Insights into the Role of Erythrina corallodendron L. in Alzheimer's Disease: in Vitro and in Silico Approach.

Alzheimer's disease (AD) is a major health problem. Cholinergic transmission is greatly affected in AD. Phytochemical investigation of the alkaloid rich fraction (AF) of Erythrina corallodendron L leaves resulted in isolation of five known alkaloids: erysodine, erythrinine, 8-oxoerythrinine, erysovine N-oxide and erythrinine N-oxide. In this study, eysovine N-oxide was reported for the second time in nature. AF was assayed for cholinesterase inhibition at the concentration of 100 µg mL-1 . AF showed a higher percent inhibition for butyrylcholinesterase enzyme (BuChE) (83.28 %) compared to acetylcholinesterase enzyme (AChE) (64.64 %). The isolated alkaloids were also assayed for their anti-BuChE effect. In-silico docking study was done for the isolated compounds at the binding sites of AChE and BuChE to determine their binding pattern and interactions, also molecular dynamics were estimated for the compound displaying the best fit for AChE and BuChE. In addition, ADME parameters and toxicity were predicted for the isolated alkaloids compared to donepezil.

Anticoagulation and bleeding in the cancer patient.

Cancer patients have an increased risk of bleeding compared to non-cancer patients with anticoagulant therapy. A bleeding risk assessment before initiation of anticoagulation is recommended. Currently low molecular weight heparin (LMWH) and direct oral anticoagulants (DOACs) are the mainstays of treatment for cancer-associated venous thromboembolism (VTE). Since DOACs are administered orally, they offer some convenience and ease of administration; however, LMWH may be preferred in certain cancers. Given the prevalence of anticoagulant therapies in cancer patients, clinical providers must be able to recognize potentially critical bleeding sites and modalities to reverse major hemorrhage. Reversal agents or antidotes to bleeding may be required when bleeding is persistent or life-threatening. These include vitamin K, fresh frozen plasma (FFP), protamine, prothrombin complex concentrate (PCC) or andexanet alfa, and idarucizumab. Inferior vena cava (IVC) filter insertion can be also considered in those with major bleeding. Evidence for timing and need for re-initiation of anticoagulant therapy after a major bleeding remains sparse, but a multi-disciplinary approach and shared decision-making can be implemented in the interim.

Evaluation of Osteopontin and Pokémon genes expression in hepatitis C virus-associated hepatocellular carcinoma.

Osteopontin and Pokémon genes may have an important role in the pathogenesis of different malignancies. Osteopontin is a glycoprotein of the extracellular matrix, and Pokémon is a regulator of transcription. Both have been hypothesized to be useful as therapeutic targets or diagnostic markers. We aim to assess the role of both in hepatocellular carcinoma and liver fibrosis due to hepatitis C virus (HCV) infection. We conducted our study on 50 patients and classified them into three groups-Group I: Patients with HCV-related hepatocellular carcinoma (HCC) (n = 30); Group II: Patients with hepatitis C cirrhosis (n = 10); and Group III: Patients with hepatitis C fibrosis (n = 10). We found high levels of Osteopontin and Pokémon gene expression in group I. Osteopontin levels were higher also in patients with liver fibrosis was correlated to high levels of parameters such as alpha fetoprotein and caspase. We conclude that HCC is associated with overexpression of both Osteopontin and Pokémon and that Osteopontin plays a significant role in liver fibrosis due to hepatitis C infection.

IL-28ß gene polymorphism determines virological response to PEGylated interferon therapy in hepatitis C virus genotype 4 Egyptian patients.

BACKGROUND: PEGylated interferon (PEG-IFN) in combination with ribavirin is the gold standard for chronic hepatitis C virus (HCV). The majority of patients received PEG-IFN/ribavirin achieve a sustained viral response (SVR), but few cases failed to respond. It was evident that host genetic factors determine the treatment-induced viral clearance as well as spontaneous response. In the current study, the rs12979860 polymorphism of IL28ß gene was analyzed and its association with the virological response to PEG-IFN treatment was determined. METHODS: One hundred and fifty Egyptian patients with HCV genotype 4 treated with PEG-IFN/ribavirin were assessed at 12 and 24 weeks of therapy, the rs12979860 genotype was determined using TaqMan-based quantitative polymerase chain reaction. RESULTS: Although the CC genotype was the most frequent (58%), the higher SVR was achieved for patients with favorable CC genotype (93%) in contrast to CT and TT genotypes. CONCLUSION: we conclude that IL28B polymorphism is highly associated with SVR to therapy in the Egyptian population infected with HCV genotype 4 and patients who carry CC genotype have a higher chance of SVR.

Caffeic Acid Modulates miR-636 Expression in Diabetic Nephropathy Rats.

We investigated the action of caffeic acid in regulating miR-636 expression level in kidney of streptozotocin-induced diabetic rats. Streptozotocin-induced diabetic rats were orally treated with caffeic acid at 40 mg/kg/day for 8 weeks. At the end of the treatment, body and kidney weight and blood glucose levels were determined, blood, urine, and kidneys were collected for biochemical and histological examination. Expression levels of miR-636 were determined in liver by qRT-PCR. Induction of diabetic nephropathy by streptozotocin was evidenced by displayed elevated levels of serum creatinine, blood urea nitrogen, microalbuminuria and urinary albumin/creatinine ratio in addition to renal hypotrophy. Caffeic acid (CA) can ameliorate renal damage and significantly decreased the fasting blood glucose, cholesterol and triglyceride in diabetic rats. CA treatment improved histological architecture in the diabetic kidney. CA significantly down regulate miR-636 expression level in the kidney of diabetic rats in comparison to healthy group. Overall, caffeic acid down regulates miR-636 expression level which is involved in development of diabetic nephropathy and might therefore be potential attractive therapeutic agent to pursue in DN.

Characterization of Crude Oil Degrading Bacteria Isolated from Contaminated Soils Surrounding Gas Stations.

A total of twenty bacterial cultures were isolated from hydrocarbon contaminated soil. Of the 20 isolates, RAM03, RAM06, RAM13, and RAM17 were specifically chosen based on their relatively higher growth on salt medium amended with 4 % crude oil, emulsion index, surface tension, and degradation percentage. These bacterial cultures had 16S rRNA gene sequences that were most similar to Ochrobactrum cytisi (RAM03), Ochrobactrum anthropi (RAM06 and RAM17), and Sinorhizobium meliloti (RAM13) with 96 %, 100 % and 99 %, and 99 % similarity. The tested strains revealed a promising potential for bioremediation of petroleum oil contamination as they could degrade >93 % and 54 % of total petroleum hydrocarbons (TPHs) in a liquid medium and soil amended with 4 % crude oil, respectively, after 30 day incubation. These bacteria could effectively remove both aliphatic and aromatic petroleum hydrocarbons. In conclusion, these strains could be considered as good prospects for their application in bioremediation of hydrocarbon contaminated environment.

Potential of bone marrow mesenchymal stem cells in management of Alzheimer's disease in female rats.

Alzheimer's disease (AD) has been called the disease of the century with significant clinical and socioeconomic impacts. Pharmacological treatment has limited efficacy and only provides symptomatic relief without long-term cure. Accordingly, there is an urgent need to develop novel and effective medications for AD. Stem cell-based therapy is a promising approach to handling neurodegenerative diseases. Therefore, the current study aimed to explore the possible therapeutic role of single intravenous injection of bone marrow derived mesenchymal stem cells (BM-MSCs) after 4 months in management of AD in the experimental model. The work also extended to compare the therapeutic potential of BM-MSCs with 2 conventional therapies of AD; rivastigmine and cerebrolysin administered daily. BM-MSCs were able to home at the injured brains and produced significant increases in the number of positive cells for choline acetyltransferase (ChAT) and survivin expression, as well as selective AD indicator-1 (seladin-1) and nestin gene expression. Histopathological examination indicated that BM-MSCs could remove beta-amyloid plaques from hippocampus. Significant improvement in these biomarkers was similar to or better sometimes than the reference drugs, clearly showing the potential therapeutic role of BM-MSCs against AD through their anti-apoptotic, neurogenic and immunomodulatory properties.

The airport gate assignment problem: a survey.

The airport gate assignment problem (AGAP) is one of the most important problems operations managers face daily. Many researches have been done to solve this problem and tackle its complexity. The objective of the task is assigning each flight (aircraft) to an available gate while maximizing both conveniences to passengers and the operational efficiency of airport. This objective requires a solution that provides the ability to change and update the gate assignment data on a real time basis. In this paper, we survey the state of the art of these problems and the various methods to obtain the solution. Our survey covers both theoretical and real AGAP with the description of mathematical formulations and resolution methods such as exact algorithms, heuristic algorithms, and metaheuristic algorithms. We also provide a research trend that can inspire researchers about new problems in this area.

Pharmacokinetic Modeling Using Real-World Data to Optimize Unfractionated Heparin Dosing in Pediatric Patients on Extracorporeal Membrane Oxygenation and Evaluate Target Achievement-Clinical Outcomes Relationship.

Unfractionated heparin (UFH) is a commonly used anticoagulant for pediatric patients undergoing extracorporeal membrane oxygenation (ECMO), but evidence is lacking on the ideal dosing. We aimed to (1) develop a population pharmacokinetic (PK) model for UFH, measured through anti-factor Xa assay; (2) optimize UFH starting infusions and dose titrations through simulations; and (3) explore UFH exposure-clinical outcomes relationship. Data from 218 patients admitted to Utah's Primary Children's Hospital were retrospectively collected. A 1-compartment PK model with time-varying clearance (CL) adequately described UFH PK. Weight on CL and volume of distribution and ECMO circuit change on CL were significant covariates. The typical estimates for initial CL and first-order rate constant to reach steady-state CL were 0.57 L/(h·10 kg) and 0.02/h. Comparable to non-ECMO patients, the typical steady-state CL was 0.81 L/(h·10 kg). Simulations showed that a 75 IU/kg UFH bolus dose followed by starting infusions of 25 and 20 IU/h/kg for patients aged younger than 6 years and 6 years or older, respectively, achieved the therapeutic target in 56.6% of all patients, whereas only 3.1% exceeded the target. The proposed UFH titration schemes achieved the target in more than 90% of patients while less than 0.63% were above the target after 24 and 48 hours of treatment. The median intensive care unit survival time in patients within and below the target at 24 hours was 136 and 66 hours, respectively. In conclusion, PK model of UFH was developed for pediatric patients on ECMO. The proposed UFH dosing scheme attained the anti-factor Xa target rapidly and safely.

Genetic variants of neurotransmitter-related genes and miRNAs in Egyptian autistic patients.

Autism is a neurodevelopmental disorder with indisputable evidence for a genetic component. This work studied the association of autism with genetic variations in neurotransmitter-related genes, including MAOA uVNTR, MAOB rs1799836, and DRD2 TaqI A in 53 autistic patients and 30 healthy individuals. The study also analyzed sequence variations of miR-431 and miR-21. MAOA uVNTR was genotyped by PCR, MAOB and DRD2 polymorphisms were analyzed by PCR-based RFLP, and miR-431 and miR-21 were sequenced. Low expressing allele of MAOA uVNTR was frequently higher in female patients compared to that in controls (OR = 2.25). MAOB G allele frequency was more significantly increased in autistic patients than in controls (P < 0.001 for both males and females). DRD2 A1+ genotype increased autism risk (OR = 5.1). Severity of autism tends to be slightly affected by MAOA/B genotype. Plasma MAOB activity was significantly reduced in G than in A allele carrying males. There was no significant difference in patients and maternal plasma MAOA/B activity compared to controls. Neither mutations nor SNPs in miR-431 and miR-21 were found among studied patients. This study threw light on some neurotransmitter-related genes suggesting their potential role in Autism pathogenesis that warrants further studies and much consideration.

Effects of throat sizing and gasification agents in a biomass downdraft gasifier: towards CO2-free syngas production.

The gasification process in a downdraft biomass gasifier is investigated using Computational Fluid Dynamics (CFD). The aim is to develop a novel approach to reduce CO2 emissions from producer syngas while increasing the higher heating value (HHV). To this end, the effects of varying the throat diameter of the gasifier and gasifying media (air and oxygen) on the performance of gasification are investigated. The results reveal that as the throat ratio decreases for oxy-gasification, more CO, H2, and CH4 are produced, thus resulting in a HHV of 12.1 MJ Nm-3. For the same working conditions (ER, MC, and feedstock), the suggested design/optimum throat ratio of 0.14 is found to reduce CO2 by ∼55% compared to any other higher throat ratios, while simultaneously increasing HHV by ∼20% for both air and oxy-gasification cases. Additionally, the suggested throat ratio increases the gasification efficiency, carbon conversion and producer gas yield by 19%, 33%, and 22% respectively. Therefore, it shows a significant potential for CO2-free syngas production in the gasification process, demonstrating a promising technique that does not require any solvents, catalysts, absorbers, or additional CO2 removal. Lower throat ratios further favour the higher yield of syngas, HHV, gasification and conversion efficiencies, with better gasifier performance.

A mini-review on liquid air energy storage system hybridization, modelling, and economics: towards carbon neutrality.

The rapid increase in energy consumption around the world is the main challenge that compromises and affects the environment. Electricity generation, which mainly depends on fossil fuels, produces around 80% of CO2 emissions released into the atmosphere. Renewables are a remarkable alternative for energy production. However, they are intermittent sources of energy. Liquid air energy storage (LAES) is a medium-to large-scale energy system used to store and produce energy, and recently, it could compete with other storage systems (e.g., compressed air and pumped hydro), which have geographical constraints, affect the environment, and have a lower energy density than that of LAES. However, the low efficiency, high payback periods, and profit values of LAES hamper its commercialization. LAES is premature to be fully studied because lack of actual operating conditions and results from large plants, which affect the techno-economic predictions, in turn, affecting technology commercialization. Furthermore, the off-design conditions are not fully covered although it is a crucial step in system performance evaluation. To this end, the current mini-review sheds light on the LAES design, history, types, limitations, and the associated techno-economic analysis. In addition, state-of-the-art modelling tools are widely explained with benefits and shortage. Furthermore, LAES integration with other systems is explained widely, as it was found to boost the system performance and increase the profit with lower payback periods.

Development of a multiscale mechanistic modeling framework integrating differential cellular kinetics of CAR T-cell subsets and immunophenotypes in cancer patients.

Chimeric antigen receptor (CAR) T-cell subsets and immunophenotypic composition of the pre-infusion product, as well as their longitudinal changes following infusion, are expected to affect CAR T-cell expansion, persistence, and clinical outcomes. Herein, we sequentially evolved our previously described cellular kinetic-pharmacodynamic (CK-PD) model to incorporate CAR T-cell product-associated attributes by utilizing published preclinical and clinical datasets from two affinity variants (FMC63 and CAT19 scFv) anti-CD19 CAR T-cells. In step 1, a unified cell-level PD model was used to simultaneously characterize the in vitro killing datasets of two CAR T-cells against CD19+ cell lines at varying effector:target ratios. In step 2, an augmented CK-PD model for anti-CD19 CAR T-cells was developed, by integrating CK dataset(s) from two bioanalytical measurements (quantitative polymerase chain reaction and flow cytometry) in patients with cancer. The model described the differential in vivo expansion properties of CAR T-cell subsets. The estimated expansion rate constant was ~1.12-fold higher for CAR+CD8+ cells in comparison to CAR+CD4+ T-cells. In step 3, the model was extended to characterize the disposition of four immunophenotypic populations of CAR T-cells, including stem-cell memory, central memory, effector memory, and effector cells. The model adequately characterized the longitudinal changes in immunophenotypes post anti-CD19 CAR T-cell infusion in pediatric patients with acute lymphocytic leukemia. Polyclonality in the pre-infusion product was identified as a categorical covariate influencing differentiation of immunophenotypes. In the future, this model could be leveraged a priori toward optimizing the composition of CAR T-cell infusion product, and further understand the CK-PD relationship in patients.

Highly Uniform Multi-Layers Reduced Graphene Oxide/Poly-2-aminobenzene-1-thiol Nanocomposite as a Promising Two Electrode Symmetric Supercapacitor under the Effect of Absence and Presence of Porous-Sphere Polypyrrole Nanomaterial.

A uniform and highly porous reduced graphene oxide/poly-2-aminobenzene-1-thiol multi-layer (R-GO/P2ABT-ML) nanocomposite was synthesized and characterized. The uniform layer structure and porosity of the nanocomposite, combined with its conductivity, make it an ideal candidate for use as a pseudo supercapacitor. To enhance the capacitance behavior, a porous ball structure polypyrrole (PB-Ppy) was incorporated into the nanocomposite. When tested at 0.2 A/g, the capacitance values of the R-GO/P2ABT-ML and R-GO/P2ABT-ML/PB-Ppy were found to be 19.6 F/g and 92 F/g, respectively, indicating a significant increase in capacitance due to the addition of PB-Ppy. The energy density was also found to increase from 1.18 Wh.kg-1 for R-GO/P2ABT-ML to 5.43 Wh.kg-1 for R-GO/P2ABT-ML/PB-Ppy. The stability of the supercapacitor was found to be significantly enhanced by the addition of PB-Ppy. The retention coefficients at 100 and 500 charge cycles for R-GO/P2ABT-ML/PB-Ppy were 95.6% and 85.0%, respectively, compared to 89% and 71% for R-GO/P2ABT-ML without PB-Ppy. Given the low cost, mass production capability, and easy fabrication process of this pseudo capacitor, it holds great potential for commercial applications. Therefore, a prototype of this supercapacitor can be expected to be synthesized soon.

Model-based approach to identify predictors of paclitaxel-induced myelosuppression in "real-world" administration.

Taxanes are currently the most frequently used chemotherapeutic agents in cancer care, where real-world use has focused on minimizing adverse events and standardizing the delivery. Myelosuppression is a well-characterized, adverse pharmacodynamic effect of taxanes. Electronic health records (EHRs) comprise data collected during routine clinical care that include patients with heterogeneous demographic, clinical, and treatment characteristics. Application of pharmacokinetic/pharmacodynamic (PK/PD) modeling to EHR data promises new insights on the real-world use of taxanes and strategies to improve therapeutic outcomes especially for populations who are typically excluded from clinical trials, including the elderly. This investigation: (i) leveraged previously published PK/PD models developed with clinical trial data and addressed challenges to fit EHR data, and (ii) evaluated predictors of paclitaxel-induced myelosuppression. Relevant EHR data were collected from patients treated with paclitaxel-containing chemotherapy at Inova Schar Cancer Institute between 2015 and 2019 (n = 405). Published PK models were used to simulate mean individual exposures of paclitaxel and carboplatin, which were linearly linked to absolute neutrophil count (ANC) using a published semiphysiologic myelosuppression model. Elderly patients (≥70 years) constituted 21.2% of the dataset and 2274 ANC measurements were included in the analysis. The PD parameters were estimated and matched previously reported values. The baseline ANC and chemotherapy regimen were significant predictors of paclitaxel-induced myelosuppression. The nadir ANC and use of supportive treatments, such as growth factors and antimicrobials, were consistent across age quantiles suggesting age had no effect on paclitaxel-induced myelosuppression. In conclusion, EHR data could complement clinical trial data in answering key therapeutic questions.

Achievement of the ESC recommendations for secondary prevention of cardiovascular risk factors in high-risk patients with type 2 diabetes: A real-world national cohort analysis.

AIM: To assess compliance with European Society of Cardiology (ESC) secondary prevention recommendations in a nationwide contemporary population with diabetes mellitus (DM) and coronary artery disease. METHOD: We conducted a retrospective observational study using linked health data in patients across Wales with DM undergoing percutaneous coronary intervention (2012-2017). The follow-up was for one year. We analysed the clinical characteristics, medications, target levels for HbA1c, low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C) and blood pressure against the ESC prevention guidelines. RESULTS: Overall, 3478 patients with diabetes had available data at 1-year post-PCI. Only 43% had HbA1c levels <53 mmol/L, but 81% had blood pressure < 140/80 (current ESC targets). Prescribing frequency of the newer hypoglycaemic agents (glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter 2 inhibitors) was suboptimal, with a higher rate in patients with HbA1c ≥53 mmol/mol. Only 51% & 27% of the patients had LDL-C levels <1.8 &1.4 mmol/L (2016 & 2019 guidelines recommendations respectively), and 55% & 34% had non-HDL-C levels <2.6 & 2.2 mmol/L (2016 & 2019 guidelines respectively). Of the uncontrolled LDL-C patients, 42% (2016 target) and 35% (2019 target) were prescribed high-intensity statins. Females were more likely to have LDL-C targets above the recommended level. CONCLUSION: Achievement of ESC treatment goals in this very-high risk cohort for DM and hyperlipidaemia was far from optimal, with a low prescription rate of the guidelines-recommended therapy. Target goals for hypertension were met more frequently. An up-to-date analysis reflecting the current practice against the most recent guidelines is warranted.

Characteristics of conventional high-risk coronary plaques and a novel CT defined thin-cap fibroatheroma in patients undergoing CCTA with stable chest pain.

BACKGROUND: Coronary computed tomography angiography (CCTA) can identify high-risk coronary plaque types. However, the inter-observer variability for high-risk plaque features, including low attenuation plaque (LAP), positive remodelling (PR), and the Napkin-Ring sign (NRS), may reduce their utility, especially amongst less experienced readers. METHODOLOGY: In a prospective study, we compared the prevalence, location and inter-observer variability of both conventional CT-defined high-risk plaques with a novel index based on quantifying the ratio of necrotic core to fibrous plaque using individualised X-ray attenuation cut-offs (the CT-defined thin-cap fibroatheroma - CT-TCFA) in 100 patients followed-up for 7 years. RESULTS: In total, 346 plaques were identified in all patients. Seventy-two (21%) of all plaques were classified by conventional CT parameters as high-risk (either NRS or PR and LAP combined), and 43 (12%) of plaques were considered high-risk using the novel CT-TCFA definition of (Necrotic Core/fibrous plaque ratio of >0.9). The majority (80%) of the high-risk plaques (LAP&PR, NRS and CT-TCFA) were located in the proximal and mid-LAD and RCA. The kappa co-efficient of inter-observer variability (k) for NRS was 0.4 and for PR and LAP combined 0.4. While the kappa co-efficient of inter-observer variability (k) for the new CT-TCFA definition was 0.7. During follow-up, patients with either conventional high-risk plaques or CT-TCFAs were significantly more likely to have MACE (Major adverse cardiovascular events) compared to patients without coronary plaques (p value 0.03 & 0.03, respectively). CONCLUSION: The novel CT-TCFA is associated with MACE and has improved inter-observer variability compared with current CT-defined high-risk plaques.

Developing the next generation of renewable energy technologies: an overview of low-TRL EU-funded research projects.

A cluster of eleven research and innovation projects, funded under the same call of the EU's H2020 programme, are developing breakthrough and game-changing renewable energy technologies that will form the backbone of the energy system by 2030 and 2050 are, at present, at an early stage of development. These projects have joined forces at a collaborative workshop, entitled ' Low-TRL Renewable Energy Technologies', at the 10th Sustainable Places Conference (SP2022), to share their insights, present their projects' progress and achievements to date, and expose their approach for exploitation and market uptake of their solutions.

Reassessing the Pediatric Dosing Recommendations for Unfractionated Heparin Using Real-World Data: A Pharmacokinetic-Pharmacodynamic Modeling Approach.

Optimal pediatric dosing of unfractionated heparin (UFH) is challenging because of the paucity of clinical outcome and pharmacokinetic-pharmacodynamic (PK/PD) studies in pediatrics. This study aimed to: (i) develop a PK/PD model for UFH, quantified by anti-factor Xa assay, and the UFH effect, measured by activated partial thromboplastin time (aPTT); and (ii) use simulations to evaluate pediatric UFH infusions for achieving the anti-factor Xa (0.3-0.7 IU/mL) therapeutic target. Electronic health record data were retrospectively collected from 633 patients aged <19 years admitted to Texas Children's Hospital. The PK/PD model was developed using a 70% (training)/30% (testing) split-sample approach. A 1-compartment PK model with linear elimination adequately described the UFH PK. An allometrically scaled body weight on clearance (CL) and volume of distribution (Vd) with an age-dependent maturation function of extracellular water on Vd were the covariates identified. Comparable with literature, the typical values for CL and Vd were 3.28 L/(h·50 kg) and 8.83 L/50 kg, respectively. A linear model adequately described the UFH-aPTT relationship with an estimated slope of 150 seconds/(IU/mL). Simulations of the currently recommended starting infusions (28 IU/h/kg for pediatrics <1 year old or 20 IU/h/kg for pediatrics >1 year old) showed that the anti-factor Xa therapeutic target was achieved only in 15.3%, 14.6%, 36.9%, and 45.11% of subjects in the age groups of <1 year, 1-6 years, 6-12 years, and 12-19 years, respectively. In conclusion, the UFH anti-factor Xa target is not achieved initially, especially in young pediatrics, suggesting the need to optimize UFH dosing to achieve higher therapeutic success.

Interspecies Comparison and Radiation Effect on Pharmacokinetics of BIO 300, a Nanosuspension of Genistein, after Different Routes of Administration in Mice and Non-Human Primates.

BIO 300, a suspension of synthetic genistein nanoparticles, is being developed for mitigating the delayed effects of acute radiation exposure (DEARE). The purpose of the current study was to characterize the pharmacokinetic (PK) profile of BIO 300 administered as an oral or parenteral formulation 24 h after sham-irradiation, total-body irradiation (TBI) with 2.5-5.0% bone marrow sparing (TBI/BMx), or in nonirradiated sex-matched C57BL/6J mice and non-human primates (NHP). C57BL/6J mice were randomized to the following arms in two consecutive studies: sham-TBI [400 mg/kg, oral gavage (OG)], TBI/BM2.5 (400 mg/kg, OG), sham-TBI [200 mg/kg, subcutaneous (SC) injection], TBI/BM2.5 (200 mg/kg, SC), sham-TBI (100 mg/kg, SC), or nonirradiated [200 mg/kg, intramuscular (IM) injection]. The PK profile was also established in NHP exposed to TBI/BM5.0 (100 mg/kg, BID, OG). Genistein-aglycone serum concentrations were measured in all groups using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. The PK profile demonstrates 11% and 19% reductions in Cmax and AUC0-inf, respectively, among mice administered 400 mg/kg, OG, after TBI/BM2.5 compared to the sham-TBI control arm. Administration of 200 mg/kg SC in mice exposed to TBI/BM2.5 showed a 53% increase in AUC0-inf but a 28% reduction in Cmax compared to the sham-TBI mice. The relative bioavailability of the OG route compared to the SC and IM routes in mice was 9% and 7%, respectively. After the OG route, the dose-normalized AUC0-inf was 13.37 (ng.h/mL)/(mg/kg) in TBI/BM2.5 mice compared to 6.95 (ng.h/mL)/(mg/kg) in TBI/BM5.0 NHPs. Linear regression of apparent clearances and weights of mice and NHPs yielded an allometric coefficient of 1.06. Based on these data, the effect of TBI/BMx on BIO 300 PK is considered minimal. Future studies should use SC and IM routes to maximize drug exposure when administered postirradiation. The allometric coefficient is useful in predicting therapeutic drug dose regimens across species for drug approval under the FDA animal rule.