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Infiltrative Diseases
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
Other agents that can stabilize TTR include epigallocatechin-3-gallate (EGCG) in green tea, which inhibits amyloid fibril formation, but further evidence is needed.54 AG-10 is a compound that stabilizes wild-type TTR and TTR Val122Ile. A phase II study of 49 patients with ATTR-CM illustrated stabilization of TTR with AG-10,55 and the phase III trial is currently ongoing. Tolcapone, a catechol-O-methyltransferase (COMT) inhibitor used as adjunctive therapy for Parkinson's disease, binds to TTR in human plasma, and stabilizes both wild-type and mutant TTR,56 although studies are still pending.
Natural Product Compounds from Plants in Neurodegenerative Diseases
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Priya Darshani, Md TanjimAlam, Prem P. Tripathi, V.S. Pragadheesh
The main therapeutic approach for PD involves the administration of L-Dopa, the precursor of dopamine to elevate its level in the brain, inhibition of monoamine oxidase (MAO), and catechol-O-methyltransferase (COMT). Ayurveda, the traditional Indian system of medicine, describes the use of four plants—Mucuna pruriens (L.) DC, Hyoscyamus reticulatus L. seeds, Withania somnifera (L.) Dunal, and Sida cordifolia L. roots—as a concoction in cow’s milk for the treatment of PD (Figure 16.2). The concoction has been reported to contain compounds like L-Dopa, neuroactive agents like hyoscyamine, somniferin and ephedrine. A prospective clinical study demonstrates the efficacy of Ayurveda treatment, in which 18 patients of PD received a mixture of warm cow’s milk (200 mL) and powdered M. pruriens (4.5 g), H. reticulatus seeds (0.75 g), W. somnifera (14.5 g) and S. cordifolia roots (14.5 g). The symptoms like tremor, bradykinesia, stiffness and cramp-like pain were improved by 61.5%, 69.2%, 100% and 75%, respectively, in patients who followed the Ayurvedic treatment (Nagashayana et al., 2000).
Cannabis
Published in Ilana B. Crome, Richard Williams, Roger Bloor, Xenofon Sgouros, Substance Misuse and Young People, 2019
Overall, studies and clinical experience, including the clinical experience of the author, suggest that adolescent brains may be particularly vulnerable to developing psychotic disorders associated with cannabis use and that some adolescents may be particularly vulnerable to the effects of THC. It has been speculated that this vulnerability may have a genetic basis and that it may be due to a variation in the gene that encodes catechol-O-methyltransferase (COMT), an enzyme that is involved in the breakdown of dopamine in the synapses (Caspi et al., 2005). However, the finding was not replicated in more recent research (Zammit et al., 2011). It is definitely more likely that multiple variations within multiple genes – rather than one single genetic polymorphism – may render a person vulnerable to developing psychosis after cannabis use (Henquet et al., 2008).
Advances in the treatment and management of frontotemporal dementia
Published in Expert Review of Neurotherapeutics, 2023
Alberto Benussi, Barbara Borroni
Tolcapone: Tolcapone, an FDA-approved medication for treating Parkinson’s symptoms, functions by raising dopamine levels in the prefrontal cortex through the inhibition of catechol-O-methyltransferase (COMT). In a Phase 2b clinical trial, researchers investigated the effects of tolcapone on 28 patients with clinically diagnosed, symptomatic bvFTD. The trial findings disclosed no substantial disparities between the tolcapone and placebo groups concerning primary or imaging outcomes. Nevertheless, significant alterations were detected in the repeatable battery for the assessment of neuropsychological status (RBANS) total scores, neuropsychiatric inventory questionnaire (NPI-Q) total scores, and clinical global impression (CGI) total scores across the two treatment conditions [114]. These findings suggest that further investigation into newer COMT inhibitors, with fewer side effects, may be warranted to potentially benefit bvFTD patients, as well as exploring additional outcome measures to better assess their efficacy.
CSF/plasma levels, transthyretin stabilisation and safety of multiple doses of tolcapone in subjects with hereditary ATTR amyloidosis
Published in Amyloid, 2022
Yusuke Takahashi, Nobuhiko Ohashi, Ken Takasone, Tsuneaki Yoshinaga, Masahide Yazaki, Michael Roberts, Paul F. Glidden, Yoshiki Sekijima
Tolcapone is an orally bioavailable catechol-O-methyl transferase (COMT) inhibitor authorised in the United States and Europe as an adjunct to levodopa and carbidopa for the treatment of Parkinson’s disease. Using a drug repurposing approach, tolcapone was shown to bind with high affinity and specificity to the two T4-binding sites of TTR, promoting its stabilisation and preventing the formation of amyloid fibrils and cytotoxic oligomeric species [7]. Of note, tolcapone was detected in the CSF of patients with Parkinson’s disease [8] and it inhibited the aggregation of highly destabilised CNS variants in vitro [7,9]. This evidence suggested that tolcapone might have a therapeutic application in the ATTR-related CNS amyloidosis, which, as described, cannot be treated efficiently by liver transplantation or current pharmacological approaches.
Detection of altered methylation of MB-COMT promotor and DRD2 gene in cannabinoid or synthetic cannabinoid use disorder regarding gene variants and clinical parameters
Published in Journal of Addictive Diseases, 2021
Yasemin Oyaci, Hasan Mervan Aytac, Ozge Pasin, Pinar Cetinay Aydin, Sacide Pehlivan
Catechol-O-methyltransferase (COMT) is the critical enzyme responsible for the metabolism of dopamine in the brain’s cortical regions.14 The COMT gene is placed on chromosome 22q11.21, has eight exons, and produces 271 amino acids, which metabolize catecholamines.15 COMT gene polymorphisms are associated with the enzyme activity: higher activity is related to the COMT Val (valine) allele, and lower activity is associated with the COMT Met allele.16,17 In codon 158 (in the rs4680 polymorphism) of the COMT gene, the Met allele’s low enzymatic activity, which provides metabolic inactivation of dopamine, may be related to SUD. While COMT gene variants affect COMT activity, epigenetic modifications, especially DNA methylation of the COMT gene, may influence gene expression. Indeed, increased COMT gene methylation was related to decreased gene expression, and tobacco use disorder (TUD)18 and alcohol use disorder (AUD)2 were found to be related to higher membrane-bound catechol-O-methyltransferase (MB-COMT) promoter methylation, suggesting lower COMT gene activity.