Oral 28-day and developmental toxicity studies of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate

Clarke, Kieran; Tchabanenko, Kirill; Pawlosky, Robert J.; Carter, E; Knight, Nicholas; Murray, Andrew J.; Cochlin, Lowri E; T, King; Wong, Aol; Roberts, Ashley; Robertson, Jeremy; Veech, Richard L.

doi:10.1016/j.yrtph.2012.04.001

Cited by 79 publications

(61 citation statements)

References 24 publications

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“…Two KEs are known to be under current study: a ) 1,3-butanediol monoester of ␤ HB (KME) ( 77,(79)(80)(81)(82)(83)(84) and b ) 3GHB ( 48,85,86 ). Studies have demonstrated that orally or intravenously administered 1,3-butanediol or glycerol esters of ␤ HB are safe and well tolerated in animals ( 80,86 ), and that the orally administered 1,3-butanediol monoester is also safe and well tolerated in humans ( 79 ).…”

Section: Kesmentioning

confidence: 99%

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Ketone body therapy: from the ketogenic diet to the oral administration of ketone ester

Hashim

VanItallie

2014

Journal of Lipid Research

118

108

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This article is available online at http://www.jlr.org family, its importance for purposes of this review is minimal.). KBs have been dubbed "metabolism's ugly duckling" because, in the mid-19th century, they were fi rst discovered in large quantities in the urine of patients succumbing to diabetic ketoacidosis. Thus, it is not surprising that physicians of the era considered KBs to be toxic byproducts of impaired carbohydrate metabolism. It took almost half a century for medical scientists to understand that KBs are normal metabolites manufactured by the liver in increasing amounts when dietary sources of carbohydrate and glucogenic amino acids are in short supply ( 1 ). Unfortunately, some physicians still fail to distinguish between the safe "physiological" hyperketonemia that occurs in healthy individuals during fasting or adherence to a ketogenic diet (KD), and the pathological, out-of-control hyperketonemia associated with insulin-defi cient diabetes.When Owen et al. ( 2 ) reported that during a prolonged fast KBs can provide 60% or more of the brain's daily energy requirement (thereby sparing ‫ف‬ 80 g/day of glucose that otherwise would have been derived largely from breakdown of the body's limited protein stores), it was finally acknowledged that, as in Hans Christian Andersen's 1843 fairy tale, the creature fi rst thought to be an ugly duckling was turning out to be an emerging swan. It became evident that the ketogenic response to starvation is an indispensable metabolic adaptation designed by nature to preserve strength and prolong life during times when food is unavailable ( 3 ) .It is now known that (in nondiabetic individuals), owing to the blood's effi cient buffering capacity, plasma KB Abstract Ketone bodies (KBs ), acetoacetate and ␤ -hydroxybutyrate ( ␤ HB), were considered harmful metabolic by-products when discovered in the mid-19th century in the urine of patients with diabetic ketoacidosis. It took physicians many years to realize that KBs are normal metabolites synthesized by the liver and exported into the systemic circulation to serve as an energy source for most extrahepatic tissues. Studies have shown that the brain (which normally uses glucose for energy) can readily utilize KBs as an alternative fuel. Even when there is diminished glucose utilization in cognition-critical brain areas, as may occur early in Alzheimer's disease (AD), there is preliminary evidence that these same areas remain capable of metabolizing KBs. Because the ketogenic diet (KD) is diffi cult to prepare and follow, and effectiveness of KB treatment in certain patients may be enhanced by raising plasma KB levels to у 2 mM, KB esters, such as 1,3-butanediol monoester of ␤ HB and glyceryl-tris-3-hydroxybutyrate, have been devised. When administered orally in controlled dosages, these esters can produce plasma KB levels comparable to those achieved by the most rigorous KD, thus providing a safe, convenient, and versatile new approach to the study and potential treatment of a variety of diseases, including epilepsy, ...

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Section: Kesmentioning

confidence: 99%

“…Studies have demonstrated that orally or intravenously administered 1,3-butanediol or glycerol esters of ␤ HB are safe and well tolerated in animals ( 80,86 ), and that the orally administered 1,3-butanediol monoester is also safe and well tolerated in humans ( 79 ).…”

Section: Kesmentioning

confidence: 99%

Ketone body therapy: from the ketogenic diet to the oral administration of ketone ester

Hashim

VanItallie

2014

Journal of Lipid Research

118

108

View full text Add to dashboard Cite

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“…readily hydrolyzed in the gut to ketone bodies, which can reach blood levels equivalent to those seen in prolonged fasting and equivalent to the K m of transport into the brain ( 18 ), without observable toxic effects ( 15,19 ). A RAT LOWERS THE BLOOD GLUCOSE, WHILE AT THE SAME TIME LOWERING BLOOD INSULIN, DEMONSTRATING THAT KETOSIS INCREASES INSULIN SENSITIVITY Blood glucose decreased by about 50% from 5 to 2.8 mM while insulin decreased from 0.54 to 0.26 ng/ml in rats fed a diet where 30% of the calories from starch were replaced with ketone esters ( 20 ).…”

Section: The Ketone Body D-␤ -Hydroxybutyrate Is a Natural Histone mentioning

confidence: 99%

Ketone ester effects on metabolism and transcription

Veech

2014

Journal of Lipid Research

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“…The sodium salt of BHB has been shown to elevate blood ketone levels in animal models [13], while esters of BHB or AcAc also promise great therapeutic potential [8,9,36]. These ketone esters of BHB are demonstrated to be safe and well tolerated in rats [84] and humans [85], while they produce fasting-level ketosis without dietary restriction. Ketone esters may represent the soughtafter "ketogenic diet in a pill" [17], but further testing of these ketogenic agents are required.…”

Section: Metabolic Supplementationmentioning

confidence: 99%

Ketosis as a treatment for multiple metabolic and neurodegenerative pathologies

Pilla¹

2017

J Transl Sci

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Oral 28-day and developmental toxicity studies of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate

Cited by 79 publications

References 24 publications

Ketone body therapy: from the ketogenic diet to the oral administration of ketone ester

Ketone body therapy: from the ketogenic diet to the oral administration of ketone ester

Ketone ester effects on metabolism and transcription

Ketosis as a treatment for multiple metabolic and neurodegenerative pathologies

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