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Thomas Müller - One of the best experts on this subject based on the ideXlab platform.
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effects of comt genotype and Tolcapone on lapses of sustained attention after sleep deprivation in healthy young men
Neuropsychopharmacology, 2018Co-Authors: Amandine Valomon, Michael Sommerauer, Christian R. Baumann, Thomas Müller, Sebastian C Holst, Alessandro Borrello, Susanne Weigend, Wolfgang Berger, Hans-peter LandoltAbstract:Tolcapone, a brain penetrant selective inhibitor of catechol-O-methyltransferase (COMT) devoid of psychostimulant properties, improves cognition and cortical information processing in rested volunteers, depending on the genotype of the functional Val158Met polymorphism of COMT. The impact of this common genetic variant on behavioral and neurophysiological markers of increased sleep need after sleep loss is controversial. Here we investigated the potential usefulness of Tolcapone to mitigate consequences of sleep deprivation on lapses of sustained attention, and tested the hypothesis that dopamine signaling in the prefrontal cortex (PFC) causally contributes to neurobehavioral and neurophysiological markers of sleep homeostasis in humans. We first quantified in 73 young male volunteers the impact of COMT genotype on the evolution of attentional lapses during 40 h of extended wakefulness. Subsequently, we tested in an independent group of 30 young men whether selective inhibition of COMT activity with Tolcapone counteracts attentional and neurophysiological markers of elevated sleep need in a genotype-dependent manner. Neither COMT genotype nor Tolcapone affected brain electrical activity in wakefulness and sleep. By contrast, COMT genotype and Tolcapone modulated the sleep loss-induced impairment of vigilant attention. More specifically, Val/Met heterozygotes produced twice as many lapses after a night without sleep than Met/Met homozygotes. Unexpectedly, Tolcapone further deteriorated the sleep loss-induced performance deficits when compared to placebo, particularly in Val/Met and Met/Met genotypes. The findings suggest that PFC dopaminergic tone regulates sustained attention after sleep loss according to an inverse U-shape relationship, independently of neurophysiological markers of elevated sleep need.
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Genotype-dependent deterioration of sustained attention by the COMT inhibitor Tolcapone after sleep deprivation
European Neuropsychopharmacology, 2018Co-Authors: Sebastian C Holst, Michael Sommerauer, Christian R. Baumann, Thomas Müller, Amandine Valomon, Alessandro Borrello, Susanne Weigend, Wolfgang Berger, Hans-peter LandoltAbstract:Introduction Elevated sleepiness and impaired vigilance due to medical disorders, is often treated by drugs that enhance dopaminergic neurotransmission, including modafinil, caffeine or cocaine [1]. Tolcapone is a brain penetrant selective inhibitor of catechol-O-methyltransferase (COMT) devoid of psychostimulant properties that leads to relatively specific increases in prefrontal cortex (PFC) dopamine signaling [2,3]. Because it hardly affects striatal domapinergic transmission, Tolcapone may mitigate subjective and behavioral consequences of sleep deprivation without unwanted psychostimulant adverse effects [2]. Tolcapone also improves cognition and cortical information processing in rested volunteers, depending on the genotype of the functional Val158Met polymorphism of COMT [3]. The impact of this common genetic variant for efficient treatment of hypersomnolence and behavioral markers of increased sleep need after sleep loss is controversial. Here we investigated the potential usefulness of Tolcapone to mitigate consequences of sleep deprivation on lapses of sustained attention, and tested the hypothesis that dopamine signaling in the prefrontal cortex (PFC) causally contributes to neurobehavioral and neurophysiological markers of human sleep homeostasis. Methods We first quantified the impact of COMT genotype (SNP-Id: rs4680) on the evolution of attentional lapses during two days of extended wakefulness in a non-Tolcapone treated group of 73 volunteers. Subsequently, in an independent group of 30 healthy male study participants, we tested whether selective inhibition of COMT activity by Tolcapone counteracts attentional and neurophysiological markers of elevated sleep need in a COMT genotype-dependent manner. 2 x 100 mg Tolcapone were administered after 11 and 23 hours, in a randomized, double-blind, placebo-controlled, cross-over design. The psychomotor Vigilance Test (PVT) and objective electroencephalogram (EEG) recordings were carried out in three-hour intervals among all 103 volunteers across the 40 hours of prolonged wakefulness. Repeated measure linear mixed-models were applied, followed by multiple comparison corrected post-hoc testing when appropriate. Results Both COMT genotype and Tolcapone modulated the sleep-loss induced impairment of vigilant attention. More specifically, data from the non-Tolcapone treated group revealed that Val/Met heterozygotes produced twice as many lapses after a night without sleep compared to Met/Met homozygotes (p Conclusions The current results demonstrate that PFC dopaminergic neurotransmission regulates attentional lapses during sleep deprivation without changing neurophysiological markers of sleep homeostasis. Intriguingly, selective inhibition of COMT can even reverse the expected beneficial effects of pharmacologically enhanced dopaminergic tone after prolonged wakefulness. These findings may have important implications, given the increased use of stimulants in healthy people aimed at improving vigilance and cognitive functions [1,4].
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Tolcapone addition improves Parkinson’s disease associated nonmotor symptoms
SAGE Publishing, 2014Co-Authors: Thomas MüllerAbstract:Background: Addition of catechol-O-methyltransferase inhibitors to a conventional levodopa/dopadecarboxylase inhibitor regimen improves motor symptoms in patients with Parkinson’s disease. Optimizing dopamine substitution is also beneficial for nonmotor features. Objectives: To investigate the efficacy of supplemental Tolcapone intake on nonmotor symptoms. Design/methods: A total of 125 levodopa-treated patients additionally took Tolcapone in this observational trial. Initially and following 4 weeks of Tolcapone intake, the neurologist scored with Unified Parkinson’s Disease Rating Scale parts I, II, IV, the nonmotor symptoms scale for Parkinson’s disease and recorded the off time. The patients rated themselves with the EuroQuol, its visual analogue scale and the nonmotor screening questionnaire. Caregivers reported the daily duration of care giving. Results: All scores improved except for Unified Parkinson’s Disease Rating Scale part IV and domains 4, 5 and 8 of the nonmotor symptoms scale for Parkinson’s disease. Conclusion: This trial demonstrates that Tolcapone addition may improve nonmotor features
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Tolcapone addition improves Parkinson's disease associated nonmotor symptoms.
Therapeutic Advances in Neurological Disorders, 2013Co-Authors: Thomas MüllerAbstract:BACKGROUND Addition of catechol-O-methyltransferase inhibitors to a conventional levodopa/dopadecarboxylase inhibitor regimen improves motor symptoms in patients with Parkinson's disease. Optimizing dopamine substitution is also beneficial for nonmotor features. OBJECTIVES To investigate the efficacy of supplemental Tolcapone intake on nonmotor symptoms. DESIGN/METHODS A total of 125 levodopa-treated patients additionally took Tolcapone in this observational trial. Initially and following 4 weeks of Tolcapone intake, the neurologist scored with Unified Parkinson's Disease Rating Scale parts I, II, IV, the nonmotor symptoms scale for Parkinson's disease and recorded the off time. The patients rated themselves with the EuroQuol, its visual analogue scale and the nonmotor screening questionnaire. Caregivers reported the daily duration of care giving. RESULTS All scores improved except for Unified Parkinson's Disease Rating Scale part IV and domains 4, 5 and 8 of the nonmotor symptoms scale for Parkinson's disease. CONCLUSION This trial demonstrates that Tolcapone addition may improve nonmotor features.
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Tolcapone in the management of Parkinson’s disease
Aging Health, 2006Co-Authors: Thomas MüllerAbstract:Adjunction of Tolcapone, the peripheral and centrally active catechol-O-methyltransferase inhibitor to levodopa/decarboxylase inhibitor improves the symptoms of Parkinson’s disease due to a prolonged elimination of levodopa. Thus, Tolcapone 100 mg three-times daily improves levodopa-associated motor complications, particularly off periods but not dyskinesias, and reduces oral levodopa requirements. The drug is generally well tolerated, and the most common side effects are dopamine-related. Thus, Tolcapone represents a useful option in Parkinson’s disease patients who receive levodopa/decarboxylase inhibitors and do not respond to or are not candidates for other additional treatments. Since Tolcapone was associated with fatal hepatic failure, it was temporarily withdrawn almost worldwide, but it is now available again with stringent liver function monitoring guidelines.
Jennifer M. Mitchell - One of the best experts on this subject based on the ideXlab platform.
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The catechol-O-methyltransferase inhibitor Tolcapone modulates alcohol consumption and impulsive choice in alcohol use disorder
Psychopharmacology, 2020Co-Authors: Allison R. Coker, Dawn N. Weinstein, Taylor A. Vega, Catriona S. Miller, Andrew S. Kayser, Jennifer M. MitchellAbstract: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: NCT 02740582
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The catechol-O-methyltransferase inhibitor Tolcapone modulates alcohol consumption and impulsive choice in alcohol use disorder.
Psychopharmacology, 2020Co-Authors: Allison R. Coker, Catriona S. Miller, Andrew S. Kayser, Dawn Weinstein, Taylor Vega, Jennifer M. MitchellAbstract: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. 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. 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. 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. These data demonstrate that COMT inhibitors such as Tolcapone may be useful therapeutics for AUD. ClinicalTrials.gov Identifier: NCT 02740582
Karin Jorga - One of the best experts on this subject based on the ideXlab platform.
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Effect of Tolcapone on the haemodynamic effects and tolerability of desipramine.
European Neurology, 2000Co-Authors: Karin Jorga, Bärbel Fotteler, M. Modi, M. RabbiaAbstract:Background and Purpose: To determine the changes in haemodynamics, tolerability and pharmacokinetics that may occur when a combination of Tolcapone and levodopa/carbidopa are given with desipramine. Methods: In a crossover study, 22 healthy subjects received desipramine during two 13-day treatment periods (25 mg t.i.d. for 3 days and 50 mg t.i.d. for 10 days), with a washout period of 10–15 days. Subjects received levodopa/carbidopa (100 mg/25 mg t.i.d. for 5 days, days 9–13) and concomitant, double-blind, randomized treatment with either Tolcapone (200 mg t.i.d.) or placebo. Results: No significant pharmacodynamic and pharmacokinetic interactions occurred between Tolcapone and desipramine. Adverse events were predictable based on the known effects of the individual drugs. Conclusions: Tolcapone can be combined with levodopa/carbidopa and desipramine in patients with Parkinson’s disease.
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Lack of interaction between Tolcapone and tolbutamide in healthy volunteers.
The Journal of Clinical Pharmacology, 2000Co-Authors: Karin Jorga, Bärbel Fotteler, Rodolfo Gasser, Ludger Banken, Herbert BirnboeckAbstract:To assess the effect of Tolcapone (an inhibitor of cytochrome P450 [CYP] 2C9 in vitro) on the pharmacokinetics and hypoglycemic effect of the CYP 2C9 substrate tolbutamide, 12 healthy male volunteers were randomized to receive a single dose of tolbutamide 500 mg plus either placebo or Tolcapone 200 mg after an overnight fast and 30 minutes after the start of a 6.5-hour 5% glucose infusion (150 mL/h). The participants crossed over to receive the alternative regimen after a washout period of at least 7 days. Tolcapone had no effect on the pharmacokinetics of tolbutamide or its metabolites and did not influence the effect of tolbutamide on plasma glucose concentrations. No serious adverse events or abnormal laboratory results or vital signs were reported. In conclusion, clinically relevant drug-drug interactions between Tolcapone and tolbutamide when given together in clinical practice appear unlikely.
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COMT inhibition with Tolcapone does not affect carbidopa pharmacokinetics in parkinsonian patients in levodopa/carbidopa (Sinemet).
British Journal of Clinical Pharmacology, 1999Co-Authors: Karin Jorga, David J. NichollAbstract:AIMS Tolcapone is a novel catechol-O-methyltransferase (COMT) inhibitor used as an adjunct to levodopa/carbidopa or levodopa/benserazide therapy to improve treatment of Parkinson's disease. The aim of the current study was to investigate the potential effect of Tolcapone on the pharmacokinetics of carbidopa. METHODS This was an open-label study in 12 parkinsonian patients receiving optimal levodopa/carbidopa therapy and Tolcapone 200 mg three times daily for 6 weeks. Blood samples were taken at baseline (i.e. before the first Tolcapone intake) and after 1-2 weeks and 6 weeks so that carbidopa pharmacokinetics before and during Tolcapone treatment could be assessed. RESULTS No changes in any pharmacokinetic parameters of carbidopa were observed. The mean AUC(0,tau) and Cmax values at baseline were 0.39 microg ml-1 h and 0. 14 microg ml-1, respectively. During Tolcapone treatment these values were on average 0.35 microg ml-1 h (AUC(0,tau), week 1-2), 0. 34 microg ml-1 h (AUC(0,tau), week 6 and 0.13 microg ml-1 (Cmax, weeks 1-2 and 6). tmax remained unchanged (approx. 2 h). CONCLUSIONS These results indicate that Tolcapone does not affect carbidopa elimination and that no interaction of any clinical relevance occurs between Tolcapone and carbidopa.
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The effect of Tolcapone on the pharmacokinetics of benserazide.
European Journal of Neurology, 1999Co-Authors: Karin Jorga, Bärbel Fotteler, Monique Schmitt, Jan Petter Larsen, Antonie Giæver Beiske, Michael Schleimer, Brit MoeAbstract:This study investigated the potential interaction between Tolcapone, a catechol-O-methyltransferase (COMT) inhibitor, and the decarboxylase inhibitor, benserazide. In an open-labelled six-week study, patients with Parkinson's disease (PD), treated with levodopa/benserazide, were given Tolcapone at 200 mg t.i.d. Blood samples for analysis of benserazide, its main active metabolite, trihydroxybenzylhydrazine, levodopa and 3-O- methyldopa (3-OMD) were collected immediately before and repeatedly after the first drug intake of the day at baseline and after 1-2 and 6 weeks of treatment. Furthermore, animal experiments were performed to determine the levels of benserazide and trihydroxybenzylhydrazine at doses for which safety had previously been established. It was shown that Tolcapone can cause an increase in benserazide plasma concentrations and that this effect is dependent on the benserazide dose. When Tolcapone was combined with 25 mg benserazide the elevation was small. Although the increase was more pronounced when Tolcapone was combined with 50 mg benserazide, the levels were still substantially lower than concentrations causing toxicity in animals. The safety margin derived from this study, together with the absence of any organic toxic effects in clinical trials, show that the observed interaction between Tolcapone and benserazide does not represent a safety concern for PD patients treated with this combination.
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The effect of Tolcapone on levodopa pharmacokinetics is independent of levodopa/carbidopa formulation.
Journal of Neurology, 1998Co-Authors: Karin Jorga, Bärbel Fotteler, Thorkild Nielsen, Greg Sedek, John AitkenAbstract:Clinical pharmacology studies have shown that the catechol-O-methyltransferase inhibitor Tolcapone increases the bioavailability area under the plasma concentration-time curve (AUC) and the plasma elimination half-life (t 1/2) of levodopa. The objective of the study was to evaluate the pharmacokinetics of levodopa and 3-O-methyldopa (3-OMD) after coadministration of Tolcapone 200 mg with levodopa/carbidopa in the following doses: 100/10 mg, 100/25 mg, 200/20 mg, 200/50 mg, 250/25 mg (all immediate-release) and 200/50 mg (controlled-release). Thirty healthy male volunteers were divided into four groups: three groups of 8 and one group of 6. Participants in the first three groups received two formulations of levodopa/carbidopa. Each dose was administered on two occasions, once with Tolcapone 200 mg andonce with placebo (four-way crossover). In the fourth group, one formulation was given on two occasions, once with Tolcapone 200 mg and oncewith placebo (two-way crossover). Dosing days were separated by a 7-day washout. The effect of Tolcapone on levodopa and 3-OMD pharmacokinetics was found to be similar with all levodopa/carbidopa formulations. The absorption of levodopa wasunaffected by Tolcapone in all treatment groups and the maximum plasma concentration (C max ) remained unchanged. When Tolcapone was given with the immediate-release formulations, levodopa AUC increased by 60–90% and levodopa t 1/2 by 20–60%. With Tolcapone and the controlled-release formulation, AUC increased by 80% and t 1/2 by 60%. With all levodopa/carbidopa formulations, 3-OMD C max decreased by 80% and AUC by 70% with Tolcapone. Thetolerability of all treatment combinations was similar. We conclude that adjunctive treatment with Tolcapone should have similar levodopa-potentiating clinical effects, regardless of the levodopa/carbidopa formulation.
Hans-peter Landolt - One of the best experts on this subject based on the ideXlab platform.
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effects of comt genotype and Tolcapone on lapses of sustained attention after sleep deprivation in healthy young men
Neuropsychopharmacology, 2018Co-Authors: Amandine Valomon, Michael Sommerauer, Christian R. Baumann, Thomas Müller, Sebastian C Holst, Alessandro Borrello, Susanne Weigend, Wolfgang Berger, Hans-peter LandoltAbstract:Tolcapone, a brain penetrant selective inhibitor of catechol-O-methyltransferase (COMT) devoid of psychostimulant properties, improves cognition and cortical information processing in rested volunteers, depending on the genotype of the functional Val158Met polymorphism of COMT. The impact of this common genetic variant on behavioral and neurophysiological markers of increased sleep need after sleep loss is controversial. Here we investigated the potential usefulness of Tolcapone to mitigate consequences of sleep deprivation on lapses of sustained attention, and tested the hypothesis that dopamine signaling in the prefrontal cortex (PFC) causally contributes to neurobehavioral and neurophysiological markers of sleep homeostasis in humans. We first quantified in 73 young male volunteers the impact of COMT genotype on the evolution of attentional lapses during 40 h of extended wakefulness. Subsequently, we tested in an independent group of 30 young men whether selective inhibition of COMT activity with Tolcapone counteracts attentional and neurophysiological markers of elevated sleep need in a genotype-dependent manner. Neither COMT genotype nor Tolcapone affected brain electrical activity in wakefulness and sleep. By contrast, COMT genotype and Tolcapone modulated the sleep loss-induced impairment of vigilant attention. More specifically, Val/Met heterozygotes produced twice as many lapses after a night without sleep than Met/Met homozygotes. Unexpectedly, Tolcapone further deteriorated the sleep loss-induced performance deficits when compared to placebo, particularly in Val/Met and Met/Met genotypes. The findings suggest that PFC dopaminergic tone regulates sustained attention after sleep loss according to an inverse U-shape relationship, independently of neurophysiological markers of elevated sleep need.
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Genotype-dependent deterioration of sustained attention by the COMT inhibitor Tolcapone after sleep deprivation
European Neuropsychopharmacology, 2018Co-Authors: Sebastian C Holst, Michael Sommerauer, Christian R. Baumann, Thomas Müller, Amandine Valomon, Alessandro Borrello, Susanne Weigend, Wolfgang Berger, Hans-peter LandoltAbstract:Introduction Elevated sleepiness and impaired vigilance due to medical disorders, is often treated by drugs that enhance dopaminergic neurotransmission, including modafinil, caffeine or cocaine [1]. Tolcapone is a brain penetrant selective inhibitor of catechol-O-methyltransferase (COMT) devoid of psychostimulant properties that leads to relatively specific increases in prefrontal cortex (PFC) dopamine signaling [2,3]. Because it hardly affects striatal domapinergic transmission, Tolcapone may mitigate subjective and behavioral consequences of sleep deprivation without unwanted psychostimulant adverse effects [2]. Tolcapone also improves cognition and cortical information processing in rested volunteers, depending on the genotype of the functional Val158Met polymorphism of COMT [3]. The impact of this common genetic variant for efficient treatment of hypersomnolence and behavioral markers of increased sleep need after sleep loss is controversial. Here we investigated the potential usefulness of Tolcapone to mitigate consequences of sleep deprivation on lapses of sustained attention, and tested the hypothesis that dopamine signaling in the prefrontal cortex (PFC) causally contributes to neurobehavioral and neurophysiological markers of human sleep homeostasis. Methods We first quantified the impact of COMT genotype (SNP-Id: rs4680) on the evolution of attentional lapses during two days of extended wakefulness in a non-Tolcapone treated group of 73 volunteers. Subsequently, in an independent group of 30 healthy male study participants, we tested whether selective inhibition of COMT activity by Tolcapone counteracts attentional and neurophysiological markers of elevated sleep need in a COMT genotype-dependent manner. 2 x 100 mg Tolcapone were administered after 11 and 23 hours, in a randomized, double-blind, placebo-controlled, cross-over design. The psychomotor Vigilance Test (PVT) and objective electroencephalogram (EEG) recordings were carried out in three-hour intervals among all 103 volunteers across the 40 hours of prolonged wakefulness. Repeated measure linear mixed-models were applied, followed by multiple comparison corrected post-hoc testing when appropriate. Results Both COMT genotype and Tolcapone modulated the sleep-loss induced impairment of vigilant attention. More specifically, data from the non-Tolcapone treated group revealed that Val/Met heterozygotes produced twice as many lapses after a night without sleep compared to Met/Met homozygotes (p Conclusions The current results demonstrate that PFC dopaminergic neurotransmission regulates attentional lapses during sleep deprivation without changing neurophysiological markers of sleep homeostasis. Intriguingly, selective inhibition of COMT can even reverse the expected beneficial effects of pharmacologically enhanced dopaminergic tone after prolonged wakefulness. These findings may have important implications, given the increased use of stimulants in healthy people aimed at improving vigilance and cognitive functions [1,4].
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Improved functional and histochemical outcomes in l-DOPA plus Tolcapone treated VMAT2-deficient mice.
Neuropharmacology, 1Co-Authors: Carlos G. Moreira, Marta Morawska, Aron Baumann, Sophie Masneuf, Michael Linnebank, Michael Sommerauer, Hans-peter Landolt, Daniela Noain, Christian R. BaumannAbstract:Abstract 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.
Allison R. Coker - One of the best experts on this subject based on the ideXlab platform.
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The catechol-O-methyltransferase inhibitor Tolcapone modulates alcohol consumption and impulsive choice in alcohol use disorder
Psychopharmacology, 2020Co-Authors: Allison R. Coker, Dawn N. Weinstein, Taylor A. Vega, Catriona S. Miller, Andrew S. Kayser, Jennifer M. MitchellAbstract: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: NCT 02740582
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The catechol-O-methyltransferase inhibitor Tolcapone modulates alcohol consumption and impulsive choice in alcohol use disorder.
Psychopharmacology, 2020Co-Authors: Allison R. Coker, Catriona S. Miller, Andrew S. Kayser, Dawn Weinstein, Taylor Vega, Jennifer M. MitchellAbstract: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. 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. 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. 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. These data demonstrate that COMT inhibitors such as Tolcapone may be useful therapeutics for AUD. ClinicalTrials.gov Identifier: NCT 02740582