Study On Pharmacological Action Of Secnidazole And Secnidazole Prodrugs

Secnidazole in recent years are widely used in abroad clinical safety, effective anti-anaerobic bacteria,Helicobacter pylori, Giardia, Trichomonas vaginalis and gastro-intestinal amoeba of 5-nitroimidazoles.In order to avoid gastrointestinal adverse reactions, and better to play the effect of oral administration, this paper carried out prodrug of secnidazole and the use of modified cyclodextrins for secnidazole to improve the solubility. We use secnidazole and its prodrug for pharmacodynamic studies. This paper also study on the complexation characteristics of secnidazole with hydroxylpropy-β-cyclodextrin which has good water solution, to improve the bioavailability and water solution of secnidazole, and provide a theoretical reference on developing the secnidazole formulations of cyclodextrin inclusion complexes in aqueous solution. The main contents are summarized below:(1) Study on pharmacological actionTrichomonas vaginalis suspension cultivated in liver extracts medium, MTT colorimetric assay and the classical microscopic counting method were applied to determine the inhibitory effects of secnidazole and its prodrugs on proliferation of trichomonas vaginalis. We establish trichomonas vaginitis in a mice model caused by trichomonas vaginalis to determine the the inhibitory effects of secnidazole and its prodrugs on trichomonas vaginalis in vivo. The results showed that the cultivation of 6h²4h period, secnidazole (0.15⁴0μg/mL), mono secnidazole succinate (10¹280μg/mL) and secnidazole succinate sodium salt (40¹280μg/mL) inhibited proliferation of trichomonas vaginalis in a time-dependent manner in the period ranged. The therapeutic effect of high, medium-dose secnidazole succinate and its sodium salt group have no significant difference with the model group of secnidazole(P>0.01), indicating that the high,medium-dose group have outstanding therapeutic effect.(2) Acute toxicity testUsing tail vein injection and orally, respectively, compared secnidazole with its prodrug of LD₅₀. The result showed that according to the Bliss method, by the mouse tail vein injection, the LD₅₀ of secnidazole is 1.431g/kg, LD₅₀ of mono secnidazole succinate is 2.939g/kg, LD₅₀ of secnidazole succinate sodium salt is 2.998g/kg. After administration by gavage in mice, the LD₅₀ of secnidazole is 2.238g/kg , LD₅₀ of mono secnidazole succinate is 9.387g/kg, LD₅₀ of secnidazole succinate sodium salt is 9.818g/kg. The result indicate that secnidazole prodrug is safer than secnidazole, but maybe have poor bioavailability.(3) Study on InclusionThe measurements of the complexation mechanism, inclusion molar ratio of the host and guest molesules and change of thermodynamic parameters were carried out by the following methods separately: phase solubility method, UV absorption spectroscopy , and equimolar series method, etc. The result indicated that an 1:1 molar ratio inclusion complex of secnidazole with HP-β-CD could be formed spontaneously. Appropriate temperature and suitable media PH probably favor the progress of complexation procedure.