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)

Single-photon emission computed tomography with 123I-iodobenzamide, a dopamine D2 receptor antagonist, was employed to study dopamine D2 receptor densities in 17 patients with biochemically proved Wilson's disease and stable neurological status with therapy and in 5 age-matched control subjects. Of the 17 patients with Wilson's disease, 5 were neurologically asymptomatic, 3 had cerebellar signs, 1 exhibited a mild parkinsonian syndrome, 7 showed a parkinsonian syndrome and cerebellar signs, and 1 had generalized dystonia and a parkinsonian syndrome. In 5 age-matched control subjects specific isotope binding as calculated by the basal ganglia to frontal cortex ratio was 1.57 +/- 0.04 (mean +/- standard deviation). The ratio in patients with Wilson's disease ranged from 1.56 +/- 0.05 (n = 5, asymptomatic patients) to 1.17 +/- 0.02 (n = 4, marked neurological impairment). We observed an almost linear correlation between the reduction of 123I-iodobenzamide (IBZM) binding and the severity of neurological signs at the time of IBZM-SPECT (correlation coefficient, -0.84; p < 0.01). We suggest that the reduction of postsynaptic striatal dopamine D2 receptors as detected by IBZM-SPECT reflects striatal neuronal damage in Wilson's disease.
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PMID:Decrease of D2 receptors indicated by 123I-iodobenzamide single-photon emission computed tomography relates to neurological deficit in treated Wilson's disease. 147 64

[123I]iodobenzamide-single photon emission computed tomography (IBZM-SPECT) was employed to study the distribution of dopamine D2 receptors in a patient with biochemically proven Wilson's disease presenting with generalized dystonia. IBZM is a dopamine D2 receptor antagonist with high affinity and specific binding to basal ganglia detectable by SPECT. IBZM-SPECT in this patient (age, 20 years) displayed a striatum to frontal cortex ratio of 1.2 compared to 1.55 +/- 0.05 (mean +/- SD) in normal controls (n = 7; mean age, 53.3 years). In parallel with this finding, MRI with heavily T2-weighted sequences showed atrophy and low signal intensity changes of the basal ganglia. There was no improvement of dystonia after a subcutaneous injection of apomorphine. In contrast, IBZM-SPECT of a neurologically asymptomatic Wilson's disease patient (age, 21 years) displayed a striatum to frontal cortex ratio of 1.6. The MRI scan of this patient was normal. It is suggested that the observed apomorphine-unresponsive generalized dystonia in this Wilson's disease patient is related to striatal lesions proven by IBZM-SPECT and MRI.
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PMID:Marked reduction of striatal dopamine D2 receptors as detected by 123IBZM-SPECT in a Wilson's disease patient with generalized dystonia. 153 31

Persistent signs of oral dyskinesia (tongue protrusion and facial grimacing) had developed as a result of earlier chronic treatment with neuroleptics in a Cebus apella monkey. When this animal was given single doses of any classical neuroleptic, a transient deterioration of dyskinesia occurred, preceded by a temporary abolishment of dyskinesia sometimes with an attack of acute dystonia. Fluphenazine (5-25 micrograms/kg) causes dose-related deteriorations of dyskinesia. Six different drugs were tested on this monkey for their capacity to elicit aggravation of dyskinetic signs: three antihistamines (brompheniramine, promethazine, diphenhydramine) and three dopamine D2 receptor antagonists (sulpiride, tiapride, metoclopramide). High doses of promethazine and diphenhydramine (5 mg/kg) induced a temporary alleviation of dyskinesia, possibly through sedation. All three D2 receptor antagonists precipitated signs of acute dystonia at some dose levels, but out of the test drugs only metoclopramide caused deterioration of dyskinetic symptoms. According to the present results only metoclopramide stands out as a drug with an inherent propensity to cause tardive dyskinesia.
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PMID:Application of a primate model for tardive dyskinesia. 684 25

Acute extrapyramidal syndromes (EPS) are one of the major limitations to effective neuroleptic treatment. These disorders have both motor (objective) and mental (subjective) aspects, which must be considered in any evaluation and differential diagnosis of treatment-related side effects. The disorders of akathisia, acute dystonia and parkinsonism have unique features that are best understood in the context of a careful assessment of patient characteristics, drug factors and temporal aspects. Though acute EPS are commonly explained on the basis of dopamine D2 receptor antagonism, data from several lines of study raise important questions about this hypothesis. The roles of receptor subtype specificity, brain region selectivity and ratios of different receptor subtype antagonism are discussed. New and novel antipsychotic drugs with low rates of EPS are important clinical advancements that will increase patients' ability to participate in therapy and rehabilitation and thus improve their quality of life.
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PMID:Motor and mental aspects of acute extrapyramidal syndromes. 791 42

Eight Cebus apella monkeys were treated with haloperidol for 2 years. Five monkeys had developed mild oral tardive dyskinesia and all were primed for neuroleptic induced dystonia, thus serving as a model for both chronic and acute extrapyramidal side effects. In this model, the partial dopamine D2 receptor agonists SDZ HDC-912, SDZ HAC-911, terguride, (-)-3-(3-hydroxyphenyl)-N-propylpiperidine) ((-)-3-PPP) and SND 919 were tested for extrapyramidal side-effect liability. Their antipsychotic potential was also tested, using a dose of dextroamphetamine producing mild stereotypy and moderate motoric unrest. For comparison, the dopamine D2 receptor agonist, LY 171555 and antagonist, raclopride were used. In contrast to the other drugs tested, SDZ HAC-911 consistently reduced oral activity, P < 0.05 (at doses from 0.005 to 0.025 mg/kg). The relative dystonic potencies were raclopride > SDZ HDC-912 > SDZ HAC-911 = terguride. Neither (-)-3-PPP nor SND 919 produced dystonia, but had observable dopamine D2 receptor agonistic effects, (-)-3-PPP producing emesis at 1-4 mg/kg and SND 919 producing motoric unrest and stereotypy at 0.05-0.25 mg/kg. Comparing the antiamphetamine effects of the more antagonist-like drugs with raclopride, the relative potencies were terguride = SDZ HAC-911 > SDZ HDC-912 > raclopride. Comparing the antiamphetamine effects of the more agonist-like drugs with LY 171555, the relative potencies were SND 919 > (-)-3-PPP > LY 171555 in relation to motoric unrest, while neither (-)-3-PPP nor LY 171555 produced inhibition of stereotypy.
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PMID:Effects of several partial dopamine D2 receptor agonists in Cebus apella monkeys previously treated with haloperidol. 810 65

Positron emission tomographic(PET) study using 18F-6-fluoro-L-dopa (18FDOPA) can provide efficient information on the pre-synaptic function of nigrostriatal dopaminergic neurons. In juvenile parkinsonism(JP), the accumulation of 18FDOPA is markedly decreased in the caudate nucleus and putamen on both hemispheres. This finding is different from those in dystonia syndromes such as dopa-responsive dystonia (DRD) and hereditary progressive dystonia with marked diurnal fluctuation(HPD), and it is rather similar to late onset of Parkinson's disease. Furthermore, we studied dopamine D2 receptor binding activity on the post-synaptic sites of the striatum using 11C-YM-09151-2(11C-YM), a highly selective dopamine D2 receptor antagonist. In JP, 11C-YM was highly accumulated in the striatum, and D2 receptor binding activity is not significantly different from that of age-matched young normal subjects, but much higher than that of aged subjects. This finding suggests that post-synaptic dopamine receptor function keeps still normal or hypersensitive in JP, and may be different from other degenerative disorders such as multiple system atrophy. Glucose metabolism using 18F-fluoro-2-deoxy-D-glucose(18FDG) was also within normal range in the cerebral cortex in JP, but was more increased in the striatum than in the cerebral cortex in some patients. These PET studies can provide efficient informations about the pathologic condition of JP.
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PMID:[PET study of dopamine metabolism and dopamine D2 receptor in juvenile parkinsonism]. 901 28

The dystonias are a group of serious movement disorders characterized by involuntary muscle spasms of different parts of the body. We recently proposed that hypofunction of dopamine D2 receptor-mediated inhibition of the indirect output pathway of the basal ganglia can result in dystonia. In this review, we discuss the results of a variety of genetic and biochemical studies in light of this hypothesis. Several forms of early-onset dystonia show distinct autosomal dominant, recessive, or X-linked genetic transmission patterns. Late onset forms of dystonia, though not showing clear Mendelian transmission patterns, also appear to be highly familial. Recently, several genetic-linkage locations have been identified for early-onset dystonia and for two of these loci, mutations decreasing dopamine synthesis have been demonstrated. Biochemical studies of monkeys and man also demonstrate that several types of dystonia occur in a dopamine-deficiency state. Similarly, mice strains developed to be deficient in several dopamine-pathway components have motor abnormalities consistent with dystonia. Hypofunction of the dopamine D2 receptor-mediated inhibition of the indirect output pathway of the putamen may be a common feature of many of these heritable and secondary dystonic syndromes.
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PMID:Mutational and biochemical analysis of dopamine in dystonia: evidence for decreased dopamine D2 receptor inhibition. 958 25

We studied pre-synaptic and post-synaptic function in the striatum of a patient with juvenile parkinsonism (JP) using positron emission tomography (PET). [18F]6-fluorodopa (18FDOPA), 11C-YM-09151-2 and [18F]fluoro-2-deoxy-d-glucose (18FDG) were used to measure fluorodopa uptake, dopamine D2 receptor binding and glucose metabolism, respectively. In this patient, 18FDOPA accumulation was decreased markedly in the caudate nucleus and the putamen bilaterally. In the images of 11C-YM-09151-2 and 18FDG, in contrast, no conspicuous changes were observed in the striatum. Thus our PET studies using 18FDOPA, 11C-YM-09151-2 and 18FDG provide a useful approach for assisting the diagnosis of JP, because the present findings are different from the results in patients with dopa-responsive dystonia and hereditary progressive dystonia with marked diurnal fluctuation. Furthermore, our findings are of particular interest in relation to the pathogenesis of JP.Copyright Lippincott-Raven Publishers
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PMID:PET study of striatal fluorodopa uptake and dopamine D2 receptor binding in a patient with juvenile parkinsonism. 1021 Aug 38

The effects of the novel compound, (-)-OSU6162 ((S)-(-)-3-methylsulfonylphenyl-1-propylpiperidine), on rotational behavior induced by dopamine receptor agonists was investigated in common marmosets (Callithrix jacchus) with unilateral 6-hydroxydopamine lesions. (-)-OSU6162 per se displayed no effect on the animals' behavior. On the other hand, pretreatment with (-)-OSU6162 attenuated rotational behavior induced by apomorphine (apomorphini hydrochloridum), L-DOPA (3,4-dihydroxyphenylalanine), and the dopamine D2 receptor agonist, quinpirole (trans-(-)-4aR-4,4a, 5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolol[3,4-g]quinoline hydrochloride), without inducing motor impairment such as akinesia or dystonia. In addition, treatment with (-)-OSU6162 for 5 consecutive days almost completely abolished the rotational behavior provoked by apomorphine and produced a transient subsensitization of such apomorphine-induced effects after it was discontinued. Moreover, pretreatment with (-)-OSU6162 in two monkeys augmented the rotational behavior elicited by the dopamine D1 receptor agonists, SKF-81297 (R(+)-6-chloro-7,8,dihydroxy-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine hydrobromide) and A-77636 ((-)-(1R, 3S)-3-adamantyl-1-(aminomethyl)-3,4-dihydro-5, 6-dihydroxy-1H-2-benzopyran hydrochloride). The findings indicate that (-)-OSU6162 can exert indirect state-dependent effects that differentially affect dopamine D1 and dopamine D2 receptor agonist-induced behavior.
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PMID:Motor effects of (-)-OSU6162 in primates with unilateral 6-hydroxydopamine lesions. 1068 84

Myoclonus-dystonia (M-D) is an autosomal dominant disorder characterized by myoclonic and dystonic muscle contractions that are often responsive to alcohol. The dopamine D2 receptor gene (DRD2) on chromosome 11q has been implicated in one family with this syndrome, and linkage to a 28-cM region on 7q has been reported in another. We performed genetic studies, using eight additional families with M-D, to assess these two loci. No evidence for linkage was found for 11q markers. However, all eight of these families showed linkage to chromosome 7 markers, with a combined multipoint LOD score of 11.71. Recombination events in the families define the disease gene within a 14-cM interval flanked by D7S2212 and D7S821. These data provide evidence for a major locus for M-D on chromosome 7q21.
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PMID:A major locus for myoclonus-dystonia maps to chromosome 7q in eight families. 1102 10


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