Effects of Betahistine Hydrochloride in Overweight Women

Current medications for the long-term treatment of obesity are moderately effective at best.
Therefore, research focusing on compounds that affect energy balance through novel mechanisms
is warranted. Preliminary human and animal data suggest central nervous system histaminergic
tone is important in the regulation of food intake. We therefore propose to study the effects
of betahistine hydrochloride, a histamine analogue which has agonist activity at the
histaminergic H1 receptor and antagonist/reverse agonist activity at the H3 receptor. Prior
animal studies have suggested that betahistine suppresses food intake and reduces body
weight, but there are sparse human data assessing the effects of betahistine on metabolism.

Betahistine s effects on women s food intake and metabolism will be evaluated through an
inpatient randomized double-blind placebo controlled dose-ranging study. We will examine the
acute effects of betahistine on food intake, hunger, and satiety, resting energy expenditure,
and on hormones and substrates relevant for body weight regulation. If results suggest
betahistine has salutary effects on food intake or metabolism in humans, these studies will
lay the groundwork for additional investigations to assess the efficacy of betahistine in the
treatment of obesity.

- INCLUSION CRITERIA:

Volunteers will qualify if they meet the following criteria:

1. Good general health. In general, subjects will be required to take no medications.
However, individuals taking medications for obesity-related co-morbid conditions, who
have not had changes in dosage for more than 6 months, may be included, at the
discretion of the principal investigator.

2. Age 18-50 years.

3. Female sex. In this pilot study, we seek to decrease the variability of subject
response to the greatest extent possible. Since women have a higher prevalence of
obesity than men, and tend to be the group that most uses weight loss pharmacotherapy,
we will only study women in the pilot investigation. Subsequent studies with include
both sexes.

4. Regular menses (either spontaneous or as a result of oral contraceptive pills) or
post-menopausal status (no menses for at least 3 months).

5. Obesity, defined as body mass index (BMI) between 30 and 40 kg/m(2) but weight under
300 lbs, in order for subject to be able to undergo DEXA scanning with the Hologic
instrument available in the Nuclear Medicine Department.

6. A negative pregnancy test at the initial evaluation. Sexually active women must be
using an effective form of birth control. These methods include abstinence, oral
contraceptives, an intrauterine device (IUD), levonogestrol implants (Norplant), or
medroxyprogesterone acetate injections (Depo-provera shots). (One of these methods
must have been used by the subject for at least two months prior to the start of the
study). If one of these cannot be used, contraceptive foam with a condom is
recommended.

7. Willingness to participate in the research protocol.

EXCLUSION CRITERIA:

Volunteers will be excluded (and referred to non-experimental treatment programs as
needed) for the following reasons:

1. A presence of major illnesses: renal, hepatic (other than obesity-related
steatosis), gastrointestinal, most endocrinologic (e.g., Cushing syndrome, hyper-
or hypothyroidism, pheochromocytoma), hematological problems or pulmonary
disorders; or porphyria;

2. History of anaphylaxis, asthma, urticaria, rhinitis, allergic rash, or other
allergic disease requiring antihistamine treatment; subjects with a history of
antihistamine treatment for a self-limited allergic reaction such as to poison
ivy or to a medication that they are no longer taking may be included at the
discretion of the primary investigator.

3. History of peptic ulcer disease;

4. Baseline QT interval prolongation (greater than or equal to 480 msec QTc) because
of reports of histaminergic compounds causing prolonged QT interval and cardiac
arrhythmias in susceptible patients (i.e. those with prolonged QT interval at
baseline);

5. Current smokers of tobacco products;

6. Self-reported lactose intolerance;

7. Self-reported food allergy to foods used in standardized food array in this
protocol or to betahistine itself;

8. Subjects following a diet with specific food requirements such as vegetarian,
vegan, or kosher because of the use of a standardized food array in this
protocol;

9. Subjects with a history of DSMIV classifiable eating disorders such as anorexia
nervosa, bulimia nervosa, or binge-eating disorder will be excluded from the
current proof-of-concept study;

10. Women with reproductive potential who are pregnant or who are currently nursing
an infant;

11. Individuals who have current substance abuse or a psychiatric disorder or other
condition that in the opinion of the investigators would impede competence or
compliance or possibly hinder completion of the study;

12. Subjects who regularly use prescription medications unrelated to the
complications of obesity (especially vasoactive compounds such as calcium channel
blockers, nitrates, beta-blockers, etc.), subjects using H2 blockers for
dyspepsia, and subjects who require chronic use of antihistamines for allergic
conditions; oral contraceptive use will be permitted, provided the contraceptive
has been used for at least two months before starting study medication. The use
of over-the-counter and prescription medications will be reviewed on a
case-by-case basis; depending on the medication, subjects who have continued to
take prescription medication for at least 3 months prior to study entry may be
eligible. Allowable medications may include statins for the treatment of
dyslipidemia and low-dose aspirin for primary prevention of acute coronary
syndrome. Medications used for the treatment of hypertension will not be allowed
because of the potential vasodilatory activity of betahistine.

13. Recent (3 months) use of anorexiant medications;

14. Weight change of more than 3% of body weight in the past two months;

15. Subjects with a consistently (2 weeks apart) elevated systolic blood pressure of
greater than 160 mm Hg and/or a diastolic blood pressure greater than 95 mm Hg.