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Background and Objectives: Oxidative stress resulting from a disturbance of the endogenous redox system is suspected in numerous diseases of the central nervous system, including epilepsy. In addition, antiseizure medications (ASMs), especially those of the old generation, may further increase oxidative stress. To evaluate the effects of ASM generation on oxidative stress, we conducted a cross-sectional study in patients with epilepsy treated with old, new, and polytherapy. Materials and Methods: The antioxidant activity of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase, as well as the concentrations of malondialdehyde, protein carbonyl, nitrate, nitrite, and glutathione in reduced and oxidized forms, were measured in 49 patients with epilepsy and 14 healthy controls. In addition, the plasma concentrations of ASMs and metabolites of carbamazepine and valproic acid were measured in the patients. Results: Patients with epilepsy showed increased activities of superoxide dismutase and catalase (p < 0.001), concentrations of glutathione disulfide and markers of nitric oxide metabolism (p < 0.001), and decreased activities of glutathione peroxidase, glutathione reductase, glutathione, and nitrite concentrations (p ≤ 0.005) compared to healthy controls. A comparison of ASM generations revealed increased levels of superoxide dismutase and catalase (p ≤ 0.007) and decreased levels of glutathione peroxidase and glutathione reductase (p ≤ 0.01) in patients treated with old ASMs compared to those treated with new generation ASMs. In addition, an increase in protein carbonyl and nitric oxide metabolites (p ≤ 0.002) was observed in patients treated with old generation ASMs compared to those treated with new generation ASMs. Most oxidative stress parameters in patients receiving polytherapy with ASMs were intermediate between the results of patients treated with the old and new generations of ASMs. Conclusions: An increase in oxidative stress markers and modulation of antioxidant enzyme activities was observed in patients with epilepsy compared to controls. The results of our study showed significantly higher oxidative stress in patients treated with old ASMs compared to those treated with new generation ASMs.
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Anticonvulsivantes , Epilepsia , Estrés Oxidativo , Superóxido Dismutasa , Humanos , Estrés Oxidativo/efectos de los fármacos , Epilepsia/tratamiento farmacológico , Epilepsia/sangre , Estudios Transversales , Anticonvulsivantes/uso terapéutico , Femenino , Masculino , Adulto , Superóxido Dismutasa/sangre , Persona de Mediana Edad , Glutatión Peroxidasa/sangre , Catalasa/sangre , Glutatión Reductasa/sangre , Ácido Valproico/uso terapéutico , Carbamazepina/uso terapéutico , Malondialdehído/sangre , Malondialdehído/análisis , Antioxidantes/uso terapéutico , Antioxidantes/metabolismo , Adulto JovenRESUMEN
The objective of the present report was to develop and validate a simple, selective, and reproducible high-performance liquid chromatography method with UV detection suitable for routine therapeutic drug monitoring of the most commonly used antiepileptic drugs and some of their metabolites. Simple precipitation of plasma proteins with acetonitrile was used for sample preparation. 10,11-dihydrocarbamazepine was used as an internal standard. Chromatographic separation of the analytes was achieved by gradient elution on a Phenyl-Hexyl column at 40 °C, using methanol and potassium phosphate buffer (25 mM; pH 5.1) as a mobile phase. The method was validated according to the FDA guidelines for bioanalytical method validation. It showed to be selective, accurate, precise, and linear over the concentration ranges of 1-50 mg/L for phenobarbital, phenytoin, levetiracetam, rufinamide, zonisamide, and lacosamide; 0.5-50 mg/L for lamotrigine, primidone, carbamazepine and 10-monohydroxycarbazepine; 0.2-10 mg/L for carbamazepine metabolites: 10,11-trans-dihydroxy-10,11-dihydrocarbamazepine and carbamazepine-10,11-epoxide; 0.1-10 mg/L for oxcarbazepine; 2-100 mg/L for felbamate and 3-150 mg/L for ethosuximide. The suitability of the validated method for routine therapeutic drug monitoring was confirmed by quantification of the analytes in plasma samples from patients with epilepsy on combination antiepileptic therapy.
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Anticonvulsivantes , Monitoreo de Drogas , Humanos , Anticonvulsivantes/química , Cromatografía Líquida de Alta Presión/métodos , Monitoreo de Drogas/métodos , Carbamazepina/química , OxcarbazepinaRESUMEN
AIMS: This study aimed to develop a population pharmacokinetic model for quantitative evaluation of the influence of genetic variants in metabolic enzymes and transporters on lamotrigine pharmacokinetics while taking into account the influence of various clinical, biochemical and demographic factors. METHODS: We included 100 patients with epilepsy on stable dosing with lamotrigine as mono or adjunctive therapy. Lamotrigine and lamotrigine N-2-glucuronide concentrations were determined in up to two plasma samples per patient. Patients were genotyped for UGT1A4, UGT2B7, ABCB1 and SLC22A1. Population pharmacokinetic analysis was performed by non-linear mixed effects modelling. Prior knowledge from previous pharmacokinetic studies was incorporated to stabilize the modelling process. A parent-metabolite model was developed to get a more detailed view on the covariate effects on lamotrigine metabolism. RESULTS: With a base model absorption rate (interindividual variability) was estimated at 1.96 h(-1) (72.8%), oral clearance at 2.32 l h(-1) (41.4%) and distribution volume at 77.6 l (30.2%). Lamotrigine clearance was associated with genetic factors, patient's weight, renal function, smoking and co-treatment with enzyme inducing or inhibiting drugs. In patients with UGT2B7-161TT genotype clearance was lower compared with GT and GG genotypes. Clearance was particularly high in patients with UGT2B7 372 GG genotype (compared with AA genotype it was 117%; 95% CI 44.8, 247% higher). CONCLUSIONS: Variability in lamotrigine pharmacokinetics is large and quantification of its sources may lead to more precise individual treatment. Genotyping for UGT2B7 may be useful in various clinical settings.
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Anticonvulsivantes/farmacocinética , Epilepsia/tratamiento farmacológico , Glucuronosiltransferasa/genética , Triazinas/farmacocinética , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Adulto , Anciano , Anciano de 80 o más Años , Anticonvulsivantes/administración & dosificación , Femenino , Genotipo , Humanos , Lamotrigina , Masculino , Persona de Mediana Edad , Modelos Biológicos , Transportador 1 de Catión Orgánico/genética , Estudios Prospectivos , Distribución Tisular , Triazinas/administración & dosificación , Adulto JovenRESUMEN
A simple, sensitive, accurate, precise and inexpensive HPLC method with fluorescence detection, suitable for routine therapeutic drug monitoring (TDM) of an antiepileptic drug topiramate, was developed and validated. The determination of plasma topiramate concentration was carried out after precolumn derivatization, using 4-chloro-7-nitrobenzofurazan as a fluorescent labeling agent and bendroflumethiazide as an internal standard. The standard calibration curve was linear over the concentration range of 0.01-24 µg/mL (r² > 0.9998). The intra- and inter-day accuracies expressed as bias were from 1.4 to 9.9% and from 1.9 to 10.2%, respectively. The intra- and inter-day precisions were below 7.9% and 2.7%, respectively. The validated method was applied for the measurement of plasma topiramate concentrations in patients with epilepsy. The reported method is appropriate for TDM of topiramate as well as for pharmacokinetic and bioequivalence studies.
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Cromatografía Líquida de Alta Presión/métodos , Monitoreo de Drogas , Fructosa/análogos & derivados , Fructosa/sangre , Humanos , Espectrometría de Fluorescencia , TopiramatoRESUMEN
BACKGROUND: The antiepileptic drug lamotrigine (LTG) shows high pharmacokinetic variability due to genotype influence and concomitant use of glucuronidation inducers and inhibitors, both of which may be frequently taken by elderly patients. Our goal was to develop a reliable quantification method for lamotrigine and its main glucuronide metabolite lamotrigine-N2-glucuronide (LTG-N2-GLU) in dried blood spots (DBS) to enable routine therapeutic drug monitoring and to identify altered metabolic activity for early detection of drug interactions possibly leading to suboptimal drug response. RESULTS: The analytical method was validated in terms of selectivity, accuracy, precision, matrix effects, haematocrit, blood spot volume influence, and stability. It was applied to a clinical study, and the DBS results were compared to the concentrations determined in plasma samples. A good correlation was established for both analytes in DBS and plasma samples, taking into account the haematocrit and blood cell-to-plasma partition coefficients. It was demonstrated that the method is suitable for the determination of the metabolite-to-parent ratio to reveal the metabolic status of individual patients. CONCLUSIONS: The clinical validation performed confirmed that the DBS technique is a reliable alternative for plasma lamotrigine and its glucuronide determination.
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Nowadays, numerous skincare routines are used to rejuvenate aging skin. Retinoids are one of the most popular ingredients used in antiaging treatments. Among the representatives of retinoids, tretinoin is considered the most effective agent with proven antiaging effects on the skin and can be found in formulations approved as medicines for topical treatment of acne, facial wrinkles, and hyperpigmentation. Other retinoids present in topical medicines are used for various indications, but only tazarotene is also approved as adjunctive agent for treatment of facial fine wrinkling and pigmentation. The most commonly used retinoids such as retinol, retinaldehyde, and retinyl palmitate are contained in cosmeceuticals regulated as cosmetics. Since clinical efficacy studies are not required for marketing cosmetic formulations, there are concerns about the efficacy of these retinoids. From a formulation perspective, retinoids pose a challenge to researchers as a result of their proven instability, low penetration, and potential for skin irritation. Therefore, novel delivery systems based on nanotechnology are being developed to overcome the limitations of conventional formulations and improve user compliance. In this review, the clinical evidence for retinoids in conventional and nanoformulations for topical antiaging treatments was evaluated. In addition, an overview of the comparison clinical trials between tretinoin and other retinoids is presented. In general, there is a lack of evidence from properly designed clinical trials to support the claimed efficacy of the most commonly used retinoids as antiaging agents in cosmeceuticals. Of the other retinoids contained in medicines, tazarotene and adapalene have clinically evaluated antiaging effects compared to tretinoin and may be considered as potential alternatives for antiaging treatments. The promising potential of retinoid nanoformulations requires a more comprehensive evaluation with additional studies to support the preliminary findings.
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Cosmecéuticos , Fármacos Dermatológicos , Humanos , Retinoides/uso terapéutico , Fármacos Dermatológicos/uso terapéutico , Cosmecéuticos/uso terapéutico , Adapaleno , Tretinoina/uso terapéuticoRESUMEN
The aim of the present report was to develop and validate simple, sensitive and reliable LC-MS/MS method for quantification of topiramate (TPM) and its main metabolites: 2,3-desisopropylidene TPM, 4,5-desisopropylidene TPM, 10-OH TPM and 9-OH TPM in human plasma samples. The most abundant metabolite 2,3-desisopropylidene TPM was isolated from patients urine, characterized and afterwards used as an authentic standard for method development and validation. Sample preparation method employs 100µL of plasma sample and liquid-liquid extraction with a mixture of ethyl acetate and diethyl ether as extraction solvent. Chromatographic separation was achieved on a 1290 Infinity UHPLC coupled to 6460 Triple Quad Mass Spectrometer operated in negative MRM mode using Kinetex C18 column (50×2.1mm, 2.6µm) by gradient elution using water and methanol as a mobile phase and stable isotope labeled TPM as internal standard. The method showed to be selective, accurate, precise and linear over the concentration ranges of 0.10-20µg/mL for TPM, 0.01-2.0µg/mL for 2,3-desisopropylidene TPM, and 0.001-0.200µg/mL for 4,5-desisopropylidene TPM, 10-OH TPM and 9-OH TPM. The described method is the first fully validated method capable of simultaneous determination of TPM and its main metabolites in plasma over the selected analytical range. The suitability of the method was successfully demonstrated by the quantification of all analytes in plasma samples of patients with epilepsy and can be considered as reliable analytical tool for future investigations of the TPM metabolism.
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Cromatografía Liquida/métodos , Fructosa/análogos & derivados , Plasma/química , Espectrometría de Masas en Tándem/métodos , Fructosa/sangre , Fructosa/química , Humanos , Extracción Líquido-Líquido/métodos , Metanol/química , Control de Calidad , Reproducibilidad de los Resultados , TopiramatoRESUMEN
Therapeutic drug monitoring (TDM) is a multi-disciplinary clinical specialty used for optimization and individualization of drug therapy in the general and special populations. Since most antiepileptic drugs (AEDs) are characterized by pronounced intra- and inter-individual variability, it can be especially valuable as an aid for dosing adjustments in patients with epilepsy. Dried blood spots (DBS) sampling technique is recognized as a suitable alternative for conventional sampling methods as TDM interventions should be applied in the most cost-effective, rational and clinically useful manner. In the present review we summarize the latest trends and applications of DBS in TDM of epilepsy. Quantification of AEDs in DBS was employed in various clinical settings and has been already reported for phenobarbital, phenytoin, valproic acid, clonazepam, clobazam, carbamazepine, topiramate, rufinamide, lamotrigine, 10-hydroxycarbazepine and levetiracetam. The major limitation of the published studies are restricted evaluation of critical parameters such as the impact of spotted blood volume, spot homogeneity and haematocrit effect, limited clinical validation and non-established correlations between the DBS and plasma concentrations of AEDs. Standardization of critical technical aspects for appropriate sampling, sample preparation and validation of the analytical procedures for quantification of the drugs, as well as appropriate interpretation of the results are the fields which should get more attention in upcoming studies. Limited data on clinical validation and the fact that this technique has been used in practice only for a few AEDs makes the routine implementation of TDM of AEDs using DBS method a big challenge that should be faced by the pharmaceutical scientists in the future.