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Boosting caffeic acid performance as antioxidant and monoamine oxidase B/catech...
Chavarria, Daniel; Benfeito, Sofia; Soares, Pedro; Lima, Carla; Garrido, Jorge; Serrão, Paula; Soares-da-Silva, Patrício; Remião, FernandoIncreased oxidative stress (OS) and depletion of nigrostriatal dopamine (DA) are closely linked to the neurodegeneration observed in Parkinson’s Disease (PD). Caffeic acid (CA)-based antioxidants were developed, and their inhibitory activities towards monoamine oxidases (MAOs) and catechol O-methyltransferases (COMT) were screened. The results showed that the incorporation of an extra double bond maintained or ...
Development of Blood−Brain Barrier Permeable Nitrocatechol-Based Catechol O‑Met...
Silva, Tiago; Mohamed, Tarek; Shakeri, Arash; Rao, Praveen P. N.; Martínez-González, Loreto; Pérez, Daniel I.; Martínez, Ana; Valente, Maria JoãoRecent efforts have been focused on the development of centrally active COMT inhibitors, which can be valuable assets for neurological disorders such as Parkinson’s disease, due to the severe hepatotoxicity risk associated with tolcapone. New nitrocatechol COMT inhibitors based on naturally occurring caffeic acid and caffeic acid phenethyl ester were developed. All nitrocatechol derivatives displayed potent inh...
Evaluation of neurotoxic and neuroprotective pathways affected by antiepileptic...
Morte, Maria I.; Carreira, Bruno P.; Falcão, Maria J.; Ambrosio, António M.; Soares-da-Silva, Patrício; Araújo, Inês M.; Carvalho, Caetana M.In this study we evaluated the neurotoxicity of eslicarbazepine acetate (ESL), and of its in vivo metabolites eslicarbazepine (S-Lic) and R-licarbazepine (R-Lic), as compared to the structurally-related compounds carbamazepine (CBZ) and oxcarbazepine (OXC), in an in vitro model of cultured rat hippocampal neurons. The non-related antiepileptic drugs (AEDs) lamotrigine (LTG) and sodium valproate (VPA) were also ...
Pharmacokinetics, brain distribution and plasma protein binding of carbamazepin...
Fortuna, Ana; Alves, Gilberto; Soares-da-Silva, Patrício; Falcão, AmílcarIn silico approaches to predict absorption, distribution, metabolism and excretion (ADME) of new drug candidates are gaining a relevant importance in drug discovery programmes. When considering particularly the pharmacokinetics during the development of oral antiepileptic drugs (AEDs), one of the most prominent goals is designing compounds with good bioavailability and brain penetration. Thus, it is expected th...
Effect of food on the pharmacokinetic profile of etamicastat (BIA 5-453)
Vaz-da-Silva, Manuel; Nunes, Teresa; Rocha, José F.; Falcão, Amílcar; Almeida, Luis; Soares-da-Silva, PatrícioBackground: Etamicastat is a novel, potent, and reversible peripheral dopamineb- hydroxylase inhibitor that has been administered orally at doses up to 600mg once daily for 10 days to male healthy volunteers and appears to be well tolerated. Objective: The aim of this study was to investigate the effect of food on the pharmacokinetics of etamicastat. Material and Methods: A single-center, open-label, randomized...
Pharmacokinetic-pharmacodynamic interaction between Nebicapone and controlled-r...
Nunes, Teresa; Rocha, José F.; Fernendes-Lopes, Carlos; Costa, Raquel; Torrão, Leonel; Loureiro, Ana I.; Falcão, Amílcar; Vaz-da-Silva, ManuelBackground: Nebicapone is a reversible catechol-O-methyltransferase (COMT) inhibitor. Coadministration of a COMT inhibitor with levodopa and a dopa-decarboxylase inhibitor (carbidopa or benserazide) increases levodopa exposure and its therapeutic effect. Objectives: The primary objective of this study was to investigate the effect of nebicapone (50, 100, and 200 mg), compared with placebo, on levodopa pharmacok...
Disposition of eslicarbazepine acetate in the mouse after oral administration
Alves, Gilberto; Figueiredo, Isabel; Castel-Branco, Margarida; Lourenço, Nulita; Falcão, Amílcar; Caramona, Margarida; Soares-da-Silva, PatrícioEslicarbazepine acetate is a promising antiepileptic drug structurally related to carbamazepine and oxcarbazepine, which is in the final phase of clinical development. The metabolism of eslicarbazepine acetate is clearly species dependent and, in this case, among small laboratory animals, the mouse seems to be the most relevant species to humans. Hence, the aim of this study was to investigate the plasma, brain...
Stereoselective disposition of S and R-licarbazepine in mice
Alves, Gilberto; Figueiredo, Isabel; Falcão, Amílcar; Castel-Branco, Margarida; Caramona, Margarida; Soares-da-Silva, PatrícioThe stereoselective disposition of S-licarbazepine (S-Lic) and R-licarbazepine (R-Lic) was investigated in plasma, brain, liver, and kidney tissues after their individual administration (350 mg/kg) to mice by oral gavage. Plasma, brain, liver, and kidney concentrations of licarbazepine enantiomers and their metabolites were determined over the time by a validated chiral HPLC-UV method. The mean concentration da...
Effect of Gender on the Pharmacokinetics of Eslicarbazepine Acetate (BIA 2-093)...
Falcão, Amílcar; Maia, Joana; Almeida, Luís; Mazur, Dago; Gellert, Manfred; Soares-da-Silva, PatrícioPurpose. To determine the effect of gender on the pharmacokinetics of eslicarbazepine acetate, a novel voltage-gated sodium channel blocker in the development for the treatment of epilepsy and bipolar disorder. Methods. Single-centre, open-label, parallel-group study in 12 female and 12 male healthy subjects. The study consisted of a single-dose (600 mg) period and a multiple-dose (600 mg, oncedaily, for 8 days...
Long-term Effect of Convulsive Behavior on the Density of Adenosine A1 and A2A ...
Rebola, Nelson; Porciúncula, Lisiane O.; Lopes, Luísa V.; Oliveira, Catarina R.; Soares-da-Silva, Patrício; Cunha, Rodrigo A.Purpose: Adenosine is a neuromodulator that has been proposed to act as an anticonvulsant mainly via inhibitory A1 receptors, but recent data show that genetic deletion of facilitatory A2A receptors might also attenuate convulsions. Since both A1 and A2A receptors are prone to down- and upregulation in different stressful situations, we investigated if convulsive behavior leads to a long-term change in A1 and A...