Bacterial toxicity of Acetaminophen and Edaravone, and their binary mixtures: experimental and predicted values using traditional and novel Van Laar-based models.

In recent years, the presence of Pharmaceutical Active Compounds (PhACs) in ecosystems has become a serious environmental problem due to their capacity to induce harmful effects at extremely low concentrations in both humans and wildlife. Water treatment plants have not been designed to remove these types of compounds efficiently. Thus, the detection of these pollutants is essential to evaluate their negative impacts and is one of the emerging issues in environmental chemistry. The main objective of this study is to determine the bacterial toxicity of two PhACs (both individually and as a mixture) through the quantification of bioluminescence inhibition in the marine bacteria Aliivibrio fischeri, a commonly used method in short-term toxicity tests. In this work, Acetaminophen and Edaravone, two drugs approved by the Food and Drug Administration, have been studied. The acute toxicity of these PhACs has been tested at two exposure times (5 and 15 min) and different concentrations, by estimation of the median effective concentration (EC50) for each individual compound or in combination at different concentrations. Moreover, the EC50 of the binary mixtures Acetaminophen/Edaravone have been forecast using two traditional predictive models, Concentration Addition and Independent Action. The results show that toxicity decreases with exposure time and depends on the concentration tested. Furthermore, a novel semi-empirical Van Laar-based model has been proposed and validated with the experimental data from this study and literature data, obtaining satisfactory estimations of the EC50 for binary mixtures.

Edaravone mitigates hemorrhagic cystitis by modulating Nrf2, TLR-4/NF-κB, and JAK1/STAT3 signaling in cyclophosphamide-intoxicated rats.

Hemorrhagic cystitis is a potentially deadly complication associated with radiation therapy and chemotherapy. This study explored the protective effect of edaravone (ED) on cyclophosphamide (CP)-induced hemorrhagic cystitis, oxidative stress, and inflammation in rats. The animals received 20 mg/kg ED for 10 days and a single injection of 200 mg/kg CP on day 7. CP induced tissue injury manifested by the diffuse necrotic changes, disorganization of lining mucosa, focal hemorrhagic patches, mucosal/submucosal inflammatory cells infiltrates, and edema. CP increased malondialdehyde (MDA), nitric oxide (NO), tumor necrosis factor-alpha, and interleukin 6 (IL-6), decreased IL-10, and upregulated toll-like receptor 4 (TLR-4), nuclear factor-kappa B (NF-κB) p65, Janus kinase 1 (JAK1), and signal transducer and activator of transcription 3 (STAT3) in the urinary bladder of rats. ED effectively prevented the histopathological alterations, decreased MDA, NO, and inflammatory mediators, and downregulated TLR-4, NF-κB, JAK1, and STAT3 in CP-induced rats. Treatment with ED upregulated ikß kinase ß, IL-10, nuclear factor-erythroid 2 related factor 2 (Nrf2), and cytoglobin, and boosted glutathione, superoxide dismutase, and glutathione S-transferase. Molecular docking simulations revealed the ability of ED to bind TLR-4, NF-κB, JAK1, and STAT3. In vitro, ED increased the cytotoxic activity of CP against HeLa, Caco-2, and K562 cell lines. In conclusion, ED prevented CP-induced hemorrhagic cystitis in rats by attenuating oxidative stress, suppressing TLR-4/NF-κB, and JAK1/STAT3 signaling and boosted Nrf2, cytoglobin, and antioxidants.