Initial Study of Fenoterol as a Treatment for Heart Failure

Fenoterol is a drug that has been used for the treatment of disease like asthma for many
years. It is available in Canada in an inhaled form where it is called Berotec . Fenoterol
stimulates receptors in the body called Beta Adrenergic Receptors and is therefore in a
family of drugs called Beta Agonists. While one particular form of the drug, called a Racemic
mixture has traditionally been used for asthma, multiple forms of the drug have now been
produced and it is possible that using one of the newer forms of the drug will have benefits
for people with heart failure.

Treatment for heart failure is a complex problem. It is a problem of the heart not pumping
enough blood to meet the demands of the body and a number of changes that ultimately prove
harmful in an attempt to compensate for this failure. Scientists have observed several
effects of Fenoterol that may prove beneficial to people with heart failure. Use of the older
Fenoterol (Racemic) mixture indicates that the drug causes the heart to pump more blood out
to the rest of the body by increasing a person s heart rate but having little to no effect on
their blood pressure. These effects provide a rationale for attempting to develop Fenoterol
as a possible treatment for congestive heart failure. It is hoped that this new form of the
drug will prove to have even more benefits.

However, the new form of the drug (called the R R form ) has not yet been tested in humans.
Animal studies and scientific understanding of these types of mixtures suggest that it will
little to no difference between it and the older Racemic form. To test this thinking and
determine what doses should be used in future studies, we will conduct a Phase I, escalating
dose study in healthy volunteers using the orally administered forms of the older Racemic
mixture and newer R R form .

This study will consist of three groups of 6 people taking doses of the drug by mouth and
then monitoring their heart rate, blood pressure, blood chemistry, genetic factors, and heart
function. The first group will get a 2.5 mg dose of the R R form of the drug on one visit and
then a 5 mg dose of the racemic mixture on the other visit. The second group will get a 5mg
dose of the R R form on one of their visits and a 10mg dose of the Racemic mixture on the
other. Finally, the third group will get a 10mg dose of the R R form on one visit and a 20mg
dose of the Racemic mixture on the other. Also, blood will be collected at regular intervals
to monitor levels of the drug, its rate of breakdown, changes in blood chemistry, and the
testing of various genes. All research will be performed at the National Institute on Aging
(NIA) Clinical Research Unit located on the 5th floor of Harbor Hospital in Baltimore, MD.

Testing the safety and breakdown of this drug and comparing it to the older Racemic form will
be an important first step in its development as a new drug for heart failure.

The specific aims are:

1. A Phase 1 study in healthy volunteers to establish the body s absorption and breakdown
of this new form of Fenoterol (R R form) in comparison with the older, established
Racemic mixture.

2. To monitor the effects of the drug on heart rate, blood pressure, and cardiac structure
and function after a person takes the drug.

Endpoint: This study will provide a safety assessment and will determine the pharmacokinetics
and bioavailability of (R,R )- and racemic Fenoterol in healthy subjects. In addition,
information will be gained about the pharmacodynamics of Fenoterol. This will provide
information for future studies that will evaluate (R,R )-Fenoterol as a potential treatment
for congestive heart failure.

-INCLUSION CRITERIA:

1. Healthy men and women

2. Age: 21-60

3. Screening laboratory evaluations with no clinically significant abnormal results:

- Chem-20 panel plus troponin

- Complete blood count with differential and platelet count

- Urinalysis with microscopic examination

- Electrocardiogram

- Echocardiogram: 2D + Doppler

- Urine drug screen

- Urine pregnancy test

4. BMI 24-30

5. Able to provide written informed consent

6. Agree to not participate in other clinical trials during the study period

7. If in child-bearing age and participating in sexual activity that could lead to
pregnancy, agree to use a medically accepted method of contraception for a woman for
at least 1 month prior to enrollment and continuing 1 month after completion of the
fifth study visit, and for a man beginning immediately after the second study visit
and continuing for 3 months after completion of the fifth study visit.

EXCLUSION CRITERIA:

1. Resting sitting blood pressure greater than 140/90 mm Hg, resting heart rate greater
than 100 bpm

2. Abnormal laboratory examination (ALT and AST greater than 1.5 times the normal range,
other labs within 10% of normal range); abnormal troponin screening level will be an
exclusion.

3. Clinically significant abnormality on EKG (major Q waves, evidence of heart block,
significant conduction disease, QT prolongation)

4. Clinically significant abnormality on Echocardiogram (ejection fraction less than 50
percent, valvular heart disease of moderate severity, pulmonary hypertension with PASP
greater than 40mm Hg)

5. Evidence of illicit drug use or alcohol abuse

6. History of Human Immunodeficiency Virus (HIV) infection

7. History of active or chronic Hepatitis B and/or C infection

8. History of malignancy (other than non-invasive skin cancer)

9. History of coronary disease, conduction system disease, pacemaker, atrial
fibrillation/flutter, ventricular tachycardia/fibrillation, significant valvular
disease, or other cardiovascular disease

10. History of asthma -- reactive airway disease

11. History of seizures or other neurologic diseases

12. History of liver or renal diseases

13. History of gastrointestinal or endocrine disorders (other than mild dyspepsia)

14. Medication use other than occasional use of over-the-counter drugs and/or
contraceptives

15. Any medication or herbal drug use within the past 3 days before study participation
other than contraceptives

16. Any medical history that, in the opinion of the investigator(s), will make
participation of the subject in the study unsafe

17. Participation in another clinical trial involving any pharmacologic agents or blood
loss within the past 30 days

18. Donation of blood or blood products within the past 56 days

19. Women who are of childbearing potential and not using acceptable forms of
contraception will be excluded.