Toxicology and Safety of Comt Inhibitors

Haasio, Kristiina

doi:10.1016/b978-0-12-381326-8.00007-7

Cited by 50 publications

(30 citation statements)

References 102 publications

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“…72 This medication has minimal side effects, mostly gastrointestinal symptoms such as nausea and diarrhea. 80 Entacapone is administered with each dose of levodopa, and a special formulation combining levodopa/ carbidopa and entacapone in a single tablet has been marketed to improve compliance. Tolcapone is another COMT inhibitor, which is both a peripherally and centrally acting COMT inhibitor that may have greater efficacy.…”

Section: Catechol-o-methyltransferase Inhibitorsmentioning

confidence: 99%

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Motor Complications of Dopaminergic Medications in Parkinson's Disease

2017

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Motor complications are a consequence of chronic treatment of Parkinson’s disease (PD) and include motor fluctuations (wearing-off phenomenon) and levodopa-induced dyskinesia. Both can have a significant impact on functionality and quality of life and thus proper recognition and management is essential. The phenomenology and temporal relationship of motor complications to the schedule of levodopa dosing can be helpful in characterizing them. There are several therapeutic approaches to motor complications, including pharmacological and surgical options. The current review summarizes the different types of motor complications according to phenomenology and the currently available medical treatments, including ongoing trials for management of this condition.

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Section: Catechol-o-methyltransferase Inhibitorsmentioning

confidence: 99%

“…Use is limited due to risk of elevated liver transaminases causing fatal hepatotoxicity. 80 Tolcapone is administered 3 times daily.…”

Section: Catechol-o-methyltransferase Inhibitorsmentioning

confidence: 99%

Motor Complications of Dopaminergic Medications in Parkinson's Disease

2017

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“…The development of new nitrocatechol‐based COMT inhibitors raises safety concerns regarding hepatotoxicity as tolcapone, after introduction into the market, was associated with serious liver toxicity events, that restricted its usage (Olanow, ). Entacapone was never associated with liver toxicity, and although in the past 10 years no more severe liver toxicity cases were reported associated with tolcapone, the mechanism of tolcapone‐induced liver toxicity is still unknown (Haasio, ). Therefore, the evaluation of potential hepatotoxicity risk of a new nitrocatechol COMT inhibitor is mandatory.…”

Section: Discussionmentioning

confidence: 97%

Pharmacological profile of opicapone, a third‐generation nitrocatechol catechol‐O‐methyl transferase inhibitor, in the rat

Bonifácio

Torrão

Loureiro

et al. 2015

British J Pharmacology

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The pharmacodynamic effects of opicapone were explored by evaluating rat COMT activity and levodopa pharmacokinetics, in the periphery through microdialysis and in whole brain. The potential cytotoxicity risk of opicapone was explored in human hepatocytes by assessing cellular ATP content and mitochondrial membrane potential. KEY RESULTSOpicapone inhibited rat peripheral COMT with ED50 values below 1.4 mg·kg −1 up to 6 h post-administration. The effect was sustained over the first 8 h and by 24 h COMT had not returned to control values. A single administration of opicapone resulted in increased and sustained plasma levodopa levels with a concomitant reduction in 3-O-methyldopa from 2 h up to 24 h post-administration, while tolcapone produced significant effects only at 2 h post-administration. The effects of opicapone on brain catecholamines after levodopa administration were sustained up to 24 h post-administration. Opicapone was also the least potent compound in decreasing both the mitochondrial membrane potential and the ATP content in human primary hepatocytes after a 24 h incubation period. CONCLUSIONS AND IMPLICATIONSOpicapone has a prolonged inhibitory effect on peripheral COMT, which extends the bioavailability of levodopa, without inducing toxicity. Thus, it exhibits some improved properties compared to the currently available COMT inhibitors. Abbreviations

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“…Haasio 2010)] carry other medical contraindications. However, DA agonists have been used safely in schizophrenia for many years (e.g., Benkert et al 1995; Kasper et al 1997), and—as suggested by Barch (2010) and others—their use in concert with antipsychotics might prevent potentially deleterious effects of subcortical D 2 activation, while permitting potentially beneficial activation of cortical D 1 receptors.…”

Section: Examples Of Candidate “Pro-ct” Drugsmentioning

confidence: 99%

Towards Medication-Enhancement of Cognitive Interventions in Schizophrenia

Chou

Twamley

Swerdlow

2012

Novel Antischizophrenia Treatments

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Current antipsychotic medications do little to improve real-life function in most schizophrenia patients. A dispassionate view of the dispersed and variable neuropathology of schizophrenia strongly suggests that it is not currently, and may never be, correctable with drugs. In contrast, several forms of cognitive therapy have been demonstrated to have modest but lasting positive effects on cognition, symptoms, and functional outcomes in schizophrenia patients. To date, attempts to improve clinical outcomes in schizophrenia by adding pro-cognitive drugs to antipsychotic regimens have had limited success, but we propose that a more promising strategy would be to pair drugs that enhance specific neurocognitive functions with cognitive therapies that challenge and reinforce those functions. By using medications that engage spared neural resources in the service of cognitive interventions, it might be possible to significantly enhance the efficacy of cognitive therapies. We review and suggest several laboratory measures that might detect potential pro-neurocognitive effects of drugs in individual patients, using a “test dose” design, aided by specific biomarkers predicting an individual’s drug sensitivity. Lastly, we argue that drug classes viewed as “counter-intuitive” based on existing models for the pathophysiology of schizophrenia—including pro-catecholaminergic and NMDA-antagonistic drugs—might be important candidate “pro-cognitive therapy” drugs.

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Toxicology and Safety of Comt Inhibitors

Cited by 50 publications

References 102 publications

Motor Complications of Dopaminergic Medications in Parkinson's Disease

Motor Complications of Dopaminergic Medications in Parkinson's Disease

Pharmacological profile of opicapone, a third‐generation nitrocatechol catechol‐O‐methyl transferase inhibitor, in the rat

Towards Medication-Enhancement of Cognitive Interventions in Schizophrenia

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