Comparative Efficacy of Drugs for the Treatment of Chronic Constipation: Quantitative Information for Medication Guidelines.

BACKGROUND: Quantitative information is scarce with regard to guidelines for currently prescribed medications for constipation. Furthermore, these guidelines do not reflect the differences in the number of bowel movements caused by each drug. GOALS: In this study, we used a model-based meta-analysis to quantitatively estimate the deviations from the baseline number of spontaneous bowel movements (SBMs) and complete spontaneous bowel movements (CSBMs) associated with pharmacotherapy for chronic constipation to bridge the knowledge gap in the guidelines for current medications. STUDY: A comprehensive survey was conducted using literature databases. In this study, we also included randomized placebo-controlled trials on chronic constipation. Pharmacodynamic models were established to describe the time course of the numbers of SBMs and CSBMs produced by each drug. RESULTS: Data from 20 studies (comprising 9998 participants and 8 drugs) were used to build this model. The results showed that bisacodyl had the greatest effect on increasing the frequency of bowel movements, whereas plecanatide yielded the lowest increase in the number of SBMs and CSBMs. After eliminating the placebo effect, the maximal increase in bowel movement frequency associated with bisacodyl was 6.8 for SBMs (95% confidence interval: 6.1-7.6) and 4.7 for CSBMs (95% confidence interval: 4.3-5.1) per week. These numbers are ∼4 times higher than the number of bowel movements produced by plecanatide. The change in the frequency of SBMs and CSBMs for other drugs, such as sodium picosulfate, velusetrag, linaclotide, elobixibat, lubiprostone, and prucalopride, was similar. The highest increases in the frequency of SBM and CSBM were 2.5 to 4 and 1 to 2.1 per week, respectively. Bisacodyl had the most noticeable loss of efficacy between week 1 and week 4; it reduced the frequencies of SBMs and CSBMs by 2.3 and 2.2, respectively. By contrast, the changes in the frequencies of SBMs and CSBMs were not as great with other drugs. CONCLUSIONS: The data provided in this study may be a valuable supplement to the medication guidelines for the treatment of chronic constipation.

[Exploration of visual check approaches in clinical data management].

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].

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].

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.

[Comparative pharmacokinetic analysis based on nonlinear mixed effect model].

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].

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.

[Anti-inflammatory effects and quantitative study of the combinations of active ingredients of Painong powder in mice].

OBJECTIVE: To study the anti-inflammatory effects of the combinations of active components of Painong powder, a compound traditional Chinese herbal medicine, and the quantitative analysis of their interactions. METHODS: The mouse model of acute inflammation with increase of capillary permeability was induced by intraperitoneal injection of acetic acid. An orthogonal design with 2 levels (used and unused) was applied to assign the combinations groups of active ingredients including naringin and neohesperidin, peoniflorin, and platycodin. Aspirin and normal saline were administered as control. The pharmacodynamic interactions were analyzed by the optical density (OD) of infiltrated Evans blue. RESULTS: The different combinations of active ingredients showed anti-inflammatory effect with different degree, and the predicted values of OD varied from 0.115 to 0.170. The maximum anti-inflammatory effect was from the combination of naringin, neohesperidin, paeoniflorin and platycodin, better than that of the saline group (P < 0.01). However, there was no significant difference as compared with the aspirin group (P > 0.05). Paeoniflorin showed a dominant contribution to the formula, and platycodin the least. The combination of all active components exhibited synergism. CONCLUSION: The results suggest that all the ingredients are efficacious constituents of the formula, and paeoniflorin shows a dominant contribution to the formula. More information about prescription compatibility can be obtained by the orthogonal simulation method.

[Quantitative approach for calculation of pharmacodynamic interactions and simulation of combined response].

OBJECTIVE: An approach is set up to calculate pharmacodynamic interaction and simulate the combined response. METHOD: 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. RESULT: 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. CONCLUSION: The approach can be used in the similar research, and it also provides predictions of component combinations from the other studies by simulation.

Tolerance and dose-volume relationship of intrathoracic stomach irradiation after esophagectomy for patients with thoracic esophageal squamous cell carcinoma.

PURPOSE: To identify the tolerance of radiation with a high prescribed dose and predictors for the development of intrathoracic stomach toxicity in patients with thoracic esophageal squamous cell carcinoma (SCC) after esophagectomy followed by gastric conduit reconstruction. MATERIALS AND METHODS: From 2011 to 2013, 105 patients after esophagectomy were treated with postoperative radiotherapy. The intrathoracic stomach was outlined with the calculation of a dose-volume histogram (DVH) for the initial intended treatment of 6020 cGy or 6300 cGy. The volume of the intrathoracic stomach receiving each dose was recorded at 10-Gy intervals between 10 and 40 Gy and at 5-Gy intervals between 40 and 60 Gy. The grade of toxicities was defined by the National Cancer Institute Common Toxicity Criteria version 4.0. RESULTS: The mean and maximum doses of the intrathoracic stomach were 2449 ± 986 cGy and 6519 ± 406 cGy, respectively. Sixteen (15.2%) and three (2.9%) experienced Common Toxicity Criteria Grade 2 and Grade 3 acute gastric toxicity. There were no Grade 4 toxicities. Fourteen patients (13.3%) exhibited late gastric complications possibly related to radiation. The volume percent of the intrathoracic stomach receiving at least 50 Gy (V50) was strongly associated with the degree of toxicity (p = 0.024, respectively). Multivariate analysis of patient and treatment-related factors revealed no other significant predictors of severe toxicities. CONCLUSIONS: The intrathoracic stomach is well tolerated with a high-dose irradiation for patients with esophageal SCC receiving radiotherapy after esophagectomy. A strong dose-volume relationship exists for the development of Grade 2 acute intrathoracic stomach toxicity in our study.

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.

Dynamic patterns of histone H3 lysine 4 methyltransferases and demethylases during mouse preimplantation development.

Extensive and dynamic chromatin remodeling occurs after fertilization, including DNA methylation and histone modifications. These changes underlie the transition from gametic to embryonic chromatin and are thought to facilitate early embryonic development. Histone H3 lysine 4 methylation (H3K4me) is an important epigenetic mechanism that associates with gene-specific activation and functions in development. However, dynamic regulation of H3K4me during early embryonic development remains unclear. Herein, the authors examined the dynamic changes of H3K4me and its key regulators (Ash1l, Ash2l, Kmt2a, Kmt2b, Kmt2c, Setd1a, Setd7, Kdm1a, Kdm1b, Kdm5a, Kdm5b, Kdm5c, and Kdm5d) in mouse oocytes and preimplantation embryos. An increase in levels of H3K4me2 and me3 was observed at the one- to two-cell stages (P < 0.05), corresponding to the period of embryonic genome activation (EGA). Subsequently, the H3K4me2 level dramatically decreased at the four-cell stage and remained at low level until the blastocyst stage (P < 0.05), whereas the H3K4me3 level transiently decreased in the four-cell embryos but steadily increased to the peak in the blastocysts (P < 0.05). The high level of H3K4me2 during the EGA was coinciding with a peak expression of its methyltransferase, ASH2L, which may stabilize this methylation level during this period. Correspondingly, a concomitant decrease in levels of its demethylases, KDM5B and KDM1A, was observed. H3K4me3 was correlated to the expression of its methyltransferase (KMT2B) and demethylase (KDM5A). Thus, these enzymes may function for the EGA and the first lineage segregation in preimplantation mouse embryos.

Quantitative analysis and simulation of anti-inflammatory effects from the active components of Paino Powder () in rats.

OBJECTIVE: To explore different combinations of the active ingredients of Paino Powder ()), including paeoniflorln, naringin, neohesperidln and platyeodin-D, which are responsible for the inhibition of carrageenin-induced edema in rats, and to evaluate the performance of the orthogonal simulation method in quantitative analysis and the simulation of the combinations. METHODS: A 1-level (used) and 2-level (unused) orthogonal design was applied to assign 7 combinations of active components. Aspirin and saline were set as the two controls. The carrageen In-Induced edema in the right hind paws of rats was established as the acute inflammation model The efficacy indices were expressed by the area under the curve (AUC) and the peak value of the swelling change (%) over time in rats. RESULTS: Compared with the saline group, the rats in active component combinations showed a significant reduction of AUG and peak value in the swelling (P<0.05). The maximum anti-inflammatory effect was from the whole four-ingredient combination. Among the four ingredients, naringin showed a dominant contribution to the combination, while paeoniflorin > platycodin-D > naringin contributed in succession. These results are consistent with the results of computer simulation. CONCLUSIONS: A single component from Paino Powder does not exhibit any anti-inflammatory effect, but some combinations show such effect. The strongest inhibition to edema comes from the full 4-ingredient combination. The orthogonal simulation method is feasible in the research on decomposed formulas of Chinese medicine.