- |||||||||| Comtan (entacapone) / Novartis, Orion Corp, Ongentys (opicapone) / Ono Pharma, Neurocrine, BIAL
PK/PD data, Review, Journal: Clinical pharmacokinetics of levodopa and relevant add-on therapies for Parkinson's disease. (Pubmed Central) - Nov 16, 2024
Opicapone induced higher levodopa plasma levels compared with the ones following application of levodopa/carbidopa alone or combined with entacapone or tolcapone. Co-administration of opicapone with its once daily intake regimen may support the efficacy of subcutaneous and intrajejunal levodopa infusions.
- |||||||||| tolcapone / Generic mfg., duloxetine / Generic mfg.
Trial completion date, Trial primary completion date: Microbiome Derived Metabolism and Pharmacokinetics (clinicaltrials.gov) - Nov 14, 2024
P1, N=14, Recruiting,
Co-administration of opicapone with its once daily intake regimen may support the efficacy of subcutaneous and intrajejunal levodopa infusions. Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Jun 2024 --> Dec 2025
- |||||||||| memantine / Generic mfg., tolcapone / Generic mfg.
Journal: Sleep deprivation-induced memory impairment: exploring potential interventions. (Pubmed Central) - Oct 23, 2024
Additionally, the emerging role of the gut-brain axis in sleep deprivation-induced memory impairment is examined, shedding light on the complex interplay between gut microbiota and cognitive functions. This comprehensive review explores the multifaceted relationship between sleep deprivation and memory impairment, delving into the neurobiological mechanisms underlying these processes and examining potential interventions.
- |||||||||| tolcapone / Generic mfg.
Journal: Discovery of a Potent, Selective, and Blood-Brain Barrier Permeable Non-nitrocatechol Inhibitor of Catechol-O-methyltransferase. (Pubmed Central) - Oct 7, 2024
A new library of non-nitrocatechol compounds (HetCAMs) was developed and their efficacy was compared to tolcapone, a standard COMT inhibitor for PD...Additionally, compound 9 is predicted to cross the blood-brain barrier (BBB) by passive diffusion and chelate divalent metals like Fe(II) and Cu(II). The results demonstrate the potential of this rational drug design strategy for developing new CNS-active drug candidates, offering symptom relief via COMT inhibition that can provide a long-term, disease-modifying outcome (chelation of divalent metals) in PD.
- |||||||||| Comtan (entacapone) / Novartis, Orion Corp
Preclinical, Journal: Modeling Lewy body disease with SNCA triplication iPSC-derived cortical organoids and identifying therapeutic drugs. (Pubmed Central) - Sep 11, 2024
Furthermore, we screened 1280 Food and Drug Administration-approved drugs and identified four candidates (entacapone, tolcapone, phenazopyridine hydrochloride, and zalcitabine) that inhibited ?-SYN seeding activity in real-time quaking-induced conversion assays with human brains, reduced ?-SYN aggregation, and alleviated mitochondrial dysfunction in SNCA triplication organoids and excitatory neurons. Our findings establish human cortical LBD models and suggest potential therapeutic drugs targeting ?-SYN aggregation for LBD.
- |||||||||| Ongentys (opicapone) / Ono Pharma, Neurocrine, BIAL
Opicapone Reduces Homocysteine Levels in Patients with Parkinson's Disease Treated with Levodopa Gel Infusion (Poster Hall (Exhibit Hall A)) - Aug 9, 2024 - Abstract #MDSCongress2024MDS_Congress_1051;
Opicapone might have the potential to reduce HCY plasmatic levels in patients with advanced PD treated by LCIG/CLES, probably by decreased peripheral conversion of levodopa to 3-O-methyldopa and, thus, also possibility to reduce the daily dose of LCIG/CLES. The change in homocysteine levels (in ?mol/l)
- |||||||||| Comtan (entacapone) / Novartis, Orion Corp
Review, Journal: The Catechol O-Methyltransferase (Pubmed Central) - May 29, 2024
Opicapone demonstrated effective control of motor symptoms and good tolerability in PD patients with EMF in routine clinical practice after 3 months. Subsequently, entacapone has been amalgamated into a triple-combination preparation (Stalevo
- |||||||||| ketoconazole / Generic mfg., tolcapone / Generic mfg.
Journal: Validating Well-Functioning Hepatic Organoids for Toxicity Evaluation. (Pubmed Central) - May 24, 2024
The organoids effectively distinguished between the toxicity levels of substances with and without hepatic toxicity. We demonstrated the potential of hepatic organoids with validated functionalities and genetic characteristics as promising models for toxicity evaluation by analyzing toxicological changes occurring in hepatoxic drug-treated organoids.
- |||||||||| tolcapone / Generic mfg.
Journal: Cellular and Mitochondrial Toxicity of Tolcapone, Entacapone, and New Nitrocatechol Derivatives. (Pubmed Central) - May 16, 2024
Our findings also suggest that (a) lipophilicity is a key property in the toxic potential of nitrocatechols; (b) the presence of a carbonyl group directly attached to the nitrocatechol ring seems to increase the reactivity of the molecule, and (c) the presence of cyano moiety in double bond stabilizes the reactivity decreasing the cytotoxicity. Altogether, the fine balance between lipophilicity and the chemical nature of the C1 substituents of the nitrocatechol ring may explain the difference in the toxicological behavior observed between tolcapone and entacapone.
- |||||||||| Trial completion: Dopaminergic Mechanisms Underlying Human Social Behavior (clinicaltrials.gov) - May 14, 2024
P1, N=70, Completed,
Altogether, the fine balance between lipophilicity and the chemical nature of the C1 substituents of the nitrocatechol ring may explain the difference in the toxicological behavior observed between tolcapone and entacapone. Recruiting --> Completed
- |||||||||| Enrollment open, Trial completion date, Trial primary completion date: Gait Analysis in Neurological Disease (clinicaltrials.gov) - Apr 4, 2024
P=N/A, N=120, Recruiting,
Overall, the results suggest that tolcapone-loaded PLGA NPs could be an interesting alternative to free tolcapone, demonstrating the same in vitro efficacy in inhibiting COMT but with a safer cytotoxic profile. Active, not recruiting --> Recruiting | Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Jun 2024 --> Jun 2025
- |||||||||| tolcapone / Generic mfg., duloxetine / Generic mfg.
Trial primary completion date: Microbiome Derived Metabolism and Pharmacokinetics (clinicaltrials.gov) - Mar 21, 2024
P1, N=14, Recruiting,
Active, not recruiting --> Recruiting | Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Jun 2024 --> Jun 2025 Trial primary completion date: Dec 2023 --> Jun 2024
- |||||||||| Review, Journal: Pharmacological management of gambling disorder: an update of the literature. (Pubmed Central) - Feb 15, 2024
The review highlights current gaps/limitations, including small sample sizes, limited diversity in participant demographics, the need for exploring different gambling subtypes and treatment responses, high placebo response rates, lack of longer-term longitudinal information, limited investigation of neurobiological correlates and co-occurring disorders, and the importance of implementation research. Further research is needed to address these gaps and explore additional medications, as well as interventions like neuromodulation.
- |||||||||| tolcapone / Generic mfg., bromocriptine / Generic mfg.
Clinical, Journal: Dopamine Modulates Effective Connectivity in Frontal Cortex. (Pubmed Central) - Dec 11, 2023
In dorsal frontal regions, effectivity connectivity strength was increased, whereas in ventral frontal regions, effective connectivity strength was decreased. These findings suggest that connections within frontal cortex are differentially modulated by dopamine, which may bias the influence that frontal regions exert over each other.
- |||||||||| tolcapone / Generic mfg.
Preclinical, Journal: Limiting Monoamines Degradation Increases L-DOPA Pro-Locomotor Action in Newborn Rats. (Pubmed Central) - Nov 3, 2023
The activity of the degrading pathways involving monoamine oxidases or catechol-O-methyltransferase was impaired by injecting nialamide or tolcapone, respectively...Our experiments support the idea that the raise of monoamines boost L-DOPA's locomotor action. Considering that both inhibitors differently altered the spinal monoamines levels in response to L-DOPA, our data also suggest that maximal locomotor response can be reached with different monoamines environment.
- |||||||||| tolcapone / Generic mfg., duloxetine / Generic mfg.
Trial completion date, Trial primary completion date: Microbiome Derived Metabolism and Pharmacokinetics (clinicaltrials.gov) - Aug 14, 2023
P1, N=14, Recruiting,
However, QoL was somewhat better in patients receiving MAOB or DA than COMT inhibitors. Trial completion date: Apr 2023 --> Dec 2024 | Trial primary completion date: Nov 2022 --> Dec 2023
- |||||||||| ciclopirox topical / Generic mfg., tolcapone / Generic mfg.
Journal: Drug repurposing of dopaminergic drugs to inhibit ataxin-3 aggregation. (Pubmed Central) - Aug 7, 2023
In agreement, treatment with levodopa ameliorated motor symptoms in a C. elegans model of MJD. These findings suggest a possible application of dopaminergic drugs to halt or reduce Atx3 accumulation in the brains of MJD patients.
- |||||||||| entacapone/levodopa/carbidopa / Generic mfg.
Review, Journal, Real-world evidence, Real-world: Real-world considerations of the use of Stalevo in Parkinson's Disease. (Pubmed Central) - Jul 25, 2023
The hepatotoxicity observed with the class comparator tolcapone has not been observed with entacapone, the COMT inhibitor in LCE, and there is no formal requirement to monitor liver function during LCE therapy. Other common side effects include diarrhoea, which is one of the more prominent non-dopaminergic adverse events, and urine discolouration, which is harmless but about which patients may require reassurance.
- |||||||||| tolcapone / Generic mfg.
Enrollment open: A Clinical Trial of Tolcapone in Obsessive Compulsive Disorder (clinicaltrials.gov) - Jul 13, 2023
P2, N=85, Recruiting,
Other common side effects include diarrhoea, which is one of the more prominent non-dopaminergic adverse events, and urine discolouration, which is harmless but about which patients may require reassurance. Not yet recruiting --> Recruiting
- |||||||||| Xadago (safinamide) / Meiji Seika, Eisai, Valeo Pharma, Zambon, Supernus Pharma, Ongentys (opicapone) / Ono Pharma, Neurocrine, BIAL
Review, Journal: Clinical benefit of MAO-B and COMT inhibition in Parkinson's disease: practical considerations. (Pubmed Central) - May 22, 2023
Here, we summarize current knowledge on both medication classes, with a focus on the added clinical value in Parkinson's disease. Furthermore, we outline practical considerations in the treatment of motor fluctuations and provide an outlook on ongoing studies with MAO-B and COMT inhibitors.
- |||||||||| tolcapone / Generic mfg.
Trial completion date, Trial initiation date, Trial primary completion date: A Clinical Trial of Tolcapone in Obsessive Compulsive Disorder (clinicaltrials.gov) - May 3, 2023
P2, N=85, Not yet recruiting,
Furthermore, we outline practical considerations in the treatment of motor fluctuations and provide an outlook on ongoing studies with MAO-B and COMT inhibitors. Trial completion date: Mar 2025 --> Jul 2025 | Initiation date: Feb 2023 --> Jun 2023 | Trial primary completion date: Feb 2025 --> Jun 2025
- |||||||||| Comtan (entacapone) / Novartis, Orion Corp
Journal: Rare Catechol-O-methyltransferase Missense Variants Are Structurally Unstable Proteasome Targets. (Pubmed Central) - Apr 19, 2023
Our results reveal that the degradation is independent of the COMT isoform as both soluble (S-COMT) and ER membrane-bound (MB-COMT) variants are degraded. In silico structural stability predictions identify regions within the protein that are critical for stability overlapping with evolutionarily conserved residues, pointing toward other variants that are likely destabilized and degraded.
- |||||||||| Review, Journal: Pharmacological Modulation of Temporal Discounting: A Systematic Review. (Pubmed Central) - Apr 13, 2023
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.
- |||||||||| tolcapone / Generic mfg.
Journal: DESI-MSI-based technique to unravel spatial distribution of COMT inhibitor Tolcapone. (Pubmed Central) - Jan 15, 2023
Indeed, DESI-MSI is a qualitative technique that allows to observe heterogeneity on distribution but more challenging regarding accurate measurements. Overall, tolcapone was successfully localized in liver and brain tissue sections using DESI-MSI, highlighting the added value that this technique could provide in assisting tissue-specific drug distribution studies.
- |||||||||| Trial completion date, Trial primary completion date: Gait Analysis in Neurological Disease (clinicaltrials.gov) - Jan 4, 2023
P=N/A, N=120, Active, not recruiting,
Overall, tolcapone was successfully localized in liver and brain tissue sections using DESI-MSI, highlighting the added value that this technique could provide in assisting tissue-specific drug distribution studies. Trial completion date: Jun 2023 --> Jun 2024 | Trial primary completion date: Jun 2023 --> Jun 2024
- |||||||||| Comtan (entacapone) / Novartis, Orion Corp
Journal: Elucidating the function of hypothetical PE_PGRS45 protein of Mycobacterium tuberculosis as an oxido-reductase: a potential target for drug repurposing for the treatment of tuberculosis. (Pubmed Central) - Dec 1, 2022
Furthermore, in-vitro and in-vivo validation will aid in drug-resistant TB treatment. HIGHLIGHTSIn-silico and in-vitro studies of hypothetical protein PE_PGRS45 (Rv2615c) of Mycobacterium tuberculosis (Mtb) reveals it to be an integral membrane proteinPE_PGRS45 protein has substrate specificity for fatty acyl Coenzyme A (fatty acyl CoA) and possess NADPH dependent oxido-reductase activityDocking and simulation studies revealed that first line anti-tubercular drug Isoniazid (INH) and other drugs with anti-TB property have strong affinity for PE_PGRS45 proteinOxido-reductase activity of PE_PGRS45 protein is inhibited by INHPE_PGRS45 protein could be targeted by drugs that can be repurposed for TB treatmentCommunicated by Ramaswamy H. Sarma.
- |||||||||| Vyndaqel (tafamidis meglumine) / Pfizer, acoramidis (AG10) / BridgeBio, AstraZeneca
Journal: Characterising diflunisal as a transthyretin kinetic stabilizer at relevant concentrations in human plasma using subunit exchange. (Pubmed Central) - Nov 30, 2022
Thus, quantification of TTR kinetic stabilisation using subunit exchange was carried out at 100, 200, 300, and 400 concentrations, all observed in patients after 250 mg BID oral dosing. A 250 M diflunisal plasma concentration reduced the wild-type TTR dissociation rate in plasma by 95%, which is sufficient to stop transthyretin aggregation, consistent with the clinical efficacy of diflunisal for ameliorating transthyretin polyneuropathy.
- |||||||||| Journal: The treatment of amyloidosis is being refined. (Pubmed Central) - Nov 19, 2022
This definition includes drugs that act on different phases of amyloidogenesis: (i) silencing of the gene encoding TTR (small interfering RNA: patisiran, vutrisiran; antisense oligonucleotides: inotersen, eplontersen; new CRISPR Cas-9 drug technology for editing in vivo DNA); (ii) stabilization of circulating TTR to inhibit its dissociation and subsequent assembly of the resulting monomers in amyloidotic fibrils (tafamidis, acoramidis, and tolcapone); (iii) destruction and re-absorption of already formed amyloid tissue deposits. Drugs related to the latter strategy (antibodies) are still the subject of Phase 1 or 2 studies.
- |||||||||| tolcapone / Generic mfg.
Journal: Development of a Highly Potent Transthyretin Amyloidogenesis Inhibitor: Design, Synthesis, and Evaluation. (Pubmed Central) - Nov 15, 2022
Departing from the crystal structure of TTR in complex with tolcapone, a potent binder in clinical trials for ATTR, we combined rational design and molecular dynamics (MD) simulations to generate a series of novel halogenated kinetic stabilizers...The TTR/M-23 crystal structure confirmed the formation of unprecedented protein-ligand contacts, as predicted by MD simulations, leading to an enhanced tetramer stability both in vitro and in whole serum. We demonstrate that MD-assisted design of TTR ligands constitutes a new avenue for discovering molecules that, like M-23, hold the potential to become highly potent drugs to treat ATTR.
- |||||||||| tolcapone / Generic mfg.
Preclinical, Journal: Effects of a New Natural Catechol-O-methyl Transferase Inhibitor on Two In Vivo Models of Parkinson's Disease. (Pubmed Central) - Nov 9, 2022
In a 6-hydroxydopamine rat model of Parkinson's disease, its co-administration at 30 mg/kg with L-DOPA enhances the effect of L-DOPA with an intensity similar to that of tolcapone 1 at 30 mg/kg but for a shorter duration...Compound 4 seems not to cross the blood-brain barrier and thus acts as a peripheral COMT inhibitor. COMT inhibition by compound 4 further validates the traditional use of M. pruriens for the treatment of Parkinson's disease, and compound 4 can thus be considered as a promising drug candidate for the development of safe, peripheral COMT inhibitors.
- |||||||||| Comtan (entacapone) / Novartis, Orion Corp, Ongentys (opicapone) / Ono Pharma, Neurocrine, BIAL
Review, Journal: Relevance of COMT inhibitors in the treatment of motor fluctuations (Pubmed Central) - Oct 12, 2022
Many patients with motor fluctuations are currently not treated with COMT inhibitors and are, therefore, unlikely to receive individually optimized drug treatment. This manuscript summarizes the results of a working group including several Parkinson's disease experts, in which the value of COMT inhibitors was critically discussed.
- |||||||||| tolcapone / Generic mfg.
Removing items from working memory engages large-scale brain networks and is sensitive to dopamine tone (SDCC Halls B-H) - Oct 10, 2022 - Abstract #Neuroscience2022NEUROSCIENCE_10381;
Although tolcapone did not significantly affect d’, activity in the right caudate and putamen, as well as bilateral anterior cingulate cortex, demonstrated a significant interaction between load and tolcapone. Together these results emphasize the active contributions of frontoparietal and higher visual areas to the removal process, and they suggest a dopaminergic influence on associated neural mechanisms.
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