RESUMO
Sertraline, a selective inhibitor of serotonin reuptake, is widely used as antidepressant in diabetic patients for improvement of depression and glycemic control. Sertraline is poorly soluble in water, which limits its oral applicability. In this work we tried to improve the pharmaceutical properties of sertraline by complexation with 2-hydroxypropyl-ß-cyclodextrin (HPßCD) and evaluated the efficacy of the HPßCD:sertraline complex in prevention of alloxan-induced lesions in rats. The solubility of sertraline increased in the presence of HPßCD and the association constant for sertraline and HPßCD was equal to 4000 ± 1000 M(-1). Two-week treatment of diabetic animals with the HPßCD:sertraline complex improved pancreatic islet morphology and ß-cell survival, which, in turn, reduced the severity of diabetes, as evidenced by lowering of blood glucose and glycated hemoglobin contents as well as normalization of serum insulin level and insulin sensitivity (HOMA-IR). The effect of the HPßCD:sertraline complex was strongly expressed in comparison with the antidiabetic effect of both the monopreparations, HPßCD and sertraline. It is suggested that the cyclodextrin derivative increased the pharmacological effect of sertraline, probably due to enhanced drug bioavailability.
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Sertralina/farmacologia , beta-Ciclodextrinas/farmacologia , 2-Hidroxipropil-beta-Ciclodextrina , Aloxano , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Feminino , Hipoglicemiantes/química , Células Secretoras de Insulina/patologia , Ratos , Ratos Wistar , Sertralina/química , beta-Ciclodextrinas/químicaRESUMO
The structural characterization of two regioisomeric products of the interaction of 2,6-bis-(4-methoxybenzylidene)-3R-methylcyclohexanone with methyl hydrazine was achieved using (1)H NMR spectral data, including chemical shifts, coupling constants and results of COSY and nuclear overhauser effect (NOE) experiments. Configurations of the new chiral centers in the (3S,3aR,6R,7E)-7-(4-methoxybenzylidene)-3,4,5,7-hexahydro-3-(4-methoxyphenyl)-2,6-dimethyl- and 2,4-dimethyl-2H-indazoles were assigned on the basis of experimental data combined with molecular modeling by the density functional theory (DFT) method. The distinction in the helical twisting power of studied compounds under addition to a nematic liquid crystal is discussed on the basis of peculiarities of the molecular structures.