薬理と治療

In recent years, the effects of non-essential amino acid, glutamine, on immune system have been focused and were found to modulate inflammatory response, gut function and improve postoperative outcome. In this review article, the effects of glutamine, given either parenteral or enteral route, to man(normal and patients with cancer), farm animals(cow and pigs with pancreatitis) and rodents (rats and mice)are looked over. In most cases, glutamine showed an improvement of survival rate, minimized infectious complications, costs and hospital-length of stay. In addition, glutamine suppressed the side effect induced by anti-cancer drugs(5-FU, doxorubicin). As one of the mechanism by which glutamine enhances immune response was suggested to be due to the activation of lymphocyte and macrophage. In vitro study, it was shown that glutamine activates lymphocyte and macrophage in a dose-related manner. Therefore, even in in vivo study, a dose-response activity of glutamine was expected. Most of the papers consist of the effect of glutamine at one dose. Thus, even if the effect of glutamine at one dose should be negative, the increase in dose of glutamine appears to show positive results. As a whole, it was confirmed that glutamine has a potentiative activity on immune response in vivo studies as well as in vitro studies.

目的生活習慣病;高血圧症,糖尿病,および高コレステロール血症の関係を,かかりつけ薬局の処方箋情報から検討する。方法アルツハイマー病薬,パーキンソン病薬,あるいはその両方を処方された方を対象に生活習慣病薬の処方頻度を調査し,多変量解析を行った。結果抗糖尿病薬,スタチンが処方群で,降圧剤処方オッズ比はそれぞれ2.257(1.196-4.260;P=0.012),2.454(1.486-4.053;P<0.001)。同様に,抗糖尿病薬,スタチン処方群で,抗糖尿病薬処方オッズ比はそれぞれ2.262(1.193-4.288;P=0.012),3.716(1.985-6.959;P<0.001)。降圧剤,スタチン群で, スタチン処方オッズ比はそれぞれ2.461(1.490-4.065;P<0.001),3.697(1.979-6.908;P<0.001)だった。いずれも,年齢,性別,AD 薬,PD薬の有無で調整した。考察降圧剤,抗糖尿病薬,スタチンの薬剤の処方には関連がある。多変量解析の結果,これは,年齢,性別,認知症薬の有無,PD 病薬と独立している。2群処方は加算的に影響する。高血圧,糖尿病,高コレステロール血症は密接に関係しあっている。【利益相反】なし

Background and Objectives For the development of fixed-dose combination tablet, the bioequivalence and the food-effect on bioavailability between the fixed-dose combination and each tablet are needed. The study objectives were to investigate the bioequivalence of fixed-dose triple combination of telmisartan 80 mg, amlodipine 5 mg and hydrochlorothiazide 12.5 mg(T80/A5/H12.5 mg), compared to co-administration of telmisartan 80 mg/amlodipine 5 mg combination tablet plus hydrochlorothiazide 12.5 mg tablet(T80/A5 mg+H12.5 mg)or to co-administration of telmisartan 80 mg/hydrochlorothiazide 12.5 mg combination tablet plus amlodipine 5 mg tablet (T80/H12.5 mg+A5 mg). In addition, the food-effect of this triple combination on the pharmacokinetics were investigated. Methods Bioequivalences were assessed in 72 Japanese healthy male adult volunteers by an open-label, randomized, single-dose, 2-group, 4-period replicated crossover design, with a washout period of at least 14 days. The food effect was assessed in 36 volunteers by an open-label, single-dose, 1 add-on period(2-period fixed-sequence for 1 group)design with a washout period of at least 14 days[NCT02121535, NCT02129192]. Results The comparison between T80/A5/H12.5 mg and either the co-administration of T80/A5 mg+H12.5 mg, or the co-administration of T80/H12.5 mg+A5 mg, revealed that, for the Cmax and AUC0-tz of telmisartan, amlodipine and hydrochlorothiazide, the two-sided 90% confidence intervals for the geometric mean ratios of T80/A5/H12.5 mg to the respective co-administration therapies were within the bioequivalence criteria(80% to 125%). In addition, the two-sided 90% confidence intervals for the geometric mean ratios suggested that the Cmax and AUC0-tz of telmisartan and the Cmax of hydrochlorothiazide were reduced by food intake. However, foods did not affect the pharmacokinetics of amlodipine. The safety profile of all of T80/A5/H12.5 mg, co-administration of T80/A5 mg+H12.5 mg, and co-administration of T80/H12.5 mg+A5 mg were similar and in line with what was already known regarding the safety profile of each of the drugs in the combination. Conclusions Bioequivalence was proven between T80/A5/H12.5 mg and either co-administration of T80/A5 mg+H12.5 mg, or T80/H12.5 mg+A5 mg. The food effect on each ingredient of T80/A5/H12.5 mg was similar to that observed with T80/A5 mg and T80/H12.5 mg.

Background and Objectives It was known that there were no drug-drug interactions between telmisartan and either amlodipine or hydrochlorothiazide in the 2-agent combinations. However there are no investigation in 3-agent co-administration of telmisartan, amlodipine and hydrochlorothiazide. This study objective was to evaluate the relative bioavailability at steady-state between new antihypertensive fixed-dose triple combination of telmisartan, amlodipine and hydrochlorothiazide, and the fixed-dose combination drugs with two agents. Methods This trial was performed in 36 Japanese healthy male adult volunteers by an open-label, randomized, multiple-dose, 6-sequence, 3-period, 3-treatment crossover design using fixed-dose combinations of telmisartan 80 mg, amlodipine 5 mg and hydrochlorothiazide 12.5 mg(T80/A5/H12.5 mg), telmisartan 80 mg and hydrochlorothiazide 12.5 mg(T80/H12.5mg), or telmisartan 80 mg and amlodipine 5 mg(T80/A5 mg)[NCT02183675]. Each treatment was administered once daily for 10 days in fasted state in the morning. Results In all formulations, telmisartan reached Cmax,ss at 0.50-0.75 hours, and was eliminated with t1/2,ss of 23.6-27.1 hours. For AUCτ,ss, the 90% confidence intervals(CIs)for the geometric mean ratio of T80/A5/H12.5 mg to T80/H12.5 mg and to T80/A5 mg were within the bioequivalence criteria(80% to 125%). The 90% CIs for the geometric mean ratios of Cmax,ss slightly exceeded the upper limit of the criteria but the point estimate were 108.4%(vs. T80/H12.5 mg)and 114.9%(vs. T80/A5 mg), and 90% CIs included the unity. Amlodipine reached Cmax,ss at 8.00 hours, and was eliminated with t1/2,ss of 42.5-43.0 hours. The 90% CIs for the geometric mean ratios of Cmax,ss and AUCτ,ss were within the bioequivalence criteria. Hydrochlorothiazide reached Cmax,ss at 1.50 hours, and was eliminated with t1/2,ss of 10.3-11.1 hours. The 90% CIs for the geometric mean ratios of Cmax,ss, AUCτ,ss and urinary excretion (Ae0-24,ss)were within the bioequivalence criteria. The safety of T80/A5/H12.5 mg was similar to T80/H12.5 mg and T80/A5 mg. Conclusions Following multiple--dose administration of T80/A5/H12.5 mg, no clinically significant pharmacokinetic interactions were observed among the ingredients. The safety and tolerability of T80/A5/H12.5 mg were favorable, as with T80/H12.5 mg and T80/A5 mg.

Objective We carried out two randomized double-blind placebo-controlled parallel group studies to evaluate the safety of long-term intake and excessive intake of the instant noodles (non-fried soba)containing highly cross-linked phosphate starch(HXLS)made from tapioca in the healthy adults including volunteers who tended to be constipated. Methods The subjects for the safety evaluation of the long-term intake study or the excessive intake study were each 24 healthy volunteers and randomly divided into two groups, respectively. In the long-term intake study, they ingested one package(107.9 g)of the test instant noodles containing 7 g per day(as fiber)of HXLS, or the same amount of the placebo instant noodles containing digestible starch instead of HXLS for 12 weeks. In the excessive intake study, they ingested one package(147.9 g)of the test instant noodles containing 21 g per day (as fiber)of HXLS, which is 3 times excess to the long-term intake study, or the placebo instant noodles per day for 4 weeks. Result No unusual changes were observed in physical, blood, urinary examination and medical interview on HXLS containing instant noodles in the long-term intake study and the excessive intake study. Conclusion These results demonstrated the safety of the instant noodles containing HXLS in the healthy adults including volunteers who tended to be constipated in both cases of the long term and excessive intake.

Background and Objective Osteoarthritis(OA)is a representative cause of knee pain in the elderly. The estimated number of Japanese patients with knee OA is approximately 25 million. Glucosamine and chondroitin are used as a supplement to reduce the symptoms of knee pain, based on the clinical trials with knee OA patients. Thus, there is essentially no study reporting on the action of glucosamine and chondroitin-containing supplement on healthy individuals. The aim of this study was to investigate the effects of glucosamine and chondroitin sulfate on gait of healthy volunteer. Methods We conducted a randomized, placebo-controlled, double-blind, clinical trial using 60 healthy participants with weak gait ability aged 40 to 68. They were administered with a glucosamine and chondroitin-containing supplement (glucosamine hydrochloride 1200 mg/day and chondroitin sulfate 60 mg/day)or a placebo for 12 weeks. The primary outcome was measured using the scores of locomo level test as well as JKOM(Japanese Knee Osteoarthritis Measure). Results In a gait ability indicator called two-step test, the score was significantly improved at 8 weeks after the intervention in the test supplement group compared with the placebo group. Furthermore, when the subjects with JKOM score≧30 were analyzed, the score of two-step test was further improved in the test supplement group. These observations suggest that a test supplement improves a gait ability of the subjects with weak gait ability. Conclusions Glucosamine and chondroitin-containing supplement improves the gait ability of healthy individuals with weak gait ability.

Objectives To investigate the dermatological effects of an Alpinia zerumbet leaves extract (ALE)on the skin of Japanese females. Methods A randomized, placebo-controlled, double-blind, parallel-group comparative study was conducted on 20 healthy females who provided informed consent. Subjects took either a beverage containing ALE or a placebo beverage once daily for eight consecutive weeks, and skin moisture content, transepidermal water loss, and skin elasticity were determined, in addition to skin texture replica analysis. Results A non-significant increase in skin moisture content was observed in the placebo group, while a significant increase in skin moisture content and a significant decrease in transepidermal water loss were observed in the ALE group. A significant increase in skin elasticity was also observed in the ALE group, whereas the skin replica analysis showed significant increases in the number of skin textures in both groups. No clinically relevant adverse events were observed throughout the study. Conclusion These findings suggested that the ALE may prevent skin dryness, moisturize the skin, and enhance skin elasticity. It was also suggested that the ALE is safe for consumption as a useful functional food.

Objectives The aim of the study was to investigate the effects of food containing asparagus extract(ONR-8)on alertness upon awakening and sleep quality on Monday in healthy participants with different sleep patterns between workdays and weekends, also known as“social jetlag". Methods We conducted a randomized, double-blind, placebo-controlled, crossover study with 50 healthy participants who delayed their sleep onset time/offset time on weekends. In Period 1, participants were randomly assigned to take either ONR-8 or placebo for 2 weeks. In Period 2, the treatments were reversed in a crossover manner. We evaluated subjective sleep quality using the St. Mary's Hospital sleep questionnaire(SMH)and a visual analogue scale (VAS), mood using the Japanese UWIST mood adjective checklist(JUMACL), and a feeling of fatigue using a VAS on 3 Monday mornings during both Period 1 and Period 2. In addition,health-related QOL was estimated by SF-36 and objective sleep parameters were evaluated by actigraphy for 1 week prior to intake and continuously during the study period. Results The SMH score for the question regarding alertness“How clear-headed did you feel after getting up this morning?"and the VAS score for sleep quality during the ONR-8 intake period were significantly improved compared to the placebo intake period. Although no signif-icant difference was observed in mood, the VAS score for a feeling of fatigue tended to be improved during the ONR-8 intake period. Mental health subscore of SF-36 was significantly better during the ONR-8 intake period than the placebo intake period. Actigraphy data showed that sleep offset time on weekends was significantly earlier during the ONR-8 intake period. In addition, there were no adverse clinical events throughout the study period. Conclusions These findings suggest that ONR-8 improved alertness upon awakening and sleep quality, and had a tendency to improve a feeling of fatigue on Monday following delayed weekend sleep timing. Furthermore, it appeared to reduce sleep-wake rhythm disturbance. These results suggest that ONR-8 has the potential to provide good Monday morning conditions and avoid Monday morning blues.