| Tolcapone, sold under the brand name Tasmar, is a medication used to treat Parkinson's disease (PD). It is a selective, potent and reversible nitrocatechol-type inhibitor of the enzyme catechol-O-methyltransferase (COMT). It has demonstrated significant liver toxicity, which has led to suspension of marketing authorisations in a number of countries.
Tolcapone appears to be peripherally selective, but can still cross into the brain in significant amounts and has been found to inhibit COMT centrally as well. In comparison with entacapone, another nitrocatechol COMT inhibitor, tolcapone has a longer half life (2.9 hours vs. 0.8 hours) and can better penetrate into the brain, acting both in the central nervous system and in the periphery. However, entacapone is less toxic for the liver. |
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| InChI=1S/C14H11NO5/c1-8-2-4-9(5-3-8)13(17)10-6-11(15(19)20)14(18)12(16)7-10/h2-7,16,18H,1H3 |
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| Cc1ccc(cc1)C(=O)c1cc(O)c(O)c(c1)[N+]([O-])=O |
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EC 2.1.1.6 (catechol O-methyltransferase) inhibitor
An EC 2.1.1.* (methyltransferase) inhibitor that interferes with the action of catechol O-methyltransferase (EC 2.1.1.6).
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antiparkinson drug
A drug used in the treatment of Parkinson's disease.
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View more via ChEBI Ontology
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(3,4-dihydroxy-5-nitrophenyl)(4-methylphenyl)methanone
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3,4-dihydroxy-4'-methyl-5-nitrobenzophenone
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ChEBI
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3,4-Dihydroxy-4'-methyl-5-nitrobenzophenone
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ChemIDplus
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3,4-dihydroxy-5-nitro-4'-methylbenzophenone
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ChEBI
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4'-methyl-3,4-dihydroxy-5-nitrobenzophenone
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ChEBI
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8151577
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Reaxys Registry Number
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Reaxys
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Nyholm D, Johansson A, Lennernäs H, Askmark H (2012)
Levodopa infusion combined with entacapone or tolcapone in Parkinson disease: a pilot trial.
European journal of neurology 19, 820-826 [PubMed:22136163]
[show Abstract]
Background and purposeCatechol-O-methyltransferase inhibitors may be used to decrease levodopa requirement. The objective was to investigate whether the levodopa/carbidopa intestinal gel infusion dose can be reduced by 20% without worsening of motor fluctuations and levodopa concentration stability when oral catechol-O-methyltransferase inhibitors are added.MethodsA short-term, randomized, partly blinded, crossover, investigator-initiated clinical trial was performed, with levodopa/carbidopa intestinal gel combined with oral entacapone and tolcapone on two different days in 10 patients. The primary outcome measure was difference in coefficient of variation of levodopa in plasma between levodopa/carbidopa, levodopa/carbidopa/entacapone, and levodopa/carbidopa/tolcapone. The secondary outcome measures other pharmacokinetic variables, patient-reported outcome, and blinded analysis of motor performance.ResultsVariation of plasma levodopa concentrations did not differ significantly between the treatments. The treatments did not differ regarding motor performance. Levodopa concentrations were significantly higher using tolcapone. Concentrations of the metabolite 3-O-methyldopa decreased gradually during catechol-O-methyltransferase inhibition.ConclusionsAccording to this small, short-term pilot study, oral catechol-O-methyltransferase inhibitors administered in 5-h intervals may be useful in cases where levodopa/carbidopa intestinal gel dose reduction is wanted. Stability of plasma levodopa levels is not significantly altered, and off-time is not increased when decreasing the levodopa/carbidopa intestinal gel dose by 20%. Rather, the dose should probably be decreased more than 20%, especially under tolcapone co-treatment, to avoid increased dyskinesias with time. | Bitsios P, Roussos P (2011)
Tolcapone, COMT polymorphisms and pharmacogenomic treatment of schizophrenia.
Pharmacogenomics 12, 559-566 [PubMed:21521027]
[show Abstract]
It is widely accepted that abnormal prefrontal cortex biology resulting in deficient cognition is a primary problem in schizophrenia and that all currently available antipsychotics fail to improve cognitive and negative symptoms originating from this deficit. Evidence from basic science has revealed the importance of prefrontal dopamine signaling for optimal prefrontal function. This article describes succinctly the progress made so far, taking into account the mechanisms involved in catechol-O-methyltransferase (COMT)-induced modulation of prefrontal dopamine signaling, the impact of COMT on cognitive function and the role of COMT gene polymorphisms. The potential role of the COMT inhibitor tolcapone to improve cognitive function in health and disease is also presented here. It will soon be understood if tolcapone represents one of the first hypothesis-driven, biology-based, genotype-specific, targeted treatments of cognitive and negative symptoms of schizophrenia. | Ebersbach G, Hahn K, Lorrain M, Storch A (2010)
Tolcapone improves sleep in patients with advanced Parkinson's disease (PD).
Archives of gerontology and geriatrics 51, e125-8 [PubMed:20381177]
[show Abstract]
Efficacy of the long-acting catechol-O-methyltransferase (COMT)-inhibitor, tolcapone on sleep quality was studied in 61 patients with advanced PD in a prospective open-label multicenter non-interventional trial. Main outcome measures were the PD sleep scale (PDSS). Further outcome measures were global clinical impression of change (GCI-C), daily off-time, activities of daily living (UPDRS part II), quality of life (EuroQoL-5D), Epworth sleepiness scale (ESS) and adverse events reports. All efficiency and safety parameters were assessed 4 weeks after the switch to tolcapone and compared to baseline. The mean±S.D. daily dose of tolcapone was 294.2±36.9 mg/day at the final assessment. The mean PDSS scores significantly improved from 21.6±8.1 at baseline to 16.3±7.7 at final assessment (p<0.0001). Consistently, daytime sleepiness was significantly reduced as reflected by lower scores on the ESS (p=0.0057). Further efficacy parameters including GCI-C, daily off-time, activities of daily living, and quality of life were also significantly improved. Tolcapone was in general well tolerated and safe. This observational study provides first evidence that tolcapone improves sleep quality and reduces daytime sleepiness in patients suffering from advanced PD. | Ries V, Selzer R, Eichhorn T, Oertel WH, Eggert K, German Tolcapone Study Group (2010)
Replacing a dopamine agonist by the COMT-inhibitor tolcapone as an adjunct to L-dopa in the treatment of Parkinson's disease: a randomized, multicenter, open-label, parallel-group study.
Clinical neuropharmacology 33, 142-150 [PubMed:20502133]
[show Abstract]
ObjectiveThis study investigated the feasibility, safety, and potential benefit in motor symptom control when switching from a dopamine agonist to tolcapone as an adjunctive therapy in patients with Parkinson's disease with a fluctuating response to levodopa (l-dopa). We determined the efficacy of 2 replacement strategies.MethodsIn this 10-week, randomized, open-label, stratified, parallel-group trial, 150 patients on a stable regimen of l-dopa/decarboxylase inhibitor in combination with bromocriptine, lisuride, or pergolide were switched to tolcapone. Primary end point was the change in daily "off" time from baseline to the end of week 10 as assessed by patient "on-off" diaries. Patients had their respective dopamine agonist reduced and finally withdrawn either by day 6 (short-term replacement, n = 72) or by day 23 (long-term replacement, n = 78).ResultsAt week 10, a significant reduction from baseline in daily "off" time (-15.9 +/- 19.3%; P < 0.001) and a significant increase of "on" time (14.6 +/- 19.8%; P < 0.001) were observed. Other efficacy variables (Unified Parkinson's Disease Rating Scale II, III, and IVb and Investigator's Global Assessment scores) improved significantly after switching to tolcapone. In general, there was no significant difference between the 2 replacement strategies. Treatment was better tolerated after the switch to tolcapone according to the IGA of tolerability.ConclusionsTolcapone, in principle, seems to be an alternative adjunct for patients, who fail to receive sufficient benefit from a dopamine agonist, for example, in case they do not tolerate an increase in dose or have unacceptable side effects. The switch from a dopamine agonist to tolcapone can be done safely within a few days. |
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