薬理と治療

The factors of developing hypertension are the sympathetic nervous system （SNS）, renin-angiotensin-aldosterone system（RAAS）, circulating blood volume and peripheral vascular tonus etc., and these factors are complexly influenced each other. Monotherapy focused on the single factor may not sometimes suppress other factors which have been activated, introducing the sufficient hypotensive effect. When the monotherapy by some medicine lowered insufficiently the blood pressure in uncontrolled hypertensive patient, change to the monotherapy with increased doses of the same drug often achieves a smaller effect than that to the combination therapy added agent in other classes. To achieve of the target level of blood pressure, the treatment with a combination of drugs which act on different factors is desired. Although, SNS and RAAS are activated by different causes, they activate the other each other and form a vicious circle of rise of blood pressure. Further rotation of the cycle leads to further increase in blood pressure. Thus, stopping the rotation of the cycle is important in the treatment of hypertension by the inhibition of SNS and RAAS appropriately together. This point of view induces the concept of the combination tablet which consists of cilnidipine inhibiting SNS through the blocking of N-typed Ca-channel and ARB, valsartan, restraining RAAS. Furthermore cilnidipine possessed L-type calcium channel blocking action inducing dilatation of blood vessels. In summary, Atedio(R) Combination Tablets, decreased blood pressure by three mechanisms. In this report, the author reviewed the action of cilnidipine, comparing to that of an ARB and selective N-typed Ca channel inhibitor ω-conotoxin（ω-CTX）and revealed the physiological and pharmacological significance of the combination of cilnidipine and valsartan that is braking the hypertensive vicious cycle.

Osimertinib is an oral, potent, irreversible EGFR tyrosine kinase inhibitor that is selective for EGFR tyrosine kinase inhibitor-sensitizing mutations and the T790M resistance mutation. This mono-anilino-pyrimidine compound is structurally distinct and offers a pharmacologically differentiated profile from other EGFR-TKIs. As compared with previous EGFR inhibitors, osimertinib shows less in vitro activity against wild-type EGFR. In studies involving in vivo xenograft and genetically engineered mouse models representing EGFR sensitizing and T790M mutant disease, osimertinib demonstrated durable tumour shrinkage. Phase I study （NCT01802632）was conducted with the primary objective of determining the safety, tolerability and efficacy of osimertinib in patients with advanced EGFR-mutated NSCLC whose disease had progressed on prior therapy with an EGFR-TKI. Among 31 patients enrolled in the dose-escalation cohorts, no dose-limiting toxic effects occurred at doses of 20-240 mg once daily. An additional 222 patients were treated in expansion cohorts. We found that osimertinib was associated with a response rate of 61％ among 127 patients with EGFR T790M, with limited skin and gastrointestinal adverse effects. This suggests that a structurally distinct EGFR inhibitor, one that is selective for the mutated form of EGFR, can be clinically effective and has a side-effect profile that is not dose-limiting in the majority of patients in whom T790M-mediated drug resistance had developed. Osimertinib received approval as the treatment for patients with EGFR T790M mutation-positive metastatic NSCLC in the US, EU and Japan. Osimertinib is being compared with platinum-based doublet chemotherapy in the confirmatory Phase III study in patients with EGFR T790M mutation-positive metastatic NSCLC who have progressed after EGFR-TKI therapy（NCT02151981）

Objectives To evaluate the safety of long-term intake or excessive intake of the carbonated beverage containing resistant maltodextrin and matured hop extract （matured hop bitter acids）. Trial design Randomized double-blinded placebo-controlling parallel-group comparison study. Methods For the safety evaluation of long-term intake or excessive intake of the carbonated beverage, double-blinded parallel group studies were performed respectively. Sixty volunteers were randomly divided into two groups for each study, and took daily 1 bottle（350 mL）of the carbonated beverage that either did or did not contain resistant maltodextrin and matured hop extract for 12 weeks（long-term intake）or 3 bottles of each beverage daily for 4 weeks（excessive intake）. Results In the long-term or excessive intake trials, no abnormal changes triggered by ingestion of the test beverage were observed in clinical findings such as laboratory blood test, urinalysis and physical examination. Conclusion These results indicated that the carbonated beverage containing resistant maltodextrin and matured hop extract were safe for long-term and excessive intake.

Objectives To evaluate the safety of excessive consumption of alpha-linolenic acid-enriched diacylglycerol（ALA-DAG）. Methods A randomized, double-blind controlled, parallel-group study in 60 healthy subjects. The subjects were randomly allocated to two groups, and ingested either control triacylglycerol （TAG; rapeseed oil）or ALA-DAG at three times the effective dose（2.50 g/d）against visceral obesity（7.50 g/d）for 4 wk. Safety parameters were assessed at the 0, 2, and 4-wk time points. Results All subjects（n＝30/group）completed the study, and were included in the intention-to-treat（ITT）samples. No adverse events associated with consumption of ALA-DAG were observed in endocrine-related factors, fat-soluble vitamins, coagulation-related factors, or other general safety parameters, such as blood biochemistries, hematology, and urinary analyses in the ITT samples. Conclusions The results suggest that the excessive consumption of dietary ALA-DAG is safe in healthy subjects.

This study aimed to evaluate the effect of mycelial extract of cultured Cordyceps sinensis（CS extract）on the sleep disturbance by placing rats on the grid suspended over water. Wake, non-rapid eye-moving（non-REM）sleep and rapid eye-moving（REM）sleep were analyzed by computer software, simultaneously measuring electroencephalogram and electromyogram. Significant increase of wake duration, decrease of non-REM sleep duration and delay of sleep latency were observed by sleep disturbance for 3 hrs, but not after 4 hr. On the REM sleep, no significant difference was observed. CS extract attenuated the increase of wake and significantly decreased non-REM sleep by the sleep disturbance. In addition, the delayed sleep latency was significantly improved. Zopiclone, hypnotic drug used in clinic, also showed the same effects as CS extract. These results show that CS extract may be useful for the treatment of stress-induced sleep disturbance. Moreover, rats showed the adaptability for stress-induced sleep disturbance at early time.

Objectives The aim of the study was to investigate the effects of food containing asparagus extract（ONR-8）on sleep conditions in evening-type individuals. Methods We conducted a randomized, double-blind, placebo-controlled, crossover, exploratory study in 20 healthy male volunteers who had an evening-type chronotype. 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. To assess performance, participants took the Psychomotor Vigilance Test（PVT）twice: once in the morning and once after lunch at 0, 1, and 2 weeks of treatment. They also completed the Athens Insomnia Scale（AIS）, the Epworth Sleepiness Scale（ESS）, a visual analogue scale（VAS）for morning appetite, the Morningness-Eveningness Questionnaire（MEQ）, and SF-36. In addition, autonomic nerve function and expression of Heat Shock Protein（HSP）70 mRNA in peripheral blood leukocytes were measured. Participants were asked to complete the OSA sleep inventory MA version during the study period and to record sleep parameters by actigraphy for 3 days prior to intake and continuously during the study period. Results The AIS score during the period of ONR-8 intake was significantly improved as compared with the placebo intake period. When we analyzed the PVT data excluding participants who fell asleep during the test, a significantly faster reaction time on the PVT after lunch was observed during the intake of ONR-8. There were no adverse clinical events throughout the study period. Conclusions These results suggest that ONR-8 improved sleep and daytime performance in evening-type individuals.

目的本研究は，ヒトのラクトビオン酸過剰摂取の安全性を，非盲検のデザインにて評価した。方法登録基準と除外基準の条件を満たした健常な日本人男女21 名を募集し，医師の判断により適格性を評価した結果，全員が試験参加となった。試験参加者はラクトビオン酸含有錠剤を1 日計15 錠（通常の5 倍量）を4 週間摂取した。後観察期間を2 週間とした。摂取前，摂取2 週後，摂取4 週後，摂取終了2 週後に身体測定・理学検査，内科的検査，末梢血液検査，尿検査，自覚症状により安全性を評価した。結果試験参加者21 名全員が試験を完遂し，分析対象者とした（男性8 名＝53.5±9.5 歳，女性13 名＝47.7±6.2 歳）。医師の判断のもと，試験期間を通じて重篤な疾病や有害事象は認められなかった。摂取前と比較して，身体測定・理学検査，末梢血液検査，自覚症状の検査では，有意な変動が散見されたが基準値の範囲内であった。尿検査でも摂取後に変動する傾向がみられたが，臨床的な問題はないと判断された。内科的検査の結果，有害事象が示されたが，試験食品摂取との因果関係はなかった。結論ヒトがラクトビオン酸を通常の5 倍量である1 日15 錠を4 週間摂取した際の安全性が認められた。