Lightweight Biobased Polyurethane Composites Derived from Liquefied Polyol Reinforced by Biomass Sources with High Mechanical Property and Enhanced Fire-Resistance Performance.

Lightweight biobased insulation polyurethane (BPU) composite foams with high fire-resistance efficiency are interested in building effective energy and low environmental impact today. This study focuses on manufacturing lightweight BPU from liquefied bamboo polyols and biomass resources, including rice husk and wood flour. Then, they are combined with three flame retardant (FR) additives, such as aluminum diethyl phosphinate, aluminum trihydroxide, and diammonium phosphate, to improve their fire resistance performance. The physicochemical properties, microstructure, thermal stability, mechanical properties, and flame-retardant properties of the BPU composites are characterized to optimize their compromise properties. The results showed that composites with optimized FRs achieved UL94 V-0 and those with nonoptimized FRs reached UL94 HB. The limiting oxygen index exhibited that the fire resistance of BPU composites could increase up to 21-37% within FR additives. In addition, the thermal stability of BPU composites was significantly improved in a temperature range of 300-700 °C and the compressive strength of the BPU composites was also enhanced with the presence of FRs. The scanning electron microscopy observation showed an influence of FRs on the morphology and cell size of the BPU composites. The bio-PU-derived samples in this study showed significantly low thermal conductivity values, demonstrating their remarkable thermal insulation effectiveness.

Formulation and Evaluation of a Self-Microemulsifying Drug Delivery System of Raloxifene with Improved Solubility and Oral Bioavailability.

Poor aqueous solubility and dissolution limit the oral bioavailability of Biopharmaceutics Classification System (BCS) class II drugs. In this study, we aimed to improve the aqueous solubility and oral bioavailability of raloxifene hydrochloride (RLX), a BCS class II drug, using a self-microemulsifying drug delivery system (SMEDDS). Based on the solubilities of RLX, Capryol 90, Tween 80/Labrasol ALF, and polyethylene glycol 400 (PEG-400) were selected as the oil, surfactant mixture, and cosurfactant, respectively. Pseudo-ternary phase diagrams were constructed to determine the optimal composition (Capryol 90/Tween 80/Labrasol ALF/PEG-400 in 150/478.1/159.4/212.5 volume ratio) for RLX-SMEDDS with a small droplet size (147.1 nm) and stable microemulsification (PDI: 0.227). Differential scanning calorimetry and powder X-ray diffraction of lyophilized RLX-SMEDDS revealed the loss of crystallinity, suggesting a molecularly dissolved or amorphous state of RLX in the SMEDDS formulation. Moreover, RLX-SMEDDS exhibited significantly higher saturation solubility and dissolution rate in water, simulated gastric fluid (pH 1.2), and simulated intestinal fluid (pH 6.8) than RLX powder. Additionally, oral administration of RLX-SMEDDS to female rats resulted in 1.94- and 1.80-fold higher area under the curve and maximum plasma concentration, respectively, than the RLX dispersion. Collectively, our findings suggest SMEDDS is a promising oral formulation to enhance the therapeutic efficacy of RLX.

Inhibitory effect of 20(S)-protopanaxadiol on cytochrome P450: Potential of its pharmacokinetic interactions in vivo.

20(S)-Protopanaxadiol [20(S)-PPD] is a fully deglycosylated ginsenoside metabolite produced by the gut microbiota in the gastrointestinal tract. Although diverse pharmacological effects have been reported, information on the pharmacokinetic interactions of 20(S)-PPD with cytochrome P450s (CYPs) remains limited. Therefore, the inhibitory potential of 20(S)-PPD on CYP enzymes, which mainly contribute to drug pharmacokinetics, was investigated in this study. The inhibitory effect of 20(S)-PPD was strong for CYP3A4 and moderate for CYP2B6 in human liver microsomes. 20(S)-PPD inhibited Cyp3a and Cyp2b in mouse liver microsomes with a potency similar to that in humans. The solubility of 20(S)-PPD in the artificial intestinal fluid was close to IC50 values of Cyp3a and Cyp2b in the mouse intestine. Systemic exposure to buspirone (Cyp3a specific substrate) and bupropion (Cyp2b specific substrate) increased significantly, whereas the area under the plasma concentration-time curve (AUC) ratio of metabolite to parent drug decreased significantly when co-administered with 20(S)-PPD in mice. The pharmacokinetics of felodipine, a widely used anti-hypertensive agent metabolized mainly by Cyp3a, was also altered following 20(S)-PPD treatment in mice. In conclusion, 20(S)-PPD likely affects the in vivo metabolism of CYP3A4 or CYP2B6 substrates, suggesting a need for careful attention when concomitantly administering 20(S)-PPD with other medications. This study will broaden our understanding of ginseng and products containing precursor ginsenosides of 20(S)-PPD for safer and more efficient use in humans.

Effects of 1α,25-dihydroxyvitamin D3 on the pharmacokinetics and biodistribution of ergothioneine, an endogenous organic cation/carnitine transporter 1 substrate, in rats.

Purpose: This study aimed to investigate the effects of 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) on the expression levels of organic cation/carnitine transporter 1 (OCTN1) as well as the pharmacokinetics and biodistribution of ergothioneine, an OCTN1 substrate, in rats. Methods: Rats pretreated with 1,25(OH)2D3 (2.56 nmol/kg/day) for four days were administered ergothioneine (2 mg/kg) intravenously. The expression levels of rat OCTN1 (rOCTN1) in organs were determined using real-time quantitative polymerase chain reaction. Ergothioneine levels in plasma, urine, and organs (with and without intravenous injection of exogenous ergothioneine) were determined using liquid chromatography-tandem mass spectrometry. Results: 1,25(OH)2D3 pretreatment resulted in a significant decrease in rOCTN1 mRNA expression levels in the kidney and brain, a significant increase in basal plasma levels of ergothioneine (from 48 h), and a significant decrease in the tissue-plasma partition coefficient (Kp) in all tissues (except the heart and lungs) and the basal urine levels of ergothioneine. After intravenous administration, the pharmacokinetic profiles of ergothioneine were consistent with the basal levels of endogenous ergothioneine, with an increase in AUC∞ by 85%, a significant decrease in total clearance by 49%, and a decrease in Vss by 32% in 1,25(OH)2D3-treated rats. The Kp value and urinary recovery of ergothioneine also decreased in the 1,25(OH)2D3-treated group. Conclusion: This study showed the effects of 1,25(OH)2D3 on the expression and function of rOCTN1 by investigating the interaction between 1,25(OH)2D3 and ergothioneine. Dose adjustment and possible changes in bioavailability should be considered before the co-administration of vitamin D or its active forms and OCTN1 substrates. Supplementary Information: The online version contains supplementary material available at 10.1007/s40005-022-00563-1.

Positioning of an unprecedented 1,5-oxaza spiroquinone scaffold into SMYD2 inhibitors in epigenetic space.

Lysine methyltransferases are important regulators of epigenetic signaling and are emerging as a novel drug target for drug discovery. This work demonstrates the positioning of novel 1,5-oxaza spiroquinone scaffold into selective SET and MYND domain-containing proteins 2 methyltransferases inhibitors. Selectivity of the scaffold was identified by epigenetic target screening followed by SAR study for the scaffold. The optimization was performed iteratively by two-step optimization consisting of iterative synthesis and computational studies (docking, metadynamics simulations). Computational binding studies guided the important interactions of the spiro[5.5]undeca scaffold in pocket 1 and Lysine channel and suggested extension of tail length for the improvement of potency (IC50: up to 399 nM). The effective performance of cell proliferation assay for chosen compounds (IC50: up to 11.9 nM) led to further evaluation in xenograft assay. The potent compound 24 demonstrated desirable in vivo efficacy with growth inhibition rate of 77.7% (4 fold decrease of tumor weight and 3 fold decrease of tumor volume). Moreover, mirosomal assay and pharmacokinetic profile suggested further developability of this scaffold through the identification of major metabolites (dealkylation at silyl group, reversible hydration product, the absence of toxic quinone fragments) and enough exposure of the testing compound 24 in plasma. Such spiro[5.5]undeca framework or ring system was neither been reported nor suggested as a modulator of methyltransferases. The chemo-centric target positioning and structural novelty can lead to potential pharmacological benefit.

Graphene Oxide and Graphene Oxide-TiO2 Nanocomposites: Synthesis, Characterization, and Rhodamine B Photodegradation Investigation.

In this study, graphene oxide (GO) sheets were successfully synthesized using two routes: conventional Hummers' (HGO) and modified Hummers' (or Marcano's) (MGO) methods. GO sheets were then assembled with TiO2 nanoparticles to form nanocomposites (i.e., HGO-TO and MGO-TO). The properties of HGO and MGO and their nanocomposites with TiO2 were evaluated by Fouriertransform infrared (FTIR), Raman, ultraviolet-visible (UV-Vis) adsorption, and diffuse reflectance (DRS) spectroscopies, X-ray diffraction (XRD), and thermal gravimetric analysis (TGA). The specific surface area, pore volume, and pore size of MGO, determined by Brunauer-Emmett-Teller (BET) equation, were 565 m²g-1, 376 cm³ g-1, and 30 nm, respectively; all of these parameters decreased after MGO was combined with TiO2. In addition, compared with HGO, MGO possessed higher oxidation level and more stable bonding with TiO2 nanoparticles. The morphology of HGO and MGO, which were characterized by scanning electron (SEM) and transmission electron microscopies (TEM), together with energy-dispersive X-ray (EDX) spectroscopy and elemental mapping technique, was determined to consist of TiO2 nanoparticle-assembled GO sheets. All GO-TiO2 nanocomposite samples exhibited a very high activity (˜100%) toward rhodamine B (RhB) dye photodegradation under natural sunlight exposure within 60 min. The obtained results for the GO-TiO2 nanocomposite showed the potential of its application in wastewater purification and other environmental aspects.

Development and Validation of a Bioanalytical LC-MS/MS Method for Simultaneous Determination of Sirolimus in Porcine Whole Blood and Lung Tissue and Pharmacokinetic Application with Coronary Stents.

Sirolimus is a hydrophobic macrolide compound that has been used for long-term immunosuppressive therapy, prevention of restenosis, and treatment of lymphangioleiomyomatosis. In this study, a simple and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed and validated for the simultaneous determination of sirolimus in both porcine whole blood and lung tissue. Blood and lung tissue homogenates were deproteinized with acetonitrile and injected into the LC-MS/MS system for analysis using the positive electrospray ionization mode. The drug was separated on a C18 reversed phase column with a gradient mobile phase (ammonium formate buffer (5 mM) with 0.1% formic acid and acetonitrile) at 0.2 mL/min. The selected reaction monitoring transitions of m/z 931.5 → 864.4 and m/z 809.5 → 756.5 were applied for sirolimus and ascomycin (the internal standard, IS), respectively. The method was selective and linear over a concentration range of 0.5-50 ng/mL. The method was validated for sensitivity, accuracy, precision, extraction recovery, matrix effect, and stability in porcine whole blood and lung tissue homogenates, and all values were within acceptable ranges. The method was applied to a pharmacokinetic study to quantitate sirolimus levels in porcine blood and its distribution in lung tissue following the application of stents in the porcine coronary arteries. It enabled the quantification of sirolimus concentration until 2 and 14 days in blood and in lung tissue, respectively. This method would be appropriate for both routine porcine pharmacokinetic and bio-distribution studies of sirolimus formulations.

Differential Effects of 1α,25-Dihydroxyvitamin D3 on the Expressions and Functions of Hepatic CYP and UGT Enzymes and Its Pharmacokinetic Consequences In Vivo.

The compound 1α,25-Dihydroxyvitamin D3 (1,25(OH)2D3) is the active form of vitamin D3 and a representative ligand of the vitamin D receptor (VDR). Previous studies have described the impacts of 1,25(OH)2D3 on a small number of cytochrome P450 (CYP) and uridine diphosphate-glucuronyltransferase (UGT) enzymes, but comparatively little is known about interactions between several important CYP and UGT isoforms and 1,25(OH)2D3 in vitro and/or in vivo. Thus, we investigated the effects of 1,25(OH)2D3 on the gene and protein expressions and functional activities of selected CYPs and UGTs and their impacts on drug pharmacokinetics in rats. The mRNA/protein expressions of Cyp2b1 and Cyp2c11 were downregulated in rat liver by 1,25(OH)2D3. Consistently, the in vitro metabolic kinetics (Vmax and CLint) of BUP (bupropion; a Cyp2b1 substrate) and TOL (tolbutamide; a Cyp2c11 substrate) were significantly changed by 1,25(OH)2D3 treatment in liver microsomes, but the kinetics of acetaminophen (an Ugt1a6/1a7/1a8 substrate) remained unaffected, consistent with Western blotting data for Ugt1a6. In rat pharmacokinetic studies, the total body clearance (CL) and nonrenal clearance (CLNR) of BUP were significantly reduced by 1,25(OH)2D3, but unexpectedly, the total area under the plasma concentration versus time curve from time zero to infinity (AUC) of hydroxybupropion (HBUP) was increased probably due to a marked reduction in the renal clearance (CLR) of HBUP. Additionally, the AUC, CL, and CLNR for TOL and the AUC for 4-hydroxytolbutamide (HTOL) were unaffected by 1,25(OH)2D3 in vivo. Discrepancies between observed in vitro metabolic activity and in vivo pharmacokinetics of TOL were possibly due to a greater apparent distribution volume at the steady-state (Vss) and lower plasma protein binding in 1,25(OH)2D3-treated rats. Our results suggest possible drug-drug and drug-nutrient interactions and provide additional information concerning safe drug combinations and dosing regimens for patients taking VDR ligand drugs including 1,25(OH)2D3.

The effect of a clinical pharmacist-led training programme on intravenous medication errors: a controlled before and after study.

BACKGROUND: Little is known about interventions to reduce intravenous medication administration errors in hospitals, especially in low- and middle-income countries. OBJECTIVE: To assess the effect of a clinical pharmacist-led training programme on clinically relevant errors during intravenous medication preparation and administration in a Vietnamese hospital. METHODS: A controlled before and after study with baseline and follow-up measurements was conducted in an intensive care unit (ICU) and a post-surgical unit (PSU). The intervention comprised lectures, practical ward-based teaching sessions and protocols/guidelines, and was conducted by a clinical pharmacist and a nurse. Data on intravenous medication preparation and administration errors were collected by direct observation 12 h/day for seven consecutive days. Generalised estimating equations (GEE) were used to assess the effect of the intervention on the prevalence of clinically relevant erroneous doses, corrected for confounding factors. RESULTS: 1204 intravenous doses were included, 516 during the baseline period (236 on ICU and 280 on PSU) and 688 during the follow-up period (407 on ICU and 281 on PSU). The prevalence of clinically relevant erroneous doses decreased significantly on the intervention ward (ICU) from 64.0% to 48.9% (p<0.001) but was unchanged on the control ward (PSU) (57.9% vs 64.1%; p=0.132). GEE analysis showed that doses on the intervention ward were 2.60 (1.27-5.31) times less likely to have clinically relevant errors (p=0.013). CONCLUSIONS: The pharmacist-led training programme was effective, but the error rate remained relatively high. Further quality improvement strategies are needed, including changes to the working environment and promotion of a safety culture.