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Tesi etd-06112014-100112


Thesis type
Tesi di dottorato di ricerca
Author
KIM, TAE WON
email address
twkim1981@gmail.com
URN
etd-06112014-100112
Title
Pharmacological Characterization of Platycodin D and Cimicoxib in Terms of Their Dynamic and Kinetic Profiles
Settore scientifico disciplinare
VET/07
Corso di studi
SCIENZE AGRARIE E VETERINARIE
Commissione
tutor Prof. Giorgi, Mario
correlatore Prof. Park, Seong Jun
correlatore Prof. Cho, Jong Ki
relatore Prof. Yun, Hyoin
controrelatore Prof. Park, Seung Chun
Parole chiave
  • terpenoid saponin
  • Platycodin D
  • PK/PD
  • NSAID
  • cimicoxib
Data inizio appello
16/05/2014;
Consultabilità
completa
Riassunto analitico
In part 1, the protective effect of the standardized aqueous extract of Platycodon grandiflorum (PG) against liver injury was explored using various chemical and surgical animal models. Moreover, additional studies were performed to confirm the pharmacological effect of platycodin D (PD).<br>First study was conducted to evaluate the protective effect of PG against chemical-induced hepatotoxicity. PG produced hepato-protective effects against TA and CCl4-induced acute hepatic injury by decreasing the nitric oxide enzyme and lipid peroxidation. In additional anti-HCV assay, PG inhibited the HCV RNA replication in Huh7 cells harbouring the HCV genotype 1b replicon. However, PG was unstable in simulated gastric juice and digested PG showed poor hepato-protective effect and decreased anti-HCV activity. Second study was performed to assess protective effect of PG on acute and chronic cholestasis-induced hepatic injury using short- and long-term bile duct ligation (BDL) model. Both in short- and long-term BDL model, increased serum liver enzymes were decreased in PG treated group in a dose-dependent manner. Moreover, decreased antioxidant enzyme levels in BDL alone group were elevated in PG-treated groups together with attenuated malondialdehyde and nitric oxide levels. Furthermore, after 28 days of PG treatment, BDL-induced hepatic injury and fibrosis were decreased with inhibited TGF-β1 expression. Third study was performed to confirm the pharmacological effect of saponin from Platycodon grandiflorum, PD was hired as a target compound. In the chronic BDL model, PD reduced oxidative stress and ameliorated apoptosis and tissue fibrosis in a cholestasis-induced hepatotoxic liver. Moreover, the expression of NF-κB and inducible nitric oxide synthase in the liver tissue were significantly decreased after PD treatment. Last study was performed to assess anti-cancer effect of PD and its synergistic effect with cisplatin. PD treatment induces apoptosis in CT26 cells in dose- and time- dependent manner. PD inhibits the growth of CT26 cells and exerts synergistic effect with cisplatin in both in vitro and in vivo study and combination treatment with PD attenuates cisplatin-induced oxidative stress. <br>Taken together, terpenoid saponin from Platycodon grandiflorum found to have pharmaceutical effect against various animal models. Further studies requested to secure safety profiles and therapeutic window before clinical application.<br>In part 2, the pharmacokinetic feature of cimicoxib, novel cyclo-oxygenase (COX)-2 selective non-steroidal anti-inflammatory drug, was explored in three different animal species including dogs, horses and donkeys.<br>First study was performed to evaluate the PK features of cimicoxib in dogs after administration of the recommended dose and after administration of a more variable dose rate in the form of the commercially available tablet. The results from the PK analysis were similar between the studies, regardless of precision of dose and fasted and fed conditions. The mean peak concentration of cimicoxib was 0.49 and 0.43 μg/mL under fasted and fed conditions, respectively. The mean half-life was about 3 h after all treatments. In addition, simulated multiple dosing data revealed that time over minimal effective concentration was similar after 1.95, 2.0 and 2.5 mg/kg dose administrations. Second study was conducted to evaluate PK and pharmacodynamic (PD) properties of cimicoxib in fasted and fed horses. Following cimicoxib administration (5 mg/kg), the mean maximum plasma concentration was 0.16 ± 0.01 µg/mL and 0.14 ± 0.03 µg/mL in fasted and fed groups, respectively. The mean time to maximum plasma concentration was delayed in the fed group (5.91 ± 3.23 h) compared with the fasted group (3.25 ± 1.17 h) without significant difference (p=0.12). In the ex vivo PD assay, the mean maximal inhibition rate of thromboxane B2 and prostaglandin E2 was about 60% and 70% respectively, in both fasted and fed groups. Third study was performed to assess the PK profiles of cimicoxib after intragastric administration in donkeys. Due to its relatively low Cmax (0.03 μg/mL) from the pilot study (2 mg/kg), the dose was increased (5 mg/kg) for the subsequent full-scale crossover study. However, the Cmax (0.02 μg/mL) and area under the curve (0.14 h × mg/mL) values obtained after 5 mg/kg administration were not dose dependent compared with those in the pilot study. <br>The drug must be explored carefully based on a species differences to secure its safe and effective clinical application. Further in vivo studies with diverse end-points are requested to obtain optimal clinical dosage regimens in difference species before its clinical use.<br><br>
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