Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0013421 (dystonia)
 8,418 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fibroblasts provide a source of living cells that can be obtained easily from humans and used to evaluate inherited differences in the activities of enzymes important in neurotransmitter and drug metabolism. Here, we describe biochemical characteristics of catechol-O-methyltransferase (COMT, EC 2.1.1.6) activity in homogenates of cultured human skin fibroblasts. Many properties of the enzyme, including apparent affinity for dihydroxybenzoic acid and S-adenosyl methionine, optimal pH and (Mg++), and inhibition by Ca++, are similar to those reported in lysates of human erythrocytes. Culture and assay conditions have been established for optimal and reproducible measurement of COMT activity in individual fibroblast lines. In 16 control lines, COMT activity ranged from 115 to 263 pmol/min/mg protein with a mean of 181 pmol/min/mg protein. Enzyme activity did not vary with the age or sex of the donor. The COMT activities in fibroblasts from eight patients with dystonia musculorum deformans, an inherited movement disorder of unknown etiology, were not significantly different from controls. Monoamine oxidase (MAO, EC 1.4.3.4) type A activity was measured in 12 lines from patients with dystonia, and values did not differ significantly from age- and sex-matched controls. We conclude that inherited variation in activity of these two catabolic enzymes is not sufficient to explain alterations in monoamine metabolism described in this disorder.
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PMID:Catechol-O-methyltransferase activity in cultured human skin fibroblasts from controls and patients with dystonia musculorum deformans. 729 45

The catechol-O-methyltransferase inhibitor tolcapone was compared with the dopamine agonist bromocriptine in an open-label, randomized trial involving 146 levodopa-treated parkinsonian patients with end-of-dose deterioration of efficacy. Tolcapone was given at a dosage of 200 mg three times daily; bromocriptine was titrated from 1.25 mg once daily at baseline to, at most, 10 mg three times daily by day 24 (mean final dose 22.4 mg/day). After 8 weeks, the tolcapone group had a significant reduction in daily levodopa dose compared with the bromocriptine group (p<0.05). No significant differences in the "on/off" time and motor disability were seen between the tolcapone and bromocriptine treatment groups. Bromocriptine induced more hallucinations, orthostatic hypotension, and nausea, whereas tolcapone therapy was associated with more muscle cramps and dystonia. These results suggest that when added to levodopa therapy, the two drugs have a different side effect profile, with the advantages for tolcapone being absence of titration and quicker efficacy.
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PMID:Efficacy and tolerability of tolcapone compared with bromocriptine in levodopa-treated parkinsonian patients. Tolcapone Study Group. 991 42

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of tolcapone are reviewed. Tolcapone is the first drug brought to market from the new class of selective and reversible inhibitors of catechol-O-methyltransferase. Tolcapone is indicated for use in the treatment of Parkinson's disease as an adjunct to levodopa-carbidopa therapy in patients who are experiencing fluctuations in symptoms and who are not responding to or are not appropriate candidates for other adjunctive therapies. The absolute bioavailability of tolcapone after an oral dose is about 65%. Clinical trials have demonstrated that tolcapone 50-200 mg three times daily reduces "off" time in patients refractory to levodopa-carbidopa, Unified Parkinson's Disease Rating Scale scores, and the dosage of levodopa-carbidopa required for symptom suppression. The most frequent adverse effects of tolcapone are dyskinesia, nausea, sleep disorders, dystonia, orthostatic hypotension, diarrhea, dizziness, and hallucinations; also, there is a potential for elevation of liver transaminase concentrations in the blood. To date, three deaths from fulminant hepatic failure in association with tolcapone have been reported. Extensive liver function testing is required of all patients before and during therapy. The recommended starting dosage is 100 mg orally three times daily as an adjunct to levodopacarbidopa therapy; a concurrent reduction in the levodopa dosage of about 30% is suggested. Patient response should be monitored carefully during the first three weeks of therapy; treatment should be discontinued in patients failing to respond during this initial use. Tolcapone is of benefit in fluctuating Parkinson's disease, but benefits must be carefully weighed against risks in individual patients.
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PMID:Tolcapone: a novel approach to Parkinson's disease. 1056 98

Elevated plasma levels of homocysteine (Hcy) are a risk factor for systemic vascular diseases, stroke and vascular dementia. In recent years, increasing Hcy levels have been detected in neurological disorders that are not vascular in origin including Alzheimer's Disease and movement disorders (MD) such as idiopathic Parkinson's Disease (PD), Huntington's Disease (HD) and primary dystonia. Hyperhomocysteinemia (HHcy) in PD results from L-Dopa administration and its O-methylation dependent from catechol-O-methyltransferase and may be implicated in the development of motor complications and non-motor symptoms, such as dementia. In a recent study, HHcy has been evidenced in HD patients, compared to controls. Because mutated Huntington protein influences Hcy metabolism by modulating cystathionine-beta-synthase activity, Hcy could represent a biological marker of neurodegeneration and could explain the leading role of cardiovascular and cerebrovascular diseases as causes of death in HD. Finally, several cases of homocystinuria associated with dystonia, and some recent reports of elevated Hcy in patients with primary adult onset dystonia have been published. Increased Hcy plasma levels may have important implications in patients affected by these basal ganglia disturbances, by exerting neurotoxic effects, contributing to neurotransmitter imbalance in motor circuits, and increasing the risk for vascular insults and cognitive dysfunctions.
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PMID:Hyperhomocysteinemia in movement disorders: Current evidence and hypotheses. 1684 41

Deep brain stimulation (DBS) has proved highly effective in the treatment for Parkinson's disease and dystonia. Presently, many types of dopamine agonists, monoamine oxidase B (MAOB) inhibitors, catechol-O-methyltransferase (COMT) inhibitor or other antiparkinsonian drugs are being developed. However, it is still very difficult to medically treat motor complications associated with levodopa therapy. Surgical intervention using DBS was possible to stimulate the subthalamic nucleus as the treatment of Parkinson's disease. Stimulation of the subthalamic nucleus improves the cardinal parkinsonian symptoms and motor complication associated with levodopa treatment. DBS is a reversible treatment and the original status could be observed by turning off the stimulation. This procedure enables the observation of clinical outcomes or brain mechanisms under both the conditions of turned on and turned off stimulations. On the other hand, dystonia is heterogeneous and refractory and hence, it has been difficult to medically treat it. Since there was no effective treatment available for patients with generalized dystonia, these patients became disabled. However, recently, bilateral pallidal DBS has been shown to markedly improve the conditions of patients with generalized dystonia, and it has proven to be a reliable treatment. There are two characteristic clinical effects of pallidal DBS on dystonia. It improves primary hereditary generalized dystonia, particularly DYT 1, more prominently than secondary dystonia and its beneficial effects are observed over a period of time course. The beneficial effects of pallidal DBS in patients with dystonia are not immediate but progress over weeks to months. The brain mechanism underlying the improvement of pallidal DBS in dystonia has been unclear. Many studies on DBS in Parkinson's disease and dystonia have been carried out to elucidate the clinical outcomes and/or the underlying neurophysiological mechanisms. In this review, the clinical outcomes of DBS for Parkinson's disease and dystonia will be focused on.
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PMID:[Deep brain stimulation for Parkinson's disease and dystonia]. 1937 17

Various movement disorders such as dystonia may acutely develop during or at emergence from general anaesthesia in patients with or without pre-existing Parkinson disease. These movements are triggered by a variety of drugs including propofol, sevoflurane, anti-emetics, antipsychotics and opioids. The postulated mechanism involves an imbalance between dopaminergic and cholinergic neurotransmitters in the basal ganglia. We report an acute, severe and generalised dystonic reaction in an otherwise healthy woman at emergence from general anaesthesia, dramatically reversed by the administration of naloxone, pointing to a potential role of the fentanyl and morphine that the patient had received. Recent literature on the mechanisms of abnormal movements induced by opioids are discussed. The severity of the reaction with usual doses of opioids, in a patient with no prior history of parkinsonism, led to further investigation that demonstrated the possibility of an enhanced susceptibility to opioids, involving a genetically determined abnormal function of glycoproteine-P and catechol-O-methyltransferase.
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PMID:Naloxone-responsive acute dystonia and parkinsonism following general anaesthesia. 1983 83