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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 -
Lancet (London, England) Sep 1998
Topics: Aged; Antiparkinson Agents; Benzophenones; Chemical and Drug Induced Liver Injury; Female; Humans; Liver Failure, Acute; Nitrophenols; Parkinson Disease; Tolcapone
PubMed: 9752821
DOI: 10.1016/s0140-6736(05)61511-5 -
Pharmacogenomics Apr 2011It is widely accepted that abnormal prefrontal cortex biology resulting in deficient cognition is a primary problem in schizophrenia and that all currently available...
It is widely accepted that abnormal prefrontal cortex biology resulting in deficient cognition is a primary problem in schizophrenia and that all currently available antipsychotics fail to improve cognitive and negative symptoms originating from this deficit. Evidence from basic science has revealed the importance of prefrontal dopamine signaling for optimal prefrontal function. This article describes succinctly the progress made so far, taking into account the mechanisms involved in catechol-O-methyltransferase (COMT)-induced modulation of prefrontal dopamine signaling, the impact of COMT on cognitive function and the role of COMT gene polymorphisms. The potential role of the COMT inhibitor tolcapone to improve cognitive function in health and disease is also presented here. It will soon be understood if tolcapone represents one of the first hypothesis-driven, biology-based, genotype-specific, targeted treatments of cognitive and negative symptoms of schizophrenia.
Topics: Antipsychotic Agents; Benzophenones; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Cognition Disorders; Dopamine; Genetic Predisposition to Disease; Genotype; Humans; Nitrophenols; Polymorphism, Genetic; Schizophrenia; Schizophrenic Psychology; Signal Transduction; Tolcapone
PubMed: 21521027
DOI: 10.2217/pgs.10.206 -
Journal of Global Antimicrobial... Sep 2020Vancomycin is a first-line antibiotic for the treatment of invasive infections in humans caused by methicillin-resistant Staphylococcus aureus (MRSA). Based on the...
OBJECTIVES
Vancomycin is a first-line antibiotic for the treatment of invasive infections in humans caused by methicillin-resistant Staphylococcus aureus (MRSA). Based on the premise that antibiotic combinations can exhibit synergistic and antagonistic interactions, medications used for the treatment of infection and other medical conditions were evaluated for their ability to alter MRSA susceptibility to vancomycin.
METHODS
A chemical library comprised of 1237 pharmacological agents was evaluated in a 96-well plate format for its ability to inhibit MRSA growth in combination with half the minimum inhibitory concentration (MIC) of vancomycin. Caspofungin and tolcapone were further assessed for synergistic potential by isobologram (checkerboard) and flow cytometric analysis. In addition, the antibacterial activity spectrum and effects of growth conditions of the two drugs were delineated by MIC determination.
RESULTS
The study identified 17 nonantibiotic library members with synergistic or additive potential, including caspofungin and tolcapone. Further analyses revealed that the respective medications for invasive candidiasis and Parkinson disease were bactericidal and bacteriostatic inhibitors of S. aureus growth. Flow cytometric analysis of viability further demonstrated that caspofungin in combination with vancomycin increased MRSA cell death in an additive manner, whereas tolcapone appeared to suppress the bactericidal action of vancomycin.
CONCLUSION
Overall, this proof of concept study concluded that nonantibiotic drugs can alter the pharmacodynamic properties of vancomycin, with potential clinical implications in patients with a MRSA infection receiving medications for other medical conditions.
Topics: Caspofungin; Drug Synergism; Humans; Methicillin-Resistant Staphylococcus aureus; Staphylococcus aureus; Tolcapone; Vancomycin
PubMed: 32247076
DOI: 10.1016/j.jgar.2020.03.014 -
Parkinsonism & Related Disorders Apr 2001Tolcapone is a catechol-ortho-methyl-tranferase (COMT) inhibitor that increases the L-DOPA half-life and the duration of effect in Parkinson's disease. We investigated...
Tolcapone is a catechol-ortho-methyl-tranferase (COMT) inhibitor that increases the L-DOPA half-life and the duration of effect in Parkinson's disease. We investigated the effect of tolcapone on the plasma catecholamine levels. We measured plasma catecholamines 2h after the first daily dose of L-DOPA or L-DOPA+tolcapone while resting and 2 and 10min after standing. We also measured the pharmacokinetics of L-DOPA and 3-OM-DOPA and the clinical response to the medication for 6h after the early morning dose. The levels of dopamine, norepinephrine, adrenaline and total catecholamines significantly increased and 3-OM-DOPA decreased with tolcapone. We did not observe significant changes in the plasma L-DOPA levels at the doses of tolcapone used in this study. Tolcapone side effects included worsening of dyskinesia and psychosis, diarrhea and elevation of liver enzymes. Twenty-four-hour ambulatory recording of arterial blood pressure and heart rate did not reveal cardiovascular side effects in patients treated with tolcapone for less than 1year. Since adrenergic stimulation may increase the hepatotoxic potential of commonly used drugs, usually thought of as safe for the liver, we postulate that some of the already reported life threatening complications of tolcapone could be related to excessive adrenergic stimulation by high catecholamine levels caused by inhibition of COMT activity.
PubMed: 11248589
DOI: 10.1016/s1353-8020(00)00027-4 -
Experimental and Therapeutic Medicine Jan 2018The aim of the study was to investigate the efficacy of homemade tolcapone in treatment of patients with Parkinson's disease (PD). Eighty patients with PD were subjected...
The aim of the study was to investigate the efficacy of homemade tolcapone in treatment of patients with Parkinson's disease (PD). Eighty patients with PD were subjected to randomized, double-blind, placebo-controlled and parallel-group study. PD patients were randomly divided into the tolcapone treatment group (41 cases) and placebo group (39 cases). Each patient received 1 pill of tolcapone or placebo, 3 times per day for 26 weeks. Efficacy was evaluated using the internationally used unified Parkinson's disease rating scale (UPDRS) scoring system for PD symptoms. After the treatment for 26 weeks, the cognitive function, tremor, muscle stiffness, voluntary movement and autonomic nerve symptoms were compared between the two groups using UPDRS scores. Compared with the placebo group, cognitive function, muscle stiffness and voluntary movement reduction were significantly improved in patients of the tolcapone group (P<0.05). However, no significant differences in UPDRS scores of autonomic nerve symptoms and tremor were found between two groups after treatment (P>0.05). Tolcapone, a catechol--methyl transferase (COMT) inhibitor, can improve the motor function of patients with PD, especially exercise and muscle stiffness. Tolcapone can also improve the cognitive function of patients.
PubMed: 29375679
DOI: 10.3892/etm.2017.5377 -
Archives of Gerontology and Geriatrics 2010Efficacy of the long-acting catechol-O-methyltransferase (COMT)-inhibitor, tolcapone on sleep quality was studied in 61 patients with advanced PD in a prospective... (Clinical Trial)
Clinical Trial
Efficacy of the long-acting catechol-O-methyltransferase (COMT)-inhibitor, tolcapone on sleep quality was studied in 61 patients with advanced PD in a prospective open-label multicenter non-interventional trial. Main outcome measures were the PD sleep scale (PDSS). Further outcome measures were global clinical impression of change (GCI-C), daily off-time, activities of daily living (UPDRS part II), quality of life (EuroQoL-5D), Epworth sleepiness scale (ESS) and adverse events reports. All efficiency and safety parameters were assessed 4 weeks after the switch to tolcapone and compared to baseline. The mean±S.D. daily dose of tolcapone was 294.2±36.9 mg/day at the final assessment. The mean PDSS scores significantly improved from 21.6±8.1 at baseline to 16.3±7.7 at final assessment (p<0.0001). Consistently, daytime sleepiness was significantly reduced as reflected by lower scores on the ESS (p=0.0057). Further efficacy parameters including GCI-C, daily off-time, activities of daily living, and quality of life were also significantly improved. Tolcapone was in general well tolerated and safe. This observational study provides first evidence that tolcapone improves sleep quality and reduces daytime sleepiness in patients suffering from advanced PD.
Topics: Activities of Daily Living; Adult; Aged; Aged, 80 and over; Antiparkinson Agents; Benzophenones; Female; Germany; Humans; Male; Middle Aged; Nitrophenols; Parkinson Disease; Prospective Studies; Quality of Life; Sleep Wake Disorders; Statistics, Nonparametric; Tolcapone; Treatment Outcome
PubMed: 20381177
DOI: 10.1016/j.archger.2010.03.008 -
Drug Testing and Analysis Apr 2019The metabolism of the masking agent tolcapone in the horse has been investigated. This substance was found to have undergone various chemical transformations that...
The metabolism of the masking agent tolcapone in the horse has been investigated. This substance was found to have undergone various chemical transformations that produced a large variety of phase I metabolites, as well as glucuronide and sulfate conjugation. Confirmation of the presence of tolcapone and the 3-O-methylated metabolite in the blood samples collected up to 240 minutes and in urine obtained up to 24 hours, was successfully conducted using both gas chromatography- and liquid chromatography-tandem mass spectrometry techniques. The 3-O-methyl tolcapone is the better marker to use in a screening method because, in comparison to tolcapone, we have found that this substance offers superior chromatographic performance that should potentially give a lower limit of detection.
Topics: Animals; Catechol O-Methyltransferase Inhibitors; Chromatography, High Pressure Liquid; Drug Monitoring; Gas Chromatography-Mass Spectrometry; Horses; Methylation; Substance Abuse Detection; Tolcapone
PubMed: 30367738
DOI: 10.1002/dta.2531 -
Nature Communications Feb 2016Transthyretin (TTR) is a plasma homotetrameric protein implicated in fatal systemic amyloidoses. TTR tetramer dissociation precedes pathological TTR aggregation. Native...
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 T4 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.
Topics: Administration, Oral; Amyloid Neuropathies, Familial; Animals; Benzophenones; Catechol O-Methyltransferase Inhibitors; Cell Line; Dimerization; Drug Repositioning; Healthy Volunteers; Humans; Mice, Transgenic; Middle Aged; Nitrophenols; Prealbumin; Protein Aggregation, Pathological; Tolcapone
PubMed: 26902880
DOI: 10.1038/ncomms10787 -
American Journal of Health-system... Aug 2000
Topics: Benzophenones; Catechol O-Methyltransferase Inhibitors; Enzyme Inhibitors; Humans; Methylation; Nitrophenols; Tolcapone
PubMed: 10965399
DOI: 10.1093/ajhp/57.16.1534