São Romão do Coronado, Portugal
São Romão do Coronado, Portugal

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Hufnagel A.,University of Duisburg - Essen | Ben-Menachem E.,Sahlgren University Hospital | Gabbai A.A.,Federal University of São Paulo | Falcao A.,University of Coimbra | And 3 more authors.
Epilepsy Research | Year: 2013

Objective: To evaluate the long-term safety, tolerability and efficacy of once-daily eslicarbazepine acetate (ESL) as adjunctive therapy in adults with partial-onset seizures. Methods: One-year open-label extension (OLE) study with ESL in patients who completed a randomised, double-blind placebo-controlled trial (study BIA-2093-302; Epilepsy Res. 89 (2010) 278-285). Starting dose was 800. mg once-daily, for 4 weeks; thereafter, dose could be individualised within the 400-1200. mg range. Doses of concomitant antiepileptic drugs were to be kept stable. Results: Overall, 325 patients were enrolled (intent-to-treat population); 223 (68.6%) patients completed 1-year of treatment. ESL median dose was 800. mg once-daily. Compared to the baseline period of the double-blind study completed prior to this OLE study, median seizure frequency decreased by 32% in weeks 1-4, and between 37% and 39% thereafter. The responder rate (seizure reduction ≥50%) was 37% during weeks 1-4 and thereafter ranged between 38% and 42% per 12-week interval. Proportion of seizure-free patients per 12-week interval ranged between 5% and 11%. Improvements from baseline in several Quality of Life in Epilepsy Inventory-31 (QOLIE-31) and Montgomery Asberg Depression Rating Scale (MADRS) scores were observed. Adverse events (AEs) were reported by 83% of patients. AEs occurring in ≥10% of patients were dizziness, headache and somnolence. AEs were usually of mild to moderate intensity. Conclusion: In this study, ESL demonstrated a sustained therapeutic effect and was well tolerated during 1-year add-on treatment of adults with partial-onset seizures. Additionally, significant improvements in quality of life domains and depressive symptoms were observed under long-term treatment with once-daily ESL. © 2012 Elsevier B.V.


Elger C.,University of Bonn | Bialer M.,Hebrew University of Jerusalem | Falcao A.,University of Coimbra | Vaz-Da-Silva M.,BIAL Portela and C S.A. | And 5 more authors.
Epilepsia | Year: 2013

Purpose Investigate the pharmacokinetics of once-daily (QD; 900 mg) and twice-daily (BID; 450 mg) regimens of eslicarbazepine acetate (ESL) and BID (450 mg) regimen of oxcarbazepine (OXC) at steady state in healthy volunteers. Methods Single-center, open-label, randomized, three-way (n = 12) crossover studies in healthy volunteers. Key Findings Mean eslicarbazepine C max,ss (in μm) following ESL QD (87.3) was 33.3% higher (p < 0.05) compared to ESL BID (65.5) and 82.1% higher (p < 0.05) compared to OXC BID (48.0). The mean area under the curve (AUC)ss,0-τ (in μmol h/L) following the last dose of an 8-day repeated dosing was 1156.3, 1117.6, and 968.4 for ESL QD, ESL BID, and OXC BID, respectively. The ratio eslicarbazepine plasma exposure (μmol h/L) to ESL daily-dose (μmol) was 0.381 (1156.3:3037.3), 0.368 (1117.6:3037.3), and 0.271 (968.4:3567.6) for ESL-QD, ESL-BID, and OXC-BID, respectively, which translates into a 40.6% increase in the ability of ESL-QD compared to OXC-BID to deliver into the plasma their major active entity eslicarbazepine. The extent of plasma exposure to ESL minor metabolites: (R)-licarbazepine and oxcarbazepine after ESL-QD was 71.5% and 61.1% lower, respectively, than after OXC-BID. Twenty, 24 and 38 treatment emergent adverse events were reported with ESL-QD, ESL-BID, and OXC-BID, respectively. Significance ESL-QD resulted in 33.3% higher peak plasma concentration (Cmax,ss) of eslicarbazepine and similar extent of plasma exposure (AUCss,0-τ) when compared to ESL-BID, which may contribute to the efficacy profile reported with once-daily ESL. In comparison to OXC-BID, administration of ESL-QD resulted in 40.6% increase in the delivery of eslicarbazepine into the plasma as well as a significantly lower systemic exposure to (R)-licarbazepine and oxcarbazepine. © 2013 International League Against Epilepsy.


Rocha J.-F.,BIAL Portela and C S.A. | Ferreira J.J.,Institute of Molecular Medicine | Falcao A.,University of Coimbra | Santos A.,BIAL Portela and C S.A. | And 7 more authors.
Clinical Pharmacology in Drug Development | Year: 2016

This study determined the effects of single doses of opicapone (OPC), a novel third-generation catechol-O-methyltransferase (COMT) inhibitor, on levodopa and 3-O-methyl-levodopa (3-OMD) pharmacokinetics (PK), COMT activity and motor fluctuations in patients with Parkinson disease (PD). Subjects received, in a double-blind manner, 25, 50, and 100mg OPC or placebo (PLC) in 4 separate treatment periods. The washout period between doses was at least 10 days. During each period, the OPC/PLC capsules were to be coadministered with the morning dose of 100/25mg levodopa/carbidopa (LC) or levodopa/benserazide (LB) on day 3. In relation to PLC, levodopa exposure increased 3.7%, 16.4%, and 34.8% following 25, 50, or 100mg OPC, respectively. Maximum S-COMT inhibition (Emax) ranged from 67.8% (25mg OPC) to 100% (100mg OPC). Peak and extent of S-COMT inhibition were dose-dependent. Maximum decrease in the plasma 3-OMD was observed following administration of 100mg OPC. Opicapone administered concomitantly with standard-release 100/25mg LC or LB improved motor performance. Treatments were generally well tolerated and safe. It was concluded that OPC is a new COMT inhibitor that significantly decreased COMT activity and increased systemic exposure to levodopa in PD patients with motor fluctuations. © 2016, The American College of Clinical Pharmacology.


Sierra-Paredes G.,University of Santiago de Compostela | Loureiro A.I.,BIAL Portela and C S.A. | Wright L.C.,BIAL Portela and C S.A. | Sierra-Marnd;o G.,University of Santiago de Compostela | And 2 more authors.
BMC Neuroscience | Year: 2014

Background: Latrunculin A microperfusion of the hippocampus induces acute epileptic seizures and long-term biochemical changes leading to spontaneous seizures. This study tested the effect of eslicarbazepine acetate (ESL), a novel antiepileptic drug, on latrunculin A-induced acute and chronic seizures, and changes in brain amino acid extracellular levels. Hippocampi of Swiss mice were continuously perfused with a latrunculin A solution (4 μM, 1 μl/min, 7 h/day) with continuous EEG and videotape recording for 3 consecutive days. Microdialysate samples were analyzed by HPLC and fluorescence detection of taurine, glycine, aspartate, glutamate and GABA. Thereafter, mice were continuously video monitored for two months to identify chronic spontaneous seizures or behavioral changes. Control EEG recordings (8 h) were performed in all animals at least once a week for a minimum of one month. Results: Oral administration of ESL (100 mg/kg), previous to latrunculin A microperfusion, completely prevented acute latrunculin A-induced seizures as well as chronic seizures and all EEG chronic signs of paroxysmal activity. Hippocampal extracellular levels of taurine, glycine and aspartate were significantly increased during latrunculin A microperfusion, while GABA and glutamate levels remained unchanged. ESL reversed the increases in extracellular taurine, glycine and aspartate concentrations to basal levels and significantly reduced glutamate levels. Plasma and brain bioanalysis showed that ESL was completely metabolized within 1 h after administration to mainly eslicarbazepine, its major active metabolite. Conclusion: ESL treatment prevented acute latrunculin A-induced seizures as well as chronic seizures and all EEG chronic signs of paroxysmal activity, supporting a possible anti-epileptogenic effect of ESL in mice. © Sierra-Paredes et al.


Igreja B.,BIAL Portela and C S.A. | Pires N.M.,BIAL Portela and C S.A. | Bonifacio M.J.,BIAL Portela and C S.A. | Loureiro A.I.,BIAL Portela and C S.A. | And 4 more authors.
Hypertension Research | Year: 2015

Hyperactivation of the sympathetic nervous system has an important role in the development and progression of arterial hypertension. This study evaluated the efficacy of etamicastat, a dopamine-β-hydroxylase (DβH) inhibitor, in controlling high blood pressure in the spontaneously hypertensive rat (SHR), either alone or in combination with other classes of antihypertensives. SHRs were administered with etamicastat by gavage, and its pharmacodynamic and pharmacokinetic properties were evaluated. Etamicastat induced a time-dependent decrease in noradrenaline-to-dopamine ratios in the heart and kidney, and had no effect on catecholamine levels in the frontal cortex of SHRs. Cardiovascular pharmacodynamic effects following administration of etamicastat alone or in combination with other classes of antihypertensive drugs were assessed by telemetry. Etamicastat was evaluated in combination with captopril, losartan, hydrochlorothiazide, metoprolol, prazosin and/or diltiazem. Etamicastat monotherapy induced a dose-dependent reduction in blood pressure without reflex tachycardia. Combination therapy amplified the antihypertensive effects of all tested drugs. In conclusion, inhibition of peripheral DβH with etamicastat, as a monotherapy or combination therapy, may constitute a valid alternative treatment for high blood pressure. © 2015 The Japanese Society of Hypertension.

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