薬理と治療

標準的治療が終了した再発・転移がん患者を効果的に治療するため，免疫療法に局所穿刺加温治療を同時施術し，ヒトへの臨床可能性を検討した。深部の腫瘍病変に対する施術は，免疫薬剤の局注機能を備えた穿刺式の微細径局所加温装置を用いて行った。参加した患者数は男15 名（平均年齢66.7 歳），女31 名（平均年齢60.4 歳），の計46 名（最小37歳，最大84 歳，平均年齢62.4 歳）であった。原疾患を分類すると，卵巣がん（1 例），腎臓がん（4 例），悪性リンパ腫（3 例），肺がん（6 例），乳がん（10 例），胃がん（2 例），子宮がん（5 例），大腸がん（5 例），膵臓がん（3 例），胸腺腫（1 例），食道がん（1 例），胆管がん（1 例），頭頸部がん（1例），咽頭がん（1 例）であった。免疫療法との併用局所加温部位数182 における評価を，全体ならびに，樹状細胞（DC）局注，活性化T 細胞（CTL）局注，加温100℃，加温60～70℃に層別結果として示した。当該加温方法と免疫細胞療法等を併用した結果は，症例部位の25％の完全奏功（CR）と30％の部分奏功（PR）であり，18％の安定（SD）を加えて，73％の部位において進行を抑えたといえる。安全性評価対象の加温処置241 件において，機器不具合16 件および有害事象15 件を認めた。本体機器の不具合10 件は初期故障と考えられた。当該機器および穿刺加温施術による比較的重篤な有害事象は3 件あったが，発現時に施術はただちに中止して鎮痛剤処方等で措置し，後遺症は認めていない。他は施術後の疼痛および生理的事象が12 件認められたがいずれも非重篤であり，その後の経過観察においてすべて寛解した。このように，当該機器および穿刺加温治療のヒトへの安全性が確認された。本穿刺加温治療は免疫療法との組合わせにより，がん対象部位に有効であり，その進行を抑えることが示唆された。

The safety of a new lactobacillus strain, Lactobacillus paracasei MCC1849, was evaluated by single-dose and 90-day repeated-dose oral toxicity tests using rats. Single dose of L. paracasei MCC1849 at 6000 mg╱kg did not induce any signs of toxicity. Repeated doses of L. paracasei MCC1849 at 1000 mg╱kg for 90 days also did not induce any signs of toxicity including clinical signs, body weights, food consumption, ophthalmoscopy, urinalysis, hematology, blood chemistry, organ weights, and gross and histopathology. The no observed adverse effect level of L. paracasei MCC1849 in a 90-day repeated dose toxicity study was judged to be greater than 1000 mg╱kg（corresponding to 3.27⊠1011 cells╱kg which would be much higher than 8.33⊠1010 cells╱kg, 100-fold the upper limit of human intake）. These results suggest that L. paracasei MCC1849 is safe for human consumption.

Objective The aim of this study was to investigate the ability of beeswax to act as blood absorption enhancer of DHA and EPA. Methods Animal study；Six rats and six mice were divided into two groups: the 0.95 mL╱kg fish oil plus 0.05 mL╱kg olive oil as control group（n＝3）and 0.95 mL╱kg fish oil plus 0.05 mL╱kg beeswax as beeswax group（n＝3）. The feed was single dose administered into the stomach using a gastric tube. To measure fatty acids, lymph and blood were collected just after administration and several time points up to 6 hours after administration. Clinical study；Eleven healthy men aged 23-41 years ingested 5 beeswax capsules（containing 80 mg DHA, 20 mg EPA and 5 mg beeswax ╱capsule） or 5 control capsules（containing 80 mg DHA and 20 mg EPA╱capsule）. For all participants the capsules intake has been separated by a washout period of seven days. In order to measure DHA and EPA plasma concentration, blood was collected before intake and several time points up to 24 hours after intake. Results In animal study, DHA and EPA plasma ratio in total plasma fatty acids was significantly increased between 3 and 6 hours from administration in beeswax group compared with control group（P＜0.05）. In clinical study, DHA and DHA plus EPA incremental concentrations were significantly higher at 2 and 4 hours after the intake of beeswax containing capsules than control capsules（P＜0.05）. Conclusions Based on the results of the present study it can be considered that the intake of beeswax containing capsules might induce an enhanced rate and extent of blood absorption of DHA and DHA plus EPA which could lead to broader benefits in other health outcomes.

Objective This study aimed to verify that the safety and effect on serum uric acid level of a dietary supplement containing vine tea extract and chitosan. Methods A randomized, double-blind, placebo-controlled, parallel-group comparison study was conducted for 78 male subjects aged 22 to 64 years whose serum uric acid levels were between 6.0 mg╱dL and 7.0 mg╱dL. The subjects consumed either a dietary supplement containing 500 mg of vine tea extract which contained 150 mg of ampelopsin and 100 mg of chitosan, or placebo for 12 consecutive weeks. The primary endpoint was the change from baseline of serum uric acid levels and the secondary endpoints were urinary uric acid excretion, uric acid clearance, creatinine clearance, and uric acid clearance -creatinine clearance rate. Results The change in serum uric acid level from baseline by the intake of the test supplement was significantly lower than that of placebo. On the other hand, in the secondary outcomes, no improvement effect by ingestion of the test food was observed. There was no safety problem of the test supplement under this test condition. Conclusions These results suggested intake of a dietary supplement containing 500 mg of vine tea extract and 100 mg of chitosan reduces serum uric acid level.

Self-induced lifestyle problems, such as stress, negative emotions, or irregular sleep-wake schedule, cause sleep disturbance. Lactoferrin has been reported to improve sleep quality and enteric environment in rats and humans. Our previous randomized placebo-controlled double-blind trial has shown that lactoferrin supplementation for 4 weeks could increase immunoglobulin A（IgA）secretion and improve sleep quality, daily mood, and enteric environment in sixty participants. In the present study, lactoferrin supplementation was evaluated in poor sleepers（total mood disturbance scores were more than the median）. In all, thirty-one participants took LLF （liposomal lactoferrin: lactoferrin 270 mg╱d）or a placebo for four weeks. Significant improvement in OSA sleep inventory for middle age and aged（OSA-MA）“sleepiness and fatigue on rising”and“initiation and maintenance of sleep”, Profile of Mood States“depression-dejection”, and stool consistency were found in the LLF group but not in the placebo group. The changes in subjective sleep quality had a significant linear correlation with the changes in the enteric environment. In conclusion, four-week lactoferrin supplementation may improve subjective sleepiness and fatigue on rising, nighttime sleep quality, daily depressed mood, and stool consistency.

Objective In order to investigate the effect of intake of Bifidobacterium longum N61-containing food on stress and fatigue, we conducted a single-blind, placebo-controlled, parallel-group comparison study with 20 to 60 years old workers who felt fatigue. Methods Eligible subjects（n＝40）consumed a heat-killed B. longum N61-containing food （group A; n＝20）or a placebo food that did not contain B. longum N61（group P; n＝20）for 8 weeks. The outcome measures were T score of POMS2-AS, score of QOL questionnaire, AIS, Factor I-V score（Zc value）of OSA-MA, total score and subscale score of PSQI-j, KGʼs Daily Life Questionnaire, serum dihydroepiandrosterone sulfate（DHEA︱S）╱cortisol ratio, serum DHEA-S, serum cortisol, salivary amylase, salivary IgA, salivary chromogranin A, salivary cortisol, and the cortisol awakening response（CAR）. The difference from pretrial value was compared between groups A and P. Results All of the subjects completed the predetermined schedule, and their data were subjected to analysis for both efficacy and safety. A confirmatory analysis was performed with 34 subjects（excluding 6 subjects）. Significant differences between groups A and P were observed in the results of QOL questionnaire（“appetite”and“sense of well-being”）. In the confirmatory analysis with 34 subjects, the following significant differences were found between groups A and P: CB（Confusion-Bewilderment）, DD（Depression-Dejection）, TA（Tension-Anxiety）, and TMD（Total Mood Disturbance）in POMS2-AS; and“execution of social role,”“sense of well-being,”and“fulfillment of life in total”in QOL questionnaire. All of the differences were preferable in group A. There were no serious adverse events related to intake of test foods. Conclusions Our results suggest that intake of B. longum N61 improves QOL, quality of sleep, and mood states.

Objective Long-term daily intake of a dietary supplement containing broccoli sprout extract （BSE）has been demonstrated to improve hepatic function in men with fatty liver. Here, we investigated the effects of BSE on hepatic function in healthy subjects. Methods A multicenter, randomized, double-blind, placebo-controlled, parallel-group comparative study was conducted in 103 healthy subjects aged 30-64 years. They were divided into two groups, BSE and placebo groups, who ingested a BSE-containing supplement（glucoraphanin（sulforaphane glucosinolate）, 24 mg╱day）or a placebo supplement, respectively, for 24 weeks. The groups were balanced for sex, age, and a serum biomarker of liver function（alanine aminotransferase: ALT）. The effects of this supplement on liver function and its safety were assessed after 0, 4, 12, and 24 weeks. Results There were no significant differences in biomarkers of liver function（ALT, aspartate aminotransferase, and γ-glutamyl transferase）between the BSE and placebo groups at all time-points of the treatment period. However, a stratified analysis by age demonstrated that serum ALT, the most specific and sensitive biomarker of liver damage, was significantly lower in middle-aged people（45-64 years）that had taken the BSE supplement for 24 weeks. Conclusions These results suggest that a dietary supplement containing BSE could prevent liver damage and maintain liver function, especially in middle-aged people.

Objective The aim of this study was to elucidate the effect of supplementation of Lactobacillus pentosus strain S-PT84（S-PT84）on the visceral fat mass reduction and its safety in human. Methods We performed a randomized, double-blind, placebo-controlled, parallel-group trial. Forty Japanese subjects（20 men and 20 women）aged from 30 to 65 years old with visceral fat area（VFA）≳100 cm2 were randomly divided into two groups and were administered either S-PT84（4.0⊠1010cells╱day）or matching placebo once a day for 8 weeks. Abdominal fat area was measured by computerized tomography before and after the 8 week supplementation in both groups. Results Total fat area（TFA）, subcutaneous fat area（SFA）, body weight and body mass index （BMI）in S︱PT84 group were significantly decreased greater than those in placebo group. There was a decreasing trend in VFA in S-PT84 group compared to placebo group. Moreover, actual values in both TFA and VFA were also significantly decreased in S-PT84 group at the end of the 8 week supplementation period. In stratified analysis in subjects with 23.0≲BMI＜30.0 at baseline, both TFA and VFA were significantly decreased in S-PT84 group at the end of the 8 week supplementation period. No adverse effects were observed in either group. Conclusions The present results indicate that the supplementation of S-PT84 decreased abdominal fat and body weight in Japanese subjects with obese tendencies.

Backgrounds Recovering early from fatigue by exercise and getting into good physical condition is an important factor to give ones best performance in an athletic competition. The amino acid-containing supplement used in this study contains arginine, ornithine, and lysine（as amino acids）in addition to glycogen, zinc, magnesium, selenium, vitamin B6, and powdered Kanka extract. Arginine, ornithine, and lysine are known to promote the secretion of growth hormone, thus playing an important role in recovery from fatigue. Objective This study aimed to verify the effect of the amino acid-containing supplement on secretion of growth hormone during exercise. Methods Adult volunteers（19 subjects）who routinely exercised were enrolled in this double-blind, crossover, placebo-controlled study. The amino acid-containing supplement and placebo were taken 15 minutes before exercise. Using an ergometer, AEROBIKEEX 80（manufactured by Combi）, exercise load was applied for 30 minutes at an exercise intensity equivalent to 60 percent maximum oxygen consumption（VO2 max）. Blood samples were taken before and after exercise, and the growth hormone leve- in the blood was measured. Results Owing to the intake of the amino acid-containing supplement and placebo 15 minutes before exercise, the growth hormone level in the blood increased from 0.99±0.29 ng╱mL and 0.56±0.21 ng╱mL before exercise to 3.20 ±0.55 ng╱mL and 2.08±0.25 ng╱mL after exercise, respectively. The growth hormone level in the blood with the amino acid-containing supplement was significantly higher compared with that in the blood with placebo after exercise. Conclusions The amino acid︱containing supplement is effective in promoting the secretion of growth hormone during exercise.

Objective VENETRON(R) is a commercial botanical product extracted from the leaves of Apocynum venetum L. and is used as a supplement as well as in various functional food products. Sleep quality is an important health issue in modern society. Therefore, we examined the safety and efficacy of VENETRON(R) in improvement of sleep quality and psychological stress. Methods In this randomized, double-blind, and placebo-controlled crossover study, 17 healthy adult participants with subjective dissatisfaction in their sleep quality orally ingested either 50 mg╱day of VENETRON(R) or placebo tablets for 8 days. The Uchida Kraepelin performance test（UK）and Uchida Kraepelin performance test questionnaire（UKQ）were performed to assess psychological stress. The Oguri-Shirakawa-Azumi Sleep Inventory MA version（OSA-MA）, immediately on rising questionnaire, and a sleep scan was performed to assess sleep quality. Results Several significant differences were observed between the groups that ingested the test product and placebo, including improvement in the initiation and maintenance of sleep in the OSA-MA, decrease in fluctuation rates of performance and increase in rate of resting effect in the UK, and decrease in mental stress feeling in the UKQ. Discussion Healthy participants with subjective dissatisfaction in their sleep quality showed improvements in sleep quality and reduction in psychological stress following ingestion of 50 mg╱day A. venetum leaf extract（VENETRON(R)）for 8 days. In addition, the test product appeared to be safe under the conditions employed in the present study.

VENETRON(R) is a commercial botanical product made from the leaves of Apocynum venetum L. It contains flavonoids, with the main functional components being hyperoside and isoquercitrin. The safety of VENETRON(R) were evaluated in animals and human clinical trials. Briefly, the 50％ lethal dose of VENETRON(R) was determined to be greater than 2000mg╱kg body weight in an acute oral toxicity study of mice. An 8-week subchronic toxicity study in rats revealed the no-observed-adverse-effect-level for VENETRON(R) to be at least 250 mg╱kg body weight╱day. Drug interaction testing indicated that VENETRON(R) did not influence cytochrome P450 3A or P-glycoprotein in rats. Furthermore, 30 healthy volunteers in Japan participated in a safety study, ingesting 50mg╱day for weeks 1-8, followed by 150mg╱day for weeks 9-12. No adverse effects resulted from taking VENETRON(R), and biochemical parameters remained within the reference ranges. Also through a placebo-controlled study with 17 healthy volunteers in Japan, ingesting 50 mg╱day for 8 days, showed no adverse effects from taking VENETRON(R). In addition, an 8-week study of 50 mg VENETRON(R)╱day was also conducted in 39 individuals in Canada, the UK, and the USA. The adverse events and blood pressure records indicated no difference between the VENETRON(R) and placebo groups. These results demonstrate the safety of VENETRON(R) and provide overall support for the potential of VENETRON(R) in various health-related applications.