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1.
J Forensic Sci ; 65(1): 288-294, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31454427

RESUMO

Lacosamide is a functionalized amino acid with antiepileptic function. Therapeutic drug monitoring (TDM) in patients for lacosamide is critical as it allows clinicians to control epileptic seizures. A single liquid-liquid extraction step was applied for the extraction of lacosamide from whole blood samples which were thereafter analyzed by GC-MS. Optimum extraction conditions were selected on the basis of experiments with various solvents at different pHs, indicating ethyl acetate at pH 12 as the most efficient parameters for the extraction of lacosamide. Method exhibited linearity from 2 to 100 µg/mL with R2  = 0.998. Accuracy and precision were evaluated at three concentrations and found to be within acceptable limits. LOD and LOQ were determined at 0.1 and 0.5 µg/mL, respectively. Lacosamide was found to be stable at storage conditions. The developed method was applied successfully in clinical samples and postmortem blood sample from an overdose case.


Assuntos
Anticonvulsivantes/sangue , Cromatografia Gasosa-Espectrometria de Massas , Lacosamida/sangue , Anticonvulsivantes/envenenamento , Monitoramento de Medicamentos , Toxicologia Forense , Humanos , Lacosamida/envenenamento , Limite de Detecção , Modelos Lineares , Extração Líquido-Líquido , Envenenamento/diagnóstico
2.
Clin Biochem ; 74: 24-30, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31672648

RESUMO

BACKGROUND: In some clinical situations (pregnancy, aging, drug resistance, toxicity), measurements of lamotrigine plasma levels may be reliable. Limited studies indicate that saliva and hair could be alternative sources for monitoring lamotrigine therapy. The drug content in hair can also be used to assess the history of drug therapy and to ascertain long-term patient compliance. The aims of this study were to 1) determine the correlations among plasma, saliva, and hair lamotrigine concentrations, 2) evaluate saliva as an alternative matrix for monitoring drug levels and 3) evaluate hair as a source of information on adherence to antiepileptic treatment and on the correlation of hair concentrations with clinical outcomes in patients with epilepsy. METHODS: Plasma, saliva, and hair lamotrigine concentrations were measured by liquid chromatography-tandem mass spectrometry in positive ionization mode. The study group (n = 85) was recruited among the epileptic patients at the Institute of Psychiatry and Neurology, Warsaw, Poland. RESULTS: Plasma concentrations were not influenced by sex, age, or the concomitant use of other antiepileptic drugs. Lamotrigine saliva and plasma concentrations were strongly correlated (r = 0.82, p < 0.001). Lamotrigine hair concentrations were correlated with the plasma concentrations (r = 0.53, p < 0.001) and daily dose in mg/kg (r = 0.23, p = 0.024). The analysis revealed no significant correlation between lamotrigine hair levels and the number of seizures in the previous 3 months (r = -0.1, p > 0.05). CONCLUSIONS: The lamotrigine saliva concentration is strongly correlated with its plasma level, and saliva can be used as an alternative matrix to plasma for monitoring. Lamotrigine can also be successfully measured in hair, and the drug levels in hair tend to be correlated with the levels in plasma. However, lamotrigine levels in hair may not correspond to clinical outcomes (i.e., seizure episodes).


Assuntos
Anticonvulsivantes/análise , Monitoramento de Medicamentos/métodos , Cabelo/química , Lamotrigina/análise , Saliva/química , Adolescente , Adulto , Idoso , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/sangue , Anticonvulsivantes/uso terapêutico , Cromatografia Líquida , Epilepsia/sangue , Epilepsia/tratamento farmacológico , Feminino , Humanos , Lamotrigina/administração & dosagem , Lamotrigina/sangue , Lamotrigina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Polônia , Convulsões/sangue , Convulsões/tratamento farmacológico , Espectrometria de Massas em Tandem , Adulto Jovem
3.
Am J Vet Res ; 80(10): 950-956, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31556719

RESUMO

OBJECTIVE: To compare pharmacokinetics of levetiracetam in serum and CSF of cats after oral administration of extended-release (ER) levetiracetam. ANIMALS: 9 healthy cats. PROCEDURES: Cats received 1 dose of a commercially available ER levetiracetam product (500 mg, PO). Thirteen blood and 10 CSF samples were collected over a 24-hour period for pharmacokinetic analysis. After 1 week, cats received 1 dose of a compounded ER levetiracetam formulation (500 mg, PO), and samples were obtained at the same times for analysis. RESULTS: CSF concentrations of levetiracetam closely paralleled serum concentrations. There were significant differences between the commercially available product and the compounded formulation for mean ± SD serum maximum concentration (Cmax; 126 ± 33 µg/mL and 169 ± 51 µg/mL, respectively), Cmax corrected for dose (0.83 ± 0.10 µg/mL/mg and 1.10 ± 0.28 µg/mL/mg, respectively), and time to Cmax (5.1 ± 1.6 hours and 3.1 ± 1.5 hours, respectively). Half-life for the commercially available product and compounded formulation of ER levetiracetam was 4.3 ± 2.0 hours and 5.0 ± 1.6 hours, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: The commercially available product and compounded formulation of ER levetiracetam both maintained concentrations in healthy cats 12 hours after oral administration that have been found to be therapeutic in humans (ie, 5 µg/mL). Results of this study supported dosing intervals of 12 hours, and potentially 24 hours, for oral administration of ER levetiracetam to cats. Monitoring of serum concentrations of levetiracetam can be used as an accurate representation of levetiracetam concentrations in CSF of cats.


Assuntos
Anticonvulsivantes/farmacocinética , Gatos/metabolismo , Levetiracetam/farmacocinética , Administração Oral , Animais , Anticonvulsivantes/sangue , Anticonvulsivantes/líquido cefalorraquidiano , Área Sob a Curva , Gatos/sangue , Gatos/líquido cefalorraquidiano , Estudos Cross-Over , Preparações de Ação Retardada/farmacocinética , Meia-Vida , Levetiracetam/administração & dosagem , Levetiracetam/sangue , Levetiracetam/líquido cefalorraquidiano , Estudos Prospectivos
4.
Neurology ; 93(12): e1212-e1226, 2019 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-31462582

RESUMO

OBJECTIVE: To evaluate efficacy and tolerability of adjunctive lacosamide in children and adolescents with uncontrolled focal (partial-onset) seizures. METHODS: In this double-blind trial (SP0969; NCT01921205), patients (age ≥4-<17 years) with uncontrolled focal seizures were randomized (1:1) to adjunctive lacosamide/placebo. After a 6-week titration, patients who reached the target dose range for their weight (<30 kg: 8-12 mg/kg/d oral solution; ≥30-<50 kg: 6-8 mg/kg/d oral solution; ≥50 kg: 300-400 mg/d tablets) entered a 10-week maintenance period. The primary outcome was change in focal seizure frequency per 28 days from baseline to maintenance. RESULTS: Three hundred forty-three patients were randomized; 306 (lacosamide 152 of 171 [88.9%]; placebo 154 of 172 [89.5%]) completed treatment (titration and maintenance). Adverse events (AEs) were the most common reasons for discontinuation during treatment (lacosamide 4.1%; placebo 5.8%). From baseline to maintenance, percent reduction in focal seizure frequency per 28 days for lacosamide (n = 170) vs placebo (n = 168) was 31.7% (p = 0.0003). During maintenance, median percent reduction in focal seizure frequency per 28 days was 51.7% for lacosamide and 21.7% for placebo. Fifty percent responder rates (≥50% reduction) were 52.9% and 33.3% (odds ratio 2.17, p = 0.0006). During treatment, treatment-emergent AEs were reported by 67.8% lacosamide-treated patients (placebo 58.1%), most commonly (≥10%) somnolence (14.0%, placebo 5.2%) and dizziness (10.5%, placebo 3.5%). CONCLUSIONS: Adjunctive lacosamide was efficacious in reducing seizure frequency and generally well tolerated in patients (age ≥4-<17 years) with focal seizures. CLINICALTRIALSGOV IDENTIFIER: NCT01921205. CLASSIFICATION OF EVIDENCE: This trial provides Class I evidence that for children and adolescents with uncontrolled focal seizures, adjunctive lacosamide reduces seizure frequency.


Assuntos
Anticonvulsivantes/administração & dosagem , Lacosamida/administração & dosagem , Convulsões/diagnóstico , Convulsões/tratamento farmacológico , Adolescente , Anticonvulsivantes/sangue , Criança , Pré-Escolar , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Lacosamida/sangue , Masculino , Estudos Prospectivos , Convulsões/sangue , Resultado do Tratamento
5.
Artigo em Inglês | MEDLINE | ID: mdl-31279290

RESUMO

Rufinamide is an antiepileptic drug approved for seizures treatment associated with Lennox-Gastaut syndrome. To support future pharmacokinetic studies in rodents, this work aimed to validate for the first time a fast and simple high-performance liquid chromatographic (HPLC) method for rufinamide quantification in mouse plasma and brain, liver and kidney tissues. For that, aliquots (100 µL) of plasma or tissues homogenates were spiked with known amounts of rufinamide and chloramphenicol (internal standard). Compounds were extracted using a combination of protein precipitation and liquid-liquid extraction. Their separation was accomplished using a LiChroCART® Purospher Star column (C18, 55 mm × 4 mm; 3 µm) protected by a LiChroCART® Purospher Star pre-column (C18, 4 mm × 4 mm; 5 µm) at 35 °C. Mobile phase [water/acetonitrile (82:18, v/v)] was isocratically pumped at 1.0 mL min-1 and detection was performed using a diode-array detector set at 210 nm. A preliminary in vivo pharmacokinetic study was also performed by orally administering rufinamide (10 mg kg-1) to mice. The bioanalytical method herein developed was validated according to international bioanalytical guidelines and showed to be selective and linear (r2 ≥ 0.9918) over the concentration range of 0.1-30 µg mL-1. Regarding quality control samples, overall imprecision was lower than 14.5% and inaccuracy ranged between -14.6% and 15.0%. In all tested matrices, rufinamide recoveries varied between 73.1% and 85.2%. This method was successfully applied in a preliminary pharmacokinetic study, suggesting to be a useful bioanalytical tool to support further non-clinical pharmacokinetic-based studies involving rufinamide.


Assuntos
Anticonvulsivantes/análise , Cromatografia Líquida de Alta Pressão/métodos , Triazóis/análise , Animais , Anticonvulsivantes/sangue , Anticonvulsivantes/isolamento & purificação , Anticonvulsivantes/farmacocinética , Cromatografia Líquida de Alta Pressão/instrumentação , Extração Líquido-Líquido , Masculino , Camundongos , Triazóis/sangue , Triazóis/farmacocinética
6.
J Chromatogr A ; 1601: 95-103, 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31208795

RESUMO

Fully automated dried blood spot (DBS) extraction systems, online coupled to standard liquid chromatography-tandem mass spectrometry (LC-MS/MS) configurations, decrease the hands-on time associated with conventional DBS analysis, resulting in a higher sample throughput, making the technique more compatible with a high-capacity bioanalytical workflow. The aim of this study was to develop and validate an LC-MS/MS method, using a DBS-MS 500 autosampler, for the determination and quantification of four anti-epileptic drugs (carbamazepine, valproic acid, phenobarbital and phenytoin) and one active metabolite (carbamazepine-10,11-epoxide) in DBS samples. Method development included thorough optimization of the fully automated extraction procedure (i.e. extraction solvent, extraction (loop) volume, internal standard application, internal standard drying time, etc.). The method was fully validated based on international guidelines. Accuracy (%bias), as well as precision (%RSD) (with a single exception) were below 13%. Neither carry-over nor unacceptable interferences were observed. All compounds were stable in DBS for at least 1 month when stored at room temperature, 4 °C and -20 °C and for at least 4 days when stored at 60 °C. Internal standard-corrected matrix effects were below 8%, with %RSDs below 9.1%. Reproducible relative recovery values (around 60% for all analytes) were obtained and the effect of the hematocrit on the relative recovery was overall limited. Successful application on capillary patient samples originating from developing countries demonstrated the applicability of the developed procedure in a remote setting.


Assuntos
Anticonvulsivantes/análise , Teste em Amostras de Sangue Seco , Monitoramento de Medicamentos/métodos , Anticonvulsivantes/sangue , Automação , Cromatografia Líquida , Teste em Amostras de Sangue Seco/normas , Monitoramento de Medicamentos/instrumentação , Humanos , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem
7.
J Chromatogr A ; 1601: 335-339, 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31155143

RESUMO

Sodium valproate is the most commonly used antiepileptic drug that patients need to keep taking over a long period of time or on a permanent basis. Its blood concentration should be accurately detected to avoid toxicity or side-effects, especially for children and the aged. Dried blood spot (DBS) sampling from finger prick is a minimally invasive and patient-friendly procedure for blood collection. However, there are few studies about rapid detection of sodium valproate in DBS samples in current literatures. In this work, we developed an ink auxiliary headspace gas chromatography mass spectrometry (GC-MS) strategy for direct detection of sodium valproate in DBS from epilepsy patients, which does not need extra solvent extraction or elution. It was discovered that carbon black ink could provide better capacity of heat absorption and dissociation, and higher quality of headspace sampling. The detection sensitivity has been improved with reported headspace GC-MS methods, and the limit of quantitation could reach to 200 ng/mL. Finally, this strategy was practically applied to quantify sodium valproate in DBS samples from 29 epilepsy patients. The result showed higher accuracy with lower relative errors by comparing with the clinical immunoassay results. In conclusion, we developed a direct detection method for DBS samples that is suitable for high-throughput clinical test with great potential for clinical application.


Assuntos
Teste em Amostras de Sangue Seco/métodos , Cromatografia Gasosa-Espectrometria de Massas , Ácido Valproico/análise , Anticonvulsivantes/análise , Anticonvulsivantes/sangue , Criança , Monitoramento de Medicamentos , Humanos , Manejo de Espécimes , Ácido Valproico/sangue
8.
Am J Emerg Med ; 37(8): 1603.e1-1603.e2, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31109780

RESUMO

Lamotrigine [LTG] is primarily an anti-epileptic drug used to treat seizure disorders, depression, and bipolar disease. It is generally well tolerated with limited side effects reported during routine use. Adverse events after overdose include neurotoxicity in the form of sedation and seizure activity, as well as cardiopulmonary toxicity in the form of sodium-channel blockade and cardiovascular collapse. There is no consensus regarding the role of hemodialysis (HD) in management of lamotrigine toxicity. Based on pharmacological properties, LTG is a candidate for extracorporeal removal, however, the successful use of HD for the treatment of this poisoning is not well described. We report the case of a 44 year-old female after a LTG overdose that experienced prolonged sedation that was ultimately treated with HD with an excellent response.


Assuntos
Anticonvulsivantes/envenenamento , Overdose de Drogas/terapia , Lamotrigina/envenenamento , Adulto , Anticonvulsivantes/sangue , Transtorno Bipolar/tratamento farmacológico , Overdose de Drogas/sangue , Feminino , Humanos , Lamotrigina/sangue , Diálise Renal
9.
Environ Health Prev Med ; 24(1): 31, 2019 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-31084599

RESUMO

In Japan, because the most common site of drowning among patients with epilepsy is the bathtub, showering is generally recommended as an alternative to bathing. We herein report a case involving a female patient with epilepsy who drowned while showering. She had been diagnosed with epilepsy approximately 25 years previously, and her condition had progressed to refractory epilepsy. Carbamazepine, levetiracetam, lamotrigine, clobazam, and perampanel were prescribed daily. One day while showering, the patient was found lying with her face immersed in water that had accumulated on the floor of the bathtub. A forensic autopsy revealed water in the stomach, trachea, and proximal regions of both lung bronchi as well as white and red foam on the pharynx and larynx. A total of 1.9 µg/mL of lamotrigine, 0.14 µg/mL of carbamazepine, and 0.069 µg/mL of perampanel were detected in the patient's blood. The patient's cause of death was determined to be drowning due to an epileptic seizure. Although the patient was prescribed five types of antiepileptic medication, only three were detected in her blood. The current case demonstrates that drowning can occur while showering, suggesting that it is unsafe for patients with medication nonadherence. To prevent unintentional deaths in the bathroom, we recommend that patients with epilepsy maintain high adherence to all prescriptions and are supervised by a family member, even when showering. The current case is the first autopsy report of a patient with epilepsy who drowned while showering.


Assuntos
Afogamento/etiologia , Afogamento/patologia , Epilepsia Resistente a Medicamentos/patologia , Adulto , Anticonvulsivantes/sangue , Anticonvulsivantes/uso terapêutico , Autopsia , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Feminino , Humanos , Japão , Adesão à Medicação
10.
J Mass Spectrom ; 54(7): 600-611, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31066158

RESUMO

A fast and simple approach to overcome challenges in emergency toxicological analysis, using ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) has been developed, for the detection of analytes in blood and urine samples from the following drug classes: analgesics, benzodiazepines, antidepressants, anticonvulsants, drugs of abuse, and pesticides. These substances are relevant in the context of emergency toxicology in Brazil. The sample preparation procedure was relatively easy and fast to perform. The method was fully validated giving limits of in the range of 0.5 and 20 ng mL-1 for blood and urine samples. The intraday and interday precision and accuracy were considered adequate for all analytes once the relative standard deviation (RSD) (%) was lower than 20% for quality control (QC) low and lower than 15% for CQ medium and high. The developed method was successfully applied to 320 real samples collected at the Poison Control Center of São Paulo, and 89.1% have shown to be positive for some of the analytes. This confirms its applicability and importance to emergency toxicological analysis, and it could be very useful in both fields of clinical and forensic toxicology.


Assuntos
/sangue , Praguicidas/sangue , Praguicidas/urina , Preparações Farmacêuticas/sangue , Preparações Farmacêuticas/urina , Analgésicos/sangue , Analgésicos/urina , Anticonvulsivantes/sangue , Anticonvulsivantes/urina , Antidepressivos/sangue , Antidepressivos/urina , Benzodiazepinas/sangue , Benzodiazepinas/urina , Brasil , Cromatografia Líquida de Alta Pressão , Humanos , Limite de Detecção , Espectrometria de Massas em Tandem
11.
Anal Bioanal Chem ; 411(15): 3353-3360, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30957206

RESUMO

Lamotrigine is one of the most widely used antiepileptic drugs in the treatment of epilepsy. This kind of drug needs to be used in the long term and should be quantitatively detected in the blood of patients to avoid drug toxicity caused by individual differences and environmental and pathological changes in the process of taking. The detection of antiepileptic drugs in human blood is challenging because of their low contents and the interference of complex matrices. Thus, the sample enrichment method has been commonly used to improve the sensitivity of detection. In this work, we have synthesized a new "bi-(4-vinyl phenylquinoline) amide" compound and used it as the monomer to produce the hyper-cross-linked microporous polymer for the enrichment of lamotrigine. This material has a high adsorption capacity, specificity, and linearity, which can improve the detection sensitivity of lamotrigine by high-performance liquid chromatography (HPLC). The mechanism of this phenomenon has also been investigated. Finally, we have developed the microporous polymer enrichment coupled with HPLC method for the quantitative determination of lamotrigine in rat and human serum samples. This method has excellent precision, accuracy, and recovery, meeting the test of biological sample. The low limit of quantitation was 0.625 µg/mL. Graphical abstract.


Assuntos
Anticonvulsivantes/sangue , Monitoramento de Medicamentos/métodos , Lamotrigina/sangue , Polivinil/química , Quinolinas/química , Microextração em Fase Sólida/métodos , Adsorção , Amidas/química , Animais , Anticonvulsivantes/isolamento & purificação , Cromatografia Líquida de Alta Pressão/métodos , Humanos , Lamotrigina/isolamento & purificação , Limite de Detecção , Masculino , Porosidade , Ratos , Ratos Sprague-Dawley
12.
Int J Pharm ; 564: 329-339, 2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31015006

RESUMO

Despite being one of the most commonly prescribed antiepileptic drugs, levetiracetam is marketed in oral and intravenous dosage forms, which are associated to drug-drug interactions and drug-resistant epilepsy (DRE). The purpose of the present study was to assess the potential of the intranasal route to deliver levetiracetam into the brain, due to the particular anatomical features of the nasal cavity. After development and characterization of the drug formulation, a thermoreversible gel loaded with levetiracetam was administered to CD-1 male mice by intranasal route and its pharmacokinetics compared to those observed after intravenous administration. Similar plasma pharmacokinetic profiles were obtained and the intranasal absolute bioavailability was 107.44%, underscoring that a high drug fraction was systemically absorbed. In brain tissue, maximum drug concentrations were 4.48 and 4.02 µg/g (intranasal vs intravenous) and the mean cerebral concentrations were significantly higher after intranasal administration. The percentage of drug targeting efficiency was 182.35% while direct transport percentage was 46.38%, suggesting that almost 50% of levetiracetam undergoes direct nose-to-brain delivery. Complementarily, an in vivo intranasal repeated dose toxicity study was performed and no relevant histopathological alterations were observed. The herein proposed non-invasive and safe intranasal administration route allowed a direct nose-to-brain delivery of levetiracetam and is a promising strategy for the treatment of DRE.


Assuntos
Anticonvulsivantes/administração & dosagem , Encéfalo/metabolismo , Hidrogéis/administração & dosagem , Levetiracetam/administração & dosagem , Mucosa Nasal/metabolismo , Administração Intranasal , Administração Intravenosa , Animais , Anticonvulsivantes/sangue , Anticonvulsivantes/farmacocinética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Hidrogéis/farmacocinética , Rim/metabolismo , Levetiracetam/sangue , Levetiracetam/farmacocinética , Pulmão/metabolismo , Masculino , Camundongos
13.
Food Chem Toxicol ; 128: 61-67, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30940594

RESUMO

Garcinia cambogia supplements are widely used for weight loss. Knowing that epilepsy patients are at greater risk of developing overweight/obesity, the investigation of herb-drug interactions involving antiepileptic drugs of narrow therapeutic index is fully justified. This work was planned to assess potential pharmacokinetic-based interactions between G. cambogia extract and lamotrigine (LTG) through two independent pharmacokinetic studies. In the first study (co-administration study), rats were orally co-administered with a single-dose of G. cambogia extract (821 mg/kg) and LTG (10 mg/kg). In the second study (pre-treatment study), rats were orally pre-treated for 14 days with G. cambogia extract (821 mg/kg/day), being LTG administered (10 mg/kg) on the 15th day. Rats of the control groups received water instead of the extract. Following LTG administration, blood samples were collected until 96 h post-dose, and plasma LTG concentrations were determined and submitted to a non-compartmental analysis. Globally, no statistically significant effects were identified in the co-administration study of G. cambogia extract and LTG. In the 14-day pre-treatment study, a statistically significant decrease in the rate of systemic exposure to LTG and an increase of apparent volume of distribution were found. Even so, a minor or no clinical impact is expected from the administration of G. cambogia dietary supplements and LTG.


Assuntos
Anticonvulsivantes/farmacocinética , Garcinia cambogia/química , Interações Ervas-Drogas , Lamotrigina/farmacocinética , Extratos Vegetais/farmacologia , Animais , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/sangue , Área Sob a Curva , Peso Corporal/efeitos dos fármacos , Suplementos Nutricionais , Meia-Vida , Lamotrigina/administração & dosagem , Lamotrigina/sangue , Masculino , Extratos Vegetais/administração & dosagem , Ratos Wistar
14.
Drug Test Anal ; 11(7): 1035-1047, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30821115

RESUMO

DP-VPA is a phospholipid prodrug of valproic acid (VPA) that is developed as a potential treatment for epilepsy. To characterize the pharmacokinetics and excretion of DP-VPA, four reliable ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) methods were validated for quantitation of DP-VPA and its metabolite, VPA, in human plasma, urine, and feces. Protein precipitation and solid-phase extraction (SPE) were used for extraction of C16, C18 homologs of DP-VPA and VPA, respectively, from plasma. Urine and fecal homogenate involving the three analytes were efficiently prepared by methanol precipitation. The determinations of C16 DP-VPA, C18 DP-VPA, and VPA were performed using the positive multiple reaction monitoring (MRM) mode and the negative single ion monitoring (SIM) mode, respectively. The analytes were separated using gradient elution on C8 or phenyl column. Satisfactory results pertaining to selectivity, linearity, matrix effect, accuracy and precision, recovery, stability, dilution integrity, carryover, and incurred sample analysis (ISR) were obtained. The calibration ranges in human plasma were as follows: 0.00200-1.00 µg/mL for C16 DP-VPA, 0.0100-5.00 µg/mL for C18 DP-VPA, and 0.0500-20.0 µg/mL for VPA. The linear ranges in urine and fecal homogenate were 0.00500-2.00 µg/mL and 0.00200-0.800 µg/mL for C16 DP-VPA, 0.00500-2.00 µg/mL and 0.0100-4.00 µg/mL for C18 DP-VPA, and 0.200-80.0 µg/mL for VPA, respectively. The intra- and inter-batch coefficients of variation in three matrices ranged from 1.7% to 12.4% while the accuracy values ranged from 85.4% to 111.7%. The developed methods were successfully applied to determine pharmacokinetics of DP-VPA tablet after a single oral dose of 1200 mg in 12 healthy Chinese subjects under fed condition.


Assuntos
Anticonvulsivantes/farmacocinética , Ácido Valproico/análogos & derivados , Ácido Valproico/farmacocinética , Adulto , Anticonvulsivantes/sangue , Anticonvulsivantes/urina , Cromatografia Líquida de Alta Pressão/métodos , Monitoramento de Medicamentos/métodos , Fezes/química , Feminino , Humanos , Limite de Detecção , Masculino , Espectrometria de Massas em Tandem/métodos , Ácido Valproico/sangue , Ácido Valproico/urina , Adulto Jovem
15.
Biopharm Drug Dispos ; 40(5-6): 165-175, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30924154

RESUMO

The metabolism and pharmacokinetics of DSP-0565 [2-(2'-fluoro[1,1'-biphenyl]-2-yl)acetamide], an antiepileptic drug candidate, was investigated in rats, dogs, and humans. In human hepatocytes, [14 C]DSP-0565 was primarily metabolized via amide bond hydrolysis to (2'-fluoro[1,1'-biphenyl]-2-yl)acetic acid (M8), while in rat and dog hepatocytes, it was primarily metabolized via both hydrolysis to M8 and hydroxylation at the benzene ring or the benzyl site to oxidized metabolites. After single oral administration of [14 C]DSP-0565 to rats and dogs, the major radioactivity fraction was recovered in the urine (71-72% of dose) with a much smaller fraction recovered in feces (23-25% of dose). As primary metabolites in their excreta, M8, oxidized metabolites, and glucuronide of DSP-0565 were detected. The contribution of metabolic pathways was estimated from metabolite profiles in their excreta: the major metabolic pathway was oxidation (57-62%) and the next highest was the hydrolysis pathway (23-33%). These results suggest that there are marked species differences in the metabolic pathways of DSP-0565 between humans and animals. Finally, DSP-0565 human oral clearance (CL/F) was predicted using in vitro-in vivo extrapolation (IVIVE) with/without animal scaling factors (SF, in vivo intrinsic clearance/in vitro intrinsic clearance). The SF improved the underestimation of IVIVE (fold error = 0.22), but the prediction was overestimated (fold error = 2.4-3.3). In contrast, the use of SF for hydrolysis pathway was the most accurate for the prediction (fold error = 1.0-1.4). Our findings suggest that understanding of species differences in metabolic pathways between humans and animals is important for predicting human metabolic clearance when using animal SF.


Assuntos
Acetamidas/farmacocinética , Anticonvulsivantes/farmacocinética , Acetamidas/sangue , Acetamidas/urina , Administração Oral , Adolescente , Adulto , Animais , Anticonvulsivantes/sangue , Anticonvulsivantes/urina , Cães , Fezes/química , Feminino , Hepatócitos/metabolismo , Humanos , Hidrólise , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Oxirredução , Ratos Sprague-Dawley , Método Simples-Cego , Especificidade da Espécie , Adulto Jovem
16.
Mater Sci Eng C Mater Biol Appl ; 99: 121-128, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30889656

RESUMO

Developing of cheap, sensitive and stable sensors plays a significant role in pharmaceutical and clinical applications. Considering the effective role of Klonopin (KNP) in the treatment of epilepsy, KNP quantification in its production process for dose adjustments and checking the purity and also after its usage by patents for bioavailability testing and effectiveness assay is vital. In present work, an efficient electrochemical sensor based on poly melamine and multiwalled carbon nanotubes nanocomposite (PMela/CNTs) was constructed which displayed effective electrochemical response toward KNP. Electrochemical impedance spectroscopy (EIS), cyclic voltammetry (CV) and square-wave voltammetry (SWV) experiments were applied for performance evaluation of the PMela/CNTs modified electrode and electrochemical redox behavior of KNP. Distinguish synergetic effect was observed between CNTs and poly melamine in response to KNP electrochemical redox reaction. A linear detection range of 0.05 to 10 µM with the detection limits of 63 nM was achieved for KNP analysis. The practical application of the PMela/CNTs modified electrode revealed satisfactory results for quantification of KNP in biological fluids.


Assuntos
Anticonvulsivantes/análise , Benzodiazepinas/análise , Clonazepam/análise , Técnicas Eletroquímicas , Nanocompostos/química , Nanotubos de Carbono/química , Triazinas/química , Anticonvulsivantes/sangue , Benzodiazepinas/sangue , Clonazepam/sangue , Eletrodos , Humanos , Concentração de Íons de Hidrogênio , Nanotubos de Carbono/ultraestrutura
17.
Seizure ; 67: 18-22, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30852267

RESUMO

PURPOSE: To investigate the correlation between steady-state plasma concentrations of perampanel (PER) with efficacy and tolerability in adult patients with difficult-to-treat epilepsy. METHODS: PER plasma concentrations were assessed at steady-state conditions in 92 adult patients (57% female, 43% male, mean age 39,5 years, age range 20-73 years). All patients had been treated with PER at a stable dose for at least 3 weeks. Clinical efficacy was assessed on the day of measuring the plasma concentrations by a retrospective analysis of the seizure frequency and adverse effects. RESULTS: The mean overall plasma concentration was 323,5 ng/ml (range 19 ng/ml - 2436 ng/ml). The corresponding mean dose was 7,5 mg (range 2 mg - 12 mg). PER dose and plasma concentration showed a close linear correlation. Plasma levels and doses varied widely concerning both efficacy and tolerability of PER. The differences between plasma levels of responders and non-responders were not statistically significant. Therefore a clinically useful general reference range could not be defined. CONCLUSION: Our data do not indicate a reliable therapeutic range for PER plasma concentrations. Individual reference ranges varied widely. Therapeutic drug monitoring (TDM) may still be helpful in certain clinical situations.


Assuntos
Anticonvulsivantes/sangue , Anticonvulsivantes/uso terapêutico , Epilepsia/sangue , Epilepsia/tratamento farmacológico , Piridonas/sangue , Piridonas/uso terapêutico , Adulto , Idoso , Anticonvulsivantes/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Piridonas/efeitos adversos , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
18.
Epilepsy Res ; 152: 1-6, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30852339

RESUMO

BACKGROUND: Body weight (BW) gain may be induced by perampanel (PER) administration, similar to the well-known adverse effects of valproic acid and gabapentin. Intellectual disability (ID) and serum PER concentration may be risk factors of BW gain. PURPOSE: This study investigated how ID and serum PER concentration are associated with PER-induced BW gain. METHODS: Subjects were 76 patients with epilepsy (41 men, aged 16-70 years). All patients were divided by intelligence quotient (IQ) into no ID (IQ ≥ 70, n = 24), mild to moderate ID (70 > IQ ≥35, n = 31), and severe to profound ID (IQ < 35, n = 21) groups. BW was measured before and 2, 4, 6, and 12 months after initiation of PER treatment, and serum PER concentration at 12 months. RESULTS: BW gains in the mild to moderate ID group at 4, 6, and 12 months were significantly (p < 0.05) higher than in the no ID and in the severe to profound ID groups. At 12 months, BW gain was associated with serum PER concentrations in the no ID (p = 0.034) and the mild to moderate ID (p = 0.001) groups but not in the severe to profound ID group. Multiple linear regression analysis found BW gain at 12 months was positively correlated with the mild to moderate ID group (ß = 0.373, p = 0.002) and serum PER concentration (ß = 0.241, p = 0.047). CONCLUSIONS: The mild to moderate ID group gained more BW than the no ID group, suggesting that PER-induced food intake was greater due to weaker behavioral control in the mild to moderate ID group. The present study suggests a linear correlation between serum PER concentration and BW change.


Assuntos
Anticonvulsivantes/sangue , Deficiência Intelectual/sangue , Piridonas/sangue , Ganho de Peso/efeitos dos fármacos , Adolescente , Adulto , Idoso , Epilepsia/sangue , Epilepsia/tratamento farmacológico , Feminino , Seguimentos , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Fatores de Tempo , Adulto Jovem
19.
Epileptic Disord ; 21(1): 48-54, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30782581

RESUMO

Several recent studies have reported potassium sodium-activated channel subfamily T member 1 (KCNT1) mutations in epilepsy patients on quinidine therapy. The efficacy and safety of quinidine for epilepsy treatment, however, remains controversial. We herein report the cases of four patients with KCNT1 mutations treated with quinidine. A reduction in seizures of more than 50% after quinidine treatment was observed in one patient with epilepsy of infancy with migrating focal seizures (EIMFS), whereas two patients with EIMFS and one with focal epilepsy did not achieve apparent seizure reduction. The relationship between quinidine dose and serum quinidine concentration was inconsistent, particularly at high quinidine doses. One patient with EIMFS developed ventricular tachycardia the day after an increase in quinidine dose from 114 to 126 mg/kg/day. The serum trough quinidine concentration and the corrected QT interval (QTc) before arrhythmia onset were 2.4 µg/ml and 420 ms, respectively, and peak serum quinidine concentration after arrhythmia onset was 9.4 µg/ml. Another patient with EIMFS showed aberrant intraventricular conduction with a quinidine dose of 74.5 mg/kg/day and a serum trough concentration of 3.2 µg/ml. Given that serum quinidine levels may elevate sharply after a dose increase, careful monitoring of electrocardiographs and serum concentrations is required. Based on a review of previous reports and our experience with this case, quinidine should be considered as a promising drug for patients with EIMFS harbouring KCNT1 mutations, however, its efficacy remains controversial due to the limited number of cases, and more information on optimal serum concentrations and appropriate titration methods is required.


Assuntos
Anticonvulsivantes/farmacologia , Arritmias Cardíacas/induzido quimicamente , Epilepsias Parciais/tratamento farmacológico , Proteínas do Tecido Nervoso/genética , Canais de Potássio/genética , Quinidina/farmacologia , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/sangue , Criança , Pré-Escolar , Monitoramento de Medicamentos , Eletrocardiografia , Feminino , Humanos , Lactente , Masculino , Quinidina/administração & dosagem , Quinidina/efeitos adversos , Quinidina/sangue
20.
Ther Drug Monit ; 41(3): 331-339, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30688867

RESUMO

BACKGROUND: Therapeutic drug monitoring (TDM) of antiepileptic drugs (AEDs) is commonly performed on plasma or serum. The use of dried plasma spots (DPSs) could represent a useful tool to facilitate sample shipment to reference laboratories. In this article, the authors describe the application of a commercially available UHPLC-MS/MS method for the determination of 9 commonly prescribed AEDs (levetiracetam, lacosamide, topiramate, ethosuximide, lamotrigine, rufinamide, zonisamide, primidone, and oxcarbazepine and its active metabolite 10-OH-monohydroxycarbazepine) to DPS collected on dried sample spot devices (DSSDs). METHOD: Fifty microliters of plasma were spotted on DSSD. After being air-dried at room temperature, they were extracted using an organic extraction solution containing the appropriate deuterated internal standards. The chromatographic separation was performed on a UHPLC reversed-phase C-18 column, and the analytes were quantified using a triple quadrupole mass spectrometer (LC-MS/MS). RESULTS: The assay was linear over the concentration ranges tested with a total runtime of 10.3 minutes. Recovery ranged from 93.7% to 106.8%. Intraday and interday precision for all quality control levels, including lower limit of quantification, ranged from 2.1% to 18.4% and 2.1% to 13.2%. Intraday and interday accuracy biases ranged from -11.7% to 14.3% and -9.2% to 8.0%. The absence of matrix effects was also tested and confirmed. Real samples derived from patients under therapy were also analyzed, and the comparison of results obtained from DSSD with those obtained from plasma showed that the 2 matrices were interchangeable. Stability tests performed on both quality controls, and real samples demonstrated that DSSDs can be easily stored and shipped at room temperature for 15 days. CONCLUSIONS: The application of the LC-MS/MS method allowed the authors to obtain a very specific, sensitive, and rapid (total runtime = 10.3 minutes) quantification of 9 AEDs starting from very low volumes of plasma samples. The main advantage of DPS over wet samples is room temperature storage and shipment, which lowers shipment costs and makes it suitable for routine TDM. Moreover, in comparison with other alternative matrices, DPS allows for the use of the same therapeutic ranges on which routine TDM is based. DPS on DSSD can thus be considered as a useful and cheap tool for the broader application of TDM.


Assuntos
Anticonvulsivantes/sangue , Plasma/química , Calibragem , Cromatografia Líquida de Alta Pressão/métodos , Teste em Amostras de Sangue Seco/métodos , Monitoramento de Medicamentos/métodos , Humanos , Limite de Detecção , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos
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