ABSTRACT
PSN-357, an effective glycogen phosphorylase (GP) inhibitor for the treatment for type 2 diabetics, is hampered in its clinical use by the poor selectivity between the GP isoforms in liver and in skeletal muscle. In this study, by the introduction of cholic acid, 9 novel potent and liver-targeted conjugates of PSN-357 were obtained. Among these conjugates, conjugate 6 exhibited slight GP inhibitory activity (IC50 = 31.17 µM), good cellular efficacy (IC50 = 13.39 µM) and suitable stability under various conditions. The distribution and pharmacokinetic studies revealed that conjugate 6 could redistribute from plasma to liver resulting in a considerable higher exposure of PSN-357 metabolizing from 6 in liver (AUCliver/AUCplasma ratio was 18.74) vs that of PSN-357 (AUCliver/AUCplasma ratio was 10.06). In the in vivo animal study of hypoglycemia under the same dose of 50 mg/kg, conjugate 6 exhibited a small but significant hypoglycemic effects in longer-acting manners, that the hypoglycemic effects of 6 is somewhat weaker than PSN-357 from administration up to 6 h, and then became higher than PSN-357 for the rest time of the test. Those results indicate that the liver-targeted glycogen phosphorylase inhibitor may hold utility in the treatment of type 2 diabetes.
Subject(s)
Cholic Acid/therapeutic use , Diabetes Mellitus, Experimental/drug therapy , Glycogen Phosphorylase/antagonists & inhibitors , Liver/metabolism , Piperidines/therapeutic use , Administration, Intravenous , Animals , Body Fluids/chemistry , Cholic Acid/chemistry , Diabetes Mellitus, Experimental/metabolism , Enzyme Assays , Glycogen Phosphorylase/metabolism , Glycogenolysis , Hep G2 Cells , Humans , Inhibitory Concentration 50 , Mice , Microsomes, Liver/metabolism , Piperidines/chemistry , Rabbits , Structure-Activity Relationship , Time Factors , Tissue DistributionSubject(s)
Coxsackievirus Infections/metabolism , Enterovirus B, Human , Myocarditis/virology , Oxidative Stress/drug effects , Selenium/pharmacology , Animals , Coxsackievirus Infections/pathology , Coxsackievirus Infections/physiopathology , Female , Glutathione Peroxidase/metabolism , Male , Mice , Superoxide Dismutase/metabolismABSTRACT
OBJECTIVE: To investigate the normal ranges of the following parameters: nasal airway resistance (NAR), nasal cavity volume (NCV), nasopharyngeal volume (NPV) and nasal minimal cross sectional area (NMCA), and the effect of postural changes on nasal cavity geometry and nasal airway resistance. METHODS: Seventy three healthy children had acoustic rhinometry (AR) test in different body positions. RESULTS: In each group, the NAR of the healthy children in the lateral, and supine positions were significantly greater than that in the sitting position, and there were no significant differences among the NAR in lateral, and supine positions; the total NCV, NPV, NMCA of the healthy children in the lateral and supine positions were significantly smaller than that in the sitting position (P < 0.05). The NAR of the 3-6 year-old group was significantly greater than that of the 7-10 and 11-14 year-old groups, significant differences were also found between the last two groups; NAR in 7-10 year-old group were greater than that in the 11-14 year-old group (all P < 0.05). The total NCV,the total NPV and the total NMCA of the 3-6 year-old group were significantly smaller than that of the 7-10 and 11-14 year-old groups, significant differences were also found between the last two groups (all P < 0.05). All three parameters' numerical value in 7-10 year-old group were smaller than that in the 11-14 year-old group. CONCLUSIONS: Postural changes may alter the NAR and the nasal cavity geometry in normal children.
