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)

At the present time, it seems unlikely that progressive neurodegenerative diseases, such as ALS, Parkinson's disease, and dementia of the Alzheimer type, are triggered by environmental agents with excitotoxic potential. These include excitotoxic agents that behave as glutamate agonists or disrupt energy metabolism: both types elicit permanent but self-limiting neuronal diseases with patterns of neuronal deficit that reflect selective chemical exposure (MPP+ and parkinsonism), differential susceptibility to energy dysmetabolism (NPA and dystonia), or the distribution of glutamate-receptors (domoic acid and memory loss). If environmental agents play an etiologic role in progressive neurodegenerative diseases, they are likely to target a critical, irreplaceable neuronal molecule that is required to maintain long-term neuronal integrity.
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PMID:Are human neurodegenerative disorders linked to environmental chemicals with excitotoxic properties? 132 79

Levodopa-induced dyskinesias (LID) in Parkinson's disease (PD) may be classified into three main categories: "On" dyskinesias, diphasic dyskinesias (DD), and "off" periods. The study of 168 parkinsonian patients showed that about half (n = 84) showed one pattern of LID only. A combination of two was present in 68, and 16 had the three presentation patterns. A fairly good correlation between type of dyskinesia and presentation pattern was established. Chorea, myoclonus, and dystonic movements occurred during the "on" period. Dystonic postures, particularly affecting the feet, were mainly present in the "off" period, but a few patients had a diphasic presentation. Repetitive stereotyped movements of the lower limbs always corresponded to DD. Acute pharmacological tests using dopamine agonists (subcutaneous apomorphine 3-8 mg; intravenous lisuride 0.1-0.15 mg) and dopamine antagonists (intravenous sulpiride 200-400 mg and intravenous chlorpromazine 25 mg) were performed in 40 patients. Dopamine agonists enhanced "on" dyskinesias and markedly reduced or abolished "off" period dystonia and DD. Dopamine antagonists reduced all types of LID but usually aggravated parkinsonism. These clinical and pharmacological results indicate that LID in PD are a heterogeneous phenomenon difficult to explain on the basis of a single pathophysiological mechanism.
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PMID:Levodopa-induced dyskinesias in Parkinson's disease: clinical and pharmacological classification. 135 58

The dopaminergic neurons of the substantia nigra pars compacta and ventral tegmental area play a crucial role in regulating movement and cognition respectively. Several lines of evidence suggest that a degeneration of dopaminergic cells in the substantia nigra produces the symptoms of Parkinson's disease. On the other hand, a hyperactivity of the dopaminergic transmission in the brain induces dyskinesia, dystonia and psychosis. It is also well established that the euphoric and rewarding responses evoked by drugs of addiction, such as amphetamine and cocaine, are mediated by central dopamine systems. Electrophysiological experiments which study the activity of single dopaminergic neurons in the ventral mesencephalon have shown that dopamine and dopaminergic drugs reduce the firing frequency of these cells. This is due to the stimulation of D2-D3 autoreceptors and to a hyperpolarization of the membrane produced by an increase in potassium conductance. In addition, substances which increase the release (amphetamine), the synthesis (levodopa) or block the uptake (cocaine, nomifensine, amineptine) of dopamine in the brain inhibit the firing activity of the dopaminergic cells throughout dopamine-mediated mechanisms. In this review, we will briefly examine the literature concerning the physiological and behavioural responses caused by dopamine and dopaminergic agents on the dopaminergic neurons of the ventral mesencephalon. Our conclusion suggests that the electrophysiological actions of dopamine and dopamine-related drugs on dopaminergic cells in the ventral mesencephalon might be indicative of the pharmacological effects of these agents on the brain.
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PMID:The electrophysiological actions of dopamine and dopaminergic drugs on neurons of the substantia nigra pars compacta and ventral tegmental area. 135 54

Pramipexole (SND 919; 2-amino-4,5,6,7-tetrahydro-6-propyl-amino-benzthiazole- dihydrochloride) was tested for its agonistic activity at pre- and postsynaptic dopamine (DA) receptors. L-Dihydroxyphenylalanine (L-dopa) accumulation in the rat striatum and limbic system and the alpha-methyltyrosine-induced reduction of DA were inhibited. Both effects were fully antagonized by haloperidol but not by the selective DA D1 receptor antagonist SCH 23390. Pramipexole decreased the levels of DA metabolites dose dependently, whereas striatal DA levels remained unchanged. In mice, pramipexole (0.001-1 mg/kg s.c.) reduced exploratory locomotor activity. In rats with unilateral striatal lesions, only weak ipsilateral rotation was produced by pramipexole at the highest dose. However, in rats with unilateral lesions of the medial forebrain bundle, pramipexole potently induced contralateral circling (ED50 0.026 mg/kg s.c.). In the N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model, pramipexole also had potent stimulatory effects. Finally, in haloperidol-sensitized monkeys, the substance did not elicit dyskinesia/dystonia when given alone, but rather inhibited those symptoms which had been induced by haloperidol (ED50 0.116 mg/kg i.m.). It is concluded that pramipexole has therapeutic potential for schizophrenic patients, as a result of its autoreceptor agonistic effects and its weak effects at normosensitive postsynaptic DA receptors. Furthermore, its potent stimulatory effects in DA-depleted animals suggest a possible use in the treatment of Parkinson's disease.
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PMID:Biochemical and pharmacological studies on pramipexole, a potent and selective dopamine D2 receptor agonist. 135 88

We recorded short-latency median nerve somatosensory evoked potentials (SEPs) in 10 patients with dystonia (6 with focal dystonia, 3 with generalized dystonia, and 1 with segmental dystonia) and compared them with those of 10 normal controls. The EEG was recorded from 29 sites on the scalp with linked earlobe electrodes for reference. Latencies and amplitudes of P15, postcentral N20 and P45, and frontal N30 were evaluated. The latencies of all potentials were the same in patients and controls. The amplitudes of P15, N20 and P45 were also the same in both groups, but the N30 amplitude of the patients was larger than of the controls. The amplitude of N30 did not vary from the affected side to the unaffected side. Previous work has shown decreased N30 amplitude in patients with Parkinson's disease. Changes in N30 amplitude may be indicative of abnormal excitatory effects on cortex resulting from disorders of the basal ganglia.
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PMID:The N30 component of somatosensory evoked potentials in patients with dystonia. 137 83

We studied the performance of sequential arm movements in 14 patients with Parkinson's disease, nine patients with Huntington's disease and seven patients with arm dystonia. The results were compared with those from normal subjects. Subjects had to perform each movement of the sequence as fast as possible, stopping as briefly as possible between two successive movements. In one set of experiments, patients with Parkinson's disease drew four different geometrical patterns in a counter-clockwise direction. The patterns consisted of two, three, four and five segments of identical length. In a second set, the subjects drew a pentagon in a counter-clockwise and a clockwise direction and each side of the pentagon singly in a counter-clockwise direction. All three groups of patients were slow in executing movements and in switching from one movement to the next. Only patients with Parkinson's disease took longer to perform the segments at the end of a sequence. In other words, their movement times lengthened progressively as the sequence progressed. This phenomenon could still be recognized when the direction and position of the segments were changed (pentagon drawn in the counter-clockwise and the clockwise direction) and when the extra-time needed, mainly due to the sequential nature of the task, was considered by computing the differences between movement times obtained during drawing of the pentagon and those obtained when each segment was traced singly. This study demonstrates that sequential movements are abnormal in Parkinson's disease, Huntington's disease and dystonia and that in the performance of long motor sequences, the deficit in sequencing movements is exacerbated only in patients with Parkinson's disease.
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PMID:Sequential arm movements in patients with Parkinson's disease, Huntington's disease and dystonia. 142 99

Dopa-responsive dystonia (DRD) is one form of childhood-onset idiopathic torsion dystonia. Adult-onset parkinsonism has appeared in several previously unaffected members in families with DRD suggesting that this may be an additional phenotypical expression of the disease. We report a family with DRD in which 2 women and 1 man, unaffected by dystonia, developed tremor-onset parkinsonism after age 50 years. The women continue on a low dosage of levodopa after 9 and 13 years of treatment, with a stable, nearly complete, symptomatic response. This contrasts to the typical long-term treatment complications observed in patients with Parkinson's disease. We assessed nigrostriatal dopaminergic function in the proband, with typical DRD, and the 2 women with parkinsonism using 6-[18F]fluoro-L-dopa positron emission tomography. All 3 had normal striatal 6-[18F]fluoro-L-dopa uptake. These observations provide compelling evidence that "benign" adult-onset parkinsonism may be an expression of the disease in some members of families with DRD and does not support consideration of the DRD gene as a risk factor for development of Parkinson's disease. There may be considerable clinical heterogeneity in DRD depending on the age at onset.
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PMID:Long-term treatment response and fluorodopa positron emission tomographic scanning of parkinsonism in a family with dopa-responsive dystonia. 144 40

In view of the encouraging results in various trials with deprenyl as an added drug therapy for Parkinson's disease, a pilot study to study deprenyl's efficacy in the Indian population was undertaken. Eleven patients were recruited in this open trial and were objectively assessed by Unified Rating Scale for Parkinsonism of Columbia University, Modified Hoehn and Yahr Staging and Schwab and England activities of daily living. Side effects, mood changes, changes in dyskinesia percentage, early morning dystonia and off period percentage were also noted. This study suggests improvement in the above parameters with minimal side effects.
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PMID:Combination therapy of parkinsonism with deprenyl. 145 57

Dystonia refers to involuntary, prolonged muscle contractions leading to sustained, often twisting, postures. High dose anticholinergic therapy for childhood onset dystonia, botulinum toxin injections for focal dystonia, and levodopa for diurnal dystonia provide symptomatic relief for some patients. Despite this, treatment of both idiopathic and secondary dystonia remains inadequate for many patients. Baclofen, a pre-synaptic acting GABA agonist, has been reported to benefit dystonia in a number of retrospective studies. Dramatic improvement in symptoms, especially in gait, was found in almost 30% of 31 children and adolescents with idiopathic dystonia in one retrospective study using doses ranging from 40 to 180 mg daily. The response to baclofen of adults with focal dystonia is less dramatic. One series of 60 adults with cranial dystonia found sustained benefit in 18%. Smaller series have not consistently found significant benefit in adults. Baclofen has been used to treat several secondary dystonias: tardive dystonia has occasionally been reported to improve and there are isolated reports of improvement in dystonia occurring in Parkinson's disease and in glutaric aciduria.
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PMID:Baclofen in the treatment of dystonia. 151 73

Recent electrophysiological studies in patients with cranial dystonia (CD) have demonstrated evidence for hyperactivity of brainstem interneurons. Tizanidine (Tz), a centrally acting skeletal muscle relaxant, is thought to act by antagonizing the activity of excitatory interneurons which mediate hypertonic processes (e.g. spasticity). Theoretically this agent may be effective in patients with CD. Ten patients were enrolled in an open-label study with a single-blind placebo wash-in. Eight patients tolerated doses of between 28-36 mg per day. For the most part tizanidine was ineffective for the symptoms of CD. This failure suggests that the reported brainstem interneuronal disturbances may not be altered by Tz. Further studies using concomitant electrophysiological assessment would be necessary to assess this possibility. Alternatively, these disturbances may not be a principle cause of the dystonic movements. The finding of similar changes in other basal ganglia diseases lacking CD (e.g. Parkinson's disease) favours this latter explanation.
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PMID:Tizanidine in cranial dystonia. 159 39


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