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Drugs Affecting the Central Nervous System
Published in Radhwan Nidal Al-Zidan, Drugs in Pregnancy, 2020
Risk Summary: It is better to be avoided during gestation because the pregnancy experience in humans is limited, and the reproduction studies in animals have shown the risk of fetal toxicity associated with the use of Tolcapone.
Movement disorders
Published in Henry J. Woodford, Essential Geriatrics, 2022
COMTi act by blocking one of the degradation pathways of levodopa (to 3-o-methyldopa) (seeFigure 9.8). Tolcapone has both central and peripheral actions but due to cases of hepatoxicity, its use is limited.39 It is only tried under expert supervision for people unresponsive to other COMTi and with regular monitoring of liver blood tests. Entacapone does not cross the blood-brain barrier. It has a half-life of just one hour and is taken with each dose of levodopa. It increases the half-life of levodopa without increasing the maximum concentration and so, should be less likely to worsen dyskinesias. The benefit is in the order of an additional 30 minutes ‘on' time with each levodopa dose.40 It can be helpful for people who are experiencing motor fluctuations.41 A 15–30% reduction in levodopa dose is recommended at the initiation of entacapone therapy. It has not been associated with hepatic toxicity. Patients should be warned that an orange discolouration of their urine could occur. It occasionally causes diarrhoea and may precipitate psychosis. Preparations containing levodopa, a decarboxylase inhibitor and entacapone in combination are available. Opicapone is a once-daily COMTi that appears similarly effective to entacapone in the treatment of PD when added to levodopa (mean age 64).42 Dyskinesias occurred in 4% of people given a placebo, 8% on entacapone and 16% on opicapone. The adverse effect profile is similar and the levodopa dose should also be reduced at commencement of opicapone. COMTi may be considered for the management of motor fluctuations in advanced PD.7
Advances in the treatment and management of frontotemporal dementia
Published in Expert Review of Neurotherapeutics, 2023
Alberto Benussi, Barbara Borroni
Tolcapone: Tolcapone, an FDA-approved medication for treating Parkinson’s symptoms, functions by raising dopamine levels in the prefrontal cortex through the inhibition of catechol-O-methyltransferase (COMT). In a Phase 2b clinical trial, researchers investigated the effects of tolcapone on 28 patients with clinically diagnosed, symptomatic bvFTD. The trial findings disclosed no substantial disparities between the tolcapone and placebo groups concerning primary or imaging outcomes. Nevertheless, significant alterations were detected in the repeatable battery for the assessment of neuropsychological status (RBANS) total scores, neuropsychiatric inventory questionnaire (NPI-Q) total scores, and clinical global impression (CGI) total scores across the two treatment conditions [114]. These findings suggest that further investigation into newer COMT inhibitors, with fewer side effects, may be warranted to potentially benefit bvFTD patients, as well as exploring additional outcome measures to better assess their efficacy.
Opicapone for the treatment of Parkinson’s disease: a review
Published in International Journal of Neuroscience, 2023
Matthew Feldman, Jason Margolesky
Tolcapone has limited use due to concerns for toxicity. Specifically, it was initially withdrawn from the market after multiple cases of acute liver failure were attributed to its use [17]. Of note, the medication is metabolized extensively in the liver. It was found to cause serum aminotransferase elevations in a hepatocellular pattern above three times the upper limit of normal in 1%-5% of patients. Many of these abnormalities were asymptomatic and self-limiting, but three of these cases led to death from acute liver failure [17]. Unlike entacapone, tolcapone can cross the blood-brain barrier, and therefore actually has some unintended central COMT inhibition [18]. Tolcapone remains off the market in several countries. Neither entacapone nor tolcapone have shown evidence of disease-modifying properties [19].
CSF/plasma levels, transthyretin stabilisation and safety of multiple doses of tolcapone in subjects with hereditary ATTR amyloidosis
Published in Amyloid, 2022
Yusuke Takahashi, Nobuhiko Ohashi, Ken Takasone, Tsuneaki Yoshinaga, Masahide Yazaki, Michael Roberts, Paul F. Glidden, Yoshiki Sekijima
Four patients (3 post-transplant, 1 with elevated AST/ALT) were assigned to receive tolcapone 300 mg/day (100-mg tablet TID) and 5 patients were assigned to receive tolcapone 600 mg/day (two 100-mg tablets TID) for 7 days (a total of 21 administrations of tolcapone). The initial dose was administered after dinner on Day 1 (at approximately 7:00 pm). On Day 8, the patients were administered study drug after breakfast (at approximately 8:00 am) and after lunch (approximately at 1:00 pm). This dosing regimen is based on the current use of tolcapone in Parkinson’s patients as described in the tolcapone product label. Tolcapone has a half-life of about 3 h, therefore multiple doses per day of the current formulation is required. While tolcapone has a relatively short half-life and is extensively metabolised in plasma, the 3-O-methyltolcapone (3-OMT) metabolite has a half-life of about 40 h and has been shown to have similar TTR tetramer stabilising activity to tolcapone [10]. Blood and CSF samples were collected from all subjects on Day 1 (pre-treatment), and Day 8 (2 h after the final tolcapone dose). Duration between the last tolcapone intake and plasma and CSF drawings were 128.2 ± 22.7 min and 130 ± 16.1 min, respectively.