Omega 3 fatty acid

 脂肪酸の炭素原子は、カルボキシル基末端から番号が付けられており、二番、三番の炭素が各々α、βと、また、メチル基末端の炭素はω炭素と呼ばれる。不飽和結合の位置は、カルボキシル基末端から数えたときはΔ で、逆にω炭素から数えたときにはω で表される。ω 脂肪酸とはCH3−CH2−CH=CH−CH2−R−COO で表示される脂肪酸を意味する。ω 脂肪酸は多価不飽和脂肪酸で、α−リノレン酸(C18:3)、イコサペンタエン酸(C20:6)、ドコサヘキサエン酸(C22:6)などが含まれる。

 ω 脂肪酸が注目されているのは、一つには、疫学的検討により魚油に含まれる長鎖不飽和ω 脂肪酸の摂取が、乳癌をはじめ、ある種の癌化を抑制している可能性が示されたこと、実験的にVEGFα等の増殖因子を抑制することが示されたこと、更に、グルタミン、アルギニン、核酸などとともに高カロリー輸液に加え術前患者に投与すると、蛋白異化を抑制し、免疫機能を亢進、創傷治癒を促進させる効果が認められたこと等に起因している。アルギニン/ω 脂肪酸/核酸(AON)の臨床的意義については、経腸栄養症例を対象とした十数個のrandomied studyと、これらをまとめた二つのメタ・アナリシスの報告がある。それらの結果では、免疫系が有意に低下した群で術後感染症の発症頻度を著明に低下させ、在院日数を短縮させる効果が示されているが、死亡率の低下には寄与していないとの報告であった。

参考文献抄録

1)Enteral nutritional supplementation with key nutrients in patients with critical illness and cancer:a meta‐analysis of randomized controlled clinical trials.

 OBJECTIVE:To conduct a meta‐analysis of 11 randomized controlled trials comparing enteral nutritional support supplemented with key nutrients versus standard enteral nutritional support to determine effects on morbidity and mortality rates and hospital stay.BACKGROUND DATA:Recent studies have shown that malnutrition occurs in up to 30% of patients undergoing gastrointestinal surgery,resulting in an increased risk of postoperative complications and death.With the realization that key nutrients can modulate inflammatory,metabolic,and immune processes,enteral nutritional regimens(supplemented with large amounts of key nutrients)have been developed for clinical use.METHODS:Eleven prospective,randomized controlled trials evaluating 1,009 patients treated with combinations of key nutrients(Impact,Immun‐Aid)ware evaluated.Outcome measures examined were the incidences of pneumonia,infectious complications,and death,and length of hospital stay.Meta‐analyses were undertaken to obtain the odds ratio and 95% confidence interval for incidences of infectious complications,pneumonia,and death,and the weighted mean difference and 95% confidence interval for length of hospital stay.RESULTS:The provision of nutritional support supplemented with key nutrients to patients with critical illness resulted in a decrease in infectious complications when compared with patients receiving standard nutritional support and a significant reduction in overall hospital stay.Similar results were documented in patients with gastrointestinal cancer.However,there were no differences between patient groups for either pneumonia or death.CONCLUSIONS:This meta‐analysis has demonstrated that nutritional support supplemented with key nutrients results in a significant reduction in the risk of developing infectious complications and reduces the overall hospital stay in patients with critical illness and in patients with gastrointestinal cancer.However,there is no effect on death.These data have important implications for the management of such patients.

Heys SD,Walker LG,Smith I,Eremin O.Ann Surg 1999 Apr:229(4):467−77

2)Immunonutrition in the critically ill:a systematic review of clinical outcome.

 OBJECTIVE:To perform a mete‐analysis addressing whether enteral nutrition with immune‐enhancing feeds benefits critically patients after trauma,sepsis,or major surgey.DATA SOURCES:Studies were identified by MEDLINE search(1967 to January 1998)for original articles in English using the search terms“human,”“enteral nutrition,”“arginine,”“nucleotides,”“omega−3 fatty acids,”“immunonutrition,”“IMPACT,”and“Immun‐Aid”Additionally,the authors of the studies and the manufacturers of the feeds were contacted for additional information.Access to original databases was obtained for the three largest studies.STUDY SELECTION:Fifteen randomized controlled trials comparing patients receiving standard enteral nutrition with patients receiving a commercially available immune‐enhancing feed with arginine with or without glutamine,nucleotides,and omega−3 fatty acids were identified by two independent reviewers(Dr.Beale and Dr.Bryg).DATA EXTRACTION:Descriptive and outcome data were extracted independently from the papers by the same two reviewers,one of whom(Dr.Bryg)analyzed the original databases.Three studies were excluded from analysis,leaving 12 studies containing 1,557 subjects,1,482 of whom were analyzed.Main outcome measures were mortality,infection,ventilator days,intensive care unit stay,hospital stay,diarrhea days,calorie intake,and nitrogen intake.The meta‐analysis was performed on an intent‐to‐treat basis.DATA SYNTHESIS:There was no effect of immunonutrition on mortality(relative risk=1.05,confidence interval [CI]=0.78,1.41;p=.76).There were significant reductions in infection rate(relative risk=0.67,CI=0.50,0.89;p=.006),ventilator days(2.6 days,CI=0.1,;p=.04),and hospital length of stay(2.9 days,CI=1.4,4.4;p=.0002)in the immunonutrition group.CONCLUSIONS:The benefits of enteral immunonutrition were most pronounced in surgical patients,although they were present in all groups.The reduction in hospital length of stay and infections has resource implications.

 

Beale RJ,Bryg DJ,Bihari DJ:Crit Care Med 1999 Dec;27(12):2799−805

3)Omega−3 fatty acid supplementation reduces tumor growth and vascular endothelial growth factor expression in a model of progressive non‐metastasizing malignancy.

 BACKGROUND:Omega−3 fatty acids,the principal component of fish oil,have been demonstrated to have antiinflammatory properties.The role of eicosapentaenoic acid(EPA)supplementation for cancer patients is currently under investigation,however,the mechanisms of EPA activity have not been defined.The purpose of this study was to characterize tumor‐specific and treatment‐specific effects of supplemental dietary EPA in an animal model of progressive malignancy.METHODS:Fischer 344 rats(200−250g)underwent flank implantation of the methylcholanthrene(MCA)−induced fibrosarcoma on day O.Rats were randomly divided into 3 treatment groups on daya 13:EPA(1mL,5.0g/kg per day)+10IU vitamin E,corn oil(1mL)+10IU vitamin E,and saline(1mL)+10IU vitamin E(vitamin E was used to prevent fatty acid oxidation).On day 14,gavage feeding was started and was continued through day 28.The animals were killed on day 29,and the tumors were removed.The tumors were weighed and divided by the tumor‐free carcass weight to obtain percentage of tumor volume,and the livers were flash frozen.Vascular endothelial growth factor‐alpha(VEGF‐alpha)and cyclo‐oxygenase2(COX−2)mRNA were measured by reverse transcription‐polymerase chain reaction(RT‐PCR).RESULTS:EPA rats had significant reductions in tumor volume compared with isocaloric corn oil and control saline animals(25%,p<.1 and 33%,p<.1,respectively).Rats receiving EPA demonstrated decreased VEGF‐alpha mRNA levels(0.023±0.001)compard with those receiving corn oil(0.129±0.047)or saline(0.150±0.026:p<.05).

 CONCLUSIONS:These data demonstrate that EPA supplementation inhibits tumor growth,potentially through alterations in the expression of the pro‐angiogenic VEGF‐alpha.The mechanism(s)of EPA as an inhibitor of tumor‐related angiogenic growth factors may be associated with COX−2 enzyme fatty acid metabolism and merits further study.

Tevar R,Jho DH,Babcock T,Helton WS,Espat NJ:J Parenter Enteral Nutr 2002 Sep‐Oct;26(5):285−9

4)Effect of a fish oil‐enriched nutritional supplement on metabolic mediators in patients with a pancreatic cancer cachexia.

 Weight loss in advanced cancer patients is refractory to conventional nutritional support.This may be due to metabolic changes mediated by proinflammatory cytokines.hormones,and tumor‐derived products.We previously showed that a nutritional supplement enriched with fish oil will reverse weight loss in patients with pancreatic cancer cachexia.The present study examines the effect of this supplement on a number of mediators thought to play a role in cancer cachexia.Twenty weight‐losing patients with pancreatic cancer were asked to consume a nutritional supplement providing 600kcal and 2g of eicosapentaenoic acid per day.At baseline and after 3wk,patients were weighed and samples were collected to measure serum concentrations of interleukin(IL)−6 and its soluble receptor,tumor necrosis factor receptors1and2,cortisol,insulin,and leptin,peripheral blood mononuclear cell production of IL−1 beta,IL−6,and tumor necrosis factor,and urinary excretion of proteolysis inducing factor.After 3 wk of consumption of the fish oil‐enriched nutritional supplement,there was a significant fall in production of IL−6(from median 16.5 to 13.7ng/ml,P=0.015),a rise in serum insulin concentration(from 3.3 to 5.0mU/l,P=0.0064),a fall in the cortisol‐to‐insulin ratio(P=0.0084),and a fall in the proportion of patients excreting proteolysis inducing factor(from 88% to 40%,P=0.008).These changes occurred in association with weight gain(median1kg,P=0.024).Various mediators of catabolism in cachexia are modulated by administration of a fish oil‐enriched nutritional supplement in pancreatic cancer patients.This may account for the reversal of weight loss in patients consuming this supplement.

Barber MD,Fearon KC,Tisdale MJ,McMillan DC,Ross JA:Nutr Cancer 2001;40(2):118−24

5)Fish and omega−3 fatty acid intake and risk of coronary heart disease in women.

 CONTEXT:Higher consumption of fish and omega−3 fatty acids has been associated with a lower risk of coronary heart disease(CHD)in men,but limited data are available regarding women.OBJECTIVE:To examine the association between fish and long‐chain omega−3 fatty acid consumption and risk of CHD in women.DESIGN,SETTING,AND PARTICIPANTS:Dietary consumption and follow‐up data from 84,688 female nurses enrolled in the Nurses’ Health Study,aged 34 to 59 years and free from cardiovascular disease and cancer at baseline in 1980,were compared from validated questionnaires completed in 1980,1984,1986,1990,and 1994.MAIN OUTCOME MEASURES:Incident nonfatal myocardial infarction and CHD deaths.RESULTS:During 16 years of follow‐up,there were 1,513 incident cases of CHD(484 CHD deaths and 1,029 nonfatal myocardinal infarctions).Compared with women who rarely ate fish(<1per month),those with a higher intake of fish had a lower risk of CHD.After adjustment for age,smoking,and other cardiovascular risk factors,the multivariable relative risks(RRs)of CHD were 0.79(95% confidence interval[CI],0.64−0.97)for fish consumption 1 to 3 times per month,0.71(95% CI,0.58−0.87)for once per week,0.69 (95% CI,0.55−0.88) for 2 to 4 times per week,and 0.66 (95% CI,0.50−0.89) for 5 or more times per week(P for trend=.001).Similarly,women with a higher intake of omega−3 fatty acids had a lower risk of CHD,with multivariable RRs of 1.0,0.93,0.78,0.68,and 0.67(P<.001 for trend)across quintiles of intake.For fish intake and omega−3 fatty acids,the inverse association appeared to be stronger for CHD deaths(multivariate RR for fish consumption 5 times per week,0.55 [95% CI,0.33−0.90]for CHD deaths vs 0.73[0.51−1.04])than for nonfatal myocardial infarction.CONCLUSION:Among women,higher consumption of fish and omega−3 fatty acids is associated with a lower risk of CHD,particulary CHD,deaths.

Hu FB,Bronner L,Willett WC,Stampfer MJ,Rexrode KM,Albert CM,Hunter D,Manson JE:JAMA 2002 Apr 10;287(14):1815−21

関 連 用 語

英文表記 略語 和文表記 定 義 ・ 備 考
Meta‐analysis   メタ・
アナリシス
いくつかの独立したデータセットを併合(combined pool)し、定量的に仮説検定する方法。1976年Glassが用語を初めて定義した。Mateとは、一段と高い理論性を有すとの意味。
Odds ratio OR オッズ比 オッズとはeventの数/non‐eventの数で表され(例:出産100人中男児の数51とすれば、出産が男児であるオッズは51/49(1.04)。オッズ比とは(治療)群のオッズを(非治療)群のオッズで徐したもの。2因子間の関連性を示す値で、1に近いほど関連性がないとみなされる。
Relative risk rr 相対危険率 例えば男児を出産する危険率(確率);risk(probability)は51/100=0.51。危険率が2倍となればrr=2、危険率が半減すればrr=0.5となる。参考:ORとrr:eventが稀な場合には、危険率とオッズは近似する。治療群29、000の死亡数が2、200の場合、危険率0.076(2200/29000)、オッズ0.082(2200/(29000−2200)。同様のことが、rrとオッズ比との関係でも成立する。メタ・アナリシスでは、Peto法によりオッズ比を併合する。
Vascular endothelial
growth factor α
VEGFα 血管内皮
増殖因子α
強力な血管新生作用を要するペプタイドで血液幹細胞の発育分化、細胞外マトリックスの再構築、炎症性サイトカインの産生等に関与する。
cyclooxygenase2 COX‐2   プロスタグランディン合成に関与する酵素で、種々の前癌、癌病変で過剰発現が認められている。COX−2は、免疫系、血管新生、アポトーシス等を介して、発癌と関わっていると考えられている。近年COX−2阻害剤が、消火器症状を起こさずNSAIDと同等の鎮痛効果を有するとして注目されている。
Proteolysis inducing factor PIF 蛋白質分解
誘導因子
最近の研究で異化状態で、ユビキチン・プロテアソーム・システムを介して、蛋白分解が起こる事が判明した。敗血症では糖コルチコイドが、癌悪液質では腫瘍が産生する硫酸糖蛋白である蛋白質分解誘導因子がプロテアソームサブユニットとユビキチン輸送蛋白〔E2(14K)〕を介し、骨格筋蛋白崩壊に関与する。
Proteasome   プロテアソーム 蛋白質分解酵素複合体で、分解される蛋白質はユビキチン鎖を付加されそれを目印にプロテアソームにより分解される。
Uniquitin‐proteasome
system
  ユビキチン・
プロテアソーム・
システム
細胞増殖を担う蛋白質の合成、分解は厳しく制御されており、ユビキチン・プロテアソーム・システムは不要となった蛋白質を速やかに分解する上で中心的役割を担っているとされる。
文責 野 口 芳 一