THE PHARMACOLOGY OF OMEGA-3 FATTY ACIDS IN MAN

许多临床研究正在进行，以了解是否富集 西方饮食中含有鱼油中的w-3脂肪酸， 动脉粥样硬化及其并发症的发展。 这个概念是基于 根据流行病学的建议， 这些脂肪酸（例如，爱斯基摩人和沿海日本人）发病率较低 中风和心肌梗塞的风险 这些数据被放大， 发现爱斯基摩人和志愿者谁消耗鱼油发展延长， 出血时间和明显改变的血小板功能，因为 最近的证据有力地表明慢性血小板活化 和内皮损伤。 很少 已经进行了关于鱼油（或二十碳五烯酸 EPA）补充对血小板-血管相互作用指数的影响 其准确反映体内前列腺素类代谢的改变，或 它评估了增加膳食EPA对许多途径的影响， 花生四烯酸（AA）代谢在完整的动物或人。由于EPA 补充可能会对拮抗AA产生不同的影响 代谢途径（例如，促聚集）血栓烷与抗聚集 前列环素）改变前列腺素的净生物学结果 前体池通过饮食手段是不可预测的。 我们建议评估喂养w-3脂肪酸对体内 通过测量AA和EPA衍生的前列腺素类的排泄来生产AA和EPA衍生的前列腺素类， 在鱼油喂养过程中使用最先进的方法检测尿液代谢产物 以及研究白三烯和羟基脂肪酸的变化 在人类细胞中通过这种喂养诱导的新陈代谢。 在建立 在正常志愿者和无症状志愿者中发生的生化变化 动脉粥样硬化，我们将试图评估生物功能的变化， 研究EPA补充剂是否能降低血压， 动脉粥样硬化与轻度未经治疗的高血压和是否EPA 影响过敏原后早期或晚期支气管反应 过敏性哮喘的挑战 在这些研究中， 毛细管柱GC/负离子化学电离MS方法 用于评估循环和循环的类型和数量的变化， 体内释放的脂氧合酶产物以及从 志愿者们在吃完饭后 通过阐明 w-3脂肪酸在人方面的环和脂氧合酶 路径，可以开发临床应用的合理基础， 允许精心设计的临床研究来评估它们在 改变人类疾病的原因。

Many clinical studies are being carried out to see if enrichment of the Western diet with w-3 fatty acids found in fish oil will prevent the development of atherosclerosis and its complications. This notion is based on the epidemiologic suggestion that populations with a high dietary intake of such fatty acids (eg. Eskimos and coastal Japanese) have a low incidence of stroke and myocardial infarction. These data are amplified by the finding that Eskimos and volunteers who consume fish oil develop prolonged bleeding times and apparently altered platelet function ex vivo, since recent evidence strongly suggests a role for chronic platelet activation and endothelial damage in the development of atherosclerosis. Very few studies have been performed on the effects of fish oil (or eicosapentaenoic acid, EPA) supplementation on indices of platelet-vascular interactions which accurately reflect alterations in prostanoid metabolism in vivo, or which assess the effects of increased dietary EPA on the many pathways of arachidonic acid (AA) metabolism in intact animals or man. Since EPA supplementation probably will have different effects on antagonistic AA metabolic pathways (eg. proaggregatory) thromboxane vs antiaggregatory prostacyclin) the net biologic result of altering the prostaglandin precursor pool by dietary means is unpredictable. We propose to assess the effects of feeding w-3 fatty acids on in vivo production of AA and EPA derived prostanoids by measuring the excretion of urinary metabolites with state-of-the-art methods during fish oil feeding as well as to study alterations in leukotriene and hydroxy fatty acid metabolism induced in human cells by such feeding. After establishing the biochemical changes which take place in normal volunteers and asymptomatic atherosclerotics, we will attempt to assess changes in biologic function by investigating whether EPA supplementation lowers blood pressure in atherosclerotics with mild untreated hypertension and whether EPA influences the early or late phase bronchial responses after allergen challenge in allergic asthmatics. During these studies newly developed capillary column GC/negative ion chemical ionization MS methods will be employed to assess changes in the types and amounts of cyclo and lipoxygenase products released in vivo and by cells isolated from volunteers after EPA feeding. By clarifying the clinical pharmacology of w-3 fatty acids in man in regards to both the cyclo and lipoxygenase pathways, a rational basis for clinical applications can be developed, allowing well-designed clinical studies to assess their potential in modifying the cause of human disease.