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Acta Medica Okayama Feb 2002Parkinson's disease (PD) is one of the main causes of neurological disability in the elderly. Levodopa is the gold standard for treating this disease, but chronic... (Review)
Review
Parkinson's disease (PD) is one of the main causes of neurological disability in the elderly. Levodopa is the gold standard for treating this disease, but chronic levodopa therapy is complicated by motor fluctuation and dyskinesia. The catechol-O-methyltransferase (COMT) inhibitors represent a new class of antiparkinsonian drugs. When coadministered with levodopa/decarboxylase inhibitor, 2 COMT inhibitors, tolcapone and entacapone have been shown to improve the clinical benefit of levodopa. COMT activity is genetically polymorphic, and individuals with the low activity (COMT(L/L)) genotype have a thermolabile COMT protein; studies suggest that this genotype is less common in Asians than in Caucasians. Differences in COMT activity may determine the individual response to levodopa and result in ethnic differences in PD susceptibility. Our recent study suggests that the COMTL allele can interact with the MAOB gene to increase the occurrence of PD in Taiwanese. In order to understand this new class of antiparkinsonian drugs, we review their basic properties, pharmacology, and clinical efficacy. The frequency distribution of COMT genetic polymorphisms among different populations and its implications in the etiology and drug response is also discussed.
Topics: Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Enzyme Inhibitors; Genetic Predisposition to Disease; Humans; Parkinson Disease
PubMed: 11873938
DOI: 10.18926/AMO/31725 -
Neuropsychiatric Disease and Treatment 2022COMT (catechol--methyltransferase) inhibitors are key therapeutic agents in the management of motor fluctuations (MF) in patients with Parkinson's disease (PD). As... (Review)
Review
COMT (catechol--methyltransferase) inhibitors are key therapeutic agents in the management of motor fluctuations (MF) in patients with Parkinson's disease (PD). As levodopa/DDCI add-on therapy, their main benefit lies in increasing ON-time and reducing OFF-time for PD patients in the middle stages of the disease. Two of the three available COMT inhibitors, tolcapone and entacapone, have been approved for over two decades. Opicapone, a third-generation COMT inhibitor approved in 2016, was designed with the aim of overcoming specific challenges of the earlier generation compounds, specifically hepatotoxicity and short effect duration. This review aims at highlighting the specific properties and characteristics of opicapone, namely combining efficacy with good tolerability as demonstrated in the registration studies and since then confirmed under real-world conditions. Opicapone has been shown to be effective in patients with early, as well as late motor fluctuations. Whilst patients in the earlier Hoehn and Yahr stages benefit more than patients in later stages, the incidence of dyskinesia in patients with recent onset MF is around half that of patients with more established fluctuations. With the added advantage of a once-daily administration, this particular COMT inhibitor provides a simple, yet effective therapy for patients with Parkinson's disease and MF.
PubMed: 35968514
DOI: 10.2147/NDT.S279362 -
Clinical Interventions in Aging 2009Levodopa has been the gold standard therapy for the motor symptoms of Parkinson's disease for more than three decades. Although it remains the most effective treatment,... (Review)
Review
Levodopa has been the gold standard therapy for the motor symptoms of Parkinson's disease for more than three decades. Although it remains the most effective treatment, its long-term use is associated with motor fluctuations and dyskinesias that can be disabling for patients and difficult for physicians to manage medically. In the last 10 years, the catechol-O-methyltransferase (COMT) inhibitor tolcapone has been studied for its efficacy as an adjunctive treatment to levodopa plus a dopa decarboxylase inhibitor. Adjunctive therapy with tolcapone can significantly reduce the dose of levodopa required. Moreover, treatment with tolcapone significantly reduces wearing off and on-off periods in fluctuating patients and improves 'on' time in patients with stable disease. Tolcapone has assumed a new place in the arsenal of medications for Parkinson's disease. This paper reviews the pharmacology, safety and efficacy of tolcapone in patients with advanced Parkinson's disease. After some initial concerns about its safety, tolcapone has been shown to be safe if used and monitored according to guidelines regarding liver function. Tolcapone produces expected dopaminergic side effects, including headache, nausea, insomnia, as well as diarrhea; however, these side effects are generally mild and as a rule do not result in discontinuation of therapy.
Topics: Antiparkinson Agents; Benzophenones; Drug-Related Side Effects and Adverse Reactions; Humans; Levodopa; Nitrophenols; Parkinson Disease; Tolcapone; Treatment Outcome
PubMed: 19503773
DOI: 10.2147/cia.s3787 -
European Journal of Clinical... Jun 2021Tolcapone is an efficacious catechol-O-methyltransferase inhibitor for Parkinson's disease (PD). However, safety issues hampered its use in clinical practice. We aimed...
PURPOSE
Tolcapone 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.
METHODS
We 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.
RESULTS
Thirty-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.
CONCLUSION
Literature 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.
Topics: Antiparkinson Agents; Catechol O-Methyltransferase Inhibitors; Chemical and Drug Induced Liver Injury; Humans; Levodopa; Liver Function Tests; Parkinson Disease; Quality of Life; Randomized Controlled Trials as Topic; Severity of Illness Index; Tolcapone
PubMed: 33415500
DOI: 10.1007/s00228-020-03081-x -
Journal of Alzheimer's Disease : JAD 2020There are currently no disease-targeted treatments for cognitive or behavioral symptoms in patients with behavioral variant frontotemporal dementia (bvFTD). (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
There are currently no disease-targeted treatments for cognitive or behavioral symptoms in patients with behavioral variant frontotemporal dementia (bvFTD).
OBJECTIVE
To determine the effect of tolcapone, a specific inhibitor of Catechol-O-Methyltransferase (COMT), in patients with bvFTD.
METHODS
In this randomized, double-blind, placebo-controlled, cross-over study at two study sites, we examined the effect of tolcapone on 28 adult outpatients with bvFTD. The primary outcome was reaction time on the N-back cognitive test. As an imaging outcome, we examined differences in the resting blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) signal intensity between subjects on placebo versus tolcapone performing the N-back test. Secondary outcomes included measures of cognitive performance and behavioral disturbance using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Neuropsychiatric Inventory-Questionnaire (NPI-Q), and Clinical Global Impressions scale (CGI).
RESULTS
Tolcapone was well tolerated and no patients dropped out. The most frequent treatment-related adverse event during tolcapone treatment was elevated liver enzymes (21%). There were no significant differences between tolcapone treatment and placebo in the primary or imaging outcomes. However, there were significant differences between RBANS total scores (p < 0.01), NPI-Q total scores (p = 0.04), and CGI total scores (p = 0.035) between treatment conditions which were driven by differences between baseline and tolcapone conditions. Further, there was a trend toward significance between tolcapone and placebo on the CGI (p = 0.078).
CONCLUSIONS
Further study of COMT inhibition and related approaches with longer duration of treatment and larger sample sizes in frontotemporal lobar degeneration-spectrum disorders may be warranted.
Topics: Aged; Aged, 80 and over; Behavioral Symptoms; Brain; Catechol O-Methyltransferase Inhibitors; Cognition; Cross-Over Studies; Double-Blind Method; Female; Frontotemporal Dementia; Humans; Male; Middle Aged; Tolcapone; Treatment Outcome
PubMed: 32444540
DOI: 10.3233/JAD-191265 -
Healthcare (Basel, Switzerland) Apr 2023Temporal discounting is a phenomenon where a reward loses its value as a function of time (e.g., a reward is more valuable immediately than when it delays in time). This... (Review)
Review
Temporal discounting is a phenomenon where a reward loses its value as a function of time (e.g., a reward is more valuable immediately than when it delays in time). This is a type of intertemporal decision-making that has an association with impulsivity and self-control. Many pathologies exhibit higher discounting rates, meaning they discount more the values of rewards, such as addictive behaviors, bipolar disorder, attention-deficit/hyperactivity disorders, social anxiety disorders, and major depressive disorder, among others; thus, many studies look for the mechanism and neuromodulators of these decisions. This systematic review aims to investigate the association between pharmacological administration and changes in temporal discounting. A search was conducted in PubMed, Scopus, Web of Science, Science Direct and Cochrane. We used the PICO strategy: healthy humans (P-Participants) that received a pharmacological administration (I-Intervention) and the absence of a pharmacological administration or placebo (C-Comparison) to analyze the relationship between the pharmacological administration and the temporal discounting (O-outcome). Nineteen studies fulfilled the inclusion criteria. The most important findings were the involvement of dopamine modulation in a U-shape for choosing the delayed outcome (metoclopradime, haloperidol, and amisulpride). Furthermore, administration of tolcapone and high doses of d-amphetamine produced a preference for the delayed option. There was a time-dependent hydrocortisone effect in the preference for the immediate reward. Thus, it can be concluded that dopamine is a crucial modulator for temporal discounting, especially the D2 receptor, and cortisol also has an important time-dependent role in this type of decision. One of the limitations of this systematic review is the heterogeneity of the drugs used to assess the effect of temporal discounting.
PubMed: 37046974
DOI: 10.3390/healthcare11071046 -
Journal of Experimental Pharmacology 2020Treatment-resistance is a frequent condition for obsessive-compulsive disorder (OCD). Over the past decades, a lot of effort has been made to address this issue, and... (Review)
Review
Treatment-resistance is a frequent condition for obsessive-compulsive disorder (OCD). Over the past decades, a lot of effort has been made to address this issue, and several augmentation strategies of serotonergic drugs have been investigated. Antidopaminergic drugs are considered the first choice as augmentation strategy for treatment-resistant OCD patients, but they seem to work only for a subset of patients, and none of them have been officially approved for OCD. Recently, the role of glutamate and inflammation in OCD pathophysiology clearly emerged, and this has led to several investigations on glutamatergic and anti-inflammatory agents. Results seem promising but still inconclusive. Probiotic interventions (considered to modulate the immune systems and the brain activity) are gaining attention in several psychiatric fields but are still at their early stages in the OCD field. Research on new treatment approaches for OCD is moving forward, and more than one hundred interventional trials are ongoing around the world. While the vast majority of these trials involve neuromodulation and psychotherapeutic approaches, only a small proportion (around 20%) involve the investigation of new pharmacological approaches (tolcapone, nabilone, psilocybin, troriluzole, nitrous oxide, rituximab, naproxen, and immunoglobulins). Here, we provide a comprehensive review of investigational and experimental drugs to treat OCD.
PubMed: 33447096
DOI: 10.2147/JEP.S255375 -
Frontiers in Microbiology 2020Ebola virus (EBOV), the causative pathogen of the deadly EBOV disease (EVD), can be transmitted sexual transmission. Seminal amyloid fibrils have been found enhancers...
Ebola virus (EBOV), the causative pathogen of the deadly EBOV disease (EVD), can be transmitted sexual transmission. Seminal amyloid fibrils have been found enhancers of EBOV infection. Currently, limited preventive vaccine or therapeutic is available to block EBOV infection through sexual intercourse. In this study, we repurpose tolcapone, a US Food and Drug Administration (FDA)-approved agent for Parkinson's disease, as a potent inhibitor of seminal amyloid fibrils, among which semen-derived enhancer of viral infection (SEVI) is the best-characterized. Tolcapone binds to the amyloidogenic region of the SEVI precursor peptide (PAP248-286) and inhibits PAP248-286 aggregation by disrupting PAP248-286 oligomerization. In addition, tolcapone interacts with preformed SEVI fibrils and influences the activity of SEVI in promoting infection of pseudovirus (PsV) carrying the envelope glycoprotein (GP) of the EBOV Zaire or Sudan species (Zaire PsV and Sudan PsV, respectively). Tolcapone significantly antagonizes SEVI-mediated enhancement of both Zaire PsV and Sudan PsV binding to and subsequent internalization in HeLa cells. Of note, tolcapone is also effective in inhibiting the entry of both Zaire PsV and Sudan PsV. Tolcapone inhibits viral entry possibly through binding with critical residues in EBOV GP. Moreover, the combination of tolcapone with two small-molecule entry inhibitors, including bepridil and sertraline, exhibited synergistic anti-EBOV effects in semen. Collectively, as a bifunctional agent targeting the viral infection-enhancing amyloid and the virus itself during sexual intercourse, tolcapone can act as either a prophylactic topical agent to prevent the sexual transmission of EBOV or a therapeutic to treat EBOV infection.
PubMed: 32425892
DOI: 10.3389/fmicb.2020.00504 -
Psychiatria Danubina Mar 2009The first effective drugs for Parkinson's disease (PD) were anticholinergics, introduced at the end of 19.th century by Charcot. Since the introduction of levodopa in... (Comparative Study)
Comparative Study Review
The first effective drugs for Parkinson's disease (PD) were anticholinergics, introduced at the end of 19.th century by Charcot. Since the introduction of levodopa in the sixties of the previous century, many new drugs have emerged for the treatment of Parkinson's disease: dopamine agonists (ergot as well as non-ergot, bromocriptine, pergolide, mirapexine, ropinirole), MAO B inhibitors (selegiline, rasagiline), amantadine, COMT inhibitors (entacapone, tolcapone). In all stages of the disease, levodopa remains the most effective drug for improving motor symptoms in PD. However, long term treatment with levodopa is accompanied by the development of motor fluctuations, dyskinesia, cognitive and neuropsychiatric adverse effects and increasingly diverse spectrum of drugs is needed to alleviate motor and nonmotor symptoms. Some of these drugs have caused considerable concern and controversies and were regarded at certain points as the 'bad guys' of Parkinson's disease pharmacological armamentarium. In the article, a short review of 'bad guys' including anticholinergics, selegiline, tolcapone and dopamine agonists, is given.
Topics: Antiparkinson Agents; Benzophenones; Cholinergic Antagonists; Cognition; Dopamine Agonists; Humans; Levodopa; Nitrophenols; Parkinson Disease; Randomized Controlled Trials as Topic; Selegiline; Survival Rate; Tolcapone; Treatment Outcome
PubMed: 19270634
DOI: No ID Found -
The International Journal of... Dec 2017Failure of procognitive drug trials in schizophrenia may reflect the clinical heterogeneity of schizophrenia, underscoring the need to identify biomarkers of treatment... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Failure of procognitive drug trials in schizophrenia may reflect the clinical heterogeneity of schizophrenia, underscoring the need to identify biomarkers of treatment sensitivity. We used an experimental medicine design to test the procognitive effects of a putative procognitive agent, tolcapone, using an electroencephalogram-based cognitive control task in healthy subjects.
METHODS
Healthy men and women (n=27; ages 18-35 years), homozygous for either the Met/Met or Val/Val rs4680 genotype, received placebo and tolcapone 200 mg orally across 2 test days separated by 1 week in a double-blind, randomized, counterbalanced, within-subject design. On each test day, neurocognitive performance was assessed using the MATRICS Consensus Cognitive Battery and an electroencephalogram-based 5 Choice-Continuous Performance Test.
RESULTS
Tolcapone enhanced visual learning in low-baseline MATRICS Consensus Cognitive Battery performers (d=0.35) and had an opposite effect in high performers (d=0.5), and enhanced verbal fluency across all subjects (P=.03) but had no effect on overall MATRICS Consensus Cognitive Battery performance. Tolcapone reduced false alarm rate (d=0.8) and enhanced frontal P200 amplitude during correctly identified nontarget trials (d=0.6) in low-baseline 5 Choice-Continuous Performance Test performers and had opposite effects in high performers (d=0.5 and d=0.25, respectively). Tolcapone's effect on frontal P200 amplitude and false alarm rate was correlated (rs=-0.4, P=.05). All neurocognitive effects of tolcapone were independent of rs4680 genotype.
CONCLUSION
Tolcapone enhanced neurocognition and engaged electroencephalogram measures relevant to cognitive processes in specific subgroups of healthy individuals. These findings support an experimental medicine model for identifying procognitive treatments and provide a strong basis for future biomarker-informed procognitive studies in schizophrenia patients.
Topics: Adolescent; Adult; Benzophenones; Brain; Brain Mapping; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Choice Behavior; Cognition; Cross-Over Studies; Double-Blind Method; Evoked Potentials; Female; Genotype; Healthy Volunteers; Humans; Learning; Male; Neuropsychological Tests; Nitrophenols; Photic Stimulation; Tolcapone; Young Adult
PubMed: 29020372
DOI: 10.1093/ijnp/pyx074