Exploration and reflection on evaluation methodology of human use experience for new Chinese drug development / 中国中药杂志

The "triple combination" review system provides an opportunity for the transformation of human use experience into new Chinese drugs. However, there are some methodological and technical limitations in the assessment of human experience. Hence, the efficacy and safety evaluation methods should be established in accordance with the characteristics of Chinese herbs. This study summarized some evidence-based methodology to promote the transformation of human use experience to new Chinese drugs, mainly including the individualized pragmatic randomized controlled trial(RCT), cluster RCT, single-case RCT, single arm RCT with objective performance criteria, and partially nested RCT. As the real world data can be used to support the transformation of human experience, attention should be paid to convenient and efficient collection of data, prudent selection of design types, and adoption of appropriate ana-lysis methods to deal with confounding bias, including multi-factor regression model and propensity score. The newly proposed mixed research method can also be utilized to assess the human use experience, which is suitable for mining the theory of traditional Chinese medicine(TCM) and expert experience from different aspects. Meanwhile, considering the study design requirements and TCM cha-racteristics, this study put forward the common problems and solutions in the development of new Chinese drugs based on human use experience, including how to select the feasible outcome indicators, how to collect prescription data in the case of herb and dosage adjustment, and how to evaluate the comprehensive effectiveness of TCM from the perspective of "combination of disease and syndrome".

Placebo control and its methodological issues on clinical trials of acupuncture therapy / 中国针灸

The paper introduces the placebo acupuncture simulation devices commonly used in clinical trial of acupuncture therapy. These devices are composed of Streitberger, Park, Takakura, Foam and Phantom acupuncture. Because acupuncture therapy is a kind of complex intervention, there are the controversies in methodology for the acupuncture placebo control of clinical trial. Placebo acupuncture may be an effective control, with a certain of specific therapeutic effect. The blinding effect of placebo acupuncture is highly questioned, specially, the sensation of deqi is hardly imitated during acupuncture. On these grounds, in this research, the suggestions has been proposed on the selection and the setting of placebo control in clinical trial of acupuncture therapy.

Sample size estimation in acupuncture and moxibustion clinical trials / 中国针灸

The appropriate sample size estimation is very important in the design of clinical trials. However, insufficient or inappropriate sample size estimation is still a prominent problem in the currently published acupuncture and moxibustion clinical trials. At present, the superiority test, non-inferiority test and equivalence test have been widely used in acupuncture and moxibustion clinical trials. This article focuses on the application, calculation methods and PASS11 software using of these three hypothesis test types. In view of the problems in the estimation of sample size in acupuncture and moxibustion clinical trials, the particularity of sample size estimation in acupuncture and moxibustion is summarized from the aspects of parameter setting, ratio of intervention group and control group, and multi-group comparison, in order to guide acupuncture clinical researchers to correctly estimate sample size when conducting clinical trials.

Effects of thyroid hormone on macrophage dysfunction induced by oxidized low-density lipoprotein / 生理学报

It has been recognized that patients with hypothyroidism have higher risks of atherosclerosis and coronary heart disease, however, the mechanisms are largely unknown. Considering that macrophage dysfunction plays an important role in the formation and development of atherosclerosis plaques, this study aimed to investigate the direct effects of thyroid hormone on macrophage functions and to provide new insight for the mechanism of hypothyroid atherosclerosis. RAW264.7 cells (mouse leukaemic monocyte macrophage cell line) were incubated with oxidized low-density lipoprotein (oxLDL) to establish macrophage foam cells model in vitro, and the protective effects of different concentration of thyroxine (T4) on the macrophage foam cells function were explored. The proliferation, migration and cell aging of macrophages were detected by MTT method, scratch test and β-galactosidase staining respectively. The ELISA method was used to detect the secretion of tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and interleukin-1β (IL-1β). Western blot analysis was applied to measure the phosphorylation of focal adhesion kinase (FAK), which was required for the process of proliferation and migration of macrophages. The results showed that oxLDL significantly inhibited the macrophage proliferation and migration, induced cell senescence, and promoted the secretion of TNF-α, MCP-1, and IL-1β; while T4 reversed those effects of oxLDL on macrophage in a concentration-dependent manner. Moreover, oxLDL increased the phosphorylation of FAK in macrophage, while T4 concentration-dependently reversed the effect. These results suggest that T4 modulates macrophage proliferation, migration, senescence, and secretion of inflammation factors in a concentration-dependent way.

Up-regulation of Fas ligand expression by sirtuin 1 in both flow-restricted vessels and serum-stimulated vascular smooth muscle cells / 中国医学科学杂志(英文版)

<p><b>OBJECTIVE</b>To study the role of sirtuin 1 (SIRT1) in Fas ligand (FasL) expression regulation during vascular lesion formation and to elucidate the potential mechanisms.</p><p><b>METHODS</b>SIRT1 and FasL protein levels were detected by Western blotting in either mouse arteries extract or the whole rat aortic vascular smooth muscle cell (VSMC) lysate. Smooth muscle cell (SMC)-specific human SIRT1 transgenic (Tg) C57BL/6 mice and their littermate wild-type (WT) controls underwent complete carotid artery ligation (ligation groups) or the ligation-excluded operation (sham groups). The carotid arteries were collected 1 day after operation. Reverse transcription-polymerase chain reaction was performed to detect the mRNA levels of SIRT1 and FasL. Luciferase reporter assays were performed to detect the effect of WT-SIRT1, a dominant-negative form of SIRT1 (SIRT1H363Y), and GATA-6 on the promoter activity of FasL. Flow cytometry assay was applied to measure the hypodiploid DNA content of VSMC so as to monitor cellular apoptosis.</p><p><b>RESULTS</b>SIRT1 was expressed in both rat aortic VSMCs and mouse arteries. Forced SIRT1 expression increased FasL expression both in injured mouse carotid arteries 1 day after ligation (P<0.001) and VSMCs treated with serum (P<0.05 at the transcriptional level, P<0.001 at the protein level). No notable apoptosis was observed. Furthermore, transcription factor GATA-6 increased the promoter activity of FasL (P<0.001). The induction of FasL promoter activity by GATA-6 was enhanced by WT-SIRT1 (P<0.001), while SIRT1H363Y significantly relieved the enhancing effect of WT-SIRT1 on GATA-6 (P<0.001).</p><p><b>CONCLUSIONS</b>Overexpression of SIRT1 up-regulates FasL expression in both flow-restricted mouse carotid arteries and serum-stimulated VSMCs. The transcription factor GATA-6 participates in the transcriptional regulation of FasL expression by SIRT1.</p>