Enhanced ophthalmic bioavailability and stability of atropine sulfate via sustained release particles using polystyrene sulfonate resin.

Atropine sulfate (ATS) eye drops at low concentrations constitute a limited selection for myopia treatment, with challenges such as low ophthalmic bioavailability and inadequate stability. This study proposes a novel strategy by synthesizing ophthalmic sodium polystyrene sulfonate resin (SPSR) characterized by a spherical shape and uniform size for cationic exchange with ATS. The formulation of ATS@SPSR suspension eye drops incorporates xanthan gum and hydroxypropyl methylcellulose (HPMC) as suspending agents. In vitro studies demonstrated that ATS@SPSR suspension eye drops exhibited sustained release characteristics, and tropic acid, its degradation product, remained undetected for 30 days at 40 °C. The ATS levels in the tear fluids and aqueous humor of New Zealand rabbits indicated a significant increase in mean residence time (MRT) and area under the drug concentration-time curve (AUC0-12h) for ATS@SPSR suspension eye drops compared to conventional ATS eye drops. Moreover, safety assessment confirmed the non-irritating nature of ATS@SPSR suspension eye drops in rabbit eyes. In conclusion, the cation-responsive sustained-release ATS@SPSR suspension eye drops enhanced the bioavailability and stability of ATS, offering a promising avenue for myopia treatment.

Hydrogeochemical and environmental isotope study of Topusko thermal waters, Croatia.

Thermal waters in Topusko (Croatia), with temperatures of up to 65 °C, have been used for heating, health, and recreational tourism for the past fifty years. Hydrogeochemical monitoring can provide insights into deeper geological processes and indicate system changes from baseline levels. It helps to identify potential anthropogenic impacts, as well as natural changes. Hydrogeochemical, geothermometrical, and environmental isotope studies of thermal waters in Topusko were conducted to improve the existing conceptual model of the Topusko hydrothermal system (THS), providing a baseline for continuous monitoring of the thermal resource. 2-year thermal springs and precipitation monitoring took place from March 2021 until March 2023. Major anions and cations, stable and radioactive isotopes (i.e. 18O, 2H, SO42-, 3H and 14C) and geothermometers were used to assess the origin of thermal waters in Topusko and their interaction with thermal aquifer. The results indicate the meteoric origin of thermal water, which was recharged in colder climatic conditions around the late Pleistocene-Early Holocene. Thermal water was last in contact with the atmosphere before approximately 9.5 kyr. Ca-HCO3 hydrochemical facies suggests carbonate dissolution as the dominant process driving the solute content. Geothermometrical results indicate an equilibrium temperature in the reservoir of 90 °C.

Multienvironmental tracers in coastal aquifer (Morocco): A window into groundwater mixing and risk to contamination.

In many coastal areas in Morocco, groundwater (GW) constitutes an important water supply for human activities. Intensive pumping makes GW highly susceptible to contamination, affecting its quality and then human health. This work aims to assess and improve the application of environmental isotopes in exploring the connections between GW recharge and discharge, as well as to identify the direction, age, and speed of GW flow, in the coastal aquifer system of the Akermoud plain. A total of 23 boreholes and wells were sampled during two sampling campaigns in 2017 and 2018, including 11 samples from the shallow aquifer and 12 samples from the deep aquifer. A set of chemical and isotopic tracers (δ18 O, δ2 H, 3 H, δ13 C, 14 C, and 3 He) is used to track water and solute from input to output of the investigated system. Stable isotopes distinguish recharge at different altitudes for the shallow and deep aquifers. Both aquifers reveal consistently low values of 3 H (between 0.3 and 0.9 tritium units) and from 28% to 64% of modern carbon for six boreholes. According to 14 C correction models, GW has ages ranging from 3300 to 11,000 years before present. GW flows from SSE to NNW and discharge along the Atlantic coast of Akermoud plain with a velocity ranging from 0.41 to 1.8 m/year. PRACTITIONER POINTS: The use of environmental tracers helps determine the origin of salinity and identify the recharge area. Investigating the MRT of groundwater resources is essential, especially in arid regions. Evaluating the efficiency of isotopic tracing is crucial in assessing the risk of groundwater contamination. The findings provide insights for stakeholders to promote more sustainable groundwater management in coastal areas.

Characterizing a design space for a twin-screw wet granulation process: A case study of extended-release tablets.

Twin-screw wet granulation is an emerging continuous manufacturing technology for solid oral dosage forms. This technology has been successfully employed for the commercial manufacture of immediate-released tablets. However, the higher polymer content in extended-release (ER) formulations may present challenges in developing and operating within a desired design space. The work described here used a systematic approach for defining the optimum design space by understanding the effects of the screw design, operating parameters, and their interactions on the critical characteristics of granules and ER tablets. The impacts of screw speed, powder feeding rate, and the number of kneading (KEs) and sizing elements on granules and tablets characteristics were investigated by employing a definitive screening design. A semi-mechanistic model was used to calculate the residence time distribution parameters and validated using the tracers. The results showed that an increase in screw speed decreased the mean residence time of the material within the barrel, while an increase in the powder feeding rate or number of KEs did the opposite and increased the barrel residence time. Screw design and operating parameters affected the flow and bulk characteristics of granules. The screw speed was the most significant factor impacting the tablet's breaking strength. The dissolution profiles revealed that granule characteristics mainly influenced the early phase of drug release. This study demonstrated that a simultaneous optimization of both operating and screw design parameters was beneficial in producing ER granules and tablets of desired performance characteristics while mitigating any failure risks, such as swelling during processing.

Sequential loss-on-ignition as a simple method for evaluating the stability of soil organic matter under actual environmental conditions.

Soil organic matter (SOM) is one of the largest carbon (C) reservoirs on Earth, and therefore its stability attracts a great deal of interest from the perspective of the global C cycle. This study examined the applicability of loss-on-ignition with a stepwise increase in temperature (SIT-LOI) of soil to evaluate the stability of SOM using soil samples having different organic matter (OM) and mineral contents and different mean residence times (MRTs) for SOM. The responses of SOM to the SIT-LOI varied depending on the samples but were all successfully approximated by a liner regression model as a function of the temperature of LOI. The slope value in the liner model that determines the residual potential of carbon during the SIT-LOI highly correlated with MRT of SOM, suggesting that this value reflects the overall stability of SOM over a range of soil properties. This hypothesis was consistent with the observation that Δ14C values of SOM decreased with increasing LOI temperature and thus, older, slower-cycling SOM was preferentially left in the soil samples by SIT-LOI. Additionally, the hypothesis was also supported by the significant correlations (p < 0.01) between the slope value and OM and mineral contents in the samples because these components are considered to regulate SOM stability. In addition to the regression analysis of the SIT-LOI data, changes in carbon to nitrogen (C/N) and carbon to hydrogen (C/H) ratios and stable carbon isotope signatures (δ13C) of the samples were investigated. The results suggest that the mineral association of SOM is an important factor characterizing the response of SOM to LOI. Hence, it was concluded that SIT-LOI is a simple and useful method for evaluating the stability of SOM under actual environmental conditions.

Subject-specific factors affecting particle residence time distribution of left atrial appendage in atrial fibrillation: A computational model-based study.

Background: Atrial fibrillation (AF) is a prevalent arrhythmia, that causes thrombus formation, ordinarily in the left atrial appendage (LAA). The conventional metric of stroke risk stratification, CHA2DS2-VASc score, does not account for LAA morphology or hemodynamics. We showed in our previous study that residence time distribution (RTD) of blood-borne particles in the LAA and its associated calculated variables (i.e., mean residence time, tm , and asymptotic concentration, C ∞) have the potential to improve CHA2DS2-VASc score. The purpose of this research was to investigate the effects of the following potential confounding factors on LAA tm and C ∞: (1) pulmonary vein flow waveform pulsatility, (2) non-Newtonian blood rheology and hematocrit level, and (3) length of the simulation. Methods: Subject-Specific data including left atrial (LA) and LAA cardiac computed tomography, cardiac output (CO), heart rate, and hematocrit level were gathered from 25 AF subjects. We calculated LAA tm and C ∞ based on series of computational fluid dynamics (CFD) analyses. Results: Both LAA tm and C ∞ are significantly affected by the CO, but not by temporal pattern of the inlet flow. Both LAA tm and C ∞ increase with increasing hematocrit level and both calculated indices are higher for non-Newtonian blood rheology for a given hematocrit level. Further, at least 20,000 s of CFD simulation is needed to calculate LAA tm and C ∞ values reliably. Conclusions: Subject-specific LA and LAA geometries, CO, and hematocrit level are essential to quantify the subject-specific proclivity of blood cell tarrying inside LAA in terms of the RTD function.

Theoretical Examination Seeking Tangible Physical Meanings of Slopes and Intercepts of Plasma Concentration-Time Relationships in Minimal Physiologically Based Pharmacokinetic Models.

In minimal physiologically based pharmacokinetic (mPBPK) models, physiological (e.g., cardiac output) and anatomical (e.g., blood/tissue volumes) variables are utilized in the domain of differential equations (DEs) for mechanistic understanding of the plasma concentration-time relationships [Formula: see text]. Although fundamental biopharmaceutical variables in terms of distribution (e.g., [Formula: see text] and [Formula: see text]) and elimination kinetics (e.g., [Formula: see text]) in mPBPK provide greater insights in comparison to classical compartment models, an absence of kinetic elucidation of slopes and intercepts in light of such DE model parameters hinders more intuitive appreciation of [Formula: see text]. Therefore, this study seeks the tangible physical meanings of slopes and intercepts of the plasma concentration-time relationships in one- and two-tissue mPBPK models (i.e., m2CM and m3CM), with respect to time parameters that are readily understandable in PK analyses, i.e., the mean residence ([Formula: see text]) and transit ([Formula: see text]) times. Utilizing the explicit equations (EEs) for the slopes, intercepts, and areas of each exponential phase in the m2CM and m3CM, we theoretically and numerically examined the limiting/boundary conditions of such kinetic properties, based on the ratio of the longest tissue [Formula: see text] to the [Formula: see text] in the body (i.e., [Formula: see text]) that is useful for dissecting complex PBPK systems. The kinetic contribution of the area of each exponential phase to the total drug exposure was assessed to identify the elimination phase between the terminal and non-terminal phases of the [Formula: see text] in the m2CM and m3CM. This assessment provides improved understanding of the complexities inherent in all PBPK profiles and models.

Automatic system dynamics characterization of a pharmaceutical continuous production line.

Continuous Manufacturing (CM) of drug products is a new approach in the pharmaceutical industry. In the presented paper, a GMP continuous wet granulation line for production of solid oral dosage forms was investigated in order to assess the system dynamics of the line and to define the best control and diversion strategy. The following steps were involved in the continuous process: dosing/feeding, blending, twin-screw wet granulation, fluid-bed drying, sieving and tableting. Two drug products with two different drug substances were compared during this study: one drug substance as model drug compound and one formulation of a currently evaluated commercial drug product. Several step tests in API concentration were performed in order to characterize the process flow and assess the process dynamics. API content was monitored in real time by Process Analytical Technologies (PAT) thanks to three Near Infrared (NIR) probes located along the process and measuring the API content after blender, after dryer and in the tablet press feed frame. The process parameter values were changed during production in order to detect the impact on the quality of the final product. An automatic residence time distribution (RTD) computation method has been developed in order automate the RTD calculation on the basis of process data to further define and monitor the system dynamics with the final aim of out of specification material diversion during the continuous production. The RTD has been seen as a process fingerprint: a change in the RTD values implies a change in the process.

Determinants of Biological Half-Lives and Terminal Slopes in Physiologically Based Pharmacokinetic Systems: Assessment of Limiting Conditions.

In pharmacokinetic (PK) analyses, the biological half-life T1/2 is usually determined in the terminal phase after drug administration, which is readily calculated from the relationship T1/2 = ln2/λz where λz is the terminal-phase slope obtainable from non-compartmental analysis (NCA). Since kinetic understanding of λz has been limited to the theory of a one-compartment model, this study seeks kinetic determinants of λz in more complex plasma concentration-time profiles. We utilized physiologically based pharmacokinetic (PBPK) systems that are consistent with the assumptions of NCA (e.g., linear PK and elimination occurring from plasma) to interrelate λz and disposition kinetic parameters of PBPK models. In a mammillary form of PBPK models, the two boundary conditions of λz are the inverses of the mean residence time in the body (1/MRTB = CL/VSS) and the mean transit time through the kinetically largest tissue (1/MTTmax = QTfdRb/VTKp). Importantly, the limiting conditions of λz between 1/MRTB and 1/MTTmax are dependent on a simple product MRTBλz (Pdet) and a simple ratio MTTmax/MRTB (Kdet), leading to introduction of the unitless product-ratio plot for determination of the limiting condition of λz in linear PK. We found that the MRTBλz value of 0.5 serves as a practical threshold determining whether λz is more closely associated with 1/MRTB or 1/MTTmax. The current theory was applied for assessment of the terminal slope λz for observed PK data of various compounds in man and rat.

A novel approach for accurate quantification of lake residence time - Lake Kinneret as a case study.

Water residence time, which is affected by increasing water demands and climate change, plays a crucial role in lakes and reservoirs since it influences many natural physical and ecological processes that eventually impact the water quality of the waterbody. Thus, accurate quantification of the water residence time and its distribution is an important tool in lake management. In this study we present a novel approach for assessing the residence time in lakes and reservoirs. The approach is based on the Leslie matrix model that was originally developed for the analysis of age-structured biological population dynamics. In this approach the water in the lake is divided into different age classes each representing the time since the "parcel" of water entered the lake and provides an overall picture of the water age structure. The traditional approach for calculating residence times, which relies only on the lake volume and annual inflow or outflow volumes thereby disregarding any previous information, is very sensitive to large interannual variation. While the proposed approach produces the fraction and volume distribution curves of all age classes within the lake for each simulated timestep. Thus, in addition to mean residence time, the fraction of young water (FYW), quantifying the "young" fraction of water in the lake can be analyzed. The same is true for any other age class of water. The approach was applied to Lake Kinneret (Sea of Galilee) historical data collected over 32 years (1987-2018) and for prediction of long-term time series based on several future scenarios (inflows and outflows). It offers a more accurate quantification of the mean residence time of water in a lake and can easily be adapted to other waterbodies. Comparison of simulation results may serve as basis for determining the lake's management policy, by controlling the inflows and outflows, that will affect both the mean residence time and the fraction of "young/old" age classes of water.

Chiral mesoporous silica nano-screws as an efficient biomimetic oral drug delivery platform through multiple topological mechanisms.

In the microscale, bacteria with helical body shapes have been reported to yield advantages in many bio-processes. In the human society, there are also wisdoms in knowing how to recognize and make use of helical shapes with multi-functionality. Herein, we designed atypical chiral mesoporous silica nano-screws (CMSWs) with ideal topological structures (e.g., small section area, relative rough surface, screw-like body with three-dimension chirality) and demonstrated that CMSWs displayed enhanced bio-adhesion, mucus-penetration and cellular uptake (contributed by the macropinocytosis and caveolae-mediated endocytosis pathways) abilities compared to the chiral mesoporous silica nanospheres (CMSSs) and chiral mesoporous silica nanorods (CMSRs), achieving extended retention duration in the gastrointestinal (GI) tract and superior adsorption in the blood circulation (up to 2.61- and 5.65-times in AUC). After doxorubicin (DOX) loading into CMSs, DOX@CMSWs exhibited controlled drug release manners with pH responsiveness in vitro. Orally administered DOX@CMSWs could efficiently overcome the intestinal epithelium barrier (IEB), and resulted in satisfactory oral bioavailability of DOX (up to 348%). CMSWs were also proved to exhibit good biocompatibility and unique biodegradability. These findings displayed superior ability of CMSWs in crossing IEB through multiple topological mechanisms and would provide useful information on the rational design of nano-drug delivery systems.

Pharmacokinetics and analytical determination of acyclovir in Asian elephant calves (Elephas maximus).

A therapeutic regimen that includes antiviral drugs is critical for the survival of Asian elephant (Elephas maximus) calves infected with elephant endotheliotropic herpesvirus hemorrhagic disease (EEHV-HD), with acyclovir showing considerable promise. The purpose of this study was to determine the pharmacokinetics and bioavailability of acyclovir following intravenous (IV) and oral (PO) administration in Asian elephants. A single dose of acyclovir (15 mg/kg, IV or 45 mg/kg, PO) was administered to four healthy elephant calves, with a minimum 2-week washout period between treatments. Serial plasma samples were collected after each injection for acyclovir analysis using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) technique. Maximum plasma acyclovir concentrations were 27.02 ± 6.79 µg/mL at 0.94 ± 0.31 h after IV administration, and 1.45 ± 0.20 µg/mL at 3.00 ± 0.70 h after PO administration. The half-life of the elimination phase (T1/2) was 5.84 ± 0.74 and 8.74 ± 2.47 h after IV and PO administration, respectively. After IV administration, acyclovir concentrations were higher than the half-maximal inhibitory concentration (IC50) of those found for herpes simplex virus (HSV) 1 and 2 in humans, and equid alpha herpesvirus-1 (EHV-1) for at least 12 h. By contrast, the bioavailability of oral administration was low, only 6.03 ± 0.87%, so higher doses by that route likely are needed to be effective. Due to the high concentration of plasma acyclovir after IV administration, the dose may need to be adjusted to prevent any negative side effects.

Impact of Indian summer monsoon in westerly dominated water resources of western Himalayas.

We used stable water isotopes of oxygen and hydrogen to identify and estimate the seasonal contribution of precipitation to the regional hydrology of Sindh and Rambiara catchments of western Himalayas. The different source waters exhibit significant spatio-temporal variations that correspond to the change in seasonal meteorology, precipitation form and moisture sources. The two-component hydrograph separation based on d-excess suggests that the western disturbances (WD) contribute dominantly (76 ± 4 %) to the regional hydrology, compared to Indian summer monsoon (ISM) rainfall (24 ± 4 %). A comparison of d-excess values of WD and ISM indicates the groundwater consists of 90 ± 3 % WD sources and 10 ± 2 % ISM sources, signifying distinct seasonal variations in groundwater recharge sources. The sine wave model results showed that the annual mean residence time (MRT) of groundwater for the Sindh catchment (5.8 ± 0.6 months) is greater than the Rambiara groundwater (3.6 ± 0.5 months). The lower isotope values observed in the river water than in the precipitation suggest its origin from the snowmelt. This study provides valuable insights into the hydrological processes operating in the high altitude Himalayan catchments to facilitate the improved understanding of runoff generation mechanisms and water resource management in future climate change scenarios.

Polyoxypregnanes as safe, potent, and specific ABCB1-inhibitory pro-drugs to overcome multidrug resistance in cancer chemotherapy in vitro and in vivo.

Multidrug resistance (MDR) mediated by ATP binding cassette subfamily B member 1 (ABCB1) is significantly hindering effective cancer chemotherapy. However, currently, no ABCB1-inhibitory drugs have been approved to treat MDR cancer clinically, mainly due to the inhibitor specificity, toxicity, and drug interactions. Here, we reported that three polyoxypregnanes (POPs) as the most abundant constituents of Marsdenia tenacissima (M. tenacissima) were novel ABCB1-modulatory pro-drugs, which underwent intestinal microbiota-mediated biotransformation in vivo to generate active metabolites. The metabolites at non-toxic concentrations restored chemosensitivity in ABCB1-overexpressing cancer cells via inhibiting ABCB1 efflux activity without changing ABCB1 protein expression, which were further identified as specific non-competitive inhibitors of ABCB1 showing multiple binding sites within ABCB1 drug cavity. These POPs did not exhibit ABCB1/drug metabolizing enzymes interplay, and their repeated administration generated predictable pharmacokinetic interaction with paclitaxel without obvious toxicity in vivo. We further showed that these POPs enhanced the accumulation of paclitaxel in tumors and overcame ABCB1-mediated chemoresistance. The results suggested that these POPs had the potential to be developed as safe, potent, and specific pro-drugs to reverse ABCB1-mediated MDR. Our work also provided scientific evidence for the use of M. tenacissima in combinational chemotherapy.

Residence time distribution study in a pilot-scale liquid phase catalytic exchange (LPCE) column packed with a mixture of hydrophobic and hydrophilic catalysts.

Residence time distribution (RTD) measurements were carried out in a packed bed column designed for exchange of hydrogen isotopes. The main objective of the study was to characterize the liquid phase mixing under various processes and operating conditions. The packed bed was composed of a mixture of two different types of catalytic packing materials, i.e., a hydrophobic material and a hydrophilic material. Technitium-99m (99mTc) as sodium pertechnetate was used as a radiotracer for RTD measurements. From the measured RTD curves, mean residence times (MRTs), liquid holdup and degree of mixing of liquid phase were evaluated. An axial dispersion model exchange with stagnant zones was used to simulate the measured RTD curves. The results of model simulation showed that volume fraction of hydrophobic to hydrophilic packing and gas/liquid superficial velocities affect the liquid holdup, bed pressure drop and liquid phase dispersion/mixing characteristics. The results of the present study will help to screen packing, optimize the volume of the packing fractions, design and construct the catalyst and optimize the operating conditions for scale up of the isotope exchange process.

Robust empirical Bayes approach for Markov chain modeling of air pollution index.

Air pollution is a matter of concern among the public, especially for those living in urban and industrial areas. Markov chain modeling is often used to model the underlying dynamics of air pollution, which involves describing the transition probability of going from one air pollution state to another. Thus, estimating the transition probability matrix for the data of the air pollution index (API) is an essential process in the modeling. However, one may observe many zero probabilities in the transition probability matrix, especially when faced with a small sample, interpreting the results with respect to the climate condition less realistic. This study proposes a robust empirical Bayes method, which incorporates a method of smoothing the zero frequencies in the count matrix, contributing to an improved estimation of the transition probability matrix. The robustness of the empirical Bayesian estimation is investigated based on Bayes risk. The transition probability matrices estimated based on the robust empirical Bayes method for the hourly API data collected from seven monitoring stations in Malaysia for the period 2012 to 2014 are used for determining the air pollution characteristics such as the mean residence time, the steady-state probability and the mean recurrence time. Furthermore, the proposed method has been evaluated by Monte Carlo simulations. Results suggest that it is quite effective in producing non-zero transition probability estimates, and superior to the maximum likelihood method in terms of minimizing the mean squared error for individual and entire transition probabilities. Therefore, the robust empirical Bayes method proves to be an improved approach to the estimation of the Markov chain. When applied to API data, it could provide important information on air pollution dynamics that may help guiding the development of proper strategies for managing the impact of air quality. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40201-020-00607-4.

Escape from abluminal LRP1-mediated clearance for boosted nanoparticle brain delivery and brain metastasis treatment.

Breast cancer brain metastases (BCBMs) are one of the most difficult malignancies to treat due to the intracranial location and multifocal growth. Chemotherapy and molecular targeted therapy are extremely ineffective for BCBMs due to the inept brain accumulation because of the formidable blood‒brain barrier (BBB). Accumulation studies prove that low density lipoprotein receptor-related protein 1 (LRP1) is promising target for BBB transcytosis. However, as the primary clearance receptor for amyloid beta and tissue plasminogen activator, LRP1 at abluminal side of BBB can clear LRP1-targeting therapeutics. Matrix metalloproteinase-1 (MMP1) is highly enriched in metastatic niche to promote growth of BCBMs. Herein, it is reported that nanoparticles (NPs-K-s-A) tethered with MMP1-sensitive fusion peptide containing HER2-targeting K and LRP1-targeting angiopep-2 (A), can surmount the BBB and escape LRP1-mediated clearance in metastatic niche. NPs-K-s-A revealed infinitely superior brain accumulation to angiopep-2-decorated NPs-A in BCBMs bearing mice, while comparable brain accumulation in normal mice. The delivered doxorubicin and lapatinib synergistically inhibit BCBMs growth and prolongs survival of mice bearing BCBMs. Due to the efficient BBB penetration, special and remarkable clearance escape, and facilitated therapeutic outcome, the fusion peptide-based drug delivery strategy may serve as a potential approach for clinical management of BCBMs.

Influence of Pyrexia on Pharmacokinetics of Azithromycin and Its Interaction With Tolfenamic Acid in Goats.

Azithromycin is a macrolide antimicrobial agent of the azalide group with a broad spectrum of activity against gram-negative and gram-positive bacterial organisms. Tolfenamic acid is a non-steroidal anti-inflammatory drug of the fenamate group, which is used extensively in humans and animals due to its anti-inflammatory, analgesic, and antipyretic properties. There is dearth of literature on any type of drug interaction between azithromycin and tolfenamic acid in any species, including human beings and alteration of its pharmacokinetics by fever. Therefore, the objective of this study was to investigate the alteration of disposition kinetics of azithromycin alone and in the presence of tolfenamic acid in Malabari goats by fever, following an intravenous administration at a dose rate of 20 mg/kg body weight. Blood samples collected from both afebrile and febrile goats at predetermined time intervals after the administration of azithromycin alone and then in combination with tolfenamic acid (2 mg/kg, intravenously), respectively, were analyzed using high-performance liquid chromatography. Non-compartmental analysis was used to determine the peak blood concentration (C max), time-to-peak plasma concentration (T max), half-life (t 1/2λz ), area under the curve (AUC 0-t, AUC 0-inf), area under the first moment curve (AUMC 0-inf), mean residence time (MRT0-inf), apparent volume of distribution at steady state (V ss), and the total body clearance of drug from the blood (Cl). In febrile animals, significant differences were noted in the values of C max, Cl, and V ss. Thus, azithromycin disappears into an additional compartment in febrile goats, which may be due to its extended cellular penetration into the inflammatory cells, resulting in anti-inflammatory activity. Tolfenamic acid significantly altered the pharmacokinetics of azithromycin in both normal and febrile animals. Tolfenamic acid, being a better anti-inflammatory agent, suppresses the inflammatory mediators, reducing the possibility of increased utilization of azithromycin in febrile condition.

Subject-Specific Calculation of Left Atrial Appendage Blood-Borne Particle Residence Time Distribution in Atrial Fibrillation.

Atrial fibrillation (AF) is the most common arrhythmia that leads to thrombus formation, mostly in the left atrial appendage (LAA). The current standard of stratifying stroke risk, based on the CHA2DS2-VASc score, does not consider LAA morphology, and the clinically accepted LAA morphology-based classification is highly subjective. The aim of this study was to determine whether LAA blood-borne particle residence time distribution and the proposed quantitative index of LAA 3D geometry can add independent information to the CHA2DS2-VASc score. Data were collected from 16 AF subjects. Subject-specific measurements included left atrial (LA) and LAA 3D geometry obtained by cardiac computed tomography, cardiac output, and heart rate. We quantified 3D LAA appearance in terms of a novel LAA appearance complexity index (LAA-ACI). We employed computational fluid dynamics analysis and a systems-based approach to quantify residence time distribution and associated calculated variable (LAA mean residence time, t m) in each subject. The LAA-ACI captured the subject-specific LAA 3D geometry in terms of a single number. LAA t m varied significantly within a given LAA morphology as defined by the current subjective method and it was not simply a reflection of LAA geometry/appearance. In addition, LAA-ACI and LAA t m varied significantly for a given CHA2DS2-VASc score, indicating that these two indices of stasis are not simply a reflection of the subjects' clinical status. We conclude that LAA-ACI and LAA t m add independent information to the CHA2DS2-VASc score about stasis risk and thereby can potentially enhance its ability to stratify stroke risk in AF patients.

Uptake and depuration kinetics of microplastics with different polymer types and particle sizes in Japanese medaka (Oryzias latipes).

Microplastic (MP) pollution and the related impacts on aquatic species have drawn worldwide attention. However, knowledge of the kinetic profiles of MPs in fish remains fragmentary. In this study, we conducted exposure and depuration tests of the following fluorescent-labeled MPs: polyethylene (PE; sphere with 200 or 20 µm diameter) and polystyrene (PS; sphere with 20 or 2 µm diameter) using juvenile Japanese medaka (Oryzias latipes). The distribution and concentration of MPs in medaka were directly determined in-situ after tissue transparency. During the 14-day exposure, MPs was mainly detected in the gastrointestinal tract, while some MPs at the size of ≤ 20 µm were located in the area of the gills and head. The bioconcentration factor (BCF; L/kg) for MPs in medaka was estimated as 74.4 (200 µm PE), 25.7 (20 µm PE), 16.8 (20 µm PS), and 139.9 (2 µm PS). Within the first five days of depuration, MPs were exponentially eliminated from the fish body, but 2 µm PS-MPs could be still detected in the gastrointestinal tract at the end of the 10-day depuration phase. Our results suggest that MPs 2 µm in diameter may pose ecological risks to aquatic species due to their relatively higher BCF and the potential for long-term persistence in the body.