Evaluating posaconazole dosing regimens of the different formulations against Aspergillus spp. in adults: a pharmacokinetic/pharmacodynamic analysis using Monte Carlo simulation.

The objective of this study was to evaluate the efficacy of various posaconazole dosing regimens of the different formulations against Aspergillus spp. in adults. Monte Carlo simulations were conducted using pharmacokinetic (PK) parameters and pharmacodynamic (PD) data to determine the probability of target attainment (PTA) and cumulative fraction of response (CFR) in terms of area under the concentration-time curve/minimum inhibition concentration (AUC/MIC) targets of posaconazole. According to the results of the PTA analysis, currently recommended clinical dosing regimens of the delayed-release tablet and intravenous (i.v.) solution were appropriate in prophylaxis against Aspergillus spp. with MICs ≤ 0.125 µg/mL. However, only high-dose regimens of the delayed-release tablet could achieve the target PTA in the treatment against Aspergillus spp. at an MIC of 0.125 µg/mL. Furthermore, the CFR was calculated for each dosing regimen. For the oral suspension, none of the simulated dosing regimens was effective against Aspergillus spp. For the delayed-release tablet and i.v. solution, the recommended dosing regimens were effective for prophylaxis of invasive fungal infections by four Aspergillus spp. (Aspergillus flavus, Aspergillus fumigatus, Aspergillus nidulans and Aspergillus terreus). However, these recommended dosing regimens were only effective for the treatment of A. terreus infection. Therefore, the high-dose regimen (200 mg oral every 12 h) of the delayed-release tablet should be recommended to achieve optimal therapeutic efficacy against four Aspergillus spp. (A. flavus, A. fumigatus, A. nidulans and A. terreus). These PK/PD-based simulations rationalise and optimise the dosing regimens of the different posaconazole formulations against Aspergillus spp. in adults.

The therapeutic effects of Jaceosidin on lipopolysaccharide-induced acute lung injury in mice.

Acute lung injury (ALI) results from various factors including uncontrolled pulmonary inflammation, oxidative damage and the over-activated complement with high mortality rates. Jaceosidin was a flavonoid compound with significant anti-complement activity. We aimed to investigate the therapeutic effects of Jaceosidin on ALI induced by lipopolysaccharide (LPS). Mice were orally administrated with Jaceosidin (15, 30 and 60 mg/kg) after LPS challenge. 24 h after LPS challenge, Jaceosidin could significantly decrease the lung wet-to-dry weight (W/D) ratio and the protein concentration in bronchoalveolar lavage fluid (BALF). Jaceosidin could down-regulate the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1ß (IL-1ß), together with up-regulation the levels of interleukin-4 (IL-4) and interleukin-10 (IL-10) in BALF. Jaceosidin could significantly decrease the levels of myeloperoxidase (MPO), cyclooxygenase-2 (COX-2) and nuclear factor-κB (NF-κB), COX-2 mRNA and NF-κB p65 mRNA together with increasing the activity of catalase (CAT). Additionally, Jaceosidin attenuated lung histopathological changes, inhibited the expressions of COX-2 and NF-κB p65 and reduced complement deposition with decreasing the levels of complement 3 (C3) and complement 3c (C3c) in serum. These data suggest that Jaceocidin may dampen the inflammatory response and decrease the levels of complement together with the antioxidant activity following LPS-induced ALI.