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PubMed1999

COMT inhibition by tolcapone further improves levodopa pharmacokinetics when combined with a dual-release formulation of levodopa/benserazide. A novel principle in the treatment of Parkinson's disease.

The objective of the study reported here was the investigation of the effect of catechol-O-methyl transferase (COMT) inhibition by tolcapone on the pharmacokinetics of levodopa and 3-O-methyldopa (3-OMD) after administration of a new dual-release formulation (dual-RF) of levodopa/benserazide (200/50). The study had a double-blind, placebo-controlled, randomized, crossover design and was conducted in 18 healthy young subjects. On the 2 treatment days, separated by a washout period of 7 days, the dual-RF was administered in combination (blinded) with tolcapone (200 mg) or placebo. Both treatment combinations were well tolerated. Tolcapone increased the bioavailability (AUC 0-infinity) and apparent elimination half-life (t(1/2)) of levodopa by 80 and 40%, respectively, compared to placebo. The maximal plasma concentration (Cmax) was slightly elevated by tolcapone. In the presence of tolcapone, formation of 3-OMD was substantially reduced. In conclusion, the effect of tolcapone on levodopa pharmacokinetics after administration of the dual-RF is similar to the one observed after immediate- and slow-RFs and leads to a marked improvement in levodopa pharmacokinetics and subsequently to an optimization of levodopa therapy.

Adolescent↗

PubMed2006

Phytoestrogen exposure, polymorphisms in COMT, CYP19, ESR1, and SHBG genes, and their associations with prostate cancer risk.

Prospective phytoestrogen exposure was assessed using both biomarkers and estimates of intake in 89 British men recruited into the Norfolk arm of the European Prospective Investigation into Cancer and Nutrition study, men who subsequently developed prostate cancer. Results were compared with those from 178 healthy men matched by age and date of recruitment. Levels of seven phytoestrogens (daidzein, genistein, glycitein, O-desmethylangolensin, equol, enterodiol, and enterolactone) were measured in spot urine and serum samples. Five single-nucleotide polymorphisms in COMT, CYP19, ESR1, and SHBG genes were genotyped. Urinary levels of all phytoestrogens correlated strongly with serum levels. Correlation coefficients ranged from 0.63 (glycitein) to 0.88 (daidzein) (P < 0.001). Urinary and serum levels correlated significantly with isoflavone intake assessed from food diaries (R = 0.15-0.20; P < 0.05) but not with that from a food-frequency questionnaire. Odds ratios for phytoestrogen exposure, as assessed using the four methods, were not significantly associated with prostate cancer risk (P = 0.15-0.94). Men with the CC genotype for the ESRI PvuII polymorphism had significantly higher risk for prostate cancer compared with men with the TT genotype [adjusted odds ratio = 4.65 (1.60-13.49); P = 0.005]. Our results utilizing a combined prospective exposure provide no evidence that phytoestrogens alter prostate cancer risk in British men, whereas the C allele for the PvuII polymorphism may be associated with increased risk.

Aged↗

PubMed1998

COMT inhibition: a new treatment strategy for Parkinson's disease.

During the initial stages of Parkinson's disease, treatment with levodopa plus a decarboxylase inhibitor (carbidopa or benserazide) provides adequate control of symptoms. However, as the disease progresses, the clinical response to treatment often begins to fluctuate, becoming increasingly correlated with fluctuations in plasma concentrations of levodopa-the "wearing-off" phenomenon. Many strategies have attempted, with various degrees of success, to increase the availability of levodopa and its active metabolites, thus reducing these fluctuations in response. This review focuses on the role of the new catechol O-methyltransferase (COMT) inhibitors tolcapone and entacapone as adjuncts to levodopa therapy. These agents act effectively and safely to increase the amount of levodopa that is available to enter the brain by extending the half-life of levodopa, resulting in more stable levels in the plasma and prolonging "on" time.

Antiparkinson Agents↗

PubMed2004

The role of COMT inhibition in the treatment of Parkinson's disease.

Several prospective double-blind, placebo-controlled trials have demonstrated that combining levodopa with the COMT inhibitor entacapone is efficacious in reducing motor fluctuations. Compared with levodopa alone, mean daily "on" time was increased by 1-1.7 hours, with a corresponding decrease in daily "off" time. In addition, some studies have shown that these benefits are associated with significant improvements in both UPDRS motor and ADL scores. These benefits have been shown to persist in long-term clinical trials with follow-up for up to 3 years. Recent studies have also examined the value of combining levodopa with entacapone in stable patients who do not experience motor response fluctuations. Here, too, benefits have been reported, especially in health-related quality of life measures. Studies to determine if administering levodopa in combination with entacapone will delay the development of dyskinesia and motor fluctuations are eagerly awaited.

Antiparkinson Agents↗

PubMed2004

Safety and tolerability of COMT inhibitors.

Combining levodopa with the catechol-O-methyltransferase (COMT) inhibitor entacapone has been shown to be an effective strategy in the management of Parkinson's disease (PD) patients experiencing motor fluctuations. Safety and tolerability information has come from postmarketing surveillance studies as well as several randomized, placebo-controlled trials with long-term open-label extension phases specifically investigating the safety and tolerability of levodopa plus entacapone. Results show the most common dopaminergic side effects to be dyskinesia and nausea, which result from the increased bioavailability of levodopa and can be readily managed. Non-dopaminergic side effects include diarrhea and harmless urine discoloration. There is no convincing evidence of hepatic injury with entacapone use, and therefore monitoring of liver enzymes is unnecessary. With over 300,000 patient-years of exposure, levodopa combined with entacapone can be considered safe and well tolerated.

Aged↗

PubMed1999

Perspectives in the treatment of Parkinson's disease: COMT inhibitors open up new treatment strategies.

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.

Journal Article↗

PubMed2006

COMT genotype influences prefrontal response to emotional distraction.

Early studies of genetic effects on brain activity have been conducted to investigate primarily either the influence of polymorphisms in dopaminergic genes, especially the catechol-O-methyltransferase (COMT) gene, on prefrontal cognitive processes such as working memory, or that of polymorphisms in the serotonin transporter gene on the amygdala response to threatening stimuli. Here, we address genetic influences on the neural systems underlying cognitive-affective interactions. Specifically, we assess the effect of the CO MT val158met polymorphism onfrontal regulation of attentionunder emotional distraction. Healthy volunteers were scanned while performing a house-matching task with affectively negative versus neutral distractors. Effects of val allele load were examined on frontal regions associated with attentional control and emotion regulation, and on parahippocampal regions associated with perception of houses. As we predicted, val load correlated positively with activity in control- and task-related regions during performance under emotional distraction. These findings provide an initial step toward identifying genetic contributions to interindividual variability in recruitment of mechanisms that regulate affective processing.

Adolescent↗

PubMed2000

Benefits of COMT inhibitors in levodopa-treated parkinsonian patients: results of clinical trials.

Recent prospective, double-blind, placebo-controlled trials have examined the long-term effects of the catechol-O-methyl transferase (COMT) inhibitors entacapone and tolcapone as adjuncts to levodopa in PD patients with wearing-off motor fluctuations. These studies demonstrate that both tolcapone and entacapone provide PD patients who suffer motor fluctuations with increased "on" time, decreased "off" time, and improved motor scores in comparison to placebo-treated patients. The improvement was observed rapidly, often being evident within days of initiating the intervention. Benefits persisted throughout the duration of the study. Increased dopaminergic side effects were observed with both drugs, but these were generally readily controlled by a concomitant reduction in levodopa dose. Tolcapone was associated with some instances of explosive diarrhea and liver enzyme elevation so that periodic monitoring of liver function was recommended. These did not occur with entacapone, and monitoring of liver function was not required. This report reviews the results of the multi-center trials of entacapone, and tolcapone.

Benzophenones↗

PubMed2000

COMT inhibitors and liver toxicity.

This paper reviews the issue of hepatotoxicity with the use of the catechol-O-methly transferase (COMT) inhibitors tolcapone and entacapone. Neither drug caused hepatotoxicity in preclinical toxicity testing. However, in clinical trials of tolcapone, liver chemistry tests were elevated more than 3 times above the upper limit of normal in approximately 1% of patients who took the 100 mg dose and in approximately 3% of patients who took the 200 mg dose. These observations led to the recommendation that periodic monitoring of liver function be performed. Post-marketing surveillance studies noted 3 instances of acute liver failure with death after 60,000 patients had received tolcapone for a total of 40,000 patient-years. For this reason, the drug was withdrawn from the market in Europe and Canada, and a black box warning issued in the United States. In contrast, clinical trials with entacapone demonstrated no increase in liver enzymes above those observed with placebo. Further, no instances of acute liver failure or death attributed to the drug have been observed in post-marketing surveillance studies. Consequently, liver monitoring is not required with this agent. These data demonstrate that tolcapone is associated with a risk of hepatotoxicity but that no such risk has been detected with entacapone.

Benzophenones↗

PubMedDate not supplied

[Role of gene polymorphism of catechol-O-methyltransferase (COMT), monoamine oxidase B (MAOB), cytochrome P450 2D6 (CYP2D6) and N-acetyltransferase 2 (NAT2) in pathogenesis of Parkinson's disease].

Factors underlying pathogenesis of diseases are currently being searched. In recent years increasing number of reports on genetic background of central nervous system diseases have appeared. In the search of factors that can precipitate degeneration of dopaminergic neurons the role of enzymes catabolising xenobiotics (CYP2D6, NAT2) and enzymes metabolising catecholamines (COMT, MAO B) has been postulated. Polymorphism of genes coding for isotypes characterised by different biological activity could be responsible for the propensity for Parkinson's disease, progression and efficacy of pharmacotherapy of the disease.

Arylamine N-Acetyltransferase↗

PubMed2002

[Dopaminergic agents, COMT inhibitors or amantadine? Proper treatment for your Parkinson patient].

Over the last six years, eight new substances for the treatment of idiopathic parkinsonism (IP) have been approved for use: four oral and one parenteral dopamine agonist (apomorphine), two COMT-inhibitors and budipine. The old drug amantadine has experienced a renaissance in the treatment of a complication occurring during long-term treatment of IP, namely levodopa-induced dyskinesia. Deep brain stimulation with programmable pulse generators and stereotactically implanted electrodes are increasingly being used in patients with severe on-off phases and levodopa dyskinesia. The treatment of Parkinson's disease unresponsive to dopaminergic substances and that associated with dementia remains problematical. In combinations of parkinsonism and dementia, the cholinesterase inhibitors are being used in particular for Lewy body dementia.

Amantadine↗

PubMed2006

Identification of COMT and ErmC inhibitors by using a microplate assay in combination with library focusing by virtual screening.

The paper describes a process of facilitated screening by using a combination of molecular modelling and a 96-well microplate assay for the identification of novel inhibitors of catechol-O-methyltransferase (COMT) and bacteria expressing ErmC. With the help of virtual screening the number of compounds processed in the in vitro screening assay was reduced from over 200,000 to 49. Out of the 49, two structurally very similar compounds were identified as confirmed hits with reasonable activity (IC50 values of 26 and 73 microM) and thus as potential core structures for further drug design and development.

Catechol O-Methyltransferase Inhibitors↗

PubMed2006

Breast cancer risk and polymorphisms in genes involved in metabolism of estrogens (CYP17, HSD17beta1, COMT and MnSOD): possible protective role of MnSOD gene polymorphism Val/Ala and Ala/Ala in women that never breast fed.

Polymorphisms in genes encoding enzymes involved in estrogen metabolism are held to be candidates for associations with breast disease, since there is evidence that circulating estrogens are associated with breast cancer risk. In this study, we evaluated the frequency of different polymorphisms related with estrogen metabolism [COMT Val158Met, CYP17 (5'UTR, T27C); HSD17beta1 Gly313Ser and MnSOD Val16Ala] in a breast cancer resistant population, the Xavante Indians, and the frequencies were compared with the ones reported in other populations where breast cancer case-control studies dealing with these polymorphisms have been carried out. The data obtained showed that, apart from the MnSOD Val16Ala polymorphism where the frequency of the variant allele was much higher than that reported in other populations, all the others were within the range reported in other populations. Considering these data we carried out a case-control study in the Portuguese population (241 cases and 457 controls) in order to evaluate the potential role of this polymorphism in breast cancer susceptibility. The results obtained did not reveal a significant association between individual genotypes and breast cancer risk. However, when the population was stratified for breast feeding, it was observed that for the patients that never breast fed the presence of the variant allele (Ala) was marginally associated with a decreased risk for this pathology (adjusted OR: 0.575 (0.327-1.011). These data seem to suggest that individuals who never breast fed with MnSOD Val16Ala variant allele are at a lower risk for breast cancer, but larger studies are required to confirm these results.

Alanine↗

PubMed1983