Development of Ketone Ester Diets

该实验室与牛津大学解剖学、生理学和遗传学系之间的一项合作项目，在国防部资助的一项研究中，一直在制备适合口服的新化学形式的酮体，并研究这些添加剂对大鼠身体和认知能力的影响。已经合成了超过30种不同的酮酯，并评估了其急性毒性、味道以及对性能和代谢参数的影响。 我们现在已经在动物研究中证明，与补充有30%的卡路里作为淀粉或脂肪的食物饮食相比，消耗酮酯饮食的大鼠在跑步机上的跑步距离增加了30%，完成8臂迷宫测试所需的时间减少了30%。 一份详细介绍这种生理和认知功能增加的手稿已提交供考虑出版。 根据与Nutritechics（多伦多）签订的合同，在大鼠中进行了28天动物毒性试验和66天毒性试验。 未观察到毒性作用。 涉及54名人类受试者的人类首次人体毒性试验是在获得美国国防部、牛津大学和Ceconium Research批准后根据合同进行的。 这些测试于2009年8月20日完成。 在血药浓度递增方案中，在6个队列的最后一个队列中，口服酮酯制剂后达到5-7 mM酮的最大血药浓度。 未观察到不良毒性反应。 随后，根据合同，由Cephalus实验室完成了人体毒性试验。 在达到超过15 mM的初始血液水平的剂量下，在人类受试者中同样没有发现毒性。我们正在等待这些研究的正式书面报告。 随后，完成畸形学研究，未观察到毒性。 轻度酮症有许多潜在的治疗用途。适合轻度酮症治疗的三种主要疾病表型为： 1)底物不足的疾病， 2)缺氧疾病， 3)自由基毒性疾病。 生产这些医用材料的资金目前尚不确定。 饮食改变生理或认知表现是一个新的领域，不仅没有得到很好的理解，而且通常认为是不可能的。 由于其广泛的应用领域，这一发现具有一定的重要性和普遍意义。

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.