Publications by authors named "Patrício Soares da Silva"

216 Publications

Antagonistic modulation of SIK1 and SIK2 isoforms in high blood pressure and cardiac hypertrophy triggered by high-salt intake.

Clin Exp Hypertens 2021 Mar 10:1-8. Epub 2021 Mar 10.

Division of Research and Development, BIAL-Portela & Cª, S.A, Coronado (S. Mamede & S. Romão), Portugal.

Salt-inducible kinases (SIKs) represent a subfamily of AMPK family kinases. SIK1 has been shown to act as a mediator during the cellular adaptation to variations in intracellular sodium in a variety of cell types. SIK2, as an isoform of the SIK family, modulates various biological functions and acts as a signal transmitter in various pathways. To evaluate the role of both SIK1 and SIK2 isoforms in blood pressure (BP), body fluid regulation and cardiac hypertrophy development, we made use of constitutive (SIK1-KO), (SIK2-KO), double (double SIK1*2-KO) knockout and wild-type (WT) mice challenged to a standard (0.3% NaCl) or chronic high-salt (HS, 8% NaCl) diet intake for 12 weeks.Mice, under a standard diet intake, had similar and normal BP. On a chronic HS intake, SIK1-KO and double SIK1*2-KO mice showed increased BP, but not WT and SIK2-KO mice. A chronic HS intake led to the development of cardiac left ventricle hypertrophy (LVH) in normotensive WT and hypertensive SIK1-KO mice, but not in SIK2-KO mice. Double SIK1*2-KO mice under standard diet intake show normal BP but an increased LV mass. Remarkably, in response to a dietary stress condition, there is an increase in BP but LVH remained unchanged in double SIK1*2-KO mice.In summary, SIK1 isoform is required for maintaining normal BP in response to HS intake. LVH triggered by HS intake requires SIK2 isoform and is independent of high BP.
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http://dx.doi.org/10.1080/10641963.2021.1896728DOI Listing
March 2021

Non-clinical toxicology evaluation of BIA 10-2474.

Crit Rev Toxicol 2021 Jan 2;51(1):65-75. Epub 2021 Feb 2.

Department of Research, BIAL - Portela & Ca, S.A, Coronado, Portugal.

In 2016, one subject died and four were hospitalized with neurological symptoms during a clinical trial with the fatty acid amide hydrolase (FAAH) inhibitor BIA 10-2474. The present paper reviews the regulatory toxicology studies that were carried out to support the clinical trial application for BIA 10-2474. Animal studies complied with national and international standards including European regulatory guidelines (e.g. EEC Council Directive 75/318/EEC and subsequent amendments). The CNS effects seen in the rat and mouse appear to be common in rodents in such studies and do not in principle seem to be of the type to generate a signal. In the same way in non-human primates, insignificant alterations in the mesencephalon, and especially of the autonomic nervous system (Meissner's plexus in the bowel) in rodents and monkeys were observed in some animals treated with a high dose. Overall, these data, as well as the extensive additional data generated since the accident, support the conclusion that the tragic fatality that occurred during the clinical trial with BIA 10-2474 was unpredictable and that the mechanism responsible remains unknown, from a non-clinical toxicological perspective.
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http://dx.doi.org/10.1080/10408444.2020.1867821DOI Listing
January 2021

Complex effects of eslicarbazepine on inhibitory micro networks in chronic experimental epilepsy.

Epilepsia 2021 02 16;62(2):542-556. Epub 2021 Jan 16.

Medical Faculty, Institute for Experimental Epileptology and Cognition Research, University of Bonn, Bonn, Germany.

Objective: Many antiseizure drugs (ASDs) act on voltage-dependent sodium channels, and the molecular basis of these effects is well established. In contrast, how ASDs act on the level of neuronal networks is much less understood.

Methods: In the present study, we determined the effects of eslicarbazepine (S-Lic) on different types of inhibitory neurons, as well as inhibitory motifs. Experiments were performed in hippocampal slices from both sham-control and chronically epileptic pilocarpine-treated rats.

Results: We found that S-Lic causes an unexpected reduction of feed-forward inhibition in the CA1 region at high concentrations (300 µM), but not at lower concentrations (100 µM). Concurrently, 300 but not 100 μM S-Lic significantly reduced maximal firing rates in putative feed-forward interneurons located in the CA1 stratum radiatum of sham-control and epileptic animals. In contrast, feedback inhibition was not inhibited by S-Lic. Instead, application of S-Lic, in contrast to previous data for other drugs like carbamazepine (CBZ), resulted in a lasting potentiation of feedback inhibitory post-synaptic currents (IPSCs) only in epileptic and not in sham-control animals, which persisted after washout of S-Lic. We hypothesized that this plasticity of inhibition might rely on anti-Hebbian potentiation of excitatory feedback inputs onto oriens-lacunosum moleculare (OLM) interneurons, which is dependent on Ca -permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Indeed, we show that blocking Ca -permeable AMPA receptors completely prevents upmodulation of feedback inhibition.

Significance: These results suggest that S-Lic affects inhibitory circuits in the CA1 hippocampal region in unexpected ways. In addition, ASD actions may not be sufficiently explained by acute effects on their target channels, rather, it may be necessary to take plasticity of inhibitory circuits into account.
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http://dx.doi.org/10.1111/epi.16808DOI Listing
February 2021

Comparative analysis of the safety and tolerability of eslicarbazepine acetate in older (≥60 years) and younger (18-59 years) adults.

Epilepsy Res 2021 Jan 10;169:106478. Epub 2020 Oct 10.

Sunovion Pharmaceuticals Inc., Marlborough, MA, USA. Electronic address:

Objective: To investigate the safety and tolerability of eslicarbazepine acetate (ESL), a once-daily oral anti-seizure drug (ASD), in older and younger adult patient populations.

Methods: Two post-hoc pooled data analyses were performed: one from three Phase III studies in patients with focal (partial-onset) seizures who were taking 1-3 concomitant ASDs; the other from five Phase II studies in patients from non-epilepsy populations not taking other ASDs chronically and/or at a clinically-effective anti-seizure dose. The frequencies of treatment-emergent adverse events (TEAEs) were calculated for the older (≥60 years) and younger (18-59 years) adults separately.

Results: In the focal seizures study pool, 4.1 % of patients (58/1431) were aged ≥60 years. The overall frequency of TEAEs was 77.5 % in older ESL-treated patients and 72.6 % in younger ESL-treated patients (p = 0.495). For patients who received placebo, the overall frequency of TEAEs was 50.0 % in the older adults and 57.5 % in the younger adults (p = 0.531). The overall placebo-adjusted frequency of TEAEs was 27.5 % in older adults and 15.1 % in younger adults. The placebo-adjusted frequencies of the TEAEs dizziness, somnolence, headache, nausea, diplopia, blurred vision, and ataxia were ≥5 % higher, and frequencies of vomiting and vertigo were ≥2 % higher in older than younger adults. The overall frequency of TEAEs leading to discontinuation was 15.0 % in older ESL-treated patients and 17.6 % in younger ESL-treated patients (p = 0.647); the frequency increased with increasing ESL dose. For patients who received placebo, the overall frequency of TEAEs leading to discontinuation was 5.6 % in older adults and 6.6 % in younger adults (p = 0.847). In the non-epilepsy study pool, 30.2 % of patients (515/1705) were aged ≥60 years. The overall frequency of TEAEs was 56.9 % in older ESL-treated patients and 58.8 % in younger ESL-treated patients. The placebo-adjusted frequencies were 14.9 % in older and 15.1 % in younger ESL-treated patients. The placebo-adjusted frequencies of the TEAEs nausea, vomiting, fatigue, and vertigo were ≥2 % higher in older adults, whereas somnolence was ≥2 % higher in younger adults. The overall frequency of TEAEs leading to discontinuation was 18.3 % in older ESL-treated patients and 12.1 % in younger ESL-treated patients (p = 0.003); frequencies were not related to ESL dose. For patients who received placebo, the overall frequency of TEAEs leading to discontinuation was 8.0 % in older adults and 5.6 % in younger adults (p = 0.407).

Conclusion: Analyses of adverse event data support the safety and tolerability of ESL in adults aged ≥60 years. In the limited number of older patients with focal seizures taking ESL plus concomitant ASDs (n = 40), the frequency of TEAEs was generally higher than in younger adults. However, in the non-epilepsy patient group (in which the number of older patients was ten times larger; 427 patients taking ESL without concomitant ASDs), no marked age-related TEAE differences were observed, suggesting that increased ASD load associated with adjunctive therapy may complicate treatment selection in older patients, due to risk of increased adverse events. As is common practice for all ASDs, balancing clinical response and tolerability is needed in this vulnerable group of patients.
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http://dx.doi.org/10.1016/j.eplepsyres.2020.106478DOI Listing
January 2021

Opicapone enhances the reversal of MPTP-induced Parkinson-like syndrome by levodopa in cynomolgus monkeys.

Eur J Pharmacol 2021 Feb 18;892:173742. Epub 2020 Nov 18.

Department of Research, BIAL-Portela & C(a), S.A, 4745-457, Coronado (S. Mamede & S. Romão), Portugal; Department of Biomedicine, Unit of Pharmacology & Therapeutics, Faculty of Medicine, University of Porto, 4200, Porto, Portugal; MedInUp - Center for Drug Discovery and Innovative Medicines, University of Porto, 4200, Porto, Portugal. Electronic address:

Opicapone is a third generation nitrocatechol catechol-O-methyltransferase inhibitor that has received regional market approval for use as adjunctive therapy to levodopa in Parkinson's disease patients with motor fluctuations. This study evaluated the effects of opicapone as adjunct to levodopa in reversing a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced Parkinson's-like syndrome in cynomolgus monkeys in during opicapone preclinical development program. A Parkinson's-like syndrome was induced in cynomolgus monkeys by daily administrations of MPTP. Evaluation of the animals included scoring with the Primate Parkinsonism Motor Rating Scale (PPMRS) and assessment of locomotor activity. MPTP produced a stable Parkinson's-like behavioural syndrome as evidenced by tremor, postural changes, rigidity, impaired movements and balance, (PPMRS scores of 10-15) and decreased locomotor activity (13% of pre-MPTP values). Opicapone treatment alone, for 14 days, did not change Parkinson's-like symptoms nor decreased subject's locomotor behaviour. Ascending combinations of levodopa/benserazide dose-dependently decreased PPMRS and improved locomotor behaviour reaching statistical significance for levodopa/benserazide doses of 18/4.5 mg/kg and those effects were enhanced in opicapone treated subjects. Opicapone treated subjects as compared vehicle-treated, had markedly reduced erythrocyte catechol-O-methyltransferase activity, significantly increased plasma levodopa levels (1.8-fold higher AUC) with no statistically significant changes in C and significantly reduced 3-OMD AUC and C values (7.8- and 6.8-fold respectively). Opicapone potentiated the improvements in Parkinson's-like symptoms produced by levodopa/benserazide combinations with concomitant increase in plasma levodopa exposure, reduction of plasma 3-O-methyldopa levels and erythrocyte catechol-O-methyltransferase activity, results that were later demonstrated in 2 large Phase 3 studies in Parkinson's disease patients.
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http://dx.doi.org/10.1016/j.ejphar.2020.173742DOI Listing
February 2021

Long-term efficacy and safety of eslicarbazepine acetate monotherapy for adults with newly diagnosed focal epilepsy: An open-label extension study.

Epilepsia 2020 10 17;61(10):2129-2141. Epub 2020 Sep 17.

Bial-Portela & Cª, S.A., Coronado, Portugal.

Objective: To assess the efficacy, safety, and tolerability of eslicarbazepine acetate (ESL) monotherapy during long-term treatment.

Methods: An open-label extension (OLE) study was conducted in adults completing a phase 3, randomized, double-blind, noninferiority trial, during which they had received monotherapy with either once-daily ESL or twice-daily controlled-release carbamazepine (CBZ-CR) for newly diagnosed focal epilepsy. In the OLE study, all patients received ESL (800-1600 mg/d) for 2 years. Primary efficacy outcome was retention time (from baseline of the OLE study). Secondary efficacy assessments included seizure freedom rate (no seizures during the OLE study) and responder rate (≥50% seizure frequency reduction from baseline of double-blind trial). Safety assessments included evaluation of treatment-emergent adverse events (TEAEs).

Results: Of 206 randomized patients, 96 who received ESL in the double-blind trial (ESL/ESL) and 88 who received CBZ-CR in the double-blind trial (CBZ-CR/ESL) were treated with ESL monotherapy (89.3% overall). Treatment retention time was similar between groups, with low probability of ESL withdrawal overall (<0.07 at any time). After 24 months, the probability of ESL withdrawal was 0.0638 (95% confidence interval [CI] = 0.0292-0.1366) in the ESL/ESL group and 0.0472 (95% CI = 0.0180-0.1210) in the CBZ-CR/ESL group. Seizure freedom rates were 90.6% (ESL/ESL) and 80.7% (CBZ-CR/ESL; P = .0531). Responder rates remained >80% in both groups throughout the study. Incidence of serious TEAEs was similar between groups (7.3% vs 5.7%; 0% vs 1.1% possibly related), as were the incidences of TEAEs considered at least possibly related to treatment (17.7% vs 18.2%) and TEAEs leading to discontinuation (3.1% vs 4.5%). The types of TEAEs were generally consistent with the known safety profile of ESL.

Significance: ESL monotherapy was efficacious and generally well tolerated over the long term, including in patients who transitioned from CBZ-CR monotherapy. No new safety concerns emerged.
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http://dx.doi.org/10.1111/epi.16666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693183PMC
October 2020

Liver says no: the ongoing search for safe catechol O-methyltransferase inhibitors to replace tolcapone.

Drug Discov Today 2020 Jul 17. Epub 2020 Jul 17.

Unit of Pharmacology & Therapeutics, Department of Biomedicine, Faculty of Medicine, University of Porto, 4200-319, Porto, Portugal; MedInUP - Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal.

Catechol O-methyltransferase (COMT) inhibitors are valuable co-adjuvant drugs in the clinical management of Parkinson's disease (PD), and recent data also suggest therapeutic benefits in other neurological disorders associated with dopamine depletion. However, the relationship between tolcapone administration with fatal cases of drug-induced liver damage gave COMT inhibitors a bad reputation as hepatotoxic drugs. Thus, there is a pressing need to feed the pipeline with safe COMT inhibitors to replace tolcapone, the only currently available COMT inhibitor that effectively reaches the brain. Recent efforts led to promising phenolic and nonphenolic COMT inhibitors, which allow isoform-specific targeting and avoid the toxicological and pharmacokinetic (PK) shortcomings of classic nitrocatechols. Here, we describe advances made in this field over the past 5 years.
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http://dx.doi.org/10.1016/j.drudis.2020.07.015DOI Listing
July 2020

Effectiveness and safety of opicapone in Parkinson's disease patients with motor fluctuations: the OPTIPARK open-label study.

Transl Neurodegener 2020 03 4;9(1). Epub 2020 Mar 4.

Research and Development Department, BIAL - Portela & CA S.A, da Siderurgia Nacional, 4745-457 S, Mamede do Coronado, Portugal.

Background: The efficacy and safety of opicapone, a once-daily catechol-O-methyltransferase inhibitor, have been established in two large randomized, placebo-controlled, multinational pivotal trials. Still, clinical evidence from routine practice is needed to complement the data from the pivotal trials.

Methods: OPTIPARK (NCT02847442) was a prospective, open-label, single-arm trial conducted in Germany and the UK under clinical practice conditions. Patients with Parkinson's disease and motor fluctuations were treated with opicapone 50 mg for 3 (Germany) or 6 (UK) months in addition to their current levodopa and other antiparkinsonian treatments. The primary endpoint was the Clinician's Global Impression of Change (CGI-C) after 3 months. Secondary assessments included Patient Global Impressions of Change (PGI-C), the Unified Parkinson's Disease Rating Scale (UPDRS), Parkinson's Disease Questionnaire (PDQ-8), and the Non-Motor Symptoms Scale (NMSS). Safety assessments included evaluation of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs).

Results: Of the 506 patients enrolled, 495 (97.8%) took at least one dose of opicapone. Of these, 393 (79.4%) patients completed 3 months of treatment. Overall, 71.3 and 76.9% of patients experienced any improvement on CGI-C and PGI-C after 3 months, respectively (full analysis set). At 6 months, for UK subgroup only (n = 95), 85.3% of patients were judged by investigators as improved since commencing treatment. UPDRS scores at 3 months showed statistically significant improvements in activities of daily living during OFF (mean ± SD change from baseline: - 3.0 ± 4.6, p < 0.0001) and motor scores during ON (- 4.6 ± 8.1, p < 0.0001). The mean ± SD improvements of - 3.4 ± 12.8 points for PDQ-8 and -6.8 ± 19.7 points for NMSS were statistically significant versus baseline (both p < 0.0001). Most of TEAEs (94.8% of events) were of mild or moderate intensity. TEAEs considered to be at least possibly related to opicapone were reported for 45.1% of patients, with dyskinesia (11.5%) and dry mouth (6.5%) being the most frequently reported. Serious TEAEs considered at least possibly related to opicapone were reported for 1.4% of patients.

Conclusions: Opicapone 50 mg was effective and generally well-tolerated in PD patients with motor fluctuations treated in clinical practice.

Trial Registration: Registered in July 2016 at clinicaltrials.gov (NCT02847442).
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http://dx.doi.org/10.1186/s40035-020-00187-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055125PMC
March 2020

Correction to: Effectiveness and safety of opicapone in Parkinson's disease patients with motor fluctuations: the OPTIPARK open-label study.

Transl Neurodegener 2020 04 28;9(1):14. Epub 2020 Apr 28.

Research and Development Department, BIAL - Portela & CA S. A, da Siderurgia Nacional, 4745-457, S Mamede do Coronado, Portugal.

An amendment to this paper has been published and can be accessed via the original article.
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http://dx.doi.org/10.1186/s40035-020-00193-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187493PMC
April 2020

Cardiometabolic and Inflammatory Benefits of Sympathetic Down-Regulation with Zamicastat in Aged Spontaneously Hypertensive Rats.

ACS Pharmacol Transl Sci 2019 Oct 4;2(5):353-360. Epub 2019 Sep 4.

Department of Research, BIAL - Portela & Ca, S.A., Coronado (S. Mamede e S. Romão) 4747-457, Portugal.

The hyperactivity of the sympathetic nervous system (SNS) plays a major role in the development and progression of several cardiovascular diseases. One strategy to mitigate the SNS overdrive is by restricting the biosynthesis of norepinephrine via the inhibition of dopamine β-hydroxylase (DBH). Zamicastat is a new DBH inhibitor that decreases norepinephrine and increases dopamine levels in peripherally sympathetic-innervated tissues. The cardiometabolic and inflammatory effects of sympathetic down-regulation were evaluated in 50 week old male spontaneously hypertensive rats (SHRs) receiving zamicastat (30 mg/kg/day) for 9 weeks. After 8 weeks of treatment, the blood pressure (BP) and heart rate (HR) were assessed by tail cuff plethysmography. At the end of the study, 24 h urine, plasma, heart, and kidney were collected for biochemical and morphometric analyses. Zamicastat-induced sympathetic down-regulation decreased the high BP in SHRs, with no observed effect on HR. The heart-to-body weight ratio was lower in SHRs treated with zamicastat, whereas the body weight and kidney-to-body weight ratio were similar between both SHR cohorts. Zamicastat-treated SHRs showed reduced 24 h urine output, but the urinary amount of protein excreted and creatinine clearance rate remained unchanged. Zamicastat treatment significantly decreased plasma triglycerides, free fatty acids, and aspartate aminotransferase levels. Aged SHRs showed higher plasma levels of inflammatory markers as compared with age-matched normotensive Wistar-Kyoto rats. The inflammatory benefits attained with DBH inhibition were expressed by a decrease in CRP, MCP-1, IL-5, IL-17α, GRO/KC, MIP-1α, and RANTES plasma levels as compared with untreated SHRs. In conclusion, DBH inhibition decreased norepinephrine levels, reduced end-organ damage, and improved cardiometabolic and inflammatory biomarkers in aged male SHRs.
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http://dx.doi.org/10.1021/acsptsci.9b00039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7089015PMC
October 2019

Efficacy and safety of eslicarbazepine acetate as adjunctive therapy for refractory focal-onset seizures in children: A double-blind, randomized, placebo-controlled, parallel-group, multicenter, phase-III clinical trial.

Epilepsy Behav 2020 04 6;105:106962. Epub 2020 Mar 6.

BIAL - Portela & Cª. S.A., S. Mamede do Coronado, Portugal; Department of Biomedicine, Pharmacology and Therapeutics Unit, Faculty of Medicine, University Porto, Porto, Portugal; MedInUP - Center for Drug Discovery and Innovative Medicines, University Porto, Porto, Portugal. Electronic address:

Purpose: This was a phase-III, randomized, double-blind, placebo-controlled study aimed to evaluate efficacy and tolerability of eslicarbazepine acetate (ESL) as adjunctive therapy in pediatric patients with refractory focal-onset seizures (FOS).

Methods: Children (2-18 years old) with FOS, receiving 1-2 antiepileptic drugs, were randomized to ESL or placebo. Treatment was started at 10 mg/kg/day, up-titrated up to 20-30 mg/kg/day, and maintained for 12 weeks, followed by one-year open-label follow-up. Primary efficacy endpoints were relative reduction in standardized seizure frequency (SSF) and proportion of responders (≥50% SSF reduction) from baseline. Safety was evaluated by the incidence of treatment-emergent adverse events (TEAEs).

Results: The intention-to-treat (ITT) set included 134 patients randomized to ESL and 129 to placebo; 89.6% and 91.5%, respectively, completed the trial. An unbalanced number of seizures at baseline were observed between groups. Least square (LS) mean relative change in SSF from baseline was higher in the ESL group (-18.1%) than in placebo (-8.6%). Proportion of responders between ESL and placebo groups was not statistically different. A post hoc analysis showed greater relative reduction in SSF in patients above 6 years old treated with ESL 20 or 30 mg/kg/day compared with placebo; this was significant in patients above 6 years old treated with ESL 30 mg/kg/day (LS mean difference: 31.9%; p = 0.0478). The observed safety profile in children was consistent with that established in adult studies.

Conclusions: Adjunctive ESL treatment was well-tolerated, but this trial failed to demonstrate that ESL was more effective than placebo in the predefined efficacy endpoints; factors that may have contributed to this outcome, affecting particularly the young age group, include etiological heterogeneity, difficulty in recognizing simple partial seizures, high seizure frequency with risk of imbalance, and underestimation of the efficacious dose range.
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http://dx.doi.org/10.1016/j.yebeh.2020.106962DOI Listing
April 2020

Regulatory safety pharmacology evaluation of BIA 10-2474.

J Pharmacol Toxicol Methods 2020 Mar - Apr;102:106677. Epub 2020 Jan 22.

Department of Research, BIAL - Portela & Cª, S.A., Coronado, Portugal.; Department of Biomedicine, Unit of Pharmacology & Therapeutics, Faculty of Medicine, Portugal and MedInUP - Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal.

The present paper describes the regulatory safety pharmacology studies that were carried out to support the clinical trial application for BIA 10-2474. Animal studies complied with worldwide regulatory guidelines (e.g. EEC Council Directive 75/318/EEC and subsequent amendments). Oral administration of BIA 10-2474 at doses of 30, 100 and 300 mg/kg to male Han Wistar rats did not cause any significant physiological or behavioral changes, affect the respiration rate or the tidal volume, the gastrointestinal transit, urinary output volume or pH, nor urinary sodium, potassium or chloride excretion. BIA 10-2474, at 30 μg/mL, slightly, but significantly, reduced the hERG outward tail currents by 10.62%, but had no effect at 1, 3 or 10 μg/mL. BIA 10-2474 (1.5, 4.5 and 15 μg/mL) had no substantial effects on resting membrane potential (RMP), maximal upstroke velocity (V), action potential amplitude (APA), action potential duration at 30%, 60% and 90% or action potential triangulation over the 30-min superfusion period in the dog isolated Purkinje fiber. In conscious dogs monitored by telemetry, BIA 10-2474 (20, 50 and 100 mg/kg p.o.) did not significantly modify arterial blood pressure as compared with controls (inter-group comparison), although a tendency toward an increase in arterial blood pressure was observed at 100 mg/kg, with systolic blood pressure being the most affected parameter. In conclusion, BIA 10-2474 had no adverse effects on any of the major vital organ systems, and, unfortunately, the data shed no further light on the mechanism(s) responsible for the clinical trial accident with BIA 10-2474.
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http://dx.doi.org/10.1016/j.vascn.2020.106677DOI Listing
November 2020

Preclinical pharmacological evaluation of the fatty acid amide hydrolase inhibitor BIA 10-2474.

Br J Pharmacol 2020 05 12;177(9):2123-2142. Epub 2020 Feb 12.

Department of Research, Bial-Portela & Cª., S.A., Coronado (S Mamede & S Romão), Portugal.

Background And Purpose: In 2016, one person died and four others had mild-to-severe neurological symptoms during a phase I trial of the fatty acid amide hydrolase (FAAH) inhibitor BIA 10-2474.

Experimental Approach: Pharmacodynamic and pharmacokinetic studies were performed with BIA 10-2474, PF-04457845 and JNJ-42165279 using mice, rats and human FAAH expressed in COS cells. Selectivity was evaluated by activity-based protein profiling (APBB) in rats. BIA 10-2474 effect in stroke-prone spontaneously hypertensive rats (SHRSP) was investigated.

Key Results: BIA 10-2474 was 10-fold less potent than PF-04457845 in inhibiting human FAAH in situ but inhibited mouse brain and liver FAAH with ED values of 13.5 and 6.2 μg·kg , respectively. Plasma and brain BIA 10-2474 levels were consistent with in situ potency and neither BIA 10-2474 nor its metabolites accumulated following repeat administration. FAAH and α/β-hydrolase domain containing 6 were the primary targets of BIA 10-2474 and, at higher exposure levels, ABHD11, PNPLA6, PLA2G15, PLA2G6 and androgen-induced protein 1. At 100 mg·kg for 28 days, the level of several lipid species containing arachidonic acid increased. Daily treatment of SHRSP with BIA 10-2474 did not affect mortality rate or increased the incidence of haemorrhage or oedema in surviving animals.

Conclusions And Implications: BIA 10-2474 potently inhibits FAAH in vivo, similarly to PF-04457845 and interacts with a number of lipid processing enzymes, some previously identified in human cells as off-targets particularly at high levels of exposure. These interactions occurred at doses used in toxicology studies, but the implication of these off-targets in the clinical trial accident remains unclear.
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http://dx.doi.org/10.1111/bph.14973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7161550PMC
May 2020

Analysis of cutaneous allergic reactions in clinical trials of eslicarbazepine acetate.

Acta Neurol Scand 2020 May 23;141(5):397-404. Epub 2020 Jan 23.

Sunovion Pharmaceuticals Inc., Marlborough, MA, USA.

Objectives: To evaluate cutaneous allergic reactions in clinical trials of adjunctive eslicarbazepine acetate (ESL) for focal seizures.

Materials And Methods: Data were analyzed from three phase III randomized, double-blind, placebo-controlled studies of adjunctive ESL in adults (placebo, n = 426; ESL, n = 1021) and two randomized, double-blind, placebo-controlled studies (and open-label extensions [OLEs]) of adjunctive ESL in children aged 4-17 years (placebo, n = 160; ESL, n = 202; OLE, n = 337).

Results: Adult studies: Rash (ESL 1.9%, placebo 0.9%) and pruritus (ESL 1.2%, placebo 0.9%) were the most frequent rash-related treatment-emergent adverse events (TEAEs). Most rash-related TEAEs were mild or moderate in severity. Incidence of rash increased with increasing ESL dose, but was not higher for patients who initiated treatment with higher ESL doses. Pediatric studies: Allergic dermatitis (ESL 3.0%, placebo 0) and rash (controlled studies: ESL 1.0%, placebo 1.3%; OLE periods: ESL ≤1.2%) were the most frequent rash-related TEAEs. There was one case of DRESS in the ESL group. Most rash-related TEAEs were mild or moderate in severity and judged as not related to treatment with ESL.

Conclusions: Serious skin rashes were rare during adult and pediatric clinical trials of ESL. Although the incidence of rash with ESL was low, it is important for patients/caregivers to be made aware of the potential signs and symptoms associated with serious skin rashes.
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http://dx.doi.org/10.1111/ane.13218DOI Listing
May 2020

Population Pharmacokinetic-Pharmacodynamic Modeling for Propofol Anesthesia Guided by the Bispectral Index (BIS).

J Clin Pharmacol 2019 Dec 3. Epub 2019 Dec 3.

Laboratory of Pharmacology, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.

This study aimed to develop a population pharmacokinetic-pharmacodynamic (PKPD) model for propofol using data prospectively collected from a heterogeneous group of adult, elderly, and obese patients using the bispectral index (BIS) as a pharmacodynamic guide. Adult, obese (body mass index ≥35 kg/m ), and elderly patients (aged >65 years) were included. Propofol infusion was started at 2000 mg/h until loss of consciousness and then guided by target BIS values (40-60). Measurements of propofol plasma concentration were performed using gas chromatography. A PKPD model was developed using NONMEM. The data set contained 423 propofol concentrations and 483 897 BIS values from 60 patients (20-92 years, 42-136 kg). A 3-compartment model was used to describe the plasma concentrations of propofol. An allometric model using lean body weight calculated by the Janmahasatian formula was found to describe the data better than total body weight for all clearance parameters, V1 and V2. An age effect was found on Q2, Q3, V1, and V3. With respect to the PD model, the use of a 2-compartment model significantly improved the model fit. Age and total body weight were included as covariates in the final pharmacodynamic model. We propose a PKPD model for propofol anesthesia with acceptable performance accuracy in a heterogeneous group of adult, elderly, and obese patients. A new method to predict propofol induction dose is presented. This method and the possibility to directly change target BIS values in opposition to the assumed target effect-site concentration constitutes certain advantages to the clinical practice.
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http://dx.doi.org/10.1002/jcph.1560DOI Listing
December 2019

Bioelectrical impedance analysis of body composition for the anesthetic induction dose of propofol in older patients.

BMC Anesthesiol 2019 10 11;19(1):180. Epub 2019 Oct 11.

Department of Biomedicine, Unit of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal.

Background: Older people are currently the fastest growing segment of the worldwide population. The present study aimed to estimate propofol dose in older patients based on size descriptors measured by bioelectrical impedance analysis (BIA).

Methods: A cross sectional study in adult and older patients with body mass index equal to or lower than 35 kg/m was carried out. BIA and Clinical Frail Scale scoring were performed during pre-operative evaluation. Propofol infusion was started at 2000 mg/h until loss of consciousness (LOC) which was defined by "loss of eye-lash reflex" and "loss of response to name calling". Total dose of propofol at LOC was recorded. Propofol plasma concentration was measured using gas chromatography/ion trap-mass spectrometry.

Results: Forty patients were enrolled in the study. Total propofol dose required to LOC was lower in Age ≥ 65 group and a higher plasma propofol concentration was measured in this group. 60% of old patients were classified as "apparently vulnerable" or "frail" and narrow phase angle values were associated with increasing vulnerability scores. In the Age ≥ 65 group, the correlation analysis showed that the relationship between propofol dose and total body weight (TBW) scaled by the corresponding phase angle value is stronger than the correlation between propofol dose and TBW or fat free mass (FFM).

Conclusions: This study demonstrates that weight-based reduction of propofol is suitable in older patients; however FFM was not seen to be more effective than TBW to predict the propofol induction dose in these patients. Guiding propofol induction dose according to baseline frailty score should also be considered to estimate individualized dosage profiles. Determination of phase angle value appears to be an easy and reliable tool to assess frailty in older patients.

Trial Registration: ClinicalTrials.gov Identifier: NCT02713698 . Registered on 23 February 2016.
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http://dx.doi.org/10.1186/s12871-019-0856-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790019PMC
October 2019

Safety Profile of Opicapone in the Management of Parkinson's Disease.

J Parkinsons Dis 2019 ;9(4):733-740

Department of Research and Development, BIAL - Portela & Ca SA, S. Mamede do Coronado, Portugal.

Background: Opicapone is a catechol O-methyltransferase (COMT) inhibitor indicated for use as adjunct to levodopa therapy in patients with Parkinson's disease (PD) and motor fluctuations.

Objective: To characterize the safety and tolerability of adjunct opicapone (25 and 50 mg) in a pooled population of levodopa-treated PD patients who participated in the opicapone Phase-3 clinical program.

Methods: Patient-level data (placebo, opicapone 25 mg and 50 mg) from the BIPARK-1 and BIPARK-2 double-blind and open-label studies were combined.

Results: Pooled analyses included 766 patients from the double-blind studies and 848 patients from the open-label studies. In the double-blind studies, 63.3% of opicapone-treated patients reported treatment-emergent adverse events (TEAEs) versus 57.2% in the placebo group. The most common TEAEs reported in the opicapone group compared to placebo were dyskinesia, constipation and insomnia. The incidence of serious TEAEs was similar across opicapone and placebo groups (3.5% versus 4.3%, respectively). Overall, 71.3% patients treated with open-label opicapone reported at least one TEAE; most occurred within the first 2 months of the open-label studies, and then decreased thereafter. Throughout the Phase-3 clinical program, there were no serious AEs suggestive of hepatic toxicity, and the incidence of gastrointestinal disorders such as nausea and diarrhea remained low (<2%). There were no relevant changes in laboratory parameters including liver enzymes, vital signs, physical or neurological examinations, or ECG readings.

Conclusions: Long-term use of opicapone once-daily over 1-year at doses of 25 mg or 50 mg was generally safe and well tolerated, supporting its clinical usefulness in the management of PD motor fluctuations.
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http://dx.doi.org/10.3233/JPD-191593DOI Listing
July 2020

Contemporary Options for the Management of Motor Complications in Parkinson's Disease: Updated Clinical Review.

Drugs 2019 Apr;79(6):593-608

Department of Neurology, Centro Hospitalar Universitário de S. João, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal.

Parkinson's disease (PD) is a chronic, progressive condition affecting around 1% of the population older than 60 years. Upon long-term treatment with levodopa, the mainstay of treatment in PD, most patients, especially younger ones exposed to higher doses, will experience symptoms related to end-of-dose deterioration, peak-dose dyskinesias, and other motor fluctuations. Therapeutic strategies are grounded on modification of oral levodopa pharmacokinetics to extend levodopa benefit and development of new routes of drug delivery (e.g., levodopa/carbidopa intestinal gel infusion) or long-acting formulations of existing dopaminergic drugs to prolong the duration of striatal dopamine receptors stimulation. As our understanding of the pathophysiology of motor complications evolves, our therapeutic armamentarium is actively expanding and the focus of research is now actively pointing to the new non-dopaminergic agents acting both within the basal ganglia and in other brain regions (e.g., drugs acting on glutamate, GABA, serotonin, and calcium channels). Despite the fact that trials comparing the different therapeutic strategies are lacking, we aimed at devising practical evidence- and experience-guided suggestions for the clinical management of motor complications, emphasizing that this should always be an individualized endeavor. This review summarizes the pharmacological management of motor complications in PD, including new formulations and routes of delivery, and the newer released drugs such as istradefylline, opicapone, safinamide, and zonisamide. Advanced therapeutic strategies for selected cases such as treatment with apomorphine and surgical techniques (deep brain stimulation) are also discussed. A comprehensive knowledge of the available options and evidence is fundamental for the successful management of these challenging complications.
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http://dx.doi.org/10.1007/s40265-019-01098-wDOI Listing
April 2019

Acute salt loading induces sympathetic nervous system overdrive in mice lacking salt-inducible kinase 1 (SIK1).

Hypertens Res 2019 08 20;42(8):1114-1124. Epub 2019 Mar 20.

BIAL-Portela & Cª, S.A., R&D, Coronado (S. Romão e S. Mamede), Portugal.

Loss of salt-inducible kinase 1 (SIK1) triggers an increase in blood pressure (BP) upon a chronic high-salt intake in mice. Here, we further addressed the possible early mechanisms that may relate to the observed rise in BP in mice lacking SIK1. SIK1 knockout (sik1) and wild-type (sik1) littermate mice were challenged with either a high-salt (8% NaCl) or control (0.3% NaCl) diet for 7 days. Systolic BP was significantly increased in sik1 mice after 7 days of high-salt diet as compared with sik1 mice and to sik1 counterparts on a control diet. The renin-angiotensin-aldosterone system and the sympathetic nervous system were assayed to investigate possible causes for the increase in BP in sik1 mice fed a 7-day high-salt diet. Although no differences in serum renin and angiotensin II levels were observed, a reduction in aldosterone serum levels was observed in mice fed a high-salt diet. Urinary L-DOPA and noradrenaline levels were significantly increased in sik1 mice fed a high-salt diet as compared with sik1 mice on a control diet. Similarly, the activity of dopamine β-hydroxylase (DβH), the enzyme that converts dopamine to noradrenaline, was significantly increased in the adrenal glands of sik1 mice on a high-salt intake compared with sik1 and sik1 mice on a control diet. Treatment with etamicastat (50 mg/kg/day), a peripheral reversible DβH inhibitor, administered prior to high-salt diet, completely prevented the systolic BP increase in sik1 mice. In conclusion, SIK1 activity is necessary to prevent the development of salt-induced high blood pressure and associated SNS overactivity.
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http://dx.doi.org/10.1038/s41440-019-0249-zDOI Listing
August 2019

Effects of nepicastat upon dopamine-β-hydroxylase activity and dopamine and norepinephrine levels in the rat left ventricle, kidney, and adrenal gland.

Clin Exp Hypertens 2020 1;42(2):118-125. Epub 2019 Mar 1.

Department of Biomedicine, Unit of Pharmacology and Therapeutics, Faculty Medicine, University of Porto, Porto, Portugal.

: Evaluate the activity of dopamine-β-hydroxylase (DβH) as well as the effect of the DβH inhibitor nepicastat upon enzyme activity and levels of dopamine (DA) and norepinephrine (NE) in the rat left ventricle, kidney, and adrenal glands.: DβH assay consisted of the enzymatic hydroxylation of tyramine into octopamine, and DA and NE tissues levels were quantified by HPLC-ED.: Nepicastat (30 mg/kg, p.o.) reduced DβH activity by 93% and 80% in the adrenals at 4 h and 8 h postdrug administration, accompanied by significant reductions in NE and epinephrine tissue levels and an increase in DA levels and of DA/NE tissue ratios, with similar findings for NE, DA and of DA/NE tissue ratios in left ventricle and kidney. DβH activity in the left ventricle and kidney showed a high degree of variability, which does not allow corroboration of the effects of nepicastat upon catecholamine tissue levels.: The assay of DβH activity in heart and kidney lacks the necessary robustness, but DβH activity in the adrenals appears to be an appropriate marker. However, the effect size upon DA/NE tissue ratios (an indirect measure of DβH activity) as induced by nepicastat was very similar in sympathetically innervated tissues, left ventricle and kidney, and the adrenal medulla.
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http://dx.doi.org/10.1080/10641963.2019.1583245DOI Listing
March 2020

Repurposing nitrocatechols: 5-Nitro-α-cyanocarboxamide derivatives of caffeic acid and caffeic acid phenethyl ester effectively inhibit aggregation of tau-derived hexapeptide AcPHF6.

Eur J Med Chem 2019 Apr 4;167:146-152. Epub 2019 Feb 4.

CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Rua do Campo Alegre s/n, 4169-007, Porto, Portugal. Electronic address:

Polyphenols like caffeic acid and its phenethyl ester have been associated with potent anti-aggregating activity. Accordingly, we screened a library of polyphenols and synthetic derivatives thereof for their capacity to inhibit tau-aggregation using a thioflavin T-based fluorescence method. Our results show that the nitrocatechol scaffold is required for a significant anti-aggregating activity, which is enhanced by introducing bulky substituents at the side chain. A remarkable increase in activity was observed for α-cyanocarboxamide derivatives 26-27. Molecular docking studies showed that the amide bond provides superior conformational stability in the steric zipper assembly of tau, which drives the increase in activity. We also found that derivatives 24-27 were potent chelators of copper(II) - a property of pharmacological significance in abnormal protein aggregation. These small molecules can provide promising leads to develop new drugs for tauopathies and AD. These findings open a new window on the repurposing of nitrocatechols beyond their established role as catechol-O-methyltransferase inhibitors.
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http://dx.doi.org/10.1016/j.ejmech.2019.02.006DOI Listing
April 2019

Pharmacodynamic evaluation of novel Catechol-O-methyltransferase inhibitors.

Eur J Pharmacol 2019 Mar 24;847:53-60. Epub 2019 Jan 24.

Department of Biomedicine, Unit of Pharmacology and Therapeutics, Faculty Medicine, University of Porto, Portugal; MedInUP - Center for Drug Discovery and Innovative Medicines, University of Porto, Portugal. Electronic address:

Currently, peripheral COMT inhibitors have an important role in the treatment of Parkinson's disease, and central COMT inhibitors have a potential role in the treatment of various neuropsychiatric disorders, such as attention deficit hyperactivity disorder. Adverse reactions, low bioavailability and short elimination half-lives have prompted the development of new selective COMT inhibitors. The objective of this study was to evaluate the pharmacodynamic properties of novel tight-binding COMT inhibitors (NC, NE, NDE, NCAPE, CNCAFBn, CNCAPE, NCAFBn, CNCAPA, CNCABA and CNCAHA) and compared to standard inhibitors tolcapone and entacapone. The activity of soluble (S) and membrane bound (MB) COMT from rat liver and brain was assessed in the presence of varying concentrations of each inhibitor. NE and NC behaved most potently against liver S-COMT, and CNCAPE was the most potent inhibitor against brain MB-COMT. The cytotoxicity of tolcapone and CNCAPE in human neuroblastoma SK-N-SH cells and human liver adenocarcinoma SK-HEP-1 cells was also assessed. At lower concentrations, CNCAPE did not reduce cell viability, suggesting that CNCAPE may have a potential therapeutic role as a centrally active COMT inhibitor.
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http://dx.doi.org/10.1016/j.ejphar.2019.01.027DOI Listing
March 2019

Effects of zamicastat treatment in a genetic model of salt-sensitive hypertension and heart failure.

Eur J Pharmacol 2019 Jan 26;842:125-132. Epub 2018 Oct 26.

Department of Research, BIAL - Portela & Cª, S.A., Coronado (S. Romão e S. Mamede), Portugal; Department of Pharmacology & Therapeutics, Faculty of Medicine, University of Porto, Portugal; MedInUP - Center for Drug Discovery and Innovative Medicines, University of Porto, Portugal. Electronic address:

Hyperactivity of sympathetic nervous system plays an important role in the development and progression of cardiovascular diseases. An approach to mitigate the enhanced sympathetic nervous system drive is restricting the biosynthesis of noradrenaline via inhibition of the enzyme dopamine β-hydroxylase (DβH), that catalyzes the hydroxylation of dopamine to noradrenaline in sympathetic nerves. The aim of the present study was to evaluate the effects of zamicastat, a novel DβH inhibitor that decreases noradrenaline and increases dopamine levels in peripheral sympathetically innervated tissues, on the hemodynamic and cardiometabolic parameters in salt-induced hypertension and heart failure in the Dahl salt-sensitive (SS) rat. Zamicastat (10, 30 and 100 mg/kg body weight) was tested acutely against salt-induced hypertension in the Dahl SS rat. Chronic zamicastat treatment (30 mg/kg/day) was evaluated against salt-induced cardiac hypertrophy and biomarkers of cardiometabolic risk and inflammation in Dahl SS rats and upon the survival rate in aged Dahl SS rats fed a high-salt diet. The reduction in the sympathetic tone attained with zamicastat shaped a dose- and time-dependent effect on blood pressure. Prolonged treatment with zamicastat ameliorated end-organ damage, metabolic syndrome and inflammation hallmarks in hypertensive Dahl SS rats. Survival rate of Dahl SS rats fed a high-salt diet demonstrated that zamicastat increased median survival of Dahl SS rats fed a high-salt diet. The use of DβH inhibitors, like zamicastat, is a promising approach to treat hypertension, heart failure and cardiovascular diseases where a reduction in the sympathetic tone has beneficial effects.
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http://dx.doi.org/10.1016/j.ejphar.2018.10.030DOI Listing
January 2019

Safety, Tolerability and Efficacy of Eslicarbazepine Acetate as Adjunctive Therapy in Patients Aged ≥ 65 Years with Focal Seizures.

Drugs Aging 2018 12;35(12):1109-1117

Department of Research and Development, BIAL-Portela & Cª, S.A., À Avenida da Siderurgia Nacional, 4745-457, Coronado (S. Romão e S. Mamede), Portugal.

Background: The incidence of epilepsy is high within the first few years of life, stabilizes over the second through fifth decades, and then rises again. Treatment of elderly patients with antiepileptic drugs (AEDs) is complicated by increased sensitivity to drug effects, altered pharmacokinetics and an increased risk for drug interactions due to polytherapy. On the other hand, the safety and efficacy data of AEDs attained during clinical development programmes are relatively limited for this age group.

Objective: The aim of this study was to evaluate the safety, tolerability and efficacy of eslicarbazepine acetate (ESL) as adjunctive therapy in patients aged ≥ 65 years with focal-onset seizures (FOS).

Methods: This was an international, multicentre, open-label, non-controlled, single-arm, post-European approval commitment study with flexible doses of ESL between 400 and 1200 mg/day. Seventy-two elderly patients with at least two FOS in the prior 4 weeks, and treated with one or two AEDs, were enrolled. The study consisted of an 8-week baseline, followed by a 26-week treatment period during which the investigator was allowed to up- or down-titrate the ESL dose, and a 4-week follow-up period. Safety and tolerability were assessed as well as mental sedation, cognitive mental state and suicidal ideation. Efficacy was assessed based on patient diaries regarding the absolute and relative changes in seizure frequency, change in intellectual impairment and quality of life.

Results: Overall, 47 (65.3%) patients experienced 152 treatment-emergent adverse events (TEAEs). The most frequent were dizziness (12.5%), somnolence (9.7%), fatigue, convulsion and hyponatraemia (8.3% each). All patients that experienced hyponatraemia (6/72) recovered without sequelae. Three patients died during the study (due to cardiac failure, glioblastoma multiforme and ischaemic stroke, all considered unrelated to ESL). Overall, 16 (22.2%) patients discontinued prematurely due to TEAEs. The incidences of clinically significant findings were low for vital signs, ECG, physical and neurological examinations. No TEAEs of hypothyroidism were reported; however, 24 (33.3%) patients presented post-baseline shifts from normal to decreased free T4 levels (not clinically significant). ESL decreased standardized seizure frequency from a mean of 4.8 seizures at baseline to 3.6 seizures at endpoint (p > 0.05); and mean number of days with seizures significantly decreased from 4.1 (baseline) to 2.8 at endpoint (p = 0.0408).

Conclusion: ESL taken once daily (400-1200 mg) as adjunctive therapy in patients aged ≥ 65 years was found to be safe, well tolerated and efficacious (EudraCT number: 2009-012587-14).
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http://dx.doi.org/10.1007/s40266-018-0602-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6267536PMC
December 2018

Inhibition of catechol-O-methyltransferase in the cynomolgus monkey by opicapone after acute and repeated administration.

Neuropharmacology 2018 12 2;143:282-288. Epub 2018 Oct 2.

Research Headquarters, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Osaka, Japan. Electronic address:

Introduction: The aim of the study was to clarify the dose response for inhibition of catechol-O-methyltransferase (COMT) by opicapone, a third generation COMT inhibitor, after acute and repeated administration to the cynomolgus monkey with pharmacokinetic evaluation at the higher dose.

Methods: Three cynomolgus monkeys were used in the study. In the first experiment, COMT inhibition was evaluated over 24 h after the first and at 24 h after the last of 14 daily oral administrations of vehicle, 1, 10 and 100 mg/kg opicapone using a crossover design. In the second experiment, the effect of the maximally effective dose, 100 mg/kg, was retested under the same conditions with additional monitoring of plasma opicapone levels to explore the relationship between pharmacokinetics and pharmacodynamics.

Results: Opicapone dose-dependently inhibited COMT activity, significantly so at 10 and 100 mg/kg. Maximal inhibition was 13.1%, 76.4% and 93.2% at 1, 10 and 100 mg/kg respectively, and COMT remained significantly inhibited at 24 h after 10 and 100 mg/kg (42.6% and 60.2% respectively). Following repeated administration of opicapone residual COMT inhibition at 24 h was 15-25% greater at all doses. In contrast to its pharmacodynamic effect, opicapone was rapidly absorbed and eliminated, with no accumulation in plasma following repeated administration.

Conclusion: Opicapone showed sustained and dose-dependent COMT inhibition despite being rapidly eliminated from plasma and with no evidence for accumulation in plasma after 14 days administration. Opicapone fills the unmet need for a compound with sustained COMT inhibition which will improve levodopa bioavailability in patients with Parkinson's disease.
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http://dx.doi.org/10.1016/j.neuropharm.2018.10.001DOI Listing
December 2018

Discovery of a Potent, Long-Acting, and CNS-Active Inhibitor (BIA 10-2474) of Fatty Acid Amide Hydrolase.

ChemMedChem 2018 10 11;13(20):2177-2188. Epub 2018 Sep 11.

Laboratory of Pharmacology, Department of Research and Development, BIAL-Portela & Cª., S.A., À Avenida da Siderurgia Nacional, 4745-457, Coronado (S. Romão and S. Mamede), Portugal.

Fatty acid amide hydrolase (FAAH) can be targeted for the treatment of pain associated with various medical conditions. Herein we report the design and synthesis of a novel series of heterocyclic-N-carboxamide FAAH inhibitors that have a good alignment of potency, metabolic stability and selectivity for FAAH over monoacylglycerol lipase (MAGL) and carboxylesterases (CEs). Lead optimization efforts carried out with benzotriazolyl- and imidazolyl-N-carboxamide series led to the discovery of clinical candidate 8 l (3-(1-(cyclohexyl(methyl)carbamoyl)-1H-imidazol-4-yl)pyridine 1-oxide; BIA 10-2474) as a potent and long-acting inhibitor of FAAH. However, during a Phase I clinical trial with compound 8 l, unexpected and unpredictable serious neurological adverse events occurred, affecting five healthy volunteers, including the death of one subject.
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http://dx.doi.org/10.1002/cmdc.201800393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6582431PMC
October 2018

Effects of eslicarbazepine on slow inactivation processes of sodium channels in dentate gyrus granule cells.

Epilepsia 2018 08 28;59(8):1492-1506. Epub 2018 Jun 28.

Institute of Experimental Epileptology and Cognition Research, University of Bonn, Bonn, Germany.

Objective: Pharmacoresistance is a problem affecting ∼30% of chronic epilepsy patients. An understanding of the mechanisms of pharmacoresistance requires a precise understanding of how antiepileptic drugs interact with their targets in control and epileptic tissue. Although the effects of (S)-licarbazepine (S-Lic) on sodium channel fast inactivation are well understood and have revealed maintained activity in epileptic tissue, it is not known how slow inactivation processes are affected by S-Lic in epilepsy.

Methods: We have used voltage clamp recordings in isolated dentate granule cells (DGCs) and cortical pyramidal neurons of control versus chronically epileptic rats (pilocarpine model of epilepsy) and in DGCs isolated from hippocampal specimens from temporal lobe epilepsy patients to examine S-Lic effects on sodium channel slow inactivation.

Results: S-Lic effects on entry into and recovery from slow inactivation were negligible, even at high concentrations of S-Lic (300 μmol/L). Much more pronounced S-Lic effects were observed on the voltage dependence of slow inactivation, with significant effects at 100 μmol/L S-Lic in DGCs from control and epileptic rats or temporal lobe epilepsy patients. For none of these effects of S-Lic could we observe significant differences either between sham-control and epileptic rats, or between human DGCs and the two animal groups. S-Lic was similarly effective in cortical pyramidal neurons from sham-control and epileptic rats. Finally, we show in expression systems that S-Lic effects on slow inactivation voltage dependence are only observed in Na 1.2 and Na 1.6 subunits, but not in Na 1.1 and Na 1.3 subunits.

Significance: From these data, we conclude that a major mechanism of action of S-Lic is an effect on slow inactivation, primarily through effects on slow inactivation voltage dependence of Na 1.2 and Na 1.6 channels. Second, we demonstrate that this main effect of S-Lic is maintained in both experimental and human epilepsy and applies to principal neurons of different brain areas.
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http://dx.doi.org/10.1111/epi.14504DOI Listing
August 2018

Polyamine Modulation of Anticonvulsant Drug Response: A Potential Mechanism Contributing to Pharmacoresistance in Chronic Epilepsy.

J Neurosci 2018 06 22;38(24):5596-5605. Epub 2018 May 22.

Institute for Experimental Epileptology and Cognition Research,

Despite the development of numerous novel anticonvulsant drugs, ∼30% of epilepsy patients remain refractory to antiepileptic drugs (AEDs). Many established and novel AEDs reduce hyperexcitability via voltage- and use-dependent inhibition of voltage-gated Na channels. For the widely used anticonvulsant carbamazepine (CBZ), use-dependent block of Na channels is significantly reduced both in experimental and human epilepsy. However, the molecular underpinnings of this potential cellular mechanism for pharmacoresistance have remained enigmatic.Here, we describe the mechanism that leads to the emergence of CBZ-resistant Na channels. We focused on the endogenous polyamine system, which powerfully modulates Na channels in a use-dependent manner. We had shown previously that the intracellular polyamine spermine is reduced in chronic epilepsy, resulting in increased persistent Na currents. Because spermine and CBZ both bind use-dependently in spatial proximity within the Na channel pore, we hypothesized that spermine loss might also be related to diminished CBZ response. Using the pilocarpine model of refractory epilepsy in male rats and whole-cell patch-clamp recordings, we first replicated the reduction of use-dependent block by CBZ in chronically epileptic animals. We then substituted intracellular spermine via the patch pipette in different concentrations. Under these conditions, we found that exogenous spermine significantly rescues use-dependent block of Na channels by CBZ. These findings indicate that an unexpected modulatory mechanism, depletion of intracellular polyamines, leads both to increased persistent Na currents and to diminished CBZ sensitivity of Na channels. These findings could lead to novel strategies for overcoming pharmacoresistant epilepsy that target the polyamine system. Pharmacoresistant epilepsy affects ∼18 million people worldwide, and intense efforts have therefore been undertaken to uncover the underlying molecular and cellular mechanisms. One of the key known candidate mechanisms of pharmacoresistance has been a loss of use-dependent Na channel block by the anticonvulsant carbamazepine (CBZ), both in human and experimental epilepsies. Despite intense scrutiny, the molecular mechanisms underlying this phenomenon have not been elucidated. We now show that a loss of intracellular spermine in chronic epilepsy is a major causative factor leading to the development of CBZ-resistant Na currents. This finding can be exploited both for the screening of anticonvulsants in expression systems, and for novel strategies to overcome pharmacoresistance that target the polyamine system.
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http://dx.doi.org/10.1523/JNEUROSCI.0640-18.2018DOI Listing
June 2018

Effectiveness of opicapone and switching from entacapone in fluctuating Parkinson disease.

Neurology 2018 05 25;90(21):e1849-e1857. Epub 2018 Apr 25.

From the Instituto de Medicina Molecular (J.J.F.), Faculty of Medicine, University of Lisbon; CNS-Campus Neurológico Sénior (J.J.F.), Torres Vedras, Portugal; University College London (A.J.L.), Reta Lila Weston Institute, UK; Department of Neurology (W.P.), Medical University Innsbruck, Austria; Université de Toulouse (O.R.), CHU de Toulouse, Institut National de la Santé et de la Recherche Médicale, Department of Neurosciences and Clinical Pharmacology, Clinical Investigation Center 1436, and NeuroToul Center of Excellence in Neurodegeneration France; Department of Research and Development (J.-F.R., P.S.-d.-S.), BIAL-Portela & Ca SA, S. Mamede do Coronado, Portugal; Department of Biostatistics (B.K.), Clinipace Worldwide, Eschborn, Germany; and Department of Pharmacology and Therapeutics (P.S.-d.-S.), Faculty of Medicine, University Porto, Portugal.

Objective: To evaluate the effectiveness of opicapone as add-on to levodopa and the effects of switching from entacapone over 1 year of treatment in patients with fluctuating Parkinson disease.

Methods: After completion of a placebo- and entacapone-controlled double-blind study of opicapone (5, 25, or 50 mg), 495 patients continued to a 1-year extension phase in which patients were treated with opicapone. Patients began with once-daily opicapone 25 mg for 1 week, followed by individually tailored levodopa and/or opicapone dose adjustments. The primary efficacy variable was the change from baseline in absolute "off" time based on patient diaries. Other outcomes included proportion of responders, scale-based assessments, and standard safety assessments.

Results: One year of treatment with opicapone reduced "off" time by a half-hour (33.8 minutes) vs the open-label baseline and >2 hours (126.9 minutes) vs the double-blind baseline. Whereas patients who were originally treated with opicapone 50 mg in the double-blind phase maintained their efficacy, switching treatments led to further decreases in "off" time (-64.9, -39.3, -27.5, and -23.0 minutes for switching from placebo, entacapone, and opicapone 5 and 25 mg, respectively). Dyskinesia was the most frequently reported adverse event (14.5%) and was managed by adjustment of dopaminergic therapy. No new safety concerns were observed with long-term opicapone administration.

Conclusion: Long-term use of opicapone provided sustained efficacy over 1 year. Switching from entacapone to opicapone led to enhanced efficacy under the conditions of the study.

Classification Of Evidence: This study provides Class III evidence that for patients with Parkinson disease and end-of-dose motor fluctuations, long-term use (52 weeks) of opicapone is well tolerated and reduces "off" time.
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http://dx.doi.org/10.1212/WNL.0000000000005557DOI Listing
May 2018

Eslicarbazepine acetate exposure in pregnant women with epilepsy.

Seizure 2018 May 10;58:72-74. Epub 2018 Apr 10.

Dept. Research & Development, BIAL - Portela & C(a),, S.A., 4745-457 Coronado (S. Romão e S. Mamede), Portugal(1); Dept. of Biomedicine, Pharmacology and Therapeutics Unit, Faculty of Medicine, University Porto, Porto, Portugal; MedInUP, Center for Drug Discovery and Innovative Medicines, University Porto, Porto, Portugal.

Purpose: Epilepsy is a common neurologic disorder requiring continued treatment during pregnancy. Treatment with antiepileptic drugs (AEDs) is needed for seizure control, but the risk of adverse events has to be minimized for both mother and foetus. Available data on pregnancy and foetal/postnatal outcomes following eslicarbazepine acetate (ESL) exposure via parent is herein presented for the first time.

Methods: ESL's global safety database was reviewed to identify pregnancy cases with exposure to ESL reported up to October 21st, 2017. The EMBASE™ and MEDLINE databases were searched to identify literature reports of such cases published between May 1st, 2009 and October 21st, 2017.

Results: Overall, 91 notifications of pregnancy were identified, of which 79 involved ESL exposure: 28 during clinical trials and 51 from 8-years of post-marketing surveillance. Thirty pregnancies resulted in live birth without congenital anomalies; in 25 pregnancies the outcome was ongoing and 3 was unknown; 18 cases resulted in abortion (10 spontaneous and 8 induced) and congenital anomalies were identified in 5 cases (no clear relationship with ESL was established). ESL was used concomitantly to other AEDs in 11 of the 15 pregnancies for which the outcome was spontaneous abortion and congenital anomaly. Literature review did not yield additional information.

Conclusions: Available data are insufficient to draw conclusions regarding ESL use during pregnancy. Although no particular safety problem was identified, ESL exposure during pregnancy will continue to be monitored and evaluated.
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http://dx.doi.org/10.1016/j.seizure.2018.04.007DOI Listing
May 2018