Dose-escalation study of octanoic acid in patients with essential tremor

Voller, Bernhard; Lines, Emily; McCrossin, Gayle; Tinaz, Sule; Lungu, Codrin; Grimes, George J.; Starling, Judith; Potti, Gopal K.; Buchwald, Péter; Haubenberger, Dietrich; Hallett, Mark

doi:10.1172/jci83621

Cited by 22 publications

(21 citation statements)

References 17 publications

(25 reference statements)

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“…The safety data did not identify any major concerns with toxicity or tolerability. Dose escalation of octanoic acid did not reach doselimiting toxicity levels [Voller et al 2016]. Secondary efficacy measures suggested a dosedependent reduction of tremor and additional studies are needed to explore safety at higher dose ranges and to confirm dose-dependent efficacy.…”

Section: Octanolmentioning

confidence: 90%

Emerging strategies in the management of essential tremor

Hedera

2016

Ther Adv Neurol Disord

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Currently available therapies for essential tremor (ET) provide sufficient control only for less than a half of patients and many unmet needs exist. This is in part due to the empiric nature of existing treatment options and persisting uncertainties about the pathogenesis of ET. The emerging concept of ET as a possible neurodegenerative disorder, better understanding of associated biochemical changes, including alterations in the γ-aminobutyric acid (GABA)-ergic system and gap junctions, and the identification of the role of the leucine-rich repeat and immunoglobulin-like domain-containing 1 (LINGO-1) gene in ET pathogenesis suggest new avenues for more targeted therapies. Here we review the most promising new approaches to treating ET, including allosteric modulation of GABA receptors and modifications of the LINGO-1 pathway. Medically refractory tremor can be successfully treated by high-frequency deep brain stimulation (DBS) of the ventral intermediate nucleus, but surgical therapies are also fraught with limitations due to adverse effects of stimulation and the loss of therapeutic response. The selection of additional thalamic and extrathalamic targets for electrode placements and the development of a closed-loop DBS system enabling automatic adjustment of stimulation parameters in response to changes in electrophysiologic brain activity are also reviewed. Tremor cancellation methods using exoskeleton and external hand-held devices are also briefly discussed.

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Section: Octanolmentioning

confidence: 90%

Emerging strategies in the management of essential tremor

Hedera

2016

Ther Adv Neurol Disord

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“…Each phase included baseline testing, 3 weeks of consecutive drug dosing, and post‐testing at the end of each 3‐week drug period, with a 2‐week intervening washout. With an established elimination half‐life of OA at 150 minutes, this washout period well exceeds any potential for residual effects from phase 1 to phase 2. To control for possible order effects, a randomized, counterbalanced list (generated by an independent person) was used to assign drug order for each participant upon enrollment.…”

Section: Methodsmentioning

confidence: 99%

“…The long‐chain alcohol 1‐octanol and its derivative octanoic acid (OA) have been studied in ET of the limbs as a potential treatment for tremor, which may have similar mechanisms of action as ethanol, one of the most effective tremor‐reducing agents . Studies to date have shown that 1‐octanol or OA can reduce the severity of tremor in the hands by as much as 41%, with minimal/mild side effects . Treatment of EVT with OA may be advantageous to BTA due to its effect on the peripheral and central nervous system regions, its potential diffuse effects on muscles across multiple speech sub‐systems that are affected by EVT, and the reported positive effect of its related parent compound ethanol for improving voice tremor …”

Section: Introductionmentioning

confidence: 99%

“…15,16 Studies to date have shown that 1-octanol or OA can reduce the severity of tremor in the hands by as much as 41%, with minimal/ mild side effects. [17][18][19][20] Treatment of EVT with OA may be advantageous to BTA due to its effect on the peripheral and central nervous system regions, 21,22 its potential diffuse effects on muscles across multiple speech subsystems that are affected by EVT, and the reported positive effect of its related parent compound ethanol for improving voice tremor. 7,23 Controlled investigations of alternative pharmacologic interventions for EVT are critical to improved clinical care and level of evidence for treatment decisions.…”

Section: Introductionmentioning

confidence: 99%

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The Effect of Octanoic Acid on Essential Voice Tremor: A Double‐Blind, Placebo‐Controlled Study

et al. 2018

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Objectives/Hypothesis The purpose of this study was to determine the effects of octanoic acid on acoustic, perceptual, and functional aspects of essential voice tremor (EVT). Study Design Prospective, double‐blind, placebo‐controlled, crossover study. Methods Sixteen participants with a diagnosis of EVT were randomized to a 3‐week dosing condition of octanoic acid or placebo, followed by a 2‐week washout period and crossover to the other condition for an additional 3 weeks. Baseline and post‐testing sessions were completed before and at the completion of each condition. Primary outcome measures were the magnitude of amplitude and frequency tremor, measured from the acoustic signal. Secondary outcomes were auditory‐perceptual ratings of tremor severity and self‐ratings of voice handicap. Results Magnitude of amplitude and frequency tremor were significantly lower after 3 weeks of octanoic acid dosing as compared to the placebo condition. Auditory‐perceptual ratings of tremor severity did not show significant differences between conditions. A trend toward better voice was seen for the sustained vowel ratings, but not the sentence‐level ratings. No significant differences between conditions were seen on self‐reported voice disability as assessed on the Voice Handicap Index‐10. Conclusions The results of this controlled investigation support the potential utility of octanoic acid for reducing the magnitude of tremor in people with EVT. Further research is needed to determine whether different dosing or treatment combinations can improve functional communication in EVT. Level of Evidence 1 Laryngoscope, 129:1882–1890, 2019

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“…The long chain alcohol 1-octanol has been explored for potentially achieving similar beneficial effects in alcohol-responsive ET without the risk of intoxication. Octanoic acid (OA), the product of rapid metabolism of 1-octanol, is well tolerated in ET up to a dose of 128 mg/kg (Voller et al, 2016). Our previous study (Haubenberger et al, 2013) using a crossover design showed that OA was safe and potentially effective in reducing postural tremor in ET.…”

Section: Introductionmentioning

confidence: 99%