1-Octanol to Treat Essential Tremor
1-Octanol to Treat Essential Tremor
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 dose.

 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.
INCLUSION CRITERIA:

 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).

 EXCLUSION CRITERIA:

 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 intoxicating
 drug.

 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 metabolites