Liver-related safety assessment of green tea extracts in humans: a systematic review of randomized controlled trials.

There remain liver-related safety concerns, regarding potential hepatotoxicity in humans, induced by green tea intake, despite being supposedly beneficial. Although many randomized controlled trials (RCTs) of green tea extracts have been reported in the literature, the systematic reviews published to date were only based on subjective assessment of case reports. To more objectively examine the liver-related safety of green tea intake, we conducted a systematic review of published RCTs. A systematic literature search was conducted using three databases (PubMed, EMBASE and Cochrane Central Register of Controlled Trials) in December 2013 to identify RCTs of green tea extracts. Data on liver-related adverse events, including laboratory test abnormalities, were abstracted from the identified articles. Methodological quality of RCTs was assessed. After excluding duplicates, 561 titles and abstracts and 119 full-text articles were screened, and finally 34 trials were identified. Of these, liver-related adverse events were reported in four trials; these adverse events involved seven subjects (eight events) in the green tea intervention group and one subject (one event) in the control group. The summary odds ratio, estimated using a meta-analysis method for sparse event data, for intervention compared with placebo was 2.1 (95% confidence interval: 0.5-9.8). The few events reported in both groups were elevations of liver enzymes. Most were mild, and no serious liver-related adverse events were reported. Results of this review, although not conclusive, suggest that liver-related adverse events after intake of green tea extracts are expected to be rare.

A randomized double blind placebo-controlled clinical trial of Hochuekkito, a traditional herbal medicine, in the treatment of elderly patients with weakness N of one and responder restricted design.

OBJECTIVE: To evaluate the effects of Hochuekkito, a traditional Japanese and Chinese medicine, in the treatment of elderly patients with general weakness. To devise a suitable study design for assessing the clinical effectiveness of traditional herbal medicines. METHODS: Fifteen elderly patients (mean +/- SD: age 78.4 +/- 7.8; m/f 3/12) participated in this study. A multicenter, prospective, randomized, double-blind, placebo-controlled study with N of one and responder restricted design was performed. After the run-in period, the patients were divided into responders and non-responders. Only responders were entered in the study, and were randomized into three groups: an active-placebo group, a placebo-active group and an active-active group. The study consisted of two 6-week terms with a 2-week washout period in between. We assessed the Short Form 36 Health Survey (SF-36) and Profile of Mood States (POMS) as an endpoint of quality of life (QOL). In addition, we assessed the biodefense status by measuring the natural killer cytolytic activity (NK activity), IL-2 producing activity of peripheral lymphocytes, lymphocyte proliferating activity and lymphocyte cell-surface antigens. RESULTS: The physical component summary of the SF-36 analysis significantly improved in the Hochuekkito-treated group. Four components (A-H: anger-hostility, F: fatigue, T-A: tension-anxiety, C: confusion) out of six improved in the Hochuekkito-treated group in the POMS analysis. Lymphocyte proliferating activity improved in the Hochuekkito-treated group but not significantly. Concerning the surface antigens of peripheral lymphocytes, the population of CD3 positive cells and CD3CD4 double positive cells increased in the Hochuekkito-treated group. CONCLUSION: We revealed that Hochuekkito improved the QOL and immunological status of elderly patients with weakness by randomized controlled trial. Our study design might be useful for assessing the efficacy of traditional herbal medicine in the future.

[Subrenal capsule assay as a chemosensitivity test (III)--Comparison of host reaction, experimental chemotherapy and use of nude mice].

We studied fundamentally subrenal capsule assay, using human tumor specimens (gastric, breast and pancreas cancers) serially transplanted in nude mice. Any prominent difference of host reaction was not found between the host of BALB/c-nu/+, BALB/c-+/+ and CDF1 mice. Using immunocompetent BALB/c-nu/+ mice, experimental chemotherapy with mitomycin C (MMC) and 5-fluorouracil (5-FU) was carried out. On day 6, macroscopic and histological findings corresponded relatively well with 5-FU effect but not with MMC. Using BALB/c-nu/nu mice, we tried 15-day SRC assay. When the sensitivity of anti-cancer drugs was compared between early and intermediate phase after inoculation, no obvious difference was found macroscopically and histologically. BALB/c-nu/nu mouse will be useful as a host of SRC assay, and could be applicable to clinical fresh cases.

[Subrenal capsule assay for chemosensitivity test (II)--Sequential changes in the implanted tumor tissue and histological findings].

We carried out fundamental subrenal capsule assay methodology, using tumor specimens of human cancer xenografts (breast cancer and colon cancer) serially transplanted into nude mice. With regard to sequential changes in the tumor grafts implanted under the renal space of immunocompetent mice, tumor size was largest macroscopically around day 6 after inoculation, and later involuted gradually. Histological findings showed that implanted tumor tissues were preserved to a moderate extent until day 4 after inoculation, but leukocyte infiltration by host reaction had begun by day 4, and tumor tissues were almost replaced by host reactive tissues on day 6. Labeling index scoring did not indicate growth of implanted tumor cells. We found that macroscopic tumor size was largest around day 6 because we measured tumor size with involved leukocyte infiltration, and the macroscopic tumor did not represent the true extent of the tumor tissue.

[Application to chemosensitivity tests of the human tumor-nude mouse system and subrenal capsule assay system].

Since 1974, approximately 200 fresh cancer tissues obtained from various types of cancer patients were inoculated into athymic BALB/c nude mice, of which 30 percent were taken and grown in the subcutaneous space of mice. Among them 15 lines of gastrointestinal and breast cancer xenografts were selected for experimental single agent chemotherapy. The response rates of 14 drugs examined in this xenograft system were compared with the cumulative clinical response rate of each drug in the same type of cancer. Drugs which were clinically effective against one type of tumor were found to be also effective against the corresponding xenograft in nude mice. Thus the human cancer-nude mouse system was considered useful as a predictive secondary screening method for new drugs. This evidence suggested to us the feasibility of utilizing the system as a chemosensitivity test for determining the drugs effective for an individual human malignancy. In our present study, the responses to 15 experimental chemotherapies with single agent or drug combination of 11 lines of cancer xenografts in nude mice were directly compared with the clinical response in each donor patient to the corresponding chemotherapy. Good correlation was obtained between these respective results, the overall predictive accuracy of the experimental results being 93%. Therefore, if the rate of transplantability to nude mice were to be improved, this nude mouse system would become a promising tool for the individual chemosensitivity test. The subrenal capsule (SRC) assay recently introduced by Bogden and his colleagues has excited much attention among Japanese clinical oncologists. In our study, cancer tissues implanted under the renal capsule 6 days after inoculation, did not show marked proliferation and a high percentage of implants was almost replaced by host reactive tissue. It therefore seems necessary to solve some fundamental problems before we can apply this assay method to clinical chemosensitivity trial.