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Acta Pharmaceutica Sinica ; (12): 1621-1626, 2021.
Article in Chinese | WPRIM | ID: wpr-881566


Hyperuricemia is not only the biochemical basis of gout, but also closely related to the development of metabolic syndrome, cardiovascular diseases, chronic kidney disease, etc. Xanthine oxidase (XOD) is the key catalytic enzyme for uric acid biosynthesis, therefore the vital target for anti-hyperuricemic drugs. In this study, compound CC18022 was designed and synthesized specifically targeting to XOD. Molecular docking analysis indicated a fairly tight binding between CC18022 and XOD. In the in vitro study, CC18022 significantly inhibited XOD activity with a half maximal inhibitory concentration (IC50) value in the order of nmol·L-1, which is relative to the XOD inhibitor febuxostat. By using both acute and chronic hyperuricemic mice model, compound CC18022 was found to have serum uric acid-lowering effect in a dose-dependent manner in vivo. The animal welfare and experimental processes were in accordance with the provisions of the Animal Ethics Committee of the Institute of Materia Medica, Chinese Academy of Medical Sciences. In the acute hyperuricemic mice, CC18022 significantly inhibited serum XOD activity, and also the XOD activity in intestine and liver, which were related to purine absorption and metabolism. Therefore, the novel compound CC18022 exhibited significant inhibition on XOD activity and anti-hyperuricemic effects, making it a favorable candidate for further research.

Article in Chinese | WPRIM | ID: wpr-332521


<p><b>OBJECTIVE</b>To investigate the effect of penehyclidine hydrochloride (PHC) in a rat model of renal injury induced by hemorrhagic shock and lipopolysaccharides (LPS).</p><p><b>METHODS</b>Forty-five healthy Wistar rats were randomized into sham operated group, model group, and 3 penehyclidine hydrochloride (PHC) dose (1, 2 and 3 mg/kg) groups (PHC1, PHC2, and PHC3 groups, respectively). The arterial blood samples were collected to determine the concentrations of serum tumor necrosis factor-α (TNF-α), interleukin-8 (IL-8), interleukin-1 (IL-1), urine creatinine (Cr) and blood urine nitrogen (BUN), and the renal tissues were collected to measure the expressions of ICAM-1 and nuclear factor-κB (NF-κB) and observe the pathological changes.</p><p><b>RESULTS</b>TNF-α, IL-8, IL-1, Cr, BUN, ICAM-1 and NF-κB in the 3 PHC groups were significantly lower than those in the model group (P<0.05). TNF-α, IL-8, IL-1, Cr and BUN were significantly lower in PHC1 (P<0.05) than in the PHC2 and PHC3 groups, and ICAM-1 and NF-κB were similar between 3 PHC groups (P>0.05). Compared with the model group, the 3 PHC groups showed lessened pathological changes in the renal tubules.</p><p><b>CONCLUSION</b>PHC has protective effects against renal injury induced by hemorrhagic-endotoxin shock in rats, and treatment with 1 mg/kg PHC produces the most significant protective effect.</p>

Acute Kidney Injury , Drug Therapy , Animals , Intercellular Adhesion Molecule-1 , Metabolism , Interleukin-1 , Blood , Interleukin-8 , Blood , Kidney , Metabolism , Kidney Tubules , Metabolism , Lipopolysaccharides , Male , NF-kappa B , Metabolism , Quinuclidines , Pharmacology , Rats , Rats, Wistar , Shock, Hemorrhagic , Blood , Metabolism , Tumor Necrosis Factor-alpha , Blood