-
Psychopharmacology Oct 2020Individuals suffering from alcohol use disorder (AUD) demonstrate difficulty with decision-making and impulsivity that may be associated with impaired frontal cortical... (Randomized Controlled Trial)
Randomized Controlled Trial
RATIONALE
Individuals 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.
OBJECTIVES
To 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.
METHODS
We 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.
RESULTS
Tolcapone 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.
CONCLUSIONS
These data demonstrate that COMT inhibitors such as tolcapone may be useful therapeutics for AUD.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02740582.
Topics: Adult; Alcohol Drinking; Alcoholism; Catechol O-Methyltransferase Inhibitors; Choice Behavior; Cross-Over Studies; Double-Blind Method; Female; Humans; Impulsive Behavior; Male; Tolcapone; Young Adult
PubMed: 32617646
DOI: 10.1007/s00213-020-05599-5 -
CMAJ : Canadian Medical Association... Apr 1999
Topics: Antiparkinson Agents; Benzophenones; Canada; Catechol O-Methyltransferase Inhibitors; Chemical and Drug Induced Liver Injury; Drug Approval; Humans; Nitrophenols; Tolcapone
PubMed: 10207353
DOI: No ID Found -
Neurotherapeutics : the Journal of the... Apr 2008Symptomatic medical therapies for Parkinson's disease (PD) have been disease modifying and have led to improvement in daily function, quality of life, and survival. For... (Review)
Review
Symptomatic medical therapies for Parkinson's disease (PD) have been disease modifying and have led to improvement in daily function, quality of life, and survival. For 40 years, these therapies have been primarily dopaminergic, and currently include the dopamine (DA) precursor levodopa (LD), DA agonists, catechol-O-methyltransferase (COMT) inhibitors, and monoamine oxidase (MAO) inhibitors. The roles of all these classes of agents have evolved, with significant changes occurring since the early 2000s. This article reviews the current literature for each of these classes of drugs, with a focus on efficacy and place in the therapeutic scheme. Levodopa is no longer considered to be toxic and, thus, its early use is not only appropriate but recommended. Ergot agonists are no longer in use, and new agents administered in patch form or subcutaneous injections have been approved. The COMT inhibitor tolcapone, with its significant efficacy, has been reintroduced, and two new MAO inhibitors have been approved. Selected safety issues are discussed, including the incidence of melanoma in relation to LD; pathological gambling and DA agonists; hepatic toxicity of tolcapone; and the tyramine or so-called cheese reaction with MAO B inhibitors. The article closes with a discussion of future directions and new drugs under development.
Topics: Antipsychotic Agents; Clinical Trials as Topic; Drug Evaluation; Humans; Parkinson Disease
PubMed: 18394561
DOI: 10.1016/j.nurt.2007.12.001 -
Neuropharmacology Dec 2020Parkinson disease is typically treated with L-3,4-dihydroxyphenylalanine (or levodopa) co-prescribed with concentration stabilizers to prevent undesired motor...
Parkinson disease is typically treated with L-3,4-dihydroxyphenylalanine (or levodopa) co-prescribed with concentration stabilizers to prevent undesired motor fluctuations. However, the beneficial role of the chronic combined therapy on disease progression has not been thoroughly explored. We hypothesized that tolcapone, a catechol-O-methyl-transferase inhibitor, co-administered with levodopa may offer beneficial long-term disease-modifying effects through its dopamine stabilization actions. Here, we followed vesicular monoamine transporter 2-deficient and wild-type mice treated twice daily per os with vehicle, levodopa (20 mg/kg), tolcapone (15 mg/kg) or levodopa (12.5 mg/kg) + tolcapone (15 mg/kg) for 17 weeks. We assessed open field, bar test and rotarod performances at baseline and every 4th week thereafter, corresponding to OFF-medication weeks. Finally, we collected coronal sections from the frontal caudate-putamen and determined the reactivity level of dopamine transporter. Vesicular monoamine transporter 2-deficient mice responded positively to chronic levodopa + tolcapone intervention in the bar test during OFF-periods. Neither levodopa nor tolcapone interventions offered significant improvements on their own. Similarly, chronic levodopa + tolcapone intervention was associated with partially rescued dopamine transporter levels, whereas animals treated solely with levodopa or tolcapone did not present this effect. Interestingly, 4-month progression of bar test scores correlated significantly with dopamine-transporter-label density. Overall, we observed a moderate functional and histopathological improvement effect by chronic dopamine replacement when combined with tolcapone in vesicular monoamine transporter 2-deficient mice. Altogether, chronic stabilization of dopamine levels by catechol-O-methyl-transferase inhibition, besides its intended immediate actions, arises as a potential long-term beneficial approach during the progression of Parkinson disease.
Topics: Animals; Antiparkinson Agents; Behavior, Animal; Catechol O-Methyltransferase Inhibitors; Dopamine Plasma Membrane Transport Proteins; Eating; Levodopa; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Parkinson Disease; Psychomotor Performance; Tolcapone; Vesicular Monoamine Transport Proteins
PubMed: 33038358
DOI: 10.1016/j.neuropharm.2020.108353 -
ENeuro 2020Gambling disorder is a behavioral addiction associated with impairments in value-based decision-making and cognitive control. These functions are thought to be regulated... (Randomized Controlled Trial)
Randomized Controlled Trial
Gambling disorder is a behavioral addiction associated with impairments in value-based decision-making and cognitive control. These functions are thought to be regulated by dopamine within fronto-striatal circuits, but the role of altered dopamine neurotransmission in the etiology of gambling disorder remains controversial. Preliminary evidence suggests that increasing frontal dopamine tone might improve cognitive functioning in gambling disorder. We therefore examined whether increasing frontal dopamine tone via a single dose of the catechol--methyltransferase (COMT) inhibitor tolcapone would reduce risky choice in human gamblers ( = 14) in a randomized double-blind placebo-controlled crossover study. Data were analyzed using hierarchical Bayesian parameter estimation and a combined risky choice drift diffusion model (DDM). Model comparison revealed a nonlinear mapping from value differences to trial-wise drift rates, confirming recent findings. An increase in risk-taking under tolcapone versus placebo was about five times more likely, given the data, than a decrease [Bayes factor (BF) = 0.2]. Examination of drug effects on diffusion model parameters revealed that an increase in the value dependency of the drift rate under tolcapone was about thirteen times more likely than a decrease (BF = 0.073). In contrast, a reduction in the maximum drift rate under tolcapone was about seven times more likely than an increase (BF = 7.51). Results add to previous work on COMT inhibitors in behavioral addictions and to mounting evidence for the applicability of diffusion models in value-based decision-making. Future work should focus on individual genetic, clinical and cognitive factors that might account for heterogeneity in the effects of COMT inhibition.
Topics: Bayes Theorem; Catechol O-Methyltransferase; Cross-Over Studies; Dopamine; Gambling; Humans
PubMed: 32341121
DOI: 10.1523/ENEURO.0461-19.2020 -
British Journal of Clinical Pharmacology Oct 1999To investigate the rate of excretion and routes of metabolism of tolcapone, a novel inhibitor of catechol-O-methyltransferase (COMT). (Clinical Trial)
Clinical Trial
AIMS
To investigate the rate of excretion and routes of metabolism of tolcapone, a novel inhibitor of catechol-O-methyltransferase (COMT).
METHODS
Six healthy male volunteers were given 200 mg [14C]-tolcapone (approximately 50 muCi) orally. To assess excretion balance and to identify metabolites, urine and faeces were collected before administration and until radioactivity fell below 75 d min-1 ml-1 (urine) and 100 d min-1 mg-1 (faeces). Blood samples were collected frequently before and after administration to determine plasma radioactivity, to identify tolcapone metabolites and to measure plasma tolcapone and its methylated derivative 3-O-methyltolcapone (3-OMT).
RESULTS
The mean proportion of the dose excreted in urine was 57.3% and in faeces 40.5%. Excretion was almost complete (more than 95%) in all participants after 9 days. The major early metabolite present in plasma was the 3-O-beta, d-glucuronide conjugate, which was detectable within 2 h after dosing. The major late metabolite in plasma was 3-OMT. The 3-O-beta, d-glucuronide was also the most abundant metabolite in urine and faeces, accounting for 27% and 33%, respectively, of the total radioactivity excreted by these routes and for 26% of the original dose. Reduction of the nitro moiety yields an amine derivative, detected in both urine and faeces, with subsequent modifications, such as acetylation of the amine group and conjugation with glucuronic acid or sulphate, or both. Oxidative reactions due to cytochrome P450 enzymes are of small significance, as is 3-O-methylation by COMT.
CONCLUSIONS
Tolcapone is almost completely metabolized and excreted in urine and faeces (only 0.5% of tolcapone was excreted unchanged); glucuronidation is the most important route of metabolism. The relatively long duration of excretion is caused by the long half-life of 3-OMT.
Topics: Adult; Benzophenones; Catechol O-Methyltransferase Inhibitors; Chromatography, High Pressure Liquid; Enzyme Inhibitors; Feces; Glucuronides; Humans; Male; Mass Spectrometry; Nitrophenols; Oxidation-Reduction; Time Factors; Tolcapone
PubMed: 10583021
DOI: 10.1046/j.1365-2125.1999.00036.x -
Current Treatment Options in Psychiatry Jun 2014Preclinical and clinical research implicate several neurotransmitter systems in the pathophysiology of gambling disorder (GD). In particular, neurobiological research...
Preclinical and clinical research implicate several neurotransmitter systems in the pathophysiology of gambling disorder (GD). In particular, neurobiological research suggests alterations in serotonergic, dopaminergic, glutamatergic and opioidergic functioning. The relative efficacy of medications targeting these systems remains a topic of ongoing research, and there is currently no Food and Drug Administration (FDA) approved medication with an indication for GD. Considering co-occurring disorders may be particularly important when devising a treatment plan for GD: extant data suggest that the opioid antagonist naltrexone may by the most effective form of current pharmacotherapy for GD, particularly for individuals with a co-occurring substance-use disorder (SUD) or with a family history of alcoholism. In contrast, lithium or other mood stabilizers may be most effective for GD for patients presenting with a co-occurring bipolar-spectrum disorder (BSD). Further, serotonin reuptake inhibitors (SRIs) may be efficacious in reducing GD symptoms for individuals also presenting with a (non-BSD) mood or anxiety disorder. Finally, elevated rates of GD (and other Impulse Control Disorders; ICDs) have been noted among individuals with Parkinson's Disease (PD), and clinicians should assess for vulnerability to GD when considering treatment options for PD. Reducing levodopa or dopamine agonist (DA) dosages may partially reduce GD symptoms among patients with co-occurring PD. For GD patients not willing to consider drug treatment, n-acetyl cysteine or behavioral therapies may be effective. Ongoing research into the effectiveness of combined behavioral and pharmacotherapies is being conducted; thus combined treatments should also be considered.
PubMed: 24904757
DOI: 10.1007/s40501-014-0014-5 -
The FEBS Journal Jan 2021Hereditary transthyretin amyloidosis (ATTR) is a disease characterized by the extracellular deposition of transthyretin (TTR) amyloid fibrils. Highly destabilizing TTR...
Hereditary transthyretin amyloidosis (ATTR) is a disease characterized by the extracellular deposition of transthyretin (TTR) amyloid fibrils. Highly destabilizing TTR mutations cause leptomeningeal amyloidosis, a rare, but fatal, disorder in which TTR aggregates in the brain. The disease remains intractable, since liver transplantation, the reference therapy for systemic ATTR, does not stop mutant TTR production in the brain. In addition, despite current pharmacological strategies have shown to be effective against in vivo TTR aggregation by stabilizing the tetramer native structure and precluding its dissociation, they display low brain permeability. Recently, we have repurposed tolcapone as a molecule to treat systemic ATTR. Crystal structures and biophysical analysis converge to demonstrate that tolcapone binds with high affinity and specificity to three unstable leptomeningeal TTR variants, stabilizing them and, consequently, inhibiting their aggregation. Because tolcapone is an FDA-approved drug that crosses the blood-brain barrier, our results suggest that it can translate into a first disease-modifying therapy for leptomeningeal amyloidosis. DATABASES: PDB codes for A25T-TTR, V30G-TTR, and Y114C-TTR bound to tolcapone are 6TXV, 6TXW, and 6XTK, respectively.
Topics: Amyloid; Amyloid Neuropathies, Familial; Antiparkinson Agents; Binding Sites; Cloning, Molecular; Crystallography, X-Ray; Drug Repositioning; Escherichia coli; Gene Expression; Genetic Vectors; Humans; Kinetics; Models, Molecular; Mutation; Neuroprotective Agents; Prealbumin; Protein Aggregates; Protein Binding; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Denaturation; Protein Folding; Protein Interaction Domains and Motifs; Protein Multimerization; Protein Structure, Tertiary; Recombinant Proteins; Tolcapone; Urea
PubMed: 32324953
DOI: 10.1111/febs.15339 -
Alcohol (Fayetteville, N.Y.) Mar 2018Polymorphisms of the catechol-O-methyl transferase (COMT) gene have been associated with alcoholism, suggesting that alterations in the metabolism of catecholamines may...
Polymorphisms of the catechol-O-methyl transferase (COMT) gene have been associated with alcoholism, suggesting that alterations in the metabolism of catecholamines may be a critical component of the neuropathology of alcoholism. In the current experiments, the COMT inhibitor tolcapone was utilized in an operant behavioral model of reinforcer-seeking and drinking to determine if this compound was capable of remediating the excessive seeking and drinking phenotype of the alcohol-preferring P rat. Tolcapone was administered to male and female alcohol-reinforced P and Wistar rats. Additionally, tolcapone was administered to male sucrose-reinforced P and Wistar rats to determine if its effects also extended to a natural reinforcer. Animals were trained to make an operant response that resulted in 20 min uninterrupted access to the reinforcer solutions. Tolcapone had no effect in female rats on either seeking or consumption of ethanol. However, reductions of both reinforcer seeking and consumption were observed in male P rats, but only of seeking in Wistars. In separate experiments, using reinforcer naïve male and female animals, COMT expression was assessed via Western Blot analysis. Sex differences in COMT expression were also observed, where male P rats exhibited a marked reduction in protein expression relative to females in the PFC. Sex differences were not observed for Wistars or in the striatum and hippocampus. These data complement our previous findings in which tolcapone reduced cue-evoked responses in P rats and further suggest clinical utility of COMT inhibitors in the treatment of addiction disorders, specifically in male high drinkers.
Topics: Alcohol Drinking; Animals; Behavior, Addictive; Benzophenones; Brain; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Dose-Response Relationship, Drug; Female; Gene Expression Regulation, Enzymologic; Male; Nitrophenols; Rats; Rats, Wistar; Sex Characteristics; Species Specificity; Tolcapone
PubMed: 29310047
DOI: 10.1016/j.alcohol.2017.08.007 -
Journal of Neurology, Neurosurgery, and... Sep 2007The safety and tolerability of adjunctive tolcapone initiated simultaneously with levodopa was evaluated with a focus on increases in liver transaminase and... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
The safety and tolerability of adjunctive tolcapone initiated simultaneously with levodopa was evaluated with a focus on increases in liver transaminase and hepatotoxicity.
METHODS
677 levodopa-naïve patients with early stage Parkinson's disease (PD) were randomised to receive placebo or tolcapone 100 mg three times daily, added to standard doses of levodopa plus carbidopa or benserazide.
RESULTS
Increases in liver transaminase above the upper limit of normal (ULN) occurred in 69/342 (20.2%) and 92/335 (27.5%) patients in the placebo and tolcapone groups, respectively. Increases > or = 3 times the ULN occurred in 4/342 (1.2%) and 6/335 (1.8%) patients receiving placebo and tolcapone, respectively (p = 0.5). Liver transaminase values returned to normal in 65% of placebo and 80% of tolcapone treated patients. No instances of serious hepatotoxicity were seen. Diarrhoea was the most commonly reported AE-36/342 (11.0%) placebo v 98/335 (29.0%) tolcapone-and caused discontinuation in 9.9% of tolcapone treated patients. Overall, study discontinuation due to adverse effects was 2.9% in the placebo group and 17.3% in the tolcapone group.
CONCLUSIONS
Tolcapone seemed to be safe and was generally well tolerated as an adjunctive treatment in patients starting treatment with carbidopa/levodopa for symptomatic PD. Mild increases in transaminase levels--< 3 times the ULN--occurred commonly in both placebo and tolcapone treated patients, whereas potentially serious increases of up to > or = 3 times the ULN were infrequent.
Topics: Adult; Aged; Aged, 80 and over; Alanine Transaminase; Antiparkinson Agents; Aspartate Aminotransferases; Benzophenones; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Middle Aged; Nitrophenols; Parkinson Disease; Tolcapone
PubMed: 17098835
DOI: 10.1136/jnnp.2006.097154