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Inhibitors of catechol- O -methyltransferase (COMT) are commonly used as an adjunct to levodopa in patients with Parkinson’s disease (PD) for the amelioration of wearing-off symptoms. This narrative review aims to discuss the role of COMT inhibitors on peripheral levodopa metabolism and continuous brain delivery of levodopa, and to describe their metabolic properties. Oral application of levodopa formulations with a dopa decarboxylase inhibitor (DDI) results in fluctuating levodopa plasma concentrations, predominantly due to the short half-life of levodopa and its slowing of gastric emptying. Following transport across the blood–brain barrier and its metabolic conversion to dopamine, these peripheral ‘ups and downs’ of levodopa are reflected in fluctuating dopamine levels in the synaptic cleft between presynaptic and postsynaptic dopaminergic neurons of the nigrostriatal system. As a result, pulsatile postsynaptic dopaminergic stimulation takes place and results in the occurrence of motor complications, such as wearing-off and dyskinesia. More continuous plasma behaviour was observed after the combination of levodopa/DDI formulations with COMT inhibitors. These compounds also weaken a levodopa/DDI-related homocysteine increase, as biomarker for an impaired methylation capacity, which is involved in an elevated oxidative stress exposure. These findings favour the concept of chronic levodopa/DDI application with concomitant inhibition of COMT and monoamine oxidase, since deamination of dopamine via this enzyme also generates free radicals. This triple combination is suggested as standard levodopa application in patients with PD who need levodopa, if they will tolerate it.

PurposeTolcapone is an efficacious catechol-O-methyltransferase inhibitor for Parkinson’s disease (PD). However, safety issues hampered its use in clinical practice. We aimed to provide evidence of safety and efficacy of tolcapone by a systematic literature review to support clinicians’ choices in the use of an enlarging PD therapeutic armamentarium.MethodsWe searched PubMed for studies on PD patients treated with tolcapone, documenting the following outcomes: liver enzyme, adverse events (AEs), daily Off-time, levodopa daily dose, unified Parkinson’s disease rating scale (UPDRS) part-III, quality of life (QoL), and non-motor symptoms. FAERS and EudraVigilance databases for suspected AEs were interrogated for potential additional cases of hepatotoxicity.ResultsThirty-two studies were included, for a total of 4780 patients treated with tolcapone. Pertaining safety, 0.9% of patients showed liver enzyme elevation > 2. Over 23 years, we found 7 cases of severe liver injury related to tolcapone, 3 of which were fatal. All fatal cases did not follow the guidelines for liver function monitoring. FAERS and EudraVigilance database search yielded 61 reports of suspected liver AEs possibly related to tolcapone.Pertaining efficacy, the median reduction of hours/day spent in Off was 2.1 (range 1–3.2), of levodopa was 108.9 mg (1–251.5), of “On” UPDRS-III was 3.6 points (1.1–6.5). Most studies reported a significant improvement of QoL and non-motor symptoms.ConclusionLiterature data showed the absence of relevant safety concerns of tolcapone when strict adherence to hepatic function monitoring is respected. Given its high efficacy on motor fluctuations, tolcapone is probably an underutilized tool in the therapeutic PD armamentarium.

Levodopa treatment remains the gold standard for Parkinson’s disease, but shortcomings related to the pharmacological profile, notably, oral administration and the consequent occurrence of motor complications, have led to the development of several add-on levodopa treatments or to research to improve the method of delivery. Motor fluctuations, and to a lesser extent non-motor fluctuations, concern half of the patients with Parkinson’s disease after 5 years of disease and patients identified them as one of their most bothersome symptoms. Catechol- O -methyl transferase inhibitors (COMT-Is) are one of the recommended first-line levodopa add-on therapies for the amelioration of end-of dose motor fluctuations in patient with advanced Parkinson’s disease. Currently, two peripheral COMT-Is are considered as first-line choices - entacapone (ENT), which was approved by the US Food and Drug Administration in 1999 and the European Committee in 1998; and opicapone (OPC), which was approved by the European Committee in 2016. A second-line COMT-I that requires regular hepatic monitoring, tolcapone (TOL), was approved by the Food and Drug Administration in 1998 and the European Committee in 1997. Of note, OPC also received Food and Drug Administration approval in 2021, but it is still only marketed in a few countries, including Germany, UK, Spain, Portugal, Italy, Japan, and USA, while ENT and TOL have a wider market. Our narrative review summarizes the pharmacokinetic/pharmacodynamic properties, clinical efficacy in terms of motor fluctuations, motor/non-motor symptoms, quality of life, and safety data of these three COMT-Is, as evidenced by randomized clinical trials, as well as by real-life observational studies. Overall, a phase III non-inferiority trial showed a similar effect between ENT and OPC on off-time (−60.8 min/day and −40.3 min/day, vs placebo, respectively), with a possible additional off-time reduction of 39 min/day, obtained when there is a switch from ENT to OPC. Concomitantly, TOL can reduce off-time by an average of 98 min/day. A significant though discrete concomitant reduction on the Unified Parkinson's Disease Rating Scale motor section (2–3 points) is obtained with all three drugs vs placebo. Data on quality of life are fewer and more heterogeneous, with positive results obtained especially in open-label studies. Effects on non-motor symptoms were investigated as secondary outcome only in a few studies, frequently by means of non-specific scales and a benefit was observed in open-label studies. Dopaminergic adverse effects were the most frequent, dyskinesia being the most common for the three drugs eventually requiring levodopa dose reductions. No urine discoloration and a very low incidence of diarrhea were found with OPC compared with ENT and TOL. Regular hepatic monitoring is needed only for TOL. A combination of COMT-Is with new formulations of levodopa, including the subcutaneous, intrajejunal, or new extended-release formulation, merits further exploration to improve the management of both mild and severe motor fluctuations.

Alcohol Use Disorder (AUD) is characterized by loss of control over drinking. Behavioral control is mediated, in part, by cortical dopamine signaling. Inhibition of catechol-O-methyltransferase (COMT), the enzyme primarily responsible for cortical dopamine inactivation, may increase cortical dopamine, especially among individuals with genetically mediated lower dopaminergic tone, such as COMT rs4680 (val158met) val-allele homozygotes. This study was a randomized, placebo-controlled, pharmacogenetic trial of the COMT inhibitor tolcapone. Ninety non-treatment-seeking AUD individuals were prospectively genotyped for rs4680 and randomized to tolcapone (200 mg t.i.d.) or placebo for 8 days. At baseline and on day 7, peripheral COMT activity was assayed, and participants completed an fMRI alcohol cue-reactivity task; on day 8, they completed a bar-lab paradigm. Primary outcomes were: (1) natural drinking during the medication period; (2) alcohol self-administration in the bar lab; and (3) alcohol cue-elicited cortical (right inferior frontal gyrus [rIFG]) and ventral striatal activation. At baseline, the rs4680 val-allele had an additive effect on COMT activity. Tolcapone, relative to placebo, reduced COMT activity in all genotype groups. COMT genotype moderated tolcapone’s effect on drinking during the medication period and in the bar lab, such that tolcapone, relative to placebo, reduced drinking only among val-allele homozygotes. Tolcapone did not affect cue-elicited ventral striatal activation but reduced rIFG activation; less rIFG activation on day 7 was associated with less drinking during the medication period. Taken together, these data suggest that COMT inhibition may reduce drinking specifically among individuals genetically predisposed to excessive COMT activity and potentially low cortical dopamine tone.ClinicalTrials.gov identifier: NCT02949934 https://clinicaltrials.gov/ct2/show/NCT02949934

The relationship between dopamine (DA) tone in the prefrontal cortex (PFC) and PFC-dependent cognitive functions (for example, working memory, selective attention, executive function) may be described by an inverted-U-shaped function, in which both excessively high and low DA is associated with impairment. In the PFC, the COMT val158met single nucleotide polymorphism (rs4680) confers differences in catechol- O -methyltransferase (COMT) efficacy and DA tone, and individuals homozygous for the val allele display significantly reduced cortical DA. Many studies have investigated whether val158met genotype moderates the effects of dopaminergic drugs on PFC-dependent cognitive functions. A review of 25 such studies suggests evidence for this pharmacogenetic effect is mixed for stimulants and COMT inhibitors, which have greater effects on D 1 receptors, and strong for antipsychotics, which have greater effects on D 2 receptors. Overall, COMT val158met genotype represents an enticing target for identifying individuals who are more likely to respond positively to dopaminergic drugs.

Transthyretin (TTR) is a plasma homotetrameric protein implicated in fatal systemic amyloidoses. TTR tetramer dissociation precedes pathological TTR aggregation. Native state stabilizers are promising drugs to treat TTR amyloidoses. Here we repurpose tolcapone, an FDA-approved molecule for Parkinson’s disease, as a potent TTR aggregation inhibitor. Tolcapone binds specifically to TTR in human plasma, stabilizes the native tetramer in vivo in mice and humans and inhibits TTR cytotoxicity. Crystal structures of tolcapone bound to wild-type TTR and to the V122I cardiomyopathy-associated variant show that it docks better into the TTR T 4 pocket than tafamidis, so far the only drug on the market to treat TTR amyloidoses. These data indicate that tolcapone, already in clinical trials for familial amyloid polyneuropathy, is a strong candidate for therapeutic intervention in these diseases, including those affecting the central nervous system, for which no small-molecule therapy exists. Misfolding of transthyretin can cause amyloid aggregation disorders that can be treated by stabilizing the tetrameric form with tafamidis. Here the authors show that tolcapone, a drug already FDA-approved for Parkinson disease, has strong transthyretin stabilizing function and might be a superior therapeutic option for CNS amyloidosis as it can cross the blood brain barrier.

The catechol- -methyltransferase (COMT) inhibitor tolcapone constitutes a potentially useful probe of frontal cortical dopaminergic function. The aim of this systematic review was to examine what is known of effects of tolcapone on human cognition in randomized controlled studies. The study protocol was preregistered on the Open Science Framework. A systematic review was conducted using PubMed to identify relevant randomized controlled trials examining the effects of tolcapone on human cognition. Identified articles were then screened against inclusion and exclusion criteria. Of the 22 full-text papers identified, 13 randomized control trials were found to fit the pre-specified criteria. The most consistent finding was that tolcapone modulated working memory; however, the direction of effect appeared to be contingent on the COMT polymorphism (more consistent evidence of improvement in Val-Val participants). There were insufficient nature and number of studies for meta-analysis. The cognitive improvements identified upon tolcapone administration, in some studies, are likely to be due to the level of dopamine in the prefrontal cortex being shifted closer to its optimum, per an inverted U model of prefrontal function. However, the results should be interpreted cautiously due to the small numbers of studies. Given the centrality of cortical dopamine to understanding human cognition, studies using tolcapone in larger samples and across a broader set of cognitive domains would be valuable. It would also be useful to explore the effects of different dosing regimens (different doses; and single versus repeated administration).

Catechol-O-methyltransferase (COMT) inhibitors are used to alleviate motor fluctuations, such as wearing-off, in people with Parkinson’s disease (PwPD). Opicapone, a COMT inhibitor has long-lasting efficacy when administered once daily, but there is limited real-world clinical data in Japanese participants. This study aimed to evaluate the one-year continuation rate of opicapone in Japanese PwPD in real-world clinical practice and to identify factors influencing this continuation rate. This retrospective study analyzed data from 58 Japanese PwPD treated with opicapone at the Department of Neurology, Fukuoka University Hospital. We compared patients who continued opicapone for one year with those who discontinued it and examined factors influencing the continuation rate. Among the 58 PwPD, 26 (44.8%) continued opicapone for one year. Binomial logistic regression analysis identified male sex (odds ratio: 0.223, 95 % confidence interval: 0.056-0.878) and switching from entacapone (odds ratio: 0.215, 95 % confidence interval: 0.056-0.825) as significant factors influencing the one-year continuation rate. Switching to opicapone in patients with suboptimal responses to entacapone may enhance the continuation rate. •One-year continuation rate of opicapone in Japanese patients with Parkinson's disease was 44.8 %.•Patients of male sex and those who switched from entacapone had higher continuation rates of opicapone.•Poor efficacy was the most common reason for opicapone discontinuation.•Adverse events, including dyskinesia and hallucinations, occurred mostly within the first three months of starting opicapone.•Opicapone may improve motor symptoms in patients inadequately controlled with entacapone.

Background Catechol‐O‐methyl transferase (COMT) inhibitors are routinely used to manage motor fluctuations in Parkinson's disease (PD). We assessed the effect of opicapone on motor symptom severity in levodopa‐treated patients without motor complications. Methods This was a randomized, double‐blind, 24‐week, placebo‐controlled study of opicapone 50 mg as adjunct to levodopa (NCT04978597). Levodopa‐treated patients without motor complications were randomized to 24 weeks of double‐blind treatment with adjunct opicapone 50 mg or matching placebo. The primary efficacy endpoint was the mean change from baseline to week 24 in Movement Disorder Society‐Unified Parkinson's Disease Rating Scale Part III (MDS‐UPDRS‐III) total score. Results A total of 355 patients were randomized (opicapone 50 mg n = 177, placebo n = 178) and 322 (91%) completed the double‐blind period. The adjusted mean [95% CI] change from baseline to week 24 in MDS‐UPDRS‐III subscore was −6.5 [−7.9, −5.2] in the opicapone group versus −4.3 [−5.7, 3.0] in the placebo group resulting in a significant difference of −2.2 [−3.9, −0.5] favoring opicapone (p = 0.010). There was no difference in the incidence of patients who developed motor complications (5.5% with opicapone vs. 9.8% with placebo) and the incidence of adverse events considered related to study medication was similar between groups (opicapone 10.2% vs. placebo 13.5%). Conclusions Treatment with once‐daily adjunct opicapone was well tolerated, improved motor severity, and did not induce the development of motor complications. These results support the clinical usefulness of opicapone in the management of PD patients without motor complications.

RationaleIndividuals suffering from alcohol use disorder (AUD) demonstrate difficulty with decision-making and impulsivity that may be associated with impaired frontal cortical function. Therapeutics that enhance frontal dopamine tone could decrease impulsivity and in turn reduce alcohol consumption in individuals with AUD.ObjectivesTo determine if the catechol-O-methyltransferase (COMT) inhibitor tolcapone can attenuate alcohol consumption in individuals with AUD and whether this attenuation correlates with tolcapone-induced changes in laboratory-based decision-making tasks.MethodsWe used daily self-report and a novel group laboratory bar task to assess the effects of randomized double-blind crossover administration of tolcapone (100 mg TID for 5 days) on alcohol consumption and laboratory tasks assessing impulsivity in 55 non-treatment-seeking subjects with AUD.ResultsTolcapone significantly reduced self-reported alcohol consumption (t (54) = 2.05, p = 0.045). The effects of tolcapone on drinking significantly correlated with changes in impulsive decision-making, such that subjects with the greatest decrease in impulsive choice on tolcapone also reported the greatest decrease in alcohol consumption (r (45) = 0.40, p = 0.0053). We did not see effects of tolcapone on laboratory bar consumption. Adverse event (AE) reporting was low, with no significant difference in frequency or severity of AEs on tolcapone versus placebo.ConclusionsThese data demonstrate that COMT inhibitors such as tolcapone may be useful therapeutics for AUD.Trial registrationClinicalTrials.gov Identifier: NCT 02740582