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PurposeNitisinone inhibits the cytochrome P450 (CYP) subfamilies CYP2C9, CYP2D6, and CYP2E1 and the organic anion transporter (OAT) isoforms OAT1 and OAT3 in vitro. Since the effect of nitisinone on these enzymes and transporters in humans is still unknown, the purpose of this study was to evaluate the effect of nitisinone on these CYP subfamilies and OAT isoforms.MethodsThis was an open-label, nonrandomized, two-arm, phase 1 study (EudraCT: 2016-004297-17) in healthy volunteers. The substrates (tolbutamide, metoprolol, and chlorzoxazone for the respective CYPs and furosemide for the OATs) were administered as single doses, before and after 15 days of once daily dosing of 80 mg nitisinone, to determine the AUC∞ ratios ([substrate+nitisinone]/[substrate]). Nitisinone pharmacokinetics, safety, and tolerability were also assessed, and blood and urine were collected to determine substrate and nitisinone concentrations by LC-MS/MS.ResultsThirty-six subjects were enrolled with 18 subjects included in each arm. The least square mean ratio (90% confidence interval) for AUC∞ was 2.31 (2.11–2.53) for tolbutamide, 0.95 (0.88–1.03) for metoprolol, 0.73 (0.67–0.80) for chlorzoxazone, and 1.72 (1.63–1.81) for furosemide. Clinically relevant nitisinone steady-state concentrations were reached after 12 days: mean Cav,ss of 94.08 μM. All treatments were well tolerated, and no safety concerns were identified.ConclusionsNitisinone did not affect CYP2D6 activity, was a weak inducer of CYP2E1, and was a weak inhibitor of OAT1 and OAT3. Nitisinone was a moderate inhibitor of CYP2C9, and treatment may therefore result in increased plasma concentrations of comedications metabolized primarily via this enzyme.Clinical trial registry identificationEudraCT 2016-004297-17.

Curcumin, a pharmacological agent found in turmeric’s rhizome, has been studied for its various therapeutic properties. However, its clinical development is hindered by its instability and low solubility in water, resulting in inadequate oral bioavailability. Two potential curcumin analogs, 2,5-bis(4’-hydroxy-3’,5’-dimethoxybenylidene)cyclopentanone (PGV-5) and 2,6-bis(4’-hydroxy-3’,5’-dimethoxybenylidene)cyclohexanone (HGV-5), are being developed to address this issue and enhance their therapeutic efficacy. The study aims to screen novel curcumin analog compounds by integrating in silico assessment of ADME properties, acute toxicity studies, and computational analysis. PGV-5 and HGV-5 are classified as Global Harmonized System of Classification and Labeling of Chemicals (GHS) class 4 and class 5, respectively, in acute toxicity assessment, as they cause histopathological changes in the heart and lungs. Their ADME profile indicates they serve as effective P-glycoprotein (P-gp) inhibitors, making them potential candidates for development as anti-multidrug resistance agents, particularly in cancer cells. Molecular docking on P-gp revealed significant inhibitory capability relative to curcumin, exhibiting comparable binding characteristics to the native ligand, as evidenced by superior docking scores. Subsequent molecular dynamics simulations confirmed the stable interaction of both compounds with P-gp, with HGV-5 showing the most favorable binding free energy. Target gene mapping revealed several pivotal targets including AKT1, STAT3, EGFR, and NF-κB1. These findings suggest that PGV-5 and HGV-5 merit further research as agents against multidrug-resistant in cancer, regardless of their toxicity profiles. Further confirmation of their effects requires more laboratory studies and clinical trials.

Introduction In hereditary tyrosinemia type 1 (HT1) patients, the dose of NTBC that leads to the absence of toxic metabolites such as succinylacetone (SA) is still unknown. Therefore, the aims of this study were to investigate the variation and concentrations of 2-(2-nitro-4-trifluormethyl-benzyl)-1,3-cyclohexanedione (NTBC) during the day in relation to the detection of SA, while comparing different dosing regimens. Methods All patients were treated with NTBC (mean 1.08 ± 0.34 mg/kg/day) and a low phenylalanine-tyrosine diet. Thirteen patients received a single dose of NTBC and five patients twice daily. Home bloodspots were collected four times daily for three consecutive days measuring NTBC and SA concentrations. Statistical analyses were performed by using mixed model analyses and generalized linear mixed model analyses to study variation and differences in NTBC concentrations and the correlation with SA, respectively. Results NTBC concentrations varied significantly during the day especially if NTBC was taken at breakfast only ( p  = 0.026), although no significant difference in NTBC concentrations between different dosing regimens could be found ( p  = 0.289). Momentary NTBC concentrations were negatively correlated with SA ( p  < 0.001). Quantitatively detectable SA was only found in subjects with once daily administration of NTBC and associated with momentary NTBC concentrations <44.3 μmol/l. Discussion NTBC could be less stable than previously considered, thus dosing NTBC once daily and lower concentrations may be less adequate. Further research including more data is necessary to establish the optimal dosing of NTBC.

The intensive use of agrochemicals has played an important role in increasing agricultural production. One of the impacts of agrochemical use has been changes in population structure of soil microbiota. The aim of this work was to analyze the adaptive strategies that bacteria use to overcome oxidative stress caused by mesotrione, which inhibits 4-hydroxyphenylpyruvate dioxygenase. We also examined antioxidative stress systems, saturation changes of lipid membranes, and the capacity of bacteria to degrade mesotrione. Escherichia coli DH5-á was chosen as a non-environmental strain, which is already a model bacterium for studying metabolism and adaptation. The results showed that this bacterium was able to tolerate high doses of the herbicide (10× field rate), and completely degraded mesotrione after 3 h of exposure, as determined by a High Performance Liquid Chromatography. Growth rates in the presence of mesotrione were lower than in the control, prior to the period of degradation, showing toxic effects of this herbicide on bacterial cells. Changes in the saturation of the membrane lipids reduced the damage caused by reactive oxygen species and possibly hindered the entry of xenobiotics in the cell, while activating glutathione-S-transferase enzyme in the antioxidant system and in the metabolizing process of the herbicide. Considering that E. coli DH5-α is a non-environmental strain and it had no previous contact with mesotrione, the defense system found in this strain could be considered non-specific. This bacterium system response may be a general adaptation mechanism by which bacterial strains resist to damage from the presence of herbicides in agricultural soils.

A new designer drug, a dissociative anesthetic, and a putative N-methyl-D-aspartate receptor antagonist, methoxetamine (MXE) noted by the EU Early Warning System has been already identified as a cause of several fatalities worldwide. The primary objective of this work was to develop a suitable sample preparation method allowing for isolation of MXE and its main metabolites in high yields from rat brain, liver, and lungs. For the purpose of the project, MXE and five metabolites were synthesized in-house, specifically O-desmethyl-normethoxetamine, O-desmethylmethoxetamine, dihydro-O-desmethylmethoxetamine, normethoxetamine, and dihydromethoxetamine. A sample preparation procedure consisted in the homogenization of the tissue applying salting-out-assisted liquid–liquid extraction (SALLE). A subsequent liquid chromatography-mass spectrometry (LC-MS) analysis was based on reversed-phased chromatography hyphenated with a triple quad MS system in a positive electrospray mode. Multiple reaction monitoring (MRM) was used for qualification and quantification of the analytes. The quantification was based on the application of an isotopically labeled internal standard, normethoxetamine-d₃. The matrix-matched calibrations were prepared for each type of matrix with regression coefficients 0.9943–1.0000. The calibration curves were linear in the concentration range of 2.5–250 ng g⁻¹. Limits of quantification (LOQs) were estimated as 2.5 and 5 ng g⁻¹, respectively. Recovery (80–117 %) and matrix effect (94–110 %) at 100 ng g⁻¹ and intra- and inter-day accuracy and precision at low (2.5 ng g⁻¹), middle (25 ng g⁻¹), and upper (250 ng g⁻¹) concentration levels for all the analytes in all three types of tissues were also determined. The developed analytical method was applied to a set of real samples gathered in toxicological trials on rats and MXE, and its metabolites were determined successfully.

A sensitive and accurate high performance liquid chromatography with ultraviolet/visible light detection (HPLC-UV/VIS) method for the quantification of 2,6-bis-(4-hydroxy-3-methoxybenzylidene)-cyclohexanone (BHMC) in rat plasma was developed and validated. BHMC and the internal standard, harmaline, were extracted from plasma samples by a simple liquid–liquid extraction using 95% ethyl acetate and 5% methanol. Plasma concentration of BHMC and internal standard were analyzed by reversed phase chromatography using a C18 column (150 × 4.6 mm I.D., particle size 5 µm) and elution with a gradient mobile phase of water and methanol at a flow rate of 1.0 mL/min. Detection of BHMC and internal standard was done at a wavelength of 380 nm. The limit of quantification was 0.02 µg/mL. The calibration curves was linear (R2 > 0.999) over the concentration range of 0.02–2.5 µg/mL. Intra- and inter-day precision were less than 2% coefficient of variation. The validated method was then applied to a pharmacokinetic study in rats by intravenous administration of BHMC at a single dose of 10 mg/kg. Pharmacokinetic parameters such as half-life, maximum plasma concentration, volume of distribution, clearance and elimination rate constant for BHMC were calculated.

NTBC (2-(2-nitro-4-trifluoromethylbenzoyl)-1,3cyclohexanedione) is the mainstay of treatment in tyrosinemia type 1 (HT 1). The current recommendation is to divide the total daily dose of NTBC into two doses. We monitored the plasma NTBC concentrations in a series of seven patients who were changed from multiple divided doses to a single daily dose of NTBC. Two additional patients were started on a single daily dose of NTBC after the diagnosis of HT 1 was established. In three patients, NTBC kinetics were performed over 6 and 24 hours, respectively. The use of multiple divided doses or a single daily dose did not significantly affect plasma NTBC concentrations or the mean daily dose needed to attain therapeutic plasma NTBC concentrations. Moreover, kinetic studies demonstrated that plasma NTBC concentrations were completely stable over a period of 24 hours with a single dose regimen, as expected given the known NTBC plasma half life of 54 hours. Although these preliminary results need to be confirmed in more patients, our findings show that administration of NTBC in a single daily dose may be as effective as a multiple-dose regimen in reaching therapeutic plasma NTBC concentrations and suppressing succinylacetone formation in patients with HT 1. In fact, single dose treatment may increase patients’ compliance with the drug treatment and improve metabolic control.

Methoxetamine (MXE; 2-(3-methoxyphenyl)-2-( N -ethylamino)-cyclohexanone), a ketamine analog, is a new designer drug and synthesized for its longer lasting and favorable pharmacological effects over ketamine. The aims of the presented study were to identify the phases I and II metabolites of MXE in rat and human urine by GC-MS and LC-high-resolution (HR)-MS n and to evaluate their detectability by GC-MS and LC-MS n using authors’ standard urine screening approaches (SUSAs). Furthermore, human cytochrome P450 (CYP) enzymes were identified to be involved in the initial metabolic steps of MXE in vitro, and respective enzyme kinetic studies using the metabolite formation and substrate depletion approach were conducted. Finally, human urine samples from forensic cases, where the ingestion of MXE was suspected, were analyzed. Eight metabolites were identified in rat and different human urines allowing postulation of the following metabolic pathways: N -deethylation, O -demethylation, hydroxylation, and combinations as well as glucuronidation or sulfation. The enzyme kinetic studies showed that the initial metabolic step in humans, the N -deethylation, was catalyzed by CYP2B6 and CYP3A4. Both SUSAs using GC-MS or LC-MS n allowed monitoring an MXE intake in urine.

Modified QuEChERS-HLPC (quick, easy, cheap, effective, rugged and safe) methods for the analysis of mesotrione in maize and soil were developed and validated. At three fortification levels of 0.01, 0.1 and 0.5 mg kg −1 mesotrione, the recoveries of mesotrione in maize plants, maize and soil were in the range of 85.95 %–96.05 %, with relative standard deviations (RSD) of 2.89 %–9.83 %. The limit of quantification (LOQ) of method was 0.001 mg kg −1 for maize and soil. In the supervised field trials, the degradation rates of mesotrione were described using first-order kinetics and mesotrione dissipation in maize plants coincided with C t  = 1.735e −1.0194t with the half-life 3.94 days in Tianjin, and C t  = 4.9536e −0.7237t with the half-life 5.10 days in Jilin. As for soil, C t  = 20.272e −1.208t with the half-life 2.98 days in Tianjin, and C t  = 5.5835e −8141t with the half-life 4.49 days in Jilin. At pre-harvest interval (PHI) of 0 and 20 days, the final residue levels of mesotrione could not be detected in maize and soil at the recommended dosage and 1.5 times recommended dosage.