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Women with substance use disorders (SUDs) are more inclined to use drugs and relapse for regulating emotions compared to men. This study aimed to explore the effects of group music and imagery in alleviating anxiety, depression, emotion regulation difficulties, and craving for women with methamphetamine use disorder (MUD) in a compulsory rehabilitation context. A total of 90 women with MUD were randomly assigned to the music therapy treatment arm (n = 45) or control treatment arm (n = 45). Participants in the music therapy treatment arm received 12 biweekly sessions of group music and imagery (GrpMI) and those in the control treatment arm received 6 weeks of usual care. Anxiety, depression, emotion regulation difficulties, and craving were assessed at pre-test and post-test. After the intervention, participants in the GrpMI group reported significantly greater improvements than those in the control group for state anxiety (F = 6.27; p =.02; Partial η2 =.13), trait anxiety (F = 4.49; p =.04; Partial η2 =.09), depression (F = 5.48; p =.02; Partial η2 =.11), and craving (F = 4.53; p =.04; Partial η2 =.09). There was no significant difference between groups in emotion regulation difficulties (F =.95, p =.34, Partial η2 =.09). GrpMI significantly decreased depression, anxiety, and craving for women with MUD. Emotion regulation ability may need a longer period of treatment for significant improvement. Future studies could add long-term follow-up and compare the effects of group music therapy in women versus men with SUDs. [ABSTRACT FROM AUTHOR]

Objective: To compare the treatment effects of laparoscopy versus laparotomy on heterotopic pregnancy (HP) after in vitro fertilization‐embryo transfer (IVF‐ET). Methods: The retrospective case–control study enrolled 109 patients diagnosed with HP after IVF‐ET treatment in our hospital from January 2009 to March 2020. All patients received surgical treatment by either laparoscopy or laparotomy. Data for general characteristics, diagnostic features, surgical parameters, as well as perinatal and neonatal outcomes were collected. Results: Sixty‐two patients received laparoscopy and 47 received laparotomy. Significantly lower percentage of large hemoperitoneum (P = 0.001), shorter surgery duration (P < 0.001), less intraoperative blood loss (P = 0.001), higher rates of general anesthesia (P < 0.001), and lower cesarean section rates for singletons (P = 0.003) were found in the laparoscopy group. The perinatal and neonatal outcomes were comparable between the two groups. When interstitial pregnancy was considered alone, the surgical blood loss was significantly reduced in the laparoscopy group (P = 0.021), but there was no significant difference in hemoperitoneum, surgery duration, or perinatal and neonatal outcomes in singletons. Conclusion: Both laparoscopy and laparotomy are effective surgical treatments for HP after IVF‐ET. Laparoscopy is minimally invasive but laparotomy can be an alternative in emergency situations. Synopsis: Laparoscopy is an effective, safe and minimally invasive treatment for heterotopic pregnancy after in vitro fertilization and embryo transfer. [ABSTRACT FROM AUTHOR]

As the effect of P-glycoprotein (P-gp) transport on antidepressant delivery has been extensively evaluated using in vitro cellular and in vivo rodent models, an increasing number of publications have addressed the effect of P-gp in limiting brain penetration of antidepressants and causing treatment-resistant depression in current clinical therapies. However, contradictory results have been observed in different systems. It is of vital importance to understand the potential for drug interactions related to P-gp at the blood-brain barrier (BBB), and whether coadministration of a P-gp inhibitor together with an antidepressant is a good clinical strategy for dosing of patients with treatment-resistant depression. In this review, the complicated construction of the BBB, the transport mechanisms for compounds that cross the BBB, and the basic characteristics of antidepressants are illustrated. Further, the reliability of different systems related to antidepressant brain delivery, including in vitro bidirectional transport cell lines, in vivo Mdr1 knockout mice, and chemical inhibition studies in rodents are analyzed, supporting a low possibility that P-gp affects currently marketed antidepressants when these results are extrapolated to the human BBB. These findings can also be applied to other central nervous system drugs. [ABSTRACT FROM AUTHOR]

Abstract: A liquid chromatography/tandem mass spectrometry (LC–MS/MS) method was established for the determination of 5-aminoimidazole-4-carboxamide (AICA) in human plasma. The method included a solvent extraction of AICA as an ion pair with 1-pentanesulfonate ion and a separation on a Hypersil ODS2 column with the mobile phase of methanol–water (68:32, v/v). Determination was performed using an electrospray ionization source in positive ion mode (ESI+). Multiple reaction monitoring (MRM) was utilized for the detection monitoring m/z at 127→110 for AICA, and 172→128 for IS. The calibration curve was linear within a range from 20 to 2000ng/mL and the limit of quantity for AICA in plasma was 20ng/mL. RSD of intra-assay and inter-assay were no more than 5.90% and 5.65%. [Copyright &y& Elsevier]

Abstract: A simple and sensitive method for simultaneous determination of the active compound, thiamphenicol (TAP) and its prodrug, thiamphenicol glycinate (TG) in human plasma and urine is described. The procedure involved extraction of TG and TAP with ethyl acetate (plasma) or 100-fold dilution with the mobile phase (urine) followed by determination by reversed-phase high performance liquid chromatography (HPLC) with UV detection at 224nm. Separation of the compounds was achieved on a column packed with Hypersil ODS2. The mobile phase consisted of acetonitrile–water containing 0.003M tetrabutyl ammonium bromide and 0.056M ammonium acetate (87:13, v/v) with a flow rate of 1.0ml/min. The chromatograms did not contain interfering peaks due to the suitable extraction procedure and chromatographic conditions. The calibration curves of TG and TAP were linear ranging from 0.78 to 100μg/ml in plasma and in urine. The intra-day and inter-day relative standard deviations (S.D.) were less than 10%. The recoveries of TG and TAP in plasma and urine were above 80%. TG was not stable in plasma samples and after extraction at ambient temperature or in freeze–thaw cycles, and hence the samples for injection on HPLC column should be stored in refrigerator or under ice cooling prior to analysis, and the plasma samples should not experience the freeze–thaw cycle more than one time. Unlike TAP, TG could not be detected in most urine samples. Application of this method demonstrated that it was feasible for the clinical pharmacokinetic study. [Copyright &y& Elsevier]

Abstract: A HPLC method for determination of trans-resveratrol concentrations in rat plasma was developed. Plasma samples were treated with acetonitrile to deposit proteins. The analysis used a Hypersil ODS2 C18 column (5μm, 4.6mm×250mm) and methanol/distilled water as the mobile phase (flow-rate=1mL/min). The UV detection wavelength was 303nm, and chlorzoxazone was used as the internal standard. The calibration curve was linear over the range of 0.02–40μg/mL with a correlation coefficient of 0.9997. This concentration range corresponds well with the plasma concentrations of resveratrol in pharmacokinetic studies. There was 98.7%, 91.3% and 84.4% recovery from 0.02, 0.4 and 40μg/mL plasma samples respectively. The R.S.D. of intra- and inter-day assay variations were all less than 12%. This HPLC assay is a quick, precise and reliable method for the analysis of resveratrol in pharmacokinetic studies. [Copyright &y& Elsevier]

Music serves as a prevalent emotional regulation tool among young people. However, the correlational and causal relationships between music use, emotion regulation ability, and emotional symptoms remain unclear. This study aimed to investigate the associations and causal relationships between healthy and unhealthy music use, emotion regulation ability, and emotional symptoms, including alexithymia, depression, and anxiety. This study included 16,588 college students nationwide in China. All participants were assessed online with the Healthy‐Unhealthy Music Scale (HUMS), the Regulatory Emotional Self‐Efficacy Scale (RESE), the Toronto Alexithymia Scale (TAS‐20), and the 10‐item Kessler Psychological Stress Scale (K10) using a cluster convenience sampling method. We applied a regularized partial correlation network (RPCN) and Bayesian network to analyze the network characteristics of the outcomes. In the RPCN analysis, healthy music use showed the second strongest expected influence (one‐step) and correlated positively with emotion regulation self‐efficacy while inversely correlating with externally oriented thinking of alexithymia and depression. The Bayesian network indicated that healthy music use was located downstream of the network, positively predicted by managing anger‐irritation and expressing positive affect in emotion regulation self‐efficacy. In contrast, unhealthy music use in the RPCN displayed the strongest bridge strength and bridge expected influence (one‐step). It negatively correlated with expressing positive affect in emotion regulation self‐efficacy and positively correlated with alexithymia, anxiety, and depression. The Bayesian network highlighted that unhealthy music use was positively affected by anxiety, depression, and difficulty identifying feelings. In addition, managing despondency‐distress influences difficulty identifying feelings through depression, subsequently affecting unhealthy music use and, finally, influencing externally oriented thinking. This study provides a novel framework for understanding the role of emotion regulation self‐efficacy and alexithymia in the relationship between music use and emotional symptoms. Emotion regulation and mental health may benefit from music‐based interventions and therapies informed by the findings of this study. [ABSTRACT FROM AUTHOR]

Several commonly used opioid analgesics, such as fentanyl, sufentanil, alfentanil, and hydrocodone, are by report primarily metabolized by the CYP3A4 enzyme. The concurrent use of ritonavir, a potent CYP3A4 inhibitor, can lead to significant drug interactions. Using physiologically based pharmacokinetic (PBPK) modeling and simulation, this study examines the effects of different dosing regimens of ritonavir on the pharmacokinetics of these opioids. The findings reveal that co-administration of ritonavir significantly increases the exposure of fentanyl analogs, with over a 10-fold increase in the exposure of alfentanil and sufentanil when given with ritonavir. Conversely, the effect of ritonavir on fentanyl exposure is modest, likely due to additional metabolism pathways. Additionally, the study demonstrates that the steady-state exposure of hydrocodone and its active metabolite hydromorphone can be increased by up to 87% and 95%, respectively, with concurrent use of ritonavir. The extended-release formulation of hydrocodone is particularly affected. These insights from PBPK modeling provide valuable guidance for optimizing opioid dosing and minimizing the risk of toxicity when used in combination with ritonavir-containing prescriptions. [ABSTRACT FROM AUTHOR]

This study evaluated the subacute toxicity and toxicokinetics of a potential anti-cancer drug candidate, pterostilbene, in rats. Animals were orally administered at two repeated doses of 200 and 500 mg/kg for 28 days. No mortality was observed during the 28 days of continuous administration of pterostilbene. Body weight and food consumption in each group increased steadily, while no significant difference was found. Liver weight in the 500 mg/kg female, but not male group increased with mild cytoplasmic vacuoles observed in histopathological study. Toxicokinetics was assessed by measuring plasma concentrations of pterostilbene on the first and 28th day of administration using UPLC–MS/MS. Toxicokinetic parameters showed that AUC0–t significantly increased in all animals, while the increase in females was greater than males. System exposure of pterostilbene appeared to be linear within the administrated dose range. In conclusion, our findings suggested a minimal subacute toxicity profile of pterostilbene, which could strongly support further development of this compound as a novel anti-cancer agent. [ABSTRACT FROM AUTHOR]

SH-1028 is a novel, potent, and highly selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) developed for the treatment of T790M Mutation-positive non-small cell lung cancer (NSCLC). The objective was to develop an LC-MS/MS method for the simultaneous determination of SH-1028 and its metabolites, Imp2 and Imp3, in human plasma. The plasma samples were extracted through protein precipitation with acetonitrile on wet ice conditions. A rapid, sensitive, and specific method was developed and successfully applied to evaluate the pharmacokinetic (PK) properties of SH-1028 in patients with advanced NSCLC following single and multiple doses of SH-1028 (60 mg). After single-dose administration, the Cmax of SH-1028, Imp2, and Imp3 was 11.2, 50.2, and 7.99 ng/mL, respectively. The mean AUC0–24 h was 138, 602, and 76.7 h*ng/mL, respectively. And the terminal half-life time was 19.9, 14.4, and 26.1 h, respectively. After multiple-dose administration, SH-1028 exhibited a slight accumulation, with a mean accumulation ratio (RAUC) of 2.00. The study assessed the PK properties of SH-1028 following single and multiple doses in patients with advanced NSCLC and would provide meaningful information for the further development of SH-1028. [ABSTRACT FROM AUTHOR]

Background: Straw return may affect the soil nitrogen (N) balance by changing soil carbon (C) and N components and contents. To understand how straw return affects the soil N fixation capacity, the relationship between biological N fixation and changes in soil C and N contents at different depths need to be examined. Methods: Soil samples were collected at 20-cm intervals from 0 to 100 cm after five years of a rice-rape rotation system with straw return (ST) and without (CK). Organic C and inorganic N contents, potential N fixation rate, and abundance and population composition of N-fixing bacteria were analyzed at different soil depths. Results: Compared with CK, ST increased soil organic C (SOC), particulate organic C (POC), mineral-associated organic C (MOC), and total N (TN) but decreased nitrate–N (NO3−-N). Straw return also increased the abundance of N-fixing bacteria from 2.9- to 18-fold at depths from 0 to 40 cm and increased the potential N fixation rate at 0–20 cm by 25%. The annual biological N fixation rates at 0–60 cm by soil N-fixing bacteria were estimated to be approximately 0.13–2.70 and 0.12–2.16 kg·ha−1 in ST and CK, respectively. Long-term ST significantly affected the composition of N-fixing bacteria at depths from 0 to 40 cm. Conclusions: Long-term straw return can increase the abundance of the N-fixing bacteria and effectively alter the structure of the N-fixing bacterial community. SOC, POC, TN, and NO3−-N were the main environmental factors driving changes in abundance, activity, and population composition of soil N-fixing bacteria under ST. [ABSTRACT FROM AUTHOR]

Oroxylin A, the main component of Scutellaria baicalensis Georigi has been widely studied due to its well-known pharmacological effects. According to previous studies, Oroxylin A with low bioavailability was converted into glucuronidation and sulphonated metabolites, which had high exposure in plasma and generated certain activities. It is necessary to study the metabolites and metabolic pathways of Oroxylin A. This study aimed to explore the metabolites of Oroxylin A in liver microsomes, primary hepatocyte incubation samples of five different species (human, monkey, dog, mouse, rat), and in bile, urine and faeces of rats. It would provide a systematic description of metabolic pathway of Oroxylin A. Also, a method of high-performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry detector (HPLC-Q-TOF-MS/MS) for identification of each metabolite in various biological matrices was developed. This experiment illustrated that phase II metabolites were the main form of Oroxylin A in vitro and in excretion of rats, accompanied with a small amount of phase I metabolites. Furthermore, there were obvious species differences among the metabolism in vitro, especially in phase II. Monkeys and rats may be more suitable for preclinical research than dogs and mice as non-rodent or rodent species. [ABSTRACT FROM AUTHOR]

Abstract: A simple, accurate, precise, specific and reproducible high-performance liquid chromatography (HPLC) method was developed for determination of trans-polydatin, a natural strong anti-oxidative compound, in rat plasma and cell suspension. The assay procedure involved simple liquid–liquid extraction, the supernatant liquid was added an equal volume of water to avoid solvent effect. The detection of the analyte peak was achieved by monitoring the eluate using a UV detector set at 303nm. The analysis used a Hypersil ODS2 C18 column (5μm, 4.6mm×250mm) and methanol/distilled water as the mobile phase (flow rate=1mL/min). A total analytical run was achieved within 6.0min and calibration curve was linear over a wide concentration range of 0.25–40μg/mL for plasma sample and 1.0–500μM for cell suspension, the coefficients of correlation were 0.9997 and 0.9999 or better, respectively. There was 80.7±7.86%, 96.8±3.20% and 102.7±9.72% recovery from 0.5, 10, and 40μg/mL plasma samples, respectively. Intra- and inter-batch accuracy and precision were acceptable for the both matrices. The RSD of intra- and inter-day assay variations were all less than 10%. Both analyte and IS were stable in the battery of stability studies, freeze–thaw cycles. The described assay method was applied to pharmacokinetic studies in rats and a human colon adenocarcinoma cell line (Caco-2) successfully. The application of the assay to determine the pharmacokinetic is described. [Copyright &y& Elsevier]

Abstract: A pharmacokinetic study was carried out in rats to investigate the effects of experimental hepatic injury on the liver glucuronidation and bile excretion of ketoprofen (KP) and its glucuronides (KPGs). In vivo, KP (20mg/kg b.w.) was intravenously administered to carbon tetrachloride (CCl4) or alpha-naphthylisothiocyanate (ANIT) induced hepatic injury male rats. Concentrations of KP and its glucuronides (S-KPG and R-KPG) in plasma and bile were determined by RP-HPLC. It was observed that there was significant difference in the accumulative bile excretion of KPGs between the CCl4 intoxicated rats and the normal rats (54±18.3% versus 90±6.9%), while it was extremely inhibited in ANIT intoxicated rats (2.0±3.1% versus 90±6.9%). As the result of reduction of KPGs excreted in bile, the area under the curve (AUC(0–∞)) of KP and KPGs were higher in blood in CCl4 and ANIT hepatic injury rats than those of the normal rats. Specifically, ANIT caused approximately 10-fold elevation of AUC(0–∞) of plasma S-KPG. In microsomal incubations experiment, the glucuronyltransferase activity was impaired in CCl4 and ANIT intoxicated rats. It suggested that the glucuronyltransferase activity was impaired in CCl4 and ANIT intoxicated rats, while the bile excretion function was suppressed extremely in ANIT intoxicated rats. [Copyright &y& Elsevier]

Purpose: 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. Methods: 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. Results: 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. Conclusions: Our study systematically explored the pharmacokinetic characteristics of Sul and successfully developed the PBPK model to predict of its clinical PK. [ABSTRACT FROM AUTHOR]

Poria cocos (Schw.) Wolf (Polyporaceae, P.cocos), which is born on the pine root, has a history of more than two thousand years of medicine in China. P.cocos was first recorded in the Shennong's Herbal Classic, studies have proved its lipid-lowering effect. The aim of study was to investigate the underlying mechanism of P.cocos extract on hyperlipidemia. Male Sprague-Dawley (SD) rats aged 9–12 weeks were intraperitoneally (IP) injected with Triton-WR 1339 to establish an acute hyperlipidemia model. At 0 h and 20 h after the model was established, low and high doses of P.cocos extract or simvastatin were given twice. After 48 h, the rats were sacrificed, and liver and serum samples were collected for analysis. The cell model was constructed by treating L02 cells with 1% fat emulsion-10% FBS–RPMI 1640 medium for 48 h. At the same time, low and high doses of P.cocos extract and simvastatin were administered. Oil red O staining was used to evaluate the lipid accumulation in the cells, and H&E staining was used to evaluate the liver lesions of rats. Real-time quantitative PCR and western blotting were used to detect the expressions of lipid metabolism-related genes. P.cocos extract relieved lipid accumulation in vitro and alleviated hyperlipidemia in vivo. Both gene and protein expressions of peroxisome proliferator-activated receptor α (PPARα) were shown to be up-regulated by P.cocos extract. Additionally, P.cocos extract down-regulated the expressions of fatty acid synthesis-related genes sterol regulatory element-binding protein-1 (SREBP-1), Acetyl-CoA Carboxylase 1 (ACC1) and fatty acid synthase (FAS), while up-regulated the expressions of cholesterol metabolism-related genes liver X receptor-α (LXRα), ATP-binding cassette transporter A1 (ABCA1), cholesterol 7alpha-hydroxylase (CYP7A1) and low density lipoprotein receptor (LDLR), which were reversed by the treatment with the PPARα inhibitor GW6471. P.cocos extract ameliorates hyperlipidemia and lipid accumulation by regulating cholesterol homeostasis in hepatocytes through PPARα pathway. This study provides evidence that supplementation with P.cocos extract could be a potential strategy for the treatment of hyperlipidemia. [Display omitted] • P.cocos extract alleviated hyperlipidemia in vivo and in vitro. • P.cocos extract regulated lipid metabolism in hepatocytes. • P.cocos extract regulated lipid metabolism in hepatocytes via PPARα pathway. • PPARα inhibitor GW6471 attenuated the lipid-lowering effect of P.cocos extract. • Triterpenes were the main active ingredients in the lipid-lowering P.cocos extract. [ABSTRACT FROM AUTHOR]

A chiral UPLC-MS/MS method was developed and validated to determine oxiracetam enantiomers in human plasma, urine, and feces. The R-Oxiracetam and S-Oxiracetam were quantified using a CHIRALPAK ®AD3 column at 25 ℃, and the resolution was greater than 3.2. The S-Oxiracetam is the eutome r that isresponsible for the treatment of various brain damage. Isocratic elution was conducted at a flow rate of 0.9 mL/min for 6 min using the mixture of methanol and acetonitrile (methanol:acetonitrile, 15:85) containing 0.3‰ formic acid. The methods showed linearity at the range of 0.5–100 µg/mL for each oxiracetam enantiomer. A comprehensive validation process was carried out, covering aspects including linearity, selectivity, carryover, accuracy, precision, interferences, matrix effect, recovery, dilution integrity and stability in matrix and solution. The validated methods were successfully applied to quantifying R-Oxiracetam and S-Oxiracetam in human plasma, urine, and feces of 12 healthy subjects treated with either a single dose of 2 g S-Oxiracetam injection or 4 g Oxiracetam injection in a phase-I clinical trial. There was no significant difference for plasma pharmacokinetic parameters of S-Oxiracetam between the two regimens (P＞0.05). The S-Oxiracetam and Oxiracetam were primarily eliminated through urine in their original form, with cumulative excretion rates of 92.16% and 85.92%, respectively, within 24 h after administration. Enantiomers interconversion was not observed in the plasma, urine, or feces. The results of this study suggest that replacing 4 g Oxiracetam injection with 2 g S-Oxiracetam injection could offer clinical benefits by lowering the dosage and mitigating potential risks, based on the pharmacokinetic characteristics. [Display omitted] • Novel LC-MS/MS method was developed for S-Oxiracetam and R-Oxiracetam analysis in human plasma, urine, and feces. • The method was extensively validated according to the recommendations of regulatory agencies. • The method was successfully applied to a phase-I comparative pharmacokinetic clinical study. • The human pharmacokinetic characteristics of 2 g S-Oxiracetam injection and 4 g Oxiracetam injection were compared. • Oxiracetam enantiomers are non-interconvertible in human. Replacing oxiracetam with S-Oxiracetam could decrease the dosage. [ABSTRACT FROM AUTHOR]

Ursolic acid (UA) is a common pentacyclic triterpene phytochemical with various pharmacological activities. However, UA is classified as a class IV drug in BCS system and its development as an oral drug is limited. Pulmonary delivery is an effective way to improve the bioavailability of drugs with low absorption. In this study, the differences in pharmacokinetic behaviors of UA after pulmonary and oral administration was explored in rats. Compared with oral administration, the plasma concentration of UA increased rapidly after pulmonary administration, and the bioavailability increased about 80 times. UA instantly accumulated in the lungs after pulmonary administration, and the pulmonary AUC 0-t /dose increased by 114 times compared to oral dosing. Incubation experiments showed that the metabolism of UA in rat lung microsomes was significantly reduced compared with that in liver microsomes, in which the clearance rate of phase I and phase II metabolism was reduced by 14.7 times and 1.4 times respectively. These results indicated that pulmonary administration could improve the bioavailability of UA and reduce its metabolism. This study not only provides a preferable route of administration for the application of UA but also offers new insights for the development of phytochemical drug candidates with poor pharmacokinetic properties. [ABSTRACT FROM AUTHOR]

Purpose: To investigate whether the CYP3A4/5 and ABC transporter genetic polymorphisms could affect the pharmacokinetics of lenvatinib in Chinese healthy subjects. Methods: Thirty-two healthy Chinese volunteers were enrolled and took oral administration of 8 mg lenvatinib. Plasma concentration of lenvatinib was determined by UPLC-MS/MS, the CYP3A4*1G, CYP3A5*3, ABCB1 (3435 C>T, 1236 C>T, 2677 G>T/A), ABCG2 (421 C>A, 34 G>A), and ABCC2-24 C>T genotypes were determined by SnapShot Technique. Results: In ABCB1 3435T carriers (n = 19), AUC0–120h (815.7 (701.9–923.9) ng·h/mL) and AUC0-∞ (843.3 (722.2–977.7) ng·h/mL) were significantly higher than ABCB1 3435CC homozygous subjects (n = 13, 575.3 (513.7–756.9) ng·h/mL and 590.0 (540.5–782.0) ng·h/mL, respectively); on the contrary, the clearance (CL/F) of ABCB1 3435T carriers was significantly lower (9.5 (8.2–11.1) L/h vs. 13.6 (10.4–14.8) L/h). And the Cmax in CYP3A4*1G/*1G allele carrier subjects was higher than *1 carrier (73.4 ng/mL vs. 53.5 (46.1–60.6) ng/mL), but did not reach the level of significantly statistical difference. Genetic polymorphisms of ABCC2, ABCG2, and CYP3A5 could not influence pharmacokinetic parameters of lenvatinib. Conclusions: This work presented an evidence that the ABCB1 3435 C>T polymorphism could significantly affect the exposure and clearance of lenvatinib. These findings may explain the reasons for the huge inter-individual differences in lenvatinib, and should contribute to clinical individualized treatment. [ABSTRACT FROM AUTHOR]

Oroxylin A, obtained from the root of Scutellaria baicalensis Georgi, is a flavonoid with antitumor and other pharmacological activities. Our previous studies showed for the first time that it is mainly metabolized to oroxylin A sodium sulfonate by sulfotransferase enzymes in beagle dogs. In this study, rapid, universal, selective, and robust ultra‐high‐performance liquid chromatography–tandem mass spectrometry methods were established and fully validated to quantitatively detect oroxylin A, oroxylin A 7‐O‐glucuronide, and oroxylin A sodium sulfonate in beagle dog plasma. The quantitative analysis for oroxylin A sodium sulfonate was reported for the first time. Plasma samples were processed with acetonitrile, a universal protein precipitant. Gradient elution was performed to resolve carryover effects and to achieve separation efficiency and sufficient chromatographic retention. The linear relationships of oroxylin A, oroxylin A 7‐O‐glucuronide, and oroxylin A sodium sulfonate in plasma were in the range of 2.0–500.0, 5.0–500.0, and 1.881–940.5 ng/mL, respectively. The assay method was successfully applied to pharmacokinetic study. This is the first paper that reveals the pharmacokinetic profile of oroxylin A, oroxylin A 7‐O‐glucuronide, and oroxylin A sodium sulfonate after single‐dose intravenous and oral administration of Oroxylin A in beagle dogs. [ABSTRACT FROM AUTHOR]

What is known and objective: Clinical use of fluconazole against fungal infections in renal transplant patients is complicated by the potentially marked and unpredictable drug‐drug interactions (DDIs). We report a case of tacrolimus‐fluconazole DDI in a stable renal transplant recipient and describe the mechanism, magnitude and duration of this DDI through a literature review. Case summary: A 38‐year‐old woman experienced a 9.1‐fold increase in dose‐normalized tacrolimus trough level (trough concentration/weight‐normalized daily dose) and an 87% decrease in weight‐normalized daily dose (daily dose/body weight) in the treatment of documented Candida albicans oesophagitis by fluconazole. After discontinuation of fluconazole for 161 day, a 26% reduction in weight‐normalized daily dose was required to maintain therapeutic exposure. What is new and conclusion: Oral fluconazole has a more significant impact on its drug interactions with tacrolimus than intravenous fluconazole. Gene screening for CYP3A5 6986 A>G and ABCB1 3435 C>T in organ transplant recipients may help in preventing DDI and facilitating tacrolimus dose adjustment. [ABSTRACT FROM AUTHOR]

Returning crop residues is a possible practice for balancing soil carbon (C) loss. The turnover rate of organic C from crop residues to soil C is dependent on soil microbial community dynamics. However, the relationship between any temporal changes in the soil microbial community after crop straw inputs and the dynamics of straw-C distribution in the soil organic carbon (SOC) pool remains unclear. The present study investigated the allocation of straw-C into soil dissolved organic carbon (DOC), microbial biomass carbon (MBC), particulate organic carbon (POC) and mineral-associated organic carbon (MaOC) using stable isotope probing, as well as the temporal changes in the soil bacterial and fungal communities using high-throughput sequencing. After the first 180 days of straw decomposition, approximately 3.93% and 19.82% of straw-C was transformed into soil MaOC and POC, respectively, while 0.02% and 2.25% of straw-C was transformed into soil DOC and MBC, respectively. The temporal change of the soil microbial community was positively correlated with the dynamics of straw-C distribution to SOC (R > 0.5, P < 0.05). The copiotrophic bacteria (e.g., Streptomyces, Massilia and Sphingobacterium), cellulolytic bacteria and fungi (e.g., Dyella and Fusarium, Talaromyces), acidophilic bacteria (e.g., Edaphobacter and unclassified Acidobacteriaceae), denitrifying and N-fixing microbes (e.g., Burkholderia-Paraburkholderia, Paraphaeosphaeria and Bradyrhizobium), and fungi unclassified Sordariomycetes were significantly correlated with straw-C distribution to specific SOC fractions (P < 0.05), which explained more than 90% of the variation of straw-C allocation into soils. Copiotrophic, certain cellulolytic and denitrifying microbes had positively correlated with DOC- and MaOC-derived from straw, and other cellulolytic fungi (e.g., Talaromyces) and specific bacteria (e.g. Bradyrhizobium) were positively correlated with POC-derived from straw. Our results highlight that the temporal change of soil microbial community structure well reflects the conversion and distribution process of straw-C to SOC fractions. [ABSTRACT FROM AUTHOR]

1. Afatinib is an oral, selective tyrosine kinase inhibitor (TKI) primarily transported by P-glycoprotein (MDR1, gene code ABCB1) and breast cancer resistance protein (BCRP, gene code ABCG2). In the present study, the effects of ABCB1 and ABCG2 genetic polymorphisms on the pharmacokinetics of afatinib in healthy Chinese were investigated. 2. Blood samples from 24 healthy participants who received afatinib were used for genotyping ABCB1 (1236C>T, 2677G > T/A, 3435C>T) and ABCG2 (34G>A, 421C>A) polymorphisms. Subsequently, the association between afatinib plasma concentrations and target single-nucleotide polymorphisms (SNPs) was analyzed. 3. Among the five polymorphisms, plasma concentrations of afatinib in healthy subjects with ABCB1 1236CC–3435CC were remarkably higher than in other genotype subjects. No significant differences of afatinib exposure were found between the ABCG2 wild-type and heterozygous groups. 4. The ABCB1 genetic polymorphism influenced the plasma exposure of afatinib, and gene testing before drug administration may be useful for clinically individualized use of afatinib. Our data suggest the usefulness of afatinib pharmacogenetics in treatment optimization. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: Our aim was to evaluate the influence of genetic polymorphisms involved in the metabolism and transportation of deferasirox on deferasirox pharmacokinetics in the Chinese population. Methods: Thirty-eight healthy Chinese subjects were administered with a single dose of 20 mg kg−1 deferasirox. Allelic discriminations for eight single-nucleotide polymorphisms (SNPs) in UDP-glucuronosyltransferase 1A1, 1A3 (UGT1A1, UGT1A3), multidrug resistance protein 2 (MRP2, ABCC2), and breast cancer resistance protein (BCRP, ABCG2) were performed. The concentrations of deferasirox in the plasma were determined by UPLC-MS/MS. Results: Subjects carrying ABCC2 c.-24 T allele had a 65% higher clearance (CL/F) and 42% lower area under the concentration–time curve from 0 to 72 h (AUC0-72h) as compared with non-carriers (P = 0.008, P = 0.011, respectively). ABCC2 c.-24 T was also associated with 59% shorter half-life (T1/2) and 17% shorter mean residence time (MRT) (P = 0.030, P = 0.014, respectively). ABCC2 1249A was associated with a marginal increase in deferasirox Cmax (P = 0.07). Genetic polymorphisms of UGT1A1, UGT1A3, and ABCG2 did not significantly influence the pharmacokinetics of deferasirox. Subjects with UGT1A1 211GG-(-1352)CC-(-3156)GG haplotype had higher AUC0-72h than others. Since only two subjects were recruited in the GG-CC-GG group, further confirmative studies were warranted. Conclusions: ABCC2 c.-24 C>T was associated with the pharmacokinetic variability of deferasirox in Chinese subjects. This study revealed an important role of MRP2 in the pharmacokinetics of deferasirox and drew attention to drug combination with MRP2 inhibitors like cyclosporine and methotrexate in deferasirox therapy. [ABSTRACT FROM AUTHOR]

To assess changes in soil salinity and salinity leaching following rainfall when food waste biogas effluent was used as a fertilizer in a humid region, a field experiment was conducted in 2020–2022 focused on broccoli drip fertigation with different percentages of biogas effluent. Five treatments consisted of 0% (CF), 25% (T25), 50% (T50), 75% (T75), and 100% (T100) biogas effluent blended with fresh water, with the same total N, P, and K. The experiment included a control (CK) that consisted of drip irrigation without fertilizer. The electrical conductivity of soil saturation paste extract (EC e), soluble sodium, sodium adsorption ratio (SAR), cation ratio of structural stability (CROSS), and broccoli yield were monitored. Drip fertigation with biogas effluent (electrical conductivity=19.0 dS/m) increased soil salinity and the EC e rose as the biogas effluent percentage increased, especially in the 0–20 cm soil profile. The T25, T50, T75, and T100 treatment EC e values were 1.2–2.2 times those of the CF treatment. Soluble sodium, SAR, and CROSS increased during the fertilization season. However, compared with CF, 25–100% biogas effluent drip fertigation did not significantly affect broccoli yield. During the post season, the soil salinity was effectively leached by rainwater. After one study year of rotation, there was almost no significant difference in EC e between treatments, but the soluble sodium, SAR, and CROSS values were significantly higher in T100 than in the CF treatment. In other words, when the total applied fresh water amount (including rainfall and irrigation) is more than 45–48 times the biogas effluent application amount (i.e., irrigation with a biogas effluent concentration of ≤75%), it may not significantly increase the soil soluble sodium. In conclusion, drip fertigation with biogas effluent can be used for broccoli fertigation in humid areas, and treatment with≤ 75% biogas effluent is suggested. Combined with the local rainfall depth, a biogas effluent application depth of ≤ 28–30 mm/year may be feasible. • Drip fertigation with food waste biogas effluent (BE) increased soil salinity. • The increased salinity can be effectively leached by rainwater in humid areas. • 100% BE was challenging due to increased soil soluble sodium. • BE did not significantly affect broccoli yield. • The advised application depth of BE is ≤ 28–30 mm/year. [ABSTRACT FROM AUTHOR]

Vincristine (VCR) has been used in the treatment of lung cancer. To improve its efficacy, the designs of elevating lung exposure to drug and decreasing the clearance with extended time were brought out. Pulmonary delivery is regarded as a good choice in pulmonary diseases treatment. Spray-drying is a technology for the preparation of drugs that can be delivered to lung via a dry powder inhaler. The results showed an appropriate particle size and shape for the pulmonary delivery. The aerosol behaved a sustained-release profile while VCR solution released rapidly within 10 h. The antitumor activity was characterized by 3-(4, 5-dimethylthiazol-2-yl) -2, 5-diphenyltetrazolium bromide assay, and half maximal inhibitory concentration values of VCR-liposomes spray-dried powder were 24.42 ± 1.88 nM and 55.28 ± 4.76 nM in MCF-7 and A549 cells, respectively. Compared with the free VCR, the aerosol performed better pharmacokinetic behavior: increased maximum concentration (630.8%) and systemic exposure (429.6%) and decreased elimination half-life (81.1%). The clearance was decreased by 83.2%. Comprehensively, the pulmonary delivery seemed to be a recommendable way to effectively treat the pulmonary disease. [ABSTRACT FROM AUTHOR]

A simple, sensitive, specific, accurate liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for determination of chlorzoxazone in human plasma was developed and validated to evaluate the pharmacokinetic characteristics of chlorzoxazone test or reference formulation. Sample preparation was achieved by one step protein precipitation and dilution with acetontrile. The chromatographic separation was performed at 40°C with a gradient mobile phase (0.3 mL/min) and a Shimadzu VP-ODS C18 analytical column (column size: 150 × 2.0 mm). TSQ quantum access triple-quadrapole MS/MS detection was operated in a negative mode by multiple reaction monitoring. Ion transitions at m/z 168.0→132.1 for chlorzoxazone and m/z 451.3→379.3 for repaglinide (internal standard) were used for the LC-MS/MS analysis. The calibration was linear (r ≥ 0.995) over the tested concentration range of 0.2–20 μg/mL for chlorzoxazone in plasma. Precision, accuracy, recovery, matrix effect and stability for chlorzoxazone were evaluated and were excellent within the range of tested concentrations. This method was successfully applied to a bioequivalence study in 20 healthy Chinese volunteers. This method could also contribute to the personalized medication and therapeutic drug monitoring of chlorzoxazone. [ABSTRACT FROM AUTHOR]

17β-estradiol (E2) and aquaporin 2 (AQP2) are associated with endometrial receptivity, and E2 directly regulates AQP2 expression in endometrial cancer cells. The present study aimed to investigate the role of AQP2 in embryo implantation. Normal endometrial samples were collected at the Women's Hospital (Hangzhou, China) from women seeking in vitro fertilization and embryo transfer; women with endometrial abnormalities were excluded from the study. Samples were categorized into early-mid proliferative, late proliferative, early secretory, mid-secretory and late secretory phase groups, according to the menstrual cycle. The mRNA and protein expression levels of AQP2 were assessed in normal human endometrium in response to E2 via reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. The effects of AQP2 on spheroid attachment were assessed using an in vitro co-culture assay with small interfering (si)RNA against AQP2. The highest expression levels of AQP2 were observed in the late proliferative and mid-secretory phases, with the lowest levels detected in the early proliferative and late secretory phases. In addition, treatment with 10−9 or 10−7 M E2 for 24 h upregulated AQP2 in the cultured endometrium. Knockdown of AQP2 by siRNA significantly decreased JAr spheroid attachment; however, this effect was significantly reversed when AQP2 siRNA-transfected cells were treated with 10−7 M E2. The results of the present study suggested that AQP2 expression levels in human endometrium may be mediated by estrogen, and low AQP2 expression levels may be a potential cause of impaired uterine receptivity. [ABSTRACT FROM AUTHOR]

Highlights • A new UPLC-MS/MS method was developed for determining tebipenem in human plasma. • The method was validated according to the guidelines of European Medicines Agency. • High throughput, sensitivity, and reliability were achieved. • The method was applied to a pharmacokinetic study of tebipenem in human volunteers. Abstract A rapid and sensitive ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for determining tebipenem (TBPM) in human plasma. Plasma samples were prepared following a single-step protein precipitation method using acetonitrile and 3-morpholinopropanesulfonic acid (MOPS, pH 7.0, 50 mM) which equal volume of plasma samples were added for stabilizing the analyte. Separation was achieved using an ACQUITY UPLC BEH C18 (1.7 μm, 2.1 × 50 mm) column. A repeated gradient program was employed for reducing the carryover effect, and the total chromatographic run time was 3.0 min. Method validation results showed TBPM was linear in its analytical range i.e. between 0.1–20 μg/mL (r2>0.99), and the lower limit of quantification (LLOQ) was 0.1 μg/mL. The intra-run and inter-run precision (coefficient of variation, CV) was within 3.81%, and the accuracy (relative error, RE) was within ± 8.56%. The carryover was restricted below 8.1%. Matrix effects were minimal, and recovery of TBPM was 90.19–95.74%. The stability of TBPM in plasma sample stored at room temperature (25 °C) for 4 h, at −20 °C for 3 days, at −80 °C for 30 days, five freeze-thaw cycles at −80 °C and processed samples at auto sampler vials (8 °C) for 24 h were within 91.11–106.33%. Finally, the validated method was successfully applied to a pharmacokinetic study of TBPM in healthy volunteers after oral administration of tebipenem pivoxil (TBPM-PI). [ABSTRACT FROM AUTHOR]

Abstract Ethnopharmacological relevance Fructus Gardenia (FG) is a widely used bitter and cold herb for clearing heat and detoxicating. Currently, toxicity of FG and its relative formula has been reported in many clinical and animal studies. However, no systematic research has been carried out on FG-related gastrointestinal (GI) injury which has been emphasized in China since the Ming Dynasty. Aim of the study The purpose of this article is to investigate whether FG could damage GI and explore the mechanisms involved. Material and methods FG was given to male mice by 7-day intragastric administration at average doses of 0.90 g (L group), 1.50 g (M group), and 3.00 g (H group) crude drug/kg FG. Comprehensive understanding of changes in weight, diarrhea degree, stool routine, histomorphology and inflammatory factors of stomach, small intestine, and colon for evaluating the effect of different doses of FG on GI injury. Moreover, metabolomics-based mechanisms exploration of FG on GI injury was carried out via HPLC-Q-TOF/MS analysis on mice urine. Results High dose FG caused GI injury with serious diarrhea, decreased weight, abnormal stool routine, sever alteration in histomorphology of small intestine and colon (mild change in stomach), and significant change in inflammatory factors. The results of metabolomics suggested that 55 endogenous metabolites dispersed in 21 significantly altered metabolic pathways in 3.00 g/kg crude FG treated mice. The hub metabolites of GI injury were mainly related with vitamin B6 metabolism, phenylalanine metabolism, arachidonic acid metabolism, and taurine and hypotaurine metabolism via correlated network analysis. Conclusion FG affected the normal functions of GI via the regulating a variety of metabolic pathways to an abnormal state, and our results provided a research paradigm for the GI-injury of the relative bitter and cold traditional Chinese medicines. Graphical abstract fx1 [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract Pulmonary delivery of anti-cancer drugs in the form of nanoparticulate dry powders is considered a promising modality for treating lung cancer. However, it is not known whether the pharmacodynamics and pharmacokinetics of nano-preparations are altered after co-spray drying. In this study, we compared the physicochemical property, anti-cancer activity, tumor targeting and pharmacokinetic behavior of docetaxel-loaded folic acid-conjugated liposomes (LPs-DTX-FA) with those of dry powder prepared by co-spray-drying LPs-DTX-FA. The particle size and PDI after re-dispersion of the powder were increased. The re-dispersed liposomes showed increased cellular uptake via micropinocytosis and exhibited higher cytotoxicity than LPs-DTX-FA. Tumor targeting of re-dispersed liposomes was less effective compared with LPs-DTX-FA but the metabolism of re-dispersed liposomes was decreased. Tracheal administration resulted in a 45-fold higher concentration of docetaxel in the lung of Sprague Dawley rats at 30 min as compared with intravenous administration. Our results indicated that co-spray drying did change the properties, while tracheal administration of the dry powder provided higher drug exposure at the tumor site without increasing the exposure of other organs. Thus, inhaled dry powders might be clinically effective for treatment of lung cancer. [ABSTRACT FROM AUTHOR]

Objectives: The present study was designed to assess the pharmacokinetic and pharmacodynamic performance of inhaled recombinant human insulin (rh‐insulin) dry powders together with their safety profiles after 14‐day inhalation. Methods: In the pharmacokinetic and pharmacodynamic study, pulmonary surfactant (PS)‐loaded and phospholipid hexadecanol tyloxapol (PHT)‐loaded rh‐insulin dry powders were intratracheally administered to male rats at the dose of 20 U/kg. Novolin R was used as control. Serum glucose and rh‐insulin concentrations were determined by glucose oxidase method and human rh‐insulin CLIA kit, respectively. For the safety study, rats were exposed to rh‐insulin dry powders or air for 14‐day by nose‐only inhalation chambers. Bronchoalveolar lavage and histopathology examinations were performed after inhalation. Key findings: There were no significant differences in the major pharmacokinetic and pharmacodynamic parameters between PS‐loaded and PHT‐loaded rh‐insulin dry powders. The relative bioavailabilities and pharmacodynamic availabilities were 39.9%, 25.6% for PS‐loaded dry powders and 30.1%, 23% for PHT‐loaded dry powders, respectively. Total protein was the only injury marker that was significantly altered. Histopathology examinations showed the ranking of irritations (from slight to severe) were PHT‐loaded rh‐insulin, negative air control and PS‐loaded rh‐insulin. Conclusions: Both PS‐ and PHT‐loaded rh‐insulin dry powders were able to deliver rh‐insulin systemically with appropriate pharmacokinetic, pharmacodynamic and safety profiles. [ABSTRACT FROM AUTHOR]

Triacontanol (TA, C30H62O), abundantly present in plant cuticle waxes and bee waxes, has been found to display promising anti-neoplastic potentials. As a long chain fatty alcohol, TA possesses limited aqueous solubility, which hinders its medicinal application. To overcome its solubility barrier, a polymer prodrug was synthesized through attaching TA to poly ethylene glycol (PEG), using succinic acid as a linker with bifunctional amide and ester bonds. Anti-neoplastic effects of PEG-TA were assessed in LoVo and MCF7 cells, anti-proliferative and apoptosis-inducing activities were subsequently confirmed in mouse xenograft model. Encouragingly, PEG-TA possessed selective anti-cancer ability. It did not exhibit significant cytotoxicity on normal cells. Mechanistic examination revealed inhibition of NF-κB nuclear translocation, suppression on matrix degradation enzyme and down-regulation of angiogenic signaling might contribute to its anti-malignant effects. Pharmacokinetics clearly indicated PEGylated TA (named as mPEG2K-SA-TA) substantially enhanced TA delivery with increased plasma exposure (19,791 vs. 336.25 ng·mL−1·h−1, p < .001), mean residence time (8.46 vs. 2.95 h, p < .001) and elimination half-life (7.78 vs. 2.57 h, p < .001) compared to those of original TA. Moreover, mPEG2K-SA-TA appeared to be safe in preliminary toxicological assessment. PEGylated TA also emerged as a functional carrier to deliver hydrophobic chemotherapeutic agents, since it readily self-assembled to micelles in aqueous solution with a low critical micelle concentration (CMC, 19.1 µg·mL−1). Conclusively, PEG-TA conjugate displayed superior anti-neoplastic activities and low toxicity, as well as facilitated the delivery of other hydrophobic agents, which appeared to be an innovative strategy for cancer therapy. [ABSTRACT FROM AUTHOR]

Picrorhiza scrophulariiflora Pennell, a well-known Chinese herb, has been traditionally utilized as an antioxidant and anti-inflammatory agent. One of its main bioactive components is Picroside II, a glycoside derivative. However, there is limited information on the effects of Picroside II on the activity of cytochrome P450 (CYP) enzymes nor on potential herb-drug interactions are rarely studied. The purpose of the study was to investigate the effects of Picroside II on the activity of cytochrome P450 enzymes in vitro and in vivo and its potential herb-drug interactions. Specific probe substrates were employed to assess the effect of Picroside II on the activity of P450 enzymes. The inhibitory effects of Picroside II on CYP enzymes were assayed both in human (i.e., 1A, 2C9, 2C19, 2D6, 2E1, and 3A) and rat (i.e., 1A, 2C6/11, 2D1, 2E1, and 3A) liver microsomes in vitro. The inductive effects were investigated in rats following oral gavage of 2.5 mg/kg and 10 mg/kg Picroside II. A specific Ultra Performance Liquid Chromatography-Tandem Mass Spectrometry (UPLC-MS/MS) method was developed to determine the formation of specific metabolites. Enzyme inhibition results showed that Picroside II (0.5–200 μM) had no evident inhibitory effects on rat and human liver microsomes in vitro. Interestingly, the administration of multiple doses of 10 mg/kg Picroside II inhibited the activity of CYP2C6/11 by reducing the rate of formation of 4-hydroxydiclofenac and 4-hydroxymephenytoin, while Picroside II at 2.5 mg/kg increased the activity of CYP3A by promoting the formation of 1-hydroxymidazolam and 6-hydroxychlorzoxazone in rats. In addition, there were negligible effects on CYP1A, CYP2D1, and CYP2E1 in rats. The results indicated that Picroside II modulated the activities of CYP enzymes and was involved in CYP2C and CYP3A medicated herb-drug interactions. Therefore, careful monitoring is necessary when Picroside II is used in combination with related conventional drugs. [Display omitted] • Picroside II had no inhibition on CYP450s in human and rat microsomes in vitro. • Picroside II could inhibit CYP2C and induce CYP3A in rats in vivo. • Picroside II could cause herb-drug interactions via cytochrome P450. [ABSTRACT FROM AUTHOR]

Aim: The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model for sinogliatin (HMS-5552, dorzagliatin) by integrating allometric scaling (AS), in vitro to in vivo exploration (IVIVE), and steady-state concentration-mean residence time (Css-MRT) methods and to provide mechanistic insight into its pharmacokinetic properties in humans.Methods: Human major pharmacokinetic parameters were analyzed using AS, IVIVE, and Css-MRT methods with available preclinical in vitro and in vivo data to understand sinogliatin drug metabolism and pharmacokinetic (DMPK) characteristics and underlying mechanisms. On this basis, an initial mechanistic PBPK model of sinogliatin was developed. The initial PBPK model was verified using observed data from a single ascending dose (SAD) study and further optimized with various strategies. The final model was validated by simulating sinogliatin pharmacokinetics under a fed condition. The validated model was applied to support a clinical drug-drug interaction (DDI) study design and to evaluate the effects of intrinsic (hepatic cirrhosis, genetic) factors on drug exposure.Results: The two-species scaling method using rat and dog data (TS-rat,dog) was the best AS method in predicting human systemic clearance in the central compartment (CL). The IVIVE method confirmed that sinogliatin was predominantly metabolized by cytochrome P450 (CYP) 3A4. The Css-MRT method suggested dog pharmacokinetic profiles were more similar to human pharmacokinetic profiles. The estimated CL using the AS and IVIVE approaches was within 1.5-fold of that observed. The Css-MRT method in dogs also provided acceptable prediction of human pharmacokinetic characteristics. For the PBPK approach, the 90% confidence intervals (CIs) of the simulated maximum concentration (Cmax), CL, and area under the plasma concentration-time curve (AUC) of sinogliatin were within those observed and the 90% CI of simulated time to Cmax (tmax) was closed to that observed for a dose range of 5-50 mg in the SAD study. The final PBPK model was validated by simulating sinogliatin pharmacokinetics with food. The 90% CIs of the simulated Cmax, CL, and AUC values for sinogliatin were within those observed and the 90% CI of the simulated tmax was partially within that observed for the dose range of 25-200 mg in the multiple ascending dose (MAD) study. This PBPK model selected a final clinical DDI study design with itraconazole from four potential designs and also evaluated the effects of intrinsic (hepatic cirrhosis, genetic) factors on drug exposure.Conclusions: Sinogliatin pharmacokinetic properties were mechanistically understood by integrating all four methods and a mechanistic PBPK model was successfully developed and validated using clinical data. This PBPK model was applied to support the development of sinogliatin. [ABSTRACT FROM AUTHOR]

1.YMR-65, 5-(5-bromo-1-methyl-1H-indol-3-yl)-3-(3-methoxyphenyl)-4, 5-dihydro-1H-pyrazole-1-carboxamide, is a new tubulin polymerization inhibitor with encouraging anticancer activity. 2.The validated ultra-performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS) method was successfully applied to the pharmacokinetics, tissue distribution and excretion study of YMR-65 after oral and intravenous administration. The area under concentration-time curve (AUC0-∞) for YMR-65 were 151.67 ± 54.48 and 459.45 ± 49.23 ng/ml*h for oral and intravenous administration at the dosage of 1.5 mg/kg, respectively and the oral bioavailability was about 33.01%. Moreover, YMR-65 was extensively distributed in heart, liver, spleen, lung, kidney, stomach, intestine and testis and the highest were detected in heart, followed by stomach, intestine and liver. The majority of YMR-65 was excreted via feces and its accumulative excretion ratio during the period of 96 h was 19.83 ± 3.01%, but only 1.54 ± 0.37 and 0.215 ± 0.026% for urine within 96 h and bile within 10 h after intravenous administration, respectively, though the fecal and urine excretion were incomplete within 96 h. 3.In summary, this study defined the pharmacokinetic characteristics of YMR-65 in vivo and the important data can be a useful resource for further research and development. [ABSTRACT FROM AUTHOR]

YMR-65​, 5-(5-bromo-1-methyl-1H-indol-3-yl)-3-(3-methoxyphenyl)-4, 5-dihydro-1H-pyrazole-1-carboxamide, is a potential tubulin inhibitor exhibiting good anticancer activity. In our study, we illustrated the biological activities in HepG2 cells and the pharmacodynamic and pharmacokinetic profiles were evaluated in murine H22 hepatoma-bearing mice. Molecular docking assay and colchicine competition assay indicated that YMR-65 could bind tightly to the colchicine binding site of tubulin. Further investigation demonstrated that YMR-65 arrested cells in the G2/M phase of cell cycle and induced apoptosis in HepG2 cells. Compared with control group, the tumor growth inhibition determined by final relative volume of tumor/the initial tumor volume were 32.57%, 24.00% and 34.95%, respectively, for YMR-65 (10 mg/kg), YMR-65 (20 mg/kg) and CA4P (10 m/kg) groups. Besides there were no obvious body change or tissue damage (enhanced by histopathology study). YMR-65 administration at 10 and 20 mg/kg in H22 tumor-bearing mice resulted in 1.87- and 1.80-fold longer half time (t 1/2 ) and 0.36- and 0.78-fold lower area under concentration-time curve (AUC 0–∞ ) in plasma in contrast with normal mice at 10 mg/kg. Furthermore, YMR-65 showed a wide distribution to various tissues or tumor and the highest distribution index (the ratio of AUC tissue or tumor /AUC plasma ) was found in tumor, which implied that it might accumulate in tumor after administration. In brief, our results indicated that YMR-65 was a promising candidate with high antitumor efficacy and low tissue damage. [ABSTRACT FROM AUTHOR]

1. β-caryophyllene alcohol (BCPA) has shown therapeutic promise in the treatment of asthma and inflammation with low toxicity. The aim of the current study was to report the pharmacokinetic profiles of BCPA in rats and dogs. 2. Following intravenous administration, BCPA exhibited moderate volumes of distribution (Vz) ranging from 5.63 to 8.97 L/kg in rats and low Vz (2.89 ± 1.12 L/kg) in dogs. Systemic plasma clearance was high in both species, resulting in a short elimination half-life ranging from 29.6 to 48.3 min. In rats, the intravenous pharmacokinetics was dose dependent. The measured oral bioavailability was low in rats for BCPA solution (1.17 ± 0.78%), suspension (1.21 ± 0.33%) and PEG formulation (6.22 ± 2.63%). The bioavailability was lower in dogs for BCPA solution (0.12 ± 0.05%) and PEG formulation (0.25 ± 0.07%), indicating significant species difference. However, treatment of plasma samples with β-glucuronidase increased the systematic exposure of BCPA as assessed from AUC (0-∞) by 24.7- or 2.62-fold in rats and dogs, respectively, which suggested glucuronidation was a significant metabolic pathway for BCPA possibly due to first-pass metabolism. 3. In summary, this was the first preclinical pharmacokinetic investigation of BCPA in animals, providing vital knowledge for further preclinical research and subsequent clinical trials. [ABSTRACT FROM AUTHOR]

PEGylation techniques have been increasingly employed in drug delivery system and chemical modification of compounds with low aqueous solubility. Triacontanol (TA) is a natural product with several pharmacological activities, but its low aqueous solubility significantly limited its application. PEGylated triacontanol (PEG-TA) was designed as the prodrug to improve the aqueous solubility and pharmacokinetic properties of TA. On the basis of salting-out assisted liquid-liquid extraction (SALLE) and saponification sample preparation procedure, a reliable gas chromatography tandem mass spectrometric (GC–MS/MS) method was developed and validated for the quantification of PEG-TA and its metabolite TA in rat plasma after separation and transformation. Acetonitrile-methanol (9:1, v/v) and ammonium acetate (10 M) were utilized to separate PEG-TA and TA (including conjugated TA with fatty acid). Saponification facilitated the complete conversion of PEG-TA into TA, so PEG-TA could be indirectly quantified. The results revealed that the GC–MS/MS method had excellent selectivity, accuracy and linearity. Calibration curves were linear (R 2 >0.99) within the range of 20.0–1000.0 ng/mL for TA and 100.0–10,000.0 ng/mL for PEG-TA. The intra- and inter-day precision of quality control samples were within 15%, and their accuracy values varied from 93.54% to 113.38%. This analytical method has been successfully applied to pharmacokinetic study of PEG-TA. This study can facilitate the further exploration and quantification of PEGylated prodrugs. [ABSTRACT FROM AUTHOR]

Targeting therapy of anti-cancer drugs has been gaining increasing attention. Cell pharmacokinetics have been used for in vitro disposition evaluation, as well as drug–drug interaction for anti-cancer drugs, revealing their fate after entering tumor. Flavonoid compound oroxylin A (OA) possesses strong anti-cancer effects especially on the liver and breast cancer. However, despite the low bioavailability, the disposition of OA and its active metabolite in the target cancer cells remained unclear. In current study, a highly sensitive and selective solid phase extraction (SPE)-UPLC–MS/MS method was developed and validated to simultaneously quantify the concentrations of OA and its major active metabolite oroxylin A 7- O - d -glucuronide (OG) in HepG2 cell lysate and multiple subcellular organelle fractions. The proposed method appeared to be suitable for the analysis with desirable linearity(R 2  > 0.99). The relative standard deviations (RSDs) of intra- and inter-assay precision and accuracy were less than 9.9% and −7.7%, 8.4% and 11% for OA and OG in cell lysate respectively. The intra- precision and accuracy was less than 9.5% and −11.3%, 9.4% and 12.3% for OA and OG in subcellular organelles respectively. The range of absolute recovery of this method in the cell lysate was from 73.1% ± 1.4% to 87.9% ± 6.7%. The RSDs of matrix effects of the quality control (QC) samples were below 15%. The uptake and distribution experiments demonstrated a time-dependent transport characteristic in HepG2 cell lines. Furthermore, both OA and OG were mainly distributed into nuclei after taken up by the tumor cells. In addition, OG was also distributed into mitochondria, which indicates another potential target of OG. The present study, for the first time, reports the in vitro cell pharmacokinetics profiles of OA and OG in tumor cell lines in vitro . [ABSTRACT FROM AUTHOR]

1. Case reports have shown that coadministration of fenofibric acid (FA) could increase bleeding risks of warfarin, but the mechanisms remained unknown. We therefore investigated the pharmacokinetic and pharmacodynamic interaction between warfarin and FA in rats. 2. Rats received warfarin alone (2 mg/kg) or coadministered with FA (100 mg/kg). FA significantly increased the exposure to warfarin, and decreased that to 7-hydroxywarfarin in rats nearly by two-fold, meanwhile increased Cmaxand prolonged t1/2of warfarin. Anticoagulant activity significantly increased, with prothrombin time (PT) up to 199 ± 33 s in coadministered group (approximately ten-fold compared with rats received warfarin alone). Incubation experiments illustrated FA inhibited CYP2C6 and CYP3A1/2 with the IC50 values of 6.98 and 16.14 μM, and inhibited the metabolism of warfarin (Kivalue of 2.21 μM). Meanwhile, FA decreased the plasma protein binding of warfarinin vitro. 3. Our data suggested that the altered pharmacokinetics and pharmacodynamics of warfarin in rats was primarily attributed to the inhibition of metabolism. Anticoagulant activity monitoring or warfarin dose lowering needs to be considered when patients are coadministered with FA. [ABSTRACT FROM PUBLISHER]

Abstract: Emotion is presumed as a major reason for smoking, but this hypothesis needs support from data with high ecological validity. Regulatory emotional self‐efficacy (RESE) is key for emotion regulation, therefore RESE is likely to moderate the relationship between emotional states and smoking. The present study used the ecological momentary assessment (EMA) to record the levels of pleasure, arousal, and smoking craving in 33 male current smokers' daily lives, and examined the moderating effect of RESE in the prediction relationship between emotion and craving. The results showed that either end of the pleasure dimension, namely the high positive or high negative affect, predicted higher smoking craving. A similar pattern was also discovered in the arousal dimension, in which either of the activation and deactivation ends predicted higher smoking craving. Moreover, the prediction of negative affect on smoking craving was weakened by higher RESE, especially by the higher self‐efficacy in managing negative emotions. In conclusion, smoking craving is closely related with immediate emotional states, and RESE reveals promising value in the reduction of smoking behavior. We discuss the possibility of expanding the RESE frame. [ABSTRACT FROM AUTHOR]

Prostate cancer (PC) is a major cause of cancer-related male death in worldwide and the identification of new and improved potent anti-PC molecules is constantly required. A novel scaffold of tetrahydroisoquinoline thiohydantoin was rationally designed based on the enzalutamide structures and our pre-work, leading to the discovery of a series of new antiproliferative compounds. Several new analogues displayed improved androgen receptor (AR) antagonistic activity, while maintaining the higher selective toxicity toward LNCaP cells (AR-rich) versus DU145 cells (AR-deficient) compared to enzalutamide. In fact, compound 55 exhibited promising in vitro antitumor activity by impairing AR unclear translocation. More importantly, 55 showed better pharmacokinetic properties compared to the compound 1 reported in our pre-work. These results demonstrate a step towards the development of novel and improved AR antagonists. [ABSTRACT FROM AUTHOR]

Triacontanol (TA, C30H62O), abundantly present in plant cuticle waxes and bee waxes, has been found to display promising anti-neoplastic potentials. As a long chain fatty alcohol, TA possesses limited aqueous solubility, which hinders its medicinal application. To overcome its solubility barrier, a polymer prodrug was synthesized through attaching TA to poly ethylene glycol (PEG), using succinic acid as a linker with bifunctional amide and ester bonds. Anti-neoplastic effects of PEG-TA were assessed in LoVo and MCF7 cells, anti-proliferative and apoptosis-inducing activities were subsequently confirmed in mouse xenograft model. Encouragingly, PEG-TA possessed selective anti-cancer ability. It did not exhibit significant cytotoxicity on normal cells. Mechanistic examination revealed inhibition of NF-κB nuclear translocation, suppression on matrix degradation enzyme and down-regulation of angiogenic signaling might contribute to its anti-malignant effects. Pharmacokinetics clearly indicated PEGylated TA (named as mPEG2K-SA-TA) substantially enhanced TA delivery with increased plasma exposure (19,791 vs. 336.25 ng·mL−1·h−1, p < .001), mean residence time (8.46 vs. 2.95 h, p < .001) and elimination half-life (7.78 vs. 2.57 h, p < .001) compared to those of original TA. Moreover, mPEG2K-SA-TA appeared to be safe in preliminary toxicological assessment. PEGylated TA also emerged as a functional carrier to deliver hydrophobic chemotherapeutic agents, since it readily self-assembled to micelles in aqueous solution with a low critical micelle concentration (CMC, 19.1 µg·mL−1). Conclusively, PEG-TA conjugate displayed superior anti-neoplastic activities and low toxicity, as well as facilitated the delivery of other hydrophobic agents, which appeared to be an innovative strategy for cancer therapy. [ABSTRACT FROM AUTHOR]

When the multilayer adsorption of lead (Pb) and fulvic acid (FA) occurs on algal surface, the adsorption capacity of Pb on the algae will increase dramatically, thus increasing the environmental risk of Pb. However, the corresponding mechanism and the influence of environmental factors on the multilayer adsorption remain unclear. Here, microscopic observation methods and batch adsorption experiments were exactly designed to investigate the adsorption behavior of multilayer adsorption of Pb and FA on algal surface. The results of Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS) revealed that carboxyl groups were the major functional groups responsible for the binding of Pb ions in multilayer adsorption, and its number was more than that in monolayer adsorption. The solution pH, with an optimal pH of 7, was a critical factor influencing the occurrence of multilayer adsorption because it influences the protonation of the involved functional groups and determines the concentration of Pb2+ and Pb-FA in the solution. Increasing the temperature was beneficial for multilayer adsorption, with ΔH for Pb and FA varied from +17.12 to +47.68 kJ/mol and +16.19 to +57.74 kJ/mol, respectively. The multilayer adsorption of Pb and FA onto algal surface also followed the pseudo-second order kinetic model, but was extremely slower than the monolayer adsorption of Pb and FA by 30 times and 15 orders of magnitude, respectively. Therefore, the adsorption of Pb and FA in the ternary system had a different adsorption behavior than that in the binary system, which verified the presence of multilayer adsorption of Pb and FA and further support the multilayer adsorption mechanism. This work is important to provide data support for water ecological risk prevention and control of heavy metals. [Display omitted] • The number of carboxyl groups around Pb increased in the multilayer adsorption. • FA provided carboxyl groups to combine with Pb to form the multilayer adsorption. • Multilayer adsorption required more energy and time than monolayer adsorption. • The occurrence of multilayer adsorption was highly dependent on the solution pH. [ABSTRACT FROM AUTHOR]

The purpose of this study was to develop a nanocarrier system for codelivery of paclitaxel (PTX) and piperlongumine (PL) and investigate the therapeutic potential of improving efficacy and reducing toxicity. PTX and PL were formulated into poly lactic-co-glycolic acid and D-α-tocopheryl polyethylene glycol succinate via organic solvent evaporation method. The average diameter was 117.1 ± 1.9 nm, and the zeta potential was −43.25 ± 2.76 mV. PL facilitated the cellular uptake of PTX, and the increased cytotoxicity was similarly displayed. The formulation with the PTX/PL concentration ratio at 1:200 showed the best antitumor activity, the IC 50 of PTX were 5.10 ± 0.08 nM in HepG2 cells, and 3.79 ± 1.01 nM in Michigan Cancer Foundation–7 cells. Correspondingly, the combination index was 0.79 and 0.76. Furthermore, intracellular uptake of PTX toward HepG2 cells in coencapsulated nanoparticles was significantly more than free solution. In addition, the antitumor effect of PTX/PL-PTNPs in the HepG2 xenograft tumor model suggested that the nanoparticles showed a higher antitumor efficacy with reduced toxicity to other tissues compared with free PTX. In summary, the results indicated that PTX/PL-PTNPs processed well characteristics and enhanced its therapeutic efficacy; thus, this delivery system could be clinically effective for treatment of cancers. [ABSTRACT FROM AUTHOR]