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Seppo Kaakkola - One of the best experts on this subject based on the ideXlab platform.
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problems with the present Inhibitors and a relevance of new and improved COMT Inhibitors in parkinson s disease
International Review of Neurobiology, 2010Co-Authors: Seppo KaakkolaAbstract:Entacapone and tolcapone are reversible COMT Inhibitors which have been approved for clinical use in patients with Parkinson disease (PD). Nebicapone is a third COMT inhibitor which has been studied in humans. COMT Inhibitors are used in combination with levodopa and a dopa decarboxylase (DDC) inhibitor. Each of them has problems either in pharmacokinetics, pharmacodynamics, clinical efficacy, or in safety. All three Inhibitors have short elimination half-lives, about 2-3h. Tolcapone is longer acting and more potent COMT inhibitor than entacapone; nebicapone lies in between. However, none of the present Inhibitors cause a complete peripheral COMT inhibition. Tolcapone and nebicapone have increased more levodopa AUC than entacapone which is reflected also in their clinical efficacy. The most common adverse event with COMT Inhibitors is dyskinesia which is usually managed by decreasing levodopa dose. The greatest problem with tolcapone and probably also with nebicapone is their liver toxicity which is not seen with entacapone. Tolcapone causes severe diarrhea more often than entacapone. Though the present COMT Inhibitors have improved significantly the treatment of advanced PD patients, they still have several problems and weaknesses leaving room for developing better COMT Inhibitors.
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clinical advantages of COMT inhibition with entacapone a review
Journal of Neural Transmission, 2004Co-Authors: A. Gordin, Seppo Kaakkola, Heikki TeravainenAbstract:Two catechol-O-methyltransferase (COMT) Inhibitors, entacapone and tolcapone, were developed during the 1990’s to be used as adjuncts to levodopa (LD) – dopa decarboxylase (DDC) Inhibitors in the treatment of Parkinson’s disease (PD). Entacapone is currently in wide clinical use, while tolcapone can be used in restricted indications only, due to its hepatotoxicity. COMT Inhibitors prolong the elimination of LD, while DDC Inhibitors mainly increase its absorption; both mechanisms leading to increased bioavailability of LD. The pharmacokinetic properties of LD, carbidopa and entacapone are quite similar, and entacapone is administered concomitantly with LD plus carbidopa. Entacapone prolongs the clinical effect of each LD dose by 30 to 40 minutes; this effect is seen already after the first entacapone dose. When LD is administered in several frequent daily doses, addition of entacapone reduces the daily fluctuations of plasma LD by 30 to 40%.
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Clinical pharmacology, therapeutic use and potential of COMT Inhibitors in Parkinson's disease
Drugs, 2000Co-Authors: Seppo KaakkolaAbstract:When peripheral decarboxylation is blocked by carbidopa or benserazide, the main metabolic pathway of levodopa is O-methylation by catechol-O-methyltransferase (COMT). Entacapone and tolcapone are new potent, selective and reversible nitrocatechol-type COMT Inhibitors. Animal studies have demonstrated that entacapone mainly has a peripheral effect whereas tolcapone also inhibits O-methylation in the brain. In human volunteers, both entacapone and tolcapone dose-dependently inhibit the COMT activity in erythrocytes, improve the bioavailability and decrease the elimination of levodopa, and inhibit the formation of 3-O-methyldopa (3-OMD). Entacapone is administered with every scheduled dose of levodopa whereas tolcapone is administered 3 times daily. The different administration regimens for these agents are based on their different pharmacokinetic and pharmacodynamic profiles. Both entacapone and tolcapone enhance and extend the therapeutic effect of levodopa in patients with advanced and fluctuating Parkinson's disease. They prolong the duration of levodopa effect. Clinical studies show that they increase the daily ON time by an average 1 to 3 hours, improve the activities of daily living and allow daily levodopa dosage to be decreased. Correspondingly, they significantly reduce the daily OFF time. No comparative studies between entacapone and tolcapone have been performed. Tolcapone also appears to have a beneficial effect in patients with nonfluctuating Parkinson's disease. The main adverse effects of the COMT Inhibitors are related to their dopaminergic and gastrointestinal effects. Enhancement of dopaminergic activity may cause an initial worsening of levodopa-induced adverse effects, such as dyskinesia, nausea, vomiting, orthostatic hypotension, sleep disorders and hallucinations. Levodopa dose adjustment is recommended to avoid these events. Tolcapone is associated with diarrhoea in about 16 to 18% of patients and entacapone in less than 10% of patients. Diarrhoea has led to discontinuation in 5 to 6% of patients treated with tolcapone and in 2.5% of those treated with entacapone. Urine discoloration to dark yellow or orange is related to the colour of COMT Inhibitors and their metabolites. Elevated liver transaminase levels are reported in 1 to 3% of patients treated with tolcapone but very rarely, if at all, in patients treated with entacapone. The descriptions of acute, fatal fulminant hepatitis and potentially fatal neurological reactions, such as neuroleptic malignant syndrome and rhabdomyolysis, in association with tolcapone led to the suspension of its marketing authorisation in the European Community and Canada. In many other countries, the use of tolcapone is restricted to patients who are not responding satisfactorily to other therapies. Regular monitoring of liver enzymes is required if tolcapone is used. No such adverse reactions have so far been described for entacapone and no laboratory monitoring has been proposed. COMT Inhibitors added to levodopa therapy are beneficial, particularly in patients with fluctuating disease. They may be combined with other antiparkinsonian drugs, such as dopamine agonists, selegiline and anticholinergics without adverse interactions. They provide a new treatment possibility in patients with Parkinson's disease who have problems with their present levodopa therapy.
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catechol o methyltransferase COMT biochemistry molecular biology pharmacology and clinical efficacy of the new selective COMT Inhibitors
Pharmacological Reviews, 1999Co-Authors: Pekka T. Männistö, Seppo KaakkolaAbstract:[Axelrod et al. (1958)][1] first described the enzyme-catalyzed O- methylation of catecholamines and other catechols in the late 1950s. The enzyme responsible for the O- methylation, catechol- O -methyltransferase (COMT; EC[2.1.1.6][2]),2 was partly purified and characterized by the same group ([
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effects of catechol o methyltransferase Inhibitors and l 3 4 dihydroxyphenylalanine with or without carbidopa on extracellular dopamine in rat striatum
Journal of Neurochemistry, 1993Co-Authors: Seppo Kaakkola, Richard J. WurtmanAbstract:: The effects of two new catechol-O-methyltransferase (COMT) Inhibitors, OR-611 and Ro 40-7592, in combination with L-3,4-dihydroxyphenylalanine (L-dopa) with or without carbidopa on extracellular levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3-O-methyldopa (3-OMD), and 5-hydroxyindoleacetic acid in rat striatum were studied. A dose of 10 mg/kg i.p. of Ro 40-7592 alone, in contrast to the same dose of OR-611, decreased the dialysate level of HVA and increased that of DOPAC; this dose was thus used to differentiate between the effects of central and peripheral COMT inhibition. L-Dopa (50 mg/kg i.p.) alone slightly increased extracellular levels of DA, DOPAC, and HVA. The effects of L-dopa were potentiated by carbidopa (50 mg/kg i.p.), and even 3-OMD levels in dialysate samples became detectable. Both OR-611 and Ro 40-7592 significantly further increased the DA and DOPAC efflux from striatum produced by L-dopa. This increase was more pronounced when carbidopa was added to the treatment. OR-611 did not modify the effect of L-dopa or carbidopa/L-dopa on dialysate HVA levels, whereas Ro 40-7592 markedly reduced those levels. Both OR-611 and Ro 40-7592 very clearly suppressed dialysate 3-OMD levels produced by carbidopa/L-dopa. Ro 40-7592 was more effective than OR-611 in potentiating the effects of L-dopa or carbidopa/L-dopa. These in vivo data show that the new COMT Inhibitors markedly inhibit the O-methylation of L-dopa and increase its availability to brain, which is reflected as increased DA formation. A significant effect can be achieved even by inhibiting only the peripheral COMT activity. The data suggest that COMT Inhibitors may be of clinical importance as adjuncts in the treatment of Parkinson's disease.
Maki Okada - One of the best experts on this subject based on the ideXlab platform.
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microdialysis with radiometric monitoring of l β 11c dopa to assess dopaminergic metabolism effect of Inhibitors of l amino acid decarboxylase monoamine oxidase and catechol o methyltransferase on rat striatal dialysate
Journal of Cerebral Blood Flow and Metabolism, 2011Co-Authors: Maki Okada, Ryuji Nakao, Rie Hosoi, Mingrong Zhang, Toshimitsu Fukumura, Kazutoshi Suzuki, Osamu InoueAbstract:The catecholamine, dopamine (DA), is synthesized from 3,4-dihydroxy--phenylalanine (-DOPA) by aromatic -amino acid decarboxylase (AADC). Dopamine metabolism is regulated by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT). To measure dopaminergic metabolism, we used microdialysis with radiometric detection to monitor -[β-11C]DOPA metabolites in the extracellular space of the rat striatum. We also evaluated the effects of AADC, MAO, and COMT Inhibitors on metabolite profiles. The major early species measured after administration of -[β-11C]DOPA were [11C]3,4-dihydroxyphenylacetic acid ([11C]DOPAC) and [11C]homovanillic acid ([11C]HVA) in a 1:1 ratio, which shifted toward [11C]HVA with time. An AADC inhibitor increased the uptake of -[β-11C]DOPA and -3-O-methyl-[11C]DOPA and delayed the accumulation of [11C]DOPAC and [11C]HVA. The MAO and COMT Inhibitors increased the production of [11C]3-methoxytyramine and [11C]DOPAC, respectively. These results reflect the -DOPA metabolic pathway, suggesting that this method may be useful for assessing dopaminergic metabolism.
Ventura - One of the best experts on this subject based on the ideXlab platform.
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COMT Inhibitors and liver toxicity. Discussion
Neurology, 2000Co-Authors: Paul A. Watkins, Olanow, Rascol, Obeso, Koller, Lewitt, Ventura, DingemanseAbstract: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 100mg dose and in approximately 3% of patients who took the 200mg 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.
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Benefits of COMT Inhibitors in levodopa-treated parkinsonian patients : Results of clinical trials. Discussion
Neurology, 2000Co-Authors: Karl Kieburtz, Olanow, Rascol, Obeso, Dingemanse, Jean Hubble, Waters, Schapira, Stocchi, VenturaAbstract:Article abstract-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.
Jean Hubble - One of the best experts on this subject based on the ideXlab platform.
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Benefits of COMT Inhibitors in levodopa-treated parkinsonian patients: results of clinical trials.
Neurology, 2000Co-Authors: Karl Kieburtz, Jean HubbleAbstract:Abstract 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.
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Benefits of COMT Inhibitors in levodopa-treated parkinsonian patients : Results of clinical trials. Discussion
Neurology, 2000Co-Authors: Karl Kieburtz, Olanow, Rascol, Obeso, Dingemanse, Jean Hubble, Waters, Schapira, Stocchi, VenturaAbstract:Article abstract-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.
Patricio Soaresdasilva - One of the best experts on this subject based on the ideXlab platform.
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redefining the strategy for the use of COMT Inhibitors in parkinson s disease the role of opicapone
Expert Review of Neurotherapeutics, 2021Co-Authors: P Jenner, Joaquim J. Ferreira, José-francisco Rocha, Patricio Soaresdasilva, Olivier RascolAbstract:Levodopa remains the gold-standard Parkinson’s disease (PD) treatment, but the inevitable development of motor complications has led to intense activity in pursuit of its optimal delivery.Periphera...
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liver says no the ongoing search for safe catechol o methyltransferase Inhibitors to replace tolcapone
Drug Discovery Today, 2020Co-Authors: Maria Paula Serrão, Tiago Barros Silva, Fernanda Borges, Patricio SoaresdasilvaAbstract:Catechol O-methyltransferase (COMT) Inhibitors are valuable co-adjuvant drugs in the clinical management of Parkinson's disease (PD), and recent data also suggest therapeutic benefits in other neurological disorders associated with dopamine depletion. However, the relationship between tolcapone administration with fatal cases of drug-induced liver damage gave COMT Inhibitors a bad reputation as hepatotoxic drugs. Thus, there is a pressing need to feed the pipeline with safe COMT Inhibitors to replace tolcapone, the only currently available COMT inhibitor that effectively reaches the brain. Recent efforts led to promising phenolic and nonphenolic COMT Inhibitors, which allow isoform-specific targeting and avoid the toxicological and pharmacokinetic (PK) shortcomings of classic nitrocatechols. Here, we describe advances made in this field over the past 5 years.
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opicapone as adjunct to levodopa therapy in patients with parkinson disease and motor fluctuations a randomized clinical trial
JAMA Neurology, 2017Co-Authors: Andrew J. Lees, Joaquim J. Ferreira, Patricio Soaresdasilva, Olivier Rascol, Werner Poewe, J F Rocha, Michelle Mccrory, Bipark Study InvestigatorsAbstract:Importance Catechol O -methyltransferase (COMT) Inhibitors are an established treatment for end-of-dose motor fluctuations associated with levodopa therapy in patients with Parkinson disease (PD). Current COMT Inhibitors carry a high risk for toxic effects to hepatic cells or show moderate improvement. Opicapone was designed to be effective without the adverse effects. Objective To evaluate the efficacy and safety of 25- and 50-mg/d dosages of opicapone compared with placebo as adjunct to levodopa therapy in patients with PD experiencing end-of-dose motor fluctuations. Design This phase 3 international, multicenter outpatient study evaluated a 25- and a 50-mg/d dosage of opicapone in a randomized, double-blind, 14- to 15-week, placebo-controlled clinical trial, followed by a 1-year open-label phase during which all patients received active treatment with opicapone. Patients with PD who experienced signs of end-of-dose deterioration and had a mean total awake off-time (state of akinesia or decreased mobility) of at least 1.5 hours, not including morning akinesia, were enrolled. Data were collected from March 18, 2011, through June 25, 2013. Data from the evaluable population were analyzed from July 31, 2013, to July 31, 2014. Main Outcomes and Measures The primary efficacy outcome of the double-blind phase was the change from baseline in absolute off-time vs placebo based on patient diaries. The open-label phase focused on maintenance of treatment effect in off-time. Results A total of 427 patients (258 men [60.4%] and 169 women [39.6%]; mean [SD] age, 63.1 [8.8] years) were randomized to a 25-mg/d (n = 129) or a 50-mg/d (n = 154) dosage of opicapone or to placebo (n = 144). Of these, 376 patients completed the double-blind phase and entered the open-label phase, of whom 286 completed 1 year of open-label treatment. At the end of the double-blind phase, the least squares mean change (SE) in off-time was −64.5 (14.4) minutes for the placebo group, −101.7 (14.9) minutes for the 25-mg/d opicapone group, and −118.8 (13.8) minutes for the 50-mg/d opicapone group. The adjusted treatment difference vs placebo was significant for the 50-mg/d opicapone group (treatment effect, −54.3 [95% CI, −96.2 to −12.4] minutes; P = .008), but not for the 25-mg/d opicapone group (treatment effect, −37.2 [95% CI, −80.8 to 6.4] minutes; P = .11). The off-time reduction was sustained throughout the open-label phase (−126.3 minutes at 1-year open-label end point). The most common adverse events in the opicapone vs placebo groups were dyskinesia, constipation, and dry mouth. Fifty-one patients (11.9%) discontinued from the study during the double-blind phase. Conclusions and Relevance Treatment with a 50-mg once-daily dose of opicapone was associated with a significant reduction in mean daily off-time in levodopa-treated patients with PD and motor fluctuations, and this effect is maintained for at least 1 year. Opicapone was safe and well tolerated. Trial Registration clinicaltrials.gov Identifier:NCT01227655
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kinetics and crystal structure of catechol o methyltransferase complex with co substrate and a novel inhibitor with potential therapeutic application
Molecular Pharmacology, 2002Co-Authors: Maria João Bonifácio, Margarida Archer, Maria L. Rodrigues, Pedro M. Matias, David A. Learmonth, Maria Arménia Carrondo, Patricio SoaresdasilvaAbstract:Catechol- O -methyltransferase (COMT; E.C. 2.1.1.6) is a ubiquitous enzyme in nature that plays an important role in the metabolism of catechol neurotransmitters and xenobiotics. In particular, inactivation of drugs such asl-3,4-dihydroxyphenylalanine (l-DOPA) via O -methylation is of relevant pharmacological importance, because l-DOPA is currently the most effective drug used in the treatment of Parkinson's disease. This justified the interest in developing COMT Inhibitors as potential adjuncts to l-DOPA therapy. The kinetics of inhibition by BIA 3-335 (1-[3,4-dihydroxy-5-nitrophenyl]-3-( N -3′-trifluormethylphenyl)-piperazine-1-propanone dihydrochloride) were characterized using recombinant rat soluble COMT. BIA 3-335 was found to act as a potent, reversible, tight-binding inhibitor of COMT with a K i of 6.0 ± 1.6 nM and displaying a competitive inhibition toward the substrate binding site and uncompetitive inhibition toward the S -adenosyl-l-methionine (SAM) binding site. The 2.0-A resolution crystal structure of COMT in complex with its cosubstrate SAM and a novel inhibitor BIA 3-335 shows the atomic interactions between the important residues at the active site and the inhibitor. This is the first report of a three-dimensional structure determination of COMT complexed with a potent, reversible, and tight-binding inhibitor that is expected to have therapeutic applications.