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[Research] [Main References] [Full Articles] [French Text] [Abstracts]

  • J Neural Transm. 2002 Nov;109(11):1391-401.
  • Different toxicological profile of two COMT inhibitors in vivo: the role of uncoupling effects.

    Haasio K, Nissinen E, Sopanen L, Heinonen EH.

    Orion Corporation, Orion Pharma, Espoo, Finland. kristiina.haasio@orionpharma.com

    The toxicity profiles of entacapone and tolcapone, novel catechol- O-methyl-transferase (COMT) inhibitors, have been reported to differ from each other. It has also been shown that tolcapone, but not entacapone, is a potent uncoupler of oxidative phosphorylation in vitroat low micromolar concentrations. Signs of hepatotoxicity induced by tolcapone treatment have been previously reported in toxicological studies and in clinical use.The present study was designed to investigate the mechanism of hepatotoxicity of tolcapone and its possible relationship to uncoupling of oxidative phosphorylation in vivo. A 15-day oral toxicity study with entacapone or tolcapone (300 and 500 mg/kg/day) was carried out, and 2, 4-dinitrophenol (DNP), a known uncoupling agent of oxidative phosphorylation, served as a positive reference substance (20 mg/kg/day). No treatment related findings were observed in entacapone-treated rats. Clinical chemistry parameters regarding hepatocellular damage were increased in tolcapone and DNP-treated animals. The energy status measured as ATP/ADP ratio from the liver samples and energy charge (EC) in liver cell mitochondria were diminished both in tolcapone- and in DNP-treated rats. These signs together with clinical symptoms consisting of increased respiration, decreased activity and drowsiness, and elevation of the rectal body temperature observed in tolcapone- and DNP-treated animals suggest a relationship between the treatment and uncoupling of oxidative phosphorylation in vivo.
     
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  • Drug Saf. 2003;26(11):743-7.
  • Tolcapone-related liver dysfunction: implications for use in Parkinson's disease therapy.

    Borges N.

    Faculdade de Ciencias da Nutricao e Alimentacao da Universidade do Porto, Porto, Portugal. nunoborges@fcna.up.pt

    Levodopa is the cornerstone of idiopathic Parkinson's disease (PD) treatment. However, after long-term use of levodopa, a significant percentage of patients experience motor fluctuations, which worsen their quality of life. Catechol-O-methyltransferase (COMT) inhibitors reduce levodopa metabolism and enhance the respective plasma levels, resulting in improvements in symptoms and overall quality of life.Tolcapone was the first drug of this class to be marketed, but was withdrawn in the European Union due to its implication in the deaths of three PD patients due to hepatic failure. Three deaths from fulminant hepatic failure in 40000 patient-years is a number that is 10-100 times higher than the expected incidence in the general population and, according to the manufacturer's own information, the number is probably underestimated due to under-reporting of cases.In the US, tolcapone was not withdrawn, but restrictive liver enzyme monitoring measures were issued by authorities, which severely limited its use. No further deaths from hepatic failure were reported since these measures were implemented.The mechanisms by which tolcapone may induce liver toxicity are still under debate. It was thought that mitochondrial uncoupling of oxidative phosphorylation by tolcapone, and consequent impairment of energy production by hepatocytes, could be responsible for the observed effects.Some experts consider that the restrictive guidelines issued in the US regarding tolcapone use may be loosened with no consequential reductions in safety. It was suggested that ongoing clinical information about safety should be considered and periodical revisions of the restrictions made accordingly. The identification of the molecular and biochemical basis of tolcapone hepatotoxicity, when completed, should also provide important indications for the clinical use of this drug.In conclusion, appropriate monitoring of liver function can ensure adequate safety in PD patients receiving tolcapone, who can therefore benefit from the symptomatic improvements obtained with this drug.
     

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  • Expert Opin Drug Saf. 2003 May;2(3):263-7.
  • Hepatotoxic profile of catechol-O-methyltransferase inhibitors in Parkinson's disease.

    Benabou R, Waters C.

    The Center for Parkinson's Disease and Other Movement Disorders, New York-Presbyterian Hospital, Columbia Presbyterian Medical Center, The Neurological Institute, 710 West 168th Street, Room 350, New York, NY 10032, USA. RBenabou@neuro.columbia.edu

    Entacapone and tolcapone are selective catechol-O-methyltransferase (COMT) inhibitors developed recently as adjuncts to levodopa for the treatment of Parkinson's disease (PD). They extend the duration of action of levodopa. As a result, they increase 'on' time, decrease 'off' time and improve motor scores in patients with motor fluctuations. Both benefits and main side effects are related to increased dopaminergic activity. This paper reviews the use of those COMT inhibitors in PD with particular focus on the issue of hepatotoxicity. Neither tolcapone nor entacapone caused hepatotoxicity in preclinical studies. However, in 1998, four patients who were using tolcapone presented with serious liver dysfunction; three of them died due to acute liver failure. Tolcapone is now known to have the potential to cause hepatotoxicity in clinical use and experimental studies. It is now recommended that tolcapone be administered only in patients with motor fluctuations who are no longer satisfactorily treated with other medications for PD. Routine liver monitoring is now mandatory with this agent. Entacapone has been described as a well-tolerated and safe drug in recent experimental studies, human clinical trials and postmarketing surveillance. It can be offered to any patient with motor fluctuations and routine liver monitoring is not required.
     
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  • The Lancet 1998; 352:958
  • DOI:10.1016/S0140-6736(05)61511-5
  • Tolcapone and fulminant hepatitis
  • Fr←d←ric Assal mailto:Frederic.Assal@hcuge.chmailto:Frederic.Assal@hcuge.cha, Laurent Spahr a, Antoine Hadengue a, Laura Rubbici-Brandt b and Pierre R Burkhard a
  • References
  • Tolcapone is a selective and reversible catechol-O methyltransferase inhibitor that has been introduced for the treatment of motor fluctuations in Parkinson's disease. The drug acts by prolonging the plasma half-life of levodopa, therefore extending its duration of action. Trials have shown that tolcapone is effective and well tolerated.1 Elevation of liver enzymes has been described, mainly of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Thus far, tolcapone has not been associated with symptomatic hepatotoxicity.
  • A 74-year-old woman with a 20-year history of Parkinson's disease was admitted in our hospital with confusion, falls, and jaundice. She had been satisfactorily treated with levodopa/benserazide 100 mg/25 mg three times a day and amantadine 100 mg twice daily for the past 15 years. Other medications were etilefrine 10 mg three times a day for orthostatic hypotension, a combination of amiloride 2·5 mg and hydrochlorothiazide 25 mg twice a week for leg oedema, and oxazepam 15 mg at night. Hepatic aminotransferases have been checked repeatedly and were normal. 9 weeks before admission, amantadine was stopped and tolcapone 100 mg twice daily started. On admission, she was jaundiced, disoriented, sleepy, and had a mild asymmetric akinetic-rigid syndrome with resting tremor. Her bilirubin was 367 μmol/L, AST 2541 IU/L, ALT 2904 IU/L, lactic dehydrogenase 1548 IU/L, alkaline phosphatase 177 IU/L, γ-glutamyltranspeptidase 311 IU/L, and ammonia 102 μmol/L. Prothrombin time was 21 s. Screening for autoantibodies was negative. Hepatitis B surface antigen, and hepatitis C and hepatitis A IgM antibodies were negative. Apart from a slightly hyperechoic liver, abdominal ultrasonography was normal. A liver biopsy was done by the transjugular route and showed severe centrolobular necrosis and a lobular inflammatory infiltrate mostly composed of plasma cells and eosinophils. Despite discontinuation of tolcapone, she rapidly deteriorated and she died in hepatic coma 14 days after admission. Permission for necropsy was denied.
  • We believe that there was a causal relationship because of the short time between starting tolcapone and acute liver failure: histological findings supporting a drug-related hepatotoxicity; exclusion of other causes of hepatitis; and that tolcapone is known occasionally to induce elevation of liver aminotransferases. In three long-term double-blind placebo-controlled trials,2ヨ4 including 451 patients with Parkinson's disease treated with tolcapone 100 mg (227 patients) or 200 mg three times (224 patients), 16 (3·5%) developed raised aminotransferase (more than three times the upper limit of normal). Elevations were found between 6 and 12 weeks after starting tolcapone and returned to baseline within weeks, with or without discontinuing the drug. These biological changes were not clearly dependent on the dose (seven patients in the 100 mg group vs nine patients in the 200 group). ALT was more often elevated than AST

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  • Dig Dis Sci. 2000 Sep;45(9):1881-4.
  • Tolcapone-related fulminant hepatitis: electron microscopy shows mitochondrial alterations.

    Spahr L, Rubbia-Brandt L, Burkhard PR, Assal F, Hadengue A.

    Department of Neurology, University Hospital, Geneva, Switzerland.

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  • Eur Neurol. 2001;46(3):158-60.
  • Neuroleptic malignant-like syndrome and acute hepatitis during tolcapone and clozapine medication.

    Blum MW, Siegel AM, Meier R, Hess K.

    Department of Clinical Pharmacology and Toxicology, University Hospital, Zurich, Switzerland.
  • The Lancet 1998; 352:1313-1314
  • DOI:10.1016/S0140-6736(05)70527-4
  • Tolcapone and neurotoxicity in Parkinson's disease
  • Wilfried Kuhn a cor1cor1, Dirk Woitalla a, Manfred Gerlach a, Hermann Russ a and Thomas Mller a
  • Sir
  • Tao Xie and colleagues (June 21, p 1966)1 postulate a direct antidepressant effect of central catechol-O-methyltransferase inhibitors (COMT-I), such as tolcapone, because of an increased concentration of norepinephrine and S-adenosy1-Lmethionine (SAM) in the brain. Despite acute beneficial effects of central COMT-I on motor disability and depression, chronic treatment might induce neurotoxicity by blocking the physiological role of COMT. Physiologically, it eliminates biologically active toxic catechols and other hydrolated metabolites with potential endogenous or exogenous toxicity.
  • COMT catalyses O-methylation of levodopa and dopamine to 3-Omethyldopa and 3-O-methyldopamine with SAM as methyldonor. There is experimental evidence that administration of tolcapone produces important COMT inhibition in the central nervous system with a concomitant dose-dependent increase of SAM in rat striatum.2
  • However, intracerebroventricular injection of SAM in rats causes symptoms similar to those of Parkinson's disease, which are caused by substantia nigra degeneration and tyrosine hydroxylase depletion.3 Although the mechanism of this toxic process is unclear, central COMT-I might accelerate nigrostriatal degeneration in Parkinson's disease by a SAM-dependent increase of, for example, N-methylatian reactions.
  • Tolcapone significantly increases 3,4-dihydroxyphenylacetic acid and lowers homovanillic acid and 3-methoxytyramine in the whole brain of the rat.4 This effect is caused by reduced conversion of 3,4-dihydroxyphenylacetic acid to homovanillic acid by COMT and indicates enhanced oxidative desamination of dopamine via the monoaminooxidase (MAO)-metabolising pathway. Thus, increase of oxidative stress may be expected in neuronal and glial cells because of generation of H2O2 and neurocytotoxic hydroxyl radicals via MAO-A or MAO-B or both. Miller and colleagues5 have shown in an in-vitro model of catecholamine auto-oxidation that replacement of dopamine and levodopa by their O-methylated metabolites 3-OMD and 3-OMDA significantly decreases the rate of oxidation.5 Thus, O-methylation might be of physiological importance in the brain's antioxidant defence against catecholamine auto-oxidation.
  • Central COMT-inhibition could induce neurotoxicity in patients with Parkinson's disease. However, experimental and clinical data on longterm effects are lacking.

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  • Mov Disord. 2002 Nov;17(6):1362-5; discussion 1397-1400.
  • Entacapone-induced hepatotoxicity and hepatic dysfunction.

    Fisher A, Croft-Baker J, Davis M, Purcell P, McLean AJ.

    Department of Geriatric Medicine, The Canberra Hospital, Canberra, Australia.

    We describe 2 patients with Parkinson's disease who developed hepatotoxicity associated with the use of entacapone, a novel, mainly peripheral acting inhibitor of catechol-D-methyltransferase. Hepatotoxicity resolved rapidly with discontinuation of the drug. Analysis of causality in a further case initially linked to entacapone exposure was confounded by conflicting serial adverse reaction reports. Copyright 2002 Movement Disorder Society

  • Mov Disord. 2002 Nov;17(6):1362-5; discussion 1397-1400.
  • Entacapone-induced hepatotoxicity and hepatic dysfunction.

    Fisher A, Croft-Baker J, Davis M, Purcell P, McLean AJ.

    Department of Geriatric Medicine, The Canberra Hospital, Canberra, Australia.

    We describe 2 patients with Parkinson's disease who developed hepatotoxicity associated with the use of entacapone, a novel, mainly peripheral acting inhibitor of catechol-D-methyltransferase. Hepatotoxicity resolved rapidly with discontinuation of the drug. Analysis of causality in a further case initially linked to entacapone exposure was confounded by conflicting serial adverse reaction reports. Copyright 2002 Movement Disorder Society
  • Fundam Clin Pharmacol. 2003 Feb;17(1):113-6.
  • Excessive daytime sleepiness and 'sleep attacks' induced by entacapone.

    Bares M, Kanovsky P, Rektor I.

    1st Department of Neurology and Movement Disorders Centre, St Anne Hospital, Masaryk University, Brno, Czech Republic. martin.bares@fnusa.cz

    Three patients with advanced Parkinson's disease, all of whom developed excessive daytime sleepiness and 'sleep attacks' after the administration of entacapone, are described. This is another demonstration that inappropriate daytime sleep episodes are not exclusive to dopamine agonists.
     
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  • Drugs R D. 2003;4(5):310-1.

    Related Articles, Links

     

    Related Articles, Links


    Entacapone/levodopa/carbidopa combination tablet: Stalevo.

    [No authors listed]

    Entacapone (Comtess/Comtan) is Orion Pharma's original proprietary catechol-O-methyl transferase (COMT) inhibitor. Entacapone is able to slow down degradation of levodopa and improve the availability and efficacy of each levodopa dose, hence its use as a complement to levodopa/carbidopa in patients with Parkinson's disease. In order to simplify the daily dosing of these medications, Orion has developed an entacapone/levodopa/carbidopa combination tablet. Three tablet strengths are being developed so as to cover the most common clinical dosing needs. In September 2000, Orion signed a marketing and distribution agreement with Novartis for the combination tablet. Under the terms of the agreement, Orion has exclusive marketing rights for the product in Germany, the UK, Ireland, the Nordic and Baltic countries, and several Eastern European countries. Novartis has exclusive rights to the US and territories other than those markets for which Orion holds market exclusivity. Orion also has the option to co-promote the product in France, Spain and several other countries. In June 2003, the US FDA approved the entacapone/levodopa/carbidopa combination tablet (Stalevo) for the treatment of patients with idiopathic Parkinson's disease who experience signs and symptoms of end-of-dose 'wearing off'. Market launch of the product is expected toward the end of 2003 in the US. Also in June 2003, the Committee for Proprietary Medicinal Products of the European Agency for the Evaluation of Medicinal Products adopted a positive opinion of the combination tablet. In September 2002, Orion submitted an application for the approval of the combination product in the European Union. It is expected that the product will be marketed in the European Union in early 2004. Orion estimates that about two of three fluctuating Parkinson's disease patients will be able to be treated effectively with the triple combination tablet.
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  • Drugs R D. 2003;4(5):310-1.
  • Entacapone/levodopa/carbidopa combination tablet: Stalevo.

    [No authors listed]

    Entacapone (Comtess/Comtan) is Orion Pharma's original proprietary catechol-O-methyl transferase (COMT) inhibitor. Entacapone is able to slow down degradation of levodopa and improve the availability and efficacy of each levodopa dose, hence its use as a complement to levodopa/carbidopa in patients with Parkinson's disease. In order to simplify the daily dosing of these medications, Orion has developed an entacapone/levodopa/carbidopa combination tablet. Three tablet strengths are being developed so as to cover the most common clinical dosing needs. In September 2000, Orion signed a marketing and distribution agreement with Novartis for the combination tablet. Under the terms of the agreement, Orion has exclusive marketing rights for the product in Germany, the UK, Ireland, the Nordic and Baltic countries, and several Eastern European countries. Novartis has exclusive rights to the US and territories other than those markets for which Orion holds market exclusivity. Orion also has the option to co-promote the product in France, Spain and several other countries. In June 2003, the US FDA approved the entacapone/levodopa/carbidopa combination tablet (Stalevo) for the treatment of patients with idiopathic Parkinson's disease who experience signs and symptoms of end-of-dose 'wearing off'. Market launch of the product is expected toward the end of 2003 in the US. Also in June 2003, the Committee for Proprietary Medicinal Products of the European Agency for the Evaluation of Medicinal Products adopted a positive opinion of the combination tablet. In September 2002, Orion submitted an application for the approval of the combination product in the European Union. It is expected that the product will be marketed in the European Union in early 2004. Orion estimates that about two of three fluctuating Parkinson's disease patients will be able to be treated effectively with the triple combination tablet.
     
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  • Drugs R D. 2003;4(5):310-1.
  • Entacapone/levodopa/carbidopa combination tablet: Stalevo.

    [No authors listed]

    Entacapone (Comtess/Comtan) is Orion Pharma's original proprietary catechol-O-methyl transferase (COMT) inhibitor. Entacapone is able to slow down degradation of levodopa and improve the availability and efficacy of each levodopa dose, hence its use as a complement to levodopa/carbidopa in patients with Parkinson's disease. In order to simplify the daily dosing of these medications, Orion has developed an entacapone/levodopa/carbidopa combination tablet. Three tablet strengths are being developed so as to cover the most common clinical dosing needs. In September 2000, Orion signed a marketing and distribution agreement with Novartis for the combination tablet. Under the terms of the agreement, Orion has exclusive marketing rights for the product in Germany, the UK, Ireland, the Nordic and Baltic countries, and several Eastern European countries. Novartis has exclusive rights to the US and territories other than those markets for which Orion holds market exclusivity. Orion also has the option to co-promote the product in France, Spain and several other countries. In June 2003, the US FDA approved the entacapone/levodopa/carbidopa combination tablet (Stalevo) for the treatment of patients with idiopathic Parkinson's disease who experience signs and symptoms of end-of-dose 'wearing off'. Market launch of the product is expected toward the end of 2003 in the US. Also in June 2003, the Committee for Proprietary Medicinal Products of the European Agency for the Evaluation of Medicinal Products adopted a positive opinion of the combination tablet. In September 2002, Orion submitted an application for the approval of the combination product in the European Union. It is expected that the product will be marketed in the European Union in early 2004. Orion estimates that about two of three fluctuating Parkinson's disease patients will be able to be treated effectively with the triple combination tablet.
     
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  • Dig Dis Sci. 2000 Sep;45(9):1881-4.
  • Tolcapone-related fulminant hepatitis: electron microscopy shows mitochondrial alterations.

    Spahr L, Rubbia-Brandt L, Burkhard PR, Assal F, Hadengue A.

    Department of Neurology, University Hospital, Geneva, Switzerland.
  • Neurology. 2004 Jan 13;62(1 Suppl 1):S64-71.
  • Levodopa/carbidopa/entacapone (Stalevo).

    Hauser RA.

    Department of Neurology, University of South Florida and Tampa General Healthcare, Tampa, Florida 33606, USA.

    A levodopa/carbidopa/entacapone combination product (Stalevo) was recently approved to treat patients with idiopathic Parkinson's disease (PD) who experience end-of-dose "wearing-off." Stalevo is available in dose combinations of levodopa/carbidopa/entacapone 50/12.5/200 mg (Stalevo 50), 100/25/200 mg (Stalevo 100), and 150/37.5/200 mg (Stalevo 150). A series of pharmacokinetic studies demonstrated bioequivalence between Stalevo and corresponding dosages of levodopa/carbidopa plus entacapone. A clinical advantage of Stalevo is that patients can take one pill rather than two (or more) separate tablets. In addition, Stalevo 50 and 100 tablets are smaller than entacapone tablets. These advantages may be particularly beneficial for patients taking many pills, those who have difficulty following complex medication regimens, and those with swallowing difficulty. Most PD patients taking levodopa/carbidopa immediate-release (IR) plus entacapone can be directly switched to the corresponding dose Stalevo product. For fluctuating PD patients taking levodopa/carbidopa IR without entacapone, switching to the corresponding Stalevo tablet is analogous to adding entacapone. In switching patients who are receiving levodopa/carbidopa controlled-release (CR), it should be noted that the bioavailability of levodopa from levodopa/carbidopa CR is approximately 70-75% that of levodopa/carbidopa IR products, including Stalevo.
  • Anesthesiology. 2000 Dec;93(6):1562.
  • Severe hypertension following ephedrine administration in a patient receiving entacapone.

    Renfrew C, Dickson R, Schwab C.
     

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  • Rev Neurol (Paris). 2005 Nov;161(11):1113-5.
  • [Serious tolpcapone-induced hepatitis 17 months after commencing treatment]

    [Article in French]

    Korri H, Awada A.

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  • Rev Neurol (Paris). 2005 Nov;161(11):1113-5.
  • [Serious tolpcapone-induced hepatitis 17 months after commencing treatment]

    [Article in French]

    Korri H, Awada A.
  • Vol 161 - N° 11 - Novembre 2005
    p. 1113 - 1115
    © Masson, Paris, 2005
    Lettre à l’éditeur
  • Effets indésirables hépatiques graves sous tolcapone survenus 17 mois après le début du traitement
  • H. Korri[1][2] , A. Awada[2]
  • [1] Service de Neurologie, Hôpital Bahman,
  • [2] Service de Neurologie, Hôtel-Dieu de France, Beyrouth, Liban.
  • Tirés à part : A. A wada,
    [3] Service de Neurologie, Hôtel-Dieu de France, boulevard Naccache, Achrafieh, Beyrouth, Liban. Emailawadaadnan@yahoo.com
  • Le tolcapone (Tasmar®, Hoffman Laroche, Suisse) est un inhibiteur de la catéchol-O-méthyl-transférase (COMT) qui a été mis sur le marché européen en août 1997 pour traiter les fluctuations motrices associées à la L-dopa dans les cas de maladie de Parkinson avancée (Raiput et al., 1997). Il a toutefois été retiré du marché européen en novembre 1998 après la publication de quatre cas d’effets indésirables hépatiques graves dont trois mortels (Assal et al., 1998 ; Olanow et al., 2000). Trois de...
  • Clin Liver Dis. 2002 May;6(2):381-97.
  • Drug hepatotoxicity.

    Goodman ZD.

    Division of Hepatic Pathology and the Veterans Administration Special Reference Laboratory for Pathology, Armed Forces Institute of Pathology, Room 3107, 14th Street and Alaska Avenue, NW, Washington, DC 20306, USA. goodman@afip.osd.mil

    Drug-induced liver disease is a relatively common, but often unrecognized, cause of liver injury, primarily because the diagnosis is often not entertained clinically. In addition, drugs are great imitators, capable of producing nearly any clinical scenario and histopathologic lesion. Thus, when dealing with a liver biopsy from a patient with an undiagnosed liver disease, the diagnosis of drug hepatotoxicity is made by first having a high index of suspicion, and then by careful correlation of histopathologic findings with both clinical and laboratory data and with a search for appropriate precedents in the medical literature.

[Research] [Main References] [Full Articles] [French Text] [Abstracts]