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Biogenic amines
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
Patterns of neurotransmitter metabolites in the CSF in this and other disorders of neurotransmitter metabolism are shown in Table 17.1. In patients with AADC deficiency, levels of HVA, HIAA, and MHTG are low. Levels of 3-O-methyldopa are markedly elevated. Levels of L-DOPA and 5-HT are elevated, but less so. This pattern was found in 100 percent of patients [3]. The only item in the differential diagnosis of this pattern is a severe reduction of vitamin B6 observed in deficiency of pyridox(am)ine 5′-phosphate oxidase (PNPO), because this enzyme is responsible for the maintenance of pyridoxal phosphate (PLP) levels in the central nervous system (CNS). Mutations in the PNPO gene for this enzyme lead to deficiency of PLP and the same pattern of CSF metabolites as in AADC deficiency [15]. PLP is the cofactor for the AADC enzyme. Measurement of plasma AADC activity or PLP in the CSF will distinguish AADC deficiency from PNPO deficiency. Levels of vanillactic acid and its derivatives vanilpyruvic acid and N-acetylvanilalanine are elevated in urine, and this may be the first clue as to the diagnosis as it is found on organic acid analysis of the urine. On the other hand, its elevation may be mild [3, 12]. The compound is formed from transamination of accumulated 3-O-methyldopa. In a pilot study, 3-O-methyldopa is being investigated for newborn screening of AADC deficiency in Taiwan with promising initial results and an estimated incidence of AADC deficiency of 1:32,000 (95% confidence interval: 1:12,443-1:82,279).
Parkinson’s Disease and Aging: Presynaptic Nigrostriatal Function
Published in W. R. Wayne Martin, Functional Imaging in Movement Disorders, 2019
A second major component, 3-O-methyl-6-FD (3-OMFD), also contributes to the background activity. Home and colleagues have shown that in rats given tritiated levodopa, O- methylation occurs rapidly outside the brain by COMT in liver, and other sites.28 3-O-methyldopa is readily transported across the blood brain barrier and is thought to be responsible for much of the background activity seen in autoradiographic studies.28,29 5-Fluorodopa also undergoes rapid O-methylation.30 Although it has been suggested that 6-FD undergoes O-methylation much less readily than does 5-FD,31 our studies show that when 6-FD is given to human subjects pretreated with carbidopa the O-methylated form rapidly appears in the blood,32 possibly because of increased 6-FD availability resulting from peripheral ALAAD inhibition.
Sympathetic Neurotransmission
Published in Kenneth J. Broadley, Autonomic Pharmacology, 2017
COMT inhibitors currently have no therapeutic applications of their peripheral action, however, they are being developed as adjuncts to L-dopa in the treatment of Parkinson’s disease. The reasoning behind this is as follows. Endogenous and administered L-dopa are normally converted to dopamine by dopa-decarboxylase (Figure 2.4). When L-dopa is combined with a carboxylase inhibitor such as benserazide (in MadoparR) or carbidopa (in SinemetR), the peripheral levels of dopa increase. Dopa is then substantially O-methylated to 3-O-methyldopa (3-OMD) (Figure 2.11). This is inactive and has a very long half-life (~15 hr). It accumulates in the plasma and is then transported into the brain by the same carrier that transports dopa. The advantages of combining with MAO inhibitors have already been described, however the further addition of an orally active COMT inhibitor would also permit a reduction of the dose and frequency of administration of dopa. The formation of 3-OMD in the periphery would be reduced, resulting in improved bioavailability of dopa for the brain. An example of this type of inhibitor is tolcapone (Figure 2.18).
The launch of opicapone for Parkinson’s disease: negatives versus positives
Published in Expert Opinion on Drug Safety, 2018
Ana Castro Caldas, Tiago Teodoro, Joaquim J Ferreira
Catechol-O-methyltransferase (COMT) inhibitors represent an important arsenal to block peripheral levodopa metabolism. Through inhibition of levodopa conversion to 3-O-methyldopa, COMT inhibitors prolong the plasma half-life of levodopa and reduce the peak variations of plasma levodopa levels [1,2]. This allows a more regular dopamine supply to the striatum. In turn, this leads to a decrease OFF time, thus improving motor impairment [3]. Therefore, COMT inhibitors are recommended as a treatment for the end-of-dose phenomenon in Parkinson’s disease (PD) [4].
Comparative examination of levodopa pharmacokinetics during simultaneous administration with lactoferrin in healthy subjects and the relationship between lipids and COMT inhibitory activity in vitro
Published in Nutritional Neuroscience, 2022
Masahiro Nagai, Madoka Kubo, Rina Ando, Masayuki Ikeda, Hiroshi Iwamoto, Yasuhiro Takeda, Masahiro Nomoto
A two-stage crossover open-label study was conducted in the Phase I unit of Ehime University Hospital. The subjects were alternately allocated to two groups in order of body weight (Figure 2). The washout time was determined from the time that the concentration of 3-O-methyldopa (3-OMD) returned to the initial level. bLF taken concurrently with levodopa preparations was supplied by Morinaga Milk Industry Co., Ltd. (Tokyo, Japan). The levodopa/benserazide (100 mg/25 mg per tablet) used was Ecdoparl® (Kyowa Hakko Kirin Co., Ltd., Tokyo, Japan). Benserazide is a DCI. The subjects fasted after dinner the previous day and orally took one tablet of Ecdoparl® and bLF powder (1.0 g) dissolved in 100 mL of water. If bLF was not administered, then one tablet of Ecdoparl® was taken orally with 100 mL of water. Blood was collected prior to ingestion and 15, 30, and 45 min and 1, 1.25, 1.5, 2, 2.5, 3, 3.5, and 4 h after ingestion. On the day of the study, the subjects fasted until the end of blood collection. The subjects were allowed to drink water freely. During the study period, the subjects were prohibited from using any drugs other than those routinely used at the time of registration. In addition, the subjects were interviewed regarding their subjective and objective symptoms, examined, and observed. We did not conduct daily dietary control or dietary surveys. The primary endpoints were levodopa area under the curve (AUC), Cmax, time of the maximum plasma concentration (Tmax), elimination half-life (t1/2), and blood concentrations at each blood collection time point. Secondary endpoints included AUC, Cmax, Tmax, and t1/2, and blood concentrations of 3-OMD, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) at different collection time points.
Pharmacogenetics and levodopa induced motor complications
Published in International Journal of Neuroscience, 2019
Kallirhoe Kalinderi, Vasileios Papaliagkas, Liana Fidani
COMT is an enzyme that inactivates biologically active or toxic catechols and degradates catecholamine neurotransmitters, including dopamine [7]. It is implicated in the metabolism of L-dopa, however the produced 3-O-methyldopa (3-OMD) exerts no therapeutic effect in PD and evenmore antagonizes the L-dopa’s therapeutic action. In contrast, COMT inhibitors, such as Tolcapone and Entacapone, have been proved to be beneficial agents in PD treatment as they reduce the conversion of L-dopa to 3-OMD and thus improve its bioavailability in the brain [8, 9]. Opicapone is also a recently introduced third generation, highly potent and effective COMT inhibitor [10]. The COMT gene is localized on chromosome 22q11.1–q11.2, has two promoters and consists of six exons [11]. It encodes two major protein isoforms, a soluble cytoplasmic (S-COMT) and a membrane-bound (MB-COMT) isoform. These isoforms differ by the inclusion of an extra 50 hydrophobic amino acids in MB-COMT [12]. MB-COMT is the dominant allozyme in the brain and has a greater affinity and metabolizing capacity for catecholamines, including dopamine [13, 14]. A common G1947A polymorphism in exon 4 of the COMT gene, termed rs4680, causes a valine to methionine substitution at codon 108 of the soluble form and codon 158 of the membrane-bound form (sometimes referred to as Val108/158Met) in the COMT protein. This amino acid change results in altered activity of both S-COMT and MB-COMT and has generally been thought to be the main source of genetic variation in COMT enzyme activity [15, 16]. Actually, the genetically polymorphic COMT enzyme activity displays a trimodal distribution; high activity in Val/Val (or HH) genotype, intermediate activity in Val/Met genotype, and low activity in Met/Met (or LL) genotype. The Val (variant G) allele confers thermostability, whereas the Met (variant A) allele is thermolabile. Patients with the A/A genotype have been documented to experience more frequently severe dyskinesias and other motor fluctuations [17]. The doses of L-dopa treatment have previously been found to be influenced by specific COMT haplotypes [18] whereas in a recent study, patients with COMT (rs4680) LL genotype experienced more frequently levodopa-induced-dyskinesia (LID) [19]. However, other studies have failed to confirm this association [20–22].