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1.
Acta Neurol Scand ; 140(6): 422-428, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31498422

RESUMO

OBJECTIVE: To assess the effectiveness and tolerability of eslicarbazepine acetate (ESL) monotherapy in routine clinical practice for the treatment of focal-onset seizures. METHODS: Multicenter, retrospective, observational study conducted in patients older than 16 years treated with ESL as first-line monotherapy or converted to ESL monotherapy from polytherapy or other monotherapy. Outcomes included 1-year retention rate, seizure-free rates after 6 and 12 months of monotherapy treatment, and safety/tolerability issues. RESULTS: A total of 256 patients were included (106 first-line and 150 conversion to monotherapy; 56 patients aged >65 years). Overall, the 1-year retention rate was 79% (72.7% in the ≥65 years subgroup) and seizure-free rates at 6 and 12 months were 59.3% and 55.3% (72.2% and 67.3% in the ≥65 years subgroup), without significant differences when comparing first-line vs conversion-to-ESL monotherapy groups (P = .979). However, the conversion group was heterogeneous and included 43 (29.1%) patients that were seizure free the year prior ESL introduction. A substantially higher proportion of patients remained seizure free for the entire follow-up among those who initiated ESL due to tolerability problems compared with those treated due to inadequate seizure control (71.4% vs 37.3%). Overall, 62 of 256 (24.2%) patients reported AEs (39.3% in >65 years subgroup) and led to discontinuation in 20/256 (7.8%) patients (12.5% in >65 years subgroup). Commonly reported AEs were somnolence (6.6%), dizziness (6.3%), and headache (4.3%). Hyponatremia was recorded in five patients, the majority (4/5) of whom were older than 65 years. CONCLUSIONS: Eslicarbazepine acetate was effective and well-tolerated as first-line or conversion to monotherapy in a clinical setting in adult and elderly patients with focal-onset seizures.


Assuntos
Anticonvulsivantes/uso terapêutico , Dibenzazepinas/uso terapêutico , Convulsões/tratamento farmacológico , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
2.
Methods Mol Biol ; 2019: 171-180, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31359396

RESUMO

Dysregulation of retinoic acid signaling is implicated in several human cancer types, including melanoma where the gene encoding retinoic acid receptor beta (RARß) is frequently silenced by promoter hypermethylation. In this chapter, we describe some of the experimental procedures that we have used to characterize the role of RARß signaling on the regulation of cellular metabolism in melanoma. Central to these studies is the use of the Seahorse XF Analyzer, which allows real-time assessment of the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in cultured cells as readouts for oxidative phosphorylation and glycolysis, respectively. The levels of RARß signaling can be modulated using RARß agonists (e.g., all-trans retinoic acid) and antagonists (e.g., LE135). The bioenergetic profiles of melanoma cells in response to RARß modulators and other metabolic modifiers can be the basis for defining new therapeutic strategies.


Assuntos
Técnicas de Cultura de Células/métodos , Dibenzazepinas/farmacologia , Melanoma/metabolismo , Metabolômica/métodos , Receptores do Ácido Retinoico/metabolismo , Tretinoína/farmacologia , Animais , Linhagem Celular Tumoral , Glicólise/efeitos dos fármacos , Humanos , Mitocôndrias/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , Consumo de Oxigênio , Fenótipo , Transdução de Sinais/efeitos dos fármacos , Smegmamorpha/metabolismo
3.
Epilepsia ; 60(7): 1341-1352, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31260089

RESUMO

OBJECTIVE: To examine the frequency of hyponatremia and potentially related symptoms in clinical trials of eslicarbazepine acetate (ESL) in adults with focal- (partial-) onset seizures. METHODS: This post hoc, exploratory analysis included data from three controlled phase 3 trials of adjunctive ESL (400-1200 mg once daily), two phase 3 trials of ESL monotherapy (1200-1600 mg once daily), and their open-label extension studies. Exploratory endpoints included clinical laboratory measurements of serum sodium concentrations ([Na+ ]), incidences of hyponatremia-related treatment-emergent adverse events (TEAEs), and incidences of TEAEs that are potential symptoms of hyponatremia. RESULTS: The controlled trials of adjunctive ESL and ESL monotherapy included 1447 (placebo, n = 426; ESL, n = 1021) and 365 (ESL, n = 365) patients, respectively; 639 and 274 patients continued onto uncontrolled, open-label extensions. In the controlled and uncontrolled trials ≤3.3% of patients taking ESL had a minimum postdose [Na+ ] measurement ≤125 mEq/L, <9% had a >10 mEq/L decrease in [Na+ ] from baseline, <6% had a hyponatremia-related TEAE, and <2% discontinued the controlled trials due to a hyponatremia-related TEAE. Hyponatremia appeared to be more frequent in the monotherapy (vs adjunctive therapy) trials; in the controlled trials of adjunctive ESL and ESL monotherapy, incidence generally increased with increasing ESL dose. The majority of patients with an investigator-reported TEAE of "hyponatremia" or "blood sodium decreased" did not have a corresponding laboratory [Na+ ] measurement ≤125 mEq/L. Some symptoms potentially related to hyponatremia (including nausea and vomiting) were more frequent in patients with a minimum postdose [Na+ ] measurement ≤125 mEq/L. SIGNIFICANCE: Reductions in serum sodium concentrations and hyponatremia-related TEAEs occurred in a small number of patients taking ESL. Suspected hyponatremia should be confirmed and monitored via [Na+ ] measurements.


Assuntos
Anticonvulsivantes/efeitos adversos , Dibenzazepinas/efeitos adversos , Epilepsia/tratamento farmacológico , Hiponatremia/induzido quimicamente , Sódio/sangue , Adolescente , Adulto , Idoso , Anticonvulsivantes/uso terapêutico , Dibenzazepinas/uso terapêutico , Epilepsias Parciais/tratamento farmacológico , Humanos , Pessoa de Meia-Idade , Adulto Jovem
4.
Artigo em Inglês | MEDLINE | ID: mdl-31299362

RESUMO

We developed an online solid phase extraction procedure using a hydrophilic-lipophilic balance sorbent, with reversed-phase liquid chromatography-high-resolution mass spectroscopy for the determination of oxcarbazepine and its active metabolite licarbazepine in plasma samples. The analytes were detected using a high-resolution Q Orbitrap mass spectrometer with targeted-selected ion monitoring (t-SIM) in positive scan mode. Under the optimized conditions, the method was linear with R2 values >0.99. The method was linear from 0.008 to 2.000 µg mL-1 and the lower limit of quantification was 0.008 µg mL-1 for both oxcarbazepine and licarbazepine. Recoveries ranged from 92.34 to 104.27% and from matrix-matched samples from 94.26 to 104.19%. The intraday and interday precision RSD values were <9.13% with an associated accuracy of 92.71 to 104.06%. The total time for the one step online procedure was only 8 min. This method provides a direct and accurate measurement for therapeutic drug monitoring of oxcarbazepine and its active metabolite licarbazepine.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Dibenzazepinas/isolamento & purificação , Oxcarbazepina/isolamento & purificação , Extração em Fase Sólida/métodos , Espectrometria de Massas em Tandem/métodos , Dibenzazepinas/sangue , Humanos , Oxcarbazepina/sangue
5.
Br J Cancer ; 121(2): 157-171, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31239543

RESUMO

BACKGROUND: Recurrence after >5-year disease-free survival affects one-fifth of breast cancer patients and is the clinical manifestation of cancer cell reactivation after persistent dormancy. METHODS: We investigated cellular dormancy in vitro and in vivo using breast cancer cell lines and cell and molecular biology techniques. RESULTS: We demonstrated cellular dormancy in breast cancer bone metastasis, associated with haematopoietic stem cell (HSC) mimicry, in vivo competition for HSC engraftment and non-random distribution of dormant cells at the endosteal niche. Notch2 signal implication was demonstrated by immunophenotyping the endosteal niche-associated cancer cells and upon co-culture with sorted endosteal niche cells, which inhibited breast cancer cell proliferation in a Notch2-dependent manner. Blocking this signal by in vivo acute administration of the γ-secretase inhibitor, dibenzazepine, induced dormant cell mobilisation from the endosteal niche and colonisation of visceral organs. Sorted Notch2HIGH breast cancer cells exhibited a unique stem phenotype similar to HSCs and in vitro tumour-initiating ability in mammosphere assay. Human samples confirmed the existence of a small Notch2HIGH cell population in primary and bone metastatic breast cancers, with a survival advantage for Notch2HIGH vs Notch2LOW patients. CONCLUSIONS: Notch2 represents a key determinant of breast cancer cellular dormancy and mobilisation in the bone microenvironment.


Assuntos
Neoplasias Ósseas/secundário , Neoplasias da Mama/patologia , Células-Tronco Hematopoéticas/fisiologia , Receptor Notch2/fisiologia , Animais , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Dibenzazepinas/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Osteoblastos/fisiologia , Receptor Notch2/antagonistas & inibidores , Transdução de Sinais/fisiologia
6.
J Clin Psychopharmacol ; 39(4): 297-304, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31188233

RESUMO

PURPOSE/BACKGROUND: Patients with schizophrenia are vulnerable to pneumonia. Clozapine is associated with the greatest risk of pneumonia. We investigated the risk factors of pneumonia in patients with schizophrenia who use clozapine. METHODS/PROCEDURES: We used a large cohort of patients with schizophrenia (N = 22,774) who newly use clozapine (baseline). We divided the data set into a training cohort (entry between 1998 and 2008, n = 18,496) and test cohort (entry between 2009 and 2012, n = 4278), where 483 and 168 patients developed pneumonia requiring hospitalization within 1 year after baseline, respectively. For prediction, we developed a static model using Cox proportional hazards regression and a dynamic model using Cox regression with time-dependent modeling. Areas under receiver operating curves (AUCs) for the predictive model were estimated in the training cohort and then in the test cohort for validation. FINDINGS/RESULTS: Based on the baseline characteristics, the static model for predicting pneumonia in 3 periods (90, 180, and 365 days) was unsatisfactory (AUCs, 0.64, 0.64, and 0.65, respectively). The predictors were older age, male sex, history of nonpsychiatric hospitalization, dementia, asthma, and tuberculosis within 1 year before baseline. However, the results were improved (AUCs, 0.83, 0.79, and 0.77, respectively) after control for time-dependent variables, namely, duration of clozapine use and concomitant medications (ie, benzodiazepines, valproic acid, systemic corticosteroids). IMPLICATIONS/CONCLUSIONS: Several risk factors for predicting subsequent pneumonia after initial use of clozapine were explored, including older age, male, history of nonpsychiatric hospitalization, dementia, asthma, tuberculosis, benzodiazepines, valproic acid, systemic corticosteroids, and the use duration of clozapine. Clinical staff can use the risk factors to administer evidence-based treatment.


Assuntos
Antipsicóticos/efeitos adversos , Clozapina/efeitos adversos , Dibenzazepinas/efeitos adversos , Pneumonia/etiologia , Esquizofrenia/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonia/epidemiologia , Fatores de Risco , Taiwan/epidemiologia
7.
Epilepsy Res ; 153: 59-65, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30999260

RESUMO

OBJECTIVE: To assess the long-term safety and efficacy of eslicarbazepine acetate (ESL) monotherapy in adults with focal seizures (FS). METHODS: Study 050 was a long-term, multicenter, open-label (OL) safety extension of two conversion-to-ESL monotherapy studies in adults with refractory FS. After participating in Study 045 or 046, patients started on ESL 1600 mg once daily (QD) (or 1200 mg if they previously had a dose reduction), and could adjust the dose 400 mg/week to a dose between 800-2400 mg QD. Patients could add up to two additional antiepileptic drugs (AEDs). This post-hoc analysis focuses on the actual monotherapy subgroup, which included patients in Studies 045/046/050 who did not add additional AEDs. Study endpoints included treatment retention time, time on ESL monotherapy, change in standardized seizure frequency (SSF), change in quality of life (QoL) in epilepsy (QOLIE-31) and Montgomery-Åsberg Depression Rating Scale (MADRS) scores, and incidence of treatment-emergent adverse events (TEAEs); serious adverse events (SAEs), TEAEs leading to discontinuation, and TEAEs related to allergic reaction, hyponatremia and thyroid function were also evaluated. RESULTS: There were 274 patients in the Study 050 full intent-to-treat (ITT) population and 140 patients in the actual monotherapy subgroup. Median treatment retention time and time on ESL monotherapy were both >5 years. Median reduction in SSF from baseline was 66.4% in the full ITT population and 78.3% in the actual monotherapy subgroup; responder (≥50% reduction in SSF) rates were 62.4% and 74.3%, respectively. QOLIE-31 scores increased from baseline in the full ITT population and the actual monotherapy subgroup (4.1- and 7.5-point increases, respectively). MADRS scores decreased from baseline in both the full ITT population and the actual monotherapy subgroup (0.7- and 2.9-point decreases, respectively). TEAEs occurred in 85.4% of patients in the full ITT population and 81.4% of patients in the actual monotherapy subgroup. Incidences of SAEs and TEAEs leading to discontinuation, as well as dizziness, depression, fall, partial seizures with secondary generalization, and complex partial seizures, were higher in the full ITT population than in the actual monotherapy subgroup. Allergic reactions, hyponatremia, and hypothyroidism were infrequent, particularly in the actual monotherapy subgroup. CONCLUSIONS: The results of this post-hoc analysis suggest that long-term treatment with ESL was effective and well tolerated, both as a monotherapy and in combination with other AEDs for FS. QoL and tolerability appeared to be better, and incidence of depression lower, in the patient population taking ESL as a monotherapy, compared with the population that included patients taking ESL as an adjunctive therapy.


Assuntos
Anticonvulsivantes/uso terapêutico , Dibenzazepinas/uso terapêutico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Convulsões/tratamento farmacológico , Resultado do Tratamento , Adolescente , Adulto , Idoso , Depressão/diagnóstico , Depressão/etiologia , Método Duplo-Cego , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Convulsões/complicações , Convulsões/psicologia , Adulto Jovem
8.
Acta Neurol Scand ; 140(1): 48-55, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30953593

RESUMO

INTRODUCTION: Aggressive behavior is commonly associated with epilepsy and can be influenced by the antiepileptic drugs (AEDs) taken. Sodium channel blockers, specifically the carboxamides derivatives such as carbamazepine and oxcarbazepine, are some of the AEDs considered to have a favorable psychiatric effect profile. OBJECTIVES: We aimed to assess whether the carboxamide analogue eslicarbazepine acetate (ESL) has any effect on the levels of anger in patients with epilepsy. MATERIAL AND METHODS: We prospectively recruited adult patients with epilepsy on treatment with ≦2 active AEDs, who required AED addition or substitution, excluding patients with active psychiatric disorders. All patients completed anger level (STAXI-2), depression-anxiety (HADS), and quality of life (QOLIE-10) assessments, and were evaluated at baseline and within 3-6 months after treatment initiation. RESULTS: Of 78 patients receiving ESL, as add-on therapy or in substitution of a previous AED, were recruited into the ESL group, with an average age of 48 years and 54% men. We used a control group of 58 patients receiving AEDs other than carboxamides. CONCLUSIONS: Patients overall showed improvements in anger levels, mood, and quality of life during the follow-up. A history of psychiatric disorders was a limiting factor to improve anger levels. As compared to controls, anger levels improved in ESL patients independently from seizure control. Therefore, ESL seems to exert a favorable influence on the anger levels of otherwise healthy patients with epilepsy, including those unresponsive to seizure control. The potential ESL anti-aggressive effect should be studied in patients with epilepsy and active psychiatric disorders.


Assuntos
Ira/efeitos dos fármacos , Anticonvulsivantes/uso terapêutico , Dibenzazepinas/uso terapêutico , Epilepsia/tratamento farmacológico , Epilepsia/psicologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Bloqueadores dos Canais de Sódio/uso terapêutico
9.
Artigo em Inglês | MEDLINE | ID: mdl-30856604

RESUMO

In this work, we developed and validated the specific, sensitive and simple LC-MS/MS method for quantification of eslicarbazepine in human plasma. The analyte samples were prepared through a simple one-step protein precipitation method by acetonitrile. The chromatographic separation was operated on an economical Hanbon ODS-2 C18 column (150 mm × 2.1 mm, 10 µm) with isocratic elution using 10 mM ammonium acetate containing 0.01% formic acid and acetonitrile (72:28, v/v) as the mobile phase at the flow rate of 0.5 mL/min. The mass quantification was carried on the multiple reaction monitoring (MRM) of the transitions of m/z 255.1 → 194.1 for eslicarbazepine and m/z 446.1 → 321.1 for glipizide (the internal standard), respectively. The established method was validated with acceptable specificity, linearity, accuracy, precision, extraction recovery, matrix effect and stability in accordance with FDA regulations. At last, the validated method was successfully applied to determination of eslicarbazepine in human plasma obtained from clinical study.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Dibenzazepinas/sangue , Dibenzazepinas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Dibenzazepinas/química , Humanos , Limite de Detecção , Modelos Lineares , Reprodutibilidade dos Testes
10.
Artigo em Inglês | MEDLINE | ID: mdl-30660838

RESUMO

Carbamazepine (CBZ) was considered as the drug of choice in the treatment for various forms of epilepsy, yet the non-negligible adverse effects of CBZ suspend as the major concern for rational and efficient clinical medication. This study developed a method for the simultaneous determination of CBZ and its seven metabolites acridine (AI), iminostilbene (IM), acridone (AO), carbamazepine­10,11­epoxide (CBZ­EP), 10,11­dihydro­10,11­trans­dihy­droxy­carbamazepine (CBZ­DiOH), 2­hydroxycarbamazepine (2­OH­CBZ) and 3­hydroxycarbamazepine (3­OH­CBZ) with phenacetin as the internal standard (IS) using ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Plasma samples were purified with the one-step 96-well protein precipitation plate. Chromatographic separation was achieved on an Agilent Eclipse XDB-C18 (1.8 µm, 2.1 mm × 50 mm) chromatography column carrying the mobile phrase of acetonitrile and 0.1% formic acid in a gradient elution at a flow rate 0.3 mL/min. Agilent G6460 MS/MS in the positive MRM mode using electrospray ionization (ESI) was applied for quantification of target compounds. CBZ and its seven metabolites showed good linear correlation coefficient (r > 0.990). Intra-day and inter-day precision (CV) were no >15%. This method was successfully accomplished within 5 min which was especially applicable for therapeutic drug monitoring (TDM) of CBZ and its metabolites in epileptic patients, and it provided insights for toxicological studies to achieve a rational and effective individualized administration in clinical practice.


Assuntos
Carbamazepina/sangue , Dibenzazepinas/sangue , Epilepsia/sangue , Acridinas , Cromatografia Líquida de Alta Pressão , Monitoramento de Medicamentos , Humanos , Metaboloma , Espectrometria de Massas em Tandem
11.
PLoS One ; 14(1): e0210362, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30699147

RESUMO

A number of drug-releasing contact lenses are currently being studied to address issues inherent in eye drops as a drug delivery method. In this study, we developed epinastine hydrochloride-releasing daily soft contact lenses for treatment of allergic conjunctivitis and examined their in vitro and in vivo performance. Preformed soft contact lenses with/without ionic functional groups were soaked in a solution of epinastine hydrochloride in phosphate-buffered saline to prepare epinastine hydrochloride-releasing soft contact lenses. Among these contact lenses with different ionicities, anionic lenses demonstrated the maximum, relatively linear epinastine hydrochloride release, in vitro. The amount of epinastine hydrochloride release was directly proportional to the concentration of the epinastine hydrochloride solution used to prepare the contact lens. The epinastine hydrochloride-releasing anionic soft contact lens also demonstrated prolonged drug release and significantly greater efficacy compared with epinastine hydrochloride eye drops 12 h after treatment, in vivo. Further studies are required to determine the appropriate amount of epinastine hydrochloride to be contained in the anionic soft contact lenses.


Assuntos
Lentes de Contato Hidrofílicas , Dibenzazepinas/administração & dosagem , Dibenzazepinas/farmacocinética , Antagonistas dos Receptores Histamínicos H1/administração & dosagem , Antagonistas dos Receptores Histamínicos H1/farmacocinética , Imidazóis/administração & dosagem , Imidazóis/farmacocinética , Animais , Conjuntivite Alérgica/induzido quimicamente , Conjuntivite Alérgica/tratamento farmacológico , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Cobaias , Histamina/toxicidade , Técnicas In Vitro , Masculino , Soluções Oftálmicas , Concentração Osmolar
12.
Biomed Pharmacother ; 109: 93-102, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30396096

RESUMO

BACKGROUND: Macrophage polarization has been reported to induce podocyte injury, which is a typical characteristic of diabetic nephropathy (DN). Trichosanthes kirilowii is an herb showing renal protective effect as well as immune-regulating effect. Therefore, it was hypothesized that the renal protective effect of Trichosanthes kirilowii was associated with its modulation on macrophage polarization. In the current study, we tested the hypothesis by subjecting DN rats to treatment of Trichosanthes kirilowii lectin (TKL), an active component of Trichosanthes kirilowii. METHOD: DN was induced using streptozocin (STZ) method, and after 3 days, treatments were performed with different doses of TKL for eight weeks. The effect of TKL on the renal function, structure, and inflammation was assessed. To explain the pathway mediating the effect of TKL on renal tissues, the expressions of markers involved in macrophage polarization, podocyte proliferation, and Notch signaling were determined. Moreover, the DN rats were further administrated with Notch signaling inhibitor, Dibenzazepine (DIB), to verify the key role of Notch signaling in the renal protective effect of TKL. RESULTS: STZ induced damages in renal function and structure, which was attenuated by TKL of different doses. Moreover, STZ also increased the production of TNF-α and iNOS while suppressed the production of IL-10 and arginase-1 (Arg-1). The induced inflammation by STZ was inhibited by TKL. The polarization of macrophage into M1 type during the development of DN was blocked by TKL, contributing to the increased proliferation potential of podocytes. Regarding Notch signaling, TKL administration inhibited the activation of the pathway by suppressing the expression of Notch1, NICD1, and Hes1. The administration of DIB had similar effect to that of TKL administration on renal function and structure. CONCLUSIONS: The study for the first time showed that TKL attenuated deterioration in renal structure and function by increasing M2 macrophage proportion via inhibition of Notch signaling.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Lectinas de Plantas/farmacologia , Trichosanthes/química , Animais , Proliferação de Células/efeitos dos fármacos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/patologia , Dibenzazepinas/farmacologia , Relação Dose-Resposta a Droga , Macrófagos/metabolismo , Masculino , Fenótipo , Lectinas de Plantas/administração & dosagem , Lectinas de Plantas/isolamento & purificação , Podócitos/efeitos dos fármacos , Podócitos/metabolismo , Ratos , Ratos Wistar , Receptores Notch/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estreptozocina/toxicidade
13.
Acta Neurol Scand ; 139(1): 49-63, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30176048

RESUMO

OBJECTIVES: To assess the effectiveness and safety/tolerability of eslicarbazepine acetate (ESL) monotherapy in clinical practice in Europe. MATERIALS AND METHODS: Euro-Esli was a pooled analysis of 14 European clinical practice studies. Responder rate (≥50% seizure frequency reduction) and seizure freedom rate (seizure freedom at least since prior visit) were assessed after 3, 6 and 12 months of ESL treatment and at last visit. Adverse events (AEs) and AEs leading to ESL discontinuation were assessed throughout follow-up. A subanalysis was conducted to assess outcomes for patients treated initially with ESL monotherapy and for patients treated at the last visit with ESL monotherapy. RESULTS: ESL was used as monotherapy in 88/2045 (4.3%) patients initially and in 229/1340 (17.1%) patients at the last visit. At 12 months, responder and seizure freedom rates were 94.1% and 88.2%, respectively, in patients treated initially with ESL monotherapy, and 93.2% and 77.4%, respectively, in patients treated at the last visit with ESL monotherapy. Corresponding values for patients treated initially with ESL adjunctive therapy were 74.8% and 39.0%, respectively; and for patients treated at the last visit with ESL adjunctive therapy, corresponding values were 70.4% and 25.9%, respectively. Safety and tolerability were generally comparable in patients treated with ESL as monotherapy or adjunctive therapy. The most commonly reported AEs (≥5% of patients in any group) were dizziness, somnolence, instability/ataxia, and fatigue. CONCLUSIONS: These clinical practice data support the use of ESL as monotherapy, as well as adjunctive therapy, for focal-onset seizures, complementing evidence from clinical trials.


Assuntos
Anticonvulsivantes/uso terapêutico , Dibenzazepinas/uso terapêutico , Convulsões/tratamento farmacológico , Adulto , Ataxia/induzido quimicamente , Tontura/induzido quimicamente , Europa (Continente) , Fadiga/induzido quimicamente , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sonolência , Vertigem/induzido quimicamente
15.
Neurologia ; 34(6): 386-395, 2019.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-28215909

RESUMO

INTRODUCTION: Eslicarbazepine acetate (ESL), together with carbamazepine and oxcarbazepine, belongs to the dibenzazepine family. According to the latest clinical practice guidelines, tricyclic antidepressants, dual antidepressants (venlafaxine, duloxetine), and some antiepileptics (gabapentin, pregabalin) are first-line drugs for neuropathic pain; tramadol, lidocaine 5% patches, and capsaicin 8% patches are considered second-line drugs; and strong opioids constitute a third line of treatment. Such other antiepileptics as lamotrigine and lacosamide are not authorised as treatments for neuropathic pain by the regulatory agencies, but are nonetheless prescribed off-label in routine clinical practice. Carbamazepine, on the other hand, is indicated for trigeminal and glossopharyngeal neuralgia. DEVELOPMENT: We conducted a literature search to gather evidence on the use of ESL for neuropathic pain, headache, and cranial neuralgia. CONCLUSIONS: Evidence is insufficient to recommend ESL for neuropathic pain, headache, and cranial neuralgia. Most of the available evidence comes from open and observational studies with small sample sizes and no control group; however, their favourable results call for further studies on the usefulness of ESL for neuropathic pain, headache, and cranial neuralgia.


Assuntos
Anticonvulsivantes/uso terapêutico , Dibenzazepinas/uso terapêutico , Nervo Glossofaríngeo , Cefaleia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Nervo Trigêmeo , Humanos , Espanha
16.
Life Sci ; 214: 167-175, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30393024

RESUMO

AIMS: Eslicarbazepine acetate (ESL) is a novel dibenzazepine antiepileptic, that has demonstrated efficacy against trigeminal pain, both in preclinical and clinical studies. However, ESL's mechanism of antinociceptive action remains uncertain. Here, we aimed to examine the contribution of adrenergic/cholinergic/opioid receptors to the antinociceptive effects of ESL in a trigeminal pain model, as these neurotransmitter systems are known to have an important role in the modulation of trigeminal nociception. MAIN METHODS: ESL's effects in the orofacial formalin test were examined following peroral and local peripheral administration (subcutaneous, into the perinasal region). The involvement of adrenergic/cholinergic/opioid receptors was evaluated by intraperitoneally pretreating mice with an appropriate antagonist immediately after peroral application of ESL. We used antagonists of α1­adrenergic (prazosin), α2­adrenergic (yohimbine), ß­adrenergic (non-selective, propranolol and ß1-selective, metoprolol), muscarinic (atropine), nicotinic (mecamylamine) and opioid receptors (naloxone). Additionally, the role of peripheral α2­adrenergic, ß1­adrenergic, muscarinic and opioid receptors was evaluated by co-injecting ESL with an antagonist into the perinasal area. KEY FINDINGS: ESL dose-dependently reduced formalin-induced nociceptive behavior after systemic and local peripheral application. Systemic administration of yohimbine, propranolol, metoprolol, atropine and naloxone inhibited ESL's antinociceptive effects in a dose-related manner. Prazosin and mecamylamine did not produce inhibitory effects. Local application of yohimbine, atropine and naloxone into the perinasal area also produced a dose-related inhibition of ESL's efficacy, whereas metoprolol failed to inhibit the local antinociceptive effects of ESL. SIGNIFICANCE: This study suggests that ESL's efficacy against trigeminal nociception is mediated by peripheral (and possibly central) α2­adrenergic, muscarinic and opioid receptors, as well as central ß1­adrenergic receptors.


Assuntos
Analgésicos/farmacologia , Dibenzazepinas/farmacologia , Dor/tratamento farmacológico , Antagonistas Adrenérgicos/farmacologia , Animais , Atropina/farmacologia , Antagonistas Colinérgicos/farmacologia , Formaldeído/toxicidade , Masculino , Camundongos , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Receptores Adrenérgicos/fisiologia , Receptores Colinérgicos/fisiologia , Receptores Opioides/fisiologia , Neuralgia do Trigêmeo/tratamento farmacológico , Ioimbina/farmacologia
17.
PLoS One ; 13(11): e0206701, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30383855

RESUMO

Intestinal mucus layer disruption and gut microflora modification in conjunction with tight junction (TJ) changes can increase colonic permeability that allows bacterial dissemination and intestinal and systemic disease. We showed previously that Citrobacter rodentium (CR)-induced colonic crypt hyperplasia and/or colitis is regulated by a functional cross-talk between the Notch and Wnt/ß-catenin pathways. In the current study, mucus analysis in the colons of CR-infected (108 CFUs) and Notch blocker Dibenzazepine (DBZ, i.p.; 10µmol/Kg b.w.)-treated mice revealed significant alterations in the composition of trace O-glycans and complex type and hybrid N-glycans, compared to CR-infected mice alone that preceded/accompanied alterations in 16S rDNA microbial community structure and elevated EUB338 staining. While mucin-degrading bacterium, Akkermansia muciniphila (A. muciniphila) along with Enterobacteriaceae belonging to Proteobacteria phyla increased in the feces, antimicrobial peptides Angiogenin-4, Intelectin-1 and Intelectin-2, and ISC marker Dclk1, exhibited dramatic decreases in the colons of CR-infected/DBZ-treated mice. Also evident was a loss of TJ and adherens junction protein immuno-staining within the colonic crypts that negatively impacted paracellular barrier. These changes coincided with the loss of Notch signaling and exacerbation of mucosal injury. In response to a cocktail of antibiotics (Metronidazole/ciprofloxacin) for 10 days, there was increased survival that coincided with: i) decreased levels of Proteobacteria, ii) elevated Dclk1 levels in the crypt and, iii) reduced paracellular permeability. Thus, enteric infections that interfere with Notch activity may promote mucosal dysbiosis that is preceded by changes in mucus composition. Controlled use of antibiotics seems to alleviate gut dysbiosis but may be insufficient to promote colonic crypt regeneration.


Assuntos
Citrobacter rodentium , Colo/imunologia , Infecções por Enterobacteriaceae/imunologia , Muco/imunologia , Receptores Notch/antagonistas & inibidores , Animais , Animais não Endogâmicos , Colite/tratamento farmacológico , Colite/imunologia , Colite/patologia , Colo/efeitos dos fármacos , Colo/microbiologia , Colo/patologia , Dibenzazepinas/farmacologia , Modelos Animais de Doenças , Disbiose/tratamento farmacológico , Disbiose/imunologia , Disbiose/patologia , Infecções por Enterobacteriaceae/tratamento farmacológico , Infecções por Enterobacteriaceae/patologia , Inibidores Enzimáticos/farmacologia , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Knockout , Muco/microbiologia , Receptores Notch/genética , Receptores Notch/metabolismo , Transdução de Sinais/efeitos dos fármacos , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/imunologia , Junções Íntimas/patologia
18.
Int J Pharm Compd ; 22(5): 433-439, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30384342

RESUMO

Eslicarbazepine acetate is an anticonvulsant drug with a recent U.S. Food and Drug Administration approval for expanded use in children and adolescents. Currently, eslicarbazepine acetate is only available in the U.S. as 200-mg to 800-mg strength tablets (Aptiom), which are not easy to administer for pediatric patients. This study was initiated to develop an oral suspension formulation for extemporaneous compounding by pharmacists and to generate stability data for storage recommendations. Nine suspension formulations of eslicarbazepine acetate were prepared from Aptiom tablets and commercially available liquid vehicles using the standard mortar/pestle method. The vehicles varied mainly in their solvents, viscosities, and sweeteners. The formulations were evaluated for ease of preparation, physical properties, and initial potency. Two lead formulations were selected for a two-month stability study at room temperature or under refrigeration (2°C to 8°C). The stability samples were withdrawn at pre-determined time points and analyzed by visual inspection, pH measurement, and a stability-indicating high-performance liquid chromatographic assay. The majority of the 9 formulations were found to be easy to prepare and administer at a concentration of 40-mg/mL eslicarbazepine acetate. Particle settling was observed in several formulations over time, but they were re-suspended satisfactorily upon shaking. Two suspensions in 50:50 v/v mixtures of Ora-Sweet or Ora-Sweet SF with Ora-Plus were selected as the lead formulations for the two-month stability study. At the initiation of the study, all samples appeared as white and smooth suspensions with pH ranging from 4.39 to 4.46. The high-performance liquid chromatographic results confirmed that the initial samples contained 100.4% to 102.2% of the label claim strength. Over two months of storage at room temperature or refrigeration, there were no significant changes in visual appearance, re-suspendability, pH, or potency for any samples. No new degradation peaks were observed in any highperformance liquid chromatograms. Based on the study results, two eslicarbazepine acetate suspensions are recommended for extemporaneous compounding from Aptiom tablets. The formulations consist of 40 mg/mL eslicarbazepine acetate in 50:50 v/v Ora-Sweet:Ora-Plus or Ora-Sweet SF:Ora-Plus. Once prepared, these suspensions can be stored at room temperature or under refrigeration for up to two months.


Assuntos
Dibenzazepinas/química , Composição de Medicamentos , Administração Oral , Estabilidade de Medicamentos , Suspensões
19.
Drugs Aging ; 35(12): 1109-1117, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30387043

RESUMO

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).


Assuntos
Anticonvulsivantes/administração & dosagem , Dibenzazepinas/administração & dosagem , Convulsões/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/uso terapêutico , Dibenzazepinas/efeitos adversos , Feminino , Humanos , Masculino , Qualidade de Vida , Resultado do Tratamento
20.
Epilepsy Res ; 147: 80-86, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30278294

RESUMO

OBJECTIVE: To evaluate and compare the effects of concomitant lamotrigine (LTG) or carbamazepine (CBZ) on the incidence of treatment-emergent adverse events (TEAEs) in patients taking adjunctive eslicarbazepine acetate (ESL) for focal (partial-onset) seizures (FS). METHODS: These post-hoc analyses of data pooled from three randomized, double-blind, placebo-controlled studies of adjunctive ESL (BIA-2093-301, -302 and -304) included adults (≥16 years) with FS refractory to 1-3 antiepileptic drugs (AEDs). Patients were randomized equally to placebo, ESL 400 mg (Studies 301 and 302 only), 800 mg, or 1200 mg once daily (8-week baseline, 2-week titration, and 12-week maintenance periods). TEAEs, TEAEs leading to discontinuation, and serious AEs (SAEs) were evaluated in patients taking, or not taking, LTG (excluding those taking CBZ or phenytoin [PHT]; i.e., the +LTG and -LTG/-CBZ subgroups), or CBZ (excluding those taking LTG or PHT; i.e., the +CBZ and -LTG/-CBZ subgroups) at baseline. RESULTS: LTG was used concomitantly by 248 patients (+LTG; placebo, n = 81; ESL, n = 167) and CBZ by 613 patients (+CBZ; placebo, n = 172; ESL, n = 441); 361 patients were taking neither LTG nor CBZ (-LTG/-CBZ; placebo, n = 109; ESL, n = 252). The overall incidence of TEAEs with ESL (any dose) was numerically higher for +CBZ (77%) than for +LTG (73%) or -LTG/-CBZ (68%; statistical significance not tested). Among patients taking ESL, dizziness, diplopia, and vomiting were reported more frequently in the +CBZ subgroup (30%, 14%, and 10%, respectively) than in the +LTG (16%, 8%, 5%) or -LTG/-CBZ (11%, 3%, 5%) subgroups. The overall incidence of TEAEs leading to discontinuation with ESL was higher for +CBZ (21%) than for +LTG (13%) or -LTG/-CBZ (15%). Dizziness leading to discontinuation with ESL was reported more frequently in the +CBZ subgroup than in the +LTG or -LTG/-CBZ subgroups (9%, 3%, and 3%, respectively). The overall incidence of SAEs in patients taking ESL was comparable across subgroups (+LTG, 5%; +CBZ, 6%; -LTG/-CBZ, 5%). The results were similar when evaluating placebo-adjusted incidences. CONCLUSION: There was a potential pharmacodynamic interaction between AEDs with a putatively similar mechanism of action, with a seemingly lesser interaction between ESL and LTG versus ESL and CBZ. If combining ESL with LTG or CBZ, clinicians should be aware of the potential risk for an increased incidence of TEAEs typically associated with voltage-gated sodium channel inhibitors (e.g., dizziness, blurred vision, vertigo, diplopia, headache, or vomiting).


Assuntos
Anticonvulsivantes/uso terapêutico , Convulsões/tratamento farmacológico , Adolescente , Adulto , Carbamazepina/uso terapêutico , Criança , Dibenzazepinas/uso terapêutico , Diplopia/induzido quimicamente , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Lamotrigina/uso terapêutico , Masculino , Ensaios Clínicos Controlados Aleatórios como Assunto , Vômito/induzido quimicamente , Adulto Jovem
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