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.

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National Institute on Alcohol Abuse and Alcoholism
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Clarke, Kieran; Tchabanenko, Kirill; Pawlosky, Robert et al. (2012) Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects. Regul Toxicol Pharmacol 63:401-8
Veech, Richard L; Valeri, C Robert; VanItallie, Theodore B (2012) The mitochondrial permeability transition pore provides a key to the diagnosis and treatment of traumatic brain injury. IUBMB Life 64:203-7
Clarke, Kieran; Tchabanenko, Kirill; Pawlosky, Robert et al. (2012) Oral 28-day and developmental toxicity studies of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate. Regul Toxicol Pharmacol 63:196-208