Sustained oxidation of Tea-Fe(III)/H2O2 simultaneously achieves sludge reduction and carbamazepine removal: The crucial role of EPS regulation.

Establishing an economic and sustained Fenton oxidation system to enhance sludge dewaterability and carbamazepine (CBZ) removal rate is a crucial path to simultaneously achieve sludge reduction and harmless. Leveraging the principles akin to "tea making", we harnessed tea waste to continually release tea polyphenols (TP), thus effectively maintaining high level of oxidation efficiency through the sustained Fenton reaction. The results illustrated that the incorporation of tea waste yielded more favorable outcomes in terms of water content reduction and CBZ removal compared to direct TP addition within the Fe(III)/hydrogen peroxide (H2O2) system. Concomitantly, this process mainly generated hydroxyl radical (•OH) via three oxidation pathways, effectively altering the properties of extracellular polymeric substances (EPS) and promoting the degradation of CBZ from the sludge mixture. The interval addition of Fe(III) and H2O2 heightened extracellular oxidation efficacy, promoting the desorption and removal of CBZ. The degradation of EPS prompted the transformation of bound water to free water, while the formation of larger channels drove the discharge of water. This work achieved the concept of treating waste with waste through using tea waste to treat sludge, meanwhile, can provide ideas for subsequent sludge harmless disposal.

Mechanistic investigation of the electricity and gallic acid synergistically accelerated Fe(III)/Fe(II) cycle for the degradation of carbamazepine.

This study investigated the application of a natural plant polyphenol, gallic acid (GA) to form complex with iron to promote the redox cycle of Fe(III)/Fe(II) under neutral initial pH conditions in the electrochemical (EC) system for activation of peroxymonosulfate (PMS) to efficiently degrade carbamazepine (CBZ). Results demonstrated that the synergistic effects of GA and EC significantly improved the removal efficiency, and the EC/GA/Fe(III)/PMS system effectively removed 100% of CBZ within a wide initial pH range of 3.0-7.0. The optimum stoichiometric ratio of GA to Fe(III) was found as 2:1. Investigations including quenching experiment, chemical probe analysis, and electron paramagnetic resonance (EPR) analysis were conducted to identify the primary reaction radicals as •OH, SO4•-, along with the 1O2 and Fe(IV). In the EC/GA/Fe(III)/PMS system, the synergistic effect of GA and electrochemistry led to a remarkable enhancement in the generation of •OH. Furthermore, the complexation reduction mechanism of GA and Fe(III) was proposed based on experimental and instrumental analyses, which demonstrated that the semi-quinone products of GA were the main substances promoting the Fe(III)/Fe(II) cycle. Mass spectrometry results showed that CBZ generated 27 byproducts during degradation, with formic acid as the main product of GA. The degradation efficiency of the EC/GA/Fe(III)/PMS system remained stable and excellent, exhibiting remarkable performance in the presence of various inorganic anions, including Cl- and NO3-, as well as naturally occurring organic compounds such as fulvic acid (FA). Overall results indicated that the EC/GA/Fe(III)/PMS system can be applied to effectively treat practical wastewater treatment without requirement of pH adjustment.

In Silico Optimization of Frizzled-8 Receptor Inhibition Activity of Carbamazepine: Designing New Anti-Cancer Agent.

BACKGROUND: Frizzled-8 (FZD8) receptor is a therapeutic target for cancer treatment and recent research has shown that carbamazepine (CBZ) can inhibit this receptor. OBJECTIVE: In this work, it has been tried to optimize CBZ to enhance its binding capacity to the N6W binding site of FZD8 by using structure-based drug design methods. METHODS: CBZ and its 83 derivatives were docked to the N6W binding site of FZD8. RESULTS: Docking results show that two compounds 79 and 82 have the smallest binding energies and are fitted to the N6W binding site. Compounds C79 and C82 have been synthesized by replacing a hydrogen atom of the seven-membered ring in CBZ with benzoate and nicotinate groups, respectively. In addition, docking results show that a trifluoromethyl on one of the phenyl rings is favorable for improving the FZD8 inhibition activity of the molecule. CONCLUSION: Both molecules C79 and C82 were subjected to molecular dynamics (MD) simulation. MD results show that FZD8-C82 complex is stable and this compound binds to the N6W binding site more strongly than compounds C79 and CBZ.

Degradation of carbamazepine by high-voltage direct current gas-liquid plasma with the addition of H2O2 and Fe2.

Carbamazepine (CBZ) is a typical psychotropic pharmaceutical which is one of the most commonly detected persistent pharmaceuticals in the environment. The degradation of CBZ in the aqueous solution was studied by a direct current (DC) gas-liquid phase discharge plasma combined with different catalysts (H2O2 or Fe2+) in this study. The concentrations of reactive species (H2O2, O3, and NO3-) and •OH radical yield in the liquid were measured during the discharge process. The various parameters that affect the degradation of CBZ, such as discharge powers, initial concentrations, initial pH values, and addition of catalysts, were investigated. The energy efficiency was 25.2 mg·kW-1·h-1 at 35.7 W, and the discharge power at 35.7 W was selected to achieve the optimal balance on the degradation effect and energy efficiency. Both acidic and alkaline solution conditions were conducive to promoting the degradation of CBZ. Both H2O2 and Fe2+ at low concentration (10-100 mg/L of Fe2+, 0.05-2.0 mmol/L of H2O2) were observed contributing to the improvement of the CBZ degradation rate, while the promotional effect of CBZ degradation was weakened even inhibition would occur at high concentrations (100-200 mg/L of Fe2+, 2.0-5.0 mmol/L of H2O2). The degradation rate of CBZ was up to 99.1%, and the total organic carbon (TOC) removal efficiency of CBZ was up to 67.1% in the plasma/Fe2+ (100 mg/L) system at 48 min, which suggested that high degradation rate and mineralization efficiency on CBZ could be achieved by employing Fe2+ as a catalyst. Based on the intermediate products identified by Ultra Performance Liquid Chromatography Tandem Mass Spectrometry (UPLC-MS), the possible degradation pathways were proposed. Finally, the growth inhibition assay with Escherichia coli (E. coli) showed that the toxicity of plasma/Fe2+-treated CBZ solution decreased and a relatively low solution toxicity could be achieved. Thus, the plasma/catalyst could be an effective technology for the degradation of pharmaceuticals in aqueous solutions.

Distinct effects on cAMP signaling of carbamazepine and its structural derivatives do not correlate with their clinical efficacy in epilepsy.

The antiepileptic sodium channel blocker, carbamazepine, has long been known to be able to attenuate cAMP signals. This could be of clinical importance since cAMP signaling has been shown to be involved in epileptogenesis and seizures. However, no information on the ability to affect cAMP signaling is available for the marketed structural derivatives, oxcarbazepine and eslicarbazepine acetate or their dominating metabolite, licarbazepine. Thus, we employed a HEK293 cell line stably expressing a cAMP biosensor to assess the effect of these two drugs on cAMP accumulation. We find that oxcarbazepine does not affect cAMP accumulation whereas eslicarbazepine acetate, surprisingly, is able to enhance cAMP accumulation. Since the transcription of ADCY8 (adenylyl cyclase isoform 8; AC8) has been found to be elevated in epileptic tissue from patients, we subsequently expressed AC8 in the HEK293 cells. In the AC8-expressing cells, oxcarbazepine was now able to attenuate whereas eslicarbazepine maintained its ability to increase cAMP accumulation. However, at all concentrations tested, licarbazepine demonstrated no effect on cAMP accumulation. Thus, we conclude that the effects exerted by carbamazepine and its derivatives on cAMP accumulation do not correlate with their clinical efficacy in epilepsy. However, this does not disqualify cAMP signaling per se as a potential disease-modifying drug target for epilepsy since more potent and selective inhibitors may be of therapeutic value.

Antiepileptic Drug Carbamazepine Binds to a Novel Pocket on the Wnt Receptor Frizzled-8.

Misregulation of Wnt signaling is common in human cancer. The development of small molecule inhibitors against the Wnt receptor, frizzled (FZD), may have potential in cancer therapy. During small molecule screens, we observed binding of carbamazepine to the cysteine-rich domain (CRD) of the Wnt receptor FZD8 using surface plasmon resonance (SPR). Cellular functional assays demonstrated that carbamazepine can suppress FZD8-mediated Wnt/ß-catenin signaling. We determined the crystal structure of the complex at 1.7 Å resolution, which reveals that carbamazepine binds at a novel pocket on the FZD8 CRD. The unique residue Tyr52 discriminates FZD8 from the closely related FZD5 and other FZDs for carbamazepine binding. The first small molecule-bound FZD structure provides a basis for anti-FZD drug development. Furthermore, the observed carbamazepine-mediated Wnt signaling inhibition may help to explain the phenomenon of bone loss and increased adipogenesis in some patients during long-term carbamazepine treatment.

Insights on adsorption of carbamazepine onto iron oxide modified diatomaceous earth: Kinetics, isotherms, thermodynamics, and mechanisms.

To ameliorate adsorbent recovery by an external magnetic field, naturally occurring diatomaceous earth (DE) was modified with iron-oxide, characterized and applied for adsorption of carbamazepine (CBZ) from synthetic wastewater using batch equilibration method. The fabricated adsorbent was characterized using XRF, XRD, SEM-EDX, FT-IR, BET surface area analysis, VSM and pH of point of zero charge (pHpzc) determination. The adsorption rate was described by the pseudo-first-order (PFO) model suggesting a physisorption controlled rate-determining step. Equilibrium adsorption data were fitted to linear and nonlinear isotherm models, viz Langmuir and Freundlich models, and were best described by Freundlich nonlinear equations implying heterogeneous multilayer adsorption. The best-fitting kinetic and isotherm model was determined using four mathematical error functions. The thermodynamic parameters, namely enthalpy (ΔH = -26.4 kJ mol-1), Gibbs free energy (ΔG = -2.22 kJ mol-1 at 298 K), entropy (ΔS = -34.0 kJ mol-1), indicated that the adsorption was a spontaneous, exothermic, and physical process. The adsorption mechanism is postulated to involve cation-π interactions. Modified diatomaceous earth is a potentially excellent, low-cost, and novel sorbent for CBZ adsorption with 88% removal in 180 min and provides a possible alternative adsorbent for wastewater treatment.

Understanding the Effects of a Polymer on the Surface Dissolution of Pharmaceutical Cocrystals Using Combined Experimental and Molecular Dynamics Simulation Approaches.

The molecular interactions between the surfaces of cocrystals [i.e., flufenamic acid and theophylline (FFA-TP), flufenamic acid and nicotinamide (FFA-NIC), and carbamazepine and nicotinamide (CBZ-NIC)] and the polymers [i.e., polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), and copolymer of vinylpyrrolidone (60%)/vinyl acetate (40%) (PVP-VA)] were investigated through combined experimental and molecular dynamics simulation approaches to resolve the mechanisms of cocrystal dissolution and precipitation. It was found that adsorption of the polymers on the surfaces of cocrystals might prevent the precipitation of the parent drug and alter the dissolution rate. The effect of polymers on precipitation could be determined by the cocrystal dissolution rate, the interactions of polymers with the surfaces of cocrystals, the characters of the noncovalent bonds formed between the polymers and the cocrystal surfaces, and the mobility and conformation of the polymers. The etching experiments of single cocrystals revealed that FFA-NIC and CBZ-NIC appeared as surface precipitation cocrystals while FFA-TP could lead to bulk precipitation. Both PVP and PVP-VA were good precipitation inhibitors for FFA-NIC, and they could completely inhibit the recrystallization of FFA III on the surfaces of dissolving cocrystals. In addition, as the adsorption of the polymer was slower than dissolution rate of the cocrystals, PVP and PVP-VA could only partially inhibit the recrystallization of CBZ dihydrate on the surface of CBZ-NIC. While PEG had no inhibitory effect on the surface crystallization of FFA-NIC and CBZ-NIC, due to its weak interactions with the surfaces of the cocrystals, it enhanced the dissolution performance of FFA-TP. In contrast, PVP and PVP-VA reduced the dissolution rate of FFA-TP and subsequently undermined the performance of cocrystals. Taken together, the approach of combining experimental and molecular dynamics simulation provided insights into the mechanisms of cocrystal dissolution as well as the polymers acting as inhibitory excipients for precipitation/recrystallization, making contribution to the development of novel formulations.

Carbamazepine promotes specific stimuli-induced NLRP3 inflammasome activation and causes idiosyncratic liver injury in mice.

The occurrence of idiosyncratic drug-induced liver injury (IDILI) is a leading cause of post-marketing safety warnings and withdrawals of drugs. Carbamazepine (CBZ), widely used as an antiepileptic agent, could cause rare but severe idiosyncratic liver injury in humans. Although recent studies have shown that inflammasome is implicated in CBZ-induced hepatocellular injury in vitro, the precise pathogenesis of hepatotoxicity remains largely unexplored. Here we report that CBZ causes idiosyncratic liver injury through promoting specific stimuli-induced NLRP3 inflammasome activation. CBZ (40 µM) enhances NLRP3 inflammasome activation triggered by adenosine triphosphate (ATP) or nigericin, rather than SiO2, monosodium urate crystal or intracellular lipopolysaccharide (LPS). In addition, CBZ has no effect on NLRC4 or AIM2 inflammasome activation. Mechanistically, synergistic induction of mitochondrial reactive oxygen species (mtROS) is a crucial event in the enhancement effect of CBZ on ATP- or nigericin-induced NLRP3 inflammasome activation. Moreover, the "C=C" on the seven-membered ring and "C=O" on the nitrogen of CBZ may be contribute to NLRP3 inflammasome hyperactivation and hepatotoxicity. Notably, in vivo data indicate that CBZ (50 mg/kg) causes liver injury in an LPS (2 mg/kg)-mediated susceptibility mouse model of IDILI, accompanied by an increase in caspase-1 activity and IL-1ß production, whereas the combination of CBZ and LPS does not exhibit the effect in NLRP3-knockout mice. In conclusion, CBZ specifically promotes ATP- or nigericin-induced NLRP3 inflammasome activation and causes idiosyncratic liver injury. Our findings also suggest that CBZ may be avoided in patients with NLRP3 inflammasome activation-related diseases that are triggered by ATP or nigericin, which may be risk factors for IDILI.

Strategy of combining radiation with ferrate oxidation for enhancing the degradation and mineralization of carbamazepine.

In this study, the strategy of combining radiation with ferrate oxidation was proposed to decrease the adsorbed dosse and enhance the mineralization of carbamazepine in aqueous solution. Compared to single radiation (800 Gy), the combined process of ferrate pretreatment and radiation required lower dose (600 Gy) for totally removing carbamazepine. During the combined process, the removal efficiency of total organic carbon (TOC) reached 22.2%. However, the removal efficiencies of carbamazepine and TOC decreased when ferrate and radiation were used simultaneously, indicating that the addition of ferrate during the radiation process had negative effect on the removal of carbamazepine. In contrast, the radiation followed by ferrate oxidation presented the best performance in decreasing the absorbed dose and enhancing the mineralization of carbamazepine. Carbamazepine could be completely removed under all conditions. TOC removal efficiency reached 18.3%, 31.3%, 52.9% and 60.6%, respectively, at the adsorbed dose of 100, 300, 600 and 800 Gy when 0.4 mM ferrate was adopted. The enhanced TOC removal could be due to the enhanced oxidation capacity of ferrate caused by the pH decrease at the end of radiation and the further oxidation of intermediate products formed during the radiation process by ferrate. Seven degradation products were identified in total, and thus the degradation pathway of carbamazepine was proposed. This study provides a possible way to decrease the adsorbed dose and enhance the mineralization of carbamazepine by radiation.

A proof of concept study demonstrating that environmental levels of carbamazepine impair early stages of chick embryonic development.

Carbamazepine (CBZ) is an anticonvulsant drug used for epilepsy and other disorders. Prescription of CBZ during pregnancy increases the risk for congenital malformations. CBZ is ubiquitous in effluents and persistent during wastewater treatment. Thus, it is re-introduced into agricultural ecosystems upon irrigation with reclaimed wastewater. People consuming produce irrigated with reclaimed wastewater were found to be exposed to CBZ. However, environmental concentrations of CBZ (µgL-1) are magnitudes lower than its therapeutic levels (µgml-1), raising the question of whether and how environmental levels of CBZ affect embryonic development. The chick embryo is a powerful and highly sensitive amniotic model system that enables to assess environmental contaminants in the living organism. Since the chick embryonic development is highly similar to mammalians, yet, it develops in an egg, toxic effects can be directly analyzed in a well-controlled system without maternal influences. This research utilized the chick embryo to test whether CBZ is embryo-toxic by using morphological, cellular, molecular and imaging strategies. Three key embryonic stages were monitored: after blastulation (st.1HH), gastrulation/neurulation (st.8HH) and organogenesis (st.15HH). Here we demonstrate that environmental relevant concentrations of CBZ impair morphogenesis in a dose- and stage- dependent manner. Effects on gastrulation, neural tube closure, differentiation and proliferation were exhibited in early stages by exposing embryos to CBZ dose as low as 0.1µgL-1. Quantification of developmental progression revealed a significant difference in the total score obtained by CBZ-treated embryos compared to controls (up to 5-fold difference, p<0.05). Yet, defects were unnoticed as embryos passed gastrulation/neurulation. This study provides the first evidence for teratogenic effect of environmental-relevant concentrations of CBZ in amniotic embryos that impair early but not late stages of development. These findings call for in-depth risk analysis to ensure that the environmental presence of CBZ and other drugs is not causing irreversible ecological and public-health damages.

Complex amorphous solid dispersions based on poly(2-hydroxyethyl methacrylate): Study of drug release from a hydrophilic insoluble polymeric carrier in the presence and absence of a porosity increasing agent.

Amorphous solid dispersions are nowadays typically made up of a drug compound and a water-soluble polymer. However, recently it has been demonstrated that amorphous solid dispersions based on insoluble polymers have a different and more delayed drug release profile, resulting in a prolonged duration of supersaturation. In this paper, binary and ternary amorphous solid dispersions based on poly(2-hydroxyethyl methacrylate) were prepared through spray drying to further investigate the potential of this type of carrier. As drug release from this matrix system was expected to be dictated by a diffusion-driven process, porosity of the formulation was adjusted by the inclusion of a water-soluble polymer. The solid state of the formulations was characterized with modulated differential scanning calorimetry, X-ray powder diffraction and thermogravimetric analysis. The release of drug and of the porosity increasing agent was measured in acidic and neutral conditions. In addition, the release performance of the spray dried product was compared with the drug release from poly(2-hydroxyethyl methacrylate) beads, which had already been reported in literature. It appeared that in the case of the spray dried poly(2-hydroxyethyl methacrylate), drug and porosity increasing agent could only be released to a certain extent due to entrapment of both compounds in the poly(2-hydroxyethyl methacrylate) network. While the chemical crosslinks of poly(2-hydroxyethyl methacrylate) beads ensured a more rigid structure with sufficient free space for drug diffusion, the spray dried product was susceptible to intense physical crosslinking upon contact with the dissolution medium.

Mechanics of tablet formation: a comparative evaluation of percolation theory with classical concepts.

The present study is based on the fundamentals of percolation theory and its application in understanding compression and compaction of powder materials. Four materials, i.e. carbamazepine, microcrystalline cellulose, crospovidone and croscarmellose sodium, with dissimilar deformation and compaction behavior were selected to validate the hypotheses of percolation phenomenon. The values of two percolation thresholds, i.e. bond and site, corresponding to the lower and intermediate compression pressures, were determined using Heckel equation. The compactibility of powder materials was evaluated using classical models as well as the power law equation. The values of percolation thresholds were found to better assess the deformation behavior of powder materials compared to the values of mean yield pressure. The power law equation demonstrated better prediction of compactibility of powder materials compared to the classical models. The value of the critical exponent, q, determined using power law equation by plotting tensile strength vs. normalized relative density of powder compacts was found to be closer to the theoretical value of 2.70. Furthermore, the theoretical knowledge of percolation thresholds of individual powder components in the binary mixture was found to be helpful in improving compaction properties of the poorly compactible material, i.e. carbamazepine. Thus percolation theory can be helpful in predicting compression and compaction behavior of powder materials and serve as a potent tool for the successful design of tablet formulations.

Allosteric Interactions in Human Cytochrome P450 CYP3A4: The Role of Phenylalanine 213.

The role of Phe213 in the allosteric mechanism of human cytochrome P450 CYP3A4 was studied using a combination of progesterone (PGS) and carbamazepine (CBZ) as probe substrates. We expressed, purified, and incorporated into POPC Nanodiscs three mutants, F213A, F213S, and F213Y, and compared them with wild-type (WT) CYP3A4 by monitoring spectral titration, the rate of NADPH oxidation, and steady-state product turnover rates with pure substrates and substrate mixtures. All mutants demonstrated higher activity with CBZ, lower activity with PGS, and a reduced level of activation of CBZ epoxidation by PGS, which was most pronounced in the F213A mutant. Using all-atom molecular dynamics simulations, we compared the dynamics of WT CYP3A4 and the F213A mutant incorporated into the lipid bilayer and the effect of the presence of the PGS molecule at the allosteric peripheral site and evaluated the critical role of Phe213 in mediating the heterotropic allosteric interactions in CYP3A4.

1H NMR Relaxation Study to Evaluate the Crystalline State of Active Pharmaceutical Ingredients Containing Solid Dosage Forms Using Time Domain NMR.

The aim of this study was to demonstrate the usefulness of the time domain nuclear magnetic resonance (TD-NMR) method to characterize the crystalline state of active pharmaceutical ingredients (APIs) containing solid dosage forms. In this study, carbamazepine and indomethacin are used as models for poorly water-soluble APIs. First, we measured the T1 and T2 relaxation behavior of crystalline and amorphous APIs. From the results, we were able to confirm that the T1 relaxation time measured by TD-NMR is an effective parameter for distinguishing between crystalline and amorphous states in powdered APIs. We then examined physical mixtures of APIs with polyvinylpyrrolidone and their solid dispersion. The results indicated that TD-NMR allows the evaluation of not only the crystalline form of APIs but also the miscibility of APIs and polymers. In the final phase of the study, we conducted continuous monitoring of the crystalline state of APIs incorporated into physical mixtures during the thermal stress test. Conversion to crystalline forms of the APIs was successfully monitored based on the T1 relaxation behavior. Our findings led us to conclude that TD-NMR is useful as a new approach to evaluate the crystalline state of APIs.

The first-line antiepileptic drug carbamazepine: Reaction with biologically relevant free radicals.

Carbamazepine (CBZ) is one of the most widely used antiepileptic drugs by both adults and children. Despite its widespread use, CBZ is associated with central nervous system toxicity and severe hypersensitivity reactions, which raise concerns about its chronic use. While the precise mechanisms of CBZ-induced adverse events are still unclear, metabolic activation to the epoxide (CBZ-EP) has been thought to play a significant role. This work reports first-hand evidence that CBZ reacts readily with biologically relevant thiyl radicals with no need for bioactivation. Using liquid chromatography coupled with high resolution mass spectrometry, multiple products from direct reaction of CBZ with glutathione (GSH) and N-acetyl-L-cysteine (NAC) were unequivocally identified, including the same product obtained upon ring-opening of CBZ-EP. The product profile is complex and consistent with radical-mediated mechanisms. Importantly, side products and adducts compatible with this non-enzymatic pathway were identified in liver extracts from CBZ-treated Wistar rats. The reaction of CBZ with GSH and NAC is more extensive in the presence of oxygen. Taking into consideration that GSH conjugation is, in general, a detoxification pathway, these results suggest that under hyperoxia/oxidative stress conditions the bioavailability of the parent drug may be compromised. Additionally, this non-enzymatic process can be anticipated to play, at least in part, a role in the onset of CBZ-induced adverse reactions due to the concomitant generation of reactive oxygen species. Therefore, the search for causal relationships between the formation of non-enzymatically-driven CBZ products and the occurrence of CBZ-induced adverse events in human patients merits further research, aiming the translation of basic mechanistic findings into a clinical context that may ultimately lead to a safer CBZ prescription.

Critical assessment of approaches for molecular docking to elucidate associations of HLA alleles with adverse drug reactions.

Adverse drug reactions have been linked with genetic polymorphisms in HLA genes in numerous different studies. HLA proteins have an essential role in the presentation of self and non-self peptides, as part of the adaptive immune response. Amongst the associated drugs-allele combinations, anti-HIV drug Abacavir has been shown to be associated with the HLA-B*57:01 allele, and anti-epilepsy drug Carbamazepine with B*15:02, in both cases likely following the altered peptide repertoire model of interaction. Under this model, the drug binds directly to the antigen presentation region, causing different self peptides to be presented, which trigger an unwanted immune response. There is growing interest in searching for evidence supporting this model for other ADRs using bioinformatics techniques. In this study, in silico docking was used to assess the utility and reliability of well-known docking programs when addressing these challenging HLA-drug situations. The overall aim was to address the uncertainty of docking programs giving different results by completing a detailed comparative study of docking software, grounded in the MHC-ligand experimental structural data - for Abacavir and to a lesser extent Carbamazepine - in order to assess their performance. Four docking programs: SwissDock, ROSIE, AutoDock Vina and AutoDockFR, were used to investigate if each software could accurately dock the Abacavir back into the crystal structure for the protein arising from the known risk allele, and if they were able to distinguish between the HLA-associated and non-HLA-associated (control) alleles. The impact of using homology models on the docking performance and how using different parameters, such as including receptor flexibility, affected the docking performance were also investigated to simulate the approach where a crystal structure for a given HLA allele may be unavailable. The programs that were best able to predict the binding position of Abacavir were then used to recreate the docking seen for Carbamazepine with B*15:02 and controls alleles. It was found that the programs investigated were sometimes able to correctly predict the binding mode of Abacavir with B*57:01 but not always. Each of the software packages that were assessed could predict the binding of Abacavir and Carbamazepine within the correct sub-pocket and, with the exception of ROSIE, was able to correctly distinguish between risk and control alleles. We found that docking to homology models could produce poorer quality predictions, especially when sequence differences impact the architecture of predicted binding pockets. Caution must therefore be used as inaccurate structures may lead to erroneous docking predictions. Incorporating receptor flexibility was found to negatively affect the docking performance for the examples investigated. Taken together, our findings help characterise the potential but also the limitations of computational prediction of drug-HLA interactions. These docking techniques should therefore always be used with care and alongside other methods of investigation, in order to be able to draw strong conclusions from the given results.

Kinetics and mechanisms of the degradation of PPCPs by zero-valent iron (Fe°) activated peroxydisulfate (PDS) system in groundwater.

The abatement of pharmaceuticals and personal care products (PPCPs), including carbamazepine (CBZ), acetaminophen (ACP) and sulfamethoxazole (SMX), by zero-valent iron (Fe°) activated peroxydisulfate (PDS) system (Fe°/PDS) in pure water and groundwater was investigated. The removal rates of CBZ, ACP and SMX were 85.4%, 100% and 73.1%, respectively, within 10 min by Fe°/PDS in pure water. SO4•-, •OH and O2•- were identified in the Fe°/PDS system, and O2•- was indicated to play an important role in the ACP degradation. The degradation of PPCPs increased with increasing dosages of Fe° and PDS or with decreasing pH and initial PPCP concentrations. Interestingly, the degradation of PPCPs by Fe°/PDS was significantly enhanced in groundwater compared with that in pure water, which was partially attributed to SO42- and Cl-. The first-order constants of CBZ, ACP and SMX increased from 0.021, 0.242 and 0.013 min-1 to 0.239, 2.536 and 0.259 min-1, and to 0.172, 1.516 and 0.197 min-1, respectively, with increasing the concentrations of SO42- and Cl- to 100 mg/L and 10 mg/L, respectively. This study firstly reports the unexpected enhancement of groundwater matrix on the degradation of micropollutants by Fe°/PDS, demonstrating that Fe°/PDS can be an efficient technology for groundwater remediation.

Comparative study of substituted poly(4-vinylbenzyl chloride/ethylene glycol dimethacrylate) sorbents for enrichment of selected pharmaceuticals and estrogens from aqueous samples.

This study reports the syntheses of four polymeric sorbents based on nucleophilic substitution of Poly(4-vinylbenzylchloride/ethylene glycol dimethacrylate). Polymerization was executed by a simple thermal initiated bulk polymerization procedure. Ground polymer particles were functionalized through reaction with the nucleophiles triethylamine, imidazole, piperidine and pyrrolidine. Mixed-mode phases were characterized by infrared spectroscopy, nitrogen sorption porosimetry and potentiometric titration for determination of chloride content. Furthermore, materials were tested and evaluated for enrichment of seven pharmaceutical and endocrine-disrupting compounds at low ng mL-1 levels. Results demonstrate that the imidazole modified sorbent led to high and constant recovery rates for nearly all tested compounds. Therefore, this polymer was further tested for applicability with two environmental samples. Spiked tap and river water showed similar results as in evaluation experiments. Moreover, the developed method was validated regarding linearity, repeatability, instrumental limits and stability of analytes according to international guidelines.

Supramolecular Metal-Phenolic Gels for the Crystallization of Active Pharmaceutical Ingredients.

The use of supramolecular gel media for the crystallization of active pharmaceutical ingredients (APIs) is of interest for controlling crystal size, morphology, and polymorphism, as these features determine the performance of pharmaceutical formulations. In contrast to supramolecular systems prepared from synthetic gelators, herein, supramolecular metallogels based on a natural polyphenol (tannic acid) are used for the crystallization of APIs. The gel-grown API crystals exhibit considerable differences in size, morphology, and polymorphism when compared with those formed in solutions. These physical features can also be tailored by varying the gel composition and additives, suggesting an influence of the gel medium on the crystallization outcomes. Furthermore, these gel-API crystal composites can be used for sustained drug release, indicating their potential as drug delivery systems. The facile preparation of these supramolecular gels and the use of naturally abundant components in their synthesis provide a generic platform for studying gel-mediated crystallization of diverse APIs.