Development of Ketone Ester Diets

在国防部资助的一项研究中，该实验室与牛津大学解剖学、生理学和遗传学系合作开展了一项研究，该项目一直在制备适合口服的新的酮体化学形式，并调查饮食中这些添加剂对大鼠身体和认知表现的影响。已经合成了30多种不同的酮酯，并对其急性毒性、味道以及对性能和代谢参数的影响进行了评估。 我们现在已经在动物研究中证明，与饮食中添加30%卡路里淀粉或脂肪的饮食相比，食用酮酯饮食的大鼠在跑步机上的距离增加了30%，完成8臂迷宫测试的时间减少了30%。一份详细描述这种生理和认知功能增加的手稿已经提交考虑出版。 根据与多伦多营养科技公司签订的合同，进行了28天的动物毒性试验和66天的老鼠毒性试验。没有发现任何毒性影响。涉及54名人类受试者的人类第一次毒性试验是在获得国防部、牛津大学和Cetero Research批准后，根据合同进行的。这些测试已于2009年8月20日完成。在一个逐步升高的血药浓度方案中，在6个队列的最后一个队列中，口服酮酯制剂后达到了5-7毫米酮的最大血药浓度。未观察到不良反应。 随后，Cetero实验室根据合同完成了人体毒性测试。同样，在初始血液浓度超过15 mM的剂量下，受试者没有观察到任何毒性。我们正在等待这些研究的正式书面报告。 随后，完成了畸胎学研究，没有发现任何毒性。 轻型酮症有许多潜在的治疗用途。适合治疗轻型酮症的三种主要疾病表型是： 1)底物缺乏症， 2)缺氧性疾病， 3)自由基毒性疾病。 目前，用于医疗用途的这些材料的生产资金还不确定。 饮食在生理或认知方面的改变是一个新的领域，不仅没有被很好地理解，而且通常被认为是不可能的。因此，这一发现具有一定的重要性和普遍意义，因为它具有广泛的应用领域。

A collaborative project between this laboratory and the Departments of Anatomy, Physiology and Genetics, Oxford University, in a study funded by the Department of Defense, has been preparing new chemical forms of ketone bodies suitable for oral consumption and investigating the effects of these additives to the diet on physical and cognitive performance in the rat. Over 30 different ketone esters have been synthesized and evaluated for acute toxicity, taste and effects upon performance and metabolic parameters. We have now demonstrated in animal studies, that rats consuming a ketone ester diet showed a 30% increase in treadmill distance run and a 30% decrease in the time taken to complete an 8 arm maze test as compared to a chow diet supplemented either with 30% of calories as starch or fat. A manuscript detailing this increase in physiological and cognitive function has been submitted for consideration for publication. Under a contract to Nutritechics, Toronto, 28-day animal toxicity and a 66-day toxicity tests in rats. No toxic effects noted. Human first in human toxicity trails involving 54 human subjects were conducted under contract after approved by the DoD, Oxford, and Cetero Research. These tests were completed on August 20, 2009. In an escalating blood level protocol, maximum blood levels of 5-7 mM ketones were achieve after oral ingestion of the ketone ester formulation in the final of 6 cohorts. No untoward toxic reactions were observed. Subsequently, human toxicity tests were completed under contract by Cetero Laboratories. Again no toxicity was noted in human subjects at dose achieving initial blood levels over 15 mM. We are awaiting a formal written report of these studies. Subsequently, teratology study was completed and no toxicity was noted. There are a number of potential therapeutic uses of mild ketosis. The three major disease phenotypes suitable for treatment with mild ketosis are: 1) diseases of substrate insufficiency, 2) diseases of hypoxia, 3) disease of free radical toxicity. The funding of the production of these materials for medical uses is uncertain at present. Dietary alterations in either physiological or cognitive performance is a new area, that is not only not well understood but is generally not believed to be possible. This finding is therefore of some importance and general significance because of its wide area of application.