Review of the toxicologic properties of medium-chain triglycerides

Traul, Karl A.; Driedger, Albert A.; Ingle, D. L.; Nakhasi, Dilip K.

doi:10.1016/s0278-6915(99)00106-4

Cited by 373 publications

(181 citation statements)

References 36 publications

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“…Second, reaching the plasma concentrations of octanoic acid achieved in this study would require a lower oral dose of octanoic acid than that of 1-octanol. Finally, octanoic acid also has Food and Drug Administration generally recognized as safe status and human dietary consumption of up to 710 mg/kg is considered safe [22].…”

Section: Discussionmentioning

confidence: 99%

An Open-Label, Single-Dose, Crossover Study of the Pharmacokinetics and Metabolism of Two Oral Formulations of 1-Octanol in Patients with Essential Tremor

et al. 2011

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Existing therapeutic options for management of essential tremor are frequently limited by poor efficacy and adverse effects. Likely the most potent tremor suppressant used is ethanol, although its use is prohibitive due to a brief therapeutic window, and the obvious implications of excessive alcohol use. Longer-chain alcohols have been shown to suppress tremor in harmaline animal models, and appear to be safe and well tolerated in 2 prior studies in humans. Here we report on the findings of a phase I/II study of 1-octanol designed to explore pharmacokinetics, efficacy, and safety. The most significant finding was the identification of octanoic acid as the product of rapid 1-octanol metabolism. Furthermore, the temporal profile of efficacy closely matches the plasma concentration of octanoic acid. Therefore, these findings identify a novel class of compound (e.g., carboxylic acids) with tremor suppressive properties in ET. Administration of 1-octanol also appears to be safe based on various measures collected. Essential tremor (ET) is the most common tremor disorder, with tremors occurring during static posturing or movement. These tremors are known to briefly improve in many cases after alcohol (ethanol) consumption. Two previous studies of a longer chain alcohol, 1-octanol, have demonstrated longer duration tremor-suppressive effects without the occurrence of intoxication. The aim of this study was to characterize the pharmacokinetics of 1-octanol and its primary metabolite octanoic acid using two formulations, along with additional safety and efficacy measures. Participants with proven ethanol-responsive ET were recruited into 1 of 2 parts: (part A) a dose escalation study (1-64 mg/kg; n=4), and (part B) a fixed dose (64 mg/kg; n=10) balanced, open-label crossover design. Two participants in part B then completed an exploratory part C evaluating 128 mg/kg. Plasma samples were collected at 10 intervals during a 6-hour period postingestion. Efficacy was assessed using spirography, whereas safety was assessed with electrocardiograms, vital signs, adverse effects surveys, and an intoxication assessment. Plasma concentrations of 1-octanol were detect- Neurotherapeutics (2011) 8:753-762 DOI 10.1007 able at low levels whereas octanoic acid (OA) concentrations were approximately 100-fold higher. The half-life of OA was 87.6minutes. This was matched by a clinical reduction in tremor severity of 32% at 90 minutes, assessed using spirography. The safety profile was favorable, with the most commonly reported adverse effect being dysgeusia (38%). Early detection and higher plasma concentrations of OA are a product of rapid metabolism of 1-octanol.OA pharmacokinetics mirrored the timing of clinical improvement. These findings provide preliminary evidence for a new class of compound that may be effective in the treatment of ET.

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Section: Discussionmentioning

confidence: 99%

An Open-Label, Single-Dose, Crossover Study of the Pharmacokinetics and Metabolism of Two Oral Formulations of 1-Octanol in Patients with Essential Tremor

et al. 2011

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“…Medium-chain triglycerides (MCTs), constituents of coconut and palm kernel oils, are composed of predominantly glycerol esters of MCFAs and have a favorable safety profile for the treatment of various disorders (27). MCTs of coconut oil contain 67% octanoic acid (8:0), 27 % decanoic acid (10:0), and 6% other fatty acids, but it is not clear whether 2-decenoic acid (10:1; DA) is included.…”

Section: Daee May Be a Promising Candidate As An Antidepressant Drugmentioning

confidence: 99%

2-Decenoic acid ethyl ester possesses neurotrophin-like activities to facilitate intracellular signals and increase synapse-specific proteins in neurons cultured from embryonic rat brain

et al. 2010

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We presently found that medium-chain fatty acids (MCFAs) with 8-12 carbons and their esters facilitated activation (phosphorylation) of mitogen-activated protein kinases (MAPK)/extracellular signal-regulated kinases (ERK) 1/2 of cultured embryonic cortical/hippocampal neurons. In particular, trans-2-decenoic acid ethyl ester (DAEE) had the most potent activity. Additionally, DAEE activated phosphatidylinositol 3-kinase and cAMP-response element binding protein (CREB), suggesting that DAEE generates similar intracellular signal as neurotrophins. Therefore, details of the signal elicited by DAEE were examined in comparison with those of a neurotrophin, brain-derived neurotrophic factor (BDNF). We found that 1) DAEE phosphorylated MAPK/ERK1/2 via MEK activation without the involvement of tyrosine kinases of neurotrophin Trk receptors; 2) DAEE activated CREB predominantly through MAPK/ERK1/2 activation, not through other pathways such as cAMP/protein kinase A; and 3) DAEE increased the expression of mRNAs of BDNF and neurotrophin-3 and the protein content of synapse-specific proteins such as synaptophysin, synapsin-1, and syntaxin. Based on these observations we propose that DAEE and some other derivatives of MCFAs having neurotrophin-like neurotrophic activities may become therapeutic tools for certain neurological or psychiatric disorders.

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“…In addition, medium chain triglycerides such as caprylic acid are widely used for foods, drugs, and cosmetics. Therefore, those are essentially non-toxic, and it was reported that they have virtually no potential as dermal irritants (Traul et al, 2000).…”

Section: Resultsmentioning

confidence: 99%

Pharmacokinetic characteristics of formulated alendronate transdermal delivery systems in rats and humans

et al. 2010

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Review of the toxicologic properties of medium-chain triglycerides

Cited by 373 publications

References 36 publications

An Open-Label, Single-Dose, Crossover Study of the Pharmacokinetics and Metabolism of Two Oral Formulations of 1-Octanol in Patients with Essential Tremor

An Open-Label, Single-Dose, Crossover Study of the Pharmacokinetics and Metabolism of Two Oral Formulations of 1-Octanol in Patients with Essential Tremor

2-Decenoic acid ethyl ester possesses neurotrophin-like activities to facilitate intracellular signals and increase synapse-specific proteins in neurons cultured from embryonic rat brain

Pharmacokinetic characteristics of formulated alendronate transdermal delivery systems in rats and humans

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