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1.
Biomed Chromatogr ; 34(1): e4695, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31469425

RESUMO

A novel and robust two-dimensional liquid chromatography with ultraviolet detection method (2D-LC-UV) was developed and validated for high-throughput determination of the concentrations of valproic acid (VPA) in human plasma. This 2D-LC system was composed of a first-dimensional LC column, a second-dimensional LC column and an intermediate transfer column. The sample was directly injected into the 2D-LC system after an easy protein precipitation treatment. After online preconcentration and primary separation by the first-dimensional column, the target was captured by an intermediate column and then transferred to second-dimensional column for analysis. The system transferred the target through "central cutting" mode whereby the drug peak was not subject to interference from the matrix. The analysis cycle time was completed within 7.0 min. Compared with other methods that have been developed, the analysis time was reduced and the operation was much easier without any derivatization. The calibration curve was linear over the 5.90-188.94 µg/ml range for the VPA concentrations. The intra-day and inter-day precisions were <5.6%. The recoveries were in the range from 95.2 to 98.0%. This method appears to be sensitive, precise, rapid and low-cost for the quantification of VPA in serum sample.


Assuntos
Cromatografia Líquida/métodos , Ácido Valproico/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Estabilidade de Medicamentos , Humanos , Limite de Detecção , Modelos Lineares , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Ácido Valproico/química , Ácido Valproico/isolamento & purificação , Adulto Jovem
3.
Eur J Med Chem ; 183: 111650, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31539780

RESUMO

Inspired by the traditional Chinese herbal pair of Polygala tenuifolia-Acori Tatarinowii for treating epilepsy, 33 novel substituted cinnamic α-asaronol esters and analogues were designed by Combination of Traditional Chinese Medicine Molecular Chemistry (CTCMMC) strategy, synthesized and tested systematically not only for anticonvulsant activity in three mouse models but also for LDH inhibitory activity. Thereinto, 68-70 and 75 displayed excellent and broad spectra of anticonvulsant activities with modest ability in preventing neuropathic pain, as well as low neurotoxicity. The protective indices of these four compounds compared favorably with stiripentol, lacosamide, carbamazepine and valproic acid. 68-70 exhibited good LDH1 and LDH5 inhibitory activities with noncompetitive inhibition type, and were more potent than stiripentol. Notably, 70, as a representative agent, was also shown as a moderately positive allosteric modulator at human α1ß2γ2 GABAA receptors (EC50 46.3 ±â€¯7.3 µM). Thus, 68-70 were promising candidates for developing into anti-epileptic drugs, especially for treatment of refractory epilepsies such as Dravet syndrome.


Assuntos
Anisóis/química , Anticonvulsivantes/química , Cinamatos/química , Medicamentos de Ervas Chinesas/química , Ésteres/química , L-Lactato Desidrogenase/antagonistas & inibidores , Polygala/química , Regulação Alostérica , Animais , Anisóis/farmacologia , Anticonvulsivantes/farmacologia , Carbamazepina/química , Carbamazepina/farmacologia , Cinamatos/farmacologia , Dioxolanos/química , Dioxolanos/farmacologia , Desenho de Drogas , Medicamentos de Ervas Chinesas/farmacologia , Ésteres/farmacologia , Humanos , Medicina Tradicional Chinesa , Camundongos , Estrutura Molecular , Neuralgia/prevenção & controle , Receptores de GABA-A/metabolismo , Relação Estrutura-Atividade , Ácido Valproico/química , Ácido Valproico/farmacologia
4.
AAPS PharmSciTech ; 20(3): 135, 2019 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-30830506

RESUMO

Lung cancer patients develop acquired resistance to tyrosine kinase inhibitors including erlotinib (ERL) after few months of primary treatment. Evidently, new chemotherapy strategies to delay or overcome the resistance are urgently needed to improve the clinical outcome in non-small cell lung cancer (NSCLC) patients. In this paper, we have investigated the cytotoxic interaction of ERL and valproic acid (VA) in ERL-resistant NSCLC cells and developed a liquisolid formulation of ERL-VA for improving oral bioavailability of ERL. ERL is weakly basic, biopharmaceutical classification system (BCS) class II drug with extremely poor aqueous solubility while VA is a branched chain fatty acid. Ionic interaction between ERL and VA (1:2 M ratio) resulted in significant enhancement in saturation solubility of ERL at different pH range. Liquisolid formulation of ERL-VA (EVLF) developed using PEG 400 and mesoporous calcium silicate was characterized for solid state and in vitro dissolution in biorelevant dissolution medium (FaSSIF and FeSSIF). Cytotoxicity of ERL was enhanced by 2-5 folds on co-incubation with VA in HCC827/ERL cell line. Flow cytometry analysis using AnnexinV-FITC assay demonstrated that VA and ERL alone have poor apoptotic effect on HCC827/ERL cells while combination showed around 69% apoptotic cells. Western blot analysis confirmed the role of survivin in overcoming resistance. In vivo pharmacokinetic studies of EVLF in rats demonstrated a 199% relative bioavailability compared to ERL suspension. Thus, EVLF could be a promising alternative to current ERL formulations in the treatment of NSCLC.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Sobrevivência Celular/efeitos dos fármacos , Cloridrato de Erlotinib/química , Cloridrato de Erlotinib/farmacologia , Neoplasias Pulmonares/patologia , Ácido Valproico/química , Ácido Valproico/farmacologia , Administração Oral , Animais , Antineoplásicos/farmacocinética , Disponibilidade Biológica , Compostos de Cálcio/química , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Cloridrato de Erlotinib/farmacocinética , Humanos , Neoplasias Pulmonares/metabolismo , Polietilenoglicóis/química , Ratos , Ratos Sprague-Dawley , Silicatos/química , Solubilidade , Ácido Valproico/farmacocinética
5.
Chem Biodivers ; 16(3): e1800497, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30614625

RESUMO

2-Chloro-2'-deoxyadenosine (cladribine, 1) was acylated with valproic acid (2) under various reaction conditions yielding 2-chloro-2'-deoxy-3',5'-O-divalproyladenosine (3) as well as the 3'-O- and 5'-O-monovalproylated derivatives, 2-chloro-2'-deoxy-3'-O-valproyladenosine (4) and 2-chloro-2'-deoxy-5'-O-valproyladenosine (5), as new co-drugs. In addition, 6-azauridine-2',3'-O-(ethyl levulinate) (8) was valproylated at the 5'-OH group (→9). All products were characterized by 1 H- and 13 C-NMR spectroscopy and ESI mass spectrometry. The structure of the by-product 6 (N-cyclohexyl-N-(cyclohexylcarbamoyl)-2-propylpentanamide), formed upon valproylation of cladribine in the presence of N,N-dimethylaminopyridine and dicyclohexylcarbodiimide, was analyzed by X-ray crystallography. Cladribine as well as its valproylated co-drugs were tested upon their cancerostatic/cancerotoxic activity in human astrocytoma/oligodendroglioma GOS-3 cells, in rat malignant neuro ectodermal BT4Ca cells, as well as in phorbol-12-myristate 13-acetate (PMA)-differentiated human THP-1 macrophages. The most important result of these experiments is the finding that only the 3'-O-valproylated derivative 4 exhibits a significant antitumor activity while the 5'-O- as well as the 3',5'-O-divalproylated cladribine derivatives 3 and 5 proved to be inactive.


Assuntos
2-Cloroadenosina/análogos & derivados , Antineoplásicos/farmacologia , Azauridina/farmacologia , Desoxiadenosinas/farmacologia , Ácido Valproico/farmacologia , 2-Cloroadenosina/síntese química , 2-Cloroadenosina/química , 2-Cloroadenosina/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Azauridina/síntese química , Azauridina/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Desoxiadenosinas/síntese química , Desoxiadenosinas/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Interações Hidrofóbicas e Hidrofílicas , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Ácido Valproico/síntese química , Ácido Valproico/química
6.
J Chromatogr Sci ; 57(2): 101-107, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30285097

RESUMO

A specific GC-MS method has been developed, optimized and validated for the determination of five genotoxic impurities namely Methyl bromide (Me.-Br), Ethyl bromide (Et.-Br), Isopropyl bromide (Ipr.-Br), n-Propyl bromide (n-Pr.-Br) and n-Butyl bromide (n-But.-Br) in Divalproex sodium (DPS) drug substance. Chromatographic separation of five genotoxic impurities was achieved on DB-1 column (30 m × 0.32 mm, 3.0 µm), consists of 100% dimethyl polysiloxane as stationary phase and passing helium carrier gas. The mass fragments (m/z) were selected for the quantification of Me.-Br (m/z 94), Et.-Br (m/z 108), Ipr.-Br (m/z 122), n-Pr.-Br (m/z 122) and n-But.-Br (m/z 136). Bromide ion (m/z 79) was the qualifier ion for the analytes [(Me.-Br), (Et.-Br), (Ipr.-Br), (n-Pr.-Br) and (n-But.-Br)]. The performance of the method was assessed by evaluating the specificity, linearity, sensitivity, precision and accuracy experiments. The established limit of detection and limit of quantification values for the genotoxic impurities were in the range of 0.005-0.019 µg mL-1. The correlation coefficient values of the linearity experiment were in the range of 0.9947-0.9983. The average recoveries for the accuracy were in the range of 97.6-111.3%. The results proved that the method is suitable for the determination of Me.-Br, Et.-Br, Ipr.-Br, n-Pr.-Br and n-But.-Br contents in divalproex sodium.


Assuntos
Contaminação de Medicamentos , Cromatografia Gasosa-Espectrometria de Massas/métodos , Mutagênicos/análise , Ácido Valproico/análise , Limite de Detecção , Modelos Lineares , Reprodutibilidade dos Testes , Ácido Valproico/química , Ácido Valproico/normas
7.
Biomed Chromatogr ; 33(3): e4440, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30456910

RESUMO

Valproic acid (VPA) pharmacokinetics is highly variable and monitoring of blood levels is necessary to determine its appropriate dosage. This study aimed to establish and validate a novel derivatization method for the determination of VPA. The method was based on the catalytic effect of tetramethylammonium hydroxide using 2,4'-dibromoacetophenone as a derivatization reagent. After derivatization, samples were injected into the HPLC system for analysis. The method showed a good linearity in the range of 1.0-200.7 µg mL-1 , and the limit of quantification was 1 µg mL-1 . All values of the accuracy and relative standard deviations were acceptable for the analyses of biological samples. The recoveries were in the range from 91.6 to 97.4% for VPA with RSD <3.9%. A novel and high conversion-rate derivatization method has been developed and validated for the determination of VPA in human serum. It can be applied to the analysis of VPA in clinic serum samples.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Compostos de Amônio Quaternário/química , Ácido Valproico/sangue , Humanos , Limite de Detecção , Modelos Lineares , Reprodutibilidade dos Testes , Ácido Valproico/química
8.
Eur J Pharm Biopharm ; 135: 13-24, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30529296

RESUMO

The efficacy of narrow therapeutic index (NTI) drugs is closely related to their plasma concentration-time profile. Particularly for these compounds interindividual variability of gastrointestinal (GI) parameters relevant to in vivo drug release may result in fluctuations of the plasma concentration. The present study focused on assessing the influence of individual GI pH- and transit profiles on drug release of enteric valproate tablet formulations by means of individualized in vitro dissolution experiments. After initial experiments simulating GI passages in average healthy adults, a novel in vitro dissolution model was used to simulate individual GI pH- and transit profiles with physiologically relevant dissolution media. Based on the dissolution profiles obtained in these experiments, individual in silico plasma profiles were generated and compared to fasted in vivo data applying a mean Euclidean distance approach. Simulated individual gastric residence time was identified as crucial parameter determining the onset of absorption, whereas the shape of the plasma profile is mainly influenced by individual valproate pharmacokinetics. The novel in vitro and in silico methods used in this study are promising tools for estimating in vivo drug release and plasma concentration in individual subjects and thus may contribute to a prospective risk assessment for NTI formulations.


Assuntos
Anticonvulsivantes/administração & dosagem , Química Farmacêutica/métodos , Simulação por Computador , Ácido Valproico/administração & dosagem , Administração Oral , Adulto , Anticonvulsivantes/química , Anticonvulsivantes/farmacocinética , Liberação Controlada de Fármacos , Jejum , Trânsito Gastrointestinal , Humanos , Concentração de Íons de Hidrogênio , Medição de Risco/métodos , Comprimidos com Revestimento Entérico , Índice Terapêutico do Medicamento , Ácido Valproico/química , Ácido Valproico/farmacocinética
9.
Pharm Dev Technol ; 24(4): 455-464, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30396305

RESUMO

The objective of the research was to demonstrate the plasticization properties of divalproex sodium, due to its component-valproic acid, on ethyl cellulose, which could prove beneficial for film fabrications or hot melt extrusion based formulations. Films containing 10-50% w/w (DVS/EC) as dry weight were prepared using solvent evaporation method and characterized using texture analyzer, hybrid rheometer, differential scanning calorimetry, thermogravimetry, X-ray diffractometry, polarized microscopy, FTIR, and Raman spectroscopy. It was found that there was a decrease in average peak load, melt viscosity, and glass transition temperature (Tg) while increase in elongation, with increase in concentration of DVS in the films. These results demonstrate the plasticization tendency of DVS on EC, which was attributed to the presence of valproic acid (fatty acid) in DVS. XRD studies showed amorphous nature of the films; however, polarized microscopy revealed the presence of scattered undissolved sodium valproate crystals. The presence of a single Tg established complete miscibility between valproic acid and EC. Films showed reasonable physical stability (similar Tg) at 45 °C/75% RH for 2 weeks (open condition), attributable to the similar solubility parameters of DVS and EC. FTIR and Raman spectroscopy results proved the presence of hydrogen bonding between DVS and EC.


Assuntos
Plastificantes/análise , Plastificantes/química , Análise Espectral Raman/métodos , Ácido Valproico/análise , Ácido Valproico/química , Varredura Diferencial de Calorimetria/métodos , Fenômenos Químicos , Química Farmacêutica/métodos , Reologia/métodos , Espectroscopia de Infravermelho com Transformada de Fourier/métodos
10.
Chem Phys Lipids ; 218: 125-135, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30582895

RESUMO

Lipid bilayers of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) were prepared in two forms, as a suspension of multilamellar spherical vesicles and as planar membranes deposited on a conductive solid support. We used Fourier Transformed Infrared (FTIR) and Raman spectroscopic techniques to study the lipid vesicles while the solid supported bilayers were characterized by using electrochemical experiments (cyclic voltammetry and impedance). Valproic acid (Valp) was either present in the solution or incorporated into the lipid structure. As the Valp:DMPC ratio increases the phase transition temperature decreases while the phase transition becomes less marked. Moreover, for the Valp:DMPC complex species a slight decrease in the number of gauche isomers was observed relative to the number of trans isomers what corresponds to an increase in the packing density of the acylic chains. Based on derived electrical properties of the supported membranes it can be concluded that Valp induces the formation of pores and other defects in the lipid films. Valp incorporated into the membrane is seriously detrimental to the bilayer stability.


Assuntos
Bicamadas Lipídicas/química , Fosfatidiletanolaminas/química , Ácido Valproico/química , Estrutura Molecular , Fosfatidiletanolaminas/síntese química
11.
Drug Des Devel Ther ; 12: 3951-3960, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30510403

RESUMO

Background: Random skin flaps are commonly applied during plastic surgery, but distal flap necrosis limits their clinical applications. Valproic acid (VPA), a histone deacetylase inhibitor and a traditional antiepileptic agent, may promote flap survival. Materials and methods: Sprague-Dawley rats were randomly divided into VPA-treated and control groups. All rats received VPA or saline by intraperitoneal injections once daily for 7 days after the modified McFarlane flap model was established. On postoperative day 7, flap survival, laser Doppler blood flow, and water content were examined for flap viability, hematoxylin and eosin staining (H&E), immunohistochemistry (IHC), and Western blot analysis, and the status of angiogenesis, apoptosis, and oxidative stress were detected in the ischemic flaps. Results: VPA increased the survival area, blood flow, and number of microvessels in skin flaps on postoperative day 7 and reduced edema. VPA promoted angiogenesis by enhancing vascular endothelial growth factor (VEGF) mRNA transcription and upregulating VEGF and cadherin 5 expression, inhibited apoptosis via reduction of caspase 3 cleavage, and relieved oxidative stress by increasing superoxide dismutase (SOD) and glutathione (GSH) levels and reducing the malondialdehyde (MDA) level. Conclusion: VPA promoted random skin flap survival by enhancing angiogenesis and inhibiting oxidative stress and apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Neovascularização Patológica/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Pele/efeitos dos fármacos , Retalhos Cirúrgicos , Ácido Valproico/farmacologia , Animais , Injeções Intraperitoneais , Masculino , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Ratos , Ratos Sprague-Dawley , Pele/metabolismo , Ácido Valproico/administração & dosagem , Ácido Valproico/química
12.
Histochem Cell Biol ; 150(4): 395-401, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30145684

RESUMO

Valproate (VPA), an FDA approved anti-epileptic drug with a half-life of 12-18 h in humans, has been shown to perturb the vacuolar proton pump (vH+-ATPase) function in yeasts by inhibiting myo-inositol phosphate synthase, the first and rate-limiting enzyme in inositol biosynthesis, thereby resulting in inositol depletion. vH+-ATPase transfers protons (H+) across cell membranes, which help maintain pH gradients within cells necessary for various cellular functions including secretion. This proton pump has a membrane (V0) and a soluble cytosolic (V1) domain, with C-subunit associated with V1. In secretory cells such as neurons and insulin-secreting beta cells, vH+-ATPase acidifies vesicles essential for secretion. In this study, we demonstrate that exposure of insulin-secreting Min6 cells to a clinical dose of VPA results in inositol depletion and loss of co-localization of subunit C of vH+-ATPase with insulin-secreting granules. Consequently, a reduction of glucose-stimulated insulin secretion is observed following VPA exposure. These results merit caution and the reassessment of the clinical use of VPA.


Assuntos
Glucose/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Ácido Valproico/farmacologia , Animais , Secreção de Insulina , Camundongos , Células Tumorais Cultivadas , Ácido Valproico/química
13.
Bioorg Med Chem Lett ; 28(12): 2217-2221, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29759727

RESUMO

Addition of the valproic acid (histone deacetylases inhibitor) to a culture of an endophytic fungus Diaporthe sp. harbored from Datura inoxia significantly altered its secondary metabolic profile and resulted in the isolation of three novel compounds, identified as xylarolide A (1), diportharine A (2) and xylarolide B (3) along with one known compound xylarolide (4). The structures of all the compounds (1-4) were determined by detailed analysis of 1D and 2D NMR spectroscopic data. The relative configurations of compounds 1-3 were determined with the help of NOESY data and comparison of optical rotations with similar compounds with established stereochemistry. All the isolated compounds were screened for antibacterial, antioxidant and cytotoxic activities. Xylarolide A (1) and xylarolide (4) displayed significant growth inhibition of MIAPaCa-2 with an IC50 of 20 and 32 µM respectively and against PC-3 with an IC50 of 14 and 18 µM respectively. Moreover, compound 1 displayed significant DPPH scavenging activity with EC50 of 10.3 µM using ascorbic acid as a positive control.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Ascomicetos/química , Datura/microbiologia , Peptídeos Cíclicos/farmacologia , Ácido Valproico/farmacologia , Antibacterianos/química , Antibacterianos/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Ascomicetos/crescimento & desenvolvimento , Ascomicetos/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Datura/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Escherichia coli/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Conformação Molecular , Peptídeos Cíclicos/química , Peptídeos Cíclicos/metabolismo , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade , Ácido Valproico/química
14.
Dalton Trans ; 47(16): 5714-5724, 2018 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-29632937

RESUMO

The [Os(η6-pcym)(dpa)(VP)]PF6 (1-VP) complex contains the histone deacetylase (HDAC) inhibitor valproate (2-propylpentanoate; VP) as a monodentate O-donor ligand and shows ca. 3-fold higher in vitro cytotoxicity against A2780 human ovarian carcinoma cells than its chlorido analogue [Os(η6-pcym)(dpa)Cl]PF6 (1-Cl); pcym = 1-methyl-4-(propan-2-yl)benzene (p-cymene), dpa = 2,2'-dipyridylamine. The complex 1-VP showed promising selectivity towards the A2780 ovarian carcinoma cell line (IC50 = 20.9 µM) over normal human hepatocytes (IC50 > 200.0 µM). Moreover, the complex 1-VP was found to be inactive against MCF-7 (breast adenocarcinoma), PANC-1 (pancreatic adenocarcinoma) and HT-29 (colon carcinoma) up to a concentration of 100 µM. Detailed flow cytometry studies indicated that treatment of A2780 cells with complex 1-VP led to induction of apoptosis, production of reactive oxygen species (ROS) and superoxide (SO) anion radicals, as well as mitochondrial membrane potential depletion and cell cycle perturbations. The microscopic assessment (standard hematoxylin/eosin staining) revealed signs of morphological changes associated with the progression of apoptosis in A2780 cells treated with the IC50 concentration of the complex 1-VP. Consistent with the intracellular production of ROS and SO, the complex 1-VP induced hydroxyl radical formation, as proved by EPR spin trapping experiments. This case study suggests that replacement of the chlorido ligand of half-sandwich Os(ii) complexes by a releasable monodentate biologically active ligand (e.g., VP used in this study) is an effective strategy for the development of novel non-platinum cytotoxic agents.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Osmio/química , 2,2'-Dipiridil/análogos & derivados , 2,2'-Dipiridil/química , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Humanos , Concentração Inibidora 50 , Membranas Mitocondriais/efeitos dos fármacos , Monoterpenos/química , Espécies Reativas de Oxigênio/metabolismo , Superóxidos/metabolismo , Ácido Valproico/análogos & derivados , Ácido Valproico/química
15.
Pharmazie ; 73(2): 76-79, 2018 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-29442008

RESUMO

Orfiril® long is a widely used antiepileptic drug preparation despite being characterized by features associated with susceptibility to ethanol induced changes to drug release. In vitro dissolution studies revealed that 30 % ethanol was required in order to cause dose dumping of valproic acid within two hours at pH 1. However, after exposure to only 5 % of ethanol for 45 minutes at pH 1, the subsequent release of sodium valproate increased by ~ 10 % for the first two hours in ethanol-free media of pH 6.8. The drug solubility increases with pH, likely to also increase the vulnerability to ethanol. This indicates that Orfiril® long is affected by exposure to low concentrations of ethanol as well, only that this effect was exclusively displayed at an elevated pH value not part of the standard regulatory recommendations. Even so, simplified pharmacokinetic simulations revealed no risk of a lower therapeutic effect. Postponing the drug intake in case of moderate drinking, likely to increase the risk of omission altogether, is therefore not necessary. However, for slim patients with a small volume of distribution and low tolerability, a longer duration of mild side effects such as drowsiness and nausea might be experienced.


Assuntos
Anticonvulsivantes/química , Depressores do Sistema Nervoso Central/química , Etanol/química , Ácido Valproico/química , Consumo de Bebidas Alcoólicas , Anticonvulsivantes/farmacocinética , Depressores do Sistema Nervoso Central/farmacologia , Simulação por Computador , Interações de Medicamentos , Liberação Controlada de Fármacos , Etanol/farmacologia , Humanos , Concentração de Íons de Hidrogênio , Solubilidade , Ácido Valproico/farmacocinética
16.
Leg Med (Tokyo) ; 31: 66-73, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29413992

RESUMO

A new high-throughput method was developed for analysis of valproate in human plasma samples by QuEChERS extraction and gas chromatography-tandem mass spectrometry (GC-MS/MS). Plasma samples (0.2 ml) spiked with valproate and secobarbital-d5 (internal standard) were diluted with 1.3 ml of distilled water. Acetonitrile (1 ml) was added followed by 0.4 g MgSO4 and 0.1 g NaOAC. After a centrifugation step (2000 g for 10 min), 1 ml of the supernatant was transferred to a dispersive-solid phase extraction (dSPE) tube containing 150 mg MgSO4 and 50 mg C18. This mixture was vortexed and centrifuged at 3000 g for 5 min, and then the upper layer was evaporated to dryness under a stream of nitrogen. The residue was dissolved in 40 µl ethyl acetate, and a 1-µl aliquot was injected into the GC-MS/MS. The GC separation of the compounds was achieved on a fused-silica capillary column Rxi-5Sil MS (30 m × 0.25 mm i.d.; 0.25-µm film thickness) and detected by MS/MS operating in electron ionization ion source mode. The regression equations showed excellent linearity (r > 0.9997) from 50 to 5000 ng/ml for plasma, with limit of detection of 10 ng/ml. The extraction efficiency of valproate for plasma ranged between 71.2%-103.5%. The coefficient of variation was <18.5%. The method was successfully applied to actual analyses of an autopsy case. This method can be useful for simple and reliable measurements of valproate in clinical and toxicological analyses; it can be integrated in screening and simultaneous determination methods for multiple drugs and poisons in the further studies.


Assuntos
Anticonvulsivantes/sangue , Cromatografia Gasosa-Espectrometria de Massas/métodos , Espectrometria de Massas em Tandem/métodos , Ácido Valproico/sangue , Adulto , Anticonvulsivantes/química , Feminino , Patologia Legal , Humanos , Secobarbital/sangue , Secobarbital/química , Ácido Valproico/química
17.
Epilepsy Res ; 139: 171-179, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29371041

RESUMO

Valproic acid (VPA) is an antiepileptic drug (AED) that has the broadest spectrum across all types of seizures and epileptic syndromes. Unfortunately, approximately 30% of epileptic patients are refractory to the classical AED. Metal ions have been frequently incorporated into pharmaceuticals for therapeutic or diagnostic purposes and research. In this preliminary study, we assess the embryo toxicity and the anticonvulsant activity of 4 novel metallodrugs, with Zn+2 and Cu+2, a derivative of valproic acid and the N-donor ligand in an adult zebrafish epileptic seizure model induced by pentylenetetrazole. The most toxic complex was [Cu(Valp)2Bipy], in which the LC50 was 0.22 µM at 48 h post fertilization (HPF) and 0.12 µM at 96 HPF, followed by [Zn(Valp)2Bipy] (LC50 = 10 µM). These same metallodrugs ([Cu(Valp)2Bipy] 10 mM/kg and [Zn(Valp)2Bipy] 30 mM and 100 mM/kg) displayed superior activity, thus reducing the seizure intensity by approximately 20 times compared to sodium valproate (175 mM/kg). Overall, [Cu(Valp)2Bipy] showed the best anticonvulsant effects. However, because of the toxicity of copper, [Zn(Valp)2Bipy] is considered the most promising anticonvulsant for future studies.


Assuntos
Anticonvulsivantes/farmacologia , Cobre/farmacologia , Teratogênios/farmacologia , Ácido Valproico/farmacologia , Compostos de Zinco/farmacologia , Animais , Anticonvulsivantes/química , Anticonvulsivantes/toxicidade , Cobre/química , Cobre/toxicidade , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/patologia , Epilepsia/tratamento farmacológico , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Compostos Organometálicos/toxicidade , Pentilenotetrazol , Dados Preliminares , Convulsões/tratamento farmacológico , Teratogênios/química , Teratogênios/toxicidade , Ácido Valproico/química , Ácido Valproico/toxicidade , Peixe-Zebra , Compostos de Zinco/química , Compostos de Zinco/toxicidade
18.
Artigo em Inglês | MEDLINE | ID: mdl-29158280

RESUMO

Bacteriophage therapy is a promising alternative treatment to antibiotics, as it has been documented to be efficacious against multidrug-resistant bacteria with minimal side effects. Several groups have demonstrated the efficacy of phage suspension in vivo to treat lung infections using intranasal delivery; however, phage dry-powder administration to the lungs has not yet been explored. Powder formulations provide potential advantages over a liquid formulation, including easy storage, transport, and administration. The purpose of this study was to assess the bactericidal activities of phage dry-powder formulations against multidrug-resistant (MDR) strain Pseudomonas aeruginosa FADDI-PA001 in a mouse lung infection model. Phage PEV20 spray dried with lactose and leucine produced an inhalable powder at a concentration of 2 × 107 PFU/mg. P. aeruginosa lung infection was established by intratracheal administration of the bacterial suspension to neutropenic mice. At 2 h after the bacterial challenge, the infected mice were treated with 2 mg of the phage powder using a dry-powder insufflator. At 24 h after the phage treatment, the bacterial load in the lungs was decreased by 5.3 log10 (P < 0.0005) in the phage-treated group compared with that in the nontreated group. Additionally, the phage concentration in the lungs was increased by 1 log10 at 24 h in the treated group. These results demonstrate the feasibility of a pulmonary delivery of phage PEV20 dry-powder formulation for the treatment of lung infection caused by antibiotic-resistant P. aeruginosa.


Assuntos
Antibacterianos/farmacologia , Bacteriófagos/química , Pós/farmacologia , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/efeitos dos fármacos , Ácido Valproico/análogos & derivados , Células A549 , Administração por Inalação , Animais , Carga Bacteriana/efeitos dos fármacos , Modelos Animais de Doenças , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Inaladores de Pó Seco/métodos , Células HEK293 , Humanos , Pulmão/microbiologia , Camundongos , Tamanho da Partícula , Terapia por Fagos/métodos , Infecções por Pseudomonas/microbiologia , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/microbiologia , Ácido Valproico/química
19.
Zh Nevrol Psikhiatr Im S S Korsakova ; 117(11): 129-134, 2017.
Artigo em Russo | MEDLINE | ID: mdl-29265098

RESUMO

The article summarizes domestic and international studies on the development and clinical investigation of valproates including multiple studies of a research team directed by the author. Valproate targets are considered in biological and clinical aspects. A spectrum of action and advantages of the brand drug (depakine) compared to generics and other antiepileptic drugs are discussed. A number of recommendations for practitioners about using valproates are proposed.


Assuntos
Anticonvulsivantes , Epilepsia/tratamento farmacológico , GABAérgicos , Ácido Valproico , Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Medicamentos Genéricos , GABAérgicos/química , GABAérgicos/farmacologia , GABAérgicos/uso terapêutico , Humanos , Federação Russa , Ácido Valproico/química , Ácido Valproico/farmacologia , Ácido Valproico/uso terapêutico
20.
J Chromatogr Sci ; 55(9): 891-898, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-29048489

RESUMO

A specific GC method has been developed, optimized and validated for the determination of seven related substances namely N,N-dimethyl valpronamide, valeric acid, 2-methyl valeric acid, 2-ethyl valeric acid, 2-isopropyl valeric acid, 2-n-butyl valeric acid and 2-propyl-2-pentenoic acid in divalproex sodium (DPS) drug substance. Chromatographic separations of these seven impurities were achieved on DB-FFAP column (30 m × 0.53 mm, 1.0 µm), which consists nitroterephthalic acid modified polyethylene glycol material as stationary phase. DPS is a coordination complex of the sodium valproate and valproic acid (VPA). Nonanoic acid is used as internal standard. All the seven related substances, VPA and nonanoic acid were extracted into dichloromethane and monitored by GC with flame ionization detector. The performance of the developed method was assessed by evaluating specificity, linearity, sensitivity, precision, accuracy and robustness. Forced degradation experiments were conducted to evaluate the degradation behavior of DPS. The established limits of detection (LODs) and limits of quantification (LOQs) values for the related substances were in the ranges of 4-5 and 12-15 µg mL-1, respectively. Further, for VPA, LOD and LOQ values were 4 and 12 µg mL-1, respectively. The correction factors of these related substances with respect to VPA and lie between 0.92 and 1.44. The average recoveries were in the range of 92.4-108.4%.


Assuntos
Cromatografia Gasosa/métodos , Ácido Valproico , Limite de Detecção , Modelos Lineares , Ácidos Pentanoicos/análise , Ácidos Pentanoicos/química , Reprodutibilidade dos Testes , Ácido Valproico/análogos & derivados , Ácido Valproico/análise , Ácido Valproico/química
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