Mean Residence Time Research Articles

Disposition of enrofloxacin in plasma, pulmonary epithelial lining fluid, peritoneal fluid, and cerebrospinal fluid of healthy mares.

To investigate the disposition of enrofloxacin and its active metabolite, ciprofloxacin, in plasma, pulmonary epithelial lining fluid (PELF), peritoneal fluid, and CSF in horses following IV administration of enrofloxacin at doses of 5 mg/kg and 7.5 mg/kg of body weight. 6 healthy, mature mares were randomly assigned to receive a single dose of enrofloxacin at either 5 mg/kg or 7.5 mg/kg in a crossover design with a washout period of 10 days. Concentrations of enrofloxacin and ciprofloxacin were determined in plasma, PELF, peritoneal fluid, and CSF. Both doses of enrofloxacin were generally well tolerated. One horse developed focal, self-limiting limb edema. The median maximum concentration extrapolated to time 0 and area under the plasma concentration-versus-time curve from time 0 to the last quantifiable time point (24 hours) for enrofloxacin in plasma were significantly greater when horses were given enrofloxacin at 7.5 mg/kg. Similarly, the median elimination rate constant, half-life of the terminal phase, peak serum concentration (Cmax), area under the plasma concentration-versus-time curve from time 0 to the last quantifiable time point (24 hours), area under the plasma concentration-versus-time curve extrapolated to infinity, and mean residence time for ciprofloxacin in plasma were significantly greater following administration of enrofloxacin at 7.5 mg/kg. There were no significant differences between doses in any of the measured pharmacokinetic variables in PELF. There was no apparent pharmacokinetic advantage of enrofloxacin at the 7.5-mg/kg dose for susceptible isolates; however, this dose achieved higher concentrations and prolonged persistence in fluid matrices. Further studies are required to evaluate repeated administration at this dose for tolerability and clinical efficacy. Despite the wide use of enrofloxacin in horses, pharmacokinetic data is limited. This study provides pharmacokinetic data that can be used in a clinical setting.

Development and Evaluation of Polymethacrylate-Based Ophthalmic Nanofiber Inserts Containing Dual Drug-Loaded Dorzolamide and Timolol: In Vivo Study in Rabbit's Eye.

Background/objectives: The aim of the study was to create a nanofiber insert incorporating Timolol (TIM) and Dorzolamide (DOR), targeting the management of glaucoma. This condition encompasses a variety of chronic, advancing ocular disorders typically associated with elevated intraocular pressure (IOP). Methods: The insert was made of Eudragite RL100 (EUD) polymer, a biocompatible material with high bioavailability, using the electrospinning method. The inserts were studied for morphology, drug-polymer interaction, physicochemical properties, and in vitro drug-release study. The pharmacokinetic properties of fibers were examined alongside consideration for irritation using a rabbit model and cell compatibility. Results: The results of the in vitro drug-release test showed retention and controlled release of both DOR/TIM over 80 h. Morphological examination demonstrated uniform nanofibers with mean diameters < 465 nm. The cell compatibility test showed a high percentage of cell survival, and none of the formulations irritated the rabbit's eye. The Area Under the Curve (AUC0-72) for DOR and TIM in EDT formulations was approximately 3216.63 ± 63.25 µg·h/mL and 2598.89 ± 46.65 µg·h/mL, respectively, with Mean Residence Times (MRTs) of approximately 21.6 ± 0.19 h and 16.29 ± 6.44 h. Conclusions: Based on the results, the dual drug-loaded nanofiber preservative-free system can potentially be a suitable alternative to eye drops and can be used to reduce fluctuation and dose frequency.

Development of Pluronic-Based Micelles from Palm Oil Bioactive Compounds Incorporated by a Dissolvable Microarray Patch to Enhance the Efficacy of Atopic Dermatitis Therapy.

The high content of vitamin E, including tocopherols and tocotrienols (TCF-TTE), in palm oil (Elaeis guineensis) has made it a promising candidate for the alternative treatment of atopic dermatitis (AD). However, the limited solubility of TCF-TTE has restricted its therapeutic efficacy. In this study, pluronic-based micelles (MCs) encapsulating palm oil-derived TCF-TTE were formulated with dissolvable microarray patch-micelles (DMP-MC) using carboxymethyl cellulose (CMC) synthesized from empty fruit bunches of palm to optimize its delivery for AD. The MC was prepared using a direct dissolution method using Pluronic F68 and F127. The results showed that MC increased the solubility of TCF-TTE, which was further confirmed by an in vitro study where 90.23 ± 2.07% TCF and 4.56 ± 1.36% TTE were released compared to the unencapsulated TCF-TTE extract. Furthermore, CMC biopolymers and MC integrated into DMP-MC with polyvinylpyrrolidone (PVP) exhibited favorable physical properties, such as mechanical strength and penetration ability. DMP-MC also exhibited a better platform with lower permeation, indicating higher retention and increased localized effects on AD skin than cream-MC. Additionally, dermatokinetic profile parameters showed significant improvement. The mean residence time (MRT) parameter indicated that TCF-TTE was retained for longer times 19.28 ± 0.02 h and 20.68 ± 0.01 h. Moreover, an in vivo study revealed that DMP-MC could relieve AD symptoms more rapidly than oral doses and cream-MC, indicating that DMP-MC proved to be more efficient. Furthermore, DMP-MC showed no tissue destruction (granulation and fibrosis) in rats treated with DMP-MC on the seventh day. Therefore, this study successfully developed the MC formula in DMP-MC formulation using synthesized CMC, which could potentially improve AD's therapeutic efficacy.

An Injectable Oil-Based Depot Formulation of N-Acyloxymethyl Prodrug of Ropivacaine for Long-Acting Local Analgesia: Formulation Development and In Vitro/In Vivo Evaluation.

Objectives: The development of novel long-acting injectables for local anesthetics is necessary to effectively manage the acute postoperative pain. The aim of this study was to prepare an injectable oil-based formulation of ropivacaine (ROP) prodrug (ropivacaine stearoxil, ROP-ST) and to investigate the pharmacokinetics and pharmacodynamics after injectable administration. Methods: A novel N-acyloxymethyl prodrug of ROP, i.e., ROP-ST, was synthesized and its physicochemical properties such as log P, solubility and stability characterized. A soybean oil-based depot of ROP-ST was prepared, and the in-vitro release of ROP-ST was evaluated using an "inverted-cup" method. Pharmacokinetic profiles and tissue retention properties were investigated after intramuscular administration of the formulation in rats. The analgesic efficacy was assessed via a von Frey monofilaments test by measuring the paw withdrawal thresholds. Results: The structure of ROP-ST was ascertained with clear 1H NMR assignment and accurate mass-to-charge ratio. The high Log P value of ROP-ST (9.16) demonstrated extremely low aqueous solubility, but the prodrug is biolabile when in contact with plasma or liver esterase. Intramuscular injection of ROP-ST oil solution in rats provided a significantly higher mean residence time without a very clear plasma peak of ROP. In a postoperative pain model of rats, the injection of ROP-ST oil solution into the vicinity of the sciatic nerve in the right ankle effectively controlled the postoperative pain for at least 72 h. Conclusions: The injectable oil-based depot formulation of N-acyloxymethyl prodrug of ROP may provide a new opportunity of long-acting local analgesia for postoperative pain.

Deep terrestrial indigenous microbial community dominated by Candidatus Frackibacter

Characterizing deep subsurface microbial communities informs our understanding of Earth’s biogeochemistry as well as the search for life beyond the Earth. Here we characterized microbial communities within the Kidd Creek Observatory subsurface fracture water system with mean residence times of hundreds of millions to over one billion years. 16S rRNA analysis revealed that biosamplers well isolated from the mine environment were dominated by a putatively anaerobic and halophilic bacterial species from the Halobacteroidaceae family, Candidatus Frackibacter. Contrastingly, biosamplers and biofilms exposed to the mine environment contained aerobic Sphingomonas taxa. δ13C values of phospholipid fatty acids and putative functional predictions derived from 16S rRNA gene profiles, imply Candidatus Frackibacter may use carbon derived from ancient carbon-rich layers common in these systems. These results indicate that Candidatus Frackibacter is not unique to hydraulically fracked sedimentary basins but rather may be indigenous to a wide range of deep, saline groundwaters hosted in carbon-rich rocks.

Pharmacokinetics of cisplatin in the systemic versus hyperthermic intrathoracic or intraperitoneal chemotherapy

ObjectiveTo compare the pharmacokinetics and adverse effects of cisplatin administered via intravenous infusion for systemic chemotherapy (SC) versus injection into the perfusate during hyperthermic intrathoracic chemotherapy (HITHOC) or hyperthermic intraperitoneal chemotherapy (HIPEC).MethodsTotal 60 patients who received SC, HITHOC, or HIPEC in the Department of Oncology, Tangdu Hospital, were enrolled into this study. After administering same dose of cisplatin (40 mg) via either intravenous infusion (SC group) or injection into the perfusate during the HITHOC or HIPEC procedure, concentration of cisplatin in the plasma as well as in the hyperthermic perfusate at various time points was quantified by HPLC analysis. The area under the plasma or perfusate concentration–time curve over the last 24h dosing interval (AUC0–24h), mean residence time over the 24 h (MRT0–24h), terminal elimination half-life (t1/2z), time to peak concentration (Tmax), apparent clearance (Clz/F), and peak concentration (Cmax) in the perfusate and plasma were compared.ResultsIn the perfusate, the AUC0–24h (64.32 ± 27.12 µg/mL·h) and Cmax (21.62 ± 5.88 µg/mL) were significantly higher in the HITHOC group compared to that in the HIPEC group (31.68 ± 13.29 µg/mL·h and 16.96 ± 5.54 µg/mL, respectively, p ≤ 0.01). In contrast, MRT0–∞, t1/2z, and Clz/F were significantly lower in the HITHOC group compared to that in the HIPEC group (p < 0.01). In the plasma, average AUC0–24h and Cmax of the HITHOC group were 2.57 ± 0.55 µg/mL·h and 0.26 ± 0.08 µg/mL, respectively, which were significantly lower than that of systemic chemotherapy (SC) group (3.26 ± 0.56 µg/mL·h and 0.69 ± 0.14 µg/mL, respectively, p < 0.01), but no difference compared to that of HIPEC group (3.02 ± 0.52 µg/mL·h and 0.40 ± 0.15 µg/mL, respectively, p > 0.05). In contrast, MRT0-24h and Tmax in the plasma of HITHOC group were significantly longer compared to that of SC group (p < 0.05), but no significant difference compared to that of HIPEC group (p > 0.05). Absolute bioavailability of cisplatin in the thoracic (HITHOC group) and abdominal (HIPEC group) cavities was 20 and 10 times higher than that in the blood administered intravenously (SC group), respectively. There was no significant difference in the incidence of adverse events among the three groups (p < 0.05).ConclusionThe current study demonstrated that, in the perfusate, AUC0–24h and Cmax of cisplatin was significantly higher in the group of HITHOC compared to that of HIPEC, and that, in the plasma, AUC0–24h and Cmax of cisplatin was lower in the group of HITHOC compared to that of HIPEC or SC group. This study provided pharmacokinetic evidence to further support the concept that topical application of chemotherapeutic drug through minimally invasive HITHOC or HIPEC may enhance local exposure compared to systemic chemotherapy for the patients with malignant pleural effusion or ascites.

Development of an HPLC–UV method for quantification of posaconazole in low-volume plasma samples: design of experiments and machine learning models

Posaconazole (PCZ) is a triazole antifungal agent with a broad-spectrum activity. Our research aims to present a novel approach by combining a 2-level fractional factorial design and machine learning to optimize both chromatography and extraction experiments, allowing for the development of a rapid method with a low limit of quantification (LOQ) in low-volume plasma samples. The PCZ retention time at the optimized condition (organic phase 58%, methanol 6%, mobile pH = 7, column temperature: 39 °C, and flow rate of 1.2 mL/min) was found to be 8.2 ± 0.2 min, and the recovery of the PCZ at the optimized extraction condition (500 µL extraction solvent, NaCl 10% w/v, plasma pH = 11, extraction time = 10 min, and centrifuge time = 1 min) was calculated above 98%. The results of machine learning models were in line with the results of experimental design. Method validation was performed according to ICH guideline. The method was linear in the range of 50–2000 ng/mL and LOQ was found to be 50 ng/mL. Additionally, the validated method was applied to analyze PCZ nanomicelles and conduct pharmacokinetic studies on rats. Half-life (t1/2), mean residence time (MRT), and the area under the drug concentration–time curve (AUC) were found to be 7.1 ± 0.6 h, 10.5 ± 0.9 h, and 1725.7 ± 44.1 ng × h/mL, respectively.Graphical

Pharmacodynamics and pharmacokinetics of rocuronium in sevoflurane-anesthetized Thoroughbred horses.

To investigate the pharmacodynamics and pharmacokinetics of rocuronium administered by bolus injection to sevoflurane-anesthetized horses. Prospective, experimental, crossover study. Five healthy adult Thoroughbred horses (body mass 368-470 kg, three females and two males). Each horse was anesthetized twice with sevoflurane and assigned to be administered rocuronium bromide intravenously: 0.2 mg kg-1 (R02) or 0.4 mg kg-1 (R04). There was a minimum 2 week washout period between experiments. During anesthesia, the peroneal nerve was stimulated (train-of-four) and neuromuscular function was assessed with acceleromyography. Plasma rocuronium concentrations were measured using liquid chromatography-tandem mass spectrometry. Pharmacodynamic and pharmacokinetic data are presented as mean ± standard deviation and were statistically compared between R02 and R04 with a Student's paired t-test. Significance was set at p < 0.05. Complete neuromuscular blockade was observed in all horses. The duration of action was significantly shorter for R02 (42.5 ± 11.2 minutes) than for R04 (67.0 ± 17.8 minutes, p= 0.003). Plasma concentrations of rocuronium showed a biphasic elimination pattern. Systemic clearance was significantly higher for R04 (2.12 ± 1.15 mL minute-1 kg-1) than for R02 (1.07 ± 0.46 mL minute-1 kg-1, p= 0.034). Mean residence time was significantly shorter for R04 (109 ± 73.1 minutes) than for R02 (183 ± 64.6 minutes, p= 0.015). Rocuronium induced complete neuromuscular blockade with both R02 and R04, and exhibited a dose-dependent duration of action. Significantly higher systemic clearance and shorter mean residence time for the high dose (R04) were observed compared with the low dose (R02). The prolonged clearance of rocuronium in horses contributed to its extended duration of action in this species.

The Effect of Extracorporeal Membrane Oxygenation on the Pharmacokinetics of Dexmedetomidine Hydrochloride.

Our objective was to explore the effects of extracorporeal membrane oxygenation (ECMO) on the pharmacokinetics of dexmedetomidine hydrochloride via vitro and in vivo experiments DESIGN: A single-center animal investigation. An experimental animal facility in a tertiary hospital. Eighteen male Landrace pigs. For the in vitro experiment, ECMO circuits were primed with whole blood solutions of dexmedetomidine at different concentrations and ran ex vivo. The adsorption rates of dexmedetomidine hydrochloride in ECMO circuits and control glass tubes were compared at 60 minutes, 5 hours, and 10 hours after the start of the in vitro experiment. In the in vivo experiment, 12 Landrace pigs were randomly allocated to the venovenous ECMO group or the control group. Dexmedetomidine hydrochloride (1 μg/kg) was administered to both groups. Blood samples were collected at 0 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, 2 hours, 3 hours, 5 hours, 7 hours, and 10 hours after administration. The plasma concentrations of dexmedetomidine were measured, and pharmacokinetic analysis was conducted in both groups. The results revealed no significant difference in adsorption rates of dexmedetomidine hydrochloride in ECMO circuits at 60 minutes and 5 hours, but differences were observed at 10 hours. In vivo experiment, pharmacokinetic analysis revealed no significant difference in the area under the curve (AUC0-t), AUC0-∞, distribution half-life, elimination half-life, clearance, apparent volume of distribution, mean residence time or peak drug concentrations between the 2 groups (p > 0.05). The ECMO circuit had an adsorption effect on dexmedetomidine hydrochloride, but this effect was not sufficient to impact the in vivo pharmacokinetics of dexmedetomidine significantly. The effect of ECMO on the pharmacokinetics of dexmedetomidine hydrochloride was not significant.

Phase I pharmacokinetic study of etmaben, a malonic acid derivative

Introduction. Etmaben is a malonic acid derivative that has shown cardiotropic activity and is a promising candidate for treating ischemic heart disease and chronic heart failure. It is currently undergoing Phase I clinical trials, and its pharmacokinetics have not yet been studied in humans.Aim. The aim of the study is to investigate the pharmacokinetics of Etmaben, film-coated tablets, 300 mg (SPCPU, Russia) in healthy volunteers after fasting administration of different doses following both single and multiple dosing over a 7-day period.Materials and methods. The open-label, non-randomized clinical trial involved 48 healthy volunteers divided into 6 cohorts. Volunteers in cohort 1 received a single dose of 600 mg of etmaben, cohort 2 received 900 mg, and cohort 3 received 1200 mg. Cohorts 4, 5, and 6 received daily doses of 600 mg, 900 mg, and 1200 mg, respectively. Plasma concentrations of etmaben were measured using high-performance liquid chromatography with tandem mass spectrometry detection. Pharmacokinetic parameters were calculated using Microsoft Excel with the Boomer extension (Department of Pharmacokinetics and Drug Metabolism, Allergan, Irvine, CA 92606, USA).Results and discussion. Pharmacokinetic parameters were calculated for 6 cohorts of 8 volunteers after single and multiple dosing of Etmaben at doses of 600, 900, and 1200 mg. The maximum plasma concentration (Cmax) of etmaben was reached on average within 0.5 h. Cmax values ranged from 2.708 ± 1.461 µg/mL to 19.871 ± 4.415 µg/mL. The maximum half-life was 0.874 ± 0.236 h, with an elimination rate constant not exceeding 1.053 ± 0.149 h–1. The mean residence time (MRT) of etmaben in plasma did not exceed 1.527 ± 0.272 h. The average volume of distribution was above 45 L, and clearance exceeded 42 L, indicating significant tissue distribution and rapid drug elimination. Due to low area under the curve values and high elimination rates, the accumulation of etmaben is minimal.Conclusion. Pharmacokinetic parameters were calculated, and averaged pharmacokinetic profiles were constructed in linear and semilogarithmic coordinates after single and multiple dosing of various etmaben doses. This study represents the first investigation of etmaben pharmacokinetics in humans, paving the way for subsequent clinical trials.

Assessment of Bacteriophage Pharmacokinetic Parameters After Intra-Articular Delivery in a Rat Prosthetic Joint Infection Model.

Prosthetic joint infections (PJIs) are a serious complication of orthopedic surgery. Bacteriophage (phage) therapy shows promise as an adjunctive treatment but requires further study, particularly in its pharmacokinetics. Consequently, we performed a pharmacokinetic assessment of phage therapy for PJIs using a Staphylococcus epidermidis Kirschner wire-based prosthesis rat model. We used 52 male Sprague-Dawley rats in four groups: negative controls (no phage, sterile implant), PJI controls (bacteria, no phage), sterile phage (phages given, sterile implant), and PJI (bacteria, phages given). The PJI groups were inoculated with ~106 CFU of S. epidermidis. The groups receiving phage were intra-articularly injected with ~108 PFU of vB_SepM_Alex five days post-implantation. The rats were euthanized between 30 min and 48 h post-injection. The measured phage concentrations between the PJI rats and the sterile controls in periarticular tissues were not significantly different. In a noncompartmental pharmacokinetic analysis, the estimated phage half-lives were under 6 h (combined: 3.73 [IQR, 1.45, 10.07]). The maximum phage concentrations were reached within 2 h after administration (combined: 0.75 [0.50, 1.75]). The estimated phage mean residence time was approximately three hours (combined: 3.04 [1.44, 4.19]). Our study provides a preliminary set of pharmacokinetic parameters that can inform future phage dosing studies and animal models of phage therapy for PJIs.

Solution of the space-fractional diffusion equationon bounded domains of superdiffusive phenomena.

Space-fractional diffusion equationsfind widespread application in nature. They govern the anomalous dynamics of many stochastic processes, generalizing the standard diffusion equationto superdiffusive behavior. Strikingly, the solution of space-fractional diffusion equationson bounded domains is still an open problem. This is in part due to the difficulty of handling nonlocal boundary conditions ascribed to the space-fractional derivative, leading to the failure of standard methods. Here we revisit the space-fractional diffusion equationin one spatial dimension with bounded domains and present a solution in terms of weighted Jacobi polynomials. Calculated eigenvalues and eigenfunctions in the superdiffusive regime show remarkable agreement with results from numerical discretization of the space-fractional derivative operator and Monte Carlo simulations. To exemplify, we apply the proposed solution to obtain the exact mean residence time or mean first-passage time, first-passage-time distribution, and survival probability, in agreement with known results for the superdiffusive regime. The system of equationsconverges rather fast for the first eigensolutions, as is desirable for practical application purposes in superdiffusive phenomena.

Probing Single-Molecule Dynamics in Self-Assembling Viral Nucleocapsids.

All viruses on Earth rely on host cell machinery for replication, a process that involves a complex self-assembly mechanism. Our aim here is to scrutinize in real time the growth of icosahedral viral nucleocapsids with single-molecule precision. Using total internal reflection fluorescence microscopy, we probed the binding and unbinding dynamics of fluorescently labeled capsid subunits on hundreds of immobilized viral RNA molecules simultaneously at each time point. A step-detection algorithm combined with statistical analysis allowed us to estimate microscopic quantities such as the equilibrium binding rate and mean residence time, which are otherwise inaccessible through traditional ensemble-averaging techniques. Additionally, we could estimate a set of rate constants modeling the growth kinetics from nonequilibrium measurements, and we observed an acceleration in growth caused by the electrostatic screening effect of monovalent salts. Single-molecule fluorescence imaging will be crucial for elucidating virus self-assembly at the molecular level, particularly in crowded, cell-like environments.

Simultaneous determination and toxicokinetic study of six compounds from Zhachong Shisanwei Pills in plasma of chronic cerebral ischemia rats by LC-MS/MS

A liquid chromatography-tandem mass spectrometry method was established and validated for determining the concentrations of costunolide(CO), piperine(PI), agarotetrol(AG), glycyrrhizic acid(GL), vanillic acid(VA), and glycyrrhetinic acid(GA) in rat plasma. This method was then applied to the toxicokinetic study of these six compounds in rats with chronic cerebral ischemia(CCI) following multiple oral doses of Zhachong Shisanwei Pills. Finally, the effects of continuous multiple-dose administration of Zhachong Shisanwei Pills on the liver of CCI rats were investigated. The results showed that after oral administration of different doses of Zhachong Shisanwei Pills, the in vivo exposure of AG, VA, and GA was relatively high, with AUC_(0-∞) values ranging from 604.0-2 494.2, 1 305.4-4 634.5, and 2 177.5-4 045.7 h·ng·mL~(-1), respectively, while the exposure of CO, PI, and GL was relatively low, with AUC_(0-∞) values ranging from 37.8-238.2, 2.4-17.0, and 146.9-408.5 h·ng·mL~(-1), respectively. The C_(max) and AUC_(0-∞) of the six compounds were positively correlated with the administered dose. The T_(max) of PI and AG ranged from 0.3 to 2.0 h, their T_(1/2) ranged from 0.8 to 2.9 h, and their mean residence time(MRT) ranged from 1.0 to 3.7 h. The T_(max) of GL and VA was shorter(0.4-1.9 h), while their T_(1/2)(2.6-5.9 h) and MRT(2.5-8.5 h) were longer. Both CO and GA exhibited a bimodal phenomenon, with T_(max) ranging from 1.6 to 6.6 h, T_(1/2) ranging from 2.8 to 7.7 h, and MRT ranging from 4.1 to 12.9 h. Liver histopathology after 28 days of continuous multiple-dose administration of Zhachong Shisanwei Pills showed that the liver tissue remained normal at a low dose(crude drug 0.8 g·kg~(-1), approximately 5 times the clinical equivalent dose). However, as the dose increased(crude drug 1.1-3.0 g·kg~(-1), 6.9-18.8 times the clinical equivalent dose), varying degrees of liver damage were observed. Blood biochemical tests revealed no significant changes in the serum levels of alanine aminotransferase(ALT), aspartate aminotransferase(AST), alkaline phosphatase(ALP), and total bile acid(TBA) in CCI rats from administration groups 1 to 3(crude drug 0.8, 1.1, 1.5 g·kg~(-1)). However, ALT, AST, ALP, and TBA levels in groups 4 and 5(crude drug 2.1, 3.0 g·kg~(-1)) showed significant increases. This study preliminarily elucidated the toxicokinetic characteristics of the six compounds in Zhachong Shisanwei Pills and their effects on liver tissue in CCI rats, providing data as a reference for clinical use.

210Po and 210Pb Distributions Along the GEOTRACES Pacific Meridional Transect (GP15): Tracers of Scavenging and Particulate Organic Carbon (POC) Export

AbstractDistributions of the natural radionuclide 210Po and its grandparent 210Pb along the GP15 Pacific Meridional Transect provide information on scavenging rates of reactive chemical species throughout the water column and fluxes of particulate organic carbon (POC) from the primary production zone (PPZ). 210Pb is in excess of its grandparent 226Ra in the upper 400–700 m due to the atmospheric flux of 210Pb. Mid‐water 210Pb/226Ra activity ratios are close to radioactive equilibrium (1.0) north of ∼20°N, indicating slow scavenging, but deficiencies at stations near and south of the equator suggest more rapid scavenging associated with a “particle veil” located at the equator and hydrothermal processes at the East Pacific Rise. Scavenging of 210Pb and 210Po is evident in the bottom 500–1,000 m at most stations due to enhanced removal in the nepheloid layer. Deficits in the PPZ of 210Po (relative to 210Pb) and 210Pb (relative to 226Ra decay and the 210Pb atmospheric flux), together with POC concentrations and particulate 210Po and 210Pb activities, are used to calculate export fluxes of POC from the PPZ. 210Po‐derived POC fluxes on large (&gt;51 μm) particles range from 15.5 ± 1.3 mmol C/m2/d to 1.5 ± 0.2 mmol C/m2/d and are highest in the Subarctic North Pacific; 210Pb‐derived fluxes range from 6.7 ± 1.8 mmol C/m2/d to 0.2 ± 0.1 mmol C/m2/d. Both 210Po‐ and 210Pb‐derived POC fluxes are greater than those calculated using the 234Th proxy, possibly due to different integration times of the radionuclides, considering their different radioactive mean‐lives and scavenging mean residence times.

Deep eutectic solvent combined with permeation enhancer strategy to convert tandospirone from oral to transdermal formulations improving drug bioavailability

Tandospirone(Tan) is a commonly used drug for anxiety treatment. However, it has a significant first-pass effect and needs to be taken three times a day. To increase the bioavailability of the drug and reduce the number of administrations, this work amid to prepare a Tan patch that can be administered once a day by using the strategy of therapeutic deep eutectic solvent(THEDES) in cooperation with chemical permeation enhancer(CPE). In this study, four organic acids and five permeation enhancers were selected, and the optimized formulation was obtained by single-factor investigation and Box-Behnken design. The optimized formulation could significantly enhance drug loading by 2.5-fold and skin permeation up to 586.6 ± 17 μg/cm2 in rats. Based on pharmacokinetic results, compared to oral administration, the drug exhibited a substantially elevated bioavailability, registering a 17-fold increase(from 3.01 % to 52.17 %), alongside a 10-fold rise in the mean residence time(MRT). Meanwhile, the patch was not irritating. The results of the mechanistic study showed that levulinic acid(LeA) acted as a bridge to increase the interaction between the Tan and the matrix and inhibited the crystallization of the drug in the patch, and THEDES together with CPE improved the matrix fluidity and skin permeability. This study provides a reference for the joint application of THEDES and CPEs in patch development.

Application of continuous stirring tank reactor for controllable synthesis of Cu7S4 nanocrystals

As a typical model for a chemical reactor in industry, the continuous stirring tank reactor has been widely used in waste-water treatment, industrial catalysis, and biological fermentation as well as great application prospects in the synthesis of nanomaterials. In this report, a convenient lab-scale continuous stirring tank reactor was assembled and utilized to synthesize Cu7S4 nanocrystals by injecting cupric bromide and sulfur solution in the presence of ascorbic acid and polyethyleneimine at 60 °C. The morphology control of Cu7S4 nanocrystals was accomplished by simply adjusting the agitation speed. Cu7S4 nanofibers with an average diameter of 48 ± 4.42 nm and a length of several micrometers were obtained at 80 rpm. Cu7S4 nanoplates with a thickness of 89 ± 13.56 nm and a plane size of 103 ± 16.47 nm were synthesized at 90 rpm, and the size of the nanoplates was regulated by continuously increasing the agitation speed from 90 rpm to 1000 rpm. Furthermore, the influences of two additional conditions (the mean residence time and the concentration of the feed solution) on the morphology of Cu7S4 nanocrystals, were also investigated. Therefore, these results could facilitate the understanding of the behaviors of CSTR in the synthesis of Cu7S4 nanocrystals and could also provide an important reference for the continuous synthesis of other nanoparticles.

Unveiling the Performance of SCAN Functional for Studying the Hydrated Ion in Solution: A Hybrid Forces Molecular Dynamics Study of La3+ Hydration

ABSTRACTSCAN/molecular mechanics molecular dynamics (SCAN/MM MD) simulations have been employed to investigate the structural and dynamical properties of La3+ in aqueous solution. These simulations revealed the presence of two distinct hydration shells, with the first shell exhibiting a La‐O bond distance of 2.56 Å. The water molecules in this initial hydration shell displayed a mean residence time (MRT) of 208 ps, suggesting a less rigid structure. Five successful ligand exchange events occurred within a simulation duration of 100 ps. The stretching frequency of La‐O was found to be 331 cm−1, with a force constant of 92 N/m. Notably, the data obtained from the SCAN/MM MD simulation demonstrated good agreement with experimental findings.

The conversion of biomass to biochar decreases soil organic and inorganic carbon-derived CO2 emissions under different water conditions in karst regions

Due to the unique geological background and climatic condition, karst soils in southwest China are mainly developed on carbonate rocks and accompanied by frequent dry-wet alternations. Therefore, the effects of biomass (BS) and biochar (BC) on the soil carbon pools (especially inorganic carbon) in karst regions are different from those in non-karst regions. In order to understand the responses of soil organic carbon (SOC) and soil inorganic carbon (SIC)-derived CO2 emissions to BS and BC amendments under different water conditions in karst regions, a microscopic study under dry-wet alternate (DW) and constant moisture (CM) conditions was established to investigate the stability of BC, BS, and their effects on SOC and SIC pools by isotope double-labeling methods. Results showed that the contribution rates of SOC and SIC to soil CO2 emissions were 51.55 %–99.52 %, 0.48 %–48.45 % and 60.55 %–97.72 %, 2.28 %–39.45 % under DW and CM conditions, respectively. Compared with the control, BS application under different water conditions increased SOC and SIC-derived CO2 emissions by 929.78˗1443.39 % and 169.69˗335.71 %, respectively. However, BC amendment significantly decreased SOC and SIC-derived CO2 emissions, especially in the DW condition. The mean residence time (the inverse of the decomposition rate) of BC in karst soils under different conditions ranged from 657 to 3105 years, which was much higher than those of BS (7˗18 years). Therefore, the conversion of BS to BC in karst regions enhances carbon sequestration due to its stability of recalcitrant carbon, the decrease of SOC and SIC- derived CO2 emissions. This study is helpful to understand the quantification of CO2 sources from calcareous soils and elucidate the environmental behaviors and carbon sequestration potentials of BC or BS amendments in karst regions.

Epidermal Growth Factor Intralesional Delivery in Chronic Wounds: The Pioneer and Standalone Technique for Reversing Wound Chronicity and Promoting Sustainable Healing.

The early expectations about growth factors' (GFs') discovery as an undisputed therapeutic solution for chronic wounds progressively eclipsed when they failed to accelerate acute wound closure and restore the healing trajectory of stagnant ulcers. Critical knowledge about chronic wound biology and GF pharmacology was a conundrum at that time. Diabetes undermines keratinocytes' and fibroblasts' physiology, impairing skin healing abilities. Diabetic ulcers, as other chronic wounds, are characterized by hyperinflammation, unbalanced proteolytic activity, catabolism, and free radical cytotoxicity. This hostile scenario for the chemical stability, integrity, and functionality of GFs led to the conclusion that topical administration may jeopardize GFs' clinical effectiveness. Epidermal growth factor (EGF) has a proximal position in tissues homeostasis by activating survival and mitogenic pathways from embryonic life to adulthood. Seminal experiments disclosed unprecedented pharmacological bounties of parenterally administered EGF. Accordingly, the experience accumulated for more than 20 years of EGF intralesional infiltration of diabetic wound bottoms and edges has translated into sustained healing responses, such as low recurrences and amputation rates. This delivery route, in addition to being safe and tolerated, has shown to restore a variety of circulating biochemical markers ordinarily disturbed in diabetic conditions. EGF infiltration triggers a cascade of local fibroblast reactions, supporting its molecular integrity, prolonged mean residence time, and ultimately eliciting its receptor trafficking and nuclear translocation. The intralesional delivery route seems to warrant that EGF reaches wound fibroblasts' epigenetic core, mitigating the consequences of metabolic memory imprinting.