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Patricio Soaresdasilva - One of the best experts on this subject based on the ideXlab platform.

  • effects of esLicarbazepine on slow inactivation processes of sodium channels in dentate gyrus granule cells
    Epilepsia, 2018
    Co-Authors: Dominik Holtkamp, Patricio Soaresdasilva, Thoralf Opitz, Simon Hebeisen, Heinz Beck
    Abstract:

    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 Nav 1.2 and Nav 1.6 subunits, but not in Nav 1.1 and Nav 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 Nav 1.2 and Nav 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.

  • pharmacokinetics and tolerability of esLicarbazepine acetate and oxcarbazepine at steady state in healthy volunteers
    Epilepsia, 2013
    Co-Authors: Christian E. Elger, Amilcar Falcao, Patricio Soaresdasilva, Meir Bialer, Luís Pereira De Almeida, Teresa G. Nunes, Manuel Vazdasilva
    Abstract:

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

  • steady state plasma and cerebrospinal fluid pharmacokinetics and tolerability of esLicarbazepine acetate and oxcarbazepine in healthy volunteers
    Epilepsia, 2013
    Co-Authors: Teresa G. Nunes, Amilcar Falcao, Patricio Soaresdasilva, José Francisco Rocha, Luís Pereira De Almeida
    Abstract:

    SUMMARY Purpose: To evaluate the pharmacokinetics and tolerability of once-daily esLicarbazepine acetate (ESL) and twicedaily oxcarbazepine (OXC) and their metabolites in cerebrospinal fluid (CSF) and plasma following repeated oral administration. Methods: Single-center, open-label, randomized, parallelgroup study in healthy volunteers. Volunteers in ESL group (n = 7) received 600 mg on days 1‐3 and 1,200 mg on days 4‐9, once daily. Volunteers in the OXC group (n = 7) received 300 mg on days 1‐3 and 600 mg on days 4‐9, twice daily. Plasma and CSF sampling was performed following the last dose. Key Findings: EsLicarbazepine was the major drug entity in plasma and CSF, accounting for, respectively, 93.84% and 91.96% of total exposure in the ESL group and 78.06% and 76.42% in the OXC group. The extent of exposure to drug entities R-Licarbazepine and oxcarbazepine was approximately four-fold higher with OXC as compared with ESL. There was relatively little fluctuation from peak-to-trough (ratio) in the CSF for both esLicarbazepine (ESL = 1.5; OXC = 1.2) and R-Licarbazepine (ESL = 1.2; OXC = 1.2). In contrast, oxcarbazepine showed larger differences between peak and trough (ESL = 3.1; OXC = 6.4). A total of 84 and 24 treatment-emergent adverse events (TEAEs) were reported with OXC and ESL, respectively. Significance: In comparison to OXC, administration of ESLresultedinmoreesLicarbazepine,lessR-Licarbazepine, and less oxcarbazepine in plasma and CSF, which may correlate with the tolerability profile reported with ESL. The smaller peak-to-trough fluctuation of esLicarbazepine in CSF (a measure of sustained delivery to the brain) than in plasma supportsonce-daily dosing of ESL.

  • development and validation of an enantioselective liquid chromatography tandem mass spectrometry method for the separation and quantification of esLicarbazepine acetate esLicarbazepine r Licarbazepine and oxcarbazepine in human plasma
    Journal of Chromatography B, 2011
    Co-Authors: A I Loureiro, Patricio Soaresdasilva, Carlos Fernandeslopes, Lyndon C Wright
    Abstract:

    Abstract The purpose of this study was develop and validate a sensitive and specific enantioselective liquid–chromatography/tandem mass spectrometry (LC–MS/MS) method, for the simultaneous quantification of esLicarbazepine acetate (ESL), esLicarbazepine (S-Lic), oxcarbazepine (OXC) and R-Licarbazepine (R-Lic) in human plasma. Analytes were extracted from human plasma using solid phase extraction and the chromatographic separation was achieved using a mobile phase of 80% n-hexane and 20% ethanol/isopropyl alcohol (66.7/33.3, v/v). A Daicel CHIRALCEL® OD-H column (5 μm, 50 mm × 4.6 mm) was used with a flow rate of 0.8 mL/min, and a run time of 8 min. ESL, S-Lic, R-Lic, OXC and the internal standard, 10,11-dihydrocarbamazepine, were quantified by positive ion electrospray ionization mass spectrometry. The method was fully validated, demonstrating acceptable accuracy, precision, linearity, and specificity in accordance with FDA regulations for the validation of bioanalytical methods. Linearity was proven over the range of 50.0–1000.0 ng/mL for ESL and OXC and over the range of 50.0–25,000.0 ng/mL for S-Lic and R-Lic. The intra- and inter-day coefficient of variation in plasma was less than 9.7% for ESL, 6.0% for OXC, 7.7% for S-Lic and less than 12.6% for R-Lic. The accuracy was between 98.7% and 107.2% for all the compounds quantified. The lower limit of quantification (LLOQ) was 50.0 ng/mL for ESL, S-Lic, OXC and R-Lic in human plasma. The short-term stability in plasma, freeze–thaw stability in plasma, frozen long-term stability in plasma, autosampler stability and stock solution stability all met acceptance criteria. The human plasma samples, collected from 8 volunteers, showed that this method can be used for therapeutic monitoring of ESL and its metabolites in humans treated with ESL.

  • a chiral liquid chromatography method for the simultaneous determination of oxcarbazepine esLicarbazepine r Licarbazepine and other new chemical derivatives bia 2 024 bia 2 059 and bia 2 265 in mouse plasma and brain
    Biomedical Chromatography, 2011
    Co-Authors: Ana Fortuna, Amilcar Falcao, Gilberto Alves, A M Almeida, Bruno Silva Lopes, Patricio Soaresdasilva
    Abstract:

    Recently, in silico models have been developed to predict drug pharmacokinetics. However, before application, they must be validated and, for that, information about structurally similar reference compounds is required. A chiral liquid chromatography method with ultraviolet detection (LC-UV) was developed and validated for the simultaneous quantification of BIA 2–024, BIA 2–059, BIA 2–265, oxcarbazepine, esLicarbazepine (S-Licarbazepine) and R-Licarbazepine in mouse plasma and brain. Compounds were extracted by a selective solid-phase extraction procedure and their chromatographic separation was achieved on a LiChroCART 250–4 ChiraDex column using a mobile phase of water–methanol (92:8, v/v) pumped at 0.7 mL/min. The UV detector was set at 235 nm. Calibration curves were linear (r2 ≥ 0.996) over the concentration ranges of 0.2–30 µg/mL for oxcarbazepine, esLicarbazepine and R-Licarbazepine; 0.2–60 µg/mL for the remaining compounds in plasma; and 0.06–15 µg/mL for all the analytes in brain homogenate. Taking into account all analytes at these concentration ranges in both matrices, the overall precision did not exceed 9.09%, and the accuracy was within ±14.3%. This LC-UV method is suitable for carrying out pharmacokinetic studies with these compounds in mouse in order to obtain a better picture of their metabolic pathways and biodistribution. Copyright © 2011 John Wiley & Sons, Ltd.

Amilcar Falcao - One of the best experts on this subject based on the ideXlab platform.

  • HPLC–DAD Method for the Quantification of Carbamazepine, Oxcarbazepine and their Active Metabolites in HepaRG Cell Culture Samples
    Chromatographia, 2016
    Co-Authors: Ana Ferreira, Amilcar Falcao, Márcio Rodrigues, Gilberto Alves
    Abstract:

    A new, sensitive and fast high-performance liquid chromatography–diode-array detection assay is herein reported, for the first time, to simultaneously quantify carbamazepine (CBZ), oxcarbazepine (OXC), and the active metabolites carbamazepine-10,11-epoxide (CBZ-E) and Licarbazepine (LIC) in HepaRG cell culture medium samples. Chromatographic separation of analytes (CBZ, CBZ-E, OXC, LIC) and internal standard (IS) was achieved in less than 15 min on a C_18-column, at 35 °C, using a mobile phase composed of water/methanol/acetonitrile (69:25:6 v/v/v) pumped at 1 mL min^−1. The analytes and IS were detected at 215 nm. The method proved to be selective, accurate ( bias  ± 14.6 %), precise (coefficient of variation ≤13.1 %) and linear ( r ^2 ≥ 0.9901) over the concentration ranges of 0.1–15 μg mL^−1 for CBZ; 0.1–5 μg mL^−1 for CBZ-E and OXC; and 0.1–40 μg mL^−1 for LIC. Furthermore, the absolute recovery of the analytes ranged from 64.5 to 96.9 % and their stability was demonstrated in the studied conditions. This validated HPLC assay will be a suitable tool to support future in vitro metabolism profiling, drug interaction and other pharmacokinetic-based studies in HepaRG cells involving these antiepileptic drugs (CBZ and OXC) and their main metabolites.

  • liquid chromatographic assay based on microextraction by packed sorbent for therapeutic drug monitoring of carbamazepine lamotrigine oxcarbazepine phenobarbital phenytoin and the active metabolites carbamazepine 10 11 epoxide and Licarbazepine
    Journal of Chromatography B, 2014
    Co-Authors: Ana Fortuna, Ana Ferreira, Márcio Rodrigues, Paula De Oliveira, Joana Francisco, Luisa Rosado, Pedro Rosado, Amilcar Falcao
    Abstract:

    Abstract A new, sensitive and fast high-performance liquid chromatography–diode-array detection assay based on microextraction by packed sorbent (MEPS/HPLC-DAD) is herein reported, for the first time, to simultaneously quantify carbamazepine (CBZ), lamotrigine (LTG), oxcarbazepine (OXC), phenobarbital (PB), phenytoin (PHT), and the active metabolites carbamazepine-10,11-epoxide (CBZ-E) and Licarbazepine (LIC) in human plasma. Chromatographic separation of analytes and ketoprofen, used as internal standard (IS), was achieved in less than 15 min on a C18-column, at 35 °C, using acetonitrile (6%) and a mixture (94%) of water–methanol–triethylamine (73.2:26.5:0.3, v/v/v; pH 6.5) pumped at 1 mL/min. The analytes and IS were detected at 215, 237 or 280 nm. The method showed to be selective, accurate [bias ±14.8% (or ±17.8% in the lower limit of quantification)], precise [coefficient variation ≤9.7% (or ≤17.7% in the lower limit of quantification)] and linear (r2 ≥ 0.9946) over the concentration ranges of 0.1–15 μg/mL for CBZ; 0.1-20 μg/mL for LTG; 0.1–5 μg/mL for OXC and CBZ-E; 0.2–40 μg/mL for PB; 0.3–30 μg/mL for PHT; and 0.4–40 μg/mL for LIC. The absolute extraction recovery of the analytes ranged from 57.8 to 98.1% and their stability was demonstrated in the studied conditions. This MEPS/HPLC-DAD assay was successfully applied to real plasma samples from patients, revealing to be a cost-effective tool for routine therapeutic drug monitoring of CBZ, LTG, OXC, PB and/or PHT.

  • pharmacokinetics and tolerability of esLicarbazepine acetate and oxcarbazepine at steady state in healthy volunteers
    Epilepsia, 2013
    Co-Authors: Christian E. Elger, Amilcar Falcao, Patricio Soaresdasilva, Meir Bialer, Luís Pereira De Almeida, Teresa G. Nunes, Manuel Vazdasilva
    Abstract:

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

  • first hplc uv method for rapid and simultaneous quantification of phenobarbital primidone phenytoin carbamazepine carbamazepine 10 11 epoxide 10 11 trans dihydroxy 10 11 dihydrocarbamazepine lamotrigine oxcarbazepine and Licarbazepine in human plasma
    Analytical Abstracts, 2013
    Co-Authors: Ana Serralheiro, Gilberto Alves, Ana Fortuna, Marilia Rocha, Amilcar Falcao
    Abstract:

    A sensitive and fast high-performance liquid chromatographic method coupled with ultraviolet detection is herein reported for the simultaneous determination of human plasma concentration of six antiepileptic drugs frequently used in clinical practice (phenobarbital (PB), primidone (PRM), phenytoin (PHT), carbamazepine (CBZ), lamotrigine (LTG), oxcarbazepine (OXC)) and some of their main metabolites, carbamazepine-10,11-epoxide (CBZ-E), 10,11-trans-dihydroxy-10,11-dihydrocarbamazepine (trans-diol) and Licarbazepine (Lic). Sample preparation consisted of a deproteinization step with methanol followed by a solid-phase extraction procedure. Chromatographic separation was achieved in approximately 15 min on a reversed-phase C18 column using a mobile phase composed by water-methanol-acetonitrile-triethylamine (68.7:25:6:0.3, v/v/v/v; pH 6.5) pumped isocratically at 1.0 mL/min. The detector was set at 237 nm. Calibration curves were linear with regression coefficients greater than 0.992 over the concentration ranges 0.25-100 µg/mL for PB, 0.4-50 µg/mL for PRM, 0.5-50 µg/mL for PHT, 0.1-50 µg/mL for CBZ, LTG and CBZ-E, 0.1-25 µg/mL for OXC, 0.25-10 µg/mL for trans-diol and 0.15-80 µg/mL for Lic. Inter- and intra-day imprecision did not exceed 12.15% and inaccuracy was within ±14.91%. Absolute mean recoveries ranged from 78.49 to 101.04% and no interferences were observed at the retention times of the analytes and internal standard (ketoprofen). This bioanalytical method was successfully applied to real plasma samples from epileptic patients and it seems to be a suitable tool for routine therapeutic drug monitoring and also to support other clinical pharmacokinetic-based studies.

  • steady state plasma and cerebrospinal fluid pharmacokinetics and tolerability of esLicarbazepine acetate and oxcarbazepine in healthy volunteers
    Epilepsia, 2013
    Co-Authors: Teresa G. Nunes, Amilcar Falcao, Patricio Soaresdasilva, José Francisco Rocha, Luís Pereira De Almeida
    Abstract:

    SUMMARY Purpose: To evaluate the pharmacokinetics and tolerability of once-daily esLicarbazepine acetate (ESL) and twicedaily oxcarbazepine (OXC) and their metabolites in cerebrospinal fluid (CSF) and plasma following repeated oral administration. Methods: Single-center, open-label, randomized, parallelgroup study in healthy volunteers. Volunteers in ESL group (n = 7) received 600 mg on days 1‐3 and 1,200 mg on days 4‐9, once daily. Volunteers in the OXC group (n = 7) received 300 mg on days 1‐3 and 600 mg on days 4‐9, twice daily. Plasma and CSF sampling was performed following the last dose. Key Findings: EsLicarbazepine was the major drug entity in plasma and CSF, accounting for, respectively, 93.84% and 91.96% of total exposure in the ESL group and 78.06% and 76.42% in the OXC group. The extent of exposure to drug entities R-Licarbazepine and oxcarbazepine was approximately four-fold higher with OXC as compared with ESL. There was relatively little fluctuation from peak-to-trough (ratio) in the CSF for both esLicarbazepine (ESL = 1.5; OXC = 1.2) and R-Licarbazepine (ESL = 1.2; OXC = 1.2). In contrast, oxcarbazepine showed larger differences between peak and trough (ESL = 3.1; OXC = 6.4). A total of 84 and 24 treatment-emergent adverse events (TEAEs) were reported with OXC and ESL, respectively. Significance: In comparison to OXC, administration of ESLresultedinmoreesLicarbazepine,lessR-Licarbazepine, and less oxcarbazepine in plasma and CSF, which may correlate with the tolerability profile reported with ESL. The smaller peak-to-trough fluctuation of esLicarbazepine in CSF (a measure of sustained delivery to the brain) than in plasma supportsonce-daily dosing of ESL.

Gilberto Alves - One of the best experts on this subject based on the ideXlab platform.

  • HPLC–DAD Method for the Quantification of Carbamazepine, Oxcarbazepine and their Active Metabolites in HepaRG Cell Culture Samples
    Chromatographia, 2016
    Co-Authors: Ana Ferreira, Amilcar Falcao, Márcio Rodrigues, Gilberto Alves
    Abstract:

    A new, sensitive and fast high-performance liquid chromatography–diode-array detection assay is herein reported, for the first time, to simultaneously quantify carbamazepine (CBZ), oxcarbazepine (OXC), and the active metabolites carbamazepine-10,11-epoxide (CBZ-E) and Licarbazepine (LIC) in HepaRG cell culture medium samples. Chromatographic separation of analytes (CBZ, CBZ-E, OXC, LIC) and internal standard (IS) was achieved in less than 15 min on a C_18-column, at 35 °C, using a mobile phase composed of water/methanol/acetonitrile (69:25:6 v/v/v) pumped at 1 mL min^−1. The analytes and IS were detected at 215 nm. The method proved to be selective, accurate ( bias  ± 14.6 %), precise (coefficient of variation ≤13.1 %) and linear ( r ^2 ≥ 0.9901) over the concentration ranges of 0.1–15 μg mL^−1 for CBZ; 0.1–5 μg mL^−1 for CBZ-E and OXC; and 0.1–40 μg mL^−1 for LIC. Furthermore, the absolute recovery of the analytes ranged from 64.5 to 96.9 % and their stability was demonstrated in the studied conditions. This validated HPLC assay will be a suitable tool to support future in vitro metabolism profiling, drug interaction and other pharmacokinetic-based studies in HepaRG cells involving these antiepileptic drugs (CBZ and OXC) and their main metabolites.

  • first hplc uv method for rapid and simultaneous quantification of phenobarbital primidone phenytoin carbamazepine carbamazepine 10 11 epoxide 10 11 trans dihydroxy 10 11 dihydrocarbamazepine lamotrigine oxcarbazepine and Licarbazepine in human plasma
    Analytical Abstracts, 2013
    Co-Authors: Ana Serralheiro, Gilberto Alves, Ana Fortuna, Marilia Rocha, Amilcar Falcao
    Abstract:

    A sensitive and fast high-performance liquid chromatographic method coupled with ultraviolet detection is herein reported for the simultaneous determination of human plasma concentration of six antiepileptic drugs frequently used in clinical practice (phenobarbital (PB), primidone (PRM), phenytoin (PHT), carbamazepine (CBZ), lamotrigine (LTG), oxcarbazepine (OXC)) and some of their main metabolites, carbamazepine-10,11-epoxide (CBZ-E), 10,11-trans-dihydroxy-10,11-dihydrocarbamazepine (trans-diol) and Licarbazepine (Lic). Sample preparation consisted of a deproteinization step with methanol followed by a solid-phase extraction procedure. Chromatographic separation was achieved in approximately 15 min on a reversed-phase C18 column using a mobile phase composed by water-methanol-acetonitrile-triethylamine (68.7:25:6:0.3, v/v/v/v; pH 6.5) pumped isocratically at 1.0 mL/min. The detector was set at 237 nm. Calibration curves were linear with regression coefficients greater than 0.992 over the concentration ranges 0.25-100 µg/mL for PB, 0.4-50 µg/mL for PRM, 0.5-50 µg/mL for PHT, 0.1-50 µg/mL for CBZ, LTG and CBZ-E, 0.1-25 µg/mL for OXC, 0.25-10 µg/mL for trans-diol and 0.15-80 µg/mL for Lic. Inter- and intra-day imprecision did not exceed 12.15% and inaccuracy was within ±14.91%. Absolute mean recoveries ranged from 78.49 to 101.04% and no interferences were observed at the retention times of the analytes and internal standard (ketoprofen). This bioanalytical method was successfully applied to real plasma samples from epileptic patients and it seems to be a suitable tool for routine therapeutic drug monitoring and also to support other clinical pharmacokinetic-based studies.

  • a chiral liquid chromatography method for the simultaneous determination of oxcarbazepine esLicarbazepine r Licarbazepine and other new chemical derivatives bia 2 024 bia 2 059 and bia 2 265 in mouse plasma and brain
    Biomedical Chromatography, 2011
    Co-Authors: Ana Fortuna, Amilcar Falcao, Gilberto Alves, A M Almeida, Bruno Silva Lopes, Patricio Soaresdasilva
    Abstract:

    Recently, in silico models have been developed to predict drug pharmacokinetics. However, before application, they must be validated and, for that, information about structurally similar reference compounds is required. A chiral liquid chromatography method with ultraviolet detection (LC-UV) was developed and validated for the simultaneous quantification of BIA 2–024, BIA 2–059, BIA 2–265, oxcarbazepine, esLicarbazepine (S-Licarbazepine) and R-Licarbazepine in mouse plasma and brain. Compounds were extracted by a selective solid-phase extraction procedure and their chromatographic separation was achieved on a LiChroCART 250–4 ChiraDex column using a mobile phase of water–methanol (92:8, v/v) pumped at 0.7 mL/min. The UV detector was set at 235 nm. Calibration curves were linear (r2 ≥ 0.996) over the concentration ranges of 0.2–30 µg/mL for oxcarbazepine, esLicarbazepine and R-Licarbazepine; 0.2–60 µg/mL for the remaining compounds in plasma; and 0.06–15 µg/mL for all the analytes in brain homogenate. Taking into account all analytes at these concentration ranges in both matrices, the overall precision did not exceed 9.09%, and the accuracy was within ±14.3%. This LC-UV method is suitable for carrying out pharmacokinetic studies with these compounds in mouse in order to obtain a better picture of their metabolic pathways and biodistribution. Copyright © 2011 John Wiley & Sons, Ltd.

  • a chiral hplc uv method for the quantification of dibenz b f azepine 5 carboxamide derivatives in mouse plasma and brain tissue esLicarbazepine acetate carbamazepine and main metabolites
    Journal of Separation Science, 2011
    Co-Authors: Ana Fortuna, Amilcar Falcao, Gilberto Alves, Joana Bicker, Patricio Soaresdasilva
    Abstract:

    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 (r(2) ≥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.

  • binding of Licarbazepine enantiomers to mouse and human plasma proteins
    Biopharmaceutics & Drug Disposition, 2010
    Co-Authors: Ana Fortuna, Amilcar Falcao, Gilberto Alves, Patricio Soaresdasilva
    Abstract:

    Racemic Licarbazepine (Lic) is the active metabolite of oxcarbazepine (OXC) and esLicarbazepine acetate (ESL), appearing in human plasma as S-Licarbazepine (S-Lic) and R-Licarbazepine (R-Lic). However, human metabolism of OXC and ESL to Lic differs in the S-Lic/R-Lic enantiomeric ratio observed in plasma. S-Lic appears in higher proportion after ESL administration than after OXC (95% versus 80%). Enantioselective pharmacokinetics of Lic enantiomers have been found in mice after their separate administration and in humans following OXC treatment. Since protein binding of drugs may be enantioselective and a determining factor of pharmacokinetics, the binding of S-Lic and R-Lic to mouse and human total plasma proteins and, specifically, to human serum albumin (HSA) and α1-acid glycoprotein (AGP) were herein investigated for the first time. Free and bound fractions of S-Lic and R-Lic were separated by ultrafiltration after previous in vitro incubation of spiked plasma samples and protein solutions with each enantiomer at 10, 25 and 50 µg/ml. The results revealed that the extent of binding of Lic enantiomers to total plasma proteins was 30% and independent of the drug concentration and species considered. The data also suggest that the binding of Lic enantiomers to HSA is greater than that to AGP. Moreover, absence of enantioselectivity in the binding of Lic enantiomers to mouse and human plasma proteins and to HSA and AGP is evident. In conclusion, these findings suggest that the enantioselectivity observed in vivo in the biodisposition of S-Lic and R-Lic is not dependent on their affinity to plasma proteins. Copyright © 2010 John Wiley & Sons, Ltd.

Anthony H Dickenson - One of the best experts on this subject based on the ideXlab platform.

  • neuropathy following spinal nerve injury shares features with the irritable nociceptor phenotype a back translational study of oxcarbazepine
    European Journal of Pain, 2019
    Co-Authors: Ryan Patel, Mateusz Kucharczyk, Carlota Montagutbordas, Stevie Lockwood, Anthony H Dickenson
    Abstract:

    BACKGROUND: The term 'irritable nociceptor' was coined to describe neuropathic patients characterized by evoked hypersensitivity and preservation of primary afferent fibres. Oxcarbazepine is largely ineffectual in an overall patient population, but has clear efficacy in a subgroup with the irritable nociceptor profile. We examine whether neuropathy in rats induced by spinal nerve injury shares overlapping pharmacological sensitivity with the irritable nociceptor phenotype using drugs that target sodium channels. METHODS: In vivo electrophysiology was performed in anaesthetized spinal nerve ligated (SNL) and sham-operated rats to record from wide dynamic range (WDR) neurones in the ventral posterolateral thalamus (VPL) and dorsal horn. RESULTS: In neuropathic rats, spontaneous activity in the VPL was substantially attenuated by spinal lidocaine, an effect that was absent in sham rats. The former measure was in part dependent on ongoing peripheral activity as intraplantar lidocaine also reduced aberrant spontaneous thalamic firing. Systemic oxcarbazepine had no effect on wind-up of dorsal horn neurones in sham and SNL rats. However, in SNL rats, oxcarbazepine markedly inhibited punctate mechanical-, dynamic brush- and cold-evoked neuronal responses in the VPL and dorsal horn, with minimal effects on heat-evoked responses. In addition, oxcarbazepine inhibited spontaneous activity in the VPL. Intraplantar injection of the active metabolite Licarbazepine replicated the effects of systemic oxcarbazepine, supporting a peripheral locus of action. CONCLUSIONS: We provide evidence that ongoing activity in primary afferent fibres drives spontaneous thalamic firing after spinal nerve injury and that oxcarbazepine through a peripheral mechanism exhibits modality-selective inhibitory effects on sensory neuronal processing. SIGNIFICANCE: The inhibitory effects of lidocaine and oxcarbazepine in this rat model of neuropathy resemble the clinical observations in the irritable nociceptor patient subgroup and support a mechanism-based rationale for bench-to-bedside translation when screening novel drugs.

  • neuropathy following spinal nerve injury shares features with the irritable nociceptor phenotype a back translational study of oxcarbazepine
    European Journal of Pain (2018) (In press)., 2018
    Co-Authors: Ryan Patel, Mateusz Kucharczyk, Carlota Montagutbordas, Stevie Lockwood, Anthony H Dickenson
    Abstract:

    BACKGROUND: The term 'irritable nociceptor' was coined to describe neuropathic patients characterised by evoked hypersensitivity and preservation of primary afferent fibres. Oxcarbazepine is largely ineffectual in an overall patient population but has clear efficacy in a sub-group with the irritable nociceptor profile. We examine whether neuropathy in rats induced by spinal nerve injury shares overlapping pharmacological sensitives with the irritable nociceptor phenotype using drugs that target sodium channels. METHODS: In vivo electrophysiology was performed in anaesthetised spinal nerve ligated (SNL) and sham-operated rats to record from wide dynamic range (WDR) neurones in the ventral posterolateral thalamus (VPL) and dorsal horn. RESULTS: In neuropathic rats, spontaneous activity in the VPL was substantially attenuated by spinal lidocaine, an effect that was absent in sham rats. The former measure was in part dependent on ongoing peripheral activity as intraplantar lidocaine also reduced aberrant spontaneous thalamic firing. Systemic oxcarbazepine had no effect on wind-up of dorsal horn neurones in sham and SNL rats. However, in SNL rats, oxcarbazepine markedly inhibited punctate mechanical, dynamic brush and cold-evoked neuronal responses in the VPL and dorsal horn, with minimal effects on heat-evoked responses. In addition, oxcarbazepine inhibited spontaneous activity in the VPL. Intraplantar injection of the active metabolite Licarbazepine replicated the effects of systemic oxcarbazepine supporting a peripheral locus of action. CONCLUSIONS: We provide evidence that ongoing activity in primary afferent fibres drives spontaneous thalamic firing after spinal nerve injury, and that oxcarbazepine through a peripheral mechanism exhibits modality-selective inhibitory effects on sensory neuronal processing. This article is protected by copyright. All rights reserved.

Zhihui Hao - One of the best experts on this subject based on the ideXlab platform.