Yinghua Lv

Quantitative efficacy of soy isoflavones on menopausal hot flashes

AIM This study aimed to quantitate the efficacy of soy isoflavones in the treatment of menopausal hot flashes. METHODS Model based meta-analysis (MBMA) was used to quantitate the efficacy of soy isoflavones. We conducted a systemic literature search to build a time-effect model for placebo and soy isoflavones in treating menopausal hot flashes. Studies were identified, subjected to inclusion and exclusion criteria, and reviewed. RESULTS From 55 articles, 16 studies of soy isoflavones met the inclusion criteria, and contained 65 and 66 mean effect values in placebo and soy isoflavone groups, respectively, from about 1710 subjects. Interestingly, the developed model was found to describe adequately the time course of hot flashes reduction after administration of placebo and soy isoflavones. Using this model, we found that the maximal percentage change of hot flashes reduction by soy isoflavones was 25.2% after elimination of the placebo effect, accounting for 57% of the maximum effects of estradiol (Emax-estradiol  = 44.9%). However, a time interval of 13.4 weeks was needed for soy isoflavones to achieve half of its maximal effects, much longer than estradiol, which only required 3.09 weeks. These results suggest that treatment intervals of 12 weeks are too short for soy isoflavones, which require at least 48 weeks to achieve 80% of their maximum effects. CONCLUSIONS Soy isoflavones show slight and slow effects in attenuating menopausal hot flashes compared with estradiol.

Sample sizes in dosage investigational clinical trials: a systematic evaluation.

The main purpose of investigational phase II clinical trials is to explore indications and effective doses. However, as yet, there is no clear rule and no related published literature about the precise suitable sample sizes to be used in phase II clinical trials. To explore this, we searched for clinical trials in the ClinicalTrials.gov registry using the keywords “dose-finding” or “dose–response” and “Phase II”. The time span of the search was September 20, 1999, to December 31, 2013. A total of 2103 clinical trials were finally included in our review. Regarding sample sizes, 1,156 clinical trials had <40 participants in each group, accounting for 55.0% of the studies reviewed, and only 17.2% of the studies reviewed had >100 patient cases in a single group. Sample sizes used in parallel study designs tended to be larger than those of crossover designs (median sample size 151 and 37, respectively). In conclusion, in the earlier phases of drug research and development, there are a variety of designs for dosage investigational studies. The sample size of each trial should be comprehensively considered and selected according to the study design and purpose.

Comparative efficacy of five long-term weight loss drugs: quantitative information for medication guidelines

Quantitative information is scarce in current obesity medication guidelines, and they do not clearly reflect the differences in the efficacy characteristics among various drugs. This study quantitatively assessed the efficacy characteristics of five FDA‐approved long‐term weight loss drugs. Potentially eligible studies were obtained from public databases. Using the differences in the weight change from baseline between the drug group and the corresponding placebo group as the major indicator of efficacy, a time‐effect model was established, and crucial pharmacodynamic parameters, such as the maximal efficacy, drug onset time and rate of body weight regain after the maximal efficacy point, were used to reflect the differences in efficacy among the five drugs. Finally, 50 reports (involving 43,443 participants) were included. After deducting the placebo effects, the maximal efficacies (95% CI) of orlistat (120 mg), lorcaserin, naltrexone–bupropion, phentermine–topiramate (PT, 7.5/46 mg) and liraglutide were −2.94 (−5.82, −1.27), −3.06 (−4.39, −1.71), −6.15 (−9.78, −3.25), −7.45 (−9.76, −3.88) and −5.50 (−10.62, −2.97) kg at weeks 60, 54, 67, 59 and 65 respectively, and their rates of body weight regain were 0.51, 0.48, 0.91, 1.27and 0.43 kg per year respectively. The 1‐year dropout rates of orlistat, lorcaserin, naltrexone‐bupropion, PT and liraglutide were 29.0, 40.9, 49.1, 34.9 and 24.3% respectively. In addition, a significant dose–effect correlation was observed for orlistat and PT. This study provides valid quantitative information for medication guidelines.

Quantitative analysis of placebo response and factors associated with menopausal hot flashes

Objective: The aim of the study was to quantitatively analyze the placebo response and the factors associated with menopausal hot flashes. Methods: The PubMed and Cochrane Library databases were searched for placebo-controlled trials that reported the treatment of menopausal hot flashes, with a retrieval deadline of December 31, 2015. The clinical and demographic characteristics of participants and placebo responses, defined as the percentage of reduction in hot flashes at each observation time point compared with that of baseline values, were extracted from the studies. Model-based meta-analysis was used to describe the time course of placebo response and identify the related factors. Results: Eighty-five trials in 78 articles, involving 8,302 women, were included in the analysis. Of these, 47 trials were about hormonal drugs, 37 were about nonhormonal drugs, and 1 included both hormonal and nonhormonal drugs. Our results indicated that the placebo responses for hot flashes increased in a time-dependent manner and reached a plateau after week 12. Additionally, the placebo responses were significantly higher in the trials of hormonal drugs than in the trials of nonhormonal drugs at week 24 (−51.2% vs -40.4%; P < 0.05), and the difference between them was comparable with the effect of paroxetine. Conclusions: The placebo response for menopausal hot flashes was related to the active comparator; a higher response rate was observed in trials of hormonal drugs than in trials of nonhormonal drugs. These findings suggest that subjective expectations affect the treatment efficacy of menopausal hot flashes.

The Characteristics of TCM Clinical Trials: A Systematic Review of ClinicalTrials.gov

Objective The aim of this review is to characterize current status of global TCM clinical trials registered in ClinicalTrials.gov. Methods We examined all the trials registered within ClinicalTrials.gov up to 25 September 2015, focusing on study interventions to identify TCM-related trials, and extracted 1,270 TCM trials from the data set. Results Overall, 691 (54.4%) trials were acupuncture, and 454 (35.8%) trials were herbal medicines. Differences in TCM trial intervention types were also evident among the specific therapeutic areas. Among all trials, 55.7% that were small studies enrolled <100 subjects, and only 8.7% of completed studies had reported results of trials. As for the location, the United States was second to China in conducting the most TCM trials. Conclusion This review is the first snapshot of the landscape of TCM clinical trials registered in ClinicalTrials.gov, providing the basis for treatment and prevention of diseases within TCM and offering useful information that will guide future research on TCM.

Population pharmacokinetics of adefovir dipivoxil tablets in healthy Chinese volunteers.

AIM To develop a population pharmacokinetic model of adefovir dipivoxil in healthy volunteers and evaluate the effect of individual factors on the pharmacokinetics of adefovir dipivoxil. METHODS Plasma concentration data collected from 32 healthy Chinese subjects in a Phase I clinical study was pooled. Subjects received a single oral dose of 10 mg, 20 mg, or 30 mg adefovir dipivoxil, or multiple doses of 10 mg once a day for 9 days. Plasma concentrations of adefovir dipivoxil were measured using a validated liquid chromatography-mass spectrometric method. A nonlinear mixed-effect model was used to analyze the plasma concentration data of adefovir dipivoxil in healthy volunteers and to calculate the relevant parameters as well as inter- and intra-individual variability. RESULTS The time course of adefovir dipivoxil concentration is best described by a first-order absorption and first-order elimination two-compartment model with lag time. The final estimate of total body clearance (CL) is 56.9 L/h and 78.7 L/h for single and multiple dosing regimen, respectively; the volume distribution of the central compartment (V2) is 106 L; inter-compartmental clearance (Q) is 220 L/h; volume distribution of the peripheral compartment (V3) is 498 L and 800 L for single and multiple dosing regimen, respectively; absorption rate is 0.509 h-1; and lag time is 0.315 hours. The inter-individual variabilities of CL and V2 were 22.4% and 58.9%, respectively. The proportional error of residual variability is 14.1% and the additive error is 0.30 ng/L. The final pharmacokinetic model was evaluated using a bootstrap method. CONCLUSIONS A nonlinear mixed effect model for oral adefovir dipivoxil formulations was developed in healthy Chinese subjects. A multiple dosing regimen may significantly increase the body clearance and volume distribution of the peripheral compartment compared to a single dosing regimen. *These authors contribute equally to this work.

Model-based comparing efficacy of fluoxetine between elderly and non-elderly participants with major depressive disorder

BACKGROUND The high heterogeneity was existed among the studies of the elderly participants with major depressive disorder (MDD), which may lead to incorrect conclusions in the previous meta-analysis. This study used model based meta-analysis to compare the efficacy of fluoxetine between the elderly and non-elderly participants with MDD and to explain the heterogeneity among the studies. METHODS A comprehensive literature search was conducted in the public databases, involving utilization of fluoxetine for treating MDD in the acute-phase. The time-efficacy model was established based on the changes of the Hamilton Depression Rating Scale (HDRS) score compared to baseline level. The efficacy features and related factors of fluoxetine in the elderly participants were investigated by comparing with the non-elderly population. RESULTS Sixty-one studies encompassing 4058 participants were included in the analysis. We found the trial design of placebo controlled vs. comparator controlled was a significant impact factor for the efficacy of fluoxetine. The typical decrease rate of HDRS score in the elderly participants was strikingly lower than that of the non-elderly participants at week 8, with 39.9% vs. 49.1% in the placebo controlled trial and 46.5% vs. 57.2% in the comparator controlled trial. LIMITATION The efficacy of other antidepressants except fluoxetine in the elderly participants need to be explored in the future study. CONCLUSIONS The efficacy of fluoxetine in the elderly participants was lower than that of the non-elderly participants. The heterogeneity of the trial design should be distinguished when comparing the efficacy of antidepressants between the elderly and non-elderly MDD participants.

A Review of Ginseng Clinical Trials Registered in the WHO International Clinical Trials Registry Platform

Although ginseng has long been broadly used in clinical settings around the world, few clinical trials on ginseng have been conducted. The objective of this study was to provide a comprehensive evaluation of the characteristics of ginseng clinical trials registered in the WHO International Clinical Trials Registry Platform (ICTRP) as of December 2017 regarding their frequency, design, type of ginseng, dosage, duration, condition, funding sources, and publication status. A total of 134 ginseng clinical studies were registered from 2002 to 2017, of which 60.4% were completed and 23.1% are actively recruiting participants. A large number of trials were associated with aspects of high-quality trial design. Overall, 94% of the trials employed randomized allocation to study arms, 78.4% were double-blind studies using placebo as one of the control groups, and 71% were published as completed trials. Trials whose sample size was restricted to fewer than 100 participants accounted for 74.7% of the total. Of the primary funding sources for ginseng studies, 67.2% were nonindustry organizations. The ginseng clinical trials were heterogeneous with respect to ginseng species and variety, indications, dose, duration, and participant characteristics. Clearly, stricter and methodologically suitable studies are needed to demonstrate the efficacy and safety of ginseng.

Advantage of population pharmacokinetic method for evaluating the bioequivalence and accuracy of parameter estimation of pidotimod.

OBJECTIVE This study was aimed at exploring the accuracy of population pharmacokinetic method in evaluating the bioequivalence of pidotimod with sparse data profiles and whether this method is suitable for bioequivalence evaluation in special populations such as children with fewer samplings. Methods In this single-dose, two-period crossover study, 20 healthy male Chinese volunteers were randomized 1 : 1 to receive either the test or reference formulation, with a 1-week washout before receiving the alternative formulation. Noncompartmental and population compartmental pharmacokinetic analyses were conducted. Simulated data were analyzed to graphically evaluate the model and the pharmacokinetic characteristics of the two pidotimod formulations. Various sparse sampling scenarios were generated from the real bioequivalence clinical trial data and evaluated by population pharmacokinetic method. RESULTS The 90% confidence intervals (CIs) for AUC0-12h, AUC0-∞, and Cmax were 97.3 - 118.7%, 96.9 - 118.7%, and 95.1 - 109.8%, respectively, within the 80 - 125% range for bioequivalence using noncompartmental analysis. The population compartmental pharmacokinetics of pidotimod were described using a one-compartment model with first-order absorption and lag time. In the comparison of estimations in different dataset, the estimation of random three- and< fixed four-point sampling strategies can provide results similar to those obtained through rich sampling. The nonlinear mixed-effects model requires fewer data points. Moreover, compared with the noncompartmental analysis method, the pharmacokinetic parameters can be more accurately estimated using nonlinear mixed-effects model. CONCLUSIONS The population pharmacokinetic modeling method was used to assess the bioequivalence of two pidotimod formulations with relatively few sampling points and further validated the bioequivalence of the two formulations. This method may provide useful information for regulating bioequivalence evaluation in special populations.