薬理と治療
Volume 43, Issue 9, 2015
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TOPIC
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コラム
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REVIEW
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寒冷環境下におけるEPA の生理学的役割―EPA が多彩な生物活性を示す理由―
43巻9号(2015);View Description Hide DescriptionAll living organisms have evolved from a hyperthermophilic common ancestor (Commonote), which was proposed by Woese, and then, even in low optimal growth temperatures, some creatures can survive by maintaining plasma membrane fluidity. Various creatures, from microorganisms to mammals, that grow and survive in a cold environment defend themselves from the cold-induced reduction in their plasma membrane fluidities by increasing the EPA concentration in their membrane. A cold stimulus activates desaturases in the tissues of organisms, resulting in production of a considerable amount of EPA and elevating plasma membrane EPA concentrations. In cold ambient temperatures, TRPM8 is activated at higher temperatures by reduced plasma membrane fluidity. Furthermore, a cold stimulus activates the sympathetic nervous system; increases blood pressure, heart rate, and blood noradrenalin levels; decreases blood TG levels; and caused abnormal electrocardiograms and hypercoagulable state. Heat is produced by accelerated β-oxidation. The parasympathetic nervous system is also activated to counteract the excessive sympathetic nervous system activation. A cold environment causes a chronic inflammatory state and hypercoagulable state that consists of increases in blood fibrinogen and platelet aggregation. As a result, cardiovascular diseases are aggravated, and cardiovascular events occur at a higher frequency in the winter.In contrast, in a normothermic environment, the well-known actions of EPA includeincreased membrane fluidity, decreased blood TG levels, stimulation of beta-oxidation, parasympathetic system activation, improvements in abnormal electrocardiograms, and inhibition of chronic inflammation, hypercoagulation and cardiovascular diseases. Interestingly, a number of targets of these actions of EPA correspond respectively to the biological phenomena changed by cold temperatures. Therefore, it is presumed that EPA can affect cold-related changes in analogy using Gnomonic Structure. This analogy is supported by the fact that EPA increases membrane fluidity, inhibits platelet aggregation and decreases blood TG not only in non-cold conditions but also in cold conditions like Greenland. The various actions of EPA, which have been confirmed in a normothermic environment, are analogically considered to regulate various changes in a cold environment. In other words, the intrinsic role of EPA is suggested as protection of the organism from cold via a number of different actions. Various biological activities of EPA, originating from this defense against the cold, have been recognized as the diverse actions of EPA in a normothermic environment. This hypothesis might explain the diversity of actions of EPA.
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ORIGINAL ARTICLES
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CIA マウスの滑膜線維芽細胞における炎症性サイトカインに対するTriptolide の影響
43巻9号(2015);View Description Hide DescriptionObjectives Triptolide, a compound originally isolated from Tripterygium wilfordii Hook F (TWHF), a vine used in China for autoimmune diseases such as rheumatoid arthritis(RA), is known to have immunosuppressive and anti-inflammatory effects. However, its mechanism of action is not well understood. In this study, we examined the effect of triptolide on inflammatory cytokines using synovial fibroblasts obtained from collagen-induced arthritis(CIA)mice, a commonly used model in RA studies. Methods CIA was induced in 7-week︱old BALB╱c mice using a mouse monoclonal anti-typeⅡ collagen 5-clone antibody cocktail. On day 10, we collected synovial fibroblasts from the articular cartilage of both knees and used cells at passage 4︱9. We replaced the culture media of cells with triptolide and lipopolysaccharide(LPS). We then measured the inflammatory cytokines level and transcription factors level. Results LPS significantly induced the production of inflammatory cytokines such as tumor necrosis factor(TNF)-α, interleukin(IL)-1β, and IL-6, as well as that of inflammatory cytokine -related transcription factors, including nuclear factor(NF)-κB and phosphorylated IκB, in synovial fibroblasts. Triptolide significantly suppressed both LPS-induced cytokine and transcription factor expression in a dose-dependent manner. Conclusions These data suggest that triptolide directly affects fibroblasts and exerts anti-inflammatory effects by suppressing the expression of inflammatory cytokines in a paracrine manner. -
The Effect of Tolvaptan, a Vasopressin V2 Receptor Antagonist, on the Portal Venous Pressure in Rats
43巻9号(2015);View Description Hide DescriptionPurpose In order to explore whether the portal venous pressure(PVP)increases in response to administration of tolvaptan or not, we determined the effect of tolvaptan, the vasopressin V2 receptor antagonist, on PVP in in vivo anesthetized Sprague-Dawley rats with and without portal hypertension induced by bile duct ligation(BDL), and in ex vivo isolated blood-perfused rat livers. Methods In perfused livers(n=10), with measurement of PVP, hepatic venous pressure(HVP),and portal venous blood flow(Qpv), the hepatic vascular resistance(Rt(: PVP-HVP)╱Qpv)was determined. In anesthetized intact rats(n=5), the mean arterial blood pressure(MAP), PVP, and mean portal venous blood flow(PBF)were measured, and the splanchnic vascular resistance (Rspl(; MAP-PVP)╱PBF)was determined. In bile duct ligated rats(n=4), MAP and PVP were measured. Results In perfused livers, PVP and Rt were not significantly changed from the baseline of 7.1±0.2 cmH2O and 0.19±0.003 cmH2O・mL-1・min, respectively, after consecutive injections of tolvaptan at 0.001-1μM. Subsequent injections of norepinephrine at 0.001-1μM caused no significant differences in the induced increases in PVP or Rt between tolvaptan- and vehicle-treated livers, suggesting no effects of tolvaptan on the reactivity of the portal vessels to norepinephrine. An intravenous injections of tolvaptan at 0.1, 0.3 and 1 mg╱kg into anesthetized intact or bile duct ligated rats, the basal PVP levels of which were 12.6±1.1 mmHg, did not produce any significant changes in PVP or Rspl. Conclusion Tolvaptan does not affect portal venous pressure in anesthetized rats with or without portal hypertension induced by BDL, or in isolated perfused rat livers. -
Inhibitory Effects of Glycyrrhizin on Scratching Behavior in Response to Substance P,PAR—2 Agonist, and LTB4 in Mice
43巻9号(2015);View Description Hide DescriptionObjective The intravenous preparation of glycyrrhizin(GL)has been used for chronic and antihistamine-resistant pruritus, for example, in hemodialysis(HD) patients. To understand how GL shows anti-pruritic effects, we examined the effects of GL on scratching behavior elicited by histamine, substance P(SP), protease-activated receptor-2(PAR-2)agonistic peptide, or leukotriene B4(LTB4)in mice. Methods Thirty minutes after intravenous administration of GL, each pruritogen; histamine (100 nmol╱site), SP(100 nmol╱site), PAR-2 agonistic peptide(50 nmol╱site), or LTB4(0.03 nmol╱site), was intradermally injected into the back of ICR mice, and the number of scratching was counted. Further, using MiaPaca-2 human pancreatic cancer cells, the effect of GL on LTB4-induced extracellular signal regulated kinase(ERK)1╱2 phosphorylation via BLT1 was also investigated by western blot analysis. Results Intravenously injected GL significantly and dose-dependently reduced scratching induced by SP, PAR-2 agonistic peptide, or LTB4, though GL did not significantly inhibit histamine-induced scratching. Furthermore, GL reduced LTB4-induced ERK 1╱2 phosphorylation in MiaPaca-2 cells. Conclusions We demonstrate for the first time that GL has anti-pruritic effects in animal studies as reported in the clinic. Our data suggest that GL exhibits anti-pruritic effects through a different pathway than existing drugs, such as antihistamines. -
新規抗てんかん薬Lacosamide の薬物動態,安全性および忍容性の検討―日本人と中国人でのLacosamide 単回経口投与後の薬物動態パラメータの比較―
43巻9号(2015);View Description Hide DescriptionBackground and Objective The antiepileptic drug lacosamide has been approved worldwide apart from Japan and China for several years. This study evaluated the pharmacokinetics(PK), safety, and tolerability of lacosamide following a single oral administration(100 mg, 200 mg, or 400 mg)in healthy male Japanese and Chinese subjects. Methods This study used a randomized, double-blinded, placebo-controlled, 3-way cross-over design, with 3 doses of lacosamide(100 mg, 200 mg or 400 mg)administered orally to Japanese and Chinese subjects. Primary PK parameters were the maximum plasma concentration(Cmax), area under the plasma concentration-time curve(AUC), and AUC from 0 to last quantifiable concentration(AUC0-t). Pharmacogenomics of CYP2C19 and CYP2C9 were also evaluated, along with safety. Results Thirty-six subjects(18 Japanese; 18 Chinese)were enrolled and analysed in this study. Cmax, AUC, and AUC0-t were similar between Japanese and Chinese subjects. CYP2C19 mutations induced some changes in lacosamide and its main metabolite PK parameters. Increases in lacosamide AUC between CYP2C19 intermediate metabolizer vs. extensive metabolizer(EM), and between poor metabolizer(PM)vs. EM were 10% and 24%, respectively, suggesting that no dose reduction is required in PMs. However, dose- and body weight-normalized PK parameters for lacosamide and its main metabolite were similar in both ethnicities with the same CYP2C19 genotype. Lacosamide was well tolerated in both ethnicities. Conclusions Lacosamide showed similar PK between healthy male Japanese and Chinese subjects. Lacosamide administered at 100-400 mg orally was well-tolerated. These findings are consistent with the known PK and safety profiles in Caucasians. -
Focoxanthin Supplementation Reduces Body Fat in Over Weight Humans―A Randomized, Placebo Controlled Study―
43巻9号(2015);View Description Hide DescriptionFucoxanthin, a xantophyll carotenoid contained in marine foods, has been shown accelerates lipolysis of adipose tissue in cells and animals studies, although the efficacy is unclear in humans. The present study investigated the effect of fucoxanthin supplementation on body weight and abdominal fat in healthy human subjects with higher body mass index. A randomized, placebo-controlled clinical trial was performed in 19 subjects who were divided into 3 groups; placebo, fucoxanthin 2 mg╱day, and fucoxanthin 4 mg╱day groups. During 3 months of administration, the body weight of the 4 mg╱day group showed a significant reduction in all 3 months of administration period compared with the initial baseline although there was no significant difference in the placebo and 2 mg╱day groups through the administration period. Both 2 and 4 mg╱day groups showed a significant reduction of weight loss rate compared with the placebo group, and morereduction was found in 4 mg╱day group. The abdominal fat area was positively correlated with body weight loss. These results suggested that supplementation of fucoxanthin accelerates weight loss with reducing visceral fat. -
コラーゲン加水分解物の褥瘡治癒促進効果―無作為割付けプラセボ対照化二重盲検試験―
43巻9号(2015);View Description Hide DescriptionEffect of a specific collagen hydrolysate(CH), which contains bioactive dipeptides, on healing of pressure ulcer was investigated in a randomized, placebo-controlled, double-blind trial. All subjects with Stage Ⅱ or Ⅲ pressure ulcer were treated with standard therapy, and we compared CH intake and placebo intake group. End point was a comparison between groups of levels of Pressure Ulcer Scale for Healing (PUSH)score, Pressure Score Status Tool(PSST) score and decubitus area score 16 weeks after ingestion. The levels of PUSH score and PSST score in the CH group decreased significantly compared to the placebo group(P<0.01). The level of decubitus area score in the CH group was also reduced significantly(P<0.05) than the level in the placebo group. Though there was no significant difference in blood albumin level of the subjects between the two groups, an intra-group significant difference in the level was observed in the CH group. This study demonstrated that the CH intake has a pressure ulcer healing effect added to the standard therapy. -
複合サプリメント(ギムネマ酸,キトサン,緑茶エキス,桑の葉エキス,インゲン豆エキス含有)摂取による食後血中中性脂肪値上昇抑制効果検証試験―無作為化二重盲検クロスオーバー試験―
43巻9号(2015);View Description Hide DescriptionObjective The study aimed to verify that ingestion of a multiple dietary supplement containing gymnemic acid, chitosan, green tea extract, mulberry leaf extract, and kidney bean extract would reduce the postprandial serum triglyceride level of subjects. Methods A randomized, double-blind, cross-over study was conducted for 36 participants whose fasting serum triglyceride levels were 102 mg╱dL to 191 mg╱dL, ingested the multiple dietary supplement containing 9.4 mg of gymnemic acid, 100 mg of chitosan, 200 mg of green tea extract, 200 mg of mulberry leaf extract, and 4.8 mg of kidney bean extract or placebo with high fat meal(40.0 g fat). The serum triglyceride and remnant-like lipoprotein particle cholesterol(RLP-C)were determined before and 2, 3, 4, 6 hours(hr)after high fat meal ingestion. Results Intake of the multiple dietary supplement was significantly suppressed the postprandial increase in the serum triglyceride level compared to that in the placebo group. The difference was significant at 2 and 4 hr following ingestion(P< 0.01). This change was accompanied by the difference in the delta area under the curve(AUC)for serum triglyceride levels(mean ±SE:423.9±35.0 mg・h╱dL for the multiple dietary supplement intake vs. 533.3±32.2 mg・h╱dL for the placebo intake;P<0.001). We also observed significant suppression of the elevation of postprandial RLP-C level(delta RLP-C AUC:22.02±1.89 mg╱dL for the multiple dietary supplement intake vs. 28.99±1.78 mg╱dL for the placebo intake;P< 0.001). Conclusions These results suggest the multiple dietary supplement containing 9.4 mg of gymnemic acid, 100 mg of chitosan, 200 mg of green tea extract, 200 mg of mulberry leaf extract, and 4.8 mg of kidney been extract suppresses the elevation of postprandial serum triglyceride level and RLP-C in healthy subjects or subjects with moderately high fasting triglyceride levels. -
ビルベリー果実由来特定アントシアニン摂取によるVDT 負荷眼疲労の回復効果
43巻9号(2015);View Description Hide DescriptionObjective Several previous articles have considered anthocyanins(ACNs) to be beneficial to eyesight. However, much of their evidence was lacking, and the origin, kind and formation of the tested ACNs in the articles were not always specified and identified.The present study aimed to investigate the effect on eye strain of Standardized Bilberry Extract(SBE)containing a particular kind and formation of ACNs at lower dosage. Methods We conducted a randomized double-blind parallel-group study with twenty-four healthy Japanese participants aged from 20-59. The participants took either placebo or 107 mg of SBE(40 mg of Vaccinium Myrtillus ACNs: VMA)for 28 days. They used smartphones for 20 minutes to induce eye strain via visual display terminal(VDT)load and took a rest wearingan eye mask for a 10 minute recovery period. HFC-1 scores for each subjectʼs dominant eye were monitored twice; once before and once after the rest period. Results We measured the variation in the change in HFC-1 scores of both groups between the first(date 0)and second(date 28)visits. We observed the variation of the SBE group to show a significant improvement over that of the placebo group( P=0.016). Conclusions Oral SBE(40 mg of VMA)intake alleviated eye strain induced by VDT stress. -
難消化性デキストリン配合炭酸飲料による食後血糖値上昇抑制効果の検討―プラセボ対照二重盲検ランダム化クロスオーバー試験―
43巻9号(2015);View Description Hide DescriptionObjectives Itʼs well recognized that Resistant maltodextrin(RMD)is applied to many Foods for Specified Health Use for maintaining healthy intestinal regularity, blood glucose levels, and serum lipids. We studied the efficacy of a carbonated soft drink (CSD)containing RMD for suppressing the elevation of postprandial blood glucose level as for preventing the prediabetes development. Methods A randomized double-blinded crossover trial was conducted. The 42 subjects who were judged as prediabetes because of their impaired glucose tolerance, impaired fasting glucose, and╱or impaired casual blood glucose level were divided into two groups; the subjects in one group ingested the CSDs with 5 g(as dietary fiber)RMD together with test meals, the subjects in another group did placebo CSDs as the same. After one week interval, the subjects in each group ingested opposite CSDs. The levels of blood glucose and insulin were measured drawn at 0(before), 30, 60, 90, and 120 minutes after ingesting, and were compared between CSDs with and without RMD. Results Intake of CSD with RMD significantly suppressed the elevation of postprandial blood glucose levels at 60 and 90 minutes and its AUC, compared with placebo CSD. Conclusions These results indicated that the CSD supplemented with RMD suppresses the elevation of the postprandial blood glucose level.
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INFORMATION
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CONSORT 2010声明-ランダム化並行群間比較試験報告のための最新版ガイドライン-(薬理と治療2010;38:939-49. より再掲載)
43巻9号(2015);View Description Hide Description
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