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This study explored the sorption of sulfamethoxazole (SMX) and sulfapyridine (SPY) onto biochars produced from raw and anaerobically digested bagasse. Initial evaluation of six bagasse biochars showed that digested bagasse biochar prepared at 600 °C (DBG600) was the best adsorbent to remove SMX and SPY. Further laboratory batch sorption experiments showed that DBG600 adsorbed SMX and SPY from aqueous solution with maximum adsorption capacity of 54.38 and 8.60 mg g −1 , respectively. Solution pH showed strong effect on the sorption ability of DBG600 to the two antibiotics, and the sorption decreased with increasing of solution pH. Experimental and model results suggested that adsorption of SMX and SPY onto DBG600 might be controlled by the π–π interaction.

New, sustainable, and low-cost materials that can simultaneously remove a range of wastewater contaminants, such as heavy metals and pharmaceutical residues, are needed. In this work, modified biochars were produced by dip-coating hickory or bagasse biomass in carbon nanotube (CNT) suspensions with or without sodium dodecylbenzenesulfonate (SDBS)-aided dispersion prior to slow pyrolysis in a N 2 environment at 600 °C. The sulfapyridine (SPY) and lead (Pb) sorption ability of pristine hickory (HC) and bagasse (BC) biochars and the modified biochars with (HC-SDBS-CNT and BC-SDBS-CNT, respectively) and without (HC-CNT and BC-CNT) SDBS was assessed in laboratory aqueous batch single- and binary-solute system. The greatest removal of SPY and Pb was observed for HC-SDBS-CNT (86 % SPY and 71 % Pb) and BC-SDBS-CNT (56 % SPY and 53 % Pb), whereas HC-CNT, BC-CNT, and the pristine biochars removed far less. This can be attributed to the fact that surfactant could prevent the aggregation of CNTs and thus promote the distribution and stabilization of individual CNT nanoparticle on the biochar surface to adsorb the contaminants. The observation of no significant change in Pb sorption capacities of the surfactant-dispersed CNT-modified biochars in the presence of SPY, or vice versa, was indicative of site-specific sorption interactions and a lack of significant competition for functional groups by the two sorbates. These results suggest that products of hybrid technologies, such as biochars modified with CNTs, can yield multi-sorbents and may hold excellent promise as a sustainable wastewater treatment alternative.

The gut microbiome can contribute to drug metabolism and significantly influence pharmacokinetic (PK) behavior. Sulfasalazine is well‐known to be metabolized by gut bacterial azoreductases into sulfapyridine and mesalamine. Despite in vitro and in vivo evidence of the gut microbiome's role in drug metabolism, quantitative predictions of its impact on drug PK are lacking. To address this gap, we used sulfasalazine and its metabolites as a case example to build a translational modeling framework to predict the extent of gut microbiome‐mediated drug metabolism and subsequent PK of the metabolites. First, sulfasalazine conversion kinetics was measured in vitro using pooled human fecal homogenate incubation. In vitro V max was 650.5 and 200.9 pmol/min/mg feces, and K m was 3648 and 1605 μM for sulfapyridine and mesalamine formation, respectively. Based on colon and feces bacterial counts from nine healthy humans, a ratio of 0.47 was used to scale in vitro fecal V max to the colon level. Second, physiologically‐based pharmacokinetic (PBPK) models for sulfasalazine, sulfapyridine, and mesalamine were built in Simcyp and verified to predict their oral PK when dosed directly. Lastly, sulfapyridine or mesalamine PK after dosing sulfasalazine was predicted by linking the parent and metabolite PBPK models with colon luminal metabolism kinetics. The observed sulfapyridine and mesalamine PK after dosing sulfasalazine were predicted with weighted average fold‐errors of 1.21, 1.22, and 1.05 for C max , T max , and AUC, respectively. Overall, this in vitro to in vivo translation and modeling framework provides valuable insights for quantitatively predicting the in vivo impact of gut microbiome‐mediated drug metabolism. What is the current knowledge on the topic? The gut microbiome is recognized as a contributor to drug metabolism and thereby impacts drug pharmacological effect or safety. Sulfasalazine, a drug prescribed for the treatment of ulcerative colitis, is well‐known to be metabolized by the gut microbiome into two active metabolites: mesalamine and sulfapyridine. What question did this study address? The translation between in vitro gut microbiome‐mediated drug metabolism and in vivo activity and the subsequent predictions of metabolite formation and colonic absorption are the key questions to be addressed What does this study add to our knowledge? To the authors' knowledge, this is the first study using physiologically‐based pharmacokinetic (PBPK) modeling and in vitro to in vivo extrapolation (IVIVE) technique to predict gut microbiome‐mediated drug metabolism in vivo and the metabolite absorption and PK. The model was also verified extensively with clinical data. How might this change drug discovery, development, and/or therapeutics? This research provided a translational modeling framework to prospectively predict gut‐microbiome mediated drug metabolism and absorption of metabolites that can be readily applied to future projects that need exposure estimation of gut‐microbiome formed metabolites or estimation of active drug exposure for prodrugs converted in gut lumen. For example, this modeling approach enables the modeling of gut microbiome‐mediated deglucuronidation to estimate its impact on PK of UGT substrates, or it can guide the discovery strategy and human dose prediction for prodrugs leveraging gut luminal metabolism for activation.

The non-canonical NF-κB signaling (RelB/p52) pathway drives pro-labor genes in the human placenta, including corticotropin-releasing hormone (CRH) and cyclooxygenase-2 (COX-2), making this a potential therapeutic target to delay onset of labor. Here we sought to identify small molecule compounds from a pre-existing chemical library of orally active drugs that can inhibit this NF-κB signaling, and in turn, human placental CRH and COX-2 production. We used a cell-based assay coupled with a dual-luciferase reporter system to perform an in vitro screening of a small molecule library of 1,120 compounds for inhibition of the non-canonical NF-κB pathway. Cell toxicity studies and drug efflux transport MRP1 assays were used to further characterize the lead compounds. We have found that 14 drugs have selective inhibitory activity against lymphotoxin beta complex-induced activation of RelB/p52 in HEK293T cells, several of which also inhibited expression of CRH and COX-2 in human term trophoblast. We identified sulfapyridine and propranolol with activity against CRH and COX-2 that deserve further study. These drugs could serve as the basis for development of orally active drugs to affect length of gestation, first in an animal model, and then in clinical trials to prevent preterm birth during human pregnancy.

Background:AR882 is a highly selective URAT1 inhibitor in development for the treatment of gout and tophaceous gout. It has demonstrated favorable pharmacokinetics (PK) and robust efficacy in clinical studies. In AR882 phase 2 studies in patients with gout, no drug interactions (DDIs) were observed between AR882 and the commonly prescribed drugs for comorbidities such as antihyperglycemics, antihypertensives, statins and diuretics. There was no dose adjustment needed for concomitant medications while the efficacy of AR882 was steady. The lack of DDIs with these transporter-mediated drugs is consistent with the results from in vitro modeling and animal studies.Objectives:Comprehensive evaluation of AR882’s DDI potential with key renal, hepatic, and intestinal transporters that are typically associated with drugs used for comorbidity usually seen in gout patients.Methods:In in vitro studies, AR882’s interactions with various transporters were assessed in HEK293 cells expressing MATE1, MATE2-K, OATP1B1, OATP1B3, OAT1, OAT3, OCT1 and OCT2, or Caco-2 cells/membrane vesicles (P-gp and BCRP, BSEP). Substrate and inhibition assays for relevant transporters were conducted with AR882 in concentrations exceeding clinical drug concentration (i.e., at least 100-fold the Imax,u of high clinical dose at 75 mg). The obtained accumulation ratio (substrate) and the IC50 (inhibition) using model-base methods were analyzed for DDI predication. Furthermore, AR882 potential as a substrate for P-gp and BCRP transporters was assessed using tissue distribution data in rat and renal excretion data from the human ADME study using [14C]AR882. In order to determine the clinical significance of AR882’s DDI potential with BCRP, a phase 1 clinical study dosed in 10 male healthy participants with sulfasalazine 500 mg on Day 1, followed by a second single dose of sulfasalazine 500 mg on Day 4 with multiple-dose of AR882 75 mg administered once daily from Days 4 to 6. Plasma levels of sulfasalazine, as well as metabolites sulfapyridine and mesalamine were determined by LC/MS/MS analyses. PK parameters Cmax, and AUC were assessed to calculate geometric mean ratios.Results:In vitro assessments indicated that AR882 was not a substrate of any key renal and hepatic transporters. AR882 was determined to be a substrate of BCRP and P-gp; AR882 had no inhibitory effect on any transporters except for BCRP with an IC50 of 1.18 µM in animal studies, which warranted a clinical DDI study as an inhibitor of BCRP. Sulfasalazine, a clinical substrate of BCRP and a commonly used drug in autoimmune and rheumatic diseases was selected for the study. Co-administration of AR882 75 mg (maximum therapeutic dose) with sulfasalazine produced no clinically relevant alterations in pharmacokinetics (Cmax and AUC) of sulfasalazine with a geometric mean ratio of 1.09 (co-administration) verse 1.05 (sulfasalazine alone), suggesting no clinically significant BCRP-mediated DDI.Conclusion:AR882 has been comprehensively evaluated for transporter-mediated DDI potential in vitro and in clinical studies, and exhibited no DDI concerns. These findings demonstrated that AR882 can be safely given in gout patients with various comorbid conditions including diabetes, hypertension and hyperlipidemia and the concomitant medications that are primarily cleared via transporters.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:Zancong Shen Arthrosi Therapeutics Inc, Rongzi Yan Arthrosi Therapeutics Inc, Elizabeth Polvent Arthrosi Therapeutics Inc, Vijay Hingorani Arthrosi Therapeutics Inc, Shunqi Yan Arthrosi Therapeutics Inc, Robert Keenan Arthrosi Therapeutics Inc, Li-Tain Yeh Arthrosi Therapeutics Inc.

A new complex of Bi(III) and sulfapyridine was synthesized and characterized by elemental analysis, atomic absorption spectrometry, conductivity analysis, electrospray ionization mass spectrometry (ESI-MS), infrared spectroscopy, and single crystal X-ray diffraction methods. The antimicrobial and the cytotoxic activities of the compound were investigated. Elemental and conductivity analyses are in accordance to the formulation [BiCl3(C11H11N3O2S)3]. The structure of the complex reveals a distorted octahedral geometry around the bismuth atom, which is bound to three sulfonamidic nitrogens from sulfapyridine, acting as a monodentate ligand, and to three chloride ions. The presence of the compound in solution was confirmed by ESI-MS studies. The complex is 3 times more potent than the ligand against Salmonella typhimurium, 4 times against Staphylococcus aureus, Shigella dysenteriae, and Shigella sonnei and 8 times more potent against Pseudomonas aeruginosa and Escherichia coli. The compound inhibits the growth of chronic myelogenous leukemia cells with an IC50 value of 44 μM whereas the free ligand has no effect up to 100 μM.

This paper presents a comprehensive and critical comparison of four types of constructed wetlands (CWs): free water surface CW (FWSCW), vertical flow CW (VFCW), horizontal flow CW (HFCW), and hybrid CW (HCW) for the removal of 29 pharmaceuticals (PhCs) and 19 transformation products (TPs) using a global data compiled for 247 CWs reported in 63 peer-reviewed journal papers. Biodegradation (aerobic being more efficient than anaerobic) is the major removal mechanism for 16 out of 29 PhCs besides the influence of other processes (e.g., adsorption/sorption, plant uptake, and photodegradation). The HCW performed better followed by VFCW, HFCW, and FWSCW. The comparatively better removal in HCW might be due to the coexistence of aerobic and anaerobic conditions and longer hydraulic retention time considering more than one compartment enhances the removal of PhCs (e.g., diclofenac, acetaminophen, sulfamethoxazole, sulfapyridine, trimethoprim, and atenolol), which are removed under both conditions and adsorption/sorption processes. The augmentation in dissolved oxygen by the application of artificial aeration improved the removal of PhCs, which are degraded under aerobic conditions. Furthermore, the better performance of aerated CWs could be due to the establishment of various microenvironments with different physicochemical conditions (aerobic and anaerobic), which facilitated the contribution of both aerobic and anaerobic metabolic pathways in the removal of PhCs. The removal of some of the PhCs takes place by the formation of their TPs and the nature of these TPs (persistent or non-biodegradable/biodegradable) plays a major role in their removal process.

The presence of pharmaceuticals in nature systems poses a threat to the environment, plants, animals, and, last but not least, human health. Their transport in soils, waters, and sediments plays important roles in the toxicity and bioavailability of pharmaceuticals. The mobility of pharmaceuticals can be affected by their interactions with organic matter and other soil and water constituents. In this study, a model agarose hydrogel enriched by humic acid as a representative of organic matter is used as a transport medium for pharmaceuticals. Sulphapyridine (as a representative of sulphonamide antibiotics) and diclofenac (as a representative of widely used non-steroidal anti-inflammatory drugs) were chosen for experiments in diffusion cells. Pharmaceuticals were passed through the hydrogel from the donor solution to the acceptor compartment and could interact with humic acids incorporated in the hydrogel. The lag time was prolonged if the hydrogel was enriched by humic acids from 134 to 390 s for sulphapyridine and from 323 to 606 s for diclofenac. Similarly, the incorporation of humic acids in the hydrogel resulted in a decrease in the determined diffusion coefficients. The decrease was stronger in the first stage of the experiment when diffusing particles could interact with vacant binding sites.

Hepatocellular carcinoma (HCC) is a fatal tumor which is usually diagnosed at advanced stage. Molecular targeted drugs were used recently to treat HCC, however, due to serious side effects, mainly cardiotoxicity and emergence of resistance, there is demanding to explore new chemotherapeutics. 10 novel thiazoloquinoxaline derivatives coupled with different sulfonamide moieties 4(a–j) were designed and synthesized fulfilling pharmacophoric features of VEGFR-2 inhibition. Structures of all new compounds were verified via spectral and microanalytical data. After carrying in-vitro VEGFR-2 assay for compounds 4(a–j) ; sulfapyridine and sulfamethoxazole derivatives 4d and 4f showed potential inhibitory effect [61.04 and 83.35 nM], respectively, comparable to standard sorafenib [51.41 nM]. Both were then further evaluated for their cytocidal activity against HepG2 cell-line and against myocardium cells using H9C2 cell-line. As a result, only sulfapyridine derivative 4d exhibited a significant inhibition of HepG2 cells viability [IC 50  = 4.31 μM]. Furthermore, it showed relatively lower cytotoxic impact against normal H9C2 myocardium cells [IC 50 , 33.47 μM] compared to that of sorafenib [IC 50 , 98.07 μM]. In-vivo study was carried out to determine myocardium safety of compound 4d on irradiated mice (8 Gy). In-vivo results of sulfapyridine derivative 4d showed normal cardiac enzyme function (CK) and serum catalase activity with significant reductions in LDH, cardiac TNF-α and caspase-9 levels, alongside with its efficacy in suppressing the expression of hepatic VEGF. In conclusion, sulfapyridine derivative 4d could be considered a promising candidate as VEGFR-2 inhibitor with less myocardium side effect.

Rapid, efficient, versatile, easy-to-use, and non-expensive analytical approaches are globally demanded for food analysis. Many ambient ionization approaches based on electrospray ionization (ESI) have been developed recently for the rapid molecular characterization of food products. However, those approaches mainly suffer from insufficient signal duration for comprehensive chemical characterization by tandem MS analysis. Here, a commercially available disposable gel loading tip is used as a low-cost emitter for the direct ionization of untreated food samples. The most important advantages of our approach include high stability, and durability of the signal (> 10 min), low cost (ca. 0.1 USD per run), low sample and solvent consumption, prevention of tip clogging and discharge, operational simplicity, and potential for automation. Quantitative analysis of sulfapyridine, HMF (hydroxymethylfurfural), and chloramphenicol in real sample shows the limit-of-detection 0.1 μg mL−1, 0.005 μg mL−1, 0.01 μg mL−1; the linearity range 0.1–5 μg mL−1, 0.005–0.25 μg mL−1, 0.01–1 μg mL−1; and the linear fits R2 ≥ 0.980, 0.991, 0.986. Moreover, we show that tip-ESI can also afford sequential molecular ionization of untreated viscous samples, which is difficult to achieve by conventional ESI. We conclude that tip-ESI–MS is a versatile analytical approach for the rapid chemical analysis of untreated food samples.