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1.
Pain ; 158(5): 856-867, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28106668

RESUMO

The melastatin-related transient receptor potential (TRP) channel TRPM3 is a nonselective cation channel expressed in nociceptive neurons and activated by heat. Because TRPM3-deficient mice show inflammatory thermal hyperalgesia, pharmacological inhibition of TRPM3 may exert antinociceptive properties. Fluorometric Ca influx assays and a compound library containing approved or clinically tested drugs were used to identify TRPM3 inhibitors. Biophysical properties of channel inhibition were assessed using electrophysiological methods. The nonsteroidal anti-inflammatory drug diclofenac, the tetracyclic antidepressant maprotiline, and the anticonvulsant primidone were identified as highly efficient TRPM3 blockers with half-maximal inhibition at 0.6 to 6 µM and marked specificity for TRPM3. Most prominently, primidone was biologically active to suppress TRPM3 activation by pregnenolone sulfate (PregS) and heat at concentrations markedly lower than plasma concentrations commonly used in antiepileptic therapy. Primidone blocked PregS-induced Cai influx through TRPM3 by allosteric modulation and reversibly inhibited atypical inwardly rectifying TRPM3 currents induced by coapplication of PregS and clotrimazole. In vivo, analgesic effects of low doses of primidone were demonstrated in mice, applying PregS- and heat-induced pain models, including inflammatory hyperalgesia. Thus, applying the approved drug at concentrations that are lower than those needed to induce anticonvulsive effects offers a shortcut for studying physiological and pathophysiological roles of TRPM3 in vivo.


Assuntos
Analgésicos/uso terapêutico , Hiperalgesia/tratamento farmacológico , Dor/fisiopatologia , Pregnenolona/toxicidade , Primidona/uso terapêutico , Canais de Cátion TRPM/metabolismo , Inibidores da Captação Adrenérgica/farmacologia , Inibidores da Captação Adrenérgica/uso terapêutico , Analgésicos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Cálcio/metabolismo , Diclofenaco/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Gânglios Espinais/citologia , Células HEK293 , Humanos , Hiperalgesia/etiologia , Masculino , Maprotilina/farmacologia , Maprotilina/uso terapêutico , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Dor/induzido quimicamente , Limiar da Dor/efeitos dos fármacos , Técnicas de Patch-Clamp , Primidona/química , Primidona/farmacologia , Ratos
2.
J Biomol Struct Dyn ; 33(4): 911-23, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-24712318

RESUMO

Primidone (Mysoline), with the chemical formula 5-ethyl-5-phenyl-hexahydropyrimidine- 4,6-dione (C12H14N2O2), has been a valuable drug in the treatment of epilepsy. In the present work, the experimental IR and Raman spectra of solid phase primidone were recorded, and the results were compared with theoretical wavenumber values of monomer and dimer forms of the title molecule. Vibrational spectral simulations in the dimer form were carried out to improve the assignment of the bands in the solid phase experimental spectra. The possible stable conformers of free molecule were searched by means of torsion potential energy surfaces scan studies through two dihedral angles. The molecular geometries of the monomer and dimer forms of title molecule were optimized using DFT method at B3LYP/6-31++G(d,p) level of theory. Using PEDs determined the contributions of internal (stretching, bending, etc.) coordinates to each normal mode of vibration. Further, HOMO-LUMO energy gap and NBO properties of the investigated molecule in monomer and dimer forms were also calculated.


Assuntos
Anticonvulsivantes/química , Primidona/química , Ligação de Hidrogênio , Modelos Químicos , Modelos Moleculares , Conformação Molecular , Teoria Quântica , Espectroscopia de Infravermelho com Transformada de Fourier , Análise Espectral Raman , Termodinâmica
3.
J Hazard Mater ; 282: 216-23, 2015 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-24798495

RESUMO

The photochemical degradation of five pharmaceuticals was examined in two secondary wastewater effluents. The compounds, which included atenolol, carbamazepine, meprobamate, phenytoin and primidone, were evaluated for both direct and sensitized photolysis. In the two wastewaters, direct photolysis did not lead to significant compound degradation; however, sensitized photolysis was an important removal pathway for the five pharmaceuticals. Upon solar irradiation, hydroxyl radical (HO) was quantified using the hydroxylation of benzene and singlet oxygen ((1)O2) formation was monitored following the degradation of furfuryl alcohol. Degradation via sensitized photolysis was observed following five-day exposures for atenolol (69-91%), carbamazepine (67-98%), meprobamate (16-52%), phenytoin (44-85%), and primidone (34-88%). Varying removal is likely a result of the differences in reactivity with transient oxidants. Averaged steady state HO concentrations ranged from 1.2 to 4.0×10(-16)M, whereas the concentrations of (1)O2 were 6.0-7.6×10(-14)M. Partial removal due to presence of HO indicates it was not the major sink for most compounds examined. Other transient oxidants, such as (1)O2 and triplet state effluent organic matter, are likely to play important roles in fates of these compounds.


Assuntos
Radical Hidroxila/química , Luz Solar , Poluentes Químicos da Água/química , Poluentes Químicos da Água/efeitos da radiação , Atenolol/química , Carbamazepina/química , Meprobamato/química , Oxidantes/química , Fenitoína/química , Fotólise , Primidona/química , Oxigênio Singlete/química , Eliminação de Resíduos Líquidos/métodos , Águas Residuárias/química
4.
Spectrochim Acta A Mol Biomol Spectrosc ; 109: 282-97, 2013 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-23542519

RESUMO

The solid phase FTIR and FT-Raman spectra of primidone were recorded in the regions 4000-400 cm(-1) and 4000-100 cm(-1), respectively. The vibrational spectra were analysed and the observed fundamentals were assigned and analysed. The experimental wavenumbers were compared with the theoretical scaled vibrational wavenumbers determined by DFT methods. The Raman intensities were also determined with B3LYP/6-31G(d,p) method. The total electron density and molecular electrostatic potential surface of the molecule were constructed by using B3LYP/6-311++G(d,p) method to display electrostatic potential (electron+nuclei) distribution. The HOMO and LUMO energies were measured. Natural bond orbital analysis of primidone has been performed to indicate the presence of intramolecular charge transfer. The (1)H and (13)C NMR spectra were recorded and the chemical shifts of the molecule were calculated.


Assuntos
Anticonvulsivantes/química , Primidona/química , Ligação de Hidrogênio , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Teoria Quântica , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , Análise Espectral Raman
5.
Epilepsia ; 53 Suppl 8: 3-11, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23205958

RESUMO

Phenobarbital has been in clinical use as an antiepileptic drug (AED) since 1912. The initial clinical success of phenobarbital and other barbiturates affected the design of subsequent AEDs (e.g., phenytoin, primidone, ethosuximide), developed between 1938 and 1962, the chemical structures of which resemble that of phenobarbital. However, the empirical discovery of carbamazepine (1962) and the serendipitous discovery of valproic acid (1967) led to subsequent AEDs having chemical structures that are diverse and completely different from that of phenobarbital. Sixteen AEDs were introduced between 1990 and 2012. Most of these AEDs were developed empirically, using mechanism-unbiased anticonvulsant animal models. The empirical nature of the discovery of these AEDs, coupled with their multiple mechanisms of action, explains their diverse chemical structures. The antiepileptic market is therefore crowded. Future design of new AEDs must have a potential for treating nonepileptic central nervous system (CNS) disorders (e.g., bipolar disorder, neuropathic pain, migraine prophylaxis, or restless legs syndrome). The barbiturates were once used as sedative-hypnotic drugs, but have been largely replaced in this role by the much safer benzodiazepines. In contrast, phenobarbital is still used worldwide in epilepsy. Nevertheless, the development of nonsedating phenobarbital derivatives will answer a clinical unmet need and might make this old AED more attractive.


Assuntos
Anticonvulsivantes/química , Descoberta de Drogas/história , Fenobarbital/química , Anticonvulsivantes/história , Carbamazepina/química , Carbamazepina/história , Descoberta de Drogas/métodos , Epilepsia/tratamento farmacológico , Epilepsia/história , Etossuximida/química , Etossuximida/história , História do Século XX , Humanos , Mefenitoína/química , Mefenitoína/história , Mefobarbital/química , Mefobarbital/história , Fenobarbital/análogos & derivados , Fenobarbital/história , Fenitoína/análogos & derivados , Fenitoína/química , Fenitoína/história , Primidona/química , Primidona/história , Relação Estrutura-Atividade , Succinimidas/química , Succinimidas/história , Ácido Valproico/química , Ácido Valproico/história
6.
Water Res ; 46(18): 6059-68, 2012 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-23014565

RESUMO

Pilot scale experiments using an 8 g/h ozonation unit and a 1.4 m(2) slow sand filter have demonstrated that the combination of ozonation and artificial groundwater recharge is suitable for efficient reduction of bulk and trace organics. The biodegradation of dissolved organic carbon (DOC) in the slow sand filter was enhanced from 22% without pre-treatment to 34% by pre-ozonation. In addition, realistic surface water concentrations of most investigated trace organic compounds (TrOCs) including carbamazepine, sulfamethoxazole, phenazone and metoprolol were reduced below the limits of quantification. Only a few TrOCs, e.g. primidone and benzotriazole, were not efficiently removed in both treatment steps and could be detected regularly in the filter effluent. For these compounds, enhanced treatment, such as advanced oxidation processes, needs to be considered. Testing for genotoxicity and cytotoxicity did not reveal any systematic adverse effects for human health. The formation of the by-product bromate from bromide was below the limit of the German drinking water directive of 10 µg/L. No removal of bromate was observed in the aerobic slow sand filter. Additional experiments with sand columns showed that operating a preceding bank filtration step to reduce DOC can reduce oxidant demand by approximately 20%.


Assuntos
Carbono/química , Água Subterrânea/química , Compostos Orgânicos/química , Ozônio/química , Poluentes Químicos da Água/química , Purificação da Água/métodos , Antipirina/química , Carbamazepina/química , Filtração , Metoprolol/química , Primidona/química , Sulfametoxazol/química , Triazóis/química , Eliminação de Resíduos Líquidos/métodos
7.
J Phys Chem B ; 116(14): 4370-6, 2012 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-22420638

RESUMO

Understanding the dendrimer-drug interaction is of great importance to design and optimize the dendrimer-based drug delivery system. Using atomistic molecular dynamics (MD) simulations, we have analyzed the release pattern of four ligands (two soluble drugs, namely, salicylic acid (Sal), L-alanine (Ala), and two insoluble drugs, namely, phenylbutazone (Pbz) and primidone (Prim)), which were initially encapsulated inside the ethylenediamine (EDA) cored polyamidoamine (PAMAM) dendrimer using the docking method. We have computed the potential of mean force (PMF) variation with generation 5 (G5)-PAMAM dendrimer complexed with drug molecules using umbrella sampling. From our calculated PMF values, we observe that soluble drugs (Sal and Ala) have lower energy barriers than insoluble drugs (Pbz and Prim). The order of ease of release pattern for these drugs from G5 protonated PAMAM dendrimer was found to be Ala > Sal > Prim > Pbz. In the case of insoluble drugs (Prim and Pbz), because of larger size, we observe much nonpolar contribution, and thus, their larger energy barriers can be reasoned to van der Waals contribution. From the hydrogen bonding analysis of the four PAMAM-drug complexes under study, we found intermolecular hydrogen bonding to show less significant contribution to the free energy barrier. Another interesting feature appears while calculating the PMF profile of G5NP (nonprotonated)-PAMAM-Pbz and G5NP (nonprotonated)-PAMAM-Sal complex. The PMF was found to be less when the drug is bound to nonprotonated dendrimer compared to the protonated dendrimer. Our results suggest that encapsulation of the drug molecule into the host PAMAM dendrimer should be carried out at higher pH values (near pH 10). When such complex enters the human body, the pH is around 7.4 and at that physiological pH, the dendrimer holds the drug tightly. Hence the release of drug can occur at a controlled rate into the bloodstream. Thus, our findings provide a microscopic picture of the encapsulation and controlled release of drugs in the case of dendrimer-based host-guest systems.


Assuntos
Dendrímeros/química , Preparações Farmacêuticas/sangue , Alanina/sangue , Etilenodiaminas/química , Humanos , Ligação de Hidrogênio , Concentração de Íons de Hidrogênio , Simulação de Dinâmica Molecular , Fenilbutazona/sangue , Fenilbutazona/química , Primidona/sangue , Primidona/química , Ácido Salicílico/sangue , Ácido Salicílico/química
8.
J Sep Sci ; 35(3): 359-66, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22258806

RESUMO

A method for the simultaneous determination of the antiepileptic drugs, phenobarbital (PHB), phenytoin (PTN), carbamazepine (CBZ), primidone (PRM) and oxcarbazepine (OXC) in human plasma and urine samples by using micro-extraction in a packed syringe as the sample preparation method connected with LC/UV (MEPS/LC/UV) is described. Micro-extraction in a packed syringe (MEPS) is a new miniaturized, solid-phase extraction technique that can be connected online to gas or liquid chromatography without any modifications. In MEPS approximately 1 mg of the solid packing material is inserted into a syringe (100-250 µL) as a plug. Sample preparation takes place on the packed bed. The bed can be coated to provide selective and suitable sampling conditions. The new method is very promising, easy to use, fully automated, inexpensive and quick. The standard curves were obtained within the concentration range 1-500 ng/mL in both plasma and urine samples. The results showed high correlation coefficients (R(2) >0.988) for all of the analytes within the calibration range. The extraction recovery was found to be between 88.56 and 99.38%. The limit of quantification was found to be between 0.132 and 1.956 ng/mL. The precision (RSD) values of quality control samples (QC) had a maximum deviation of 4.9%. A comparison of the detection limits with similar methods indicates high sensitivity of the present method. The method is applied for the analysis of these drugs in real urine and plasma samples of epileptic patients.


Assuntos
Anticonvulsivantes/sangue , Anticonvulsivantes/urina , Extração em Fase Sólida/métodos , Anticonvulsivantes/química , Carbamazepina/análogos & derivados , Carbamazepina/sangue , Carbamazepina/química , Carbamazepina/urina , Cromatografia Líquida , Humanos , Oxcarbazepina , Fenobarbital/sangue , Fenobarbital/química , Fenobarbital/urina , Fenitoína/sangue , Fenitoína/química , Fenitoína/urina , Primidona/sangue , Primidona/química , Primidona/urina , Proibitinas , Sensibilidade e Especificidade , Extração em Fase Sólida/instrumentação , Espectrofotometria Ultravioleta
9.
Sci Total Environ ; 409(6): 1087-94, 2011 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-21211820

RESUMO

The attenuation of a diverse suite of contaminants of emerging concern (CECs) and bulk water quality changes was evaluated at a surface-spreading aquifer recharge operation across a detailed subsurface profile (9 locations), representing both short- and long-travel times (10 h to 60 days). Seventeen CECs were detected in the recharge basin and the concentrations of all were reduced during soil aquifer treatment (SAT), with 11 of the target compounds attenuated by >80% after 60 days of travel time. Select CECs (atenolol, gemfibrozil, N,N-diethly-3-methylbenzamide, meprobamate, tris(2-chloroethyl)phosphate, and primidone) and bulk water organic-carbon measurements (total organic carbon, biodegradable organic carbon, size-exclusion chromatography and fluorescence excitation-emission matrices) were identified as monitoring parameters that can be used to assess SAT performance at surface-spreading operations.


Assuntos
Água Doce/química , Poluentes Químicos da Água/análise , Atenolol/análise , Atenolol/química , Monitoramento Ambiental/instrumentação , Monitoramento Ambiental/métodos , Genfibrozila/análise , Genfibrozila/química , Meprobamato/análise , Meprobamato/química , Primidona/análise , Primidona/química , Ciclo Hidrológico , Movimentos da Água , Poluentes Químicos da Água/química , Abastecimento de Água/análise
10.
AAPS PharmSciTech ; 3(3): E23, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12916938

RESUMO

Prediction of multicomponent adsorption is still one of the most challenging problems in the adsorption field. Many models have been proposed and employed to obtain multicomponent isotherms from single-component equilibrium data. However, most of these models were based on either unrealistic assumptions or on empirical equations with no apparent definition. The purpose of this investigation was to develop a multicomponent adsorption model based on a thermodynamically consistent equation, and to validate that model using experimental data. Three barbiturates--phenobarbital, mephobarbital, and primidone--were combined to form a ternary system. The adsorption of these barbiturates from simulated intestinal fluid (without pancreatin) by activated carbon was studied using the rotating bottle method. The concentrations, both before and after the attainment of equilibrium, were determined with a high-performance liquid chromatography system employing a reversed-phase column. The proposed equation and the competitive Langmuir-like equation were both fit to the data. A very good correlation was obtained between the experimental data and the calculated data using the proposed equation. The results obtained from the original competitive Langmuir-like model were less satisfactory. These results suggest that the proposed equation can successfully predict the trisolute isotherms of the barbituric acid derivatives employed in this study.


Assuntos
Carvão Vegetal/farmacocinética , Mefobarbital/farmacocinética , Modelos Químicos , Fenobarbital/farmacocinética , Primidona/farmacocinética , Adsorção , Líquidos Corporais/química , Carvão Vegetal/química , Cromatografia Líquida de Alta Pressão/métodos , Conteúdo Gastrointestinal/química , Mefobarbital/química , Pancreatina/química , Fenobarbital/química , Valor Preditivo dos Testes , Primidona/química , Soluções , Termodinâmica
11.
AAPS PharmSciTech ; 1(3): E25, 2000 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-14727911

RESUMO

The adsorption of 3 barbiturates--phenobarbital, mephobarbital, and primidone--from simulated intestinal fluid (SIF), without pancreatin, by activated carbon was studied using the rotating bottle method. The concentrations of each drug remaining in solution at equilibrium were determined with the aid of a high-performance liquid chromatography (HPLC) system employing a reversed-phase column. The competitive Langmuir-like model, the modified competitive Langmuir-like model, and the LeVan-Vermeulen model were each fit to the data. Excellent agreement was obtained between the experimental and predicted data using the modified competitive Langmuir-like model and the LeVan-Vermeulen model. The agreement obtained from the original competitive Langmuir-like model was less satisfactory. These observations are not surprising because the competitive Langmuir-like model assumes that the capacities of the adsorbates are equal, while the other 2 models take into account the differences in the capacities of the components. The results of these studies indicate that the adsorbates employed are competing for the same binding sites on the activated carbon surface. The results also demonstrate that it is possible to accurately predict multicomponent adsorption isotherms using only single-solute isotherm parameters. Such prediction is likely to be useful for improving in vivo/in vitro correlations.


Assuntos
Adsorção , Carvão Vegetal/química , Soluções/química , Área Sob a Curva , Líquidos Corporais/química , Conteúdo Gastrointestinal/química , Mefobarbital/química , Modelos Químicos , Estrutura Molecular , Fenobarbital/química , Valor Preditivo dos Testes , Primidona/química , Propriedades de Superfície
12.
Int J Pharm ; 193(1): 107-11, 1999 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-10581427

RESUMO

This paper describes the preparation of primidone-loaded poly-epsilon-caprolactone nanocapsules according to the interfacial deposition technique. The colloidal suspension obtained showed a monomodal size distribution with a mean diameter ranging from 308 to 352 nm. By adjusting the process parameters, the encapsulation efficiency was about 74% with good reproducibility. Primidone release from the nanocapsules was found to be slower as compared to the oily control solution despite an important burst-effect. The release profile was not influenced by the pH of the release medium.


Assuntos
Caproatos/química , Química Farmacêutica/métodos , Lactonas/química , Polímeros/química , Primidona/farmacocinética , Cápsulas , Cromatografia Líquida de Alta Pressão , Concentração de Íons de Hidrogênio , Técnicas In Vitro , Óleos/química , Tamanho da Partícula , Primidona/química , Reprodutibilidade dos Testes , Solubilidade , Fatores de Tempo
13.
Int J Pharm ; 177(2): 231-45, 1999 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-10205617

RESUMO

The field of crystal structure prediction and its potential value to the pharmaceutical industry is described. The process of structure prediction employed here is summarized and the results of its application to primidone and progesterone are reported. It is shown that the process successfully generates the known polymorphs of these molecules, starting from the molecular structure alone. Observations related to the application of the structure prediction process are reported.


Assuntos
Cristalização , Modelos Químicos , Primidona/química , Progesterona/química
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