Pickettnorup0189

Exploring the need for optimization of drug exposure to improve tuberculosis (TB) treatment outcome is of great importance. We aimed to describe drug exposure at steady state as well as the population pharmacokinetics (PK) of rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA) in Chinese TB patients.

A prospective multicentre PK study of RIF, INH and PZA was conducted in China between January 2015 and December 2017. Six blood samples were collected from each subject for drug concentration measurement. Nonlinear mixed effect analyses were used to develop population PK models.

In total, 217 patients were included. OTS514 Positive correlations between body weight, clearance and volume of distribution were identified for RIF and PZA, whereas body weight only influenced clearance for INH. In addition, males had higher RIF clearance and thus lower RIF exposure than women. Acetylator status was significantly associated with INH clearance as INH exposure in intermediate and fast acetylators was significantly lower than in slow acetylators, especially in low-weight bands. Simulations also showed significantly lower drug exposures in low-weight bands for all three drugs. Patients weighing <38 kg were respectively exposed to 30.4%, 45.9% and 18.0% lower area under the concentration-time curve of RIF, INH and PZA than those weighing ≥70 kg. Higher doses by addition of one fixed-dose combination tablet or 150 mg INH were simulated and found to be effective in improving INH drug exposures, especially in low-weight bands.

PK variability of first-line anti-TB drugs is common in Chinese TB patients. The developed population PK models can be used to optimize drug exposures in Chinese patients. Moreover, standard dosing needs to be adjusted to increase target attainment.

PK variability of first-line anti-TB drugs is common in Chinese TB patients. The developed population PK models can be used to optimize drug exposures in Chinese patients. Moreover, standard dosing needs to be adjusted to increase target attainment.

Chronic hepatitis B virus (HBV) infection results in a high risk of cirrhosis and its complications, cirrhosis decompensation (DC), hepatocellular carcinoma (HCC), liver transplantation (LT), death or any of these outcomes (composite endpoint [CE]). Nucleos(t)ide analogues (NUCs) such as tenofovir or entecavir are associated with a reduction in these complications.

To compare the impact of tenofovir and entecavir on these outcomes in patients treated for HBV infection and included in the prospective Hepather cohort.

All patients with HBV infection who had received tenofovir or entecavir for more than 6months at or after entry in the ANRS CO22 cohort were selected. Patients with HDV and HCV co-infection or prior liver event were excluded. Incidence rates of events were compared using inverse probability of treatment weighting (IPW).

The cohort included 1800 patients (986 tenofovir and 814 entecavir). Median follow-up was 4.2years. The incidences of HCC, DC, LT, ACD, LRD and CE were not different between tenofovir- (1.8 (0.9; 3.2), 0.6 (0.2; 1.6), 0.2 (0.0; 0.8), 1.7 (0.8; 3.0), 0.8 (0.2, 1.8) and 4.1 (3.0; 5.4) per 1000 person-years) and entecavir-treated patients (1.6 (0.7; 3.0), 0.7 (0.2; 1.8), 0.2 (0.0; 1.0), 3.0 (1.7, 4.8), 0.5 (0.1; 1.5) and 5.0 (3.3; 7.2)) per 1000 person-years, respectively.

The risk of liver-related events or death was not different between tenofovir- and entecavir-treated patients in this large prospective cohort of predominantly non-cirrhotic French patients.

NCT019553458.

NCT019553458.Although the crosstalk between iron (Fe) and copper (Cu) homeostasis signalling networks exists in plants, the underlined molecular mechanism remains unclear. FIT (FER-LIKE IRON DEFICIENCY-INDUCED TRANSCRIPTION FACTOR) and four bHLH Ib members (bHLH38, bHLH39, bHLH100 and bHLH101) are the key regulators of Fe homeostasis. Here, we reveal that FIT and bHLH Ib control the up-regulation of Cu-uptake genes (COPT2, FRO4 and FRO5) by Fe deficiency, and Cu is required for improving plant growth under Fe-deficiency conditions. The induction of Cu-uptake gene expression and the elevation of Cu concentration are inhibited in the fit-2 or bhlh4x (the quadruple mutant of four bHLH Ib genes) under Fe-deficiency conditions. The dual overexpression of both bHLH38 (or bHLH39) and FIT activates the expression of COPT2, FRO4 and FRO5 and increases Cu accumulation. Furthermore, bHLH Ib proteins directly bind to the promoters of COPT2, FRO4 and FRO5. Either Cu supplement or overexpression of COPT2 or FRO4 improves the growth of fit-2 under Fe-deficiency conditions. Moreover, the induction of COPT2, FRO4 and FRO5 by Fe deficiency is independent of SPL7, a central regulator of Cu-deficiency responses. This work through the link between bHLH Ib/FIT and COPT2/FRO4/FRO5 under Fe-deficiency conditions establishes a new relationship between Cu and Fe homeostasis.Dufulin is a new type of chiral antiplant virus agent independently developed in China. The present study was conducted to determine the effects of different concentrations of rac-dufulin and dufulin enantiomers (1, 5, and 10 mg/L) on oxidative stress in Tubifex after exposure for 3, 7, and 14 d. Results showed that rac-dufulin and individual enantiomers had no significant effects on total protein content and glutathione reductase activities. Increased superoxide dismutase demonstrated the generation of superoxide anion radical. The increase in glutathione S-transferase may be due to detoxification mechanisms. The different changes in catalase activities could be due to oxidative stress. The increase in malondialdehyde may be due to the accumulation and toxicity of contaminations. The degradation behavior of dufulin enantiomers was studied through spiked-water and spiked-soil tests. The degradation rate of S-(+)-dufulin was faster than that of R-(-)-dufulin. The present study demonstrated the occurrence of enantioselectivity in the degradation and oxidative stress of dufulin to Tubifex. In spiked soil, the concentrations of dufulin enantiomers in underlying soil were significantly higher than those in overlying water; but after 5 d of degradation, the bioturbation of Tubifex could facilitate part of dufulin diffusing from the underlying soil into the overlying water and altered the partitioning of dufulin. The present study provided a basis for conducting environmental safety risk assessments and rationally using dufulin as a chiral pesticide. Environ Toxicol Chem 2020;392136-2146. © 2020 SETAC.