Treatment of HBV Cirrhosis with Fuzheng Huayu Tablet () and Entecavir: Design of a Randomized, Double-Blind, Parallel and Multicenter Clinical Trial / 中国结合医学杂志

BACKGROUND@#Antiviral therapy can lead to regression of fibrosis in chronic hepatitis B (CHB), but it has a limited effect on cirrhosis. Chinese medicines (CMs), particularly Fuzheng Huayu Tablet (, FZHY), have an antifibrotic effect in patients with CHB.@*OBJECTIVE@#To observe the safety and efficacy of adjunctive FZHY in patients with hepatitis B virus (HBV) cirrhosis, this study was designed as a randomized, placebo-controlled, double-blind, parallel assignment, multicenter trial at 20 centers in China. The total 700 naive patients will be enrolled with compensate cirrhosis due to HBV, and randomly assigned into 2 groups, receiving entecavir (0.5 mg, daily) and FZHY placebo (1.6 g, 3 times a day), or entecavir (0.5 mg, daily) and FZHY (1.6 g, 3 times a day), respectively. The primary endpoint was histological improvement at week 48. The secondary outcome is the decline values of liver fibrosis using the noninvasive methods from baseline to week 48 in each arm of the study. Adverse events such as stomach upset, headache, fatigue, dizziness, nausea will be strictly recorded.@*DISCUSSION@#Through this study, we hope to generate a solid evidence for the therapeutic strategy of HBV cirrhosis with a combination of anti-viral such as ETV and anti-fibrotic herbal product such as FZHY. Protocol version: Version 1.3, Date: 2014.12.4.@*TRIAL REGISTRATION NUMBER@#NCT02241590.

Efficacy and safety of the long-acting fusion inhibitor albuvirtide in antiretroviral-experienced adults with human immunodeficiency virus-1: interim analysis of the randomized, controlled, phase 3, non-inferiority TALENT study / 中华医学杂志(英文版)

BACKGROUND@#Albuvirtide is a once-weekly injectable human immunodeficiency virus (HIV)-1 fusion inhibitor. We present interim data for a phase 3 trial assessing the safety and efficacy of albuvirtide plus lopinavir-ritonavir in HIV-1-infected adults already treated with antiretroviral drugs.@*METHODS@#We carried out a 48-week, randomized, controlled, open-label non-inferiority trial at 12 sites in China. Adults on the World Health Organization (WHO)-recommended first-line treatment for >6 months with a plasma viral load >1000 copies/mL were enrolled and randomly assigned (1:1) to receive albuvirtide (once weekly) plus ritonavir-boosted lopinavir (ABT group) or the WHO-recommended second-line treatment (NRTI group). The primary endpoint was the proportion of patients with a plasma viral load below 50 copies/mL at 48 weeks. Non-inferiority was prespecified with a margin of 12%.@*RESULTS@#At the time of analysis, week 24 data were available for 83 and 92 patients, and week 48 data were available for 46 and 50 patients in the albuvirtide and NRTI groups, respectively. At 48 weeks, 80.4% of patients in the ABT group and 66.0% of those in the NRTI group had HIV-1 RNA levels below 50 copies/mL, meeting the criteria for non-inferiority. For the per-protocol population, the superiority of albuvirtide over NRTI was demonstrated. The frequency of grade 3 to 4 adverse events was similar in the two groups; the most common adverse events were diarrhea, upper respiratory tract infections, and grade 3 to 4 increases in triglyceride concentration. Renal function was significantly more impaired at 12 weeks in the patients of the NRTI group who received tenofovir disoproxil fumarate than in those of the ABT group.@*CONCLUSIONS@#The TALENT study is the first phase 3 trial of an injectable long-acting HIV drug. This interim analysis indicates that once-weekly albuvirtide in combination with ritonavir-boosted lopinavir is well tolerated and non-inferior to the WHO-recommended second-line regimen in patients with first-line treatment failure.@*TRIAL REGISTRATION@#ClinicalTrials.gov Identifier: NCT02369965; https://www.clinicaltrials.gov.Chinese Clinical Trial Registry No. ChiCTR-TRC-14004276; http://www.chictr.org.cn/enindex.aspx.

A double-blind, randomized, placebo- and positive-controlled phase III trial of 1% benvitimod cream in mild-to-moderate plaque psoriasis / 中华医学杂志(英文版)

BACKGROUND@#Benvitimod cream, a novel synthetic small molecule, was effective in treating mild-to-moderate plaque psoriasis. We conducted a phase III clinical trial to assess the efficacy and safety of benvitimod cream in patients with mild-to-moderate plaque psoriasis.@*METHODS@#We randomly assigned 686 patients (2:1:1) to receive 1% benvitimod cream, 0.005% calcipotriol ointment or placebo twice a day for 12 weeks. The primary efficacy end points were the percentage of patients with a 75% or greater reduction from baseline in the psoriasis area and severity index (PASI 75) score and with a score of 0 or 1 in static physician's global assessment (sPGA) at week 12.@*RESULTS@#The results showed that 50.4% of patients in the benvitimod group achieved PASI 75, which was significantly higher than that in the calcipotriol (38.5%, P < 0.05) and placebo (13.9%, P < 0.05) groups. The proportion of patients achieving an sPGA score 0 or 1 was 66.3% in the benvitimod group and 63.9% in the calcipotriol group, which were both significantly higher than that in the placebo group (34%, P < 0.05). In the long-term follow-up study, 50.8% of patients experienced recurrence. After retreatment with 1% benvitimod, 73.3% of patients achieved an sPGA score of 0 or 1 again at week 52. Adverse events included application site irritation, follicular papules, and contact dermatitis. No systemic adverse reactions were reported.@*CONCLUSION@#During this 12-week study, benvitimod cream was demonstrated with high effectiveness and safety in patients with mild-to-moderate plaque psoriasis.@*TRIAL REGISTRATION@#Chinese Clinical Trial Registry (ChiCTR), ChiCTR-TRC-13003259; http://www.chictr.org.cn/showprojen.aspx?proj=6300.

Effects of Traditional Chinese Medicine Shensong Yangxin Capsules on Heart Rhythm and Function in Congestive Heart Failure Patients with Frequent Ventricular Premature Complexes: A Randomized, Double-blind, Multicenter Clinical Trial / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Pharmacological therapy for congestive heart failure (CHF) with ventricular arrhythmia is limited. In the study, our aim was to evaluate the effects of Chinese traditional medicine Shensong Yangxin capsules (SSYX) on heart rhythm and function in CHF patients with frequent ventricular premature complexes (VPCs).</p><p><b>METHODS</b>This double-blind, placebo-controlled, multicenter study randomized 465 CHF patients with frequent VPCs to the SSYX (n = 232) and placebo groups (n = 233) for 12 weeks of treatment. The primary endpoint was the VPCs monitored by a 24-h ambulatory electrocardiogram. The secondary endpoints included the left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter, N-terminal pro-brain natriuretic peptide (NT-proBNP), New York Heart Association (NYHA) classification, 6-min walking distance (6MWD), Minnesota Living with Heart Failure Questionnaire (MLHFQ) scores, and composite cardiac events (CCEs).</p><p><b>RESULTS</b>The clinical characteristics were similar at baseline. SSYX caused a significantly greater decline in the total number of VPCs than the placebo did (-2145 ± 2848 vs. -841 ± 3411, P < 0.05). The secondary endpoints of the LVEF, NYHA classification, NT-proBNP, 6MWD, and MLHFQ scores showed a greater improvements in the SSYX group than in the placebo group (ΔLVEF at 12th week: 4.75 ± 7.13 vs. 3.30 ± 6.53; NYHA improvement rate at the 8th and 12th week: 32.6% vs. 21.8%, 40.5% vs. 25.7%; mean level of NT-proBNP in patients with NT-proBNP ≥125 pg/ml at 12th week: -122 [Q1, Q3: -524, 0] vs. -75 [Q1, Q3: -245, 0]; Δ6MWD at 12th week: 35.1 ± 38.6 vs. 17.2 ± 45.6; ΔMLHFQ at the 4th, 8th, and 12th week: -4.24 ± 6.15 vs. -2.31 ± 6.96, -8.19 ± 8.41 vs. -3.25 ± 9.40, -10.60 ± 9.41 vs. -4.83 ± 11.23, all P < 0.05). CCEs were not different between the groups during the study period.</p><p><b>CONCLUSIONS</b>In this 12-week pilot study, SSYX was demonstrated to have the benefits of VPCs suppression and cardiac function improvement with good compliance on a background of standard treatment for CHF.</p><p><b>TRIAL REGISTRATION</b>www.chictr.org.cn, ChiCTR-TRC-12002061 (http://www.chictr.org.cn/showproj.aspx?proj=7487) and Clinicaltrials.gov, NCT01612260 (https://clinicaltrials.gov/ct2/show/NCT01612260).</p>

Computerized system validation of clinical researches / 药学学报

Validation is a documented process that provides a high degree of assurance. The computer system does exactly and consistently what it is designed to do in a controlled manner throughout the life. The validation process begins with the system proposal/requirements definition, and continues application and maintenance until system retirement and retention of the e-records based on regulatory rules. The objective to do so is to clearly specify that each application of information technology fulfills its purpose. The computer system validation (CSV) is essential in clinical studies according to the GCP standard, meeting product's pre-determined attributes of the specifications, quality, safety and traceability. This paper describes how to perform the validation process and determine relevant stakeholders within an organization in the light of validation SOPs. Although a specific accountability in the implementation of the validation process might be outsourced, the ultimate responsibility of the CSV remains on the shoulder of the business process owner-sponsor. In order to show that the compliance of the system validation has been properly attained, it is essential to set up comprehensive validation procedures and maintain adequate documentations as well as training records. Quality of the system validation should be controlled using both QC and QA means.

Exploration of visual check approaches in clinical data management / 药学学报

Due to a great amount of data in clinical trials, the data cleansing needs to adopt a variety of measures, including the latest developed visual check approach. According to the different types of clinical data and the different stages in the course of clinical data management, this study reviews 8 types of visual graphics that show the relevance and trend among the data. The series of graphics can rapidly detect abnormal data, monitor clinical research in real-time, make the data management process much easier and improve the clinical trial efficiency and data quality.

Comparison of paper and electronic data management in clinical trials / 药学学报

Electronic case report forms (eCRFs) instead of the traditional paper case report forms (pCRFs) are increasingly used by investigators and sponsors of clinical research. We include a total of 14 phase III studies (8 pCRF, 6 eCRF) to compare paper and electronic data documentation both quantitatively and qualitatively in clinical studies. The result suggests that adaptions of electronic data capture (EDC) in clinical trials have the advantages in optimization of data capture process, improvement of data quality and earlier clinical decision compared to paper-based methods. Furthermore, the successful implementation of EDC requires accouplements with corresponding data management processes and reallocation of resources.

Quality control of clinical data management based on EDC / 药学学报

With the wide application of electronic data management (EDC), the data management is shifting to a new mode. In order to recognize the advantages of EDC, we choose 20 representative registered clinical trials, which involve 5 404 subjects and 321 sites. We found that EDC has many beneficial impacts on the course of clinical trial data management, including the process of data collection, data cleaning, data quality control and clinical trial decision-making. The result also provides a reference for the adoption of EDC in clinical trials.

A multi-center, randomized, double-blind, placebo-controlled trial of glyceryl trinitrate ointment in the treatment of anal fissure / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To evaluate the clinical efficacy and safety of glyceryl trinitrate (GTN) ointment in the treatment of anal fissure.</p><p><b>METHODS</b>In this multi-center, randomized, double-blind and placebo-controlled trial, 240 chronic anal fissure patients from 7 clinical centers were randomized to receive eight-week treatment with GTN ointment (treatment group) or vaseline ointment (control group) respectively. Healing rate, visual analogue score (VAS), maximum anal resting pressure (MARP) and adverse reactions were recorded and compared.</p><p><b>RESULTS</b>A total of 221 patients (92.1%) finished the trial, including 114 patients in treatment group (95.0%, 114/120) and 107 in control group (89.2%, 107/120). At the endpoint of treatment (56 d), 90 patients in treatment group (78.9%, 90/114) healed completely compared to 31 patients in control group (29.0%, 31/107), and decrease rates of VAS in the two groups were (94.8±15.7)% and (61.2±35.7)% respectively, both differences were statistically significant (P<0.01). MARP after first administration was (20.2±18.5) mm Hg in treatment group (n=12) and (7.1±14.7) mm Hg in control group (n=6), which was not significantly different (P=0.152). Adverse reaction incidence was higher in treatment group (42.1% vs. 9.3%, P<0.05), while these adverse reactions were mainly headache and fullness in head, which were self-limiting.</p><p><b>CONCLUSION</b>GTN ointment can effectively promote healing and relieve pain in anal fissure with safety and tolerance.</p>

Treating menopause syndrome by kuntal capsule and hormone replacement therapy: a meta-analysis of efficacy and safety comparison / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To evaluate the efficacy and safety of Kuntai Capsule (KC) and hormone replacement therapy (HRT) in treating menopause syndrome by Meta-analysis.</p><p><b>METHODS</b>Randomized controlled trials were electronically retrieved from PubMed, EMbase, The Cochrane Library, CBM, CNKI, Chinese Doctoral Dissertation Full Text Database, Chinese Outstanding Masters' Dissertation Full Text Database, and VIP database, Wanfang Database, and some other related papers were manually checked. All papers were assessed according to the Cochrane Handbook for Systematic Reviews of interventions and then effective data were analyzed by RevMan 5.0.2 Software.</p><p><b>RESULTS</b>Eight randomized control trials involving 675 patients were included. Results of Meta-analysis showed that there was no statistical difference in the Kupperman Menopausal Scores [MD = 1.91, 95% CI (-0.31, 4.12)] and the effective rate of Kupperman Menopausal Scores [OR = 1.37, 95% CI (0.66, 2.85)] between the KC group and the estrogen replacement therapy group (P > 0.05). Compared with the KC group, the E2 level [MD = -12.8, 95% CI (-22.85, -2.76)] and the FSH level [MD = 17.96, 95% CI (3.03, 32.88)] could be significantly improved in the estrogen replacement therapy group. Compared with the estrogen replacement group, KC could significantly reduce the total incidence of adverse reactions [OR = 0.41, 95% CI (0.24, 0.73)], the incidence of breast distending pain [OR = 0.65, 95% CI (0.42, 1.00)], and the incidence of vaginal bleeding [OR = 0.26, 95% CI (0.17, 0.40) ] (P < 0.05).</p><p><b>CONCLUSIONS</b>The current limited evidence showed that, when compared with the estrogen replacement therapy group, KC could also improve climacteric symptoms. It was inferior to the estrogen replacement therapy group in improving in vivo hormone levels. But it was superior in reducing the incidence of adverse reactions, breast distending pain, and vaginal bleeding.</p>

Comparative pharmacokinetic analysis based on nonlinear mixed effect model / 药学学报

Comparative pharmacokinetic (PK) analysis is often carried out throughout the entire period of drug development, the common approach for the assessment of pharmacokinetics between different treatments requires that the individual PK parameters, which employs estimation of 90% confidence intervals for the ratio of average parameters, such as AUC and Cmax, these 90% confidence intervals then need to be compared with the pre-specified equivalent interval, and last we determine whether the two treatments are equivalent. Unfortunately in many clinical circumstances, some or even all of the individuals can only be sparsely sampled, making the individual evaluation difficult by the conventional non-compartmental analysis. In such cases, nonlinear mixed effect model (NONMEM) could be applied to analyze the sparse data. In this article, we simulated a sparsely sampling design trial based on the dense sampling data from a truly comparative PK study. The sparse data were analyzed with NONMEM method, and the original dense data were analyzed with non-compartment analysis. Although the trial design and analysis methods are different, the 90% confidence intervals for the ratio of PK parameters based on 1000 Bootstrap are very similar, indicated that the analysis based on NONMEM is a reliable method to treat with the sparse data in the comparative pharmacokinetic study.

In vitro pharmacodynamic interactions of antitumor effect of the combination of adriamycin and curcumin evaluated by the parameter method and the response surface / 药学学报

The paper aimed to find the optimal combination and evaluation of the interactions of antitumor effect of the curcumin (Cur) and adriamycin (ADM) in vitro. According to the factorial design and data characteristics, the parameter method combined with the response surface approach were used to analyze the pharmacodynamic interactions of in vitro antitumor effects of the combination of Cur and ADM at different dosages. The results showed that the dose-effect relationship of the combination with the ratio of ADM-Cur 1:3 showed significant differences in comparison with either used alone. The dose-effect curve was shift left in combination. The combination of adriamycin (ADM, 0.693-2.132 micromol L(-1)) and curcumin (Cur, 2.047-6.304 micromol L(-1)) with a fixed ratio (1:3) showed a synergism. With increasing doses of the combination, there is an additive effect. Computer simulation showed a trend of decreasing difference between the observed and expected effects with the dose increasing in Cur from 6.304 to 16.0 micromol L(-1) and ADM from 2.132 to 5.3 micromol L(-1). The response surface analysis showed the optimal combination to be Cur 18.50 micromol L(-1) and ADM 3.89 micromol L(-1) with a ratio of 5:1. This study suggests that the parameter method combined with the response surface analysis provides richer and more reasonable information, and is helpful for quantitative design of drug combination therapy and to describe the nature and degree of drug interaction.

Limited sampling strategy models for estimating AUC for amlodipine in Chinese healthy volunteers / 药学学报

This study aims to save cost of sampling for estimating the area under the amlodipine plasma concentration versus time curve in 24 hours (AUC(0-24 h)). Limited sampling strategy (LSS) models was developed and validated by mutiple regression model within 4 or fewer amlodipine concentration values. Absolute prediction error (APE), root of mean square error (RMSE) and visual predict check were used as criterion. The results of Jackknife validation showed that fifteen (9.4%) of the 160 LSS based on regression analysis were not within an APE of 15% by using one concentration-time point. 156 (97.5%), 159 (99.4%) and 160 (100%) of the 160 LSS model were capable of predicting within an APE 15% by using 2, 3, 4 points, separately. Limited sampling strategies have been developed and validated for estimating AUC(0-24 h) of amlodipine. The present study indicated that the implemention of both 5 mg and 10 mg dosage could enable accurate predictions of AUC(0-24 h) by the same LSS model. This study shows that 12, 4, 24, 2 h after administration are key sampling time points. The combination of (12, 4), (12, 4, 24) or (12, 4, 24, 2 h) might be chosen as sampling hours for predicting AUC(0-24 h) in practical application according to requirement.

Quantitative approach for calculation of pharmacodynamic interactions and simulation of combined response / 中国中药杂志

<p><b>OBJECTIVE</b>An approach is set up to calculate pharmacodynamic interaction and simulate the combined response.</p><p><b>METHOD</b>An orthogonal design with 1-level = high dose and 2-level = low dose was adopted. An example of the compound with four components was applied to evaluate this quantitative approach. The bias was evaluated by the both scatter plots.</p><p><b>RESULT</b>This approach can calculate the value of each component with different dose by its contribution to combined response, and the value is related to the importance of a compound. Drug interactions were evaluated among the combinations in each group. The prediction model performed well and simulated the combined response in the different of components in combination.</p><p><b>CONCLUSION</b>The approach can be used in the similar research, and it also provides predictions of component combinations from the other studies by simulation.</p>

Quantitative analyses of the combined effects of nano red elemental selenium and glucurolactone on forming liver fibrosis induced by CCl4 in rats / 中国药理学通报

AIM: To observe the combined effects of nano red elemental selenium (Nse) and glucurolactone (Glu) on forming liver fibrosis in rats, and to search for a low dose of Nse with therapeutic effect. METHODS: According to the weighted modification method, six compound-dose groups and 2 control groups were set. The rats were given (sc) CCl4 for 10 wk, and the administration began at 4 wk. The indices related to acute liver damage were determined 3 wk after the administration, and to chronic liver damage 6 wk after the administration. RESULTS: At the stage of acute liver damage and within the therapeutic duration of 3 wk, Nse should be used at a larger dose in combination with Glu. Theoretical analysis showed that Nse 200 μg·kg-1 alone was available by the weighted modification method. However, in the combination of Nse and Glu for the chronic liver injury, Nse should be given at a low dose. There was a synergism between Nse and Glu, and some compound-dose groups showed the preventive and therapeutic effect, especially in a dose of Nse 100 μg·kg-1 + Glu 60 mg·kg-1. But theoretical analysis exhibited that Nse 100 μg · kg-1 + Glu 60 mg·kg-1 (ig) might be an optimal combination. CONCLUSION: The combination of Nse and Glu has significant effect in prevention and treatment of the live fibrosis in rats, and it can decrease dose of Nse used.

Chronic toxicity of tea polyphenols in dogs / 中国临床药理学与治疗学

Aim The chronic toxicity of tea polyphenols(TP) in dogs was observed. Methods 18 dogs were randomly divided into high, middle and low dose TP groups and one control group . When TP was given(po) by 650 mg?kg-1?d-1,65 mg?kg-1?d-1,6.5 mg?kg-1?d-1 respectively for 90 d and after TP was stopped for two weeks, the general conditions, ECG, blood routine, urine routine, serum lipids, blood sugar, coagulation time, and hepatic and kidney function were detected respectively. Results These mdices were not different from each other among the 4 groups before, during and after administration of TP . The level of serum total cholesterol was progressively decreased in TP groups. Conclusion TP has no toxic effect on dogs and can decrease the level of serum total cholesterol in normal dogs.

Timed analgesic effects by butabital, acetaminophen and caffeine in combination in mice and rats~1 / 中国临床药理学与治疗学

Aim To observe the timed analgesic effects by butabital (B), acetaminophen(A) and caffeine (C) in combination (BAC), in which the proportion was fixed as1. 25∶ 8. 1∶1. Method Three types of experimental methods, including the tailflicking method, the hot plate method and the pressurizing tail method, weretaken to determine indices at different times after the animals were adminstered(ig) high, median and low BAC dose. Results and conclusion BAC had a stronganalgesic effect in three types of experiments. The effect began 30 min after ad-ministration, arrived maximum at 1 h, decreased at 2 h and disappeared at 4 h.There was a dose-effect relationship between large and little BAC dose.