薬理と治療

Objectives ESUEEWAN(R) combination capsule（SW651K）is a generic oral anticancer drug of S-1 combination capsule. We examined the combination effect of 5-chloro-2,4-dihydroxypyridine（CDHP）and potassium oxonate（Oxo）in SW651K and the possibility of gastrointestinal tract injury under the condition to show an antitumor activity, and not to develop a diarrhea in Yoshida sarcoma-bearing rat model. Methods To confirmed the effects of CDHP and Oxo in the commercial formulation of SW651K, we investigated the interactive pharmacological effects of SW651K without CDHP （CDHP－）and SW651K without Oxo（Oxo－）, prepared according to commercial methods. These formulations were orally administered to Yoshida sarcoma-bearing rats. The pharmacokinetic profiles of tegafur（FT）, 5-fluorouracil（5-FU）, CDHP, Oxo, and α-fluoro-β-alanine （FBAL）were compared after a single dose of either SW651K or CDHP－. Antitumor effect was evaluated on the basis of tumor volume after treatment for 7 consecutive days. The effects of Oxo on enterotoxicity were evaluated on the basis of body weights, incidence of diarrhea, pathological findings, the length and weight of intestinal tissue after consecutive treatments. Results Antitumor effect was significantly increased by the addition of CDHP, which was associated with an increased 5-FU concentration in blood and tumor. Furthermore, the plasma FBAL increased with a decrease in the plasma CDHP. Oxo suppressed the diarrhea completely, but did not all other evaluation items completely. Conclusions These results suggested that it is important to carefully monitor patients for side effects in clinical practice under the condition to show an antitumor activity, and not to develop a diarrhea.

Objectives Type 2 diabetic patients have increased fracture risk and lower bone mineral density（BMD）. However, there are few reports concerning BMD and type 2 diabetes. In this study we examined whether or not BMD is lower in Japanese type 2 diabetic patients. Receptor activator of nuclear factor NF-kappaB ligand （RANCL）produced by osteoblastic cells is the essential factor for osteoclast formation, activation and survival, thus resulting in bone resorption and bone loss. From this point of view denosumab was developed as anti-RANCL antibody for the treatment of osteoporosis. Little information is available about the effects of denosumab on diabetic osteopenia. We examined the effects of denosumab or bisphosphonate in diabetic patients after 2 years treatment of teriparatide. Methods We evaluated lumbar spine BMD and femoral（proximal part）BMD in 21 diabetic patients and 11 non-diabetic subjects（50-59 years of age, female）, 35 diabetic patients and 72 non-diabetic subjects（60-69 years of age, female）, 44 diabetic patients and 272 non-diabetic subjects（70-79 years of age, female）, and 27 diabetic patients and 267 non︱diabetic subjects （80-89 years of age, female）. BMD was evaluated with dual energy X-ray absorptiometry （DEXA）according to the guideline of Japan Osteoporosis Society 2015. BMD was expressed as the percent ratio to the young adult mean BMD（20︱29 years of age）. The effects of denosumab or bisphosphonate on diabetic osteopenia after 2 years treatment of teriparatide were examined. Fifteen diabetic patients took bisphosphonate （alendronate 35 mg weekly or risedronate 17.5 mg weekly）for 1.5 years after 2 years treatment of teriparatide（20μg daily）, whereas 32 diabetic patients took denosumab（60 mg every 6 months）for 1.5 years after 2 years treatment of teriparatide（20μg daily）. BMD was checked before and 2 years after the treatment of teriparatide, and then 1 year and 1.5 years after the treatment of denosumab or bisphosphonate. Results In any age group diabetic patients had significantly（P＜0.01）lower lumbar spine BMD and femoral BMD than non-diabetic controls. In 15 diabetic patients who took bisphosphonate after 2 years teriparatide treatment lumbar spine BMD was 78.7％ after 2 years teriparatide treatment, and then 80.3％ after 1 year bisphosphonate treatment and 77.1％ after 1.5 years bisphosphonate treatment, whereas femoral BMD was 73.9％ after 2 years teriparatide treatment, and then 75.3％ after 1 year bisphosphonate treatment and 70.7％ after 1.5 years bisphosphonate treatment. There was no significant difference in BMD between 2 years teriparatide treatment and 1 year or 1.5 years bisphosphonate treatment. In 32 diabetic patients who took denosumab after 2 years teriparatide treatment lumbar spine BMD was 77.4％ after 2 years teriparatide treatment, and then 87.9％ after 1 year denosumab treatment and 94.3％ after 1.5 years denosumab treatment, whereas femoral BMD was 73.8％ after 2 years teriparatide treatment, and then 80.9％ after 1 year denosumab treatment and 88.8％ after 1.5 years denosumab treatment. BMD significantly（P＜0.01）increased after 1 year and 1.5 years denosumab treatment compared to BMD after 2 years teriparatide treatment. Conclusions This study clearly showed that type 2 diabetic patients had lower BMD than the age-matched non-diabetic subjects, suggesting the existence of osteopenia in diabetes mellitus. For diabetic osteopenia denosumab therapy after teriparatide treatment is more effective than bisphosphonate.

Objective A placebo︱controlled, randomized, double︱blind clinical trial was conducted to examine the efficacy and safety of concomitantly administering mitiglinide（Glufast tablets）for 16 weeks to type 2 diabetes mellitus patients without adequate glycemic control, despite receiving long-acting insulin only or a combination of long-acting insulin and an oral hypoglycemic agent with diet therapy. Methods One tablet of mitiglinide（10 mg）or placebo was administered three times daily before meals for 16 weeks to 178 diabetic patients receiving monotherapy with long-acting insulin or a combination of long-acting insulin and an oral hypoglycemic agent. Results The HbA1c decrease was significantly greater in the mitiglinide group than in the placebo group at the final evaluation. This decrease occurred regardless of whether or not an oral hypoglycemic agent was administered. The postprandial plasma glucose level change was significantly greater in the mitiglinide group than in the placebo group with or without oral hypoglycemic agents, at the final evaluation, showing that mitiglinide lowers postprandial plasma glucose. Thirteen patients had adverse drug reactions in the mitiglinide group. Hypoglycemia in mild and moderate severity occurred in 11 patients. However, severe hypoglycemia and treatment discontinuation case were not also observed. Conclusions Mitiglinide appears to be clinically useful as combination therapy with long-acting insulin in patients with type 2 diabetes mellitus.

Objectives Hops are the main components of beer that provide flavor and bitterness. Iso-α-acids, the bitter components of hops, have been reported to reduce body fat in humans, but the bitterness induced by effective doses of iso- α-acids precludes their acceptance as a nutrient. The matured hop bitter acids （MHBA）of oxidized hops appear to have a more pleasant bitterness compared to the sharper bitterness of iso-α-acids. We evaluated the effect of the matured hop ethanol extract（MHE）, which contains MHBA, on the body fat reduction. Methods A double-blind, placebo-controlled parallel group study was conducted on healthy subjects aged 40 to below 65 years with a BMI of 25 to below 30 kg╱m2. Ninety- three volunteers were divided into three groups and daily ingested six capsules that contained 420 mg MHE（with 70 mg MHBA）, 210 mg MHE（with 35mgMHBA）, or no MHE for 12 weeks. The primary endpoints were reduction of body weight, body mass index（BMI）, body fat percentage, total fat area and visceral fat area, and the secondary endpoints were reduction of serum triglyceride, subcutaneous fat area and waist circumference after continual ingestion of MHE for 12 weeks. Results Body fat percentage significantly reduced after 12 weeks in both MHE groups compared to the placebo group. A significant reduction was observed in the BMI, total fat area and subcutaneous fat area after 12 weeks in the MHE with 35 mg MHBA group compared to the placebo group. In the subjects which have less than 100 cm2 visceral fat area, significant reduction was observed in the visceral fat area after 12 weeks in the MHE with 35 mg MHBA group compared to the placebo group. No adverse events related to the test samples or clinically relevant abnormal changes in the circulatory, blood and urine parameters were observed in all groups.　Conclusion These results suggest that consumption of a MHE containing MHBA safely reduces body fat.

Objectives In this study, we evaluated the effect of the food containing matured hop extract （MHE）, which contains matured hop bitter acids（MHBA）, on the body fat reduction. Methods A randomized, double-blind, placebo-controlled parallel group study was conducted on healthy subjects aged 20 to 65 years with a body mass index（BMI）of 25 to below 30 kg╱m2. One hundred and thirty-two volunteers were randomly divided into three groups and daily ingested 350 mL of the beverage that contained 215 mg MHE（35 mg MHBA）, 72 mg MHE（11.7 mg MHBA）, or no MHE for 12 weeks. As primary endpoints, total fat area, subcutaneous fat area, and visceral fat area were measured 0, 8, and 12 weeks after ingestion start and body fat percentage was measured 0, 4, 8, and 12 weeks after ingestion start. As secondary endpoints, body weight, body mass index, waist circumference, and hip circumference were measured 0, 4, 8, and 12 weeks after ingestion start. Results Visceral fat area significantly reduced in the MHE with 35 mg MHBA group compared to the placebo group. In the subjects which have less than 100cm2 visceral fat area, a significant reduction was observed in the visceral fat area in the MHE with 35 mg MHBA group compared to the placebo group. Conclusion These results indicated that the food containing MHE with 35 mg MHBA had an effect on the visceral fat reduction.

Objective The study aimed to verify that ingestion of 3.57 mg astaxanthin- containing capsule for 4 weeks would examine the safety and effects on skin condition. Methods A randomized, double-blind, parallel-group, placebo-controlled study was conducted for 15 male healthy subjects aged 30 to 65 with high oxidative stress levels. The skin moistureand skin condition with the skin image analyzer were measured. Results Intake of the 3.57 mg astaxanthin-containing capsules were significant increase skin moisture（P＝0.0010）, skin color uniformity（P＝0.010）. In addition, safety of astaxanthin-containing capsules were confirmed because side effects, adverse events and remarkable changes in laboratory values were not reported during the test period. Conclusions These results suggest the supplemental intake of astaxanthin improves skin moisture and skin color in high oxidative stress subjects.