Pharmacokinetic Characteristics of Siponimod in Healthy Volunteers and Patients With Multiple Sclerosis: Analyses of Published Clinical Trials.

Objectives: This study aimed to investigate the pharmacokinetic characteristics of siponimod in healthy volunteers and patients with MS based on aggregated data from published clinical trials, and to explore the factors influencing siponimod exposure. Methods: A total of 476 siponimod plasma concentrations aggregated from 28 dosage groups (corresponding to 294 healthy volunteers and 207 patients with MS) were collected from published clinical trials. Population pharmacokinetic (PPK) analysis was performed using a nonlinear, mixed-effect modeling approach. The pharmacokinetic properties of siponimod in healthy volunteers and patients with MS were compared, and the influence of covariates on siponimod exposure was evaluated using both PPK analysis and noncompartmental analysis (NCA). Results: A one-compartment model with first-order absorption and elimination adequately described siponimod pharmacokinetics. The typical population parameter estimates of clearance (CL/F), apparent volume of distribution (V/F), and absorption rate constant (ka) were 3.17 L/h, 112.70 L, and 0.38 h-1, respectively. An 11.85% lower siponimod clearance was estimated for patients with MS relative to healthy volunteers. Subgroup analyses using NCA assessments revealed that siponimod presented an accumulation index of approximately 2 after multiple administration. Compared with nonobese participants, obese participants had a relatively lower dose-corrected area under the concentration-time curve (AUC0-∞/D) (0.31 vs. 0.42 h/L) and V/F (120.95 vs. 133.75 L), and a relatively higher CL/F (3.25 vs. 3.21 L/h). Participants with CYP2C9*2/*3, *1/*3, and *3/*3 genotypes experienced an increased (1.3- and 3.4-fold, respectively) AUC0-∞/D and a decreased (0.7- and 0.3-fold, respectively) CL/F compared with those in participants with the CYP2C9*1/*1, *1*2, and *2*2 genotypes. Fluconazole combination led to a decrease in CL/F (approximately 0.5 times) and an increase in AUC0-∞/D (approximately 1.3 times). Conclusion: Siponimod pharmacokinetic properties in healthy volunteers and patients with MS were explored using complementary model-based meta-analysis (MBMA) and NCA approaches. A slightly lower siponimod clearance was observed in patients with MS than in healthy volunteers. The dosage regimen, body mass index, CYP2C9 genetic polymorphism and fluconazole combination may had influences on siponimod pharmacokinetics. Such model paves the road to more population-based analyses in different patient populations with MS to quantify the effect of any influencing factors on siponimod pharmacokinetics.

Correlation between dementia with Lewy bodies and blood-brain barrier / 中华老年医学杂志

Dementia with Lewy bodies(DLB)is the second most common neurodegenerative dementia after Alzheimer's Disease(AD). This article will mainly elaborate the relationship between DLB and blood-brain barrier(BBB)from the following five aspects: (1)The structure and function of BBB; (2)In vivo assessment methods for the blood-brain barrier damage; (3)Evidence for the damage of blood-brain barrier in DLB; (4)The relationship between α-synuclein and the blood-brain barrier; (5)The relationship between APOE and the blood-brain barrier.Future research should focus on the pathogenesis of BBB damage in DLB patients, by which new drug targets for disease diagnosis and treatment may be found.

Branched-chain amino acids alleviate hepatic steatosis and liver injury in choline-deficient high-fat diet induced NASH mice.

BACKGROUND: For successful treatment for nonalcoholic steatohepatitis (NASH), it may be important to treat the individual causative factors. At present, however, there is no established treatment for this disease. Branched-chain amino acids (BCAAs) have been used to treat patients with decompensated cirrhosis. AIM: In order to elucidate the mechanisms responsible for the effects of BCAAs on hepatic steatosis and disease progression, we investigated the effects of BCAA supplementation in mice fed a choline-deficient high-fat diet (CDHF), which induces NASH. METHODS: Male mice were divided into four groups that received (1) choline-sufficient high fat (HF) diet (HF-control), (2) HF plus 2% BCAA in drinking water (HF-BCAA), (3) CDHF diet (CDHF-control), or (4) CDHF-BCAA for 8weeks. We monitored liver injury, hepatic steatosis and cholesterol, gene expression related to lipid metabolism, and hepatic fat accumulation. RESULTS: Serum alanine aminotransferase (ALT) levels and hepatic triglyceride (TG) were significantly elevated in CDHF-control relative to HF-control. Liver histopathology revealed severe steatosis, inflammation, and pericellular fibrosis in CDHF-control, confirming the NASH findings. Serum ALT levels and hepatic TG and lipid droplet areas were significantly lower in CDHF-BCAA than in CDHF-control. Gene expression and protein level of fatty acid synthase (FAS), which catalyzes the final step in fatty acid biosynthesis, was significantly decreased in CDHF-BCAA than in CDHF-control (P<0.05). Moreover, hepatic total and free cholesterol of CDHF-BCAA was significantly lower than those of CDHF-control. CONCLUSIONS: BCAA can alleviate hepatic steatosis and liver injury associated with NASH by suppressing FAS gene expression and protein levels.

Progress of traditional Chinese medicine researches on diabetic peripheral neuropathy / 国际中医中药杂志

Diabetic peripheral neuropathy is one of the microvascular complications of diabetes. traditional Chinese medicine (TCM) attributed it to theXiaoke disease andBizheng, with the views ofLuo disease and its TCM patterns differentiation. Based on the treatment for deficiency,Tongluo drugs were added and they made good curative effect. Recently the TCM researches on it have been deepened in the etiology, pathogenesis, treatment, experimental and clinical research, which showed some new under standings. Thus, this paper summarized the relevant researches.

Research Advance and Application of Detection Methods for Related Substances in Drugs / 中国药师

At present, drug safety has gradually become the focus of world attention, and the study and control of related sub-stances is one of the key elements for drug safety. The national drug standards are also gradually increased the control requirements for related substances. Therefore, the detection and control of related substances are extremely important in the safety of drugs. By summa-rizing the analysis methods for related substances in drugsand their application , the paper alms to provide references for quality control of drugs.

A standardized protocol for detection of ALK protein expression and gene fusion in lung adenocarcinoma cytologic specimens / 中华肿瘤杂志

<p><b>OBJECTIVE</b>The aim of this study was to establish a standardized protocol for detection of ALK protein expression and gene fusion in cytologic specimens.</p><p><b>METHODS</b>Lung adenocarcinoma cytologic specimens were collected from seven hospitals in Beijing city. A detection protocol for ALK protein expression and gene fusion was designed according to the results of comparative experiment. Ventana immunohistochemical (IHC) ALK(D5F3) detecting ALK protein expression was performed in 203 prepared formalin-fixed paraffin-embedded (FFPE) cell blocks. ALK gene fusion in 98 EGFR gene wild type cytologic specimens and in 4 bronchoalveolar lavage fluid (BL) samples was detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR). ALK gene fusion in the Ventana IHC ALK (D5F3) positive samples was further tested by fluorescence in situ hybridization (FISH). Six patients with ALK IHC-positive result were followed up to analyze the responses of crizotinib therapy. Comparative experiments: (1) Comparison of the results of 4% neutral buffered formalin fixed for different time (24 h, 48 h, 72 h) on the Ventana IHC ALK (D5F3) staining was conducted in two cases of IHC ALK positive FFPE cell blocks; (2) Comparing qRT-PCR results for ALK fusion in samples from FFPE cell blocks and cytospin prepared slides in 10 cases of lung adenocarcinoma cytologic specimens.</p><p><b>RESULTS</b>Among the specimens examined using the standardized protocol recommended by this study, 229 cases of cytologic specimens met the diagnostic criteria of lung adenocarcinoma. Among them, 207 cases obtained ALK gene test results (by at least one method), with an ALK test ratio of 90.4% (207/229). FFPE cell blocks were successfully prepared in 203 cases, Ventana IHC ALK (D5F3) were successfully performed in all the 203 FFPE cell blocks (100%), and the ALK protein positive detection rate was 10.3% (21/203). ALK fusion was tested in 98 FFPE cytologic samples of EGFR wild types by qRT-PCR, and 96 out of 98 (97.96%) cytologic samples were successfully performed.18 out of 19 IHC ALK-positive cases were verified to be of ALK fusion status by qRT-PCR. The concordance rate was 94.7% (Kappa=0.967, P<0.001) between Ventana IHC ALK (D5F3) and qRT-PCR, and the sensitivity of the Ventana IHC ALK (D5F3) assay compared with qRT-PCR was 100% and the specificity was 98.7%. FISH assay was used to verify the positive cases detected by Ventana IHC ALK (D5F3) staining. Two cases of low tumor cell content FFPE samples obtained indefinite results by FISH test. The six patients with positive ALK protein expression received crizotinib therapy, and 5 paitents got treated effectively. For two ALK IHC positive cases, which were 4% neutral buffered formalin fixed for 72 h, the result of Ventana IHC ALK (D5F3) staining became weakened obviously and uneven. In 10 cases of samples, total RNA was extracted from FFPE cytologic sections and cytospin prepared slides, and the results of qRT-PCR test and ALK gene fusion showed good concordance.</p><p><b>CONCLUSIONS</b>The standardized protocol recommended in this study expands the detection types and quantity of cytologic specimens for ALK protein expression and gene fusion and increased the detection rate. Ventana IHC ALK (D5F3) is a reliable method for detecting ALK protein expression in FFPE cell blocks. The pathologic quality control procedure prior to Ventana IHC ALK (D5F3) is crucial for the accuracy of testing the ALK gene status. When FFPE cell blocks could not be prepared or prepared unsuccessfully from the cytologic specimens, qRT-PCR may be an alternative option for the detection of ALK gene fusion.</p>

Analysis on Chemical Substances Illegally Added in TCM and Health Products / 中国药师

Recently,thesituationofchemicalsubstancesillegallyaddedinTCMandhealthproductsismoreandmorecomplex and subtle, which not only results in latent danger and harm to customers, but also induce supervision difficulty and challenge for su-pervision departments. The variety and composition of chemical substances added illegally, analytical methods and relative state laws and regulations were illustrated in detail in the paper, which can provide the basis for the rational and safe use of TCM and health prod-ucts, and provide the reference and technology support for the supervision departments.

Combination of adenovirus-mediated endostatin gene and chemotherapy in treatment of Lewis lung cancer in mice / 第二军医大学学报

Objective:To study the antitumor effect of combination therapy with adenoviral transfer of mouse endostatin gene and cyclophosphamide chemotherapy on mouse Lewis lung cancer.Methods:Mouse endostatin gene was cloned into repli-cation-defective adenovirus by virus recombination technology to construct Ad-mES,adenovirus vector coding mouse endo-statin gene,and then its biological activities were surveyed in vivo.Animal models of mouse Lewis lung carcinoma in C57BL/6mice were established and randomly divided into4groups(n=10):including control,chemotherapy,gene therapy,and chemotherapy+gene therapy group.Mice received cyclophosphamide150mg/kg s.c.3times a day in a21-d cycle for chemotherapy;control group received0.9%normal saline100?l.Ad-mES(6?10 9 pfu/100?l)were administrated by multi-spots intra-tumor injection to every mouse in gene therapy group and combination therapy group.The tumor sizes were mea-sured at different times points.The expression of endostatin after transfer was detected by Western blot and the microvessel density(MVD)of tumor was measured by immunohistochemical examination.Results:Higher titers of recombinant aden-oviruses(Ad-mES)were constructed.Combination therapy with Ad-mES and cyclophosphamide inhibited tumor growth(P

Determination of astragaloside Ⅳ in Qiluyishen Tabletes by HPLC-ELSD / 中成药

AIM: To establish a method for the determination of Astragaloside Ⅳ in Oiluyishen Tabletes(Radix Astragali, Herba Pyrolae, Rhizoma Atractylodis Macrocephalae, Poria, Radix Codonopsis,etc.) by HPLC-ELSD. METHODS: Chromatography was performed on a 5?m HIQsilC 18 column(4.6mm?250mm) at 25℃. The mobile phase composition was acetonitrile-water(34∶66). The flow rate was at 1.0mL?min -1. An evaporation light-scattering detector (ELSD) was used as detector with gas flow rate of 2.6 mL?min -1 and drift tube temperature at 100℃. RESULTS: The linear range of Astragaloside Ⅳ was in the range of 2.288～ 22.88?g, r=0.999, the average recovery was 98.8% and RSD was 1.2%. CONCLUSION: This method is simple, feasible and reproducible. It can be used for the quality control of Oiluyishen Tabletes.