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BACKGROUND: For extended-release drug formulations, effective half-life (t 1/2eff ) is a relevant pharmacokinetic parameter to inform dosing strategies and time to reach steady state. Tacrolimus, an immunosuppressant commonly used for the prophylaxis of organ rejection in transplant patients, is available as both immediate- and extended-release formulations. To the best of our knowledge, the t 1/2eff of tacrolimus from these different formulations has not yet been assessed. The objective of this study was to characterize the t 1/2eff and terminal half-life (t 1/2z ) of an extended-release once-daily tacrolimus formulation (LCPT) and twice-daily immediate-release tacrolimus (IR-Tac). METHODS: A noncompartmental analysis of pharmacokinetic data obtained from a phase 2 study in de novo kidney transplant recipients receiving either LCPT or IR-Tac was conducted. Intensive blood sampling was performed on days 1, 7, and 14, and tacrolimus whole blood concentrations were measured using a validated liquid chromatography with tandem mass spectrometry method. T 1/2eff was estimated using within-participant accumulation ratios. T 1/2z was estimated by linear regression of the terminal phase of the concentration versus time profile. RESULTS: The median accumulation ratios of LCPT and IR-Tac on day 14 were 3.18 and 2.06, respectively.The median (interquartile range; IQR) t 1/2eff for LCPT at day 14 of dosing was 48.4 (37.4-77.9) hours, whereas the t 1/2z was 20.3 (17.6-22.9) hours. For IR-Tac, the median (IQR) t 1/2eff and t 1/2z on day 14 were 12.5 (8.8-23.0) hours and 12.2 (9.2-15.7) hours, respectively. CONCLUSIONS: Consistent with its prolonged release of tacrolimus, LCPT demonstrated a higher accumulation ratio and a longer t 1/2eff compared with IR-Tac. These findings underscore the pharmacokinetic differences between different drug formulations of the same moiety and may help inform dose adjustments for LCPT in kidney transplantation.

Chronic pain represents a significant unmet medical need, affecting one-fifth of the U.S. population. EC5026 is a small molecule inhibitor of the enzyme soluble epoxide hydrolase (sEH) which is being developed as a novel non-opioid, non-NSAID analgesic. EC5026 prolongs the action of epoxy fatty acids, endogenous analgesic lipid mediators that are rapidly metabolized by sEH. We evaluated the safety and pharmacokinetic profile of EC5026 in two phase I trials, a single-ascending dose (SAD) study and a fed-fasted study. The SAD study evaluated EC5026 doses ranging from 0.5 to 24 mg in healthy volunteers. EC5026 was well tolerated. No treatment-emergent adverse events were considered related to EC5026. No apparent treatment- or dose-related trends in laboratory results, vital signs, physical examinations, or electrocardiograms were observed. A linear, near-dose-proportional increase in exposure was observed with progressive doses in the SAD study; plasma exposure was below or near the lower limit of quantification after 0.5-2 mg doses. Mean half-lives ranged from 41.8 to 59.1 h. for doses of 8-24 mg, supporting a once-daily dosing regimen. In the fed-fasted study using 8 mg EC5026 tablets, higher peak concentrations (66%) and total exposures (53%) were observed under the fed condition. Plasma concentrations declined in a monoexponential manner with mean half-lives of 59.5 h. in the fed state and 66.9 h. in the fasted state. Future clinical trials using EC5026 for the treatment of pain are justified based on the favorable outcomes from both clinical trials along with preclinical evidence of analgesic activity.

In this work we present to our knowledge the most precise measurement of the 7Be electron capture decay half-life in a host material. A silicon carbide sample with ~8.62 × 1097Be atoms was measured for 83.5 d on an ultra-low background high purity Ge detector located deep underground in the Laboratori Nazionali del Gran Sasso, Italy. The result obtained for the decay half-life is T 1/2 = 53.284 ± 0.016 d, which corresponds to an uncertainty of 0.3‰. Thanks to the high sensitivity achieved, this measurement is paving the way to further investigations on this process aiming to understand how environmental conditions may affect the decay half-life. [ABSTRACT FROM AUTHOR]

In this paper, we propose a new analytical solution of the α-decay process for the Killingbeck potential with the spherical Coulomb potential and determine the half-lives of some α-emitters with atomic number (Z) located in the region 60≤Z≤92 using the Wentzel–Kramers–Brillouin (WKB) approximation. The Killingbeck potential, with its complex form including harmonic and linear confinement terms, offers a greater richness of interaction and nuclear shape. We provide a solution to the problem of multiple turning points by showing that they can be reduced to two nonsymmetric points. Results obtained show relationships between the paramater of the nuclear potential and experimental data. Those results are compared with experimental data and other theoretical results from the literature. We find that our results are in very good agreement with the experimental data. [ABSTRACT FROM AUTHOR]

Background/Objectives: Chemoresistance of breast cancers (BCs) is a major impediment to current chemotherapeutics that urges the development of new drugs and new therapeutic approaches. To that end, phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs) were recently prepared to fulfill some of the unmet needs with classic chemotherapeutics. PAIB-SOs are prodrugs bioactivated into potent antimitotics by the cytochrome P450 1A1 (CYP1A1), which is a frequent enzyme in resistant BC cells, but mostly missing in normal cells. Our screening program studies of PAIB-SO chemolibraries selected three prototypical PAIB-SOs as antimitotic prodrugs amenable for studies using BC animal models. Methods: Healthy female CD1® IGS mice were treated with three prototypical PAIB-SOs, namely CEU-835, -934, and -938, for the determination of their toxicity and half-lives. Moreover, MCF7 tumor-bearing CD1-Foxn1nu Nude female mice were treated with the three prototypical PAIB-SOs for the determination of their antitumor activity. Results: Herein, we show that multi-intravenous administrations of CEU-835, -934, and -938 at their maximal solubilities are well tolerated in healthy female CD1® IGS mice, as depicted by the evaluation of distress behaviors, organ necropsy, total blood cell count, and histology. Moreover, the half-life of CEU-835, -934, and -938 administered intravenously in healthy CD1® IGS female mice were 8.1, 23.2, and 21.5 h, respectively. Finally, their intravenous administrations of CEU-934 and -938 decreased MCF7 tumor growth as efficiently as paclitaxel in MCF7 tumor-bearing CD1-Foxn1nu Nude mouse model. Conclusions: overall, our study demonstrated for the first time that pentyl-bearing PAIB-SOs are new CYP1A1-dependent prodrugs efficiently decrease breast cancer tumor growth, and show no side effects at their pharmacological concentration in mouse models. [ABSTRACT FROM AUTHOR]

Aflibercept and brolucizumab, two anti-VEGF agents used as intravitreal injections in ophthalmology, differ significantly in molecular weight (aflibercept—115 kDa and brolucizumab—26 kDa). Using aqueous humor samples collected after drug administration, we measured and performed a comparative analysis of pharmacokinetics and half-lives of these drugs in the human eye. Since the quantification of monoclonal antibodies (mAbs) using antigen–antibody reactions, such as ELISA, is influenced by endogenous ligands or anti-drug antibodies, we employed nano-surface and molecular-orientation limited proteolysis (nSMOL), combined with liquid chromatography–tandem mass spectrometry (LC-MS/MS), for accurate measurements. Aqueous humor samples were collected from 59 eyes of 59 patients treated with aflibercept and 52 eyes of 52 patients treated with brolucizumab. Samples were obtained with a median post-injection period of 30 (range, 2–49) days for aflibercept and 28 (range, 4–60) days for brolucizumab. A population pharmacokinetic (PPK) analysis revealed that the half-life of aflibercept in human aqueous humor was significantly shorter than that of brolucizumab, 2.88 days versus 9.00 days, respectively (p = 1.16 × 10−7). Using the same mass spectrometry conditions, we calculated the half-lives of the two drugs. These results may be useful for optimizing the efficacy of these drugs in clinical practice. [ABSTRACT FROM AUTHOR]

Background: Cell-free DNA (cfDNA) is present in healthy individuals but is elevated in those undergoing physical exertion, trauma, sepsis, and certain cancers. Maintaining cfDNA concentrations is vital for immune homeostasis and preventing inflammatory responses. Understanding cfDNA release and clearance is essential for using cfDNA as a biomarker in clinical diagnostics. We focused on the fragment size of cfDNA and investigated cfDNA dynamics and half-life, particularly the 100–250 base pair fragments. Methods: Healthy, adult men (n = 5; age 40 ± 4.1 years) were subjected to a 30 min treadmill exercise. Blood samples were collected at 0, 5, 10, 15, 30, and 60 min post-exercise using PAXgene® Blood ccfDNA tubes to stabilize and prevent nuclease-mediated cfDNA degradation and minimize genomic DNA contamination risk. The cfDNA concentration was measured using an electrophoresis-based technique (4150 TapeStation system) to quantify the concentration based on cfDNA fragment size. Results: The results showed a cfDNA half-life of 24.2 min, with a transient increase in 100–250 base pair cfDNA fragments post-exercise, likely due to nuclease activity. These levels rapidly reverted to the baseline within an hour. Conclusions: The rapid clearance of cfDNA underscores its potential as a biomarker for real-time disease monitoring and the evaluation of treatment efficacy. This study is expected to standardize cfDNA investigations, enhancing diagnosis and treatment monitoring across various disease conditions. [ABSTRACT FROM AUTHOR]

To examine the effect of organic amendments on the dissipation and nitrification inhibition activity of 2-amino 4-chloro 6-methyl pyrimidine (AM), a laboratory study was conducted on a sandy loam soil (Typic Hapludoll) receiving no organic amendments (Control) or application of farmyard manure (FYM) or pine needles biochar (PNB) @ 5 t ha−1. Dissipation of AM was initially faster during the first 7 d, and then it slowed down. Dissipation kinetics of AM conformed to the first-order model (R2 values = 0.973 to 0.981, significant at p ≤.01). The conventionally estimated time for the dissipation of half the amount of initially detected AM (half-life) was 15.9, 23.6, and 12.1 d for the control, FYM, and PNB treatments, respectively. All treatments receiving AM had numerically lower NO3−–N concentrations compared to no AM but significantly lower NO3−–N concentrations were recorded under, especially the PNB + AM treatment at 15, 30, 45, 60 and 90 d. The higher effectiveness of AM under PNB could be attributed to the sorption of AM in the micro-pores of PNB with slower release. Percent distribution of sorbed AM onto FYM and PNB revealed that desorption of sorbed AM from PNB was comparatively very limited. FTIR spectra revealed that both FYM and PNB strongly retained AM. Application of AM @1 mg kg−1 soil (equivalent to 2.24 kg ha−1) seems to effectively retard the nitrification of urea in soil amended with PNB and help reduce the leaching losses of NO3−–N in agriculture. [ABSTRACT FROM AUTHOR]

Nitrogen foam is a promising enhanced oil recovery (EOR) technique with significant potential for tertiary oil recovery. This improves the efficiency of the oil displacement during the gas drive processes while expanding the swept volume. However, in the high-temperature, high-salinity reservoirs of the Tahe Oilfield, conventional N2 foam systems show suboptimal performance, as their effectiveness is heavily limited by temperature and salinity. Consequently, enhancing the foam stability under these harsh conditions is crucial for unlocking new opportunities for the development of Tahe fracture-vuggy reservoirs. In this study, the Waring–Blender method was used to prepare weathered coal particles as a foam stabilizer. Compared to conventional foam stabilizers, weathered coal particles were found to enhance the stability of the liquid film under high-temperature and high-salinity conditions. Firstly, the foaming properties of the six foaming agents were comprehensively evaluated and their foaming properties were observed at different concentrations. YL-3J with a mass concentration of 0.7% was selected. The foaming stabilization performance of four types of solid particles was evaluated and weathered coal solid particles with a mass concentration of 15% and particle size of 300 mesh were selected. Therefore, the particle-reinforced foam system was determined to consist of "foaming agent YL-3J (0.7%) + weathered coal (15.0%) + nitrogen". This system exhibited a foaming volume of 310 mL at 150 °C and salinity of 210,000 mg/L, with a half-life of 1920 s. Finally, through interfacial tension and viscoelastic modulus tests, the synergistic mechanism between weathered coal particles and surfactants was demonstrated. The incorporation of weathered coal particles reduced the interfacial tension of the system. The formation of a skeleton at the foam interface increased the apparent viscosity and viscoelastic modulus, reduced the liquid drainage rate from the foam, and mitigated the disproportionation effect. These effects enhanced the temperature, salinity resistance, and stability of the foam. Consequently, they contributed to the stable flow of foam under high-temperature and high-salinity conditions in the reservoir, thereby improving the oil displacement efficiency of the system. [ABSTRACT FROM AUTHOR]

Hydroxylamine nitrate (HAN) is a new type of high-energy oxidant used in controllable propulsion. The present study explores the reaction mechanism of HAN using density functional theory and constructs reaction mechanism diagrams to understand the mechanism of small-molecule gas formation during the thermal decomposition of HAN. Based on transition state theory, the half-life of each reaction is calculated under standard conditions and the kinetic parameters of each reaction are scanned across the temperature range 298.15–1200 K. The research revealed a vast half-life time scale forreaction of NO generation, NO2 generation, NO+NO2 generation, N2O generation and N2 generation process, meaning thatthese reaction can not occur. The half-life of RDS5 is very short. However, the reaction is also limited by the concentration of the reactant HNO. However, increasing the temperature rapidly decreases the reaction half-life and the reaction can easily proceed. Taking 300 s as the easily reactive boundary point, the cut-off points of the rate-determining steps of Processes 1 (NO generation), 2 (NO2 generation), 3 (NO + NO2 generation), 4 and 5 (N2O generation) and 6 (N2 generation) are 466 K, 468 K, 576 K, 587 K and 402 K, respectively. The calculated reaction mechanism revealed two isomeric transformations of HNO2 and H2N2O2 and three isomeric transformations of H2N2O. Both HNO2 and H2N2O2 are transformed via H-atom transfer, while H2N2O is transformed either by H-atom transfer or intramolecular rotation. As the formation reaction of NO2 does not have the lowest free energy, the NO2 product is easily converted to other products. When NO2 coexists with NO, it is also easily converted to the stable products N2O, N2 and NH3.

The thermal neutron capture cross-section of 164Dy(n,γ)165Dy and half-life of 165Dy was determined using Neutron Activation Analysis technique. The Dy target has been irradiated by neutron using Am-Be neutron source at MCNS, MAHE, Manipal, India. Using HPGe detector, the gamma ray spectrum of the irradiated sample has been measured. The half-life of 165Dy was calculated to be 140±1min. The neutron flux distribution data from the most recent study in Ref. 12, based on the same Am-Be neutron source facility, have been used to calculate the thermal neutron cross-section of 165Dy. The thermal neutron capture cross-section is determined to be 2008±220 barns which is in good agreement with the recent measurement in Ref. 10 using neutron diffraction facility. [ABSTRACT FROM AUTHOR]

Introducing aglycosylation into therapeutic monoclonal antibodies (mAbs) can prevent side effects associated with fragment crystallizable (Fc)-mediated effector functions. This modification induces structural changes in the heavy chain constant domain 2-constant domain 3 within Fc regions, which decreases antibody stability at acidic pH and high temperature. In this study, NS101, a novel aglycosylated mAb targeting family with sequence similarity 19, A5 (FAM19A5) for neurological diseases was evaluated with respect to its developability and in vivo stability as therapeutics. When recombinant CHO cells producing NS101 were cultivated using a fed-batch mode in a 500 L bioreactor, cell growth and mAb production profiles were consistent across three consecutive runs. NS101, thus produced, features an additional intra-disulfide bond in the heavy chain complementarity-determining region 3, contributing strong and sophisticated binding to the cryptic epitope. The melting temperature (Tm) of NS101 was lower than that of commercial glycosylated therapeutic mAbs, but NS101 showed better stability at 4 °C for 36 months. The binding affinity of NS101 to FAM19A5 and neonatal Fc receptor were comparable to those of glycosylated NS101. In addition, in three human cohort groups receiving 6, 12, and 24 mg/kg of NS101, the mean half-life was 22 days, and NS101 exhibited in vivo stability, considering that the half-lives of commercialized therapeutic mAbs and endogenous IgGs are 2–4 weeks and 21 days, respectively. Taken together, the results obtained here demonstrate that NS101, a novel aglycosylated mAb, has potential as a therapeutic agent for neurological diseases. [ABSTRACT FROM AUTHOR]

Background: On 1 January 2024, a 7.6 magnitude earthquake struck the Noto Peninsula. We entered the disaster area to provide relief and set up a makeshift clinic in an evacuation center to evaluate the quality and quantity of food provided there. Methods: This cross-sectional study, of mainly older adults, was conducted to analyze the amino acid and fatty acid composition of evacuation shelter meals in comparison with the results of the Japan National Survey, mainly focused on older adults. (1) We analyzed 11 evacuation foods using the "Duplicated Combination" Model and the digestible amino acid score (DIAAS) in relation to the half-life determined by the N-terminal amino acid proteins. (2) Linoleic acid (LA) and alpha-linolenic acid (ALA) levels were compared with European Food Safety Authority (EFSA) recommendations (3). The national survey of emergency food stocks in 198 hospitals and 189 social care institutions conducted in Jan 2024 was analyzed. Results: (1) DIAAS was less than 1.00 for all 11 foods provided and was considered inadequate, (2) the half-life of the protein, whose N-terminal valine has a half-life of 100 h, must be considered a possible deficiency when living in a shelter for more than a week, (3) LA and ALA levels were less than 40% of EFSA recommended, (4) the nationwide survey found that 80% of people have a three-day supply and data on amino acids and fatty acids were not available due to a lack of questionnaires. Conclusion: Analysis of food in evacuation shelters after the Noto Peninsula earthquake revealed the quality of amino acids involved in shelter meals using DIAAS and the lack of LA and ALA for older adults. The "Duplicated Combination" model used in this analysis could be beneficial for developing improved nutrition plans in similar future scenarios, mainly for older adults. [ABSTRACT FROM AUTHOR]

Flubendiamide has label claim for managing early shoot borer (Chilo infuscatellus Snellen) of sugarcane. Since it has been registered for use in sugarcane very recently in 2019, studies on its dissipation behaviour are lacking among the published literature. Hence, the dissipation behaviour of flubendiamide was studied at its recommended (RD, 75 g a.i./ha) and double the recommended doses (2RD) in the tropical sugarcane ecosystem after being sprayed over the canopy of 45-days old crop. A method has been developed and validated to determine the residues of flubendiamide and des-iodo flubendiamide in/on sugarcane leaves and soil. The method adopted could provide 91.7 ± 2.89—97.2 ± 4.93% recoveries of both the analytes from both the matrices involved in the study. The LOQ of the method was 0.01 µg/g for the parent compound as well as its metabolite. Flubendiamide was observed to persist on the sugarcane leaves for 105 days and reached below the detectable level (BDL) of 0.01 µg/g on 120 days after treatment (DAT) irrespective of the doses involved in the study. The half-life of flubendiamide was 5.19 and 5.28 days at RD and 2RD, respectively. The metabolite des-iodo flubendiamide was not detected all through the study period on leaves. Neither the parent compound nor the metabolite was detected in the soil of tropical sugarcane ecosystem. [ABSTRACT FROM AUTHOR]

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Although recent advancements in organic–inorganic hybrid perovskites have captivated not only the community of photovoltaics but also the field of display technologies, the development of perovskite-based light-emitting diodes (PeLEDs) with pure-blue emission has lagged behind that of their green- or red-emitting counterparts in terms of optoelectronic properties and operational stability. In this study, we report a comprehensive strategy to enforce pure-blue emission of PeLEDs with high quantum efficiency and operational stability by introducing multiple cationic chlorides in perovskite layers. First we demonstrate the gradual induction of a distinct hypsochromic shift to the blue region in green-emissive CsFAPbBr3 perovskite films by incorporating bulky ammonium bromide and chloride. This shift is accomplished through dimensional and lattice structure engineering. Second, small A-site cationic chlorides are introduced to further tune the band gap and optoelectronic properties of the pure-blue PeLEDs. Finally, yttrium-(III) chloride is introduced as an additive to hamper severe phase segregation and ion migration in the perovskite emitting layers. As a result of these deliberate modifications, the proper inclusion of multiple inorganic chloride salts enforced the hypsochromic shift of the perovskite layer with a minimized defect density, leading to pure-blue electroluminescence at 472 nm with an exceptionally narrow bandwidth of 17.91 nm and an external quantum efficiency of 4.22%. The optimized chlorides also achieve superior operational stability with an electroluminescence half-life of 23 min at an initial luminance of 350 cd/m2 in an ambient atmosphere. This suggests a straightforward way to prepare practical pure-blue PeLEDs for achieving full-color perovskite display technologies. [ABSTRACT FROM AUTHOR]

Hydroxylamine nitrate (HAN) is a new type of high-energy oxidant used in controllable propulsion. The present study explores the reaction mechanism of HAN using density functional theory and constructs reaction mechanism diagrams to understand the mechanism of small-molecule gas formation during the thermal decomposition of HAN. Based on transition state theory, the half-life of each reaction is calculated under standard conditions and the kinetic parameters of each reaction are scanned across the temperature range 298.15–1200 K. The research revealed a vast half-life time scale forreaction of NO generation, NO 2 generation, NO+NO 2 generation, N 2 O generation and N 2 generation process, meaning thatthese reaction can not occur. The half-life of RDS5 is very short. However, the reaction is also limited by the concentration of the reactant HNO. However, increasing the temperature rapidly decreases the reaction half-life and the reaction can easily proceed. Taking 300 s as the easily reactive boundary point, the cut-off points of the rate-determining steps of Processes 1 (NO generation), 2 (NO 2 generation), 3 (NO + NO 2 generation), 4 and 5 (N 2 O generation) and 6 (N 2 generation) are 466 K, 468 K, 576 K, 587 K and 402 K, respectively. The calculated reaction mechanism revealed two isomeric transformations of HNO 2 and H 2 N 2 O 2 and three isomeric transformations of H 2 N 2 O. Both HNO 2 and H 2 N 2 O 2 are transformed via H-atom transfer, while H 2 N 2 O is transformed either by H-atom transfer or intramolecular rotation. As the formation reaction of NO 2 does not have the lowest free energy, the NO 2 product is easily converted to other products. When NO 2 coexists with NO, it is also easily converted to the stable products N 2 O, N 2 and NH 3. [ABSTRACT FROM AUTHOR]

This paper is devoted to the calculations of alpha decay half-lives of 1 8 6 − 2 1 8 Po (Z = 8 4) isotopes and actinide nuclei between the atomic numbers Z = 90 and Z = 102, using an energy-dependent potential model. The α -nucleus effective potential employed in this study includes a Coulomb potential, a centrifugal barrier potential, and a nuclear potential. The nuclear potential is chosen to be the energy-dependent singularized harmonic potential, typical of nuclear interactions. The role of the energy-dependent potential is very significant in this study. Indeed, when compared to the experimental data, our results are found to be improved when energy-dependent interaction potential is employed compared to when energy-independent interactions are used, especially for small values of the parameter γ as evidenced by the values of the root mean square deviation. [ABSTRACT FROM AUTHOR]

Summary: This study investigated the impact of heating temperatures (70 °C to 90 °C for up to 14 h) on lycopene and β‐carotene degradation kinetics in gac aril paste. Carotenoids extracted via low‐volume hexane‐assisted ultrasonic extraction revealed a first‐order degradation pattern with high correlation coefficients (0.96–0.97). Lycopene degraded faster at 90 °C (k = 12.05 × 102 h−1) than at 70 °C (5.41 × 102 h−1), while β‐carotene displayed relatively slower degradation. Corresponding half‐life (t1/2) values for lycopene ranged from 5.75 to 12.81 h, while β‐carotene displayed values of 9.48–20.2 h. β‐carotene showed superior thermal stability compared to lycopene across all temperatures. Additionally, colour changes indicated decreased brightness with increasing temperature. The DPPH radical scavenging activity and FRAP values decreased during gac fruit heating. Overall, this study emphasises temperature‐induced declines in lycopene and β‐carotene levels in gac aril paste and offers insights into their degradation kinetics under thermal processing. [ABSTRACT FROM AUTHOR]

An analytic solution is presented for the simultaneous substrate elimination problem that combines Michaelis-Menten (MM) consumption with an irreversible homo-dimerization process. The implicit solution involves logarithm and inverse tangent functions and perfectly agrees with the numerical solution of the differential equation. A solution is also presented for the generalized dynamical problem that simultaneously combines MM kinetics with first and second-order processes. The exact expressions for the half-life and the area under the curve are also presented for these problems. [ABSTRACT FROM AUTHOR]

In the tea-planting process, insecticides are commonly combined, potentially prolonging the pre-harvest interval and heightening the risk of dietary exposure. This study focused on three frequently used insecticides in tea cultivation: thiamethoxam, bifenthrin, and dinotefuran, aiming to investigate their dissipation behaviors and associated dietary risks upon individual and simultaneous application. The dissipation kinetics of thiamethoxam, bifenthrin, and dinotefuran were successfully characterized by first-order kinetics, yielding respective half-lives of 5.44, 9.81, and 10.16 days. Upon joint application, the dissipation half-lives of thiamethoxam and bifenthrin were notably prolonged compared with their individual applications, resulting in final concentrations after 28 days that were correspondingly elevated by 1.41 and 1.29 times. Assessment of the dietary intake risk revealed that the chronic and acute risk quotients associated with thiamethoxam and bifenthrin escalated by 1.44–1.59 times following their combined application. Although dietary risks associated with Tianmuhu white tea, as determined by the exposure assessment model, were deemed acceptable, the cumulative risks stemming from pesticide mixtures across various dietary sources warrant attention. Molecular docking analyses further unveiled that thiamethoxam and bifenthrin competitively bound to glutathione S-transferase (GST) at amino acid residues, notably at the 76th GLU and the 25th PHE, pivotal in the metabolism and absorption of exogenous substances. Moreover, the interactions between P-glycoprotein and pesticides during transport and absorption were likely to influence dissipation behaviors post-joint application. This research offers valuable insights and data support for optimizing joint pesticide application strategies and assessing risks associated with typical pesticides used in tea cultivation. [ABSTRACT FROM AUTHOR]

Decreased appetite is a common clinical problem in captive rhesus macaques (Macaca mulatta). Mirtazapine, a tetracyclic antidepressant originally developed for humans, has shown promise as a safe and effective promoter of weight gain and appetite in several veterinary species including rhesus and cynomolgus macaques. Although mirtazapine is available as oral formulations, transdermal delivery in macaques with reduced appetite would allow quick, painless, topical application. Here we describe the pharmacokinetics of a single application of a widely available veterinary transdermal mirtazapine formulation in 6 rhesus macaques. A dose of 0.5 mg/kg of transdermal mirtazapine ointment that has proven to be effective in rhesus was applied to the caudal pinnae of 3 female and 3 male young adult macaques. Serum was collected at 0, 0.5, 1, 3, 6, 8, 12, 24, 36, 48, and 72 h after administration. Our data indicate transdermal mirtazapine is absorbed at a lower level in rhesus as compared with published values in domestic cats (rhesus peak serum concentration: 1.2 ± 0.3 ng/mL), while drug half-life is longer than that reported in cats (rhesus: 33 ± 7 h). Mirtazapine reaches peak plasma concentrations in rhesus at 16 ± 10 h after administration; our model indicates that up to 5 d of serial dosing may be necessary to reach steady state. Our preliminary data also suggest that sex differences may contribute to efficacy and/or indicate sex-based differences, as male macaques reached Tmax more quickly than females (19 ± 2 h in females and 8 ± 3 h in males) and showed higher variation in half-life (33 ± 4 h in females and 34 ± 11 h in males). While previous work indicates clinical efficacy of the 0.5-mg/kg dosage in macaques, further investigation is warranted to determine if rhesus may benefit from higher recommended doses than companion animal species.

Understanding variant-specific differences in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral kinetics may explain differences in transmission efficiency and provide insights on pathogenesis and prevention. We evaluated SARS-CoV-2 kinetics from nasal swabs across multiple variants (Alpha, Delta, Epsilon, Gamma) in placebo recipients of the ACTIV-2/A5401 trial. Delta variant infection led to the highest maximum viral load and shortest time from symptom onset to viral load peak. There were no significant differences in time to viral clearance across the variants. Viral decline was biphasic with first- and second-phase decays having half-lives of 11 hours and 2.5 days, respectively, with differences among variants, especially in the second phase. These results suggest that while variant-specific differences in viral kinetics exist, post-peak viral load all variants appeared to be efficiently cleared by the host. Clinical Trials Registration. NCT04518410.