Póvoa e Meadas, Portugal
Póvoa e Meadas, Portugal

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Silva R.,University of Beira Interior | Ferreira S.,University of Beira Interior | Bonifacio M.J.,Bial | Dias J.M.L.,New University of Lisbon | And 2 more authors.
Journal of Biotechnology | Year: 2012

The aim of this work was to optimize the temperature, pH and stirring rate of the production of human soluble catechol-O-methyltransferase (hSCOMT) in a batch Escherichia coli culture process. A central composite design (CCD) was firstly employed to design the experimental assays used in the evaluation of these operational parameters on the hSCOMT activity for a semi-defined and complex medium. Predictive artificial neural network (ANN) models of the hSCOMT activity as function of the combined effects of these variables was proposed based on this exploratory experiments performed for the two culture media. The regression coefficients (R2) for the final models were 0.980 and 0.983 for the semi-defined and complex medium, respectively. The ANN models predicted a maximum hSCOMT activity of 183.73nmol/h, at 40°C, pH 6.5 and stirring rate of 351rpm, and 132.90nmol/h, at 35°C, pH 6.2 and stirring rate of 351rpm, for semi-defined and complex medium, respectively. These results represent a 4-fold increase in total hSCOMT activity by comparison to the standard operational conditions used for this bioprocess at slight scale. © 2012 Elsevier B.V.


Fortuna A.,University of Coimbra | Alves G.,University of Coimbra | Alves G.,University of Beira Interior | Falcao A.,University of Coimbra | Soares-Da-Silva P.,BIAL
Epilepsia | Year: 2012

Purpose: The rational discovery and development of new antiepileptic drugs (AEDs) with safer therapeutic index and better pharmacokinetic properties is still warranted nowadays. Because the long-term management of epilepsy is attained by means of orally administered AEDs, investigation of their potential to be well absorbed at the intestinal level is mandatory. Moreover, involvement of the efflux transport mediated by P-glycoprotein (P-gp) may compromise the systemic and central nervous system disposition of AEDs. Therefore, this study aimed at characterizing mouse jejunal passive transport and the possible active efflux mediated by P-gp of a series of dibenz[b,f]azepine-5-carboxamide derivatives (carbamazepine [CBZ], oxcarbazepine [OXC], S-licarbazepine [S-Lic], R-licarbazepine [R-Lic], carbamazepine-10,11-epoxide [CBZ-E], 10,11-trans-dihydroxy-10,11-dihydro-carbamazepine [trans-diol], and BIA 2-024), which comprise some AEDs and metabolites. Methods: Permeation studies were performed with freshly excised mouse jejunum segments mounted in Ussing chambers. Absorptive (M-S) and secretive (S-M) transports were analyzed with and without verapamil, which is a P-gp inhibitor widely recognized. Apparent permeability coefficients (P app) in both directions and in absence or presence of verapamil were determined for each test compound. The in vitro method was validated using five controls that included high and low permeable markers with known absorption fraction (Fa) and also well-known P-gp substrates. The integrity of intestinal membrane was guaranteed during the assay by measuring the transepithelial electrical resistance. Key Findings: The correlation obtained between P app(M-S) and Fa of references was high (r 2 = 0.9945), and could be used to classify the derivatives according to Biopharmaceutical Classification System: CBZ and OXC were the only classified as highly permeable. The P app(S-M) of OXC, CBZ-E, R-Lic, and BIA 2-024 were significantly higher than their P app(M-S). After verapamil addition, their P app(S-M) lowered while P app(S-M) increased, suggesting the involvement of P-gp on the transport of those compounds across mouse jejunum segments. In opposition, CBZ, S-Lic, and trans-diol presented no statistical differences between the P app values reported in both directions, with or without verapamil. The results reported herein suggest that differences in biodisposition of S-Lic and R-Lic might result from their distinct interaction with P-gp. Significance: The Ussing chamber model used herein showed to be useful for predicting Fa of AEDs and the involvement of efflux transport, namely P-gp, on their absorption. This is an important achievement as compounds that are not transported by P-gp may offer advantages when used in patients with pharmacoresistant epilepsy. © 2012 International League Against Epilepsy.


Patricio J.P.H.,BIAL | Barbosa J.P.P.,Centro Hospitalar Of Lisbon Central | Ramos R.M.M.,Centro Hospitalar Cova da Beira | Antunes N.F.P.,Centro Hospitalar Do Porto Hospital Of Santo Antonio | De Melo P.C.S.,Instituto Portugues Of Oncologia Of Lisbon
Clinical Drug Investigation | Year: 2013

Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently used in clinical practice, and are considered a first-line option for pain management. However, non-selective NSAIDs (nsNSAIDs) and new generation NSAIDs named cyclo-oxygenase-2 inhibitors (coxibs) are very different from one another and their cardiovascular and gastrointestinal safety profiles may influence prescribing. This article resulted from a search of MEDLINE/Pubmed, Cochrane Library, Bandolier, Medscape and Trip database, up to June 2011. Key words included non-steroidal anti-inflammatory, coxib and safety, with the purpose of reviewing the gastrointestinal and cardiovascular safety issues of NSAIDS and the main aspects that differentiate both classes. Selective coxibs are associated with a more favourable gastrointestinal safety profile than nsNSAIDs. In terms of the risk of cardiovascular events, there seems to be a class effect for all NSAIDs with the possible exception of naproxen. The proper usage guidelines for NSAIDs detail the importance of risk factors for each patient in addition to the differences between classes. Patients with high cardiovascular or gastrointestinal risk should avoid using NSAIDs. These medications should be used at the minimum effective dose and for the shortest time possible in all patients. © 2013 Springer International Publishing Switzerland.


Fortuna A.,University of Coimbra | Bicker J.,University of Coimbra | Alves G.,University of Coimbra | Alves G.,University of Beira Interior | And 2 more authors.
Journal of Separation Science | Year: 2011

For the first time, a selective and sensitive chiral HPLC-UV method was developed and fully validated for the simultaneous quantification of eslicarbazepine acetate (ESL), carbamazepine (CBZ), S-licarbazepine (S-Lic), R-licarbazepine (R-Lic), oxcarbazepine (OXC) and carbamazepine-10,11-epoxide (CBZ-E), in mouse plasma and brain homogenate supernatant. After the addition of chloramphenicol as the internal standard, samples were processed using an SPE procedure. The chiral chromatographic analysis was carried out on a LiChroCART 250-4 ChiraDex column, employing a mobile phase of water and methanol (88:12, v/v) pumped at 0.9 mL/min and the UV detector set at 235 nm. The assay was linear (r2≥0.995) for ESL, CBZ, OXC, S-Lic, R-Lic and CBZ-E in the range of, respectively, 0.2-4, 0.4-30, 0.1-60, 0.2-60, 0.2-60 and 0.2-30 μg/mL, in plasma, and of 0.06-1.5 μg/mL for ESL, 0.12-15 μg/mL for CBZ and CBZ-E and 0.06-15 μg/mL for OXC and both licarbazepine (Lic) enantiomers in brain homogenate supernatant. The overall precision was within 8.71% and accuracy ranged from -7.55 to 8.97%. The recoveries of all the compounds were over 92.1%. Afterwards, the application of the method was demonstrated using real plasma and brain samples obtained from mice administered simultaneously with ESL and CBZ. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Hebeisen S.,BSys GmbH Analytics | Pires N.,BIAL | Loureiro A.I.,BIAL | Bonifacio M.J.,BIAL | And 6 more authors.
Neuropharmacology | Year: 2015

This study aimed at evaluating the effects of eslicarbazepine, carbamazepine (CBZ), oxcarbazepine (OXC) and lacosamide (LCM) on the fast and slow inactivated states of voltage-gated sodium channels (VGSC). The anti-epileptiform activity was evaluated in mouse isolated hippocampal slices. The anticonvulsant effects were evaluated in MES and the 6-Hz psychomotor tests. The whole-cell patch-clamp technique was used to investigate the effects of eslicarbazepine, CBZ, OXC and LCM on sodium channels endogenously expressed in N1E-115 mouse neuroblastoma cells. CBZ and eslicarbazepine exhibit similar concentration dependent suppression of epileptiform activity in hippocampal slices. In N1E-115 mouse neuroblastoma cells, at a concentration of 250 μM, the voltage dependence of the fast inactivation was not influenced by eslicarbazepine, whereas LCM, CBZ and OXC shifted the V0.5 value (mV) by -4.8, -12.0 and -16.6, respectively. Eslicarbazepine- and LCM-treated fast-inactivated channels recovered similarly to control conditions, whereas CBZ- and OXC-treated channels required longer pulses to recover. CBZ, eslicarbazepine and LCM shifted the voltage dependence of the slow inactivation (V0.5, mV) by -4.6, -31.2 and -53.3, respectively. For eslicarbazepine, LCM, CBZ and OXC, the affinity to the slow inactivated state was 5.9, 10.4, 1.7 and 1.8 times higher than to the channels in the resting state, respectively. In conclusion, eslicarbazepine did not share with CBZ and OXC the ability to alter fast inactivation of VGSC. Both eslicarbazepine and LCM reduce VGSC availability through enhancement of slow inactivation, but LCM demonstrated higher interaction with VGSC in the resting state and with fast inactivation gating. © 2014 Elsevier Ltd.


Fortuna A.,University of Coimbra | Sousa J.,University of Coimbra | Alves G.,University of Coimbra | Alves G.,University of Beira Interior | And 2 more authors.
Analytical and Bioanalytical Chemistry | Year: 2010

For the first time, a simple, selective and accurate high-performance liquid chromatography method with ultraviolet detection was developed and validated to quantify simultaneously three structurally related antiepileptic drugs; carbamazepine, oxcarbazepine, and the recently launched eslicarbazepine acetate and their main metabolites, carbamazepine-10,11-epoxide, 10,11-trans-dihydroxy-10,11-dihydro-carbamazepine, and licarbazepine. The method involves a solid-phase extraction and a reverse-phase C18 column with 5 cm length. The mobile phase consisting of water, methanol, and acetonitrile in the ratio 64:30:6 was selected as the best one and pumped at 1 mL/min at 40 °C. The use of this recent column and an aqueous mobile phase instead of buffers gives several advantages over the method herein developed; namely the fact that the chromatographic analysis takes only 9 min. The method was validated according to the guidelines of the Food and Drug Administration, showing to be accurate (bias within ±12%), precise (coefficient variation <9%), selective and linear (r 2 > 0.997) over the concentration range of 0.05-30 μg/mL for carbamazepine; 0.05-20 μg/mL for oxcarbazepine; 0.15-4 μg/mL for eslicarbazepine acetate; 0.1-30 μg/mL for carbamazepine-10,11- epoxide; 0.1-10 μg/mL for 10,11-trans-dihydroxy-10,11-dihydro-carbamazepine, and 0.1-60 μg/mL for licarbazepine. It was also shown that this method can adequately be used for the therapeutic drug monitoring of the considered antiepileptic drugs, carbamazepine, oxcarbazepine, eslicarazepine acetate, and their metabolites. © 2010 Springer-Verlag.


Nuno Palma P.,BIAL | Joao Bonifacio M.,BIAL | Isabel Loureiro A.,BIAL | Soares-Da-Silva P.,BIAL
Journal of Computational Chemistry | Year: 2012

Alchemical free energy simulations are amongst the most accurate techniques for the computation of the free energy changes associated with noncovalent protein-ligand interactions. A procedure is presented to estimate the relative binding free energies of several ligands to the same protein target where multiple, low-energy configurational substates might coexist, as opposed to one unique structure. The contributions of all individual substates were estimated, explicitly, with the free energy perturbation method, and combined in a rigorous fashion to compute the overall relative binding free energies and dissociation constants. It is shown that, unless the most stable bound forms are known a priori, inaccurate results may be obtained if the contributions of multiple substates are ignored. The method was applied to study the complex formed between human catechol-O-methyltransferase and BIA 9-1067, a newly developed tight-binding inhibitor that is currently under clinical evaluation for the therapy of Parkinson's disease. Our results reveal an exceptionally high-binding affinity (K d in subpicomolar range) and provide insightful clues on the interactions and mechanism of inhibition. The inhibitor is, itself, a slowly reacting substrate of the target enzyme and is released from the complex in the form of O-methylated product. By comparing the experimental catalytic rate (k cat) and the estimated dissociation rate (k off) constants of the enzyme-inhibitor complex, one can conclude that the observed inhibition potency (K i) is primarily dependent on the catalytic rate constant of the inhibitor's O-methylation, rather than the rate constant of dissociation of the complex. Copyright © 2012 Wiley Periodicals, Inc.


Fortuna A.,University of Coimbra | Alves G.,University of Coimbra | Alves G.,University of Beira Interior | Soares-da-Silva P.,BIAL | And 2 more authors.
Epilepsy Research | Year: 2013

In 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 that in silico models able to predict these features may be applied during the early stages of AEDs discovery. The present investigation was mainly carried out in order to generate in vivo pharmacokinetic data that can be utilized for development and validation of in silico models.For this purpose, a single dose of each compound (1.4. mmol/kg) was orally administered to male CD-1 mice. After quantifying the parent compound and main metabolites in plasma and brain up to 12. h post-dosing, a non-compartmental pharmacokinetic analysis was performed and the corresponding brain/plasma ratios were calculated. Moreover the plasma protein binding was estimated in vitro applying the ultrafiltration procedure.The present in vivo pharmacokinetic characterization of the test compounds and corresponding metabolites demonstrated that the metabolism extensively compromised the in vivo activity of CBZ derivatives and their toxicity. Furthermore, it was clearly evidenced that the time to reach maximum peak concentration, bioavailability (given by the area under the curve) and metabolic stability (given by the AUC0-12h ratio of the parent compound and total systemic drug) influenced the in vivo pharmacological activities and must be considered as primary parameters to be investigated. All the test compounds presented brain/plasma ratios lower than 1.0, suggesting that the blood-brain barrier restricts drug entry into the brain. In agreement with in vitro studies already performed within our research group, CBZ, CBZ-10,11-epoxide and oxcarbazepine exhibited the highest brain/plasma ratios (>0.50), followed by eslicarbazepine, R-licarbazepine, trans-diol and BIA 2-024 (ratios within 0.05-0.50). BIA 2-265 was not found in the biophase, probably due to its high plasma-protein bound fraction (>90%) herein revealed for the first time.The comparative in vivo pharmacokinetic data obtained in the present work might be usefully applied in the context of discovery of new antiepileptic drugs that are derivatives of CBZ. © 2013 Elsevier B.V.


FOR EMEA MEDIA ONLY - NOT FOR SWISS/AUSTRIAN/US JOURNALISTS Zebinix® (eslicarbazepine acetate) provides a high retention rate, reduction in seizure frequency and seizure freedom with a favourable adverse event profile and an improved global clinical impression of change (CGI-C) and severity (CGI-S) when used as adjunctive therapy in people with partial onset (focal) seizures with or without secondary generalisation, according to the ESLADOBA study presented today at the American Epilepsy Society (AES) Houston, US.[1] Eslicarbazepine acetate is indicated in the European Union as adjunctive therapy in adults with partial-onset seizures with or without secondary generalisation.[2] The two-year, multi-centre, non-interventional, prospective cohort study included 52 patients (≥18 years) at 12 neurology departments in Portugal with partial onset (focal) seizures insufficiently controlled with one anti-epileptic drug (AED), who had initiated eslicarbazepine acetate as adjunctive treatment. The primary endpoint was the retention rate, defined as the proportion of patients remaining on eslicarbazepine acetate treatment at the end of follow up. Secondary endpoints included the proportion of responders (patients with at least 50% reduction in seizure frequency compared to baseline), proportion of seizure-free patients and the change in frequency for partial seizures with or without secondary generalisation.[1] In the ESLADOBA study, the retention rate was 73.0% (95% CI, 61.0-85.2). The responder rate and the rate of seizure freedom were 71.1% (95% CI, 56.7-85.5) and 39.5% (95% CI, 24.0-55.0), respectively. The seizure-free rate found in secondarily generalised seizures was 94.7% at final assessment. The median relative reduction in seizure frequency between baseline and final assessment was 82.2% (the mean time between initial and final assessment was 7.8 months).[1] A reduction in epilepsy severity was observed in 42.1% of patients and 73.6% of patients had their epilepsy "much improved" or "very much improved" and there were no cases where epilepsy was considered to be worse, according to the global clinical impression of change (CGI-C) and severity (CGI-S), which was recorded by neurologists. In this study, 23.1% (n=12) of patients experienced at least one adverse event and 19.2% (n=10) had at least one AE that was judged to be related to the study drug; 3.9% (n=2) had at least one serious adverse event. The majority adverse events were classified as mild to moderate intensity (n=14) and (n=9) were classified as severe.[1] Five patients were withdrawn from the study due to AEs. "The ESLADOBA study shows that once-daily, adjunctive eslicarbazepine acetate showed good retention rates and elicits a significant reduction in seizure frequency in patients with partial onset seizures not sufficiently controlled with monotherapy," comments Dr João Chaves, Neurologist, Santo Antonio Hospital, Centro Hospitalar Porto. "Data recorded in routine clinical practice is vital to help inform our understanding of how treatments work in the real world. These findings suggest effective seizure control and favourable tolerability of eslicarbazepine acetate adjunctive treatment in this setting," Patrício Soares-da-Silva, Director of Research & Development, Bial, Porto, Portugal. "These data underscore our commitment to support people with epilepsy to better manage their condition and live their lives to the full. We are encouraged by these data and will ensure that eslicarbazepine acetate continues to play an important role in the treatment of epilepsy for the thousands of people in Europe who live with the condition," comments Neil West, Vice President, Global Neurology Business Unit, Eisai. Eslicarbazepine acetate is a voltage-gated sodium channel blocker. It selectively targets the slow inactivated state of the sodium ion channel (which have been implicated in the pathogenesis of epilepsy), preventing its return to the active state, and thereby reduces repetitive neuronal firing.[3] Further, eslicarbazepine acetate does not inhibit potassium efflux, which may reduce the potential for repetitive neuronal firings.[4] The efficacy of eslicarbazepine acetate was demonstrated in an initial proof-of-concept phase II study[5] and three subsequent phase III randomised, placebo controlled studies in 1,049 people with refractory partial onset seizures.[6],[7],[8] Eslicarbazepine acetate is currently marketed in Europe and Russia by Bial and Bial's licensee, Eisai Europe Limited, a European subsidiary of Eisai Co., Ltd. under the trade name Zebinix® or Exalief®. In the United States and Canada eslicarbazepine acetate (tradename Aptiom®) is marketed by Sunovion Pharmaceuticals Inc., under an exclusive license from Bial. Epilepsy is one of the most common neurological conditions in the world, affecting approximately 6 million people in Europe, and an estimated 50 million people worldwide.[9],[10] Epilepsy is a chronic disorder of the brain that affects people of all ages. It is characterised by abnormal discharges of neuronal activity which causes seizures. Seizures can vary in severity, from brief lapses of attention or jerking of muscles, to severe and prolonged convulsions. Depending on the seizure type, seizures may be limited to one part of the body, or may involve the whole body. Seizures can also vary in frequency from less than one per year, to several per day. Epilepsy has many possible causes but often the cause is unknown. Founded in 1924, Bial's mission is to discover, develop and provide therapeutic solutions within the area of health. In recent decades, Bial has strategically focused on quality, innovation and internationalisation. Being the partner of choice for many pharma companies, Bial is strongly committed to therapeutic innovation, investing more than 20% of its turnover in Research and Development (R&D) every year. Bial has established an ambitious R&D programme centred in neurosciences, cardiovascular system and allergic immunotherapy. The company expects to continue to introduce new medicines and vaccines to the market in the next years, strengthening its position worldwide and accomplishing the company's purpose of "Caring for your Health." For more information about Bial, please visit http://www.bial.com . Eisai Co., Ltd. is a leading global research and development-based pharmaceutical company headquartered in Japan. We define our corporate mission as "giving first thought to patients and their families and to increasing the benefits health care provides," which we call our human health care (hhc) philosophy. With over 10,000 employees working across our global network of R&D facilities, manufacturing sites and marketing subsidiaries, we strive to realise our hhc philosophy by delivering innovative products in multiple therapeutic areas with high unmet medical needs, including Oncology and Neurology. As a global pharmaceutical company, our mission extends to patients around the world through our investment and participation in partnership-based initiatives to improve access to medicines in developing and emerging countries. For more information about Eisai Co., Ltd., please visit http://www.eisai.com 1.    Chaves J et al. Seizure control and tolerability of eslicarbazepine acetate as adjunctive therapy in adults with partial-onset seizures in routine clinical practice - ESLADOBA Study. Presented at American Epilepsy Society 2016 3.    Hebeisen S, et al. Eslicarbazepine and the enhancement of slow inactivation of voltage-gated sodium channels: a comparison with carbamazepine, oxcarbazepine and lacosamide. Neuropharmacology. 2015; 89:122-35 4.    Soares-da-Silva P, et al. Eslicarbazepine acetate for the treatment of focal epilepsy: an update on its proposed mechanisms of action. Pharmacol Res Perspect. 2015; 3:e00124 6.    Elger C, et al. Efficacy and safety of eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures: A randomised, double-blind, placebo-controlled, parallel-group phase III study. Epilepsia. 2009;50:454-63 7.    Ben-Menachem E, et al. Eslicarbazepine acetate as adjunctive therapy in adult patients with partial epilepsy. Epilepsy Res. 2010;89(2-3):278-85 8.    Gil-Nagel A, et al. Efficacy and safety of 800 and 1200 mg eslicarbazepine acetate as adjunctive treatment in  adults with refractory partial-onset seizures. Acta Neurol Scand. 2009; 120:281-87 9.    Epilepsy in the WHO European Region: Fostering Epilepsy Care in Europe. Available at: http://www.ibe-epilepsy.org/downloads/EURO%20Report%20160510.pdf Accessed November 2016 10.   Pugliatti M, et al. Estimating the cost of epilepsy in Europe: A review with economic modeling. Epilepsia. 2007:48(12):2224-33


FOR EMEA MEDIA ONLY - NOT FOR SWISS/AUSTRIAN JOURNALISTS The European Commission extended the Marketing Authorisation for Zebinix® (eslicarbazepine acetate) as a once-daily adjunctive treatment for patients aged above six years with partial-onset (focal) seizures with or without secondary generalisation.[1] Eslicarbazepine acetate was previously indicated only for the adjunctive treatment of adults aged over 18 with partial-onset seizures with or without secondary generalisation.[2] The variation to the license is based on data from one Phase III study (305), one Phase II study (208) and from population PK modelling and exposure-efficacy analyses. The Commission considered the efficacy results from the mentioned studies to be acceptable for an extension of the Marketing Authorization. The safety analyses show no new or unexpected safety findings and eslicarbazepine acetate does not appear to have negative neurocognitive consequences (power of attention, information processing and working memory).[1],[3] "We welcome the decision of the European Commission to extend the licence for once daily eslicarbazepine acetate to paediatric patients. Bial has an ongoing commitment to all people living with epilepsy and this important milestone reinforces this commitment, as well as the company's mission to care for the health of people worldwide," comments António Portela, CEO, Bial. "We are pleased to be able to offer the paediatric neurology community a new treatment option to consider when caring for children aged above six years and adolescents with partial onset seizures. Eisai recognise the importance of delivering new clinical treatments in this particular group of patients," comments Neil West, Vice President, Global Neurology Business Unit, Eisai. Eslicarbazepine acetate is a voltage-gated sodium channel blocker. It selectively targets the slow inactivated state of the sodium ion channel (which have been implicated in the pathogenesis of epilepsy), preventing its return to the active state, and thereby reduces repetitive neuronal firing.[4] Further, eslicarbazepine acetate does not inhibit potassium efflux, which may reduce the potential for repetitive neuronal firings.[5] The efficacy of eslicarbazepine acetate in adult patients was demonstrated in an initial proof-of-concept phase II study[6] and three subsequent phase III randomised, placebo controlled studies in 1,049 people with refractory partial-onset seizures.[7],[8],[9] Eslicarbazepine acetate is indicated as adjunctive therapy in adults, adolescents and children aged above 6 years, with partial-onset seizures with or without secondary generalisation. Eslicarbazepine acetate is currently marketed in Europe and Russia by Bial and by Bial's licensee, Eisai Europe Limited, a European subsidiary of Eisai Co Ltd under the trade name Zebinix® or Exalief®. In the United States and Canada eslicarbazepine acetate (tradename Aptiom®) is marketed by Sunovion Pharmaceuticals Inc under an exclusive license from Bial. Epilepsy is one of the most common neurological conditions in the world, affecting approximately 6 million people in Europe, and an estimated 50 million people worldwide.[10],[11] Epilepsy is a chronic disorder of the brain that affects people of all ages, and is a common neurological disorder in childhood, with approximately 100,000 children and adolescents diagnosed every year.[12] It is characterised by abnormal discharges of neuronal activity which causes seizures. Seizures can vary in severity, from brief lapses of attention or jerking of muscles, to severe and prolonged convulsions. Depending on the seizure type, seizures may be limited to one part of the body, or may involve the whole body. Seizures can also vary in frequency from less than one per year, to several per day. Epilepsy has many possible causes but often the cause is unknown. Founded in 1924, Bial's mission is to discover, develop and provide therapeutic solutions within the area of health. In recent decades, Bial has strategically focused on quality, innovation and internationalisation. Being the partner of choice for many pharma companies, Bial is strongly committed to therapeutic innovation, investing more than 20% of its turnover in Research and Development (R&D) every year. Bial has established an ambitious R&D programme centred in neurosciences, cardiovascular system and allergic immunotherapy. The company expects to continue to introduce new medicines and vaccines to the market in the next years, strengthening its position worldwide and accomplishing the company's purpose of "Caring for your Health." For more information about Bial, please visit http://www.bial.com About Eisai Co Ltd Eisai Co Ltd. is a leading global research and development-based pharmaceutical company headquartered in Japan. We define our corporate mission as "giving first thought to patients and their families and to increasing the benefits health care provides," which we call our human health care (hhc) philosophy. With over 10,000 employees working across our global network of R&D facilities, manufacturing sites and marketing subsidiaries, we strive to realise our hhc philosophy by delivering innovative products in multiple therapeutic areas with high unmet medical needs, including Oncology and Neurology. As a global pharmaceutical company, our mission extends to patients around the world through our investment and participation in partnership-based initiatives to improve access to medicines in developing and emerging countries. For more information about Eisai Co Ltd, please visit http://www.eisai.com References 1.  European Commission: Community register of medicinal products for human use. Product Information - Zebinix. Available at: http://ec.europa.eu/health/documents/community-register/html/h514.htm Last updated December 2016 2.  Zebinix SMPC, Available at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000988/WC500047225.pdf  Last updated: May 2016 3.  Moreira J, et al. J Neurol Sci 2015;357:e432-456 (abstract 1513; WFN15-1735; e439) 4.  Hebeisen S, et al. Eslicarbazepine and the enhancement of slow inactivation of voltage-gated sodium channels: a comparison with carbamazepine, oxcarbazepine and lacosamide. Neuropharmacology 2015; 89:122-35 5.  Soares-da-Silva P, et al. Eslicarbazepine acetate for the treatment of focal epilepsy: an update on its proposed mechanisms of action. Pharmacol Res Perspect. 2015; 3:e00124 6.  Elger C, et al. Eslicarbazepine acetate: A double-blind, add-on, placebo-controlled exploratory trial in adult patients with partial-onset seizures. Epilepsia 2007; 48:497-504 7.  Elger C, et al. Efficacy and safety of eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures: A randomised, double-blind, placebo-controlled, parallel-group phase III study. Epilepsia. 2009;50:454-63 8.  Ben-Menachem E, et al. Eslicarbazepine acetate as adjunctive therapy in adult patients with partial epilepsy. Epilepsy Res. 2010;89(2-3):278-85 9.  Gil-Nagel A, et al. Efficacy and safety of 800 and 1200 mg eslicarbazepine acetate as adjunctive treatment in  adults with refractory partial-onset seizures. Acta Neurol Scand. 2009; 120:281-87 10. Epilepsy in the WHO European Region: Fostering Epilepsy Care in Europe. Available at: http://www.ibe-epilepsy.org/downloads/EURO%20Report%20160510.pdf  Accessed November 2016 11. Pugliatti M, et al. Estimating the cost of epilepsy in Europe: A review with economic modeling. Epilepsia 2007:48(12):2224-33 12. Forsgren L, et al. The epidemiology of epilepsy in Europe - a systematic review. Eur J Neurol. 2005; 12(4):245-53

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