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

Tiapride, a substituted benzamide derivative closely related to metoclopramide, reduced levodopa-induced peak dose involuntary movements in 16 patients with idiopathic Parkinson's disease. However, an unacceptable increase in disability from Parkinsonism with aggravation of end-of-dose akinesia led to its cessation in 14 patients. Tiapride had no effect on levodopa-induced early morning of "off-period" segmental dystonia. These results fail to support the notion that levodopa-induced dyskinesias are caused by overstimulation of a separate group of dopamine receptors.
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PMID:Tiapride in levodopa-induced involuntary movements. 45 86

123I-(S-)-2-hydroxy-3-iodo-6-methoxy-N[(1-ethyl-2-pyrrolidinyl) methyl]-benzamide (123I-IBZM) is a highly selective CNS D2 dopamine receptor ligand suitable for SPECT. This study reports on IBZM-SPECT findings in 60 patients including eight controls and 52 patients presenting with disorders of the dopaminergic system, including idiopathic Parkinson's syndrome (IPS) (n = 18), Parkinson's syndromes of other aetiology (PS) (n = 24) and Wilson's disease (n = 10). SPECT was performed 2 h p.i. of 185 MBq 123I-IBZM. For semiquantitative evaluation basal ganglia to frontal cortex ratios (BG/FC ratios) were calculated. In controls BG/FC ratios of 1.55 +/- 0.05 S.D. were observed. Findings in IPS patients (BG/FC ratio: 1.51 +/- 0.05) were not different from controls. In PS patients striatal IBZM binding (BG/FC ratio: 1.35 +/- 0.11) was significantly (P less than 0.001) lower compared to the control and IPS groups. Asymptomatic patients with Wilson's disease presented normal IBZM binding. In those with neurologic symptoms IBZM fixation was markedly reduced. IBZM-SPECT has shown to be a suitable means for in vivo imaging of striatal dopamine D2 receptors in controls and various disorders of the dopaminergic system. Our preliminary data suggest that IBZM-SPECT is potentially useful for discriminating between IPS and PS (sensitivity: 100%; specificity: 83%). In patients with Wilson's disease IBZM accumulation seems to correlate with the presence of neurologic symptoms.
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PMID:SPECT imaging of dopamine D2 receptors with 123I-IBZM: initial experience in controls and patients with Parkinson's syndrome and Wilson's disease. 183 42

We report one case of parkinsonism induced by cisapride and one case of Parkinson's disease whose symptoms were worsened by cisapride. Case 1. A 75-year-old female who had suffered from constipation and loss of appetite, was treated with cisapride for her gastro-intestinal symptoms. One year later, she developed progressive parkinsonian gait, cogwheel rigidity She showed parkinsonian gait, cogwheel rigidity and slowness in motion. Two months after cisapride was discontinued, her parkinsonism and depression disappeared. Case 2. A 66-year-old female with Parkinson's disease was given cisapride for constipation. Two months after starting cisapride, her akinesia and rigidity deteriorated gradually, and she became bed-ridden with dysphagia and dyspnea. After cisapride was discontinued, her parkinsonian symptoms improved gradually, and she became ambulant three months later. Cisapride is a benzamide derivative with a prokinetic action. Experimental studies have revealed that it has indirect cholinomimetic effects and potentially stimulates the gastrointestinal motor activity without blocking dopamine receptors or activating muscarinic cholinergic receptors. However, the present cases showed that cisapride could be a dopamine receptor blocker, and either induce or worsen parkinsonism. Therefore, cisapride should be avoided or very carefully used in parkinsonian patients and old people.
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PMID:[Parkinsonism induced or worsened by cisapride]. 772 93

The main clinical features, pathophysiology and underlying mechanisms of drug-induced parkinsonism are reviewed. The clinical manifestations of drug-induced parkinsonism are often indistinguishable from idiopathic Parkinson's disease. However, some subtle differences may exist: for example drug-induced parkinsonism is often associated with tardive dyskinesias, bilateral symptoms and the absence of resting tremor, etc. Besides toxins (eg manganese, carbon monoxide or MPTP), many drugs are known to produce parkinsonism: dopamine blocking drugs (true neuroleptics used as antipsychotics: phenothiazines, butyrophenones, thioxanthenes but also sulpiride, "hidden" neuroleptics prescribed as anti-nausea or anti-vomiting drugs (such as metoclopramide and other benzamide derivatives), dopamine depleting drugs (reserpine, tetrabenazine), alpha-methyldopa, calcium channel blockers (flunarizine, cinnarizine, etc). The putative role of other drugs (eg fluoxetine, lithium, amiodarone) as well as the therapeutic management of this side effect are reviewed.
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PMID:Drug-induced parkinsonism: a review. 785 36

For effective drug therapy of Parkinson's syndrome (PS), it is necessary to distinguish between idiopathic and secondary genesis and PS in neuronal systemic degeneration. [123I]Iodobenzamide ([123I] IBZM) is a radiolabelled benzamide and binds specifically to the cerebral dopamine receptor (D2) in the basal ganglia. The purpose of this study was to determine the value of the [123I]IBZM D2-receptor SPECT in the differential diagnosis of PS. A total of 38 patients (20 females, 18 males; age 61 +/- 13.3 years), with typical extrapyramidal symptoms were investigated. Twenty suffered from idiopathic and 11 from secondary PS. Seven patients in whom a neurological disease could be excluded, served as controls. SPECT data were acquired 90 min after i.v. injection of 185-200 MBq [123I]IBZM. After reconstruction with a Butterworth filter (cutoff frequency 0.5) and attenuation correction (coefficient 0.12 cm(-1)) we quantify the IBZM basal ganglia uptake as ratio to teh frontal D2-receptor-free cortex (BG/FC). The patients with idiopathic PS (IPS) and the controls revealed high and specific IBZM uptake in the basal ganglia compared to the adjacent frontal brain tissue (IPS: BG/FC = 1.44 +/- 0.10; controls: BG/FC = 1.48 +/- 0.10). A significant decreased striatal IBZM uptake is found in cases with secondary PS (BG/FC = 1.25 +/- 0.10; p<0.0001, t-test compared to controls and IPS). The patient group with IPS can be subdivided into patients without L-dopatherapy (BG/FC = 1.49 +/- 0.07), patients with longstanding L-dopa-therapy demonstrating significantly decreased striatal IBZM uptake (BG/FC = 1.31 +/- 0.04; p<0.0001, t-test compared to controls and other IPS), which correlates pathophysiological with a reduction of free D2 receptors, and patients with de novo PS showing a slight increased striatal IBZM uptake (BG/FC = 1.56 +/- 0.05), which represents D2-receptor stimulation. [123I]IBZM-SPECT is a sensitive and non-invasive test for striatal D2-receptor density and activity which permits relatively clear discrimination between idiopathic and secondary PS and yields important information for differential therapy.
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PMID:[Dopamine (D2) receptor SPECT with 123I-iodobenzamide (IBZM) in diagnosis of Parkinson syndrome]. 865 87

Remoxipride is a novel substituted benzamide that more effectively blocks mesolimbic than striatal D2 dopamine receptors. We used remoxipride in the management of nine patients with Parkinson's disease (PD) who were experiencing visual hallucinations due to dopaminergic therapy. Remoxipride was begun in a dose of 25 mg three times daily and gradually increased to 75-225 mg/d (mean 161 mg). The psychiatric status improved in eight patients. Little or no change in the severity of parkinsonism was noted in five, a mild increase in two, and a moderate increase in two. Because one patient with moderately severe levodopa-induced dyskinesias experienced a reduction in the abnormal movements without a substantial increase in parkinsonism, we began a trial of remoxipride for disabling peak-dose dyskinesias. The trial was abandoned after every one of the first four patients entered experienced an immediate, severe, and prolonged increase in off periods with single 10- to 25-mg doses. This striking differential response to an atypical neuroleptic with weak striatal D2 antagonist properties indicates that different states of postsynaptic dopamine receptor sensitivity or synaptic dopamine levels may be associated with various disease- and treatment-related problems found in late-stage PD.
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PMID:Remoxipride in Parkinson's disease: differential response in patients with dyskinesias fluctuations versus psychosis. 866 33

Drug-induced parkinsonism(DIP) is at present the second most frequent cause of parkinsonism next to idiopathic Parkinson's disease(PD) in Japan. The ratio of the incidence of DIP to PD has been reported to be between 1:2 and 1:5, which varied at the period surveyed. The most frequent causative drugs were calcium-blocking agents, flunarizine and cinnarizine in 1980s, and they have been replaced in recent years by benzamide derivatives with antipsychotic, antiemetic or prokinetic actions, sulpiride, tiapride and metoclopraramide. The clinical features of DIP are similar to those of PD except for rather rapid progression of the symptoms. Careful neurological examination and check of all drugs the patient has taken are important for correct diagnosis. Most causative drugs act as the dopamine D2 receptor blocker in the brain and discontinuance of the drug(s) is necessary for the treatment. Parkinsonian symptoms begin to improve in several weeks and patients are relieved from the symptoms usually within several months.
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PMID:[Drug-induced parkinsonism]. 901 32

Poly(ADP-ribose) polymerase (PARP) is a DNA binding protein that uses nicotinamide adenine dinucleotide (NAD+) as a substrate. Evidence from in vitro studies on nonneuronal cells in culture have shown that when fully activated by free radical-induced DNA damage, PARP depletes cellular NAD+ and consequently adenosine triphosphate (ATP) levels within a matter of minutes, and that this depletion is associated with a cell death that can be prevented by PARP inhibitors. The present in vivo study utilized the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mouse, a model of central nigrostriatal dopamine neurotoxicity that recapitulates certain features of Parkinson's disease (PD), and one in which we have previously shown PARP inhibitors to be protective, to examine whether MPTP acutely caused region- and time-dependent changes in levels of NAD+ and ATP in the brain in vivo and whether such effects were modified by treatments with neuroprotective doses of the PARP inhibitor benzamide. The results confirm that MPTP reduces striatal ATP levels, as previously reported by Chan et al., show that MPTP causes a regionally-selective (striatal and midbrain) loss of NAD+, and indicate that the PARP inhibitor benzamide can prevent these losses without interfering with MPTP-induced striatal dopamine release. These findings suggest an involvement of PARP in the control of brain energy metabolism during neurotoxic insult, provide further evidence in support of the participation of PARP in MPTP-induced neurotoxicity in vivo and suggest that PARP inhibitors might be beneficial in the treatment of PD.
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PMID:Implication of poly (ADP-ribose) polymerase (PARP) in neurodegeneration and brain energy metabolism. Decreases in mouse brain NAD+ and ATP caused by MPTP are prevented by the PARP inhibitor benzamide. 1066 29

Brain dopamine receptor agonists alleviate the signs of Parkinson's disease, while dopamine receptor antagonists alleviate hallucinations and delusions in psychosis. The dopamine type 2 receptor (or D2) is blocked by antipsychotic drugs, including even the "atypical" drugs such as clozapine or remoxipride, in direct relation to their clinical potencies. Compared to the long form of the D2 receptor (D2(Long)), the short form (D2(Short)) may be three times more sensitive to benzamide antipsychotic drugs. Hence, it is essential to identify additional variants of dopamine receptors for which more selective antipsychotic drugs can be found. Although no family linkage has been found between the D2 receptor and schizophrenia, there can be brain region abnormalities in the RNA transcript expression of dopamine receptors. Therefore, in order to identify variant dopamine D2 receptors, we searched for mutations in the RNA transcripts for the dopamine D2 receptor in the striatum of post-mortem brains from individuals who died with psychosis, including schizophrenia. A new splice variant of the D2 receptor, D2(Longer), with a unique TG splice site, was found in one control brain and in two psychotic brains.
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PMID:New dopamine receptor, D2(Longer), with unique TG splice site, in human brain. 1071 23

Rapid eye movement (REM) sleep behaviour disorder (RBD) is characterized by complex behaviour during REM sleep. The aetiology of this disorder is still unknown, but a recent study showed an association between RBD and Parkinson's disease. We therefore studied striatal postsynaptic dopamine D2 receptor density with [123I](S)-2-hydroxy-3-iodo-6-methoxy-(1-ethyl-2-pyrrolidinylmethyl ) benzamide ([123I]IBZM) and the striatal presynaptic dopamine transporter with (N)-(3-iodopropene-2-yl)-2beta-carbomethoxy-3beta-(4-chlorop henyl) tropane ([123I]IPT) using single-photon emission computed tomography (SPECT) in patients with idiopathic RBD. We compared the [123I]IPT-SPECT results of five patients with polysomnographically confirmed idiopathic RBD with the [123I]IPT-SPECTs of seven age- and sex-matched controls without a history of sleep disorders, and of 14 patients with Parkinson's disease (Hoehn and Yahr stage I). All RBD patients had significantly reduced striatal [123I]IPT binding compared with the controls (RBD: right, 2.94 +/- 0.32, left, 3.03 +/- 0.41; controls: right, 4.41 +/- 0.17, left, 4.34 +/- 0.21; P = 0.003), but significantly higher striatal [123I]IPT binding compared with the striatum contralateral to the symptomatic body side of the Parkinson's disease patients (Parkinson's disease: ipsilateral, 3.17 +/- 0.36, P = 0.298; contralateral, 2.51 +/- 0.31, P = 0.019). Uptake of [123I]IBZM was not significantly different in the RBD group compared with the controls. This study demonstrates that [123I]IPT-SPECT is a useful diagnostic tool in RBD and that reduced striatal dopamine transporters may be a pathophysiological mechanism of idiopathic RBD. (Results are given as mean +/- standard deviation.)
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PMID:Reduced striatal dopamine transporters in idiopathic rapid eye movement sleep behaviour disorder. Comparison with Parkinson's disease and controls. 1082 54


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