A Study to Test the Safety of Combined Dosing With Aminophylline and Ambrisentan in Exercising Healthy Human Volunteers at Simulated High Altitude

Inclusion Criteria:

- Subjects must give written Informed Consent to participate in the study prior to
undergoing any screening procedures. The subject will be given a signed and dated
copy of the Informed Consent.

- Subjects must be healthy non-smoking (for 6 months or greater at commencement of
Cycle 1) adult male and female volunteers; at least 18 through 50 years at screening,
with a BMI of 18-33 kg/m2 and weighing at least 143 lbs. (65 kg). Subjects' health
status will be determined by the medical history, physical examination, vital signs,
ECG, blood chemistry, hematology, and urinalysis performed at screening.

- Subjects must be willing to fast a minimum of 2 hours prior to screening.

- Subjects must be willing to abstain from alcohol and xanthine-containing food and
beverages from 48 hours before check-in for each study day,

- Women who are of non-childbearing potential, must be:

- Surgically sterile (removal of both ovaries and/ or uterus at least 12 months prior
to dosing) and with an FSH level at screening of ≥ 40 mIU/mL.

- Naturally postmenopausal (spontaneous cessation of menses) for at least 24
consecutive months prior to dosing on Day -1, and with an FSH level at screening of ≥
40 mIU/mL.

- Women of child-bearing potential must have a negative serum or urine pregnancy test
at screening, during the study, and must agree to avoid pregnancy during study and
for three months after the last dose of study drug. Pregnancy is tested at screening,
during check-in of each testing cycle, during the follow-up visit, and at any given
point if deemed necessary to the PI or designate. During treatment, women of
child-bearing potential must use two acceptable methods of contraception at the same
time unless the subject has had a documented tubal sterilization or chooses to use a
Copper T 380A IUD or LNG 20 IUS, in which case no additional contraception is
required. Abstinence is not considered a form of contraception. Medically acceptable
contraceptives include: (1) documented surgical sterilization (such as a
hysterectomy), (2) barrier methods (such as a condom or diaphragm) used with a
spermicide, or (3) an intrauterine device (IUD) or intrauterine system (IUS).

- Male subjects must agree to take all necessary measures to avoid causing pregnancy in
their sexual partners during the study and for three months after the last dose of
study drug. Medically acceptable contraceptives include: (1) surgical sterilization
(such as a vasectomy), or (2) a condom used with a spermicidal. Contraceptive
measures such as Plan B (TM), sold for emergency use after unprotected sex, are not
acceptable methods for routine use.

- Subjects must agree not to donate blood, platelets, or any other blood components 30
days, or plasma 90 days, prior to consenting and for 1 month after the last dose.

- Male subjects must agree not to donate sperm during the study and for 12 weeks after
the last dose.

Exclusion Criteria:

- Subjects with laboratory results outside the normal range, if considered clinically
significant (CS) by the PI or delegate. In addition, subjects must have a hemoglobin
concentration of ≥ 12.0 g/dL.

- A mental capacity that is limited to the extent that the subject cannot provide legal
consent or understand information regarding the side effects of the study drug.

- Currently abusing drugs or alcohol or with a history of drug or alcohol abuse within
the past two years.

- Unwillingness or lack of ability to comply with the protocol, or to cooperate fully
with the PI and site personnel.

- Use of any of the following:

- Any concomitant medication including oral contraceptive hormones. Subjects who have
received any prescribed or non-prescribed (over-the-counter [OTC]) systemic
medication, topical medications, or herbal supplements within 14 days from Day 1. St.
John's Wort (hypericin) must not have been taken for at least 30 days prior to Cycle
1, Day 1.

- Any drugs, foods or substances known to be strong inhibitors or strong inducers of
CYP enzymes (also known as cytochrome P450 enzymes); especially CYP 1A2, or Pgp
within 7 days prior to Cycle 1, Day 1.

- Clinically significant ECG abnormality in the opinion of the PI or delegate.

- Vital signs or clinically significant laboratory values at the screening visit that
in the opinion of the PI or delegate would make the subject an inappropriate
candidate for the study.

- A VO2 max value of less than 42 mL/kg/min, as determined during exercise testing at
screening. This value represents an educated estimate, and may be changed, to include
new information, at the discretion of the PI.

- A history of, or otherwise indicated predisposition for, claustrophobia, i.e. the
fear of closed, narrow spaces (because of the limited size of the high altitude
chamber).

- A history of "undeserved" altitude sickness, i.e. altitude sickness at only moderate
altitude. This would consist of altitude-related headaches, dizziness, or nausea
during plane rides, or when traveling to moderately elevated locations of less than
2,743.2 meters/ 9,000 ft

- Has taken any other investigational drug during the 30 days prior to the screening
visit or is currently participating in another investigational drug clinical trial.

- Made any significant donation or have had a significant loss of blood within 30, or
donated plasma within 90 days of consenting.

- Receipt of a transfusion or any blood products within 90 days prior to commencement
of Cycle 1

- History or manifestation of clinically significant neurological, gastrointestinal,
renal, hepatic, cardiovascular, psychological, pulmonary, metabolic, endocrine,
hematologic or other medical disorders. For the purpose of the study, individual
fitness and health are more important than family history of disease burden as a
criterion for participation. For example, an individual may have significant family
history of cardiovascular disease; however, the individual subject's active lifestyle
makes a manifestation of such disease at young ages unlikely. To account for such
expected variation, the ultimate decision whether to exclude or include an individual
based on family history or manifestation of disease will be made by the PI. The PI
may choose to use physiological assessments, such as e.g. ECG, blood pressure, and
VO2 max fitness level as an aid for decision making.

- Any condition that might interfere with the absorption of the study medications or
influence the interpretation of the results of the study.

- Subjects who are carriers of the Hepatitis B surface antigen (HbsAg), Hepatitis C
antibody, or HIV antibody.

- Serious mental or physical illness within the past year.

- Male subjects who consume more than 28 units of alcohol per week and female subjects
who consume more than 21 units of alcohol per week (one unit of alcohol equals 250 mL
of beer, 100 mL of a medium glass of wine, or 25 mL of spirits) or those subjects who
have a significant history of alcoholism or drug/ chemical abuse within the last 2
years.

- Failure to agree to abstain from alcohol, cola, tea, coffee, chocolate and other
caffeinated drink/ food from 48 h before check-in for Cycles 1 & 2.

- Subjects who have used tobacco products or nicotine-containing products (including
smoking cessation aids, such as gums or patches) within 6 months prior to
commencement of Cycle 1

- Women of childbearing potential who are pregnant (as based on test results) or are
breast feeding

- Subjects who have a history of hypersensitivity or idiosyncratic reaction to any of
the products administered during the study.

- Subjects who, in the opinion of the PI (or delegate), should not participate in the
study.

- Subjects who are employed by the Duke Clinical Research Unit and/or the Duke
Hypobaric/ Hyperbaric Center

- Subjects who have a history of unexplained syncope or fainting from the collection of
blood; i.e., autonomic dysfunction.

- Subjects who have a history of hypotension, including orthostatic hypotension. The
ultimate decision about exclusion or inclusion of a potential subject is made by the
PI.

- Lack of ability to understand verbal and/ or written English.

- History of clinically significant illness within 4 weeks prior to commencement of
Cycle 1. In case a subject develops an illness between any of the study activities
(Screening, Cycle 1, and Cycle 2), the subject may be removed from the study, if it
deems appropriate and/ or necessary to the PI.