Effect of the area under the curve of carboplatin dosage on therapeutic efficacy and safety in Chinese patients with epithelial ovarian cancer / 西安交通大学学报(医学版)

【Objective】 To retrospectively analyze the average carboplatin dosage and calculate the area under the curve (AUC) using the Calvert formula in first-line chemotherapy in patients with epithelial ovarian cancer in The First Affiliated Hospital of Xi’an Jiaotong University so as to evaluate the effect of the AUC difference in the Chinese population on therapeutic efficacy and safety. 【Methods】 We enrolled patients who underwent first-line chemotherapy with paclitaxel and carboplatin 3-week regimen in our hospital from January 1, 2012 to January 1, 2022. According to the median of AUC, the patients were divided into high-dose group and low-dose group. The overall response rate (ORR), disease control rate (DCR), progression free survival (PFS), overall survival (OS), and the incidence of adverse events (AEs) were compared. 【Results】 A total of 153 patients were enrolled in this study and the median AUC of carboplatin was 3.981 (range 2.314-5.446). Only 10.46% patients (16/153) had an AUC above 5. There were 77 patients with the AUC0.05). The ORR in the low-dose group and the high-dose group was 59.74% and 57.89%, respectively, and the DCR was 87.01% and 85.53%, respectively. The median PFS of the two groups was 14 and 15.5 months, respectively, and the median OS was 50 and 55 months, respectively. None of the above outcomes were statistically different between the two groups (P>0.05). The two groups showed significant differences in the incidence of anemia, neutropenia, and thrombocytopenia (P<0.05). The incidence of nausea and vomiting, grade 1-2 diarrhea or constipation, and grade 1-2 fever showed significant differences (P<0.05). In addition, the incidence of dose limiting toxicity (DLT), including grade 4 thrombocytopenia and febrile neutropenia (FN), was significantly increased in the high-dose group (P<0.05). 【Conclusion】 Compared with the recommended AUC 5-6 of carboplatin abroad, the actual carboplatin dosage in the first-line chemotherapy for patients with epithelial ovarian cancer was generally insufficient in our hospital. There was no difference in therapeutic efficacy between the patients with AUC<4 and AUC≥4. However, considering the increased risk of some AEs and DLT in the high-dose group, it is not recommended to increase the carboplatin AUC blindly.

Chiral mesoporous silica nano-screws as an efficient biomimetic oral drug delivery platform through multiple topological mechanisms

In the microscale, bacteria with helical body shapes have been reported to yield advantages in many bio-processes. In the human society, there are also wisdoms in knowing how to recognize and make use of helical shapes with multi-functionality. Herein, we designed atypical chiral mesoporous silica nano-screws (CMSWs) with ideal topological structures (e.g., small section area, relative rough surface, screw-like body with three-dimension chirality) and demonstrated that CMSWs displayed enhanced bio-adhesion, mucus-penetration and cellular uptake (contributed by the macropinocytosis and caveolae-mediated endocytosis pathways) abilities compared to the chiral mesoporous silica nanospheres (CMSSs) and chiral mesoporous silica nanorods (CMSRs), achieving extended retention duration in the gastrointestinal (GI) tract and superior adsorption in the blood circulation (up to 2.61- and 5.65-times in AUC). After doxorubicin (DOX) loading into CMSs, DOX@CMSWs exhibited controlled drug release manners with pH responsiveness in vitro. Orally administered DOX@CMSWs could efficiently overcome the intestinal epithelium barrier (IEB), and resulted in satisfactory oral bioavailability of DOX (up to 348%). CMSWs were also proved to exhibit good biocompatibility and unique biodegradability. These findings displayed superior ability of CMSWs in crossing IEB through multiple topological mechanisms and would provide useful information on the rational design of nano-drug delivery systems.

An update on oral drug delivery

Orally administered drug entities have to survive the harsh gastrointestinal environment, penetrate the enteric epithelia and circumvent hepatic metabolism before reaching the systemic circulation. Whereas the gastrointestinal stability can be well maintained by taking proper measures, hepatic metabolism presents as a formidable barrier to drugs suffering from first-pass metabolism. The pharmaceutical academia and industries are seeking alternative pathways for drug transport to circumvent problems associated with the portal pathway. Intestinal lymphatic transport is emerging as a promising pathway to this end. In this review, we intend to provide an updated overview on the rationale, strategies, factors and applications involved in intestinal lymphatic transport. There are mainly two pathways for peroral lymphatic transport-the chylomicron and the microfold cell pathways. The underlying mechanisms are being unraveled gradually and nowadays witness increasing research input and applications.

Intranasal temperature-sensitive hydrogels of cannabidiol inclusion complex for the treatment of post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) is a psychiatric disease that seriously affects brain function. Currently, selective serotonin reuptake inhibitors (SSRIs) are used to treat PTSD clinically but have decreased efficiency and increased side effects. In this study, nasal cannabidiol inclusion complex temperature-sensitive hydrogels (CBD TSGs) were prepared and evaluated to treat PTSD. Mice model of PTSD was established with conditional fear box. CBD TSGs could significantly improve the spontaneous behavior, exploratory spirit and alleviate tension in open field box, relieve anxiety and tension in elevated plus maze, and reduce the freezing time. Hematoxylin and eosin and c-FOS immunohistochemistry slides showed that the main injured brain areas in PTSD were the prefrontal cortex, amygdala, and hippocampus CA1. CBD TSGs could reduce the level of tumor necrosis factor-

AncPhore: A versatile tool for anchor pharmacophore steered drug discovery with applications in discovery of new inhibitors targeting metallo-

We herein describe AncPhore, a versatile tool for drug discovery, which is characterized by pharmacophore feature analysis and anchor pharmacophore (

Notoginsenoside Ft1 acts as a TGR5 agonist but FXR antagonist to alleviate high fat diet-induced obesity and insulin resistance in mice

Obesity and its associated complications are highly related to a current public health crisis around the world. A growing body of evidence has indicated that G-protein coupled bile acid (BA) receptor TGR5 (also known as Gpbar-1) is a potential drug target to treat obesity and associated metabolic disorders. We have identified notoginsenoside Ft1 (Ft1) from

Application of AUC/MIC as the therapeutic drug monitoring target of vancomycin in patients with severe infections of multi drug resistant gram positive bacteria / 中国临床药理学与治疗学

AIM: To discuss the application and clinical significance of the ratio of area under the curve over 24 hours to minimum inhibitory concentration (AUC

Escape from abluminal LRP1-mediated clearance for boosted nanoparticle brain delivery and brain metastasis treatment

Breast cancer brain metastases (BCBMs) are one of the most difficult malignancies to treat due to the intracranial location and multifocal growth. Chemotherapy and molecular targeted therapy are extremely ineffective for BCBMs due to the inept brain accumulation because of the formidable blood‒brain barrier (BBB). Accumulation studies prove that low density lipoprotein receptor-related protein 1 (LRP1) is promising target for BBB transcytosis. However, as the primary clearance receptor for amyloid beta and tissue plasminogen activator, LRP1 at abluminal side of BBB can clear LRP1-targeting therapeutics. Matrix metalloproteinase-1 (MMP1) is highly enriched in metastatic niche to promote growth of BCBMs. Herein, it is reported that nanoparticles (NPs-K-s-A) tethered with MMP1-sensitive fusion peptide containing HER2-targeting K and LRP1-targeting angiopep-2 (A), can surmount the BBB and escape LRP1-mediated clearance in metastatic niche. NPs-K-s-A revealed infinitely superior brain accumulation to angiopep-2-decorated NPs-A in BCBMs bearing mice, while comparable brain accumulation in normal mice. The delivered doxorubicin and lapatinib synergistically inhibit BCBMs growth and prolongs survival of mice bearing BCBMs. Due to the efficient BBB penetration, special and remarkable clearance escape, and facilitated therapeutic outcome, the fusion peptide-based drug delivery strategy may serve as a potential approach for clinical management of BCBMs.

Isorhapontigenin protects against doxorubicin-induced cardiotoxicity

As an effective anticancer drug, the clinical limitation of doxorubicin (Dox) is the time- and dose-dependent cardiotoxicity. Yes-associated protein 1 (YAP1) interacts with transcription factor TEA domain 1 (TEAD1) and plays an important role in cell proliferation and survival. However, the role of YAP1 in Dox-induced cardiomyopathy has not been reported. In this study, the expression of YAP1 was reduced in clinical human failing hearts with dilated cardiomyopathy and Dox-induced

A facile and universal method to achieve liposomal remote loading of non-ionizable drugs with outstanding safety profiles and therapeutic effect

Liposomes have made remarkable achievements as drug delivery vehicles in the clinic. Liposomal products mostly benefited from remote drug loading techniques that succeeded in amphipathic and/or ionizable drugs, but seemed impracticable for nonionizable and poorly water-soluble therapeutic agents, thereby impeding extensive promising drugs to hitchhike liposomal vehicles for disease therapy. In this study, a series of weak acid drug derivatives were designed by a simplistic one step synthesis, which could be remotely loaded into liposomes by pH gradient method. Cabazitaxel (CTX) weak acid derivatives were selected to evaluate regarding its safety profiles, pharmacodynamics, and pharmacokinetics. CTX weak acid derivative liposomes were superior to Jevtana® in terms of safety profiles, including systemic toxicity, hematological toxicity, and potential central nerve toxicity. Specifically, it was demonstrated that liposomes had capacity to weaken potential toxicity of CTX on cortex and hippocampus neurons. Significant advantages of CTX weak acid derivative-loaded liposomes were achieved in prostate cancer and metastatic cancer therapy resulting from higher safety and elevated tolerated doses.

Dosificación empírica de vancomicina en neonatos: relación entre recomendación de dosis iniciales y relación área bajo la curva en 24 h/concentración inhibitoria mínima / Empiric vancomycin dosing in neonates: relationship between initial dose and 24 h area under the curve/minimum inhibitory concentration ratio

Resumen Introducción: Vancomicina es un antimicrobiano ampliamente utilizado para infecciones por Staphylococcus coagulasa negativa en neonatos; sin embargo, no existe claridad sobre la dosis empírica que asegure su eficacia terapéutica. Objetivo: Evaluar la relación entre las dosis iniciales de vancomicina utilizadas en una Unidad de Cuidado Intensivo Neonatal (UCIN) con la eventualidad de alcanzar el objetivo terapéutico de área bajo la curva sobre concentración inhibitoria mínima (ABC/CIM) mayor a 400 µg/h/mL. Materiales y Método: Estudio descriptivo y retrospectivo, realizado entre febrero 2016 y marzo 2018. Se incluyeron neonatos en tratamiento con vancomicina por sospecha/confirmación de infección por cocáceas grampositivas y medición de concentraciones plasmáticas de vancomicina al inicio del tratamiento. La probabilidad de alcanzar el objetivo terapéutico se evaluó mediante re-muestreo de valores de ABC y CIM. Resultados: Se incluyeron 38 pacientes con 49 concentraciones plasmáticas de vancomicina. Los aislados microbiológicos se confirmaron en 94,7% de los pacientes (n = 36). Los valores de ABC/CIM en dos grupos (según niveles valle de vancomicina < 10 µg/mL y ≥ 10 µg/mL), fueron de una mediana de 327 (IQ 25-75 = 174-395) y 494 (IQ 25-75 = 318-631), respectivamente (p = 0,035). Las dosis empíricas utilizadas logran logran un objetivo terapéutico (ABC/CIM > 400) de sólo 47,7% considerando CIMs en nuestra institución. Conclusiones: Teniendo en cuenta las sensibilidades institucionales, no es posible asegurar alcanzar ABC/CIM > 400 µg/h/mL. Se debe seguir investigando para replantear las actuales estrategias de dosificación y así determinar la más apropiada para neonatos.

Abstract Background: Vancomycin is used for treating coagulase-negative staphylococcus infections in neonates. However, concerns about the appropriate empirical dosing required for optimal efficacy, still remain. Aim: To assess the relationship between the initial doses of vancomycin used in a Neonatal Intensive Care Unit (NICU) with the possibility of achieving therapeutic target of AUC024h/MIC > 400 µg/h/mL. Methods: Retrospective and descriptive study carried out between February 2016 and March 2018. All neonates treated with vancomycin for suspected/proven Gram-positive infection and with at least one trough serum concentration level were included. Probability of target attainment (PTA) was evaluated through resampling of AUC and MIC values. Results: Final dataset included 38 patients and 49 trough vancomycin levels; 94.7% of these cases (n = 36) were confirmed Gram-positive infections. The median AUC/MIC values for the trough values vancomycin < 10 µg/mL group and for the ≥ 10 µg/mL group were 327 (IQR 174-395) and 494 (IQR 318-631) respectively (p = 0.035). Current empirical dosing strategy has a 47.7% PTA (AUC/MIC > 400) when taking institutional MICs into account. Conclusions: It is not possible to assure achieving a AUC/MIC > 400 µg/h/mL when considering institutional sensibilities. Current empiric dosing strategies should be reconsidered and further investigation needs to be done to help determine the appropriate empirical dosing required for optimal efficacy in neonates.

Logistic regression combined with ROC curve model to predict risk of critically ill-patients with COVID-19 / 中草药

Objective: To build a model to predict critically ill-patients with coronavirus disease 2019 (COVID-19), and provide a new idea for the rapid identification of clinical progression in the early stage of critically ill-patients. Methods: A retrospective analysis of the general data of 152 general patients and 323 critically ill-patients diagnosed with COVID-19 from Jan 17th, 2020 to Feb 25th, 2020 in Wuhan Third Hospital was carried out; At the same time, the differences in fever, blood routine, liver and kidney function, coagulation function, C-reactive protein (CRP), and nucleic acid reagent testing results from the day of admission were statistically analyzed. Factors with statistical significance were included in a multivariate logistic regression analysis to obtain independent relevant factors that affect the critical ill-patients with COVID-19. Then a prediction model was built based on these factors and its accuracy was evaluated by the receiver operating characteristic (ROC) curve. Results: The sensitivities of age, fever, neutrophil ratio, lymphocyte ratio, serum creatinine (Scr) and combined diagnosis were 0.664, 0.671, 0.607, 0.669, 0.302 and 0.710, respectively; The specificities were 0.669, 0.585, 0.795, 0.685, 0.895 and 0.802, respectively; The area under the curve (AUC) were 0.725, 0.628, 0.721, 0.681, 0.590 and 0.795, respectively; The AUC of combined diagnosis was higher than that of single diagnosis (P < 0.05). Conclusion: The logistic regression and combined with ROC curve model based on multi-factors, including age, fever status, neutrophil ratio, lymphocyte ratio, and Scr, can play a good role in predicting the occurrence of critically ill-patients with COVID-19, which is worthy of further promotion and application.

Comparison of the calculation approaches of AUC in non-compartment model pharmacokinetics / 中国临床药理学与治疗学

AIM: To study the ways of calculating area under the plasma concentration-time curve (AUC) in non-compartment model pharmacokinetics by comparing the accuracy & precision of every method. METHODS: Three methods were used to calculate the area under 0-T curve (AUC

Design, synthesis and pharmacological evaluation of 4-(3-chloro-4-(3-cyclopropylthioureido)-2-fluorophenoxy)-7-methoxyquinoline-6-carboxamide (WXFL-152): a novel triple angiokinase inhibitor for cancer therapy

Angiokinases, such as vascular endothelial-, fibroblast- and platelet-derived growth factor receptors (VEGFRs, FGFRs and PDGFRs) play crucial roles in tumor angiogenesis. Anti-angiogenesis therapy using multi-angiokinase inhibitor has achieved great success in recent years. In this study, we presented the design, synthesis, target identification, molecular mechanism, pharmacodynamics (PD) and pharmacokinetics (PK) research of a novel triple-angiokinase inhibitor WXFL-152. WXFL-152, identified from a series of 4-oxyquinoline derivatives based on a structure-activity relationship study, inhibited the proliferation of vascular endothelial cells (ECs) and pericytes by blocking the angiokinase signals VEGF/VEGFR2, FGF/FGFRs and PDGF/PDGFR simultaneously . Significant anticancer effects of WXFL-152 were confirmed in multiple preclinical tumor xenograft models, including a patient-derived tumor xenograft (PDX) model. Pharmacokinetic studies of WXFL-152 demonstrated high favourable bioavailability with single-dose and continuous multi-dose by oral administration in rats and beagles. In conclusion, WXFL-152, which is currently in phase Ib clinical trials, is a novel and effective triple-angiokinase inhibitor with clear PD and PK in tumor therapy.

Design, synthesis, and biological evaluation of novel tetrahydroprotoberberine derivatives (THPBs) as proprotein convertase subtilisin/kexin type 9 (PCSK9) modulators for the treatment of hyperlipidemia

Proprotein convertase subtilisin/kexin type 9 (PCSK9) modulators may attenuate PCSK9-induced low-density lipoprotein receptor (LDLR) degradation in lysosome and promote the clearance of circulating low-density lipoprotein cholesterol (LDL-C). A novel series of tetrahydroprotoberberine derivatives (THPBs) were designed, synthesized, and evaluated as PCSK9 modulators for the treatment of hyperlipidemia. Among them, eight compounds exhibited excellent activities in downregulating hepatic PCSK9 expression better than berberine in HepG2 cells. In addition, five compounds , , , ()-, and ()- showed better performance in the low-density lipoprotein, labeled with 1,1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanine perchlorate (DiI-LDL) uptake assay, compared with berberine at the same concentration. Compound , selected for evaluation, demonstrated significant reductions of total cholesterol (TC) and LDL-C in hyperlipidemic hamsters with a good pharmacokinetic profile. Further exploring of the lipid-lowering mechanism showed that compound promoted hepatic LDLR expression in a dose-dependent manner in HepG2 cells. Additional results of human related gene (hERG) inhibition assay indicated the potential druggability for compound , which is a promising lead compound for the development of PCSK9 modulator for the treatment of hyperlipidemia.

Association between Serum Uric Acid and Metabolic Syndrome in Koreans

Advances in coamorphous drug delivery systems

In recent years, the coamorphous drug delivery system has been established as a promising formulation approach for delivering poorly water-soluble drugs. The coamorphous solid is a single-phase system containing an active pharmaceutical ingredient (API) and other low molecular weight molecules that might be pharmacologically relevant APIs or excipients. These formulations exhibit considerable advantages over neat crystalline or amorphous material, including improved physical stability, dissolution profiles, and potentially enhanced therapeutic efficacy. This review provides a comprehensive overview of coamorphous drug delivery systems from the perspectives of preparation, physicochemical characteristics, physical stability, and performance. Furthermore, the challenges and strategies in developing robust coamorphous drug products of high quality and performance are briefly discussed.

Adapting liposomes for oral drug delivery

Liposomes mimic natural cell membranes and have long been investigated as drug carriers due to excellent entrapment capacity, biocompatibility and safety. Despite the success of parenteral liposomes, oral delivery of liposomes is impeded by various barriers such as instability in the gastrointestinal tract, difficulties in crossing biomembranes, and mass production problems. By modulating the compositions of the lipid bilayers and adding polymers or ligands, both the stability and permeability of liposomes can be greatly improved for oral drug delivery. This review provides an overview of the challenges and current approaches toward the oral delivery of liposomes.

Pharmacometabolomic prediction of individual differences of gastrointestinal toxicity complicating myelosuppression in rats induced by irinotecan

Pharmacometabolomics has been already successfully used in toxicity prediction for one specific adverse effect. However in clinical practice, two or more different toxicities are always accompanied with each other, which puts forward new challenges for pharmacometabolomics. Gastrointestinal toxicity and myelosuppression are two major adverse effects induced by Irinotecan (CPT-11), and often show large individual differences. In the current study, a pharmacometabolomic study was performed to screen the exclusive biomarkers in predose serums which could predict late-onset diarrhea and myelosuppression of CPT-11 simultaneously. The severity and sensitivity differences in gastrointestinal toxicity and myelosuppression were judged by delayed-onset diarrhea symptoms, histopathology examination, relative cytokines and blood cell counts. Mass spectrometry-based non-targeted and targeted metabolomics were conducted in sequence to dissect metabolite signatures in predose serums. Eventually, two groups of metabolites were screened out as predictors for individual differences in late-onset diarrhea and myelosuppression using binary logistic regression, respectively. This result was compared with existing predictors and validated by another independent external validation set. Our study indicates the prediction of toxicity could be possible upon predose metabolic profile. Pharmacometabolomics can be a potentially useful tool for complicating toxicity prediction. Our findings also provide a new insight into CPT-11 precision medicine.

Transformative hyaluronic acid-based active targeting supramolecular nanoplatform improves long circulation and enhances cellular uptake in cancer therapy

Hyaluronic acid (HA) is a natural ligand of tumor-targeted drug delivery systems (DDS) due to the relevant CD44 receptor overexpressed on tumor cell membranes. However, other HA receptors (HARE and LYVE-1) are also overexpressing in the reticuloendothelial system (RES). Therefore, polyethylene glycol (PEG) modification of HA-based DDS is necessary to reduce RES capture. Unfortunately, pegylation remarkably inhibits tumor cellular uptake and endosomal escapement, significantly compromising the antitumor efficacy. Herein, we developed a Dox-loaded HA-based transformable supramolecular nanoplatform (Dox/HCVBP) to overcome this dilemma. Dox/HCVBP contains a tumor extracellular acidity-sensitive detachable PEG shell achieved by a benzoic imine linkage. The and investigations further demonstrated that Dox/HCVBP could be in a "stealth" state at blood stream for a long circulation time due to the buried HA ligands and the minimized nonspecific interaction by PEG shell. However, it could transform into a "recognition" state under the tumor acidic microenvironment for efficient tumor cellular uptake due to the direct exposure of active targeting ligand HA following PEG shell detachment. Such a transformative concept provides a promising strategy to resolve the dilemma of natural ligand-based DDS with conflicting two processes of tumor cellular uptake and nonspecific biodistribution.