Effectiveness and safety of different catechol-o-methyl transferase inhibitors for patients with parkinson's disease: Systematic review and network meta-analysis.

BACKGROUND: Levodopa treatment requires the addition of other drugs, such as catechol-O-methyl transferase (COMT) inhibitors, to alleviate motor fluctuations in advanced parkinson's disease (PD). However, the optimal strategy, including the type and dose of COMT inhibitors remains unknown. This systematic review and network meta-analysis aimed to assess the efficacy and safety of different COMT inhibitors and for treating PD patients. METHODS: PubMed, Embase, Cochrane Library and Web of Science were screened up to November 20, 2022. Randomized controlled trials (RCTs) of COMT inhibitors (entacapone, opicapone, tolcapone) for PD patients were included. Eligible outcomes were total ON-time, rate of ON-time >1 h, total daily dose of levodopa therapy, mean change from baseline to final follow up in Unified Parkinson's Disease Rating Scale (UPDRS) part III scores, adverse events and dyskinesia. Network meta-analyses integrated direct and indirect evidence with placebo as a common comparator. RESULTS: We identified 18 studies with 7564 patients. Opicapone, entacapone, and tolcapone could increase total ON-time when compared with placebo. However, opicapone (25 mg, MD 4.0, 95%CrI: 1.1-7.5) and opicapone (50 mg, MD 5.1, 95%CrI: 2.2-8.7) statistically significant increase the total ON-time. opicapone and entacapone could increase the rate of ON-time >1 h when compared with placebo. Only opicapone (5 mg) showed no statistically significant with placebo (OR 1.4, 95%CrI: 0.74-2.4). We found that opicapone (50 mg, SURCA, 0.796) is the best option compared with other treatments. TOL (200 mg) was ranked highest in the rank probability test for total daily dose of levodopa therapy, followed by OPI (50 mg), TOL (400 mg) and TOL (100 mg) in order. SUCRA rankings identified TOL (200 mg) as the most likely therapy for increasing adverse events (SUCRA 27.19%), followed by TOL (400 mg, SUCRA 27.20%) and OPI (5 mg, SUCRA 30.81%). The SUCRA probabilities were 91.6%, 75.2%, 67.9%, 59.3%, 45.6%, 41.1%, 35.1%, 24.6% and 9.4% for PLA, TOL (400 mg), ENT (100 mg), ENT (200 mg), OPI (5 mg), TOL (100 mg), OPI (25 mg), OPI (50 mg), and TOL (200 mg) respectively. CONCLUSION: In conclusion, opicapone (50 mg) may be a better choice for treatment PD when compared with other COMT inhibitors.

Inhibition of catechol-O-methyltransferase (COMT) by heparin oligosaccharides with specific structures.

COMT inhibitors are commonly used to improve the effectiveness of levodopa in treating Parkinson's disease by inhibiting its conversion to 3-O-methyldopa. Because of the serious side effect of nitrocatechol COMT inhibitors, it is necessary to develop non-nitrocatechol COMT inhibitors with a higher safety profile. Heparin has been observed to bind to COMT. However, the exact functional significance of this interaction is not fully understood. In this study, the contribution of different substitution of heparin to its binding with COMT was investigated. In vitro and in vivo, heparin oligosaccharides can bind to COMT and inhibit its activity. Furthermore, we enriched the functional heparin oligosaccharides that bind to COMT and identified the sequence UA2S-GlcN(S/Ac)6(S/H)-UA2S-GlcNS6(S/H)-UA2(S/H)-GlcNS6S as the characteristic structural domain of these functional oligosaccharides. This study has elucidated the relationship between the structure of heparin oligosaccharides and their activity against COMT, providing valuable insights for the development of non-nitrocatechol COMT inhibitors with improved safety and efficacy.

Advanced Parkinson's disease treatment patterns in Italy: an observational study interim analysis.

BACKGROUND: Oral levodopa remains the mainstay of treatment for Parkinson's disease (PD). However, as PD progresses, response to treatment may fluctuate. Managing fluctuations can be demanding for clinicians and patients. There is a paucity of real-world studies reporting on PD management in patients with fluctuations in treatment response, especially in patients with advanced stages of PD. The multicentre, observational Parkinson's Disease Fluctuations treatment PAthway (PD-FPA) study describes the real-life management of response fluctuations in Italian patients with advanced PD. PATIENTS AND METHODS: PD-FPA had a retrospective and prospective phase; herein, retrospective results are presented. Ten Italian centres enrolled patients with a PD diagnosis from 10-15 years prior to study entry (T0) and who had ≥2-year history of fluctuations. Data on patient demographics, medical history, PD stage, fluctuation characteristics, symptoms, and prescribed treatments were collected at T0 and retrospectively (2 years prior to T0) via patient chart review/interview. RESULTS: Overall, 296 patients (60% male, mean age 68 years, 84% with Hoehn and Yahr scores 2-3) were enrolled. At T0, most patients (99.3%) were on oral levodopa therapy. All patients used dopaminergic medications; adjunctive medications included dopamine agonists (56%) and monoamine oxidase B (60%) and catechol-O-methyltransferase enzyme inhibitors (41%). At T0, 51% of patients had changed therapy, with response fluctuations being the most common reason (74%); wearing-off was the most common fluctuation (83%). CONCLUSION: This interim analysis of PD-FPA suggests that adequate levodopa dosing and adjunctive medications can stabilize advanced PD and provide patients with a good quality of life.

Patients with Parkinson's disease (PD) often exhibit fluctuations in their response to oral levodopa; however, real-world studies on the management of these fluctuations are lacking. This planned interim analysis of the real-world, multicentre, observational PD Fluctuations treatment Pathway (PD-FPA) study found that adequate levodopa dosing and adjunctive medications can stabilize Italian patients with advanced PD and improve their quality of life.

HR/MS-based lipidome analysis of rat brain modulated by tolcapone.

Lipids play key roles in the body, influencing cellular regulation, function, and signalling. Tolcapone, a potent catechol-O-methyltransferase (COMT) inhibitor described to enhance cognitive performance in healthy subjects, was previously shown to impact fatty acid ß-oxidation and oxidative phosphorylation. However, its impact on the brain lipidome remains unexplored. Hence, this study aimed to assess how tolcapone affects the lipidome of the rat pre-frontal cortex (PFC), a region of the brain highly relevant to tolcapone therapeutic effect, while evaluating its influence on operant behaviour. Tolcapone at 20 mg/kg was chronically administered to Wistar rats during a behavioural task and an untargeted liquid chromatography high-resolution mass spectrometry (LC-HR/MS) approach was employed to profile lipid species. The untargeted analysis identified 7227 features, of which only 33% underwent statistical analysis following data pre-processing. The results revealed an improved cognitive performance and a lipidome remodelling promoted by tolcapone. The lipidomic analysis showed 32 differentially expressed lipid species in tolcapone-treated animals (FC ≥ 1.2, p-value ≤ 0.1), and among these several triacylglycerols, cardiolipins and N-acylethanolamine (NAE 16:2) were found upregulated whereas fatty acids, hexosylceramides, and several phospholipids including phosphatidylcholines and phosphatidylethanolamines were downregulated. These preliminary findings shed light on tolcapone impact on lipid pathways within the brain. Although tolcapone improved cognitive performance and literature suggests the significance of lipids in cognition, this study did not conclusively establish that lipids directly drove or contributed to this outcome. Nevertheless, it underscores the importance of lipid modulation and encourages further exploration of tolcapone-associated mechanisms in the central nervous system (CNS).

A 12-month prospective real-life study of opicapone efficacy and tolerability in Emirati and non-White subjects with Parkinson's disease based in United Arab Emirates.

Parkinson's disease (PD) is the second most common neurodegenerative disorder, and the condition is complicated by the emergence of wearing off/motor fluctuations with levodopa treatment after a variable period. COMT inhibitors when used as adjunct therapy to levodopa tend to smoothen out these wearing off fluctuations by enhancing delivery of levodopa and increasing its bioavailability to the brain. The study was conducted to investigate the motor and nonmotor effect, safety and tolerability of the third generation once-daily COMT inhibitor (opicapone), as add-on, adjuvant therapy to levodopa and at 6 and 12 months follow-up in a real-life cohort of consecutive Emirati and non-White PD patients. A real-life observational analysis using tolerability parameters as used previously by Rizos et al. and Shulman et al. based on clinical database of cases rat Kings College Hospital Dubai Parkinson care database. This was a prospective, single-arm follow-up clinical evaluation study that evaluated the effectiveness of opicapone 50 mg once-daily regime in 50 patients diagnosed with idiopathic neurodegenerative disorder. All patients were assessed with scales used in clinical pathway and include motor Unified Parkinson's Disease Rating Scale (UPDRS), nonmotor symptom scale (NMSS), quality of life (PDQ8) Parkinson's fatigue scale (PFS16) and King's Parkinson's Pain Scale (KIPS). Out of 50 patients treated with opicapone (72% male, mean age 66.9 years (SD 9.9, range 41-82 years) and mean duration of disease 5.7 years (SD 2.5 range (2-11), there was significant statistical improvements shown in motor function-UPDRS part 3: baseline 40.64 ± 2.7, at 6 months 32.12 ± 3.14 and after 12 months 33.72 ± 3.76. Nonmotor burden NMSS: 107.00 ± 21.86, at 6 months 100.78 ± 17.28 and 12 months 96.88 ± 16.11. Reduction in dyskinesias (UPDRS part 4): baseline 8.78 ± 1.07, at 6 months 7.4 ± 0.81 and 12 months 6.82 ± 0.75. Opicapone provides beneficial motor and nonmotor effects in Emirati and other non-White Parkinson's patients, resident in UAE, proving its efficacy across different racial groups as COMT activity may vary between races.

Catechol-O-Methyltransferase inhibition and alcohol use disorder: Evaluating the efficacy of tolcapone in ethanol-dependent rats.

Alcohol Use Disorder (AUD) is a significant public health issue in the United States. It affects millions of individuals and their families and contributes to substantial societal and economic burdens. Despite the availability of some pharmacological treatments, there is still a pressing need to develop more effective therapeutic strategies to address the diverse range of symptoms and challenges associated with AUD. Catechol-O-methyltransferase (COMT) inhibition recently emerged as a promising new approach to treating AUD due to its potential to improve cognitive effects commonly associated with AUD. Tolcapone, an FDA-approved COMT inhibitor, has shown some promise for treating AUD; however, its ability to decrease drinking in ethanol-dependent rats has not been well-established. In this study, we evaluated the effects of tolcapone on operant, oral ethanol self-administration in non-dependent and dependent rats, and in rats that self-administered oral saccharin. To induce dependence, rats underwent the chronic intermittent exposure to vapor model, and their drinking levels were assessed during acute withdrawal from ethanol. Our results demonstrated that tolcapone attenuated responding for ethanol in dependent rats only, without affecting self-administration in non-dependent rats or rats self-administering saccharin. Moreover, we found that tolcapone was differentially effective in different estrous phases in female rats. These findings suggest that COMT inhibition, specifically using tolcapone, may be a valuable pharmacotherapy for treating AUD, particularly in individuals who are physically dependent on alcohol. Further research is needed to elucidate the precise mechanisms underlying the observed effects and to assess the potential of COMT inhibitors in a broader population of individuals with AUD.

Real-world evidence on levodopa dose escalation in patients with Parkinson's disease treated with istradefylline.

OBJECTIVE: Istradefylline, a selective adenosine A2A receptor antagonist, is indicated in the US and Japan as adjunctive treatment to levodopa/decarboxylase inhibitors in adults with Parkinson's disease (PD) experiencing OFF time. This study aimed to observe patterns of dose escalation of levodopa over time in patients initiated on istradefylline. METHODS: Using Japanese electronic health record data, interrupted time series analyses were used to compare levodopa daily dose (LDD, mg/day) gradients in patients before and after initiation of istradefylline. Data were analyzed by period relative to istradefylline initiation (Month 1): pre-istradefylline (Months -72 to 0), early istradefylline (Months 1 to 24), and late istradefylline (Months 25 to 72). Subgroup analyses included LDD before istradefylline initiation (<400, ≥400 to <600, ≥600 mg/day) and treatment with or without monoamine oxidase-B (MAO-B) inhibitors, catechol-O-methyltransferase (COMT) inhibitors, or dopamine agonists before istradefylline initiation. RESULTS: The analysis included 4026 patients; mean (SD) baseline LDD was 419.27 mg (174.19). Patients receiving ≥600 mg/day levodopa or not receiving MAO-B inhibitors or COMT inhibitors demonstrated a significant reduction in LDD increase gradient for pre-istradefylline vs late-phase istradefylline (≥600 mg/day levodopa, -6.259 mg/day each month, p<0.001; no MAO-B inhibitors, -1.819 mg/day each month, p = 0.004; no COMT inhibitors, -1.412 mg/day each month, p = 0.027). CONCLUSIONS: This real-world analysis of Japanese prescription data indicated that slowing of LDD escalation was observed in patients initiated on istradefylline, particularly in those receiving ≥600 mg/day levodopa, suggesting istradefylline may slow progressive LDD increases. These findings suggest that initiating istradefylline before other levodopa-adjunctive therapies may mitigate LDD increases, potentially reducing occurrence or severity of levodopa-induced complications in long-term istradefylline treatment.

Structural and Computational Analyses of the Unique Interactions of Opicapone in the Binding Pocket of Catechol O-Methyltransferase: A Crystallographic Study and Fragment Molecular Orbital Analyses.

A third-generation inhibitor of catechol O-methyltransferase (COMT), opicapone (1), has the 3-nitrocatechol scaffold as do the second-generation inhibitors such as entacapone (2) and tolcapone (3), but only 1 can sustainably inhibit COMT activity making it suitable for a once-daily regimen. These improvements should be attributed to the optimized sidechain moiety (oxidopyridyloxadiazolyl group) of 1 substituted at the 5-position of the 3-nitrocatechol ring. We analyzed the role of the sidechain moiety by solving the crystal structures of COMT/S-adenosylmethionine (SAM)/Mg/1 and COMT/S-adenosylhomocysteine (SAH)/Mg/1 complexes. Fragment molecular orbital (FMO) calculations elucidated that the dispersion interaction between the sidechains of Leu 198 and Met 201 on the ß6ß7-loop and the oxidopyridine ring of 1 were unique and important in both complexes. In contrast, the catechol binding site made a remarkable difference in the sidechain conformation of Lys 144. The ε-amino group of Lys 144 was outside of the catalytic pocket and was replaced by a water molecule in the COMT/SAH/Mg/1 complex. No nitrocatechol inhibitor has ever been reported to make a complex with COMT and SAH. Thus, the conformational change of Lys 144 found in the COMT/SAH/Mg/1 complex is the first crystallographic evidence that supports the role of Lys 144 as a catalytic base to take out a proton ion from the reaction site to the outside of the enzyme. The fact that 1 generated a complex with SAH and COMT also suggests that 1 could inhibit COMT twofold, as a typical substrate mimic competitive inhibitor and as a product-inhibition enhancer.

Opicapone versus entacapone: Head-to-head retrospective data-based comparison of healthcare resource utilization in people with Parkinson's disease new to catechol-O-methyltransferase (COMT) inhibitor treatment.

BACKGROUND AND PURPOSE: Motor fluctuations are a significant driver of healthcare resource utilization (HCRU) in people with Parkinson's disease (pwPD). A common management strategy is to include catechol-O-methyltransferase (COMT) inhibition with either opicapone or entacapone in the levodopa regimen. However, to date, there has been a lack of head-to-head data comparing the two COMT inhibitors in real-world settings. The aim of this study was to evaluate changes in HCRU and effect on sleep medications when opicapone was initiated as first COMT inhibitor versus entacapone. METHODS: In this retrospective cohort study, we assessed HCRU outcomes in pwPD naïve to COMT inhibition via UK electronic healthcare records (Clinical Practice Research Datalink and Hospital Episodes Statistics databases, June 2016 to December 2019). HCRU outcomes were assessed before (baseline) and after COMT inhibitor prescription at 0-6 months, 7-12 months and 13-18 months. Opicapone-treated pwPD were algorithm-matched (1:4) to entacapone-treated pwPD. RESULTS: By 6 months, treatment with opicapone resulted in 18.5% fewer neurology outpatient visits compared to entacapone treatment; this effect was maintained until the last follow-up (18 months). In the opicapone group, the mean levodopa equivalent daily dose decreased over the first year and then stabilized, whereas the entacapone-treated group showed an initial decrease in the first 6 months followed by a dose increase between 7 and 18 months. Neither COMT inhibitor had a significant impact on sleep medication use. CONCLUSIONS: This head-to-head study is the first to demonstrate, using 'real-world' data, that initiating COMT inhibition with opicapone is likely to decrease the need for post-treatment HCRU versus initiation of COMT inhibition with entacapone.

Synthesis and characterization of chemical engineered PLGA nanosphere: Triggering mechanism of Catechol-O-methyltransferase inhibition on in vivo neurodegeneration.

Chemically engineered PLGA nanospheres are one of the emerging technologies for treating neurodegenerative disorders by inhibiting Catechol-O-methyltransferase (COMT). PLGA-MATPM nanospheres were chemically synthesized using PLGA and MATPM (N-allyl-N-(3-(m-tolyloxy)propyl) methioninate). The tailored PLGA nanospheres induce dose-dependent COMT inhibition in competitive kinetic mode. The interactions between COMT and PLGA nanosphere are explained by spectroscopic and molecular dynamics analysis. PLGA-MATPM NPs suppressed the growth of neuroblastoma cells due to the neurodegenerative toxicity of MPTP induction, demonstrating its potency as a cure for neurological disorders. PLGA-MATPM NPs cross the blood-brain barrier more effectively than those in the blood. Furthermore, PLGA nanospheres showed the most neurodegenerative recovery against MPTP-induced C57BL/6 mice. Using magnetic resonance imaging (MRI), it was validated for quality images of cerebral blood flow (CBF).

The real-life effect of catechol-O-methyltransferase inhibition on non-motor symptoms in levodopa-treated Parkinson's disease: opicapone versus entacapone.

OBJECTIVE: To evaluate the long-term, real-life effects on non-motor symptoms (NMS) of opicapone compared to entacapone in levodopa-treated people with Parkinson's disease (PwP). METHODS: A retrospective data analysis, with pre- and post-opicapone initiation data of 17 PwP with motor fluctuations compared to a comparable group of 18 PwP introduced on entacapone. The primary outcome was changes in the NMS Scale (NMSS) total score after 1-year follow-up. Secondary outcomes included changes in the NMSS domains, and Parkinson's Disease Sleep Scale (PDSS) total and item scores after the same time span. RESULTS: Groups were comparable for baseline demographics and Parkinson's-related features (p ≥ 0.314) as well as duration of follow-up (1.33 ± 0.66 years for PwP on opicapone and 1.23 ± 0.49 years for those on entacapone; p = 0.858). PwP who were introduced on opicapone showed no changes in NMSS and PDSS total scores after 1 year (p = 0.605 and p = 0.507, respectively), whereas PwP who were introduced on entacapone showed significant worsening of NMSS and PDSS total scores at follow-up (p = 0.005 and p = 0.001, respectively). In neither group changes in individual NMSS domains from baseline to follow-up were observed (p ≥ 0.288 for entacapone and p ≥ 0.816 for opicapone, respectively). In PwP on entacapone significant worsening was seen in the distressing dreams, hallucinations, and limb numbness items of the PDSS (p ≤ 0.05). CONCLUSIONS: Introduction of opicapone in real-life PwP with motor fluctuations seems to stabilise NMS burden and aspects of sleep dysfunction, in contrast to entacapone where there was a worsening of NMS burden and PDSS scores over 1 year follow-up.

Synthesis and analysis of novel catecholic ligands as inhibitors of catechol-O-methyltransferase.

l-DOPA, a dopamine precursor, is commonly used as a treatment for patients with conditions such as Parkinson's disease. This therapeutic l-DOPA, as well as the dopamine derived from l-DOPA, can be deactivated via metabolism by catechol-O-methyltransferase (COMT). Targeted inhibition of COMT prolongs the effectiveness of l-DOPA and dopamine, resulting in a net increase in pharmacological efficiency of the treatment strategy. Following the completion of a previous ab initio computational analysis of 6-substituted dopamine derivatives, several novel catecholic ligands with a previously unexplored neutral tail functionality were synthesized in good yields and their structures were confirmed. The ability of the catecholic nitriles and 6-substituted dopamine analogues to inhibit COMT was tested. The nitrile derivatives inhibited COMT most effectively, in agreement with our previous computational work. pKa values were used to further examine the factors involved with the inhibition and molecular docking studies were performed to support the ab initio and experimental work. The nitrile derivatives with a nitro substituent show the most promise as inhibitors, confirming that both the neutral tail and the electron withdrawing group are essential on this class of inhibitors.

Rare Catechol-O-methyltransferase Missense Variants Are Structurally Unstable Proteasome Targets.

Catechol-O-methyltransferase (COMT) is a key enzyme in the metabolism of catecholamines. Substrates of the enzyme include neurotransmitters such as dopamine and epinephrine, and therefore, COMT plays a central role in neurobiology. Since COMT also metabolizes catecholamine drugs such as L-DOPA, variation in COMT activity could affect pharmacokinetics and drug availability. Certain COMT missense variants have been shown to display decreased enzymatic activity. Additionally, studies have shown that such missense variants may lead to loss of function induced by impaired structural stability, which results in activation of the protein quality control system and degradation by the ubiquitin-proteasome system. Here, we demonstrate that two rare missense variants of COMT are ubiquitylated and targeted for proteasomal degradation as a result of structural destabilization and misfolding. This results in strongly reduced intracellular steady-state levels of the enzyme, which for the L135P variant is rescued upon binding to the COMT inhibitors entacapone and tolcapone. 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.

Clinical benefit of MAO-B and COMT inhibition in Parkinson's disease: practical considerations.

Inhibitors of monoamine oxidase B (MAO-B) and catechol-O-methyltransferase (COMT) are major strategies to reduce levodopa degradation and thus to increase and prolong its effect in striatal dopaminergic neurotransmission in Parkinson's disease patients. While selegiline/rasagiline and tolcapone/entacapone have been available on the market for more than one decade, safinamide and opicapone have been approved in 2015 and 2016, respectively. Meanwhile, comprehensive data from several post-authorization studies have described the use and specific characteristics of the individual substances in clinical practice under real-life conditions. 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.

Catechol-O-methyltransferase Inhibitors from Calendula officinalis Leaf.

Calendula officinalis is commonly known as marigold and its flowers are used in herbal medicines, cosmetics, perfumes, dyes, pharmaceutical preparations, and food products. However, the utility of its leaves has not been studied in depth. The purpose of the present study was to identify the major compounds in C. officinalis leaves and to determine the inhibitory properties of the isolated compounds toward human catechol-O-methyltransferase (COMT), a key neurotransmitter involved in Parkinson's disease and depression. We isolated and identified ten compounds, including two phenylpropanoids and seven flavonoids, from C. officinalis leaf extracts, of which four flavonoids were identified from C. officinalis leaves for the first time. Eight compounds exhibited COMT inhibitory activities with IC50 values of less than 100 µM. Our results indicate that compounds in C. officinalis leaves are potentially effective for preventing Parkinson's disease and depression. Thus, C. officinalis leaves may hold promise as dietary supplements.

Two Faces of Catechol-O-Methyltransferase Inhibitor on One-Carbon Metabolism in Parkinson's Disease: A Meta-Analysis.

Levodopa (L-dopa) and catechol-O-methyltransferase (COMT) inhibition are widely used therapeutics in Parkinson's disease (PD). Despite their therapeutic effects, it was raised that nutrients involved in one-carbon metabolism can be deteriorated by PD therapies. The aim of this meta-analysis was to investigate the impact of L-dopa and COMT inhibitors on levels of homocysteine (Hcy), vitamin B12 and folate in patients with PD. A total of 35 case-control studies from 14 different countries were selected through PubMed, MEDLINE and Google Scholar and were meta-analyzed. In the L-dopa group, the Hcy level was higher compared to the PD without L-dopa group (SMD: 5.11 µmol/L, 95% CI: 3.56 to 6.66). Moreover, vitamin B12 and folate levels in the L-dopa group were lower compared to the healthy control (SMD: -62.67 pg/mL, 95% CI: -86.53 to -38.81; SMD: -0.89 ng/mL, 95% CI: -1.44 to -0.33, respectively). The COMT inhibitor group showed lower levels of Hcy (SMD: -3.78 µmol/L, 95% CI: -5.27 to -2.29) and vitamin B12 (SMD: -51.01 pg/mL, 95% CI: -91.45 to -10.57), but higher folate levels (SMD: 1.78 ng/mL, 95% CI: -0.59 to 4.15) compared to the L-dopa group. COMT inhibitors may ameliorate L-dopa-induced hyper-homocysteine and folate deficiency but exacerbate vitamin B12 deficiency.

Opicapone Pharmacokinetics and Effects on Catechol- O -Methyltransferase Activity and Levodopa Pharmacokinetics in Patients With Parkinson Disease Receiving Carbidopa/Levodopa.

OBJECTIVES: Levodopa (LD) administered with dopa decarboxylase inhibitor is predominantly metabolized in the periphery by catechol- O -methyltransferase (COMT) to 3- O -methyldopa (3-OMD). Catechol- O -methyltransferase inhibition can improve treatment outcomes by decreasing variability in circulating LD concentrations. Opicapone is a once-daily COMT inhibitor approved in the US adjunctive to carbidopa (CD)/LD in patients with Parkinson disease experiencing "OFF" episodes. This study aimed to evaluate the pharmacokinetics and pharmacodynamics of once-daily opicapone 50 mg adjunctive to CD/LD in patients with stable Parkinson disease. METHODS: Once-daily opicapone 50 mg was administered the evenings of days 1 to 14. Participants were randomized to receive CD/LD (25/100 mg) every 3 or 4 hours (Q3H or Q4H). Participants received Q3H or Q4H CD/LD on days 1, 2, and 15 and their usual CD/LD regimen on other days. Serial blood samples were collected to determine plasma opicapone, LD, and 3-OMD concentrations and erythrocyte soluble COMT (S-COMT) activity. The effects of opicapone on S-COMT, LD, and 3-OMD were assessed. Mean (SD) values are presented. RESULTS: Sixteen participants were enrolled. At steady-state (day 14), opicapone Cmax (peak plasma concentration) and AUC 0-last (area under the curve-time curve) were 459 ± 252 ng/mL and 2022 ± 783 ng/mL·h, respectively. Maximum COMT inhibition was 83.4 ± 4.9% of baseline on day 14. After opicapone administration, LD total AUC, peak concentration, and trough concentration increased; peak-to-trough fluctuation index decreased. Correspondingly, 3-OMD total AUC, peak concentration, and trough concentration decreased. CONCLUSIONS: Adding once-daily opicapone 50 mg to LD resulted in marked and extended COMT inhibition, which increased systemic exposure to LD. These changes translated into higher trough concentrations and decreased peak-to-trough fluctuations for LD.

Effect of Carbidopa Dose on Levodopa Pharmacokinetics With and Without Catechol-O-Methyltransferase Inhibition in Healthy Subjects.

BACKGROUND AND OBJECTIVES: The treatment of Parkinson's disease (PD) is still symptomatic since disease-modifying treatments for PD are not available. Oral levodopa is the gold standard for the treatment of PD motor symptoms. However, incomplete and fluctuating plasma exposure of levodopa leads to suboptimal treatment of the symptoms. The main objective of this study was to investigate to what extent increased carbidopa doses (50 and 100 mg) increase the plasma levels of 100-mg immediate-release (IR) levodopa compared to a 25-mg carbidopa dose with and without co-administration of 200 mg entacapone. METHODS: A double-blind, placebo-controlled, randomized, crossover, phase I, pharmacokinetic study with 25 healthy volunteers was conducted. In addition, a semi-mechanistic pharmacokinetic model was built to theoretically evaluate the effect of inhibiting aromatic amino acid decarboxylase (AADC) and catechol-O-methyltransferase (COMT) mediated metabolism of levodopa on the exposure of levodopa. RESULTS: The effect of increased carbidopa doses 50 and 100 mg on the total exposure (AUC) of 100 mg IR levodopa was +29% and +36%, respectively, when entacapone was co-administered. Without entacapone, the corresponding increases were +13% and +17%. With entacapone co-administration, the increased carbidopa dose also clearly increased levodopa trough concentration. There was no significant effect on the peak concentrations of levodopa. CONCLUSIONS: Increasing carbidopa doses significantly increased the exposure and reduced the fluctuation of IR levodopa in plasma during simultaneous COMT inhibition with entacapone. Theoretical pharmacokinetic simulations suggested that the plasma profile of oral IR levodopa can be even further improved by optimizing AADC and COMT inhibition.

Opicapone for the treatment of Parkinson's disease: a review.

Purpose: Levodopa formulations are the workhorses of the labor against motor symptoms management in Parkinson's disease (PD). Progression of PD on levodopa inevitably leads to motor fluctuations. It is important to understand the safety and efficacy of opicapone, the most recent addition to the clinician's armamentarium against these fluctuations.Materials and methods: We review the development of COMT inhibitors in the treatment of PD as well as the efficacy and safety data reported in the currently published literature of opicapone in PD. The "currently published literature" is defined as all published, PubMed indexed trials including the word "opicapone." Finally, we compare opicapone to the competitor pharmaceuticals on the market to treat symptom fluctuations in PD and share our opinion of opicapone's place in clinical practice.Results: From the reported results of phase 3 and 4 trials of opicapone in PD, it is a safe and efficacious option to combat motor fluctuations for our PD patients taking levodopa. A reduction of "off" time by up to 1 h per day can be expected, increasing "on" time with fewer dyskinesias. Opicapone is not generally hepatotoxic, and the most reported side-effects-dyskinesia, dry mouth, dizziness, diarrhea, and constipation-were seen in only 1.4% of the OPTIPARK (a large phase 4 clinical trial) study population.Conclusions: One should consider utilizing opicapone, perhaps in combination with other augmenting medications with different mechanisms of action, to help treat motor and non-motor fluctuations in PD.

Developmental and behavioral toxicity assessment of opicapone in zebrafish embryos.

The use of clinical psychoactive drugs often poses unpredictable threats to fetal development. Catechol-O-methyltransferase (COMT) is a key enzyme that regulates dopamine metabolism and a promising target for modulation of cognitive functions. Opicapone, a newly effective third-generation peripheral COMT inhibitor, is used for the treatment of Parkinson's disease (PD) and possibly to improve other dopamine-related disorders such as alcohol use disorder (AUD) and obsessive-compulsive disorder (OCD). The widespread use of opicapone will inevitably lead to biological exposure and damage to the human body, such as affecting fetal development. However, the effect of opicapone on embryonic development remains unknown. Here, zebrafish larvae were used as an animal model and demonstrated that a high concentration (30 µM) of opicapone exposure was teratogenic and lethal, while a low concentration also caused developmental delay such as a shortened body size, a smaller head, and reduced locomotor behaviors in zebrafish larvae. Meanwhile, opicapone treatment specifically increased the level of dopamine (DA) in zebrafish larvae. The depletion response of the total glutathione level (including oxidized and reduced forms of glutathione) and changed antioxidant enzymes activities in zebrafish larvae suggest oxidative damage caused by opicapone. In addition, enhanced glutathione metabolism and cytokine-cytokine receptor interaction were found in zebrafish larvae treated with opicapone, indicating that opicapone treatment caused an oxidation process and immune responses. Our results provide a new insight into the significant developmental toxicity of opicapone in zebrafish larvae.