Drug Exposure and Minimum Inhibitory Concentration Predict Pulmonary Tuberculosis Treatment Response.

BACKGROUND: Prospective studies correlating pharmacokinetic/pharmacodynamic (PK/PD) indices to clinical responses are urgently needed. This study aimed to find clinically relevant PK/PD thresholds that can be used for treatment optimization. METHODS: Pharmacokinetic sampling and minimum inhibitory concentration (MIC) measurements were performed for patients with culture-confirmed tuberculosis (TB). Classification and regression tree (CART) analysis was applied to obtain PK and/or PD thresholds for first-line drugs predictive of 2-week/month culture conversion, treatment outcome determined at 6-8 months, acute kidney injury (AKI), and drug-induced liver injury (DILI). Least absolute shrinkage and selection operator (LASSO) logistic regression was used for model development and validation. RESULTS: Finally, 168 and 52 patients with TB were included in development and validation cohorts for analysis, respectively. Area under the concentration-time curve (AUC)/MIC below CART-derived thresholds for pyrazinamide of 8.42, pyrazinamide of 2.79, or rifampicin of 435.45 were the predominant predictors of 2-week culture conversion, 2-month culture conversion, or treatment success, respectively. Isoniazid AUC >21.78 mg · h/L or rifampicin AUC >82.01 mg · h/L were predictive of DILI or AKI during TB treatment. The predictive performance of trained LASSO models in the validation cohort was evaluated by receiver operating characteristic curves and ranged from 0.625 to 0.978. CONCLUSIONS: PK/PD indices and drug exposure of TB drugs were associated with clinical outcome and adverse events. The effect of CART-derived thresholds for individualized dosing on treatment outcome should be studied in a randomized controlled trial.

Senna alexandrina extract supplementation reverses hepatic oxidative, inflammatory, and apoptotic effects of cadmium chloride administration in rats.

Senna alexandrina is traditionally used for its antioxidant and anti-inflammatory properties, but little information is available concerning its potential protective effects against cadmium, which is a widespread environmental toxicant that causes hepatotoxicity. Here, we explored the effects of S. alexandrina extract (SAE) on cadmium chloride (CdCl2)-induced liver toxicity over 4 weeks in rats. Rats were allocated into four groups: control, SAE (100 mg/kg), CdCl2 (0.6 mg/kg), and SAE + CdCl2, respectively. Cadmium level in hepatic tissue, blood transaminases, and total bilirubin as indicators of liver function were assessed. Oxidative stress indices [malondialdehyde (MDA), nitrate/nitrite (NO), and glutathione (GSH)], antioxidant molecules [superoxide dismutase (SOD, catalase (CAT), glutathione-derived enzymes, and nuclear factor erythroid 2-related factor 2 (Nrf2)], pro-inflammatory mediators [interleukin-1 beta (IL-1ß) and tumor necrosis factor-alpha (TNF-α)], apoptosis proteins (Bcl-2, Bax, and caspase-3), and histological alterations to the liver were examined. SAE administration before CdCl2 exposure decreased cadmium deposition in liver tissue and the blood liver function indicators. SAE pre-treatment prevented oxidative, inflammatory, and apoptotic reactions and decreased histological alterations to the liver caused by CdCl2 exposure. SAE can be used as a promising protective agent against CdCl2-induced hepatotoxicity by increasing Nrf2 expression. Graphical abstract.

Underlying the mechanism of vancomycin and human serum albumin interaction: a biophysical study.

In the present study, the binding mechanism of vancomycin with human serum albumin (HSA) was determined. Upon addition of vancomycin to HSA, the fluorescence emission was quenched and the binding constant of vancomycin with HSA was found to be 6.05 × 10(3) M(-1) at 295 K, which corresponds to -2.16 × 10(4) J·mol(-1) of free energy. The conformation of HSA was altered upon binding of vancomycin with a decrease in α helix and an increase in ß sheets and random coils, suggesting partial unfolding of the secondary structure. Molecular docking experiments found that vancomycin binds strongly with HSA at the hydrophobic pocket through hydrogen bonding and van der Waals interactions. An average binding distance of 4.71 nm has been determined on the basis of the Förster resonance energy theory. It was demonstrated that vancomycin binding to HSA causes protein structural changes.