Objective To synthesize obeticholic acid and optimize the preparation process. Method Obeticholic acid was synthesized from (E) -3α-hydroxyl-6-ethylidene-7-keto-5β-cholane-24-acid via the reactions in cluding the double bound hydrogenation, inversion of α-ethyl′s configuration, and stereospecific reduction of the carbonyl group. Results The structures of the compounds were confirmed by1 H NMR, 13 C NMR and MS data. The preparation process was optimized, with the overall yield about 69％.Conclusion An industrial process for the preparation of obeticholic acid has been developed, available for the safety and quality control as well as the quality improvement of final products, which could meet the registration requiremens of Center for Drug Evalution (CDE).

Sofosbuvir is a new type of direct-acting antiviral(DAA)drugs against hepatitis C.By competitive combination to NS5B polymerase activity sites,sofosbuvir can terminate genome synthesis of newly born virus,and finally inhibit the replication of hepatitis C virus(HCV).The research and development process of sofosbuvir is based on the principles of nucleoside antiviral drug metabolism.The subtle structure modification improves the drug′s structure stability and absorption process,which makes sofosbuvir a liver targeted anti-HCV drug.Sofosbuvir has become a clinical fundamental drug for anti-HCV infection,and then used alone or in combination with other drugs,with higher recovery rate,better safety and anti-drug resistance.This article reviews the research back?ground,development process,clinical application and synthetic methods for sofosbuvir.

OBJECTIVETo detect the expression of phosphorylated-signal transducer and activator of transcription 3 (p-Stat3) and myeloid leukemia-1 (Mcl-1) as well as their correlation, and to investigate the functional role of Stat3 and Mcl-1 in the pathogenesis of esophageal squamous cell carcinoma (ESCC).

METHODSStat3 activity in ESCC cells was inhibited with JAK/Stat3 inhibitors (AG490 or JSI-124). Specific siRNA was used to inhibit the Stat3 expression. Cell apoptosis was detected by flow cytometry. Expression of Mcl-1 protein was determined by Western blotting. Expression of phospho-Stat3 (Tyr705) and myeloid leukemia-1 (Mcl-1) proteins in ESCC tissues was detected by tissue microarray and immunohistochemistry. The relationship between p-Stat3 or Mcl-1 aberrant expression and clinicopatholohical features of ESCC was analyzed. The correlation of their expression was also analyzed.

RESULTSSuppression of the Stat3 signaling activation in ESCC cells led to marked apoptosis, and dramatic reduction of Mcl-1 protein. The positive rate of phospho-Stat3 (Tyr705) expression was 45.0% in 50/111 of the ESCC tissue samples. The lower the degree of tumor differentiation, the higher the positive rate of phospho-Stat3 (Tyr705), showing a significant difference (P = 0.018). The positive rate of Mcl-1 protein expression was 72.1% (80/111), and the lower the degree of tumor differentiation was, the higher there was the positive rate of Mcl-1, with a significant difference (P = 0.026). There was a positive correlation between the expressions of p-Stat3 and Mcl-1 proteins (P = 0.012).

CONCLUSIONSIn a subset of ESCC tissues, p-Stat3 (Tyr705) and Mcl-1 are overexpressed and positively correlated with each other, and both are correlated with tumor differentiation. Persistent activation of Stat3 contributes to apoptotic resistance in ESCC cells, and may be at least partly mediated through upregulation of Mcl-1.

Antineoplastic Agents ; pharmacology ; Apoptosis ; drug effects ; Carcinoma, Squamous Cell ; metabolism ; pathology ; Cell Differentiation ; Cell Line, Tumor ; Cell Survival ; drug effects ; Esophageal Neoplasms ; metabolism ; pathology ; Humans ; Myeloid Cell Leukemia Sequence 1 Protein ; metabolism ; Neoplasm Grading ; Neoplasm Staging ; Phosphorylation ; RNA, Small Interfering ; genetics ; STAT3 Transcription Factor ; antagonists & inhibitors ; genetics ; metabolism ; Tyrphostins ; pharmacology

OBJECTIVETo study on the effect of acteoside on learning and memory of dementia mice.

METHODMice were orally administered with acteoside for 10 days. Scopolamine was used to establish the acquired learning disability in mice. Their learning and memory were detected with a behavioral experiment (step-down test). After the behavior test, corticocerebral and hippocampus tissues of mice were detected with biochemical indexes, including GSH-Px, T-SOD, MDA, TChE and contents of protein in brain tissues.

RESULTMice were administered with acteoside for 10 d in advance to alleviate the acquired learning disability induced by scopolamine. Compared with the model group, acteoside increased the latency period in the step-down test and reduced error times. Besides, acteoside increased the activity of GSH-Px, T-SOD, TChE and protein content in their brain tissues, but decreased MDA content.

CONCLUSIONActeoside can significantly alleviate the acquired learning disability in mice induced by scopolamine. Its mechanism may be related with its effect of inhibiting the generation of free radicals in mice and improving the function of the central cholinergic system.

Animals ; Behavior, Animal ; drug effects ; Brain ; drug effects ; metabolism ; Drugs, Chinese Herbal ; administration & dosage ; pharmacology ; Glucosides ; administration & dosage ; pharmacology ; Glutathione Peroxidase ; metabolism ; Learning ; drug effects ; Male ; Memory Disorders ; chemically induced ; drug therapy ; Mice ; Phenols ; administration & dosage ; pharmacology ; Scopolamine Hydrobromide ; adverse effects ; Superoxide Dismutase ; metabolism

OBJECTIVETo establish a HPLC method for determining acetoside in rat plasma and to investigate the pharmacokinetic characteristics of acetoside in rats.

METHODSix rats were orally administered with 150 mg x kg(-1) acetoside and their blood samples were collected at different time points. The plasma concentration of acetoside was determined by reserved HPLC, and the pharmacokinetic parameters were calculated by DAS 2.0 software.

RESULTThe regression equation of acetoside in rats plasma was Y = 3.509 8X-0.096 8 (r = 0.996 8), which showed a good linear relation at 0.125-2.5 mg x L(-1). The method showed a recovery of more than 85%, and both inter-day and intra-day RSDs were less than 15%. After the oral administration of 150 mg x kg(-1) acetoside, the concentration-time curves of acetoside were expressed in a open two-compartment model. The main pharmacokinetics parameters of T(max), C(max), t(1/2alpha), t(1/2beta), AUC(0-t), AUC(0-infinity), CL/F, V/F and K(a) were respectively 0.36 h, 1.126 mg x L(-1), 0.759, 4.842 h, 3.134, 3.766 mg x h x L(-), 87.089 L x h(t) x kg(-1), 207.704 L x kg(-1) and 6.345 h(-1) respectively.

CONCLUSIONIt is first time to establish such a HPLC method to determine the concentration of acetoside in plasma. The method is so highly specified and sensitive that it can ble used in quantitative analysis in vivo on acetoside.

Animals ; Chromatography, High Pressure Liquid ; Female ; Glucosides ; chemistry ; pharmacokinetics ; Male ; Phenols ; chemistry ; pharmacokinetics ; Rats ; Rats, Sprague-Dawley

Objective To synthesize four related substances:1b,1c,1d,and 1e according to the synthetic process of aprepi-tant and its quality standard of USP and EP. Methods The impurities 1b,1c,and 1d were synthesized from 3,5-bis(trifluoromethyl) acetophenone through asymmetrical catalytic reduction reaction,condensation reaction,Grignard reaction ,catalytic hydrogenation and substitution. The impurity 1e was synthesized from(R)-α-methylbenzylamine through 7 reaction steps including esterification,reduc-tion,condensation ect. Results All the four related substances were confirmed by LC-MS and NMR. The results indicated that purity of the product surpassed 95%through HPLC. Conclusion These related substances can be taken as the references for the quality con-trol of aprepitant.

Objective: To evaluate the efficacy and safety of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) in prophylaxis neutropenia after chemotherapy in patients with lymphoma. Methods: This was a multicenter, single arm, open, phase Ⅳ clinical trial. Included 410 patients with lymphoma received multiple cycles of chemotherapy and PEG-rhG-CSF was administrated as prophylactic. The primary endpoint was the incidence of Ⅲ/Ⅳ grade neutropenia and febrile neutropenia (FN) after each chemotherapy cycle. Meanwhile the rate of antibiotics application during the whole period of chemotherapy was observed. Results: ①Among the 410 patients, 8 cases (1.95%) were contrary to the selected criteria, 35 cases (8.54%) lost, 19 cases (4.63%) experienced adverse events, 12 cases (2.93%) were eligible for the termination criteria, 15 cases (3.66%) develpoed disease progression or recurrence, thus the rest 321 cases (78.29%) were into the Per Protocol Set. ②During the first to fourth treatment cycles, the incidences of grade Ⅳ neutropenia after prophylactic use of PEG-rhG-CSF were 19.14% (49/256) , 12.5% (32/256) , 12.18% (24/197) , 13.61% (20/147) , respectively. The incidences of FN were 3.52% (9/256) , 0.39% (1/256) , 2.54% (5/197) , 2.04% (3/147) , respectively. After secondary prophylactic use of PEG-rhG-CSF, the incidences of Ⅳ grade neutropenia decreased from 61.54% (40/65) in the screening cycle to 16.92% (11/65) , 18.46% (12/65) and 20.75% (11/53) in 1-3 cycles, respectively. The incidences of FN decreased from 16.92% (11/65) in the screening cycle to 1.54% (1/65) , 4.62% (3/65) , 3.77% (2/53) in 1-3 cycles, respectively. ③The proportion of patients who received antibiotic therapy during the whole period of chemotherapy was 34.39% (141/410) . ④The incidence of adverse events associated with PEG-rhG-CSF was 4.63% (19/410) . The most common adverse events were bone pain[3.90% (16/410) ], fatigue (0.49%) and fever (0.24%) . Conclusion During the chemotherapy in patients with lymphoma, the prophylactic use of PEG-rhG-CSF could effectively reduce the incidences of grade Ⅲ/Ⅳ neutropenia and FN, which ensures that patients with lymphoma receive standard-dose chemotherapy to improve its cure rate.

Objective To observe the improvement of motor dysfunction and serum levels of C-reactive protein(CRP),blood glucose and blood lipid in post-stroke patients treated with scalp acupuncture at different needle retention time.Methods A total of 120 patients with motor dysfunction after stroke were randomly divided into control group,observation group 1 and observation group 2,with 40 cases in each group.The patients in the 3 groups were treated with scalp acupuncture,body acupuncture and routine rehabilitation exercise,once a day and 6 times a week,lasting for 2 weeks.The control group was given scalp acupuncture with retaining of needles for 30 minutes,the observation group 1 was given scalp acupuncture with retaining of needles for one hour,and the observation group 2 was given scalp acupuncture with retaining of needles for 2 hours.Before and after treatment,the 3 groups were observed in the changes of the scale scores of National Institutes of Health Stroke Scale(NIHSS),Fugl-Meyer Assessment(FM A),Berg Balance Scale(BBS)and modified Barthel Index(MBI),and the levels of laboratory indicators of peripheral blood CRP,fasting plasma glucose(FPG),total cholesterol(TC),triglyceride(TG),high-density lipoprotein cholesterol(HDL-C)and low-density lipoprotein cholesterol(LDL-C).After treatment,the clinical safety of the three groups was evaluated.Results(1)After treatment,the scale scores of NIHSS in the three groups were lower(P＜0.01)and the scale scores FMA,BBS and MBI were higher than those before treatment(P＜0.05 or P＜0.01).The comparison of post-treatment scale scores showed that the differences among the three groups were statistically significant(P＜0.01).The intergroup comparison showed that the decrease of NIHSS score and the increase of FMA,BBS and MBI scores in the observation group 2 were significantly superior to those in the control group and the observation group 1(P＜0.01);the improvement of FMA score in the observation group 1 was significantly superior to that in the control group(P＜0.01),while the improvement of NIHSS,BBS and MBI scores tended to be superior to that in the control group without statistically significant differences(P＞0.05).The results indicated that the curative effect of scalp acupuncture plus exercise regimen was positively correlated with the duration of needle retention for scalp acupuncture.(2)After treatment,the laboratory indicator levels of CRP and FPG in the peripheral blood of the three groups,the levels of TG and LDL-C in the two observation groups and the level of HDL-C in the observation group 2 were improved compared with those before treatment(P＜0.05 or P＜0.01).Statistically significant differences were presented in the post-treatment levels of CRP and TG in peripheral blood among the three groups(P＜0.05 or P＜0.01).The intergroup comparison showed that the improvement of CRP and TG levels in the observation group 2 was significantly superior to that in the control group,and the improvement of CRP level in the observation group 2 was significantly superior to that in the observation group 1,the differences being statistically significant(P＜0.05 or P＜0.01).The TC level in the three groups after treatment did not differ from that before treatment,and there was no significant difference in TC level after treatment among the three groups either(P＞0.05).(3)During the treatment,no adverse reactions such as fainting,needle breaking and hematoma occurred in the three groups,the vital signs of the patients were stable,and there were no obvious abnormal changes in pulse,blood pressure and respiratory rate.Conclusion Scalp acupuncture can effectively improve the motor function of post-stroke patients in a pasitive time-effect relationship with the needle retention,and better the curative effect can be achieved by retaining of the needle for 2 h.