humanos , Hipertensión/complicaciones , Hipertensión/fisiopatología , Cuerpos de Lewy/patología , Masculino , Persona de Mediana Edad , Ovillos Neurofibrilares/patología , Tamaño de los Órganos , Enfermedad de Parkinson/patología , Linaje , Placa Amiloide/patología , Sustancia Negra/patologíaRESUMEN
We perfused iron as FeCl(3) directly into the striatum of normal rats and used the in vivo microdialysis technique to monitor striatal levels of dopamine (DA). KCl was perfused to assess the functional integrity of the DA receptors at the end of each dialysis experiment. Cu(+2) (as CuSO(4)) and Cl(-) (as NaCl) were perfused to compare the effects of Fe(+3) to that of other heavy metal and donors of Cl(-) anion. Perfusion of FeCl(3) (1 mM for 15 min) produced a 250% increase in striatal levels of DA. Perfusion of CuSO(4) (1 mM for 15 min) or NaCl (10 mM for 15 min) did not affect striatal DA levels. There was a significant increase in DA levels with KCl stimulation (56 mM for 15 min) after perfusion with FeCl(3). We conclude that iron releases DA from striatal nerve endings without the immediate destruction of the DA terminals. The implications of chronic release of dopamine as a cause of dopaminergic cell death are discussed.
Asunto(s)
Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Compuestos Férricos/farmacología , Animales , Cloruros , Sulfato de Cobre/farmacología , Espacio Extracelular/metabolismo , Masculino , Microdiálisis , Perfusión , Cloruro de Potasio/farmacología , Ratas , Ratas Sprague-Dawley , Cloruro de Sodio/farmacologíaRESUMEN
L-dopa may be toxic to dopamine neurons, possibly due to catechol-autoxidation. Catechols are O-methylated by catechol-O-methyltransferase (COMT) in a SAM consuming reaction, preventing the initiation of catechol autoxidation. We hypothesized that SAM or SAM-precursors ameliorate L-dopa neurotoxicity, in a COMT-dependent fashion. We tested this hypothesis in primary mesencephalic cultures by adding 200 microM L-dopa with 2 mM methionine or 1 mM dimethionine or 0.5 mM SAM with or without 0.2 microM of the COMT-inhibitor 2', 5'-dinitrocatechol (OR 486). L-dopa was found to be neurotoxic as the surviving neurons had fewer and shorter processes. Methionine, dimethionine and SAM all protected DA neurons against damaged induced by L-dopa. The COMT inhibitor dinitrocatechol (DNC) completely abolished the protective effect against L-dopa toxicity. We conclude that supplementation with methionine, dimethionine or SAM ameliorates L-dopa neurotoxicity to dopamine neurons, while inhibition of COMT may aggravate or unmask L-dopa neurotoxicity.
Asunto(s)
Catecol O-Metiltransferasa/metabolismo , Levodopa/toxicidad , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fármacos Neuroprotectores/farmacología , Animales , Inhibidores de Catecol O-Metiltransferasa , Catecoles/farmacología , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Dopamina/metabolismo , Inhibidores Enzimáticos/farmacología , Levodopa/antagonistas & inhibidores , Metionina/farmacología , Neuronas/citología , Ratas , S-Adenosilmetionina/farmacologíaRESUMEN
A paucity of studies are available concerning the comparative therapeutic effectiveness of presently available dopamine agonist agents in the control of Parkinson symptoms. To provide a basis for resolving this issue, we measured the circling response in unilaterally nigrotomized (6-OHDA) rats following the administration of ropinirole, pramipexole, pergolide, bromocriptine, and cabergoline. Cabergoline, and to a lesser extent pergolide, produced the most vigorous and longest lasting circling response. This response was sustained with administration of these agents over a nine day period. Bromocriptine, pramipexole and ropinirole were all less effective. These results suggest that dopamine agonists whose effect is primarily on D1 and D2 receptors are more effective than those whose actions do not include D1 activation.
Asunto(s)
Agonistas de Dopamina/farmacología , Actividad Motora/efectos de los fármacos , Trastornos Parkinsonianos/tratamiento farmacológico , Animales , Benzotiazoles , Encéfalo/efectos de los fármacos , Encéfalo/patología , Encéfalo/fisiopatología , Bromocriptina/farmacología , Cabergolina , Esquema de Medicación , Ergolinas/farmacología , Indoles/farmacología , Masculino , Actividad Motora/fisiología , Oxidopamina/farmacología , Trastornos Parkinsonianos/fisiopatología , Pergolida/farmacología , Pramipexol , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/fisiología , Receptores de Dopamina D1/efectos de los fármacos , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/efectos de los fármacos , Receptores de Dopamina D2/metabolismo , Tiazoles/farmacologíaRESUMEN
The pandemic of von Economo's disease which began in January 1917 preceded that of influenza of 1918-1919 by more than a year. Though it has been customary to link the two it seems unlikely that the latter was responsible for the former as has been proposed. It has been assumed that von Economo's disease (ED) was caused by a virus; but in fact the etiology is in question as no virus has yet been transmitted to experimental animals or cells in culture. However, the presence of oligoclonal IgG bands in the CSF of suspected cases and the finding of chronic active lesions in the brain tissue at autopsy suggests a viral etiology. Occasional, sporadic presumed cases of the disease have been reported within the last 25 years. Encephalitides due to established neurotropic viruses or to other viruses that may on occasion invade the CNS only rarely produce parkinsonism, and when they do it differs from that seen in ED. The present report reviews the overall concept of a viral etiology of Parkinson's disease with particular reference to von Economo's disease.
Asunto(s)
Enfermedad de Parkinson Posencefalítica/virología , Virosis/complicaciones , HumanosRESUMEN
OBJECTIVE: To evaluate the nonergot dopamine agonist ropinirole as an adjunct to L-dopa in a randomized, double-blind trial in PD patients with motor fluctuations. BACKGROUND: L-dopa in the treatment of PD is associated with motor fluctuations, dyskinesia, and other adverse effects. The use of dopamine agonists in the treatment of PD delays recourse to L-dopa and thus delays the possibility of adverse effect onset. METHODS: Ropinirole (n = 95) or placebo (n = 54) was added to L-dopa, and L-dopa was then reduced in a planned manner during the 6-month trial. RESULTS: A significantly greater number of ropinirole patients were able to achieve a 20% or greater reduction in both L-dopa dose and in percent time spent "off" compared with placebo (35.0% versus 13.0%; p = 0.003). The mean daily L-dopa dose was reduced significantly with ropinirole treatment (242 mg versus 51 mg; p < 0.001) as was the percent awake time spent "off" (11.7% versus 5.1%; p = 0.039). There was no difference in the percent of patients who withdrew because of adverse effects (15.8% on ropinirole versus 16.7% on placebo). CONCLUSIONS: Ropinirole permits a reduction in L-dopa dose with enhanced clinical benefit for PD patients with motor fluctuations.
Asunto(s)
Antiparkinsonianos/administración & dosificación , Agonistas de Dopamina/administración & dosificación , Indoles/administración & dosificación , Levodopa/administración & dosificación , Enfermedad de Parkinson/tratamiento farmacológico , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Masculino , Estudios ProspectivosRESUMEN
We report a patient with a parkinsonian syndrome induced by sertraline (Zoloft), an SSRI antidepressant, whose symptoms resolved after the drug was discontinued. This case prompted us to investigate the effect of sertraline on dopamine metabolism in animals. Sertraline (30 mg/kg, i.p.) or placebo (vehicle) was administered to two groups of six normal, anesthetized rats and using cerebral microdyalisis extracellular striatal levels of dopamine, the dopamine metabolites (HVA and DOPAC), as well as the serotonin metabolite 5-HIIA were monitored. In animals pre-treated with sertraline, DOPAC, HVA, and 5-HIAA levels were significantly decreased compared to control animals (p < 0.01). These data indicate that sertraline has an effect on dopamine metabolism, which may alter function in the striatum and induce a parkinsonian syndrome.