This study will determine the optimal dose of 1-octanol that will safely reduce tremors in
patients with essential tremor-a disorder in which the hands, and sometimes the head, shake
involuntarily. Current treatments may be ineffective or produce unwanted side effects.
Ethanol (the chemical in beer and wine that causes intoxication) reduces tremor in many
patients, but patients generally don't use it regularly because it interferes with daily
activities. Laboratory studies show that 1-octanol, a drug that is similar to ethanol, may
have the same beneficial effect on tremors with less likelihood of intoxication.
Patients 21 years of age and older with essential tremor may be eligible for this 10-day
study. Candidates will be evaluated with a neurological examination, blood tests,
urinalysis and electrocardiogram (EKG). Those enrolled will be admitted to the hospital for
4 days for 1-octanol administration and monitoring. On day 1, patients will have a medical
history and physical examination. A catheter (a thin plastic tube) will be placed in a vein
of the forearm for sampling blood. Patients will take one 1-octanol capsule (at one of
seven doses) by mouth and will be monitored for tremors and drug side effects. Blood will
be sampled periodically in the first 3 hours to determine 1-octanol blood levels. On days 2
and 3, patients will be monitored for additional side effects. On days 3 and 4, laboratory
tests (blood and urine) will be done to evaluate liver and kidney function. On day 4, the
catheter will be removed and the patient will be discharged from the hospital. A follow-up
visit will be scheduled 1 week after discharge for a physical examination and blood, urine
and EKG tests.
Essential tremor is a very common movement disorder affecting approximately 1.4% of the
population. Response to medications such as beta blockers and mysoline may be only partial
or be accompanied by intolerable side effects. Roughly 80% of patients have significant
tremor reduction to ethanol although daily use of this as a treatment has potentially
serious social and legal consequences. The leading hypothesis for the pathophysiology of
essential tremor is unmasking of spontaneous oscillation of neurons in the inferior olive.
Both ethanol and 1-octanol have been shown to reduce these spontaneous oscillations in an
animal model of essential tremor; however, 1-octanol dose this at a dose much lower than an
intoxicating dose suggesting that it may be useful in the treatment of essential tremor.
Our initial study with 1-octanol at a low, single dose in patients with essential tremor
suggested it was both efficacious and safe.
This present study is planned to identify a maximum tolerated dose and broaden the safety
and efficacy data in humans. Additionally, we hope to collect further information about the
pharmacokinetics of 1-octanol. This study is designed as a phase Ia, unblinded, inpatient
study of adults with essential tremor receiving escalating doses of 1-octanol. Cohorts of
three will begin dose escalation at the dose previously studied. Each cohort will be
followed in inpatient setting for 72 hours ( and outpatient for 1 additional week) during
which adverse events, pharmacokinetics and efficacy will be assessed. If no subject
achieves dose-limiting toxicity, 3 additional subjects will be recruited to receive the next
higher dose. If 1/3 subjects achieves dose-limiting toxicity, the next cohort will receive
the same dose. Dose limiting toxicity is defined as the dose that produces dose-limiting
toxicity in at least 2 subjects. Maximum tolerated dose will be defined as the next lower
With this study, we hope to identify a range of doses that may useful in the treatment of
essential tremor and combined with the pharmacokinetic and efficacy data, design a protocol
to study multiple dose regimens over longer time periods.
Patients with essential tremor with a history or ethanol responsiveness.
Patients must be off any medications used to treat essential tremor such as mysoline or
propranalol for at least 2 weeks.
Patients must withhold ethanol and caffeine from 24 hours prior to starting the study
until study termination (10 days).
Patients with abnormalities on neurologic exam other than tremor.
Patients with a history of chronic alcohol dependence.
Patients with chronic medical conditions such as renal failure, hepatic failure and
chronic lung disease.
Patients on other chronic medications that cannot be temporarily discontinued for the
length of the study (10 days).
Patients, who for moral or religious reasons do not wish to take a potentially
Patients with abnormalities on their baseline screening laboratory tests.
Women who are pregnant or lactating.
People of Asian decent who may differ pharmocogenetically with respect to alcohol and
aldehyde dehydrogenase and may have increased sensitivity to alcohols and their