Lumiracoxib

Recent emphasis on the development of safe-and-sustainable-by-design chemicals highlights the need for methods facilitating the early assessment of persistence. Activated sludge experiments have been proposed as a time- and resource-efficient way to predict half-lives in simulation studies. Here, this persistence "read-across" approach was developed to be more broadly and robustly applicable. We evaluated 21 previously used reference plant protection products (PPPs) for their broader applicability in calibrating regression and classification models for predicting half-lives in soil (DT50_OECD307) and water-sediment systems (DT50_OECD308) based on their half-life in sludge and the organic carbon-water partition coefficient K_OC as predictors. The calibrated regression models showed satisfactory predictions of DT50_OECD307 for another 22 test PPPs. Performance was less satisfying for the prediction of DT50_OECD308 for 46 active pharmaceutical ingredients (APIs), suggesting a need for expanding the set of calibration substances and more experimental K_OC values. The classification models mostly correctly classified persistent and non-persistent test compounds for both PPPs and APIs, which is relevant for early-stage screening of persistence. Transformation products of the reference compounds in activated sludge samples were consistent with the reported degradation pathways in soil, particularly with respect to major aerobic, enzyme-catalyzed transformation reactions. Overall, "reading across" biotransformation in environmental compartments such as soils or sediments from experiments with activated sludge outperformed three widely used in silico approaches for estimating half-lives and hence has immediate potential to support early assessment of biodegradability when aiming to develop chemicals that are safe and sustainable by design.

Bothrops asper venom (Bav) contains metalloproteinases that disrupt the microvascular system, impairing muscle tissue regeneration after injury. This study investigated the impact of the cyclooxygenase-2 (COX-2) pathway on vascular injury and revascularization in muscle injuries induced by Bav. Mice were injected with Bav into the gastrocnemius muscle and treated with lumiracoxib, a selective COX-2 inhibitor, 30 min, 2 days, and 6 days post-Bav injection. Muscle tissue was analyzed at 24 h, 7 days, and 21 days post-injection. A decrease in COX-2 expression at 24 h post-Bav injection indicated significant necrosis and tissue loss. Both Bav injection and lumiracoxib treatment influenced the decrease of prostaglandin (PG)D₂ and PGE₂ production. Seven and 21 days post-Bav injections, COX-2 expression increased, along with PGDs levels unaffected by lumiracoxib, indicating that the other isoform COX-1 pathway could contribute to the release of PGs. Bav/lumiracoxib treated animals presented exacerbated limb ischemia, implying that COX-2-derived prostaglandins preserve vessel integrity. CD31, an angiogenesis marker, initially (24 h) decreased post-Bav injection but increased at 7 and 21 days in Bav/lumiracoxib mice, suggesting a down-modulatory role for COX-2-derived prostaglandins in early angiogenesis and tissue regeneration. Vascular endothelial growth factor (VEGF) production rose 7 days post-Bav injection, supporting its role in angiogenesis. Previous treatment with lumiracoxib promoted release of VEGF levels 21 days post-Bav injury showing that the inhibition of COX-2 pathway in the early stage of revascularization stimulates the neovascularization regulated by elevated release of VEGF. Similarly, metalloproteinases (MMPs), such as MMP-9, MMP-10, and MMP-13, crucial for vascular remodeling, were elevated 21 days after Bav/lumiracoxib treatment. In conclusion, the COX-2 pathway is essential to decrease the high grade of ischemia caused by acute injury induced by Bav. However, the decrease of activity in the COX-2 pathway in the first stages of revascularization contributes to the elevated production of key pro-angiogenic mediators that up-regulate the restoration of microvasculature and blood flow in muscle tissue injured by botropic venoms.