RESUMO
The purpose of this study was to develop a method for the stereoselective analysis of thioridazine-2-sulfoxide (THD-2-SO) and thioridazine-5-sulfoxide (THD-5-SO) in culture medium and to study the biotransformation of rac-thioridazine (THD) by some endophytic fungi. The simultaneous resolution of THD-2-SO and THD-5-SO diastereoisomers was performed on a CHIRALPAK AS column using a mobile phase of hexane:ethanol:methanol (92:6:2, v/v/v)+0.5% diethylamine; UV detection was carried out at 262 nm. Diethyl ether was used as extractor solvent. The validated method was used to evaluate the biotransformation of THD by 12 endophytic fungi isolated from Tithonia diversifolia, Viguiera arenaria and Viguiera robusta. Among the 12 fungi evaluated, 4 of them deserve prominence for presenting an evidenced stereoselective biotransformation potential: Phomopsis sp. (TD2) presented greater mono-2-sulfoxidation to the form (S)-(SE) (12.1%); Glomerella cingulata (VA1) presented greater mono-5-sulfoxidation to the forms (S)-(SE)+(R)-(FE) (10.5%); Diaporthe phaseolorum (VR4) presented greater mono-2-sulfoxidation to the forms (S)-(SE) and (R)-(FE) (84.4% and 82.5%, respectively) and Aspergillus fumigatus (VR12) presented greater mono-2-sulfoxidation to the forms (S)-(SE) and (R)-(SE) (31.5% and 34.4%, respectively).
Assuntos
Antipsicóticos/isolamento & purificação , Asteraceae/microbiologia , Cromatografia Líquida de Alta Pressão/métodos , Fungos/metabolismo , Tioridazina/análogos & derivados , Tioridazina/isolamento & purificação , Amilose/análogos & derivados , Amilose/química , Antipsicóticos/química , Antipsicóticos/metabolismo , Aspergillus fumigatus/isolamento & purificação , Aspergillus fumigatus/metabolismo , Biotransformação , Soluções Tampão , Carbamatos/química , Cromatografia Líquida de Alta Pressão/normas , Meios de Cultura/química , Dietilaminas/química , Etanol/química , Éter/química , Fungos/isolamento & purificação , Hexanos/química , Metanol/química , Phyllachorales/isolamento & purificação , Phyllachorales/metabolismo , Reprodutibilidade dos Testes , Solventes/química , Espectrofotometria Ultravioleta , Estereoisomerismo , Tioridazina/química , Tioridazina/metabolismoRESUMO
Thioridazine (THD) is a phenothiazine neuroleptic drug used for the treatment of psychiatric disorders. After oral administration THD is extensively biotransformed to thioridazine 2-sulfone (THD 2-SO(2)), thioridazine 5-sulfoxide (THD 5-SO) and thioridazine 2-sulfoxide (THD 2-SO). THD 2-SO and THD 5-SO have two chiral centres and therefore exist as two diastereoisomeric pairs. The degradation and epimerization of THD 2-SO in human plasma, buffer and methanolic solutions were studied using an enantioselective HPLC method. The samples were prepared by liquid-liquid extraction with diethyl ether and the chiral resolution of the enantiomers was carried out on a Chiralpak AD column using a mobile phase consisting of hexane:ethanol:2-propanol (90:7:3, v/v/v) containing 0.2% diethylamine. The method was validated and used to study the degradation and epimerization under different conditions of incubation. Our results showed that both enantiomers were stable at varying temperatures, pH and ionic strengths; however, solubility problems were observed, mainly at pH 8.5. The influence of light on stability was studied using methanolic solutions and degradation and epimerization of the THD 2-SO enantiomers were observed under UV light of 366 and 254nm, respectively.
Assuntos
Sulfóxidos/sangue , Sulfóxidos/química , Tioridazina/análogos & derivados , Tioridazina/sangue , Humanos , Conformação Molecular , Tioridazina/metabolismoRESUMO
We present two methods for the enantioselective analysis of thioridazine (THD) and thioridazine 2-sulfone (THD 2-SO(2)) in human plasma based on liquid-liquid extraction with diethyl ether and chiral resolution of the enantiomers on Chiralpak AD and Chiralcel OD-H columns, respectively. After validation, the methods were used to study the degradation and racemization of both drug and metabolite. Our results showed that both enantiomers of THD and THD 2-SO(2) were stable at varying temperatures, pH, and ionic strengths; however, solubility problems for THD and THD 2-SO(2) enantiomers were observed, mainly at pH 8.5. The influence of light on the stability of the THD and THD 2-SO(2) enantiomers was also studied. Degradation of the THD enantiomers was observed under UV light (254 and 366 nm) while THD 2-SO(2) enantiomers were stable at these wavelengths and also when exposed to visible light.
Assuntos
Tioridazina/análogos & derivados , Tioridazina/sangue , Tioridazina/química , Antipsicóticos/sangue , Antipsicóticos/química , Humanos , Concentração de Íons de Hidrogênio , Cinética , Modelos Moleculares , Conformação Molecular , Soluções , EstereoisomerismoRESUMO
Se revisa la literatura acerca del tratamiento farmacologico del transtorno del deficit de la atencion. Pocas modificaciones importantes se han realizado durante los ultimos 10 anos. Los estimulantes son efectivos en el aumento de la atencion y en la disminucion de la hiperactividad. Sin embargo persiste controversia acerca de su uso. Aunque algunso postulan efectos positivos sobre el rendimiento academico esto no es tan claro, y ademas no existe evidencia clara sobre la efectividad de los estimulantes en mejorar el pronostico a largo plazo. Se describe el uso clinico de las drogas en el TDA.