["Re-evaluation upon suspected event" is an approach for post-marketing clinical study: lessons from adverse drug events related to Bupleuri Radix preparations].

We revisited the "Xiao Chaihu Decoction event (XCHDE)" occurred in late 1980s in Japan and the Bupleuri Radix related adverse drug reaction (ADR) reports in China After careful review, comparison, analysis and evaluation, we think the interstitial pneumonitis, drug induced Liver injury (DILI) and other severe adverse drug envents (ADEs) including death happened in Japan is probably results from multiple factors, including combinatory use of XCHDE with interferon, Kampo usage under modern medicine theory guidance, and use of XCHD on the basis of disease diagnosis instead of traditional Chinese syndrome complex differentiation. There are less ADE case reports related to XCHD preparation in China compared to Japan, mostly manifest with hypersensitivity responses of skin and perfuse perspiration. The symptoms of Radix Bupleuri injection related ADEs mainly manifest hypersensitivity-like response, 2 cases of intravenous infusion instead of intramuscular injection developed hypokalemia and renal failure. One case died from severe hypersensitivity shock. In Chinese literatures, there is no report of the interstitial pneumonitis and DILI associated with XCHDG in Japan. So far, there is no voluntary monitoring data and large sample clinical research data available. The author elaborated the classification of "reevaluation" and clarified "re-evaluation upon events" included the reaction to the suspected safety and efficacy events. Based on the current status of the clinical research on the Radix Bupleuri preparations, the author points out that post-marketing "re-evaluation upon suspected event" is not only a necessity of continuous evaluation of the safety, efficacy of drugs, it is also a necessity for providing objective clinical research data to share with the international and domestic drug administrations in the risk-benefit evaluation. It is also the unavoidable pathway to culture and push the excellent species and famous brands of TCM to the international market, in that it enhances the pharmaceutical manufactures the ability to control enterprise risk and eliminate the negative impact on traditional Chinese medicine. With the widely used and ADR report concentrated Radix Bupleuri injection as an example, the author provide a new approach to post-marketing clinical research.

[Post-marketing clinical study of traditional Chinese medicine--lessons learned from comprehensive evaluation of Fufang Zaoren capsule].

By comprehensive review and analysis of post-marketing clinical research on the efficacy and safety,we concluded that Fufang Zaoren capsule has certain therapeutic effects for insomnia, although current clinical research design needs improving. The post-marketing clinical studies also showed that it causes several adverse reactions at the recommended doses, such as chills, fever, dizziness, nausea, shortness of breath, chest tightness and palpitations, whereas high doses of Fufang Zaoren capsule can cause delayed extrapyramidal symptoms. Health Canada government website also prompted the L-tetrahydropalmatine in Fufang Zaoren capsule caused liver damage in pregnant women. The authors summarized the risk points, factors and risk control in the clinical use of Fufang Zaoren capsule and also present their perspective on the research status, existing problems and corresponding countermeasures in the post-marketing clinical re-evaluation of traditional Chinese medicine.

[Effects of Xiaopi Yishen herbal extract granules in treatment of fatigue-predominant subhealth due to liver-qi stagnation and spleen-qi deficiency: a prospective, randomized, placebo-controlled and double-blind clinical trial].

BACKGROUND: The demand for effective intervention for subhealth conditions is growing with increasing numbers of people being in a state of subhealth with a poor quality of life. Future research and evaluation of the treatment methods for subhealth conditions from the perspective of traditional Chinese medicine (TCM) may provide an important direction for developing effective management of these conditions. OBJECTIVE: To evaluate the efficacy and safety of Xiaopi Yishen herbal extract granules (XPYS-HEG), a compound traditional Chinese herbal medicine for relieving fatigue and promoting a cheerful spirit for the treatment of people with fatigue-predominant subhealth due to liver-qi stagnation and spleen-qi deficiency. DESIGN, SETTING PARTICIPANTS AND INTERVENTIONS: A multi-center, randomized, double-blinded, placebo-controlled clinical study was undertaken. The study period was 18 weeks, including 6 weeks for intervention and 12 weeks for follow-up. Participants were recruited from medical center and outpatient clinics of three hospitals in China, i.e. Xiaotangshan Hospital of Beijing, the First Affiliated Hospital of Henan University of TCM and the Affiliated Hospital of Liaoning University of TCM. Two hundred participants who met the criteria of fatigue-predominant subhealth and liver-qi stagnation and spleen-qi deficiency in TCM were allocated randomly to the treatment group (XPYS, n=100) and control group (placebo, n=100). MAIN OUTCOME MEASURES: The total score of Fatigue Scale-14 (FS-14) was used to evaluate the fatigue status of subjects and the extent of liver-qi stagnation and spleen-qi deficiency syndrome was also recorded. RESULTS: Three cases in the XPYS group withdrew from the trial. There were 200 subjects who entered to full analysis set (FAS) analysis and 197 subjects fitted in the per-protocol set (PPS) analysis. (1) According to the score changes of FS-14, the effectiveness rates in the XPYS and placebo group were as follows: 14.0% vs 9.0% (FAS) and 14.4% vs 9.0% (PPS) for complete remission, 19.0% vs 15.0% (FAS) and 19.6% vs 15.0% (PPS) for obvious effects, 39.0% vs 26.0% (FAS) and 39.2% vs 26.0% (PPS) for effective, and 72.0% vs 50.0% (FAS) and 73.2% vs 50.0% (PPS) for complete efficacy. The efficacy of XPYS-HEG was superior to the placebo statistically (P<0.05). (2) According to the score changes of TCM syndrome, the effectiveness rates in the XPYS group and placebo group were as follows: 1.0% vs 0.0% (FAS) and 1.0% vs 0.0% (PPS) for complete remission, 20.0% vs 7.0% (FAS) and 19.6% vs 7.0% (PPS) for obvious effects, 29.0% vs 24.0% (FAS) and 29.9% vs 24.0% (PPS) for effective, and 50.0% vs 31.0% (FAS) and 50.5% vs 31.0% (PPS) for complete efficacy. The efficacy of XPYS-HEG was superior to that of placebo statistically (P<0.05). (3) The follow-up results at 12 weeks and 18 weeks showed that the efficacy of XPYS-HEG was superior to that of placebo statistically (P<0.05). (4) No adverse effects were found in the XPYS group. CONCLUSION: It can be concluded that XPYS-HEG is effective and safe for the treatment of people with fatigue-predominant subhealth due to liver-qi stagnation and spleen-qi deficiency.