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)

In human, catechol-O-methyltransferase (COMT: E.C. 2.1.1.6) is responsible for metabolism of catechol neurotransmitter and xenobiotics. The main clinical interest in COMT results from the possibility of using COMT inhibitors as adjuncts in the therapy of Parkinson's disease (PD) with l-DOPA. COMT is therefore a target for inhibitor development aiming at PD treatment and has been submitted to extensive structure-based drug design. Recently reported inhibitors have nitrocatechol structure that may inhibit oxidative phosphorylation and uncouple mitochondrial energy production. This work reports the first crystallographic study of Rat COMT complexed with non-nitrocatechol inhibitor. Analysis of the structural differences among the previously reported inhibitor complexes, coumarine-based inhibitor (4-phenyl-7, 8-dihydroxycoumarine: 4PCM) bound structure provides the explanation for inhibitor binding and can be used for future inhibitor design.
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PMID:Crystal structures of rat catechol-O-methyltransferase complexed with coumarine-based inhibitor. 1905 47

The first effective drugs for Parkinson's disease (PD) were anticholinergics, introduced at the end of 19.th century by Charcot. Since the introduction of levodopa in the sixties of the previous century, many new drugs have emerged for the treatment of Parkinson's disease: dopamine agonists (ergot as well as non-ergot, bromocriptine, pergolide, mirapexine, ropinirole), MAO B inhibitors (selegiline, rasagiline), amantadine, COMT inhibitors (entacapone, tolcapone). In all stages of the disease, levodopa remains the most effective drug for improving motor symptoms in PD. However, long term treatment with levodopa is accompanied by the development of motor fluctuations, dyskinesia, cognitive and neuropsychiatric adverse effects and increasingly diverse spectrum of drugs is needed to alleviate motor and nonmotor symptoms. Some of these drugs have caused considerable concern and controversies and were regarded at certain points as the 'bad guys' of Parkinson's disease pharmacological armamentarium. In the article, a short review of 'bad guys' including anticholinergics, selegiline, tolcapone and dopamine agonists, is given.
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PMID:'Bad guys' among the antiparkinsonian drugs. 1927 Jun 34

Chronic levodopa (LD)/dopadecarboxylase inhibitor (DDI) increases homocysteine generation as side reaction of O-methylation. Aim was to investigate the impact of the peripheral COMT inhibitor entacapone (EN) on plasma concentrations of homocysteine, LD and 3-O-methyl-dopa (3-OMD). Patients with Parkinson's disease (PD) received on two consecutive days in a standardised fashion one single dose of 200 mg retarded release LD/carbidopa (CD) or of 150 mg LD/CD/EN, since both were shown to have simultaneous pharmacokinetic LD behaviour. Homocysteine increased after retarded release LD/CD application, but not following LD/CD/EN intake. Homocysteine was lower during the LD/CD/EN condition 80 min after baseline when compared with its levels after LD/CD administration. LD levels simultaneously rose on both days. 3-OMD concentrations did not change. Acute LD/CD application caused a rise of homocysteine levels, which was prevented by LD/CD/EN intake. Therefore, peripheral COMT inhibition may have a beneficial effect on putative, controversially debated components of homocysteine-related progression of PD.
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PMID:Peripheral COMT inhibition prevents levodopa associated homocysteine increase. 1965 87

L-DOPA is a di-hydroxy-phenyl, catecholamine precursor, amino acid, initially considered as an inert compound and now the key stone for the treatment of Parkinson's disease (PD) and some hereditary dystonias. L-DOPA, when administered to mammals, is rapidly metabolized to dopamine and 3-OM-DOPA, and its half-life in plasma is roughly 2 hours which has been considered the explanation for some of the L-DOPA related complications in PD. There have been, therefore, sophisticated methods of improving its pharmacokinetics by the association of decarboxylase and COMT inhibitors, slow release preparations and continuous infusions. In addition to its symptomatic effects, the impact of L-DOPA on the natural course of the disease is intriguing. By alleviating motor deficits, L-DOPA may improve health quality and life span in patients with PD, but there are neurotoxic and neurotrophic effects of L-DOPA which may produce long term effects on disease progression. These effects are dependent of the dose, the status of the metabolic pathways involved in catecholamine metabolism, the balance of free radicals and their scavengers and the function of glia. Finally, there is new data suggesting that L-DOPA may be not only a catecholamine precursor but also a neurotransmitter by itself of yet unknown function.
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PMID:Half a century of L-DOPA. 1975

Cognitive abnormalities are common in Parkinson's disease, with important social and economic implications. Factors influencing their evolution remain unclear but are crucial to the development of targeted therapeutic strategies. We have investigated the development of cognitive impairment and dementia in Parkinson's disease using a longitudinal approach in a population-representative incident cohort (CamPaIGN study, n = 126) and here present the 5-year follow-up data from this study. Our previous work has implicated two genetic factors in the development of cognitive dysfunction in Parkinson's disease, namely the genes for catechol-O-methyltransferase (COMT Val(158)Met) and microtubule-associated protein tau (MAPT) H1/H2. Here, we have explored the influence of these genes in our incident cohort and an additional cross-sectional prevalent cohort (n = 386), and investigated the effect of MAPT H1/H2 haplotypes on tau transcription in post-mortem brain samples from patients with Lewy body disease and controls. Seventeen percent of incident patients developed dementia over 5 years [incidence 38.7 (23.9-59.3) per 1000 person-years]. We have demonstrated that three baseline measures, namely, age >or=72 years, semantic fluency less than 20 words in 90 s and inability to copy an intersecting pentagons figure, are significant predictors of dementia risk, thus validating our previous findings. In combination, these factors had an odds ratio of 88 for dementia within the first 5 years from diagnosis and may reflect the syndrome of mild cognitive impairment of Parkinson's disease. Phonemic fluency and other frontally based tasks were not associated with dementia risk. MAPT H1/H1 genotype was an independent predictor of dementia risk (odds ratio = 12.1) and the H1 versus H2 haplotype was associated with a 20% increase in transcription of 4-repeat tau in Lewy body disease brains. In contrast, COMT genotype had no effect on dementia, but a significant impact on Tower of London performance, a frontostriatally based executive task, which was dynamic, such that the ability to solve this task changed with disease progression. Hence, we have identified three highly informative predictors of dementia in Parkinson's disease, which can be easily translated into the clinic, and established that MAPT H1/H1 genotype is an important risk factor with functional effects on tau transcription. Our work suggests that the dementing process in Parkinson's disease is predictable and related to tau while frontal-executive dysfunction evolves independently with a more dopaminergic basis and better prognosis.
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PMID:The distinct cognitive syndromes of Parkinson's disease: 5 year follow-up of the CamPaIGN cohort. 1981 13

Parkinson's disease (PD) is caused by progressive degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNpc), resulting in the deficiency of DA in the striatum. Thus, symptoms are developed, such as akinesia, rigidity and tremor. The aetiology of neuronal death in PD still remains unclear. Several possible mechanisms of the degeneration of dopaminergic neurons are still elusive. Various mechanisms of neuronal degeneration in PD have been proposed, including formation of free radicals, oxidative stress, mitochondrial dysfunction, excitotoxicity, calcium cytotoxicity, trophic factor deficiency, inflammatory processes, genetic factors, environmental factors, toxic action of nitric oxide, and apoptosis. All these factors interact with each other, inducing a vicious cycle of toxicity causing neuronal dysfunction, atrophy and finally cell death. Considerable evidence suggests that free radicals and oxidative stress may play key roles in the pathogenesis of PD. However, currently, drug therapy cannot completely cure the disease. DA replacement therapy with levodopa (L-Dopa), although still being a gold standard for symptomatic treatment of PD, only alleviates the clinical symptoms. Furthermore, patients usually experience severe side effects several years after the L-Dopa treatment. Until now, no therapy is available to stop or at least slow down the neurodegeneration in patients. Therefore, efforts are made not only to improve the effect of L-Dopa treatment for PD, but also to investigate new drugs with both antiparkinsonian and neuroprotective effects. Here, the advantages and limitations of current and future therapies for PD were dicussed. Current therapies include dopaminergic therapy, DA agonists, MAO-B inhibitor, COMT inhibitors, anticholinergic drugs, surgical procedures such as pallidotomy and more specifically deep brain stimulation of the globus pallidus pars interna (GPi) or subthalamic nucleus (STN), and stem cell transplantation.
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PMID:Treatment strategies for Parkinson's disease. 2010 Dec 74

The diagnosis of idiopathic Parkinson's disease is based on a thorough clinical examination with demonstration of the presence of bradykinesia, as well as tremor, rigidity, postural instability and hyposmia. Symptomatic forms and atypical Parkinson syndrome should be ruled out. Nuclear medical analyses of the dopamine metabolism and the dopamine receptors are used only in exceptions to clarify difficult cases of differential diagnoses. For young patients, dopamine-agonists and, indeed, once again increasingly MAO-B inhibitors, such as rasagiline, are mainly used for therapy. Older patients und patients in advanced stages receive levodopa and a COMT inhibitor. As supplemental therapy, amantadine is given for dyskinesia and apathy and budipine is given for tremor-dominant type of Parkinson's disease. In advanced stages with motor fluctuations, apomorphine or Duodopa pumps or deep brain stimulation are employed.
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PMID:[Diagnosis and therapy of idiopathic Parkinson's disease]. 2010 16

Patients with Parkinson's disease (PD) have a high risk of psychiatric complications, like depressive or psychotic syndromes, dementia and sleep disorders. Although these disorders may even precede the onset of motor symptoms, they are often not recognized and therefore not adequately treated. This article provides a comprehensive overview of the therapeutic options of the most commonly observed psychopathological syndromes in PD. In the case of depressive syndromes medication could be optimized by making use of dopamine agonists that have been proven to have antidepressant properties. In recent studies tricyclic antidepressants showed stronger effects than SSRI. Psychotic symptoms are most often evoked by dopaminergic therapy or are seen in the course of cognitive decline. The therapeutic regimen should be built mainly on L-Dopa medication in the lowest tolerated dose, if required in combinations with COMT-Inhibitors. When antipsychotic medication is indicated, clozapine is the first choice. Quetiapine might also be useful in many patients. Psychotic symptoms in demented patients may respond to cholinesterase-inhibitors, that also delay cognitive decline. Patients with PD require an individually optimized therapeutic regimen not only for motor symptoms, but also for frequently occurring psychiatric syndromes since these strongly influence the patients' and their caregivers' quality of life, are predictors for hospitalization and therefore have great economic importance for health care systems.
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PMID:[Treatment of mental disorders in patients with Parkinson's disease]. 2042 92

Smoking has been reported to be inversely associated with Parkinson's disease (PD) in many studies, but a recent study in China found that smoking increased the risk of PD. Variants in genes associated with dopamine metabolism found to increase the risk for PD have also been associated with smoking behavior. To investigate the association between smoking and PD in a Chinese population and determine whether the genetic variants of genes involved in dopamine metabolism influence the relationship between smoking and risk for PD. Chinese PD patients were recruited from Xuanwu Hospital. Controls were sampled from community. Detailed information on life-long smoking behavior was collected by face-to-face interview. Genotypes were determined for SLC6A3 VNTR, COMT Val108/158Met and MAO-B intron13 A/G polymorphisms by PCR-RFLP, DHPLC and sequencing. Chi-square and logistic regression model were used in the analysis. 176 PD cases and 354 controls were enrolled in this study. 23.9% cases are smokers, compared to 48.0% in controls. Ever smoking is inversely associated with PD (odds ratio=0.14, 95% CI 0.08-0.26, adjusted for age and gender). None of the above-mentioned genetic polymorphisms was associated with PD risk or smoking. When each variant was included in the logistic regression model, the inverse association between smoking and PD remained the same, and the interactions between smoking and variants were not significant in the model. Our data support a reduction of PD risk associated with smoking in a Chinese population. These variants of genes associated with DA uptake and metabolism do not affect the inverse association between smoking and PD.
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PMID:Smoking, genes encoding dopamine pathway and risk for Parkinson's disease. 2060 87

Parkinson's disease is a neurodegenerative pathology which affects the dopaminergic neurons in the mesencephalon, leading to a progressive and relentless motor disability and to non-motor symptoms of different severity. The aim of this review is to summarize the features of drugs currently used in the pharmacotherapy of Parkinson's disease, with a look at their beneficial effects and limitations. Drugs acting on dopamine transmission, as L-DOPA, direct dopaminergic agonists, inhibitors for either the MAO or COMT enzymes and drugs acting on neurotransmitters other than dopamine (e.g. acetylcholine, glutamate) will be covered. Investigational drugs currently under examination for their therapeutic potential in Parkinson's disease and recent patents which may be relevant to the field will be also discussed.
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PMID:Pharmacological therapy of Parkinson's disease: current options and new avenues. 2072 38


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