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Sulcardine sulfate (Sul) is a novel antiarrhythmic agent with promising pharmacological properties, which is currently being evaluated in several clinical trials as an oral formulation. To meet the medication needs of patients with acute conditions, the injection formulation of Sul has been developed. The objective of this study was to systemically investigate the pharmacokinetic profiles of Sul after intravenous infusion. This research included the plasma protein binding and metabolic stability studies in vitro, plasma pharmacokinetics, biodistribution, excretion studies in animals, and the prediction of the clinical PK of Sul injection using a physiologically based pharmacokinetics (PBPK) model. The metabolic stability was similarly in dogs and humans but lower in rats. The plasma protein binding rates showed a concentration-dependent manner and species differences. The pharmacokinetic behavior after intravenous administration was linear in rats within the dose range of 30–90 mg/kg, but nonlinear in dogs within 30–60 mg/kg. Sul could be rapidly and widely distributed in multiple tissues after intravenous administration. About 12% of the parent compound were excreted via the urine and only a small fraction via bile and feces,and eight metabolites were found and identified in the rat excretion. The PBPK models were developed and simulated the observed PK date well in both rats and dogs. The PBPK model refined with human data predicted the PK characteristics of the first intravenous infusion of Sul in human. Our study systematically explored the pharmacokinetic characteristics of Sul and successfully developed the PBPK model to predict of its clinical PK.

The fabrication of a coffee ring was studied in this work to improve its sensitivity in detecting trace analytes based on surface-enhanced Raman scattering (SERS). Gold nanoparticles were synthesized with diameters of ~40 nm through the sodium citrate reduction method, and rhodamine 6G (R6G) was employed as a probe to evaluate the performance of the fabricated coffee rings. The results showed that the coffee ring formed from the water-washed gold nanoparticles presented more orderly and regular morphology as well as better SERS properties than the unwashed ones. Furthermore, both the concentration and the amount of gold nanoparticles were found to affect its SERS performance. Using the optimized coffee ring as a SERS substrate, trace R6G with a concentration of 5 × 10−8 M was detected. This sensing platform could realize aflatoxin B1 (AFB1) detection down to 5 × 10−7 M and was demonstrated to function well in real-sample testing.

Literature reports that Poria cocos reduces blood lipid levels; however, the underlying mechanism remains unclear. Blood lipid levels are closely related to the enterohepatic circulation of bile acids, where uptake transporters playing a significant role. P. cocos extract is commonly used in traditional prescriptions and food supplements in China. We investigated the effects of P. cocos and its five triterpene acids on bile acid uptake transporters, including intestinal apical sodium-dependent bile acid transporter (ASBT) and hepatic sodium/taurocholate cotransporting polypeptide (NTCP). Triterpene acids were fingerprinted by high-performance liquid chromatography–TripleTOF and quantified by ultraperformance liquid chromatography/tandem mass spectrometry. The inhibitory effect of P. cocos and its five major representative triterpene acids on ASBT and NTCP was investigated by in vitro assays using Xenopus oocytes expressing ASBT and NTCP. P. cocos extract exhibited significant inhibitory effects with half-maximum inhibition constants of 5.89 µg/ml and 14.6 µg/ml for NTCP and ASBT, respectively. Among five triterpene acids, poricoic acid A, poricoic acid B, and polyporenic acid C significantly inhibited NTCP function. Poricoic acid A, poricoic acid B, and dehydrotumulosic acid significantly inhibited ASBT function. The representative triterpene acid, poricoic acid A, was identified as a competitive inhibitor of NTCP with an inhibitory constant of 63.4 ± 18.7 µM. In conclusion, our results indicate that both P. cocos extract and its major triterpenes are competitive inhibitors of ASBT and NTCP. Accordingly, it was suggested that competitive inhibition of these bile acid transporters is one of the underlying mechanisms for the hypolipidemic effect of P. cocos. SIGNIFICANCE STATEMENT Poria cocos, a commonly used Chinese herbal medicine and food supplement, demonstrates significantly inhibitory effects on the function of apical sodium-dependent bile acid transporter and sodium/taurocholate cotransporting polypeptide. P. cocos has potential to reduce the blood lipid through inhibition of these uptake transporters in enterohepatic circulation of bile acid.

The unprecedented growth of passenger throughput in large airport terminals highlights the importance of analyzing passengers’ movement to achieve airport terminal’s elaborate management. Based on the theory of original social force model, video data from a departure hall of a large airport terminal in China were analyzed to summarize passengers’ path planning characteristics. Then, a double-level model was established to describe passengers’ path planning behaviors. At the decision level of the proposed model, the avoiding force model including common avoiding force and additional horizontal avoiding force was established on the basis of setting time and space limitations for taking avoiding action and was used to describe passengers’ path planning in close-range space. At the tactical level of the proposed model, the route and node choice models were established to describe passengers’ path planning in long-range space. In the route choice model, a distribution of intermediate destination areas was proposed, with detouring distance, pedestrian density, speed difference, and pedestrian distribution considered in choosing an intermediate destination area. In the node choice model, the walking distance, the quantity of people waiting, and luggage were considered in choosing a check-in counter or security check channel. The main parameters of the proposed model were confirmed according to video data. Simulation results show that the proposed model can simulate departure passengers’ path planning behaviors at an acceptable accuracy level.

MicroRNAs (miRNAs) have been used as molecular markers for various diseases. This study aimed to evaluate the predicted performance of miRNAs in fetal umbilical cord blood for detecting congenital heart disease (CHD).In this retrospective cohort study, a total of 60 pregnant women (involving 30 fetuses with CHD and 30 normal fetuses requiring induction of labor) were included. Umbilical cord blood was collected for miRNA measurement. Expression levels of the miRNAs were detected by qRT-PCR. The predictive accuracy of miRNA was assessed by constructing a receiver operating characteristic (ROC) curve and evaluated by calculating the area under the curve (AUC). The point biserial correlation coefficient (PBCC) was analyzed to evaluate the correlation of miRNA with CHD.The CHD group and control group were well-balanced in age, gravidity, and parity. miRNA-133 was not detected in all subjects. Subjects with CHD fetuses had significantly lower levels of miRNA-1, miRNA-208, and miRNA-499. Different types of CHD showed different variation trends of miRNA expression. Correlation analysis showed that expression levels of miRNA-1, miRNA-208, and miRNA-499 were negatively correlated with the occurrence of CHD, with a PBCC of -0.65, -0.47, and -0.60, respectively. miRNA-1, miRNA-208, and miRNA-499 displayed an AUC of 0.86 (95% CI, 0.76-0.96;The expression levels of miRNA-1, miRNA-208, and miRNA-499 in umbilical cord blood may be useful for predicting fetal CHD. The findings indicated that miRNAs have the potential to be a prenatal screening tool in the early diagnosis of CHD.

Random numbers are playing an increasingly important role in the modern information technology field. The methods for generating random numbers are mainly divided into two categories: analog and digital methods. Due to their portability and simple structure, digital methods have been widely used in communication and other fields. The digital method based on M-sequence is the mainstream method for generating random numbers. The existing M-sequence methods for generating random numbers have disadvantages such as insufficient period and insufficient bit width. In this paper, we propose a random number generation method based on FPGA hardware, which adds a multi-tap structure to M-sequence and synthesizes multiple parallel M-sequence outputs into a new random number generator. It implements a random number generator with arbitrary bit width and ultra-long period. Finally, we analyzed 512 k output sample data of the FPGA chip xcku040 used to implement this design. The experimental results verify the feasibility and superiority of the method.

Sulcardine sulfate (Sul) is a novel antiarrhythmic agent with promising pharmacological properties, which is currently being evaluated in several clinical trials as an oral formulation. To meet the medication needs of patients with acute conditions, the injection formulation of Sul has been developed. The objective of this study was to systemically investigate the pharmacokinetic profiles of Sul after intravenous infusion.This research included the plasma protein binding and metabolic stability studies in vitro, plasma pharmacokinetics, biodistribution, excretion studies in animals, and the prediction of the clinical PK of Sul injection using a physiologically based pharmacokinetics (PBPK) model.The metabolic stability was similarly in dogs and humans but lower in rats. The plasma protein binding rates showed a concentration-dependent manner and species differences. The pharmacokinetic behavior after intravenous administration was linear in rats within the dose range of 30-90 mg/kg, but nonlinear in dogs within 30-60 mg/kg. Sul could be rapidly and widely distributed in multiple tissues after intravenous administration. About 12% of the parent compound were excreted via the urine and only a small fraction via bile and feces,and eight metabolites were found and identified in the rat excretion. The PBPK models were developed and simulated the observed PK date well in both rats and dogs. The PBPK model refined with human data predicted the PK characteristics of the first intravenous infusion of Sul in human.Our study systematically explored the pharmacokinetic characteristics of Sul and successfully developed the PBPK model to predict of its clinical PK.

GL-V9, a derivative of wogonin, has potent anti-cancer activity. The absorption and metabolism of this compound have not been investigated systematically. This study aims to illustrate the pharmacokinetic characters of GL-V9 by exploring its metabolic status under different administration routes. To further clarify the absorption mechanism of GL-V9, an in situ single-pass perfusion model and a Caco-2 cell monolayer model were used. Meanwhile, a microsomal incubation system was used to evaluate the enzyme kinetic parameters. In vivo, the obtained gastrointestinal availability (Fa × Fg ) was 21.28 ± 5.38%. The unmetabolized fraction in the gut wall (Fgut wall ) was 98.59 ± 9.74%, while the hepatic bioavailability (Fh ) was 29.11 ± 5.22%. These results indicated that poor absorption and extensive metabolism may contribute greatly to the low bioavailability of GL-V9. The effective permeability (Peff ) in the duodenum and jejunum was 1.34 ± 0.50 × 10-4 and 0.90 ± 0.27 × 10-4 cm/s, respectively. The high permeability of GL-V9 indicated that other unknown factors (such as metabolism) may account for its systemic exposure problem. Studies in rat liver microsomal (RLMs) confirmed this hypothesis, and the Clint, CYP450s and UGT of GL-V9 was 0.20 ml/min/mg protein. In conclusion, these results suggest that GL-V9 possesses higher permeability than wogonin and the metabolism of GL-V9 is related to its disposition in rat intestine and liver.

Literature reports that

Despite their notorious adverse effects, glucocorticoids (GC, potent anti-inflammatory drugs) are used extensively in clinical management of rheumatoid arthritis (RA) and other chronic inflammatory diseases. To achieve a sustained therapeutic efficacy and reduced toxicities, macromolecular GC prodrugs have been developed with promising outcomes for the treatment of RA. Fine-tuning the activation kinetics of these prodrugs may further improve their therapeutic efficacy and minimize the off-target adverse effects. To assess the feasibility of this strategy, five different dexamethasone (Dex, a potent GC)-containing monomers with distinctively different linker chemistries were designed, synthesized, and copolymerized with N-(2-hydroxypropyl) methacrylamide (HPMA) to obtain 5 macromolecular Dex prodrugs. Their Dex releasing rates were analyzed in vitro and shown to display a wide spectrum of activation kinetics. Their therapeutic efficacy and preliminary toxicology profiles were assessed and compared in vivo in an adjuvant-induced arthritis (AA) rat model in order to identify the ideal prodrug design for the most effective and safe treatment of inflammatory arthritis. The in vivo data demonstrated that the C3 hydrazone linker-containing prodrug design was the most effective in preserving joint structural integrity. The results from this study suggest that the design and screening of different activation mechanisms may help to identify macromolecular prodrugs with the most potent therapeutic efficacy and safety for the management of inflammatory arthritis.

HPMA copolymer-based dexamethasone prodrug (P-Dex) and PEG-based dexamethasone prodrug (PEG-Dex, ZSJ-0228) were previously found to passively target the inflamed kidney and provide potent and sustained resolution of nephritis in NZB/WF1 lupus-prone mice. While both prodrug nanomedicines effectively ameliorate lupus nephritis, they have demonstrated distinctively different safety profiles. To explore the underlining mechanisms of these differences, we conducted a head-to-head comparative PK/BD study of P-Dex and PEG-Dex on NZB/WF1 mice. Overall, the systemic organ/tissue exposures to P-Dex and Dex released from P-Dex were found to be significantly higher than those of PEG-Dex. The high prodrug concentrations were sustained in kidney for only 24 h, which cannot explain their lasting therapeutic efficacy (>1 month). P-Dex showed sustained presence in liver, spleen and adrenal gland, while the presence of PEG-Dex in these organs was transient. This difference in PK/BD profiles may explain PEG-Dex’ superior safety than P-Dex.

We present a facile surface-enhanced Raman spectroscopy (SERS)-based method for the sulfite /SO2 detection with high sensitivity, high selectivity and rapid response. Spectral changes of the capture probe at 600 cm−1 and 910 cm−1 upon binding to SO2 originated from the sulfites constitutes the assay, which is demonstrated to function well in the red wine and tremella samples testing.

Objective Pulmonary delivery is an effective way to improve the bioavailability of drugs with extensive metabolism. This research was designed to study the different pharmacokinetic behaviours of small molecule drug after pulmonary delivery and intragastric (i.g) administration. Methods Raloxifene, a selective estrogen receptor modulator with low oral bioavailability (~2%), was chosen as the model drug. Studies were conducted systematically in rats, including plasma pharmacokinetics, excretion, tissue distribution and metabolism. Key findings Results showed that raloxifene solution dosed by intratracheal (i.t) administration exhibited relatively quick plasma elimination (t1/2 = 1.78 ± 0.14 h) and undetected absorption process, which was similar with intravenous injection. Compared with i.g administration, the bioavailability increased by 58 times, but the major route of excretion remained faecal excretion. Drug concentration on the bone and the target efficiency were improved by 49.6 times and five times, respectively. Benefited from quick elimination in the lung, chronic toxicity might be ignored. Conclusions Pulmonary administration improved the bioavailability of raloxifene and further increased the distribution on the target organ (bone), with no obvious impact on its excretory pattern.

Diagnostic value of four-dimensional ultrasonography with spatio-temporal image correlation (STIC) technique combined with two-dimensional ultrasonography for fetal cardiac malformation and chromosomal abnormalities in early pregnancy was investigated. Medical data of 178 pregnant women enrolled in Tianjin Central Hospital of Gynecology and Obstetrics for screening of fetal cardiac malformations and chromosomal abnormalities from January 2014 to March 2016 were collected. According to the results of the pregnant women's biopsy and the results of labor induction and delivery, 95 fetuses were diagnosed with chromosomal abnormalities and cardiac malformations, 40 fetuses with cardiac malformations and no chromosomal abnormalities, and 43 fetuses with neither cardiac malformations nor chromosomal abnormalities. Fetal cardiac malformations and chromosomal abnormalities were diagnosed by three methods: single two-dimensional ultrasonography, single four-dimensional ultrasonography with STIC, and a combination of two-dimensional ultrasonography and four-dimensional ultrasonography with STIC. The two-dimensional ultrasonography diagnosed 97 cases of fetal cardiac malformation and 61 cases of chromosomal abnormalities, four-dimensional ultrasonography with STIC diagnosed 122 cases of fetal cardiac malformation and 81 cases of chromosomal abnormalities. The combination of two-dimensional ultrasonography and four-dimensional ultrasonography diagnosed 130 cases of fetal cardiac malformation and 90 cases of chromosomal abnormalities. The sensitivities of four-dimensional ultrasonography with STIC and the combination of two-dimensional ultrasonography and four-dimensional ultrasonography were significantly higher than that of single examination by two-dimensional ultrasonography (P0.05). The diagnostic accordance rates of the single four-dimensional ultrasonography and the combined diagnosis for fetal cardiac malformations and chromosomal abnormalities were not much different (P>0.05), but both were greatly higher than that of single two-dimensional ultrasonography diagnosis (P

GL-V9 is a prominent derivative of wogonin with a wide therapeutic spectrum and potent anti-tumor activity. The metabolism characteristics of GL-V9 remain unclear. This study aimed to clarify the metabolic pathway of GL-V9 and investigate the generation of its glucuronidation metabolites in vitro and in vivo. HPLC-UV-TripleTOF was used to identify metabolites. The main metabolite that we found was chemically synthesized and the synthetic metabolite was utilized as standard substance for the subsequent metabolism studies of GL-V9, including enzyme kinetics in liver microsomes of five different species and reaction phenotyping metabolism using 12 recombinant human UDP-glucuronosyltransferase (UGT) isoforms. Results indicated that the glucuronidation reaction occurred at C5-OH group, and 5-O-glucuronide GL-V9 is the only glucuronide metabolite and major phase II metabolite of GL-V9. Among 12 recombinant human UGTs, rUGT1A9 showed the strongest catalytic capacity for the glucuronidation reaction of GL-V9. rUGT1A7 and rUGT1A8 were also involved in the glucuronidation metabolism. Km of rUGT1A7-1A9 was 3.25 &plusmn, 0.29, 13.92 &plusmn, 1.05, and 4.72 &plusmn, 0.28 &mu, M, respectively. In conclusion, 5-O-glucuronide GL-V9 is the dominant phase II metabolite of GL-V9 in vivo and in vitro, whose formation rate and efficiency are closely related to isoform-specific metabolism profiles and the distribution of UGTs in different tissues of different species.

Until today, the clinical application of phytochemicals is still limited largely due to poor oral bioavailability. Pulmonary administration is considered as an attractive alternative to oral delivery as it can improve the pharmacokinetic properties of compounds with extensive metabolism. In this study, resveratrol was selected as a study model to evaluate the feasibility of pulmonary administration in the delivery of phytochemicals, aiming to promote their therapeutic potential. The pharmacokinetic investigation on resveratrol was conducted in rats. Compared with oral delivery, resveratrol in rats after pulmonary administration showed superior absorption and bioavailability (92.95%). Directed delivery of resveratrol to lungs also showed potential usefulness in the treatment of lung diseases as drugs rapidly accumulated in lung tissues and concentrations were more than 100 times those of oral delivery at early time points. The metabolic study was carried out using rat microsomes and showed that metabolic activity of lung was much lower than that of liver. The overall results indicate that pulmonary administration is an effective strategy for both systemic and local delivery of resveratrol.