Differences in Multicomponent Pharmacokinetics, Tissue Distribution, and Excretion of Tripterygium Glycosides Tablets in Normal and Adriamycin-Induced Nephrotic Syndrome Rat Models and Correlations With Efficacy and Hepatotoxicity.

Tripterygium glycosides tablets (TGT) are widely used for treating nephrotic syndrome (NS), but hepatotoxicity is frequently reported. The presence of underlying disease(s) can alter the disposition of drugs and affect their efficacy and toxicity. However, no studies have reported the impact of NS on the ADME profiles of TGT or its subsequent impact on the efficacy and toxicity. Thus, the efficacy and hepatotoxicity of TGT were evaluated in normal and NS rats after oral administration of TGT (10 mg/kg/day) for 4 weeks. The corresponding ADME profiles of the six key TGT components (triptolide (TPL), wilforlide A (WA), wilforgine (WFG), wilfortrine (WFT), wilfordine (WFD), and wilforine (WFR)) were also measured and compared in normal and NS rats after a single oral gavage of 10 mg/kg TGT. Canonical correlation analysis (CCA) of the severity of NS and the in vivo exposure of the six key TGT components was performed to screen the anti-NS and hepatotoxic material bases of TGT. Finally, the efficacy and hepatotoxicity of the target compounds were evaluated in vitro. The results showed that TGT decreased the NS symptoms in rats, but caused worse hepatotoxicity under the NS state. Significant differences in the ADME profiles of the six key TGT components between the normal and NS rats were as follows: higher plasma and tissue exposure, lower urinary and biliary excretion, and higher fecal excretion for NS rats. Based on CCA and in vitro verification, TPL, WA, WFG, WFT, WFD, and WFR were identified as the anti-NS material bases of TGT, whereas TPL, WFG, WFT, and WFD were recognized as the hepatotoxic material bases. In conclusion, NS significantly altered the ADME profiles of the six key TGT components detected in rats, which were related to the anti-NS and hepatotoxic effects of TGT. These results are useful for the rational clinical applications of TGT.

Effect of dexmedetomidine for attenuation of propofol injection pain in electroconvulsive therapy: a randomized controlled study.

PURPOSE: Current analgesic strategies for propofol injection pain may cause adverse reactions during electroconvulsive therapy (ECT), such as shortening seizure duration. This study investigated whether dexmedetomidine could attenuate propofol injection pain in ECT. METHODS: Participants were randomly allocated to receive 0.2 µg/kg dexmedetomidine (Dex-0.2 group), 0.5 µg/kg dexmedetomidine (Dex-0.5 group) or saline (control group) prior to ECT. The composite pain scale and objective Surgical Pleth Index (SPI) were used to measure the intensity of injection pain, and the percentage of patients with pain score > 2 was the primary outcome. RESULTS: Of 137 patients recruited, 46 were assigned to each of the Dex-0.2 or Dex-0.5 groups, while 45 were in the control group. The percentage of pain score > 2 was reduced from 68.9% (31/45) in the control group to 34.8% (16/46) in the Dex-0.2 group (P < 0.001) and 15.2% (7/46) in the Dex-0.5 group (P < 0.001). The pain score and SPI at 5 s after propofol injection were greater in the control group than in the Dex-0.2 [pain scores 3 (2-4) vs. 1 (1-3), P < 0.001, SPI 76.6 ± 10.0 vs. 58.0 ± 11.0, P < 0.001] and Dex-0.5 groups [pain scores 3 (2-4) vs. 1 (0-1), P < 0.001, SPI 76.6 ± 10.0 vs. 51.2 ± 12.3, P < 0.001]. There were no significant differences in seizure duration between the three groups. No patients developed bradycardia and hypotension. CONCLUSIONS: Pretreatment with dexmedetomidine was able to reduce the propofol injection pain in ECT without interfering with the seizure duration and causing adverse effects such as bradycardia and hypotension. In addition, close monitoring of hemodynamic variables and preparation of a treatment plan and drugs for bradycardia are essential.

Pharmacodynamic analysis of target-controlled infusion of propofol in patients with hepatic insufficiency.

The effect of liver dysfunction on target-controlled infusion (TCI) of propofol remains poorly documented. The pharmacodynamic performance of propofol TCI was evaluated in a cohort of Chinese patients with hepatic insufficiency. Fifty-three patients with hepatic insufficiency were enrolled in the current prospective, observational study. Anesthesia was induced with propofol via TCI to a plasma concentration of 3 µg/ml. Following loss of consciousness (LOC), fentanyl and cisatracurium were administered. Pharmacodynamic parameters were recorded during TCI, including time to LOC, bispectral index (BIS), heart rate (HR) and blood pressure. Patients were divided into two groups based on model of end stage liver disease (MELD) score: Those with a MELD score of ≤9 and those with a MELD score of ≥10. BIS, mean arterial pressure and HR were demonstrated to vary according to time, but were not affected by liver dysfunction. Hypotension was prominent in patients with a MELD score of ≥10 30 min after induction. The proportion of bradycardia and hypotension at the other time points was not significantly different between MELD scores of ≤9 and ≥10. Notably, no bradycardia was observed in MELD of ≥10. Thus, bradycardia and hypotension was observed in patients with hepatic insufficiency over time, although patients with different severities of hepatic insufficiency did not present with different depths of anesthesia. TCI of propofol to 3 µg/ml may be not suitable for patients with hepatic insufficiency, particularly those with severe liver dysfunction. Predictive concentrations (Cp) of TCI propofol requires further investigation and adjustment in patients with hepatic insufficiency (trial registration no. ChiCTR-OCH-12002255).