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)

Parkinson disease progression is associated with the development of levodopa short-duration responses and dyskinesias, as well as gait freezing. Levodopa dose adjustment and adjunctive treatment with dopamine agonists form the major therapeutic strategies. Catechol O-methyltransferase inhibitors are also appropriate considerations, whereas other drugs, including selegiline, amantadine, anticholinergic agents, and propranolol, have a more minor role.
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PMID:Medical treatment of later-stage motor problems of Parkinson disease. 1059 54

Parkinson's disease (PD) is characterized by pathological changes which include degeneration of dopaminergic neurons in the substantia nigra pars compacta coupled with intracytoplasmic inclusions known as Lewy bodies. Neurodegeneration and Lewy bodies can also be found in the locus coeruleus, nucleus basalis, hypothalamus, cerebral cortex, cranial nerve motor nuclei, and central and peripheral components of the autonomic nervous system. PD progression is associated with the development of dementia, autonomic dysfunction, and postural instability, which do not respond well to conventional therapy. Therapeutic efforts aimed at preventing or at least delaying PD progression by reducing the overload of iron and generation of ROS, correcting the zinc deficiency may be of great benefit. Current pharmacotherapy of PD, in addition to symptomatic L-dopa treatment, includes the neuroprotective strategies with dopamine agonists, monoamine oxidase-B inhibitors (MAO-B), glutamate antagonists, catechol O-methyltransferase (COMT) inhibitors and other antioxidants or free radical scavengers. Depression, anxiety disorder and stress are all associated with PD and it is therefore necessary to include treatment regimens for these ailments in addition to the traditional pharmacotherapy for the symptoms of PD, as well as the neuroprotective measures noted above, in order to ensure the greatest possible benefit to PD patients.
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PMID:Importance of treatment of depression in assuring the most efficacious management of Parkinson's disease. 1090 82

Molecular mechanisms determining the turn-over rate and specificity of catechol O-methylation were studied by combining enzyme kinetic measurements, computational modeling of substrate properties and fitting ligands in a 3D model of the active site of the enzyme. Enzyme kinetic measurements were carried out for 46 compounds, including most clinically used catechol drugs, by using recombinant human soluble catechol O-methyltransferase (COMT). The most important mechanism decreasing the turnover rate and increasing affinity was the electron withdrawing effect of substituents. Several other mechanisms by which substituents affected reactivity and affinity were identified. Highest turnover rates were determined for unsubstituted catechol and pyrogallol. Pyrogallol derivatives generally seemed to be more specific substrates than catechols. Catecholestrogens were the most specific endogenous substrates, whereas catecholamines were rather poor substrates. Among the catechol drugs used in the L-DOPA treatment of Parkinson's disease, the COMT inhibitors entacapone and tolcapone were not methylated, whereas the DOPA decarboxylase inhibitor benserazide was 15 times more specific substrate than L-DOPA, the target of COMT inhibition. The structure-activity relationships found allow the prediction of reactivity, affinity, and specificity with useful accuracy for catechols with a wide range of structures and properties. The knowledge can be used in the evaluation of metabolic interactions of endogenous catechols, drugs and dietary catechols, and in the designing of drugs with the catechol pharmacophore.
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PMID:Molecular mechanisms controlling the rate and specificity of catechol O-methylation by human soluble catechol O-methyltransferase. 1116 Aug 77

Catechol O-methyltransferase (COMT) transfers a methyl group from S-adenosyl-L-methionine to the catechol substrate in the presence of magnesium. After the characterisation of COMT more than four decades ago, a wide variety of COMT enzyme assays have been introduced. COMT activity analysis usually consists of the handling of the sample and incubation followed by separation and detection of the reaction products. Several of these assays are validated, reliable and sensitive. Besides the studies of the basic properties of COMT, the activity assay has also been applied to explore the relation of COMT to various disease states or disorders. In addition, COMT activity analysis has been applied clinically since COMT inhibitors have been introduced as adjuvant drugs in the treatment of Parkinson's disease.
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PMID:Separation methods for catechol O-methyltransferase activity assay: physiological and pathophysiological relevance. 1245 Jun 69

Catechol O-methyltransferase (COMT) inhibition has been proposed as a means to increase levodopa bioavailability in patients with Parkinson's disease, which may be useful in reducing the total dose of levodopa, diminishing its frequency of administration and, more importantly, improving fluctuations in the response to each individual dose of levodopa, which usually develop after chronic treatment. Entacapone is a potent, selective peripheral catechol O-methyltransferase inhibitor which effectively inhibits the O-methylation of levodopa, thus increasing its central bioavailability and potentiating its behavioral effects. In clinical trials in patients with Parkinson's disease, entacapone has prolonged and improved the therapeutic effect of levodopa combined with a dopa decarboxylase inhibitor. The new drug has increased the "on" time duration, decreased the "off" time duration and has reduced the total dose requirements of levodopa. Entacapone has shown optimal tolerability at the currently recommended doses, with the added benefit of a lower required dose of levodopa. This, in turn, improves the tolerability of levodopa and thus the overall tolerability of the treatment of advanced Parkinson's disease.
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PMID:Perspectives in the treatment of Parkinson's disease: COMT inhibitors open up new treatment strategies. 1297 67

1-methyl-4-phenyl-1,2,4,6,-tetrahydropyridine (MPTP) is a selective neurotoxin that produces striatal dopamine depletion resulting in parkinsonism like symptoms in humans and is, therefore, used to generate animal models for Parkinson's disease (PD). In this study, C57BL/6N mice were treated with MPTP acutely (3x20 mg/kg, 2-hour interval, one day injection). Mice were then sacrificed 24 hours after the last injection and brain tissue was collected for analysis. Significant decrease of striatal dopamine (DA) and the metabolites (DOPAC, HVA) was observed after MPTP treatment. MPTP also reduced protein expression of tyrosine hydroxylase (TH) in the striatum. Real time RT-PCR was used to examine selective genes of the dopaminergic system in the substantia nigra. Our data demonstrated that MPTP significantly decreased gene expression of TH, dopamine transporter (DAT), and vesicle monoamine transporter (VMAT), coinciding with the pattern of dopamine concentration changes and protein expression after MPTP treatment. Although a significant decrease of DA metabolites was observed in striatum, there was no change in the expression of monoamine oxidases (MAO-A, MAO-B) or catechol O-methyltransferase (COMT), indicating that these changes might be simply a consequence of reduced monoamine levels. In addition, gene expression of alpha-synuclein was also decreased with MPTP treatment, but there was no change in beta-synuclein and parkin. This is the first study using real-time PCR to indicate that MPTP selectively alters gene expression and provides information for clinical studies in PD. Future studies will focus on gene expression of other pathways that may be affected by MPTP treatment and investigation of gene expression in specific cell types in vivo using LCM technology.
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PMID:Selective alterations of gene expression in mice induced by MPTP. 1549 5

Inhibition of the enzyme catechol O-methyltransferase offers a therapeutic handle to regulate the catabolism of catecholamine neurotransmitters, providing valuable assistance in the treatment of CNS disorders such as Parkinson's disease. A series of ribose-modified bisubstrate inhibitors of COMT featuring 2'-deoxy-, 3'-deoxy-, 2'-aminodeoxy-3'-deoxy-, and 2'-deoxy-3'-aminodeoxyribose-derived central moieties and analogues containing the carbocyclic skeleton of the natural product aristeromycin were synthesized and evaluated to investigate the molecular recognition properties of the ribose binding site in the enzyme. Key synthetic intermediates in the ribose-derived series were obtained by deoxygenative [1,2]-hydride shift rearrangement of adenosine derivatives; highlights in the synthesis of carbocyclic aristeromycin analogues include a diastereoselective cyclopropanation step and nucleobase introduction with a modified Mitsunobu protocol. In vitro biological evaluation and kinetic studies revealed dramatic effects of the ribose modification on binding affinity: 3'-deoxygenation of the ribose gave potent inhibitors (IC50 values in the nanomolar range), which stands in sharp contrast to the remarkable decrease in potency observed for 2'-deoxy derivatives (IC50 values in the micromolar range). Aminodeoxy analogues were only weakly active, whereas the change of the tetrahydrofuran skeleton to a carbocycle unexpectedly led to a complete loss of biological activity. These results confirm that the ribose structural unit of the bisubstrate inhibitors of COMT is a key element of molecular recognition and that modifications thereof are delicate and may lead to surprises.
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PMID:Bisubstrate inhibitors of catechol O-methyltransferase (COMT): the crucial role of the ribose structural unit for inhibitor binding affinity. 1689 69

Long-term care of elderly patients with Parkinson's disease (PD) is challenging for long-term care staff and physicians. Because the progression of PD varies among patients, an individualized treatment plan, updated as necessary based on disease progression, comorbid conditions, and side effects, is essential. Education regarding PD management is also needed to provide optimal care, and treatment guidelines from professional associations are available. Especially important is the management of motor complications, which usually emerge after treatment with antiparkinsonian medications, particularly levodopa/carbidopa. Current treatment strategies to avoid or treat motor complications aim at providing a more continuous (ie, physiologic) dopaminergic stimulation, rather than the pulsatile (intermittent) stimulation provided by traditional PD treatments. Catechol O-methyltransferase (COMT) inhibitors prolong the levodopa serum half-life and allow more levodopa to be delivered to the brain over a longer time, thereby smoothing dopaminergic stimulation. Dopamine agonists also provide more continuous dopaminergic stimulation but are associated with a greater likelihood of hallucinations and confusion, especially in the elderly. Treatments that reduce motor complications, allowing a higher level of functioning, lessen the burden of care in long-term care settings and increase quality of life for patients and their families.
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PMID:Long-term care of Parkinson's disease. Strategies for managing "wearing off" symptom re-emergence and dyskinesias. 1698 43

Parkinson's disease is a common neurodegenerative disorder that can cause significant disability and decreased quality of life. The cardinal physical signs of the disease are distal resting tremor, rigidity, bradykinesia, and asymmetric onset. Levodopa is the primary treatment for Parkinson's disease; however, its long-term use is limited by motor complications and drug-induced dyskinesia. Dopamine agonists are options for initial treatment and have been shown to delay the onset of motor complications. However, dopamine agonists are inferior to levodopa in controlling motor symptoms. After levodopa-related motor complications develop in advanced Parkinson's disease, it is beneficial to initiate adjuvant therapy with dopamine agonists, catechol O-methyltransferase inhibitors, or monoamine oxidase-B inhibitors. Deep brain stimulation of the subthalamic nucleus has been shown to ameliorate symptoms in patients with advanced disease. Depression, dementia, and psychosis are common psychiatric problems associated with Parkinson's disease. Psychosis is usually drug induced and can be managed initially by reducing antiparkinsonian medications. The judicious use of psychoactive agents may be necessary. Consultation with a subspecialist is often required.
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PMID:Parkinson's disease: diagnosis and treatment. 1955 11

Cognitive dysfunction commonly occurs even in the early stages of Parkinson's disease (PD). Impairment on frontostriatally based executive tasks is particularly well described but affects only a proportion of early PD patients. Our previous work suggests that a common functional polymorphism (val(158)met) within the catechol O-methyltransferase (COMT) gene underlies some of this executive heterogeneity. In particular, an increasing number of methionine alleles, resulting in lower enzyme activity, is associated with impaired performance on the "Tower of London" planning task. The main objective of this study was to investigate the underlying neural basis of this genotype-phenotype effect in PD using functional magnetic resonance imaging. We scanned 31 patients with early PD who were homozygous for either valine (val) (n = 16) or methionine (met) (n = 15) at the COMT val(158)met polymorphism during performance of an executive task comprising both Tower of London (planning) and simple subtracting ("control") problems. A cross-group comparison between genetic subgroups revealed that response times for planning problems were significantly longer in met compared with val homozygotes, whereas response times for control problems did not differ. Furthermore, imaging data revealed a significant reduction in blood oxygen level-dependent signal across the frontoparietal network involved in planning in met/met compared with val/val patients. Hence, we have demonstrated that COMT genotype impacts on executive function in PD through directly influencing frontoparietal activation. Furthermore, the directionality of the genotype-phenotype effect observed in this study, when interpreted in the context of the existing literature, adds weight to the hypothesis that the relationship between prefrontal function and dopamine levels follows as an inverted U-shaped curve.
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PMID:Catechol O-methyltransferase Val158Met genotype influences frontoparietal activity during planning in patients with Parkinson's disease. 1747 91


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