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Patrício Soares-da-silva - One of the best experts on this subject based on the ideXlab platform.

  • A single- and multiple-dose study to investigate the pharmacokinetics and pharmacodynamics of opicapone, a novel COMT Inhibitor, in rat
    Neuropharmacology, 2017
    Co-Authors: Daniela Gonçalves, Patrício Soares-da-silva, Gilberto Alves, Ana Fortuna, Maria João Bonifácio, Amílcar Falcão
    Abstract:

    Abstract Opicapone is a novel catechol- O -methyltransferase (COMT) Inhibitor that emerged to fulfil the need of a safer and more efficacious COMT Inhibitor. The present study was carried out in order to assess and compare the pharmacokinetics and pharmacodynamics (COMT inhibition) of opicapone after single and multiple oral administrations (30 mg/kg) to Wistar rats. For this purpose, at predefined time points up to 72 h post-dosing, blood, liver and kidneys were collected and, then, the concentrations of opicapone and its active metabolite (BIA 9–1079) were determined in plasma and in liver and kidney tissues, as well as the erythrocyte, liver and kidney COMT activity. No systemic, renal or hepatic accumulation of opicapone was observed following repeated administration. Furthermore, the tissue-systemic exposure relationships to opicapone suggested a low drug exposure in the liver and kidneys. After single-dosing, COMT inhibition profiles were reasonably comparable in all the studied matrices; although similar results were found after multiple-dosing, a higher degree of inhibition was observed, indicating a continuous peripheral COMT inhibition when opicapone is administered once-daily. Despite having a short elimination half-life (≤2.94 h), opicapone showed a strong and long-lasting COMT inhibition in both studies, since more than 50% of the COMT activity was still inhibited at 24 h post-dosing.

  • Metabolism of Opicapone, a Novel COMT Inhibitor, in the Rat: Characterization of In Vitro Sulfation
    The FASEB Journal, 2015
    Co-Authors: Ana I. Loureiro, Lyndon C. Wright, Carlos Fernandes-lopes, Patrício Soares-da-silva
    Abstract:

    In this study, opicapone, a novel catechol-O-methyltransferase (COMT) Inhibitor, metabolism was evaluated in the rat and the sulfotransferases (SULTs) responsible for opicapone sulfation were chara...

  • Brain and peripheral pharmacokinetics of levodopa in the cynomolgus monkey following administration of opicapone, a third generation nitrocatechol COMT Inhibitor
    Neuropharmacology, 2013
    Co-Authors: Maria João Bonifácio, Lyndon C. Wright, Leonel Torrão, J.s. Sutcliffe, Patrício Soares-da-silva
    Abstract:

    Abstract Objective The present study aimed at evaluating the effect of opicapone, a third generation nitrocatechol catechol- O -methyltransferase (COMT) Inhibitor, on the systemic and central bioavailability of 3,4-dihydroxy- l -phenylalanine (levodopa) and related metabolites in the cynomolgus monkey. Methods Four monkeys, implanted with guiding cannulas for microdialysis probes, in the substantia nigra , dorsal striatum and prefrontal cortex, were randomized in two groups that received, in a crossover design, vehicle or 100 mg/kg opicapone for 14 days. Twenty-three hours after last administration of vehicle or opicapone, animals were challenged with levodopa/benserazide (12/3 mg/kg). Extracellular dialysate and blood samples were collected over 360 min (at 30 min intervals) for the assays of catecholamine and COMT activity. Results Opicapone increased levodopa systemic exposure by 2-fold not changing C max values and reduced both 3- O -methyldopa (3-OMD) exposure and C max values by 5-fold. These changes were accompanied by ∼76–84% reduction in erythrocyte COMT activity. In dorsal striatum and substantia nigra , opicapone increased levodopa exposure by 1.7- and 1.4-fold, respectively, reducing 3-OMD exposure by 5- and 7-fold respectively. DOPAC exposure was increased by 4-fold in the substantia nigra . In the prefrontal cortex, opicapone increased levodopa exposure and reduced 3-OMD levels by 2.3- and 2.4-fold, respectively. Conclusions Opicapone behaved as long-acting COMT Inhibitor that markedly increased systemic and central levodopa bioavailability. Opicapone is a strong candidate to fill the unmet need for COMT Inhibitors that lead to more sustained levodopa levels in Parkinson's disease patients.

  • Effect of opicapone multiple-dose regimens on levodopa pharmacokinetics, motor response, and erythrocyte-COMT activity in Parkinson's patients co-administered with levodopa/dopa-decarboxylase Inhibitor
    Journal of the Neurological Sciences, 2013
    Co-Authors: Joaquim J. Ferreira, José-francisco Rocha, Amílcar Falcão, Roberto Pinto, Teresa G. Nunes, Patrício Soares-da-silva
    Abstract:

    WCN 2013 No: 1034 Topic: 2 — Movement Disorders Effect of opicapone multiple-dose regimens on levodopa pharmacokinetics, motor response, and erythrocyte-COMT activity in Parkinson's patients co-administered with levodopa/dopa-decarboxylase Inhibitor J.J. Ferreira, J.-F. Rocha, A. Falcao, R. Pinto, T. Nunes, P. Soares-da-Silva. Neurological Clinical Research Unit, Instituto de Medicina Molecular, Lisbon, Portugal; Research & Development, BIAL-PortelaC Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal; Dept. of Pharmacology & Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal Background: Opicapone (OPC) was developed to fulfil the need for more potent, safer and longer acting COMT Inhibitors. Objectives: Investigate the effect of once-daily 5, 15 and 30 mg OPC, a new COMT Inhibitor, on the levodopa pharmacokinetics, in Parkinson's Disease (PD) patients with motor fluctuations treated with standardrelease 100/25 mg levodopa/carbidopa (LC) or levodopa/benserazide (LB). Methods: This was a multicentre, double-blind, randomised, placebocontrolled study in four parallel groups of PD patients treated with LC or LB and with motor fluctuations (“wearing-off” phenomenon). Subjects were sequentially and randomly assigned to be administered, once-daily, during the 21 to 28 day maintenance phase with placebo or 5, 15 and 30 mg OPC. Subjects performed two levodopa tests, one on the morning of the day after admission and another following themaintenance phase. Subjects also kept a diary to record ON/OFF periods. Results: In relation to placebo, levodopa exposure increased 24.73%, 53.93% and 65.61% following 5, 15 or 30 mg OPC. Maximum S-COMT inhibition (Emax) ranged from 52% (5 mg OPC) to 80% (30 mgOPC). The study was not designed to detect any significant differences in motor performance, but the exploratory analysis performed shows improvement in various motor outcomes, including a dose dependent change in absolute OFF time corresponding to a percentage decrease of 0.77%, 4.16%, 29.55% and 32.71% with placebo, 5 mg, 15 mg and 30 mg OPC, respectively. Conclusion: OPC is a promising new COMT Inhibitor and deserves further clinical evaluation in larger samples of patients with PD on levodopa treatment with motor fluctuations. doi:10.1016/j.jns.2013.07.390 Abstract — WCN 2013 No: 1038 Topic: 2 — Movement Disorders Efficacy and safety of opicapone, a new COMT-Inhibitor, for the treatment of motor fluctuations in Parkinson's Disease patients: BIPARK-II study WCN 2013 No: 1038 Topic: 2 — Movement Disorders Efficacy and safety of opicapone, a new COMT-Inhibitor, for the treatment of motor fluctuations in Parkinson's Disease patients: BIPARK-II study A. Lees, J.J. Ferreira, R. Costa, J.-F. Rocha, C. Oliveira, N. Lopes, T. Nunes, P. Soares-da-Silva. National Hospital for Neurology and Neurosurgery, London, UK; Neurological Clinical Research Unit, Instituto de Medicina Molecular, Lisbon, Portugal; Research & Development, BIAL-Portela & Co. S.A., S. Mamede Coronado, Portugal; Dept. of Pharmacology & Therapeutics, Faculty of Medicine, University of Porto,

  • CHAPTER 4:Catechol‐O‐Methyl‐Transferase Inhibitors: Present Problems and Relevance of the New Ones
    Drug Discovery, 2013
    Co-Authors: P. Nuno Palma, Laszlo Erno Kiss, Patrício Soares-da-silva
    Abstract:

    Levodopa, in association with a DOPA decarboxylase Inhibitor (e.g., carbidopa or benserazide) has for many years been the undisputed gold standard drug for the symptomatic treatment of Parkinson’s disease (PD). However, given its rapid disposition and elimination in the periphery, it was hypothesized that significant enhancements in levodopa bioavailability and clinical efficacy could be achieved through co‐adjuvant therapy with a catechol‐O‐methyl‐transferase (COMT) Inhibitor. Early attempts, dating back to the late 1950s, to discover COMT Inhibitors were generally hampered by their lack of in vivo efficacy, target selectivity or by considerable toxicity. It was not until the late 1990s that entacapone and tolcapone, representatives of a new class of potent COMT Inhibitors (nitrocatechol derivatives), made their way to clinical practice for the treatment of PD. Even though these drugs have since contributed to an increase in the usefulness of levodopa therapy, each of them presents known limitations, namely concerning their clinical efficacy and safety. The unmet medical need for more efficacious and safer COMT Inhibitors has motivated intense research in this field over the last decade. Opicapone is the first, third‐generation COMT Inhibitor among the nitrocatechol derivatives under clinical development, and demonstrates superior pharmacodynamic and safety profiles in humans, over previous drugs. In this chapter, we review the major advances in this field, summarize the relevant non‐clinical and clinical human pharmacology and discuss new insights into the mechanism of action of opicapone.

Panos Bitsios - One of the best experts on this subject based on the ideXlab platform.

Lyndon C. Wright - One of the best experts on this subject based on the ideXlab platform.

Amílcar Falcão - One of the best experts on this subject based on the ideXlab platform.

  • A single- and multiple-dose study to investigate the pharmacokinetics and pharmacodynamics of opicapone, a novel COMT Inhibitor, in rat
    Neuropharmacology, 2017
    Co-Authors: Daniela Gonçalves, Patrício Soares-da-silva, Gilberto Alves, Ana Fortuna, Maria João Bonifácio, Amílcar Falcão
    Abstract:

    Abstract Opicapone is a novel catechol- O -methyltransferase (COMT) Inhibitor that emerged to fulfil the need of a safer and more efficacious COMT Inhibitor. The present study was carried out in order to assess and compare the pharmacokinetics and pharmacodynamics (COMT inhibition) of opicapone after single and multiple oral administrations (30 mg/kg) to Wistar rats. For this purpose, at predefined time points up to 72 h post-dosing, blood, liver and kidneys were collected and, then, the concentrations of opicapone and its active metabolite (BIA 9–1079) were determined in plasma and in liver and kidney tissues, as well as the erythrocyte, liver and kidney COMT activity. No systemic, renal or hepatic accumulation of opicapone was observed following repeated administration. Furthermore, the tissue-systemic exposure relationships to opicapone suggested a low drug exposure in the liver and kidneys. After single-dosing, COMT inhibition profiles were reasonably comparable in all the studied matrices; although similar results were found after multiple-dosing, a higher degree of inhibition was observed, indicating a continuous peripheral COMT inhibition when opicapone is administered once-daily. Despite having a short elimination half-life (≤2.94 h), opicapone showed a strong and long-lasting COMT inhibition in both studies, since more than 50% of the COMT activity was still inhibited at 24 h post-dosing.

  • pharmacokinetics pharmacodynamics and tolerability of opicapone a novel catechol o methyltransferase Inhibitor in healthy subjects prediction of slow enzyme Inhibitor complex dissociation of a short living and very long acting Inhibitor
    Clinical Pharmacokinectics, 2013
    Co-Authors: Luis Almeida, José-francisco Rocha, Amílcar Falcão, Roberto Pinto, Ana I. Loureiro, Lyndon C. Wright, Maria João Bonifácio, Nuno P Palma, Teresa Nunes, Patricio Soaresdasilva
    Abstract:

    Background and Objectives Opicapone is a novel catechol-O-methyltransferase (COMT) Inhibitor. The purpose of this study was to evaluate the tolerability, pharmacokinetics (including the effect of food) and pharmacodynamics (effect on COMT activity) following single oral doses of opicapone in young healthy male volunteers.

  • Effect of opicapone multiple-dose regimens on levodopa pharmacokinetics, motor response, and erythrocyte-COMT activity in Parkinson's patients co-administered with levodopa/dopa-decarboxylase Inhibitor
    Journal of the Neurological Sciences, 2013
    Co-Authors: Joaquim J. Ferreira, José-francisco Rocha, Amílcar Falcão, Roberto Pinto, Teresa G. Nunes, Patrício Soares-da-silva
    Abstract:

    WCN 2013 No: 1034 Topic: 2 — Movement Disorders Effect of opicapone multiple-dose regimens on levodopa pharmacokinetics, motor response, and erythrocyte-COMT activity in Parkinson's patients co-administered with levodopa/dopa-decarboxylase Inhibitor J.J. Ferreira, J.-F. Rocha, A. Falcao, R. Pinto, T. Nunes, P. Soares-da-Silva. Neurological Clinical Research Unit, Instituto de Medicina Molecular, Lisbon, Portugal; Research & Development, BIAL-PortelaC Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal; Dept. of Pharmacology & Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal Background: Opicapone (OPC) was developed to fulfil the need for more potent, safer and longer acting COMT Inhibitors. Objectives: Investigate the effect of once-daily 5, 15 and 30 mg OPC, a new COMT Inhibitor, on the levodopa pharmacokinetics, in Parkinson's Disease (PD) patients with motor fluctuations treated with standardrelease 100/25 mg levodopa/carbidopa (LC) or levodopa/benserazide (LB). Methods: This was a multicentre, double-blind, randomised, placebocontrolled study in four parallel groups of PD patients treated with LC or LB and with motor fluctuations (“wearing-off” phenomenon). Subjects were sequentially and randomly assigned to be administered, once-daily, during the 21 to 28 day maintenance phase with placebo or 5, 15 and 30 mg OPC. Subjects performed two levodopa tests, one on the morning of the day after admission and another following themaintenance phase. Subjects also kept a diary to record ON/OFF periods. Results: In relation to placebo, levodopa exposure increased 24.73%, 53.93% and 65.61% following 5, 15 or 30 mg OPC. Maximum S-COMT inhibition (Emax) ranged from 52% (5 mg OPC) to 80% (30 mgOPC). The study was not designed to detect any significant differences in motor performance, but the exploratory analysis performed shows improvement in various motor outcomes, including a dose dependent change in absolute OFF time corresponding to a percentage decrease of 0.77%, 4.16%, 29.55% and 32.71% with placebo, 5 mg, 15 mg and 30 mg OPC, respectively. Conclusion: OPC is a promising new COMT Inhibitor and deserves further clinical evaluation in larger samples of patients with PD on levodopa treatment with motor fluctuations. doi:10.1016/j.jns.2013.07.390 Abstract — WCN 2013 No: 1038 Topic: 2 — Movement Disorders Efficacy and safety of opicapone, a new COMT-Inhibitor, for the treatment of motor fluctuations in Parkinson's Disease patients: BIPARK-II study WCN 2013 No: 1038 Topic: 2 — Movement Disorders Efficacy and safety of opicapone, a new COMT-Inhibitor, for the treatment of motor fluctuations in Parkinson's Disease patients: BIPARK-II study A. Lees, J.J. Ferreira, R. Costa, J.-F. Rocha, C. Oliveira, N. Lopes, T. Nunes, P. Soares-da-Silva. National Hospital for Neurology and Neurosurgery, London, UK; Neurological Clinical Research Unit, Instituto de Medicina Molecular, Lisbon, Portugal; Research & Development, BIAL-Portela & Co. S.A., S. Mamede Coronado, Portugal; Dept. of Pharmacology & Therapeutics, Faculty of Medicine, University of Porto,

  • Bioanalytical chromatographic methods for the determination of catechol-O-methyltransferase Inhibitors in rodents and human samples: A review
    Analytica chimica acta, 2011
    Co-Authors: Daniela Gonçalves, Patrício Soares-da-silva, Gilberto Alves, Amílcar Falcão
    Abstract:

    In the past years, it has been recognised that the levodopa therapy may be improved with therapeutic regimens including a catechol-O-methyltransferase (COMT) Inhibitor. At the present time, tolcapone and entacapone are the only two COMT Inhibitors available in the market. However, further COMT Inhibitors are under development for Parkinson's disease, namely nebicapone and opicapone (formerly known as BIA 9-1067). In addition, the nitecapone, another well-known COMT Inhibitor, is also in preclinical development but for neuropathic pain. Since the 1990s different liquid chromatography methods have been developed and validated to quantify tolcapone, entacapone, nitecapone, nebicapone and some metabolites in biological samples, particularly in plasma samples obtained from rodent and human species. These bioanalytical methods have been primarily used to support pharmacokinetic assays with such COMT Inhibitors in non-clinical and clinical studies. As these Inhibitors present hydrophobic groups in their chemical structures, reversed-phase liquid chromatography has been used as the major approach for the determination of such compounds, especially high-performance liquid chromatography coupled to ultraviolet detection (HPLC-UV), electrochemical detection (HPLC-ECD) and mass spectrometry detection (HPLC-MS). Regarding the sample preparation, the traditional liquid-liquid extraction (LLE) and solid-phase extraction (SPE) were also the most widely used procedures for extraction of the analytes of interest prior to the analysis of samples. Thus, this review aimed to gather, for the first time, sufficient background information about the bioanalytical chromatographic methods which have been already developed and applied for the determination of tolcapone, entacapone, nitecapone, nebicapone and their metabolites. Moreover, some pharmacokinetic aspects of the COMT Inhibitors with interest from a bioanalytical perspective were also addressed.

  • Pharmacokinetic-Pharmacodynamic Interaction between Nebicapone, a Novel Catechol-O-Methyltransferase Inhibitor, and Controlled-Release Levodopa/Carbidopa 200 mg/50 mg
    Drugs in R&D, 2008
    Co-Authors: Manuel Vaz-da-silva, José-francisco Rocha, Amílcar Falcão, Teresa G. Nunes, Ana I. Loureiro, Carlos Lopes, Rita Machado, Raquel Costa, Leonel Torrão, Lyndon C. Wright
    Abstract:

    Background and objectives: Levodopa is the most effective symptomatic treatment for Parkinson’s disease (PD), but its use is often associated with development of motor complications. These adverse responses to fluctuations in dopaminergic stimulation can be reduced by concomitant administration of a catechol-O-methyltransferase (COMT) Inhibitor. Nebicapone is a new COMT Inhibitor currently being developed for use as an adjunct to levodopa/dopa decarboxylase Inhibitor in the treatment of PD. This article aimed to investigate the effect of single oral doses (50 mg, 100 mg and 200 mg) of nebicapone on levodopa pharmacokinetics and erythrocyte-soluble COMT (S-COMT) activity when coadministered with a single dose of controlled-release (CR) levodopa/carbidopa 200 mg/50 mg (Sinemet® CR 200/50) in healthy subjects (n = 16).

S.j. Gatley - One of the best experts on this subject based on the ideXlab platform.

  • Synthesis of [{sup 18}F]Ro41-0960, a potent COMT Inhibitor, for use in vivo mapping with PET
    The Journal of Nuclear Medicine, 1995
    Co-Authors: Yu-shin Ding, Y. Sugano, S.j. Gatley
    Abstract:

    Catechol-O-methyltransferase (COMPT; EC 2.1.1.6) is one of the two major enzymes which metabolize the catecholamine neurotransmitters. It is distributed throughout the body and brain and is elevated in breast cancer tissue when it plays a role in estrogen metabolism. It is also an important molecular target in the development of drugs to treat Parkinson`s disease (PD). Because COMT regulates the concentration of important neurotransmitter amines such as dopamine, there is speculation that abnormalities in its activity may be associated with neurological, and psychiatric disorders. Ro41-9060(3,4-dihydroxy-5-nitro-2{prime}-fluorobenzophenone) is a potent, fluorine containing COMT Inhibitor which has been reported to cross the blood brain barrier. It is structurally similar to Ro40-7592 which is currently undergoing clinical trials in PD. We report the synthesis of [{sup 18}F]Ro41-0960, for investigation for mapping COMT and for studies of COMT drugs. [{sup 18}F]Ro41-0960 was synthesized by the nucleophilic aromatic substitution reaction with NCA [{sup 18}F] fluoride on a protected precursor (prepared via a five-step synthesis) followed by hydrolysis with HBr (synthesis time of 100 min; radiochemical yield of 5-7% (EOB)). Though Ro41-0960 has been reported to cross the blood brain barrier, PET studies in baboon demonstrated that an almost complete absence of the drug from the brainmore » both at tracer doses and with the addition of unlabeled drug (1.5 mg/kg) at all times through a 90 min experimental interval. The plasma to brain ratios of F-18 average about 40:1. However, high uptake was observed in the kidneys and in other organs which are known to have high COMT. Studies in mice showed that at 30 min after injection of tracer, F-18 in kidneys was largely as [{sup 18}F]Ro-41-0960 and that it could be displaced with unlabeled Ro41-0960. These studies provide the first example of a positron emitter labeled COMT radiotracer.« less

  • synthesis of sup 18 f ro41 0960 a potent COMT Inhibitor for use in vivo mapping with pet
    The Journal of Nuclear Medicine, 1995
    Co-Authors: Yu-shin Ding, Y. Sugano, S.j. Gatley
    Abstract:

    Catechol-O-methyltransferase (COMPT; EC 2.1.1.6) is one of the two major enzymes which metabolize the catecholamine neurotransmitters. It is distributed throughout the body and brain and is elevated in breast cancer tissue when it plays a role in estrogen metabolism. It is also an important molecular target in the development of drugs to treat Parkinson`s disease (PD). Because COMT regulates the concentration of important neurotransmitter amines such as dopamine, there is speculation that abnormalities in its activity may be associated with neurological, and psychiatric disorders. Ro41-9060(3,4-dihydroxy-5-nitro-2{prime}-fluorobenzophenone) is a potent, fluorine containing COMT Inhibitor which has been reported to cross the blood brain barrier. It is structurally similar to Ro40-7592 which is currently undergoing clinical trials in PD. We report the synthesis of [{sup 18}F]Ro41-0960, for investigation for mapping COMT and for studies of COMT drugs. [{sup 18}F]Ro41-0960 was synthesized by the nucleophilic aromatic substitution reaction with NCA [{sup 18}F] fluoride on a protected precursor (prepared via a five-step synthesis) followed by hydrolysis with HBr (synthesis time of 100 min; radiochemical yield of 5-7% (EOB)). Though Ro41-0960 has been reported to cross the blood brain barrier, PET studies in baboon demonstrated that an almost complete absence of the drug from the brainmore » both at tracer doses and with the addition of unlabeled drug (1.5 mg/kg) at all times through a 90 min experimental interval. The plasma to brain ratios of F-18 average about 40:1. However, high uptake was observed in the kidneys and in other organs which are known to have high COMT. Studies in mice showed that at 30 min after injection of tracer, F-18 in kidneys was largely as [{sup 18}F]Ro-41-0960 and that it could be displaced with unlabeled Ro41-0960. These studies provide the first example of a positron emitter labeled COMT radiotracer.« less