Relative to hepatitis B virus(HBV)monoinfection,HBV/hepatitis D virus(HDV)co-infection may be associated with more severe liver disease,leading to increased rates of cirrhosis,hepatocellular carcinoma,hepatic decompensation,and liver failure.The treatment of chronic HDV infection is essential and urgent.No drugs with established Efficacy and safety data have been approved for the treatment of chronic HDV infection.There are several new drugs are in clinical development stage now.We review the mechanism of action,research and development progress,and clinical trial design of new drugs currently in the clinical development stage,as well as the recommendations of regulatory agencies and academia for the clinical trial design of new drugs for the treatment of chronic HDV infection.And discuss the key points of confirmatory clinical trial design.

The purpose of this research is to study the anti-atherosclerotic effects and mechanisms of berberine (BBR) in high fat diet (HFD) fed ApoE^-/- mice, and then to lay a solid foundation of the clinical studies of BBR treatment. The hyperlipidemic ApoE^-/- mice model was established by feeding HFD for 12 weeks. Mice were randomly divided into control group (chow diet), model group, BBR group (BBR-L: 50 mg·kg^-1, BBR-H: 150 mg·kg^-1) and atorvastatin (5 mg·kg^-1) group. Mice were intragastric administration with BBR in 0.5% sodium salt of caboxy methyl cellulose. After 12 weeks, enface aortas were stained with oil red O, and the lesions area were analyzed by Image J software. The inflammatory factor levels were detected by suspension microarray kits. Liver total cholesterol (TC), triglyceride (TG) and free fatty acids (FFA) were determined by commercial kits. Western blot was performed to examine the inflammatory pathway related and cholesterol and lipid transport related proteins' expression. All animal experiments were performed in accordance with the Regulation on the Administration of Laboratory Animals of Institute of Medicinal Biotechnology. After 12 weeks treatment, compared with model group, BBR treatment significantly reduced the lesions area of en face aortas and obviously inhibited serum proinflammatory factors such as IL-1β and IL-6 compared with model group. In addition, BBR treatment obviously reduced liver TC, TG and FFA levels compared with model group. Furthermore, mechanic study showed that BBR significantly inhibited MAPKs and NF-κB pathways, and increased cholesterol and lipid regulated proteins expression such as p-AMPK, LDLR, ABCA1 and SR-BI. In conclusion, BBR can obviously reduce enface aortas lesions in ApoE^-/- mice, which is related to inhibit inflammation and liver cholesterol and lipid accumulation.

Total glucosides of peony (TGP), containing the effective components of paeoniflorin (Pae), albiflorin (Alb) and so on, are effective parts of Radix Paeoniae Alba. And it possesses extensive pharmacological actions, one of which is hepatoprotective effect. In recent years, abundant of pharmacokinetics and pharmacodynamics research of TGP in hepatoprotective effects have been performed. However, the relative medicine of TGP in hepatoprotective effect has not been developed for clinical application. In order to provide reference for the development and rational clinical application of TGP, the research progresses of pharmacokinetics and pharmacodynamics of TGP in hepatoprotective effect were summarized in this paper. Pharmacokinetics research has clarified the process of absorption, distribution, metabolism and excretion of TGP in vivo, and liver injury disease can significantly influence its metabolic processes. Pharmacodynamics studies suggested that TGP can protect against acute liver injury, non-alcoholic fatty liver diseases (NAFLD), chronic liver fibrosis and liver cancer. However, the action mechanism and in vivo process about hepatoprotective effects of TGP have not been clearly revealed. How liver injury influences the metabolism of TGP and its integrated regulation through multiple targets need to be further studied. The combined pharmacokinetics and pharmacodynamics studies should be performed in favour of medicine development and clinical application of TGP in hepatoprotective effects.

BACKGROUNDBispectral index (BIS) is considered very useful to guide anesthesia care in elderly patients, but its use is controversial for the evaluation of the adequacy of analgesia. This study compared the BIS changes in response to loss of consciousness (LOC) and loss of somatic response (LOS) to nociceptive stimuli between elderly and young patients receiving intravenous target-controlled infusion (TCI) of propofol and remifentanil.

METHODSThis study was performed on 52 elderly patients (aged 65-78 years) and 52 young patients (aged 25-58 years), American Society of Anesthesiologists physical status I or II. Anesthesia was induced with propofol administered by TCI. A standardized noxious electrical stimulus (transcutaneous electrical nerve stimulation, [TENS]) was applied (50 Hz, 80 mA, 0.25 ms pulses for 4 s) to the ulnar nerve at increasing remifentanil predicted effective-site concentration (Ce) until patients lost somatic response to TENS. Changes in awake, prestimulus, poststimulus BIS, heart rate, mean arterial pressure, pulse oxygen saturation, predicted plasma concentration, Ce of propofol, and remifentanil at both LOC and LOS clinical points were investigated.

RESULTSBISLOCin elderly group was higher than that in young patient group (65.4 ± 9.7 vs. 57.6 ± 12.3) (t = 21.58, P < 0.0001) after TCI propofol, and the propofol Ce at LOC was 1.6 ± 0.3 μg/ml in elderly patients, which was significantly lower than that in young patients (2.3 ± 0.5 μg/ml) (t = 7.474, P < 0.0001). As nociceptive stimulation induced BIS to increase, the mean of BIS maximum values after TENS was significantly higher than that before TENS in both age groups (t = 8.902 and t = 8.019, P < 0.0001). With increasing Ce of remifentanil until patients lost somatic response to TENS, BISLOSwas the same as the BISLOCin elderly patients (65.6 ± 10.7 vs. 65.4 ± 9.7), and there were no marked differences between elderly and young patient groups in BISawake, BISLOS, and Ce of remifentanil required for LOS.

CONCLUSIONIn elderly patients, BIS can be used as an indicator for hypnotic-analgesic balance and be helpful to guide the optimal administration of propofol and remifentanil individually.

TRIAL REGISTRATIONCTRI Reg. No: ChiCTR-OOC-14005629; http://www.chictr.org.cn/showproj.aspx?proj=9875.

Adult ; Aged ; Electroencephalography ; drug effects ; Female ; Humans ; Male ; Middle Aged ; Movement Disorders ; physiopathology ; Pain ; physiopathology ; Piperidines ; pharmacology ; Propofol ; pharmacology ; Transcutaneous Electric Nerve Stimulation ; Unconsciousness ; physiopathology

OBJECTIVETo investigate the effects of GM1 on inducing adult rat bone marrow stromal cells (MSCs) to form neural progenitor cells and their differentiation.

METHODSPurified MSCs were induced by different components of basic fibroblast growth factor (bFGF) alone, GM1 alone or combination of bFGF with GM1. After 3 days' incubation, fibronectin and collagen I were detected with immunocytochemistry, and nestin was detected with immunofluorescence. Neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP) and galactose cerebroside (GalC) were detected with immunocytochemistry after 7 days' incubation.

RESULTSAfter induction with bFGF alone or combination of bFGF and GM1, some MSCs exhibited the phenotypes of neural progenitor cells, and then neurons and astrocytes. In these two groups, the positive cells for fibronectin and collagen I decreased markedly after 3 days' induction. At the same time, the positive cells for nestin increased markedly. After 7 days' induction, NSE and GFAP-positive cells increased significantly. Furthermore, the addition of bFGF and GM1 caused the maximal variation. However, addition of GM1 alone had no inductive effects.

CONCLUSIONSCombination of bFGF with GM1 may synergistically promote the transformation of MSCs and differentiation into neurons and astrocyte-like cells. The results suggest a promising route for the application of MSCs.

Analysis of Variance ; Animals ; Bone Marrow Cells ; Cell Differentiation ; drug effects ; physiology ; Cells, Cultured ; Drug Synergism ; Fibroblast Growth Factor 2 ; pharmacology ; Fluorescent Antibody Technique ; G(M1) Ganglioside ; pharmacology ; Immunohistochemistry ; Probability ; Rats ; Rats, Wistar ; Sensitivity and Specificity ; Stem Cells ; pathology ; physiology ; Stromal Cells ; drug effects ; physiology ; ultrastructure