Establishment of a mathematical prediction model for voriconazole stable maintenance dose: a prospective study.

Background: In patients with invasive fungal infection (IFI), the steady-state serum trough concentration (C min) of voriconazole (VCZ) is highly variable and can lead to treatment failure (C min < 0.5 mg/L) and toxicity (C min ≥ 5.0 mg/L). However, It remains challenging to determine the ideal maintenance dose to achieve the desired C min level quickly. Aims: This randomized, prospective observational single-center study aimed to identify factors affecting VCZ-C min and maintenance dose and create an algorithmic model to predict the necessary maintenance dose. MeThe study enrolled 306 adult IFI patients, split into two groups: non-gene-directed (A) (where CYP2C19 phenotype is not involved in determining VCZ dose) and gene-directed (B) (where CYP2C19 phenotype is involved in determining VCZ dose). Results: Results indicated that CYP2C19 genetic polymorphisms might significantly impact VCZ loading and maintenance dose selection. CYP2C19 phenotype, C-reaction protein (CRP), and average daily dose/body weight were significant influencers on VCZ-C min, while CYP2C19 phenotype, CRP, and body weight significantly impacted VCZ maintenance dose. A feasible predictive formula for VCZ stable maintenance dose was derived from the regression equation as a maintenance dose (mg) =282.774-0.735×age (year)+2.946×body weight(Kg)-19.402×CYP2C19 phenotype (UM/RM/NM:0, IM:1, PM:2)-0.316×CRP (mg/L) (p < 0.001). Discussion: DiThis formula may serve as a valuable supplement to the Clinical Pharmacogenetics Implementation Consortium (CPIC®) guideline for CYP2C19 and VCZ therapy, especially for IFI patients with highly variable inflammatory cytokines during VCZ therapy.

Mixing O-Containing and N-Containing Directing Groups for C-H Activation: A Strategy for the Synthesis of Highly Functionalized 2,2'-Biaryls.

A strategy combining O- and N-containing directing groups has been developed for the synthesis of 2,2'-biaryl via Pd-mediated C-H bond activation and oxidative coupling. This new transformation may proceed through a mechanism involving Pd(II) and Pd(IV) intermediates. We found the use of PTSA and HFIP to be critical for the reaction and suggest that these reagents could serve as efficient ligands for this C-C bond formation. This methodology provides broad functional group tolerance, excellent reactivity, and high yields.

Plasma levels of soluble receptor for advanced glycation end products in patients with acute respiratory distress syndrome.

The acute respiratory distress syndrome (ARDS) is a syndrome of acute respiratory failure associated with severe inflammation and diffuse alveolar damage. Recent studies have demonstrated that the soluble receptor for advanced glycation end products (sRAGE) plays an important role in the pathogenesis of ARDS. The aim of this study was to ascertain whether plasma levels of sRAGE were elevated in ARDS patients compared with appropriate controls. Furthermore, we explored whether plasma levels of sRAGE were related to disease severity, ventilatory parameters and clinical outcome. We prospectively enrolled twenty-two ARDS patients, fourteen ventilated controls and twelve healthy subjects. The Sequential Organ Failure Assessment (SOFA) score was applied to assess illness severity. In addition, ventilator parameters (arterial oxygen tension (PaO2): inspiratory oxygen fraction (FiO2) ratio, arterial carbon dioxide tension (PaCO2), tidal volume and positive end-expiratory pressure (PEEP)) of ARDS patients and ventilated controls were also recorded. Plasma samples were collected within 24 hours and levels of sRAGE were determined using a commercially available sandwich enzyme-linked immunosorbent assay (ELISA) kit. Possible correlation between plasma sRAGE levels and clinical parameters were explored using a simple linear model. Plasma sRAGE levels were significantly elevated in the plasma samples taken from patients with ARDS (1797 ± 383 pg/ml) when compared with both ventilated (650 ± 192 pg/ml, P < 0.01) and healthy (415 ± 178 pg/ml, P < 0.01) controls. Significant correlations were found between plasma sRAGE levels and PaO2:FiO2 ratio (P < 0.05, r=0.36). There was no significant difference in plasma sRAGE levels between survivors and non-survivors (P=0.34). Our results demonstrate that elevated levels of plasma sRAGE may provide a useful marker for ventilated ARDS patients. Furthermore, the relationship between plasma sRAGE levels and PaO2:FiO2 ratio in the ARDS population provides the hypothesis that ventilatory strategy may influence alveolar epithelial damage in ARDS.