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.

L-DOPA-therapy in Parkinson's disease: some personal reflections on L-DOPA therapy from Vienna and Berlin.

Dopamine was initially considered as a mere intermediate in the noradrenaline synthesis but was then found to be a neurotransmitter. Its depletion resulted in characteristic symptoms in experimental studies and could be antagonized by DOPA (3,4-dihydroxyphenylalanin), suggesting a similarity to the human disorder Parkinson´s disease (PD) and a therapeutic potential which was successfully exploited from the 1970s on. This was due to the pioneering work of Arvid Carlsson and clinicians around the world who first worked on the breakthrough of L-DOPA therapy and then on its amendment and modification and on alternative therapies for PD patients. All these developments led to the establishment of PD therapy as we know it today. It is characterized by the availability of many different compounds which are mostly employed in combination and by different methods: orally, intravenously, transdermally, subcutaneously, or duodenally. Here, we present without claim of completeness some personal reflections about causal drug developments for PD patients and reflect on some personal interactions with leading clinicians and basic researchers who cooperated with us. Such interactions are crucial for the creation, sometimes serendipitously, of fresh ideas and to further develop existing concepts to make therapeutical progress.

Real-world considerations regarding the use of the combination of levodopa, carbidopa, and entacapone (Stalevo® ) in Parkinson's disease.

An important aim in long-term levodopa therapy is to prolong the duration of symptomatic efficacy of each dose without increasing peak plasma concentrations above the threshold for the emergence of dyskinesias. One strategy is to enhance levodopa delivery to the brain by co-administering it with inhibitors of peripheral dopa-decarboxylase and catechol-O-methyltransferase (COMT). Levodopa, carbidopa and entacapone (LCE), available in a range of fixed-dose combinations as the branded formulation Stalevo® (Orion Pharma), has been developed to address this requirement and has been in general use for 20 years, having first been evaluated in randomized controlled trials. Experience with LCE has established that improved levodopa pharmacokinetics achieved with dual-enzyme inhibition are translated into improved clinical efficacy, including the possibility of reducing total levodopa dosage with no loss of therapeutic effect. The ease and tolerability of switching to LCE has been affirmed in the SIMCOM trial and by personal experience detailed in this review. Some 300,000 patient-years of safety data are available for LCE, including trial data for up to 5 years. Most adverse effects associated with LCE are attributable to the levodopa component rather than the enzyme inhibitors. 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.

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.

Effect of Opicapone on Levodopa Pharmacokinetics in Patients with Fluctuating Parkinson's Disease.

BACKGROUND: Inhibiting catechol-O-methyltransferase extends the plasma half-life of levodopa, potentially allowing physicians to optimize the levodopa regimen in patients with Parkinson's disease (PD) experiencing motor fluctuations. OBJECTIVES: To evaluate the effects of once-daily opicapone on levodopa plasma pharmacokinetics and motor response when added to two different levodopa dosing regimens. METHODS: A total of 24 patients with PD and motor fluctuations were enrolled in an exploratory, open-label, modified cross-over trial. Participants first received levodopa/carbidopa 500/125 mg (five intakes) for 2 weeks and were then randomly assigned (1:1) to levodopa/carbidopa 400/100 mg given over either four or five daily intakes plus opicapone 50 mg for an additional 2 weeks. Levodopa 12-hour pharmacokinetics was the primary outcome (ie, excluding the effect of last/evening levodopa/carbidopa intake), with motor complications evaluated as secondary outcomes. RESULTS: Over 12-hour pharmacokinetics and compared with five-intake levodopa/carbidopa 500/125 mg without opicapone, maximal levodopa concentrations were similar or nonsignificantly higher on both levodopa/carbidopa 400/100 mg regimens plus opicapone. Despite a 100 mg lower total levodopa/carbidopa daily dose, adding opicapone 50 mg at least doubled the levodopa plasma half-life and minimal concentrations, with a significant ≈30% increase in total exposure. The levodopa fluctuation index was only significantly lower for the five intakes plus opicapone regimen (difference of -71.8%; P < 0.0001). Modifications to levodopa pharmacokinetics were associated with decreased off time and increased on time. CONCLUSIONS: Combining opicapone 50 mg with a 100 mg lower daily dose of levodopa provides higher levodopa bioavailability with avoidance of trough levels. Despite the lower levodopa dose, modifying the levodopa pharmacokinetic profile with opicapone was associated with decreased off time and increased on time. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Novel formulations and modes of delivery of levodopa.

Ever since its early clinical use in the 1960s, levodopa has remained the gold standard of symptomatic efficacy in the drug treatment of Parkinson's disease (PD). Motor response fluctuations and drug-induced dyskinesias seriously compromise the unparalleled symptomatic efficacy of l-dopa during long-term treatment. Discontinuous drug delivery resulting from the short half-life of l-dopa and erratic gastrointestinal absorption plays a major role in the pathophysiology of these motor complications. Several approaches to improve the pharmacokinetics and ways of administration of l-dopa are in different stages of clinical development and include novel formulations as well as nonoral routes of drug delivery. IPX066 is a novel extended-release l-dopa capsule that has successfully completed phase III clinical trials while the l-dopa prodrug XP21279 and a gastric retention formulation ("accordion pill") are in earlier phases of clinical development. Novel enzyme inhibitors enhancing l-dopa efficacy and half-life are also still being developed, including a novel catechol-O-methyltransferase inhibitor with once-daily pharmacokinetics, and there are studies testing the effects of increasing the dose of amino acid decarboxylase inhibitors given concomitantly with l-dopa. Intrajejunal infusion of a gel formulation of l-dopa/carbidopa is in clinical use in Europe, and its efficacy to smooth out motor fluctuations has recently been shown in a randomized, controlled trial. Subcutaneous and intrapulmonal delivery routes of l-dopa have reached phase III of clinical development. After more than 50 years of clinical use, l-dopa not only remains the gold standard of symptomatic efficacy, but it also remains a drug in active clinical development.

Use of an entacapone-containing drug combination and risk of death: Analysis of the FDA AERS (FAERS) database.

To assess the signal of death associated with the use of an entacapone-containing drug combination in the FDA Adverse Event Reporting System (FAERS) database. Reports of death events submitted between January 2004 and December 2010 were retrieved and analysed by the reporting odds ratio (ROR). The ROR of case/non-case reports of death associated with an entacapone-containing drug combination was compared with the levodopa/carbidopa combination using the FDA AERS database. Eighty-seven reports linked the entacapone-containing drug combination to death, compared to 27 reports of death linking the levodopa/carbidopa combination. The ROR was statistically significant for the association between deaths with the use of an entacapone-containing drug combination (1.86 [95% CI 1.50-2.31]). In contrast, the ROR of death associated with the combination of levodopa and carbidopa was not statistically significant (0.89 [95% CI 0.61-1.30)]. Based on analysing reports in the FAERS database, there is a risk of death with the use of an entacapone-containing drug combination. These results generated a signal of death with the use of this drug. However, epidemiological studies are required to confirm this association.

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.

An update on the pharmacogenetic considerations when prescribing dopamine receptor agonists for Parkinson's disease.

INTRODUCTION: Parkinson's disease is a chronic neurodegenerative multisystemic disorder that affects approximately 2% of the population over 65 years old. This disorder is characterized by motor symptoms which are frequently accompanied by non-motor symptoms such as cognitive disorders. Current drug therapies aim to reduce the symptoms and increase the patient's life expectancy. Nevertheless, there is heterogeneity in therapy response in terms of efficacy and adverse effects. This wide range in response may be linked to genetic variability. Thus, it has been suggested that pharmacogenomics may help to tailor and personalize drug therapy for Parkinson's disease. AREAS COVERED: This review describes and updates the clinical impact of genetic factors associated with the efficacy and adverse drug reactions related to common medications used to treat Parkinson's disease. Additionally, we highlight current informative recommendations for the drug treatment of Parkinson's disease. EXPERT OPINION: The pharmacokinetic, pharmacodynamic, and safety profiles of Parkinson's disease drugs do not favor the development of pharmacogenetic tests with a high probability of success. The chances of obtaining ground-breaking pharmacogenetics biomarkers for Parkinson's disease therapy are limited. Nevertheless, additional information on the metabolism of certain drugs, and an analysis of the potential of pharmacogenetics in novel drugs could be of interest.

Optimizing levodopa therapy, when and how? Perspectives on the importance of delivery and the potential for an early combination approach.

INTRODUCTION: There is currently a resurgence of levodopa as the initial treatment of choice for most patients with Parkinson's disease, albeit at lower doses than previously used. The addition of adjuvant treatments (including MAO-B inhibitors, COMT inhibitors and dopamine agonists) is an established strategy to reduce motor complications that develop with sustained levodopa therapy. AREAS COVERED: In this narrative review, the authors discuss the evidence underpinning current levodopa optimization strategies, during early disease and once motor complications occur. To support the discussion, the authors performed a broad PubMed search with the terms 'levodopa/L-dopa/L-Dopa, and Parkinson's disease,' restricted to clinical trials. There is now a wealth of evidence that improving levodopa delivery to the brain improves outcomes and we discuss how agents can be combined earlier in the course of disease to leverage the full potential of this strategy. EXPERT OPINION: Levodopa remains the cornerstone of antiparkinsonian therapy. Several promising advances in formulation have been made and include novel extended-release oral drugs as well as non-oral delivery systems. However, evidence has long suggested that anti-parkinsonian medications may be better used in combination earlier in the disease, and consequently patients will benefit from low doses of several agents rather than ever larger levodopa doses.

Depletion of dopamine in Parkinson's disease and relevant therapeutic options: A review of the literature.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects motor and cognition functions. The etiology of Parkinson's disease remains largely unknown, but genetic and environmental factors are believed to play a role. The neurotransmitter dopamine is implicated in regulating movement, motivation, memory, and other physiological processes. In individuals with Parkinson's disease, the loss of dopaminergic neurons leads to a reduction in dopamine levels, which causes motor impairment and may also contribute to the cognitive deficits observed in some patients. Therefore, it is important to understand the pathophysiology that leads to the loss of dopaminergic neurons, along with reliable biomarkers that may help distinguish PD from other conditions, monitor its progression, or indicate a positive response to a therapeutic intervention. Important advances in the treatment, etiology, and pathogenesis of Parkinson's disease have been made in the past 50 years. Therefore, this review tries to explain the different possible mechanisms behind the depletion of dopamine in PD patients such as alpha-synuclein abnormalities, mitochondrial dysfunction, and 3,4-dihydroxyphenylacetaldehyde (DOPAL) toxicity, along with the current therapies we have and the ones that are in development. The clinical aspect of Parkinson's disease such as the manifestation of both motor and non-motor symptoms, and the differential diagnosis with similar neurodegenerative disease are also discussed.

Unveiling the biopathway for the design of novel COMT inhibitors.

Catechol-O-methyltransferase (COMT) is an enzyme responsible for the O-methylation of biologically active catechol-based molecules. It has been associated with several neurological disorders, especially Parkinson's disease (PD), because of its involvement in catecholamine metabolism, and has been considered an important therapeutic target for central nervous system disorders. In this review, we summarize the biophysical, structural, and therapeutical relevance of COMT; the medicinal chemistry behind the development of COMT inhibitors and the application of computer-aided design to support the design of novel molecules; current methodologies for the biosynthesis, isolation, and purification of COMT; and revise existing bioanalytical approaches for the assessment of enzymatic activity in several biological matrices.

Selected Natural and Synthetic Agents Effective against Parkinson's Disease with Diverse Mechanisms.

Similar to other neurodegenerative diseases, Parkinson's disease (PD) has been extensively investigated with respect to its neuropathological background and possible treatment options. Since the symptomatic outcomes are generally related to dopamine deficiency, the current treatment strate-gies towards PD mainly employ dopaminergic agonists as well as the compounds acting on dopamine metabolism. These drugs do not provide disease modifying properties; therefore alternative drug dis-covery studies focus on targets involved in the progressive neurodegenerative character of PD. This study has aimed to present the pathophysiology of PD concomitant to the representation of drugs and promising molecules displaying activity against the validated and non-validated targets of PD.

Chalcones as Potential Ligands for the Treatment of Parkinson's Disease.

Along with the increase in life expectancy, a significant increase of people suffering from neurodegenerative diseases (ND) has been noticed. The second most common ND, after Alzheimer's disease, is Parkinson's disease (PD), which manifests itself with a number of motor and non-motor symptoms that hinder the patient's life. Current therapies can only alleviate those symptoms and slow down the progression of the disease, but not effectively cure it. So now, in addition to understanding the mechanism and causes of PD, it is also important to find a powerful way of treatment. It has been proved that in the etiology and course of PD, the essential roles are played by dopamine (DA) (an important neurotransmitter), enzymes regulating its level (e.g., COMT, MAO), and oxidative stress leading to neuroinflammation. Chalcones, due to their "simple" structure and valuable biological properties are considered as promising candidates for treatment of ND, also including PD. Here, we provide a comprehensive review of chalcones and related structures as potential new therapeutics for cure and prevention of PD. For this purpose, three databases (Pubmed, Scopus and Web of Science) were searched to collect articles published during the last 5 years (January 2018-February 2022). Chalcones have been described as promising enzyme inhibitors (MAO B, COMT, AChE), α-synuclein imaging probes, showing anti-neuroinflammatory activity (inhibition of iNOS or activation of Nrf2 signaling), as well as antagonists of adenosine A1 and/or A2A receptors. This review focused on the structure-activity relationships of these compounds to determine how a particular substituent or its position in the chalcone ring(s) (ring A and/or B) affects biological activity.

Entacapone - Another Parkinson's medication associated with lymphocytic colitis.

In response to the report of Ong and colleagues of a series of patients with levodopa/dopa decarboxylase inhibitor associated microscopic colitis, we report a case of entacapone associated microscopic colitis. We agree that chronic diarrhoea in patients with Parkinson's disease should prompt consideration of drug-induced microscopic colitis as the cause.

Cost-effectiveness of opicapone and entacapone in reducing OFF-time in Parkinson's disease patients treated with levodopa/carbidopa.

AIMS: To assess from a US payer perspective the relative cost-effectiveness of the catechol-O-methyltransferase inhibitors opicapone and entacapone when used adjunctively to levodopa/carbidopa (LD/CD) in patients with Parkinson's disease (PD), based on the drugs' effects to reduce absolute OFF-time hours in PD patients. MATERIALS AND METHODS: A Markov model was created to estimate cost-effectiveness of adjunctive opicapone treatment compared with adjunctive entacapone treatment in a synthetic cohort of 1,000 patients with PD taking LD/CD. Clinical inputs were derived from clinical trials, published literature, and expert opinion. Cost data (in 2018 US dollars) were obtained from the Centers for Medicare & Medicaid Services, the Kaiser Family Foundation, and Analy$ource. Cost-effectiveness outcomes included incremental cost per OFF-time hours avoided, cost per life year gained, and cost per quality-adjusted life year (QALY) gained. Outcomes were projected over a 25-year lifetime horizon and discounted at 3% annually. RESULTS: Opicapone treatment was associated with an average of 1,187 fewer OFF-time hours per patient and an increase of 0.07 QALYs compared with entacapone. Total lifetime costs for opicapone were $3,100 higher than entacapone, resulting in an incremental cost-effectiveness ratio of $46,900 per QALY. One-way sensitivity analyses showed the model was most sensitive to mean OFF-time hours associated with opicapone and entacapone. Probabilistic sensitivity analysis suggested a 60-65% probability that opicapone was cost-effective relative to entacapone at any willingness-to-pay threshold ≥$5,000. LIMITATIONS: There exists a single head-to-head clinical trial comparing the effectiveness of opicapone with entacapone, thus the clinical inputs regarding relative treatment effect of the drugs to reduce OFF-time hours in PD patients receiving LD/CD were derived from that single non-inferiority trial. CONCLUSIONS: Add-on treatment with opicapone in PD patients receiving LD/CD appeared to be cost-effective compared with entacapone.

Cheminformatics and virtual screening studies of COMT inhibitors as potential Parkinson's disease therapeutics.

Introduction: Parkinson's Disease (PD) is a neurodegenerative central nervous system (CNS) disorder characterized by dopaminergic neuron degeneration with consequent reduction in striatal dopamine (DA) levels that leads to motor symptoms. Catechol-O-methyltransferase (COMT, E.C 2.1.1.6) inactivates dopamine and other substrates bearing catechol through the methylation of a hydroxyl group. COMT inhibition can block metabolism of catecholamines including DA. Since the increase in DA bioavailability is dependent on the inhibition of DA metabolism at the periphery, the development of COMT inhibitors as adjuvants to levodopa/aromatic amino acid decarboxylase (AADC) inhibitor treatment improves the clinical benefits of PD symptomatic treatment significantly.Areas covered: This review focuses on the contribution of computational studies to develop novel COMT inhibitors as therapeutics of Parkinson's disease with substantially improved efficacy.Expert opinion: The increasing use of in silico methods and the development of new chemoinformatic tools in combination with the knowledge gained from the development of different inhibitors studied both in silico, in vitro and in vivo, could help solve a number of issues related to the shortcomings of currently marketed treatments. They can also aid to open new avenues for centrally acting COMT inhibitors, and perhaps irreversible inhibitors, to be tested for PD and other neurological diseases.

The launch of opicapone for Parkinson's disease: negatives versus positives.

INTRODUCTION: Opicapone is a novel, third generation COMT inhibitor approved for the treatment of Parkinson's disease. Safety and tolerability data is critical to determine the benefit-harm balance and anticipate therapeutic adherence. Areas covered: This review evaluates the tolerability and safety profile of opicapone. These data were extracted from all published clinical trials, including preclinical, phase I, phase II and phase III studies as well as postmarketing data. Opicapone was safe and well tolerated, with frequencies of treatment-emergent adverse events similar to placebo. Expert opinion: Opicapone have shown a good safety and tolerability profile. This adds to its proven efficacy and convenient once-daily administration, supporting a role of opicapone as a first-line therapy for motor complications in Parkinson's disease patients.

Genetics and Treatment Response in Parkinson's Disease: An Update on Pharmacogenetic Studies.

Parkinson's disease (PD) is a complex neurodegenerative disorder characterized by a progressive loss of dopamine neurons of the central nervous system. The disease determines a significant disability due to a combination of motor symptoms such as bradykinesia, rigidity and rest tremor and non-motor symptoms such as sleep disorders, hallucinations, psychosis and compulsive behaviors. The current therapies consist in combination of drugs acting to control only the symptoms of the illness by the replacement of the dopamine lost. Although patients generally receive benefits from this symptomatic pharmacological management, they also show great variability in drug response in terms of both efficacy and adverse effects. Pharmacogenetic studies highlighted that genetic factors play a relevant influence in this drug response variability. In this review, we tried to give an overview of the recent progresses in the pharmacogenetics of PD, reporting the major genetic factors identified as involved in the response to drugs and highlighting the potential use of some of these genomic variants in the clinical practice. Many genes have been investigated and several associations have been reported especially with adverse drug reactions. However, only polymorphisms in few genes, including DRD2, COMT and SLC6A3, have been confirmed as associated in different populations and in large cohorts. The identification of genomic biomarkers involved in drug response variability represents an important step in PD treatment, opening the prospective of more personalized therapies in order to identify, for each person, the better therapy in terms of efficacy and toxicity and to improve the PD patients' quality of life.

Spotlight on opicapone as an adjunct to levodopa in Parkinson's disease: design, development and potential place in therapy.

Parkinson's disease (PD) is a progressive, chronic, neurodegenerative disease characterized by rigidity, tremor, bradykinesia and postural instability secondary to dopaminergic deficit in the nigrostriatal system. Currently, disease-modifying therapies are not available, and levodopa (LD) treatment remains the gold standard for controlling motor and nonmotor symptoms of the disease. LD is extensively and rapidly metabolized by peripheral enzymes, namely, aromatic amino acid decarboxylase and catechol-O-methyltransferase (COMT). To increase the bioavailability of LD, COMT inhibitors are frequently used in clinical settings. Opicapone is a novel COMT inhibitor that has been recently approved by the European Medicines Agency as an adjunctive therapy to combinations of LD and aromatic amino acid decarboxylase inhibitor in adult PD patients with end-of-dose motor fluctuations. We aimed to review the biochemical properties of opicapone, summarize its preclinical and clinical trials and discuss its future potential role in the treatment of PD.