Odalasvir

Antidepressants widely occur as emerging contaminants in marine coastal waters, with concentrations reported in the low ng/L range. Although at relatively lower levels with respect to other pharmaceuticals, antidepressants - fluoxetine (FLX) in particular - have attracted attention because of their striking effects exerted at low doses on marine invertebrates. In this study, the effects of four antidepressants including FLX, sertraline (SER), and citalopram, as members of the selective serotonin reuptake inhibitor (SSRI) class, and venlafaxine (VEN) as a member of the serotonin and norepinephrine reuptake inhibitor (SNRI) class, were evaluated in the mussel Mytilus galloprovincialis. In addition, the effects of two main metabolites of FLX and VEN, i.e., norfluoxetine (NFL) and O-desmethylvenlafaxine (ODV) respectively, were compared to those of the parent compounds. Eight concentrations of each drug (0.5-500 ng/L range) were tested on the early life stage endpoints of gamete fertilization and larval development at 48 h post fertilization (hpf). Egg fertilization was reduced by all compounds, except for VEN. Larval development at 48 hpf was affected by all SSRIs, but not by SNRIs. The above effects were significant but never exceeded 20 % of control values. Adult mussels were exposed in vivo for 7 days to environmental concentrations of the drugs (0.5, 5, and 10 ng/L) and a battery of eight biomarkers was assessed. Antidepressants primarily targeted lysosomal functions, decreasing haemocyte lysosome membrane stability (up to 70 % reduction) and increasing of the lysosome/cytosol ratio (up to 220 %), neutral lipid (up to 230 %), and lipofuscin (up to 440 %) accumulation in digestive gland. Only SER and NFL significantly affected catalase and glutathione-S-transferase activities in gills and digestive gland. NFL and ODV, were effective and sometimes more active than the parent compounds. All compounds impaired mussel health status, as indicated by the low to high stress levels assigned using the Mussel Expert System.

Venlafaxine (VEN), a first‐line antidepressant, and Zuojin Pill (ZJP), a common herbal medicine consisting ofRhizoma CoptidisandFructus Evodiae, are high likely co‐administered in China. ZJP could significantly inhibit VEN pharmacokinetics in vitro and in rats through suppression of CYP2D6 activity. To date, however, no clinical study has demonstrated the clinical relevance. Here, the VEN pharmacokinetics at a single dose of VEN with or without co‐administration of ZJP was compared. ZJP had a weak herb–drug interactions (HDI) on the pharmacokinetics of VEN. The geometric means ofCmaxand AUC0‐∞of VEN increased by 36.7% and 34.6%, respectively, and the corresponding 90% confidence intervals (CIs) of geometric mean ratios (GMRs) exceed outside bioequivalent range of 0.80–1.25. However, the corresponding 90% CIs of GMRs of these parameters for ODV were within the range. Since ODV exposure (AUC), approximately 3.4‐fold higher than that of VEN, hardly changed, the systemic exposure of VEN active moiety (VEN + ODV) with ZJP increased slightly (≤8.5%) compared with that of VEN alone. In addition, the incidence of VEN‐related side effects, especially gastrointestinal relevance, was significantly reduced with ZJP. Therefore, rational concomitant use of VEN and ZJP might have low risk of HDI and be promising in clinical practice.