The anti-hyperlipidemic effects of Poria cocos (Schw.) Wolf extract: Modulating cholesterol homeostasis in hepatocytes via PPARα pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: 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. AIM OF STUDY: The aim of study was to investigate the underlying mechanism of P.cocos extract on hyperlipidemia. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Unraveling a Combined Inactivation Mechanism of Cytochrome P450s by Genipin, the Major Reactive Aglycone Derived from Gardeniae Fructus.

Genipin (GP) is the reactive aglycone of geniposide, the main component of traditional Chinese medicine Gardeniae Fructus (GF). The covalent binding of GP to cellular proteins is suspected to be responsible for GF-induced hepatotoxicity and inhibits drug-metabolizing enzyme activity, although the mechanisms remain to be clarified. In this study, the mechanisms of GP-induced human hepatic P450 inactivation were systemically investigated. Results showed that GP inhibited all tested P450 isoforms via distinct mechanisms. CYP2C19 was directly and irreversibly inactivated without time dependency. CYP1A2, CYP2C9, CYP2D6, and CYP3A4 T (testosterone as substrate) showed time-dependent and mixed-type inactivation, while CYP2B6, CYP2C8, and CYP3A4 M (midazolam as substrate) showed time-dependent and irreversible inactivation. For CYP3A4 inactivation, the kinact/KI values in the presence or absence of NADPH were 0.26 or 0.16 min-1 mM-1 for the M site and 0.62 or 0.27 min-1 mM-1 for the T site. Ketoconazole and glutathione (GSH) both attenuated CYP3A4 inactivation, suggesting an active site occupation- and reactive metabolite-mediated inactivation mechanism. Moreover, the in vitro and in vivo formation of a P450-dependent GP-S-GSH conjugate indicated the involvement of metabolic activation and thiol residues binding in GP-induced enzyme inactivation. Lastly, molecular docking analysis simulated potential binding sites and modes of GP association with CYP2C19 and CYP3A4. We propose that direct covalent binding and metabolic activation mediate GP-induced P450 inactivation and alert readers to potential risk factors for GP-related clinical drug-drug interactions.

Evaluation potential effects of Picroside II on cytochrome P450 enzymes in vitro and in vivo.

ETHNOPHARMACOLOGY RELEVANCE: 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. AIM OF THE STUDY: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Preclinical pharmacokinetics, biodistribution, excretion, and plasma protein binding study of 58Fe-labeled hemin by ICP-MS.

BACKGROUND: Hemin, a stable form of heme iron, is a potential iron supplement for the treatment of iron deficiency. To date, the pharmacokinetics and in vivo ADME properties of hemin are to be elucidated. METHODS: In this study, a rapid, sensitive, and validated inductively coupled plasma mass spectrometry (ICP-MS) method was used in combination with 58Fe stable isotope labeling to systemically investigate the plasma pharmacokinetics, biodistribution, excretion, and plasma binding profiles of hemin in animals. RESULTS: Results showed that the ICP-MS method is accurate and sensitive enough to quantitatively determine the in vivo disposition process of 58Fe derived from 58Fe-labeled hemin. Following intra-gastric administration, 58Fe was rapidly absorbed in gastrointestinal tract, with Cmax of 41.1 ± 23.1 ng/mL, Tmax of 1.38 ± 0.48 h, and bioavailability of 1.12 ± 0.45 % in beagle dogs. Moreover, 58Fe was distributed to various organs including stomach, small intestine, spleen, and liver, within a few hours after intra-gastric administration in rats. Excretion of 58Fe in rats was predominantly via feces (76.3 ± 15.1 % of dosage), whereas minimally via urine (0.14 ± 0.08 % of dosage). Protein binding study revealed majority of 58Fe in plasma was bound to proteins, with average binding rates of 81.0 % and 92.7 % in human and rat plasma, respectively. CONCLUSION: In conclusion, the present study validated the work-flow of preclinical pharmacokinetic studies of iron-containing drug candidates with using ICP-MS and stable (trace) isotope labeling strategy. It also provided useful information to support the further development of hemin as a drug/nutrition supplement candidate.

Effects of ginkgo leaf tablet on the pharmacokinetics of rosiglitazone in rats and its potential mechanism.

CONTEXT: Ginkgo leaf tablet (GLT), a traditional Chinese herbal formula, is often combined with rosiglitazone (ROS) for type 2 diabetes mellitus treatment. However, the drug-drug interaction between GLT and ROS remains unknown. OBJECTIVE: To investigate the effects of GLT on the pharmacokinetics of ROS and its potential mechanism. MATERIALS AND METHODS: The pharmacokinetics of 10 mg/kg ROS with 100/200 mg/kg GLT as single-dose and 10-day multiple-dose administration were investigated in Sprague-Dawley rats. In vitro, the effects of GLT on the activity of CYP2C8 and CYP2C9 were determined in recombinant human yeast microsomes and rat liver microsomes with probe substrates. RESULTS: The t1/2 of ROS increased from 2.14 ± 0.38 (control) to 2.79 ± 0.37 (100 mg/kg) and 3.26 ± 1.08 h (200 mg/kg) in the single-dose GLT administration. The AUC0-t (139.69 ± 45.46 vs. 84.58 ± 39.87 vs. 66.60 ± 15.90 h·µg/mL) and t1/2 (2.75 ± 0.70 vs. 1.99 ± 0.44 vs. 1.68 ± 0.35 h) decreased significantly after multiple-dose GLT treatment. The IC50 values of quercetin, kaempferol, and isorhamnetin, GLT main constituents, were 9.32, 7.67, and 11.90 µmol/L for CYP2C8, and 27.31, 7.57, and 4.59 µmol/L for CYP2C9. The multiple-dose GLT increased rat CYP2C8 activity by 44% and 88%, respectively. DISCUSSION AND CONCLUSIONS: The metabolism of ROS is attenuated in the single dose of GLT by inhibiting CYP2C8 and CYP2C9 activity, and accelerated after the multiple-dose GLT treatment via inducing CYP2C8 activity in rats, indicating that the clinical dose of ROS should be adjusted when co-administrated with GLT.

Music therapy for people with substance use disorders.

BACKGROUND: Substance use disorder (SUD) is the continued use of one or more psychoactive substances, including alcohol, despite negative effects on health, functioning, and social relations. Problematic drug use has increased by 10% globally since 2013, and harmful use of alcohol is associated with 5.3% of all deaths. Direct effects of music therapy (MT) on problematic substance use are not known, but it may be helpful in alleviating associated psychological symptoms and decreasing substance craving. OBJECTIVES: To compare the effect of music therapy (MT) in addition to standard care versus standard care alone, or to standard care plus an active control intervention, on psychological symptoms, substance craving, motivation for treatment, and motivation to stay clean/sober. SEARCH METHODS: We searched the following databases (from inception to 1 February 2021): the Cochrane Drugs and Alcohol Specialised Register; CENTRAL; MEDLINE (PubMed); eight other databases, and two trials registries. We handsearched reference lists of all retrieved studies and relevant systematic reviews. SELECTION CRITERIA: We included randomised controlled trials comparing MT plus standard care to standard care alone, or MT plus standard care to active intervention plus standard care for people with SUD. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology. MAIN RESULTS: We included 21 trials involving 1984 people. We found moderate-certainty evidence of a medium effect favouring MT plus standard care over standard care alone for substance craving (standardised mean difference (SMD) -0.66, 95% confidence interval (CI) -1.23 to -0.10; 3 studies, 254 participants), with significant subgroup differences indicating greater reduction in craving for MT intervention lasting one to three months; and small-to-medium effect favouring MT for motivation for treatment/change (SMD 0.41, 95% CI 0.21 to 0.61; 5 studies, 408 participants). We found no clear evidence of a beneficial effect on depression (SMD -0.33, 95% CI -0.72 to 0.07; 3 studies, 100 participants), or motivation to stay sober/clean (SMD 0.22, 95% CI -0.02 to 0.47; 3 studies, 269 participants), though effect sizes ranged from large favourable effect to no effect, and we are uncertain about the result. There was no evidence of beneficial effect on anxiety (mean difference (MD) -0.17, 95% CI -4.39 to 4.05; 1 study, 60 participants), though we are uncertain about the result. There was no meaningful effect for retention in treatment for participants receiving MT plus standard care as compared to standard care alone (risk ratio (RR) 0.99, 95% 0.93 to 1.05; 6 studies, 199 participants). There was a moderate effect on motivation for treatment/change when comparing MT plus standard care to another active intervention plus standard care (SMD 0.46, 95% CI -0.00 to 0.93; 5 studies, 411 participants), and certainty in the result was moderate. We found no clear evidence of an effect of MT on motivation to stay sober/clean when compared to active intervention, though effect sizes ranged from large favourable effect to no effect, and we are uncertain about the result (MD 0.34, 95% CI -0.11 to 0.78; 3 studies, 258 participants). There was no clear evidence of effect on substance craving (SMD -0.04, 95% CI -0.56 to 0.48; 3 studies, 232 participants), depression (MD -1.49, 95% CI -4.98 to 2.00; 1 study, 110 participants), or substance use (RR 1.05, 95% CI 0.85 to 1.29; 1 study, 140 participants) at one-month follow-up when comparing MT plus standard care to active intervention plus standard care. There were no data on adverse effects. Unclear risk of selection bias applied to most studies due to incomplete description of processes of randomisation and allocation concealment. All studies were at unclear risk of detection bias due to lack of blinding of outcome assessors for subjective outcomes (mostly self-report). We judged that bias arising from such lack of blinding would not differ between groups. Similarly, it is not possible to blind participants and providers to MT. We consider knowledge of receiving this type of therapy as part of the therapeutic effect itself, and thus all studies were at low risk of performance bias for subjective outcomes.  We downgraded all outcomes one level for imprecision due to optimal information size not being met, and two levels for outcomes with very low sample size.  AUTHORS' CONCLUSIONS: Results from this review suggest that MT as 'add on' treatment to standard care can lead to moderate reductions in substance craving and can increase motivation for treatment/change for people with SUDs receiving treatment in detoxification and short-term rehabilitation settings. Greater reduction in craving is associated with MT lasting longer than a single session. We have moderate-to-low confidence in our findings as the included studies were downgraded in certainty due to imprecision, and most included studies were conducted by the same researcher in the same detoxification unit, which considerably impacts the transferability of findings.

Characterization of Preclinical Pharmacokinetic Properties and Prediction of Human PK Using a Physiologically Based Pharmacokinetic Model for a Novel Anti-Arrhythmic Agent Sulcardine Sulfate.

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.

Identification of Triterpene Acids in Poria cocos Extract as Bile Acid Uptake Transporter Inhibitors.

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.

A systematic metabolic pathway identification of Common Gardenia Fruit (Gardeniae Fructus) in mouse bile, plasma, urine and feces by HPLC-Q-TOF-MS/MS.

Gardeniae Fructus was a traditional Chinese medicine (TCM) containing various biological ingredients including iridoids and crocetins, monocyclic monoterpenes, organic acids, and flavonoids. However, few systematic identification studies of the bioactive components in vivo have been reported. Herein, the ingredients and metabolites of Gardeniae Fructus were investigated using high-performance liquid chromatography coupled with high-sensitivity Q-TOF mass spectrometry. A total of 45 prototype compounds in Gardeniae Fructus extract were tentatively identified. After oral administration, 69 of prototypes and metabolites were identified from mice bile, plasma, urine, and feces, in which, 31 compounds were prototypes, and 38 chemicals were metabolites. The in vivo biotransformation pathways of these metabolites were also proposed including phase I (hydrolysis, hydrogenation, oxidation, loss of O, and ketone formation, decarboxylation) and phase II reactions (glycine, cysteine, glutathione, and glutamine, and sulfate conjugation, and glucuronidation). For the first time, our results had revealed systematic metabolic profiles of ingredients in Gardeniae Fructus extract in vivo of mice and replenished novel knowledge into the explanation of effective material and/or toxicological basis of Gardeniae Fructus which deserves further investigation.

Pharmacokinetics, tissue distribution and excretion study of Oroxylin A, Oroxylin A 7-O-glucuronide and Oroxylin A sodium sulfonate in rats after administration of Oroxylin A.

Oroxylin A (OA), as a natural flavonoid extracted from the root of Scutellaria baicalensis Georgi, is a candidate drug with multiple pharmacological activities. However, pharmacokinetic studies of OA have rarely been reported up to now. The present study aim to conduct a systemic evaluation on the pharmacokinetics, tissue distribution and excretion of OA in rats, with quantification of both OA and its two metabolites, Oroxylin A 7-O-glucuronide (OG) and Oroxylin A sodium sulfonate (OS) by the sensitive and rapid UPLC-MS/MS methods. The results show that OA was rapidly eliminated in vivo after a single-dose (2 mg/kg) i.v. administration of OA. The relative bioavailability of OA in all three i.g. administration groups (40, 120, and 360 mg/kg) were <2%. The AUC0-t values of OA, OG, and OS in rats show an apparent dose-proportionality. OA, OG, and OS all underwent a rapid and widespread tissue distribution after i.g. administration (120 mg/kg) of OA. Except for stomach and intestine, the major distribution tissues of OA and its two metabolites in rats were liver, kidney, respectively. And OA was more widely distributed in tissue than its metabolites. After i.g. administration (120 mg/kg) of OA, it was mainly excreted from the feces, and OG mainly excreted from bile and urine, while OS almost free of excretion. This work present a comprehensive pharmacokinetics information for further investigation of OA and its two metabolites.

An in vitro study on interaction of anisodine and monocrotaline with organic cation transporters of the SLC22 and SLC47 families.

Current study systematically investigated the interaction of two alkaloids, anisodine and monocrotaline, with organic cation transporter OCT1, 2, 3, MATE1 and MATE2-K by using in vitro stably transfected HEK293 cells. Both anisodine and monocrotaline inhibited the OCTs and MATE transporters. The lowest IC50 was 12.9 µmol·L-1 of anisodine on OCT1 and the highest was 1.8 mmol·L-1 of monocrotaline on OCT2. Anisodine was a substrate of OCT2 (Km = 13.3 ± 2.6 µmol·L-1 and Vmax = 286.8 ± 53.6 pmol/mg protein/min). Monocrotaline was determined to be a substrate of both OCT1 (Km = 109.1 ± 17.8 µmol·L-1, Vmax = 576.5 ± 87.5 pmol/mg protein/min) and OCT2 (Km = 64.7 ± 14.8 µmol·L-1, Vmax = 180.7 ± 22.0 pmol/mg protein/min), other than OCT3 and MATE transporters. The results indicated that OCT2 may be important for renal elimination of anisodine and OCT1 was responsible for monocrotaline uptake into liver. However neither MATE1 nor MATE2-K could facilitate transcellular transport of anisodine and monocrotaline. Accumulation of these drugs in the organs with high OCT1 expression (liver) and OCT2 expression (kidney) may be expected.

Fructus Gardeniae-induced gastrointestinal injury was associated with the inflammatory response mediated by the disturbance of vitamin B6, phenylalanine, arachidonic acid, taurine and hypotaurine metabolism.

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.

Oroxylin A, a methylated metabolite of baicalein, exhibits a stronger inhibitory effect than baicalein on the CYP1B1-mediated carcinogenic estradiol metabolite formation.

Human cytochrome P450 1B1 (CYP1B1)-mediated formation of 4-hydroxyestradiol (4-OHE2) from 17ß-estradiol plays an important role in the progression of human breast cancer, while the biotransformation of 17ß-estradiol to 2-hydroxyestradiol mediated by cytochrome P450 1A1 (CYP1A1) is considered as a less harmful pathway. In this study, inhibitory effects of flavonoids baicalein and oroxylin A, a metabolite of baicalein in human body, on CYP1A1 and 1B1 activities were investigated in vitro. The inhibition intensities of baicalein and oroxylin A towards CYP1B1 were greater than towards CYP1A1 with a mixed mechanism. In addition, oroxylin A showed a stronger inhibitory effect than baicalein towards the CYP1B1-mediated 17ß-estradiol 4-hydroxylation, with the IC50 values of 0.0146 and 2.27 µM, respectively. Docking studies elucidated that oroxylin A had a stronger binding affinity than baicalein for CYP1B1. In MCF-7 cells, compared with baicalein-treated groups, oroxylin A with lower doses decreased and increased the formation of 4-OHE2 and 2-hydroxyestradiol, respectively, with a preferential induction of mRNA of CYP1A1 over CYP1B1. In conclusion, this study demonstrated that oroxylin A showed a stronger inhibitory effect than baicalein on CYP1B1-mediated 4-OHE2 formation in MCF-7 cells, providing crucial implications for their possibly preventive/therapeutic potential against breast cancer via inhibition of CYP1B1, particularly of oroxylin A.

Development of a Physiologically Based Pharmacokinetic Model for Sinogliatin, a First-in-Class Glucokinase Activator, by Integrating Allometric Scaling, In Vitro to In Vivo Exploration and Steady-State Concentration-Mean Residence Time Methods: Mechanistic Understanding of its Pharmacokinetics.

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.

The effect of music therapy on cognitive functions in patients with dementia: a systematic review and meta-analysis.

OBJECTIVES: The aim of the present study was to meta-analyze the effect of music therapy (MT) on cognitive functions in patients with dementia. METHOD: A systematic literature search was performed in Medline, PsycINFO, Embase, CINAHL and RILM up to 8 September 2016. We included all randomized controlled trials that compared MT with standard care, or other non-musical types of intervention, evaluating cognitive outcomes in patients with dementia. Outcomes included global cognition, complex attention, executive function, learning and memory, language, and perceptual-motor skills. RESULTS: From 1089 potentially relevant records, 110 studies were assessed for eligibility, and 7 met the inclusion criteria, of which 6 contained appropriate data for meta-analysis (330 participants, mean age range 78.8-86.3). Overall, random-effects meta-analyses suggested no significant effects of MT on all outcomes. Subgroup analysis found evidence of a beneficial effect of active MT on global cognition (SMD = 0.29, 95% CI 0.02 to 0.57, p = 0.04). CONCLUSION: Despite the limited evidence of the present review, it is important to continue supporting MT as a complementary treatment for older adults with dementia. RCTs with larger sample sizes are needed to better elucidate the impact of MT on cognitive functions.

Music therapy for depression.

BACKGROUND: Depression is a highly prevalent mood disorder that is characterised by persistent low mood, diminished interest, and loss of pleasure. Music therapy may be helpful in modulating moods and emotions. An update of the 2008 Cochrane review was needed to improve knowledge on effects of music therapy for depression. OBJECTIVES: 1. To assess effects of music therapy for depression in people of any age compared with treatment as usual (TAU) and psychological, pharmacological, and/or other therapies.2. To compare effects of different forms of music therapy for people of any age with a diagnosis of depression. SEARCH METHODS: We searched the following databases: the Cochrane Common Mental Disorders Controlled Trials Register (CCMD-CTR; from inception to 6 May 2016); the Cochrane Central Register of Controlled Trials (CENTRAL; to 17 June 2016); Thomson Reuters/Web of Science (to 21 June 2016); Ebsco/PsycInfo, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Embase, and PubMed (to 5 July 2016); the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), ClinicalTrials.gov, the National Guideline Clearing House, and OpenGrey (to 6 September 2016); and the Digital Access to Research Theses (DART)-Europe E-theses Portal, Open Access Theses and Dissertations, and ProQuest Dissertations and Theses Database (to 7 September 2016). We checked reference lists of retrieved articles and relevant systematic reviews and contacted trialists and subject experts for additional information when needed. We updated this search in August 2017 and placed potentially relevant studies in the "Awaiting classification" section; we will incorporate these into the next version of this review as appropriate. SELECTION CRITERIA: All randomised controlled trials (RCTs) and controlled clinical trials (CCTs) comparing music therapy versus treatment as usual (TAU), psychological therapies, pharmacological therapies, other therapies, or different forms of music therapy for reducing depression. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risk of bias, and extracted data from all included studies. We calculated standardised mean difference (SMD) for continuous data and odds ratio (OR) for dichotomous data with 95% confidence intervals (CIs). We assessed heterogeneity using the I2 statistic. MAIN RESULTS: We included in this review nine studies involving a total of 421 participants, 411 of whom were included in the meta-analysis examining short-term effects of music therapy for depression. Concerning primary outcomes, we found moderate-quality evidence of large effects favouring music therapy and TAU over TAU alone for both clinician-rated depressive symptoms (SMD -0.98, 95% CI -1.69 to -0.27, 3 RCTs, 1 CCT, n = 219) and patient-reported depressive symptoms (SMD -0.85, 95% CI -1.37 to -0.34, 3 RCTs, 1 CCT, n = 142). Music therapy was not associated with more or fewer adverse events than TAU. Regarding secondary outcomes, music therapy plus TAU was superior to TAU alone for anxiety and functioning. Music therapy and TAU was not more effective than TAU alone for improved quality of life (SMD 0.32, 95% CI -0.17 to 0.80, P = 0.20, n = 67, low-quality evidence). We found no significant discrepancies in the numbers of participants who left the study early (OR 0.49, 95% CI 0.14 to 1.70, P = 0.26, 5 RCTs, 1 CCT, n = 293, moderate-quality evidence). Findings of the present meta-analysis indicate that music therapy added to TAU provides short-term beneficial effects for people with depression if compared to TAU alone. Additionally, we are uncertain about the effects of music therapy versus psychological therapies on clinician-rated depression (SMD -0.78, 95% CI -2.36 to 0.81, 1 RCT, n = 11, very low-quality evidence), patient-reported depressive symptoms (SMD -1.28, 95% CI -3.75 to 1.02, 4 RCTs, n = 131, low-quality evidence), quality of life (SMD -1.31, 95% CI - 0.36 to 2.99, 1 RCT, n = 11, very low-quality evidence), and leaving the study early (OR 0.17, 95% CI 0.02 to 1.49, 4 RCTs, n = 157, moderate-quality evidence). We found no eligible evidence addressing adverse events, functioning, and anxiety. We do not know whether one form of music therapy is better than another for clinician-rated depressive symptoms (SMD -0.52, 95% CI -1.87 to 0.83, 1 RCT, n = 9, very low-quality evidence), patient-reported depressive symptoms (SMD -0.01, 95% CI -1.33 to 1.30, 1 RCT, n = 9, very low-quality evidence), quality of life (SMD -0.24, 95% CI -1.57 to 1.08, 1 RCT, n = 9, very low-quality evidence), or leaving the study early (OR 0.27, 95% CI 0.01 to 8.46, 1 RCT, n = 10). We found no eligible evidence addressing adverse events, functioning, or anxiety. AUTHORS' CONCLUSIONS: Findings of the present meta-analysis indicate that music therapy provides short-term beneficial effects for people with depression. Music therapy added to treatment as usual (TAU) seems to improve depressive symptoms compared with TAU alone. Additionally, music therapy plus TAU is not associated with more or fewer adverse events than TAU alone. Music therapy also shows efficacy in decreasing anxiety levels and improving functioning of depressed individuals.Future trials based on adequate design and larger samples of children and adolescents are needed to consolidate our findings. Researchers should consider investigating mechanisms of music therapy for depression. It is important to clearly describe music therapy, TAU, the comparator condition, and the profession of the person who delivers the intervention, for reproducibility and comparison purposes.

Music therapy for people with schizophrenia and schizophrenia-like disorders.

BACKGROUND: Music therapy is a therapeutic approach that uses musical interaction as a means of communication and expression. Within the area of serious mental disorders, the aim of the therapy is to help people improve their emotional and relational competencies, and address issues they may not be able to using words alone. OBJECTIVES: To review the effects of music therapy, or music therapy added to standard care, compared with placebo therapy, standard care or no treatment for people with serious mental disorders such as schizophrenia. SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Trials Study-Based Register (December 2010 and 15 January, 2015) and supplemented this by contacting relevant study authors, handsearching of music therapy journals and manual searches of reference lists. SELECTION CRITERIA: All randomised controlled trials (RCTs) that compared music therapy with standard care, placebo therapy, or no treatment. DATA COLLECTION AND ANALYSIS: Review authors independently selected, quality assessed and data extracted studies. We excluded data where more than 30% of participants in any group were lost to follow-up. We synthesised non-skewed continuous endpoint data from valid scales using a standardised mean difference (SMD). We employed a fixed-effect model for all analyses. If statistical heterogeneity was found, we examined treatment dosage (i.e. number of therapy sessions) and treatment approach as possible sources of heterogeneity. MAIN RESULTS: Ten new studies have been added to this update; 18 studies with a total 1215 participants are now included. These examined effects of music therapy over the short, medium, and long-term, with treatment dosage varying from seven to 240 sessions. Overall, most information is from studies at low or unclear risk of biasA positive effect on global state was found for music therapy compared to standard care (medium term, 2 RCTs, n = 133, RR 0.38 95% confidence interval (CI) 0.24 to 0.59, low-quality evidence, number needed to treat for an additional beneficial outcome NNTB 2, 95% CI 2 to 4). No binary data were available for other outcomes. Medium-term continuous data identified good effects for music therapy on negative symptoms using the Scale for the Assessment of Negative Symptoms (3 RCTs, n = 177, SMD - 0.55 95% CI -0.87 to -0.24, low-quality evidence). General mental state endpoint scores on the Positive and Negative Symptoms Scale were better for music therapy (2 RCTs, n = 159, SMD -0.97 95% CI -1.31 to -0.63, low-quality evidence), as were average endpoint scores on the Brief Psychiatric Rating Scale (1 RCT, n = 70, SMD -1.25 95% CI -1.77 to -0.73, moderate-quality evidence). Medium-term average endpoint scores using the Global Assessment of Functioning showed no effect for music therapy on general functioning (2 RCTs, n = 118, SMD -0.19 CI -0.56 to 0.18, moderate-quality evidence). However, positive effects for music therapy were found for both social functioning (Social Disability Screening Schedule scores; 2 RCTs, n = 160, SMD -0.72 95% CI -1.04 to -0.40), and quality of life (General Well-Being Schedule scores: 1 RCT, n = 72, SMD 1.82 95% CI 1.27 to 2.38, moderate-quality evidence). There were no data available for adverse effects, service use, engagement with services, or cost. AUTHORS' CONCLUSIONS: Moderate- to low-quality evidence suggests that music therapy as an addition to standard care improves the global state, mental state (including negative and general symptoms), social functioning, and quality of life of people with schizophrenia or schizophrenia-like disorders. However, effects were inconsistent across studies and depended on the number of music therapy sessions as well as the quality of the music therapy provided. Further research should especially address the long-term effects of music therapy, dose-response relationships, as well as the relevance of outcome measures in relation to music therapy.

Biotin-Conjugated Multilayer Poly [D,L-lactide-co-glycolide]-Lecithin-Polyethylene Glycol Nanoparticles for Targeted Delivery of Doxorubicin.

Multilayer nanoparticle combining the merits of liposome and polymer nanoparticle has been designed for the targeted delivery of doxorubicin (DOX) in cancer treatment. In this study, DOX-PLGA-lecithin-PEG-biotin nanoparticles (DOX-PLPB-NPs) were fabricated and functionalized with biotin for specific tumor targeting. Under the transmission electron microscopy observation, the lipid layer was found to be coated on the polymer core. The physical characteristics of PLPB-NPs were also evaluated. The confocal laser scanning microscopy confirmed the cellular uptake of nanoparticles and targeted delivery PLPB-NPs. The in vitro release experiment demonstrated a pH-depending release of DOX from drug-loaded PLPB-NPs. Cytotoxicity studies in HepG2 cells and in vivo antitumor experiment in tumor-bearing mice both proved DOX-PLPB-NPs showed the best inhibition effect of tumor proliferation. In biodistribution studies, DOX-PLPB-NPs showed a higher DOX concentration than free DOX and DOX-PLGA-lecithin-PEG nanoparticles (DOX-PLP-NPs) in tumor site, especially in 24 h, and the lowest DOX level in normal organs. The results were coincident with the strongest antitumor ability showed among in vivo antitumor experiment. Histopathology analysis demonstrated that DOX-PLPB-NPs exhibited the strongest antitumor ability and lowest cardiotoxicity. In brief, the PLPB-NPs were proved to be an efficient delivery system for tumor-targeting treatment.

Optimal dosing regimen of biapenem in Chinese patients with lower respiratory tract infections based on population pharmacokinetic/pharmacodynamic modelling and Monte Carlo simulation.

In this study, a population pharmacokinetic (PPK) model of biapenem in Chinese patients with lower respiratory tract infections (LRTIs) was developed and optimal dosage regimens based on Monte Carlo simulation were proposed. A total of 297 plasma samples from 124 Chinese patients were assayed chromatographically in a prospective, single-centre, open-label study, and pharmacokinetic parameters were analysed using NONMEN. Creatinine clearance (CLCr) was found to be the most significant covariate affecting drug clearance. The final PPK model was: CL (L/h)=9.89+(CLCr-66.56)×0.049; Vc (L)=13; Q (L/h)=8.74; and Vp (L)=4.09. Monte Carlo simulation indicated that for a target of ≥40% T>MIC (duration that the plasma level exceeds the causative pathogen's MIC), the biapenem pharmacokinetic/pharmacodynamic (PK/PD) breakpoint was 4µg/mL for doses of 0.3g every 6h (3-h infusion) and 1.2g (24-h continuous infusion). For a target of ≥80% T>MIC, the PK/PD breakpoint was 4µg/mL for a dose of 1.2g (24-h continuous infusion). The probability of target attainment (PTA) could not achieve ≥90% at the usual biapenem dosage regimen (0.3g every 12h, 0.5-h infusion) when the MIC of the pathogenic bacteria was 4µg/mL, which most likely resulted in unsatisfactory clinical outcomes in Chinese patients with LRTIs. Higher doses and longer infusion time would be appropriate for empirical therapy. When the patient's symptoms indicated a strong suspicion of Pseudomonas aeruginosa or Acinetobacter baumannii infection, it may be more appropriate for combination therapy with other antibacterial agents.

Randomized Trial of Group Music Therapy With Chinese Prisoners: Impact on Anxiety, Depression, and Self-Esteem.

This study investigated the effects of group music therapy on improving anxiety, depression, and self-esteem in Chinese prisoners. Two-hundred male prisoners were randomly assigned to music therapy (n = 100) or standard care (n = 100). The music therapy had 20 sessions of group therapy compared with standard care. Anxiety (State and Trait Anxiety Inventory [STAI]), depression (Beck Depression Inventory [BDI]), and self-esteem (Texas Social Behavior Inventory [TSBI], Rosenberg Self-Esteem Inventory [RSI]) were measured by standardized scales at baseline, mid-program, and post-program. Data were analyzed based on the intention to treat principle. Compared with standard care, anxiety and depression in the music therapy condition decreased significantly at mid-test and post-test; self-esteem improved significantly at mid-test (TSBI) and at post-test (TSBI, RSI). Improvements were greater in younger participants (STAI-Trait, RSI) and/or in those with a lower level of education (STAI-State, STAI-Trait). Group music therapy seems to be effective in improving anxiety, depression, and self-esteem and was shown to be most beneficial for prisoners of younger age or with lower education level.