Development of 1-Octanol as a Novel Therapy for the Treatment of Ethanol-Responsive Essential Tremor

Background

Essential tremor (ET) is a common movement disorder affecting 0.4% of the general population and up to 14% of people 65 years and older. Response to medications such as beta blockers and primidone may be of benefit, but are often accompanied by intolerable side effects. Response to ethanol, on the other hand, has a roughly 80% chance of significant tremor reduction, though daily use of this as a treatment has potentially serious medical, social, and legal consequences. Both ethanol and 1-octanol have been shown to reduce harmaline-induced tremor in rodents, an animal model of ET; however, 1-octanol does this at a dose much lower than that leading to intoxication, suggesting it may be useful in the treatment of essential tremor.

Methods

Our study population consists of adults with ethanol-responsive ET. Two formulations of 1-octanol have been utilized to date, a capsule containing 1-octanol adsorbed cellulose particles and a gelcap filled with 1-octanol in an oil-based vehicle. Primary outcome measures have included several measures including spiral drawings.

Results

Our initial findings have shown 1-octanol to be safe and effective in a placebo-controlled trial and in an open label dose-finding trial at doses up to 64 mg/kg. Two initial formulations of 1-octanol have shown an unstable shelf-life and/or poor systemic absorption. We have failed so far to develop an assay for octanol that will permit pharmacokinetic studies.

Conclusions

Octanol is a promising drug for ET, but there are problems in its development. We need to develop a satisfactory assay and a good formulation in order to proceed with further clinical trials. Lacking some of the necessary skills, our NIH team has now partnered with industry to speed up progress.