Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Regional cerebral blood flow (rCBF) changes in cortical motor areas were measured during a movement of the dominant right hand in 15 patients with Parkinson's disease deprived of their usual levodopa treatment, in 11 patients with Parkinson's disease undergoing long-term treatment with levodopa, and in 15 normal volunteers. The supplementary motor areas were significantly activated in the normal subjects and in the patients receiving levodopa but not in the patients deprived of levodopa. The contralateral primary sensory motor area was significantly activated in all three groups. The ipsilateral primary sensory motor cortex was not activated in the normal subjects and the non-treated patients but was in the patients treated with levodopa. It is concluded that the supplementary motor area hypoactivation which is observed in akinetic non-treated patients with Parkinson's disease is not present in patients undergoing long-term treatment with levodopa. This result suggests that (a) levodopa improves the functional activity of supplementary motor areas in Parkinson's disease and (b) there is no pharmacological tolerance to this effect. The ipsilateral primary motor cortex activation observed in the patients treated with levodopa could be related to levodopa-induced abnormal involuntary movements.
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PMID:Normal activation of the supplementary motor area in patients with Parkinson's disease undergoing long-term treatment with levodopa. 820 25

Abnormal involuntary movements (dyskinesias) of variable intensity eventually emerge in the majority of Parkinson's disease patients chronically treated with standard oral levodopa. They create social and physical embarrassment and narrow the therapeutic options normally proposed to improve Parkinsonian symptoms. Thus far, indirect clinical and experimental evidence has implicated the potential role of dopamine D1 receptor activation in the generation of dopa dyskinesia. In recent years, our group has tested several dopaminergic agonists of variable half-life and selectivity in monkeys rendered parkinsonian following toxic exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). These monkeys readily develop dyskinesia when treated with levodopa and provide the best animal model to study this complication. Our results in "drug-naive" and "dyskinesia-primed" MPTP animals suggest that pathological sensitisation of D2 receptor-mediated striatal outflow is necessary and sufficient for the induction of dopa dyskinesia, with perhaps a synergistic contribution from D1 receptors, and that repeated short-lived stimulation is important in the sensitisation process. This model supports the hypothesis that more continuous forms of dopaminomimetic therapy represent the best therapeutic approach for Parkinson's disease and calls for the development of novel D1 agonists for further clinical testing.
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PMID:Is striatal dopaminergic receptor imbalance responsible for levodopa-induced dyskinesia? 861 7

Dyskinesias are abnormal involuntary movements characterised by an excessive amount of movement. Typically, these movements are choreiform in nature. They may be caused by systemic, metabolic, endocrinologic, structural, vascular, infectious or inherited degenerative conditions, or be toxin- or drug-induced. With many non-drug-induced dyskinesias, treatment of the underlying condition may be sufficient to eliminate the movements, although temporary treatment may be required to control the movements if they are severe. Drug-induced dyskinesias often resolve when the offending drug is discontinued. A notable exception is tardive dyskinesia, which is caused by exposure to dopamine receptor blocking drugs, the majority of which are antipsychotic agents. Tardive dyskinesias will persist, or may even develop after the causative agent has been stopped and may not spontaneously remit. Another commonly encountered form of drug-induced dyskinesia is seen in patients with Parkinson's disease who are receiving levodopa. Medications which deplete dopamine are most successful in treating choreiform dyskinesias, although anticholinergics, GABAergics, serotonergics, and calcium channel blocking agents have been reportedly beneficial in some cases. Treatment of levodopa-induced dyskinesias requires manipulation of the patient's antiparkinsonian drug regimen.
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PMID:Pharmacological options for the management of dyskinesias. 895 55

Actigraphy measures physiological activity by using an acceleration sensor and RAM equipped with a data logger. Since actigraphy can continuously and easily record data over a long period of time without disturbing the normal activities of subjects, it is possible to analyze a large number of subjects. Actigraphy was performed in patients with Parkinson's disease who did not exhibit trembling. Results showed that the daily motor activity of patients was lower than that of the healthy individual. Daily motor activity was also found to be correlated with Hoehn-Yahr's classification. Furthermore, side-effects due to L-dopa, such as abnormal involuntary movement and on-off phenomenon, could be objective assessed. The results of long-term actigraphic examination, conducted after anti-Parkinsonian treatment, showed that akinesia improved with time. From these findings, it is concluded that actigraphy could quantitatively assess the degree of akinesia in Parkinsonian patients. Furthermore, actigraphy may be applied to the clinical assessment of drugs.
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PMID:[Objective measurement of motor activity in Parkinson's disease by actigraphy. Clinical assessment of akinesia]. 901 41

For the past 30 years levodopa (LD) has been the pharmacologic standard of care for treating idiopathic parkinsonism (Parkinson's disease or PD), a neurodegenerative disease of the central nervous system. LD is a pharmacologically inactive precursor, which is converted enzymatically to the neurotransmitter dopamine by a declining population of neurons in the substantia nigra, the most important site of the pathology of PD. Most patients experience a smooth, lasting response to small amounts of LD during the early years of treatment, but as the underlying disease gets worse, treatment-related problems arise. Motor fluctuations, which slowly emerge after 3-5 years of chronic LD therapy, gradually replace the smooth pattern of response, and more frequent dosing is required. Abnormal involuntary movements (dyskinesia), wearing-off of the motor response after a few hours, organic psychosis (confusion and hallucinations), and progressive loss of independence characterize the complicated interaction between the drug and the disease. Despite its problems, including the theoretical potential for harming neurons by inducing oxidant stress, and the recent development of other antiparkinson drugs, LD remains the most effective pharmacologic agent available for the relief of symptoms in patients with PD.
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PMID:Problems with current pharmacologic treatment of Parkinson's disease. 912 44

Eight of the first 15 patients with advanced Parkinson's disease who underwent microelectrode guided posteroventral pallidotomy developed transient abnormal involuntary movements during thermolesion, four of whom also did so during high frequency macrostimulation. Abnormal involuntary movements found before thermolesion were choreic, ballistic, or choreoathetoid in nature, usually persisted less than 60 minutes, and were contralateral to the site of thermolesion in six and bilateral in two of them. The appearance of abnormal involuntary movements during macrostimulation or thermolesion of the internal globus pallidus correlated with better surgical outcome as measured by UPDRS motor items and CAPIT timed test, so that they seem to be of prognostic value.
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PMID:Involuntary movements during thermolesion predict a better outcome after microelectrode guided posteroventral pallidotomy. 928 60

Until the introduction of L-dopa in the therapeutics of idiopathic Parkinson's disease (IPD) at the end of the 60's, treatment was essentially limited to anticholinergic drugs and surgical procedures devised to produce discrete lesions in the pallidum, ansa lenticularis and thalamus. L-dopa, associated with dopa decarboxylase inhibitors and dopaminergic agonists, gave rise to an almost complete standstill of surgical procedures. Nevertheless, natural progression of IPD with motor fluctuations and the appearance of L-dopa related abnormal involuntary movements caused surgery to reappear as a primary treatment option. The MPTP epidemic in heroin addicts was responsible for obtaining an experimental model of IPD and became the starting point for a wealth of information concerning the physiopathology of basal ganglia circuitry, neurotransmitters and specific dopaminergic, gabaergic and glutamaergic receptor subtypes involved in motor control. This information, in the context of new stereotactic techniques with modern neuroimaging, enabled old surgical procedures on the internal globus pallidus (Gpi) and thalamus to be reformulated. Additional neurophysiological guidance further improved accuracy in target finding thereby giving rise to impressive results in the symptomatic improvement of IPD including L-dopa induced dyskinesias.
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PMID:[Parkinson's disease: from pallidotomy to L-dopa and back to pallidotomy]. 943 79

Levodopa continues to be the most effective agent for the symptomatic treatment of Parkinson's disease. No other drug matches its ability to suppress parkinsonian symptoms, especially in patients with advanced disease. But over time, initial benefits begin to wane, not so much because of a decline in efficacy against core symptoms, but rather because of a rise in adverse effects. Most common are the motor response complications that appear within a few years of treatment initiation and ultimately affect most parkinsonian patients. These progressively disabling complications include response fluctuations and abnormal involuntary movements. Current evidence indicates that 'wearing-off' fluctuations, typically the first motor complication to become clinically evident, initially reflect the loss of buffering normally provided by striatal dopaminergic terminals. Thus, with increasing degeneration of the nigrostriatal system, swings in plasma levodopa concentrations associated with standard dosage regimens produce nonphysiological fluctuations in intrasynaptic dopamine. As a result of long term discontinuous stimulation, secondary changes occur at sites downstream from the dopamine system and now appear to underlie the progressive worsening of 'wearing-off' phenomena as well as the eventual appearance of other response complications. Chronic intermittent stimulation of normally tonically active dopaminergic receptors activates specific signalling cascades in striatal dopaminoceptive medium spiny neurons, and this evidently results in long term potentiation of the synaptic efficacy of glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype on these GABAergic efferents. As a consequence of their increasing sensitivity to excitation by cortical glutamatergic projections, it would, however, appear that medium spiny neuron function changes to favour the appearance of response fluctuations of the 'on-off' type and peak dose dyskinesias. The inability of standard levodopa treatment to restore striatal dopaminergic function in a more physiological manner clearly contributes to the appearance of motor complications. Continuous dopaminergic replacement not only reverses these complications in parkinsonian patients but also prevents their development in animal models of Parkinson's disease. Thus, pharmaceutical approaches that provide relatively continuous dopamine receptor stimulation might confer both prophylactic and palliative benefit to parkinsonian patients. Several such strategies are currently under development, and include various methods to prolong the duration of action of levodopa as well as the use of transdermally administered or very long acting dopamine agonists.
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PMID:The significance of continuous dopaminergic stimulation in the treatment of Parkinson's disease. 948 64

Stimulation of the thalamic nucleus ventralis intermedius (Vim) at high (130-Hz) frequency has been used over the last 8 years as a treatment in 134 patients with movement disorders (91 Parkinson's disease [PD], 23 essential tremor [ET], 21 various dyskinesias and dystonias, including four multiple sclerosis [MS]), implanted with long-term electrodes connected to a programmable stimulator. In PD patients, tremor was selectively suppressed for < or = 11 years. In ET patients, results were satisfactory, but in 35% of the cases deteriorated with time, when tremor had an action component. Other types of dyskinesias were much less influenced. Sixty-eight patients were bilaterally implanted, and 14 were implanted contralateral to a previous thalamotomy. Side effects were often minor, well tolerated, and immediately reversible. Three secondary scalp infections led to temporary removal of implanted material. There was no permanent morbidity. Long-term Vim stimulation, which is reversible, adaptable, and well tolerated, even by bilaterally operated-on (68 of 134) and by elderly patients, should replace thalamotomy in the regular surgical treatment of parkinsonian and essential tremors. More recently, we stimulated the subthalamic nucleus (STN) in 51 patients (44 bilateral) and the globus pallidus internus (GPi) in 12 patients (seven bilateral). STN stimulation has a spectacular effect on akinesia and rigidity and may improve the patients so as to maintain them all day at a level similar to their best "on" periods. A 30-50% reduction in drug dosage was possible in most of the patients. GPi stimulation has indications and effects similar to those of pallidectomy: abnormal involuntary movements are totally suppressed, whereas effects on akinesia and rigidity are not so important as they are with STN stimulation. For all three targets, morbidity is low and reversible, even when bilateral implantations are performed. The deep-brain stimulation method has now proved its safety as compared with ablative surgery and is able to provide a significant improvement to these severely disabled patients. Long-term follow up is establishing the security of the method, which should be considered in earlier stages of the disease actively to participate to rehabilitation.
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PMID:Long-term electrical inhibition of deep brain targets in movement disorders. 982 7

Abnormal involuntary movements, or dyskinesias, plague current symptomatic approaches to the treatment of Parkinson's disease. The neural mechanisms underlying the generation of dyskinesia following repeated l-3,4-dihydroxyphenylalanine (L-DOPA) or dopamine agonist administration in Parkinson's disease remain unknown. However, de novo administration of bromocriptine or lisuride to either l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned primates or patients can alleviate parkinsonian symptoms without the development of dyskinesia. In this study, we have investigated behavioral responses and alterations in the expression of opioid neuropeptide precursors preproenkephalin-A (PPE-A, encoding methionine- and leucine-enkephalin) and preproenkephalin-B (PPE-B), the precursor encoding dynorphins (dynorphin A1-17 and B1-13, leucine-enkephalin, and alpha-neoendorphin) in striatal output pathways of the 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease. Expression was assessed following repeated L-DOPA, bromocriptine, or lisuride administration. Given the functional organization of basal ganglia circuitry into anatomically discrete parallel circuits, we investigated alterations in peptide expression with reference to the detailed topography of the striatum. Following repeated L-DOPA administration (6.5 mg/kg, b.d., 21 days) in the 6-OHDA-lesioned rat a rotational response was observed. This became markedly enhanced with repeated treatment. We have previously characterized the pharmacology of this enhanced response and have suggested that it is a useful model for the elucidation of the cellular and molecular mechanisms underlying L-DOPA- and dopamine agonist-induced dyskinesia. In contrast to l-DOPA, de novo administration of bromocriptine (1 or 5 mg/kg, b.d., 21 days) or lisuride (0.01 or 0.1 mg/kg, b.d., 21 days) did not lead to an enhanced behavioral response. In vehicle-treated, 6-OHDA-lesioned animals, PPE-A expression was elevated rostrally and dorsally, while PPE-B expression was reduced in the striatum at all rostrocaudal levels. Repeated l-DOPA administration was accompanied by elevations in striatal PPE-B mRNA levels and a further elevation, above lesion-induced levels, in PPE-A expression. This further elevation was restricted to the dorsolateral striatum. However, following repeated bromocriptine or lisuride administration no increase in PPE-B expression was observed and the lesion-induced increase in PPE-A expression was normalized to prelesion levels. Increased PPE-A and PPE-B levels may, through decreasing GABA and glutamate release, respectively, in output nuclei of the basal ganglia, play a role in the development of L-DOPA- and dopamine-agonist induced dyskinesia in Parkinson's disease. These studies suggest that anti-parkinsonian treatments which are not associated with an elevation in PPE-B and/or normalize elevated PPE-A precursor expression, such as NMDA-receptor antagonists or long-acting dopamine D2 receptor agonists, e.g., cabergoline or ropinirole, may reduce dyskinesia in Parkinson's disease.
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PMID:Effect of repeated L-DOPA, bromocriptine, or lisuride administration on preproenkephalin-A and preproenkephalin-B mRNA levels in the striatum of the 6-hydroxydopamine-lesioned rat. 1007 96


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