Model-Informed Precision Dosing of Isoniazid: Parametric Population Pharmacokinetics Model Repository.

Introduction: Isoniazid (INH) is a crucial first-line anti tuberculosis (TB) drug used in adults and children. However, various factors can alter its pharmacokinetics (PK). This article aims to establish a population pharmacokinetic (popPK) models repository of INH to facilitate clinical use. Methods: A literature search was conducted until August 23, 2022, using PubMed, Embase, and Web of Science databases. We excluded published popPK studies that did not provide full model parameters or used a non-parametric method. Monte Carlo simulation works was based on RxODE. The popPK models repository was established using R. Non-compartment analysis was based on IQnca. Results: Fourteen studies included in the repository, with eleven studies conducted in adults, three studies in children, one in pregnant women. Two-compartment with allometric scaling models were commonly used as structural models. NAT2 acetylator phenotype significantly affecting the apparent clearance (CL). Moreover, postmenstrual age (PMA) influenced the CL in pediatric patients. Monte Carlo simulation results showed that the geometric mean ratio (95% Confidence Interval, CI) of PK parameters in most studies were within the acceptable range (50.00-200.00%), pregnant patients showed a lower exposure. After a standard treatment strategy, there was a notable exposure reduction in the patients with the NAT2 RA or nonSA (IA/RA) phenotype, resulting in a 59.5% decrease in AUC0-24 and 83.2% decrease in Cmax (Infants), and a 49.3% reduction in AUC0-24 and 73.5% reduction in Cmax (Adults). Discussion: Body weight and NAT2 acetylator phenotype are the most significant factors affecting the exposure of INH. PMA is a crucial factor in the pediatric population. Clinicians should consider these factors when implementing model-informed precision dosing of INH. The popPK model repository for INH will aid in optimizing treatment and enhancing patient outcomes.

2,3,5,4'- tetrahydroxystilbene-2-O-ß-D- glucopyranoside (TSG)-Driven immune response in the hepatotoxicity of Polygonum multiflorum.

ETHNOPHARMACOLOGICAL RELEVANCE: 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucopyranoside (TSG) as the primary constituent of Polygonum multiflorum Thumb. (PM) possesses anti-oxidative, antihypercholesterolemic, anti-tumor and many more biological activities. The root of PM has been used as a tonic medicine for thousands of years. However, cases of PM-induced liver injury are occasionally reported, and considered to be related to the host immune status. AIM OF THE STUDY: The primary toxic elements and specific mechanisms PM causing liver damage are still not thoroughly clear. Our study aimed to investigate the influences of TSG on the immune response in idiosyncratic hepatotoxicity of PM. MATERIALS AND METHODS: The male C57BL/6 mice were treated with different doses of TSG and the alterations in liver histology, serum liver enzyme levels, proportions of T cells and cytokines secretion were evaluated by hematoxylin and eosin (HE), RNA sequencing, quantitative real time polymerase chain reaction (qRT-PCR), Flow cytometry (FCM), and enzyme-linked immunosorbent assay (ELISA), respectively. Then, primary spleen cells from drug-naive mice were isolated and cultured with TSG in vitro. T cell subsets proliferation and cytokines secretion after treated with TSG were assessed by CCK8, FCM and ELISA. In addition, mice were pre-treated with anti-CD25 for depleting regulatory T cells (Tregs), and then administered with TSG. Liver functions and immunological alterations were analyzed to evaluate liver injury. RESULTS: Data showed that TSG induced liver damage, and immune cells infiltration in the liver tissues. FCM results showed that TSG could activate CD4+T and CD8+T in the liver. Results further confirmed that TSG notably up-regulated the levels of inflammatory cytokines including TNF-α, IFN-γ, IL-18, perforin and granzyme B in the liver tissues. Furthermore, based on transcriptomics profiles, some immune system-related pathways including leukocyte activation involved in inflammatory response, leukocyte cell-cell adhesion, regulation of interleukin-1 beta production, mononuclear cell migration, antigen processing and presentation were altered in TSG treated mice. CD8+T/CD4+T cells were also stimulated by TSG in vitro. Interestingly, increased proportion of Tregs was observed after TSG treatment in vitro and in vivo. Foxp3 and TGF-ß1 mRNA expressions were up-regulated in the liver tissues. Depletion of Tregs moderately enhanced TSG induced the secretion of inflammatory cytokines in serum. CONCLUSIONS: Our findings showed that TSG could trigger CD4+T and CD8+T cells proliferation, promote cytokines secretion, which revealed that adaptive immune response associated with the mild liver injury cause by TSG administration. Regulatory T cells (Tregs) mainly sustain immunological tolerance, and in this study, the progression of TSG induced liver injury was limited by Tregs. The results of our investigations allow us to preliminarily understand the mechanisms of PM related idiosyncratic hepatotoxicity.

Escitalopram population pharmacokinetics and remedial strategies based on CYP2C19 phenotype.

BACKGROUND AND PURPOSE: CYP2C19 is a key factor influencing escitalopram (SCIT) exposure. However, different studies reported various results. This study aims to develop a population pharmacokinetic (popPK) model characterizes the disposition of SCIT in the Chinese population. Based on the popPK model, the study simulates non-adherence scenarios and proposes remedial strategies to facilitate SCIT personalized therapy. METHODS: Nonlinear mixed-effects modeling using data from two Chinese bioequivalence studies was employed. Monte-Carlo simulation was used to explore non-adherence scenarios and propose remedial strategies based on the proportion of time within the therapeutic window. RESULTS: Results showed that a one-compartment model with transit absorption and linear elimination described the data well, CYP2C19 phenotypes and weight were identified as significant covariates impacting SCIT exposure. Patients were recommended to take the entire delayed dose immediately if the delay time was no >12 h, followed by the regular regimen at the next scheduled time. When there is one or two doses missed, taking a double dose immediately was recommended to the CYP2C19 intermediate and extensive population, and a 1.5-fold dose was recommended to the CYP2C19 poor metabolizers with the consideration of adverse effects. LIMITATION: All samples were derived from the homogenized Chinese healthy population for model building, which may pose certain constraints on the ability to identify significant covariates, such as age. CONCLUSION: The study highlights the importance of considering patient characteristics for personalized medication and offers a unique perspective on utilizing the popPK repository in precision dosing.

WGX50 mitigates doxorubicin-induced cardiotoxicity through inhibition of mitochondrial ROS and ferroptosis.

BACKGROUND: Doxorubicin (DOX)-induced cardiotoxicity (DIC) is a major impediment to its clinical application. It is indispensable to explore alternative treatment molecules or drugs for mitigating DIC. WGX50, an organic extract derived from Zanthoxylum bungeanum Maxim, has anti-inflammatory and antioxidant biological activity, however, its function and mechanism in DIC remain unclear. METHODS: We established DOX-induced cardiotoxicity models both in vitro and in vivo. Echocardiography and histological analyses were used to determine the severity of cardiac injury in mice. The myocardial damage markers cTnT, CK-MB, ANP, BNP, and ferroptosis associated indicators Fe2+, MDA, and GPX4 were measured using ELISA, RT-qPCR, and western blot assays. The morphology of mitochondria was investigated with a transmission electron microscope. The levels of mitochondrial membrane potential, mitochondrial ROS, and lipid ROS were detected using JC-1, MitoSOX™, and C11-BODIPY 581/591 probes. RESULTS: Our findings demonstrate that WGX50 protects DOX-induced cardiotoxicity via restraining mitochondrial ROS and ferroptosis. In vivo, WGX50 effectively relieves doxorubicin-induced cardiac dysfunction, cardiac injury, fibrosis, mitochondrial damage, and redox imbalance. In vitro, WGX50 preserves mitochondrial function by reducing the level of mitochondrial membrane potential and increasing mitochondrial ATP production. Furthermore, WGX50 reduces iron accumulation and mitochondrial ROS, increases GPX4 expression, and regulates lipid metabolism to inhibit DOX-induced ferroptosis. CONCLUSION: Taken together, WGX50 protects DOX-induced cardiotoxicity via mitochondrial ROS and the ferroptosis pathway, which provides novel insights for WGX50 as a promising drug candidate for cardioprotection.

Escitalopram Personalized Dosing: A Population Pharmacokinetics Repository Method.

Escitalopram (SCIT) represents a first-line antidepressant and antianxiety medication. Pharmacokinetic studies of SCIT have demonstrated considerable interindividual variability, emphasizing the need for personalized dosing. Accordingly, we aimed to create a repository of parametric population pharmacokinetic (PPK) models of SCIT to facilitate model-informed precision dosing. In November 2022, we searched PubMed, Embase, and Web of Science for published PPK models and identified eight models. All the structural models reported in the literature were either one- or two-compartment models. In order to investigate the variances in model performance, the parameters of all PPK models were derived from the literature published. A representative virtual population, characterized by an age of 30, a body weight of 70 kg, and a BMI of 23 kg/m2, was generated for the purpose of replicating these models. To accomplish this, the rxode2 package in the R programming language was employed. Subsequently, we compared simulated concentration-time profiles and evaluated the impact of covariates on clearance. The most significant covariates were CYP2C19 phenotype, weight, and age, indicating that dosing regimens should be tailored accordingly. Additionally, among Chinese psychiatric patients, SCIT showed nearly double the exposure compared to other populations, specifically when considering the same CYP2C19 population restriction, which is a knowledge gap that needs further investigation. Furthermore, this repository of parametric PPK models for SCIT has a wide range of potential applications, like design miss or delay dose remedy strategies and external PPK model validation.

Eucommia lignans alleviate the progression of diabetic nephropathy through mediating the AR/Nrf2/HO-1/AMPK axis in vivo and in vitro.

Lignans derived from Eucommia ulmoides Oliver (Eucommia lignans) inhibit the progression of inflammatory diseases, while their effect on the progression of diabetic nephropathy (DN) remained unclear. This work was designed to assess the function of Eucommia lignans in DN. The major constituents of Eucommia lignans were analyzed by UPLC-Q-TOF-MS/MS. The binding between Eucommia lignans and aldose reductase (AR) was predicted by molecular docking. Eucommia lignans (200, 100, and 50 mg·kg-1) were used in model animals to evaluate their renal function changes. Rat glomerular mesangial cells (HBZY-1) were transfected with sh-AR, sh-AMPK, and oe-AR in the presence of high glucose (HG) or HG combined with Eucommia lignans to evaluate whether Eucommia lignans affected HG-induced cell injury and mitochondrial dysfunction through the AR/Nrf2/HO-1/AMPK axis. Eucommia lignans significantly attenuated the progression of DN in vivo. Eucommia lignans notably reversed HG-induced upregulation of inflammatory cytokines and mitochondrial injury, while downregulating the levels of Cyto c, caspase 9, AR, and NOX4 in HBZY-1 cells. In contrast, HG-induced downregulation of Nrf2, HO-1 and p-AMPKα levels were abolished by Eucommia lignans. Meanwhile, knockdown of AR exerted similar therapeutic effect of Eucommia lignans on DN progression, and AR overexpression reversed the effect of Eucommia lignans. Eucommia lignans alleviated renal injury through the AR/Nrf2/HO-1/AMPK axis. Thus, these findings might provide evidence for the use of Eucommia lignans in treating DN.

Qing-Kai-Ling oral liquid alleviated pneumonia via regulation of intestinal flora and metabolites in rats.

Background: Qing-Kai-Ling (QKL) oral liquid, evolving from a classical Chinese formula known as An-Gong-Niu-Huang pills, is a well-established treatment for pneumonia with its mechanism remaining muddled. Studies have shown that the regulation of both intestinal flora and host-microbiota co-metabolism may contribute to preventing and treating pneumonia. The study aimed to investigate the potential mechanism by which QKL alleviates pneumonia from the perspective of 'microbiota-metabolites-host' interaction. Methods: We evaluated the therapeutic effects of QKL on lipopolysaccharide (LPS)-induced pneumonia rats. To explore the protective mechanism of QKL treatment, a multi-omics analysis that included 16S rDNA sequencing for disclosing the key intestinal flora, the fecal metabolome to discover the differential metabolites, and whole transcriptome sequencing of lung tissue to obtain the differentially expressed genes was carried out. Then, a Spearman correlation was employed to investigate the association between the intestinal flora, the fecal metabolome and inflammation-related indices. Results: The study demonstrated that pneumonia symptoms were significantly attenuated in QKL-treated rats, including decreased TNF-α, NO levels and increased SOD level. Furthermore, QKL was effective in alleviating pneumonia and provided protection equivalent to that of the positive drug dexamethasone. Compared with the Model group, QKL treatment significantly increased the richness and αlpha diversity of intestinal flora, and restored multiple intestinal genera (e.g., Bifidobacterium, Ruminococcus_torques_group, Dorea, Mucispirillum, and Staphylococcus) that were correlated with inflammation-related indices. Interestingly, the intestinal flora demonstrated a strong correlation with several metabolites impacted by QKL. Furthermore, metabolome and transcriptome analyses showed that enrichment of several host-microbiota co-metabolites [arachidonic acid, 8,11,14-eicosatrienoic acid, LysoPC (20:0/0:0), LysoPA (18:0e/0:0), cholic acid, 7-ketodeoxycholic acid and 12-ketodeoxycholic acid] levels and varying lung gene (Pla2g2a, Pla2g5, Alox12e, Cyp4a8, Ccl19, and Ccl21) expression were observed in the QKL group. Moreover, these metabolites and genes were involved in arachidonic acid metabolism and inflammation-related pathways. Conclusion: Our findings indicated that QKL could potentially modulate intestinal flora dysbiosis, improve host-microbiota co-metabolism dysregulation and regulate gene expression in the lungs, thereby mitigating LPS-induced pneumonia in rats. The study may provide new ideas for the clinical application and further development of QKL.

Gut microbiota affects sensitivity to immune-mediated isoniazid-induced liver injury.

Isoniazid (INH) is a highly effective single and/or combined first-line anti-tuberculosis (anti-TB) therapy drug, and the hepatotoxicity greatly limits its clinical application. INH-induced liver injury (INH-DILI) is a typical immune-mediated idiosyncratic drug-induced liver injury. Existing mechanisms including genetic variations in drug metabolism and immune responses cannot fully explain the differences in susceptibility and sensitivity to INH-DILI, suggesting that other factors may be involved. Accumulating evidence indicates that the development and severity of immune-mediated liver injury is related to gut microbiota. In this study, INH exposure caused liver damage, immune disregulation and microbiota profile alteration. Depletion of gut microbiota ameliorated INH-DILI, and improved INH-DILI-associated immune disorder and inflammatory response. Moreover, hepatotoxicity of INH was ameliorated by fecal microbiota transplantation (FMT) from INH-treated mice. Notably, Bifidobacterium abundance was significantly associated with transaminase levels. In conclusion, our results suggested that the effect of gut microbiota on INH-DILI was related to immunity, and the difference in INH-DILI sensitivity was related to the structure of gut microbiota. Changes in the structure of gut microbiota by continuous exposure of INH resulted in the tolerance to liver injury, and probiotics such as Bifidobacterium might play an important role in INH-DILI and its "adaptation" phenomenon. This work provides novel evidence for elucidating the underlying mechanism of difference in individual's response to INH-DILI and potential approach for intervening anti-TB drug liver injury by modulating gut microbiota.

["Component-target-efficacy" network analysis and experimental verification of Qingkailing Oral Preparation].

This study aims to explore the mechanism of Qingkailing(QKL) Oral Preparation's heat-clearing, detoxifying, mind-tranquilizing effects based on "component-target-efficacy" network. To be specific, the potential targets of the 23 major components in QKL Oral Preparation were predicted by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP) and SwissTargetPrediction. The target genes were obtained based on UniProt. OmicsBean and STRING 10 were used for Gene Ontology(GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment of the targets. Cytoscape 3.8.2 was employed for visualization and construction of "component-target-pathway-pharmacological effect-efficacy" network, followed by molecular docking between the 23 main active components and 15 key targets. Finally, the lipopolysaccharide(LPS)-induced RAW264.7 cells were adopted to verify the anti-inflammatory effect of six monomer components in QKL Oral Preparation. It was found that the 23 compounds affected 33 key signaling pathways through 236 related targets, such as arachidonic acid metabolism, tumor necrosis factor α(TNF-α) signaling pathway, inflammatory mediator regulation of TRP channels, cAMP signaling pathway, cGMP-PKG signaling pathway, Th17 cell differentiation, interleukin-17(IL-17) signaling pathway, neuroactive ligand-receptor intera-ction, calcium signaling pathway, and GABAergic synapse. They were involved in the anti-inflammation, immune regulation, antipyretic effect, and anti-convulsion of the prescription. The "component-target-pathway-pharmacological effect-efficacy" network of QKL Oral Preparation was constructed. Molecular docking showed that the main active components had high binding affinity to the key targets. In vitro cell experiment indicated that the six components in the prescription(hyodeoxycholic acid, baicalin, chlorogenic acid, isochlorogenic acid C, epigoitrin, geniposide) can reduce the expression of nitric oxide(NO), TNF-α, and interleukin-6(IL-6) in cell supernatant(P<0.05). Thus, the above six components may be the key pharmacodynamic substances of QKL Oral Preparation. The major components in QKL Oral Prescription, including hyodeoxycholic acid, baicalin, chlorogenic acid, isochlorogenic acid C, epigoitrin, geniposide, cholic acid, isochlorogenic acid A, and γ-aminobutyric acid, may interfere with multiple biological processes related to inflammation, immune regulation, fever, and convulsion by acting on the key protein targets such as IL-6, TNF, prostaglandin-endoperoxide synthase 2(PTGS2), arachidonate 5-lipoxygenase(ALOX5), vascular cell adhesion molecule 1(VCAM1), nitric oxide synthase 2(NOS2), prostaglandin E2 receptor EP2 subtype(PTGER2), gamma-aminobutyric acid receptor subunit alpha(GABRA), gamma-aminobutyric acid type B receptor subunit 1(GABBR1), and 4-aminobutyrate aminotransferase(ABAT). This study reveals the effective components and mechanism of QKL Oral Prescription.

Gut Microbiota Modulates the Protective Role of Ginsenoside Compound K Against Sodium Valproate-Induced Hepatotoxicity in Rat.

This study aimed to investigate the potential role of gut microbiota in the hepatotoxicity of sodium valproate (SVP) and the protective effect of ginsenoside compound K (G-CK) administration against SVP-induced hepatotoxicity in rats. Measurements of 16S rRNA showed that SVP supplementation led to a 140.749- and 248.900-fold increase in the relative abundance of Akkermansia muciniphila (A. muciniphila) and Bifidobacterium pseudolongum (B. pseudolongum), respectively (p < 0.05). The increase in A. muciniphila was almost completely reversed by G-CK treatment. The relative abundance of A. muciniphila was strongly positively correlated with aspartate transaminase (AST) and alanine aminotransferase (ALT) levels (r > 0.78, p < 0.05). The PICRUSt analysis showed that G-CK could inhibit the changes of seven pathways caused by SVP, of which four pathways, including the fatty acid biosynthesis, lipid biosynthesis, glycolysis/gluconeogenesis, and pyruvate metabolism, were found to be negatively correlated with AST and ALT levels (r ≥ 0.70, p < 0.01 or < 0.05). In addition, the glycolysis/gluconeogenesis and pyruvate metabolism were negatively correlated with the relative abundance of A. muciniphila (r > 0.65, p < 0.01 or < 0.05). This alteration of the gut microbiota composition that resulted in observed changes to the glycolysis/gluconeogenesis and pyruvate metabolism may be involved in both the hepatotoxicity of SVP and the protective effect of G-CK administration against SVP-induced hepatotoxicity. Our study provides new evidence linking the gut microbiota with SVP-induced hepatotoxicity.

A novel solid phase extraction sample preparation method for sensitively determining doxepin and N-nordoxepin in human plasma and its application in a bioequivalence study in healthy Chinese volunteers.

Doxepin, a tricyclic antidepressant (TCA), is widely used in the treatment of depressive disorder and anxiety. There are some liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods that have been reported for detecting doxepin, but inadequacies in recovery and cumbersome sample preparation obstruct the pharmacokinetics study. Therefore, we aimed to develop and validate a rapid sample preparation method based on solid-phase extraction (SPE) for the precise quantification of doxepin and its metabolites. Chromatography separation was performed on a Waters ACQUITY UPLC BEH C18 column (2.1 × 100 mm, 1.7 µm) and a mobile phase consisting of 70% of mobile phase A (0.1% formic acid and 10 mM ammonium formate) and 30% mobile phase B (0.1% formic acid in acetonitrile) at a flow rate of 0.4 mL min-1 in the step gradient elution conditions. The lower limits of quantification for doxepin and N-nordoxepin were 4 pg mL-1 and 2 pg mL-1, respectively. This method was validated with satisfactory results including good precision and accuracy. A rapid, sensitive, and specific LC-MS/MS method was developed and validated for the determination of doxepin in human plasma. This method could be applied for determining doxepin and N-nordoxepin concentrations in plasma that could be useful for bioequivalence study of 3 mg doxepin.

Development and evaluation of a new test kit for determination of immunosuppressants in blood by UHPLC-MS/MS.

In this study, we have developed and validated a new test kit that applied pure solvents instead of blood samples for determination of immunosuppressant drugs in blood by ultra high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS). We have used commercially available quality control samples to verify this new test kit, and the results showed that the performance of our new kit was comparable with commercially available kits by immunoassays. The new test kit is pure solvent-based, which saves the cost and can be directly loaded without pre-treatment, thus shortening the detection time. The agreement between pure solvent-based kit and blood-based kit was also evaluated by Bland-Altman plot and two-tailed Student's T-test. For 97.08% of the 137 Tacrolimus clinical samples, the concentration difference between these two kits was laid within 20% of the mean concentration. The concentrations of 12 cyclosporine samples and 15 sirolimus samples obtained by both kits showed no significant difference evaluated by the two-tailed Student's T-test. These results further demonstrated the good agreement between these two types of test kits. Meanwhile, our pure solvent-based test kit could be stored stably for 14 weeks at -30 °C. Therefore, the newly developed pure solvent-based test kit can be used for detecting the whole blood immunosuppressant concentration and therapeutic drug monitoring of immunosuppressants.

The NPC1L1 Gene Exerts a Notable Impact on the Reduction of Low-Density Lipoprotein Cholesterol in Response to Hyzetimibe: A Factorial-Designed Clinical Trial.

Background: Hyzetimibe is a novel inhibitor of cholesterol that specifically targets the NPC1L1 gene. Significant inter-individual variability suggests the existence of an abundance of poor responders and non-responders. In addition, the current literature is inconsistent and controversial regarding the potential impact of the Niemann-Pick C1-Like 1 (NPC1L1) gene on low-density lipoprotein cholesterol (LDL-C) reduction. In light of these concerns, we performed a high-quality clinical trial to investigate the specific characteristics of NPC1L1 gene variation on LDL-C reduction. Methods: This was a multicenter, randomized, double-blind, placebo-controlled, clinical trial with a factorial design. Qualified patients were randomly assigned to one of six treatments: placebo, hyzetimibe (10 or 20 mg), atorvastatin, and atorvastatin plus hyzetimibe (10 or 20 mg). Fasting blood samples were collected and genotyped, and the concentrations of LDL-C and the targeted drug trough were determined to investigate the association between the NPC1L1 gene expression and the reduction of LDL-C. Results: In total, 727 individuals were initially recruited; of these, 444 were eligible to begin the trial. We identified one SNP (g1679C > G) that exerted significantly different impacts on LDL-C levels. As monotherapy, CC carriers experienced significantly higher reductions in the mean LDL-C (-23.99%) than either the GG (-16.45%, p < 0.01) or GC (-13.02%, p < 0.01) carriers in the hyzetimibe (20 mg) group. In contrast, when co-administered with atorvastatin, GC carriers experienced greater LDL-C reduction than non-GC carriers (-52.23% vs. -45.03%) in the hyzetimibe (20 mg) plus atorvastatin group. Furthermore, the proportions of individuals experiencing a reduction in LDL-C by >50% increased as the dose of hyzetimibe increased from 16.1% to 65.4%. Conclusion: The g1679C > G SNP in the NPC1L1 gene is critical and exerts a differential impact on the response to hyzetimibe treatment. Heterozygotic patients respond with poor efficacy when treated by monotherapy but show good responses in terms of LDL-C reduction when hyzetimibe was co-administered with atorvastatin. To treat hypercholesterolemia in a precise manner with hyzetimibe, it is necessary to identify genotype patients for the g1679C > G SNP. We also highlight the potential necessity for identifying the appropriate subjects to be treated with ezetimibe. Clinical Trial Registration: [https://clinicaltrials.gov/], identifier [CTR20150351].

Targeting PLA2G16, a lipid metabolism gene, by Ginsenoside Compound K to suppress the malignant progression of colorectal cancer.

Introduction: Colorectal cancer (CRC) is a common malignant tumor with a high global incidence, metastasis rate and low cure rate. Changes in lipid metabolism-related genes can affect the occurrence and development of CRC, and may be a potential therapeutic target for CRC. Therefore, starting from lipid metabolism-related genes to find natural medicines for tumor treatment may become a new direction in CRC research. Objectives: This study aimed to investigate the effect of PLA2G16, a key gene involved in lipid metabolism, on the biological function of CRC, and whether the anti-CRC effect of GCK is related to PLA2G16. Methods: To explore the role of PLA2G16 in CRC in vitro and in vivo, we performed cell proliferation, migration, invasion and nude mice tumorigenesis assays. As for the mechanism, we designed RNA-seq analysis and verified by western blotting and immunofluorescence experiments. Subsequently, we found the anti-CRC effect of GCK is related to PLA2G16 through western blotting and rescue experiments. Results: We showed that PLA2G16 was significantly higher in CRC tissues than the adjacent normal appearing tissues, and high PLA2G16 expression correlates with unfavorable prognosis of CRC patients. Further, PLA2G16 promoted the malignant progression of CRC by inhibiting the Hippo signaling pathway determined by RNA-seq analysis, and GCK exerted anti-CRC effects by inhibiting the protein expression of PLA2G16 in vitro and in vivo. Conclusion: Our results suggested that PLA2G16 promote the malignant progression of CRC by inhibiting the Hippo signaling pathway and the anti-CRC effect of GCK is through inhibiting the protein expression of PLA2G16.

Formulation and development of novel control release transdermal patches of carvedilol to improve bioavailability for the treatment of heart failure.

The main aim of this study is to optimize and evaluate transdermal patch of Carvedilol by the use of different polymer and different permeation enhancers which help to release drug in controlled action and thereby increase the bioavailability of the drug. Main objective was to avoid first pass metabolism of Carvedilol. Transdermal patches were developed by solvent evaporation method. The combination of Eudragit RS-100 as rate controlling polymer and Span 80 as a permeation enhancer was found to be ideal formulation (Formulation F7) with maximum drug release i.e. 100.29 ± 0.44 % within 12 h. Formulation F7 showed maximum bioavailability and showed maximum drop of BP at 6 h. From this study the conclusion was, transdermal patch of Carvedilol which contains Eudragit RS-100 polymer and Span 80 as penetration enhancer produced sustained and continued drug release.

The Immunological Mechanisms and Immune-Based Biomarkers of Drug-Induced Liver Injury.

Drug-induced liver injury (DILI) has become one of the major challenges of drug safety all over the word. So far, about 1,100 commonly used drugs including the medications used regularly, herbal and/or dietary supplements, have been reported to induce liver injury. Moreover, DILI is the main cause of the interruption of new drugs development and drugs withdrawn from the pharmaceutical market. Acute DILI may evolve into chronic DILI or even worse, commonly lead to life-threatening acute liver failure in Western countries. It is generally considered to have a close relationship to genetic factors, environmental risk factors, and host immunity, through the drug itself or its metabolites, leading to a series of cellular events, such as haptenization and immune response activation. Despite many researches on DILI, the specific biomarkers about it are not applicable to clinical diagnosis, which still relies on the exclusion of other causes of liver disease in clinical practice as before. Additionally, circumstantial evidence has suggested that DILI is mediated by the immune system. Here, we review the underlying mechanisms of the immune response to DILI and provide guidance for the future development of biomarkers for the early detection, prediction, and diagnosis of DILI.

CYP2C19 Genotyping May Provide a Better Treatment Strategy when Administering Escitalopram in Chinese Population.

Depression disorder is one of the most serious mental illnesses in the world. Escitalopram is the essential first-line medication for depression disorder. It is the substrate of hepatic cytochrome P450 (CYP) enzyme CYP2C19 with high polymorphism. The effect of CYP2C19 on pharmacokinetics and pharmacodynamics on Caucasian population has been studied. The Clinical Pharmacogenetics Implementation Consortium Guideline provides dosing recommendations for escitalopram on CYP2C19 genotypes on the basis of the studies on Caucasian population. However, the gene frequency of the alleles of CYP2C19 showed racial differences between Chinese and Caucasian populations. Representatively, the frequency of the *2 and *3 allele, which were considered as poor metabolizer, has been shown to be three times higher in Chinese than in Caucasians. In addition, the environments might also lead to different degrees of impacts on genotypes. Therefore, the guidelines based on the Caucasians may not be applicable to the Chinese, which induced the establishment of a guideline in China. It is necessary to provide the evidence of individual treatment of escitalopram in Chinese by studying the effect of CYP2C19 genotypes on the pharmacokinetics parameters and steady-state concentration on Chinese. In this study, single-center, randomized, open-label, two-period, two-treatment crossover studies were performed. Ninety healthy Chinese subjects finished the trials, and they were included in the statistical analysis. The pharmacokinetics characteristics of different genotypes in Chinese were obtained. The results indicate that the poor metabolizer had higher exposure, and increased half-life than the extensive metabolizer and intermediate metabolite. The prediction of steady-state concentration based on the single dose trial on escitalopram shows that the poor metabolizer might have a higher steady-state concentration than the extensive metabolizer and intermediate metabolite in Chinese. The results indicate that the genetic testing before medication and the adjustment of escitalopram in the poor metabolizer should be considered in the clinical treatments in Chinese. The results provide the evidence of individual treatment of escitalopram in Chinese, which will be beneficial for the safer and more effective application of escitalopram in the Chinese population. Clinical Trial Registration: identifier ChiCTR1900027226.

The efficacy and toxicity of antineoplastic antimetabolites: Role of gut microbiota.

The incidence and mortality of cancer are rapidly growing all over the world. Nowadays, antineoplastic antimetabolites still play a key role in the chemotherapy of cancer. However, the interindividual variations in the efficacy and toxicity of antineoplastic antimetabolites are nonnegligible challenges to their clinical applications. Although many studies have focused on genetic variation, the reasons for these interindividual variations have still not been fully understood. Gut microbiota is reported to be associated with the efficacy and toxicity of antineoplastic antimetabolites. In this review, we summarize the interaction of antineoplastic antimetabolites on gut microbiota and the influences of shifted gut microbiota profiles on the efficacy and toxicity of antineoplastic antimetabolites. The factors affecting the efficacy and toxicity of antineoplastic antimetabolites via gut microbiota are also discussed. In addition, we present our viewpoints that regulating the gut microbiota may increase the efficacy and decrease the toxicity of antineoplastic antimetabolites. This will help us better understand the new mechanism via gut microbiota and promote individualized use of antineoplastic antimetabolites.

Trimethylamine N-Oxide Exacerbates Renal Inflammation and Fibrosis in Rats With Diabetic Kidney Disease.

The gut microbiota plays a pivotal role in the onset and development of diabetes and its complications. Trimethylamine N-oxide (TMAO), a gut microbiota-dependent metabolite of certain nutrients, is associated with type 2 diabetes and its complications. Diabetic kidney disease (DKD) is one of the most serious microvascular complications. However, whether TMAO accelerates the development of DKD remains unclear. We tested the hypothesis that TMAO accelerates the development of DKD. A high-fat diet/low-dose streptozotocin-induced diabetes rat model was established, with or without TMAO in the rats' drinking water. Compared to the normal rats, the DKD rats showed significantly higher plasma TMAO levels at the end of the study. TMAO treatment not only exacerbated the kidney dysfunction of the DKD rats, but also renal fibrosis. Furthermore, TMAO treatment activated the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome and resulted in the release of interleukin (IL)-1ß and IL-18 to accelerate renal inflammation. These results suggested that TMAO aggravated renal inflammation and fibrosis in the DKD rats, which provides a new perspective to understand the pathogenesis of DKD and a potential novel target for preventing the progression of DKD.