Dose-Related Inflammatory Effects of Intravenous Endotoxin in Humans

Normal healthy subjects will be recruited and consented for the study. Following completion
of the study, the bio-marker samples will be sent to Dr. Anthony Suffredini a collaborator
and Deputy Chief & Senior Investigator Department of Critical Care Medicine at the National
Institutes of Health (NIH). All samples will be de-identified and analyzed at the NIH; the
results of which will be reviewed by both Drs. Suffredini and Noveck. Statistical analysis
will be performed at the NIH by the Department of Statistics from which manuscripts will be
written for publication.

Inclusion Criteria:

- Healthy men and women between the ages of 18-40 years, inclusive, at the time of
Informed Consent. Healthy is defined as no clinically relevant abnormalities
identified by a detailed medical history, full physical examination, including blood
pressure and pulse rate measurement, 12-lead ECG or clinical laboratory tests.

- Agreement by female subjects with reproductive potential to be using an adequate
method of contraception and agrees to continue using this method for the duration of
the study. Female subjects must also agree to the use of TWO reliable methods of
contraception following receiving study drug; if sexually active, which can include:
condoms, spermicidal gel, diaphragm, hormonal or non-hormonal intrauterine device,
surgical sterilization, an oral contraceptive pill (OCP), and depot progesterone
injections.

- Body Mass Index (BMI) of 18-32 kg/m2 and a total body weight >50 kg (110 lb), but <95
kg.

- The subject has demonstrably adequate veins for IV catheter insertion.

- Evidence of a personally signed and dated informed consent document indicating that
the subject (or a legal representative) has been informed of all the pertinent
aspects of the study.

- Subjects who are willing and able to comply with the scheduled visits, laboratory
tests, and other study procedures.

- Male subjects agree that they [or their female partner(s)] will use an acceptable
contraceptive regimen throughout the duration of the study. Acceptable contraception
for a subject (or female partner) is being surgically sterilized; or willing to use
condoms plus contraceptive foam or jelly (with all female partners who are not
surgically sterilized).

- The subject has the ability and willingness to comply with protocol requirements
during the study, including fasting and refraining from alcohol, nicotine and
caffeine consumption from 48h prior to check-in until discharge from the unit.

- On the morning of endotoxin, Study Day 1, prior to dosing, the subject must have a
normal stable baseline body temperature defined as the average of three consecutive
oral temperatures (recorded, repeatedly, approximately every 10-15 seconds) between
97.0 degrees F (36.1°C) and 98.8 degrees F (37.1°C) and do not differ by >0.4 degrees
F (>0.2 degrees C).

- The subject has a high probability for compliance with and completion of the study.

Exclusion Criteria:

- Evidence or history of clinically significant dental (presence of abscess),
hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular,
hepatic, psychiatric, neurologic, or allergic disease.

- A positive urine drug test for cannabinoids, amphetamines, barbiturates, cocaine,
opiates, benzodiazepines, phencyclidine, and/or methadone and alcohol (breathalyzer)
test at either Screening or Day -1.

- History or evidence of habitual use of tobacco- or nicotine-containing products
within 3 months of screening.

- A positive serum pregnancy test (females only) at Screening or a positive urine
pregnancy test at check-in.

- Subjects who have previously received endotoxin (LPS) within the previous 6 months or
known hypersensitivity to endotoxin at any time.

- Subjects who have experienced cold/flu symptoms (i.e., runny nose, cough, and/or
fever) or received any antibiotic treatment within 30 days or has undergone a
surgical procedure within 60 days prior of the endotoxin challenge

- History of recurrent or chronic infections of any type such as tuberculosis,
sinusitis, urinary tract infection, respiratory tract or dental (abscess) infection,
etc. Also excluded are subjects with recurrent oral or genital herpes, recurrent
herpes zoster, or any infection otherwise judged by the investigator to have the
potential for exacerbation by participation in the study.

- History of syncope or symptoms of lightheadedness associated with blood draws

- History of regular alcohol consumption exceeding 7 drinks/week for females or 14
drinks/week for males (1 drink = 5 ounces (150 mL) of wine or 12 ounces (360 mL) of
beer or 1.5 ounces (45 mL) of hard liquor) within 6 months of Screening or history of
drug use within 12 months prior to study drug administration, which the Investigator
considers abusive.

- Treatment with an investigational drug within 30 days (or as determined by the local
requirement) or 5 half-lives, whichever is longer, preceding the first dose of study
medication. Also, if received an immunosuppressive drug or had received a vaccination
within 3 months of Day 1

- Screening supine BP >140 or <100 mm Hg (systolic), or >90 or <60 mmHg (diastolic);
following at least 5 minutes of rest. If BP is >140 or <100 mm Hg (systolic), or >90
or <60 mm Hg (diastolic), the BP should be repeated two more times and the median of
the three systolic and the median of the three diastolic BP values should be used to
determine the subject's eligibility. If either of the median values is outside of the
criteria above, the subject is excluded.

- Resting heart rate (HR) at screening or check-in on Day -1 <50 bpm (beats per minute)
following at least 10 minutes of rest from either vital signs or ECGs. If HR is <50
bpm, the HR should be repeated two more times and the median of the three HR values
should be used to determine the subject's eligibility. If the median value is <50
bpm, the subject is excluded.

- 12 lead ECG demonstrating HR < 50 bpm, QTc >450 or a QRS interval >120 msec at
screening of check-in. If the heart rate or QTc exceeds 450 msec, or QRS exceeds 120
msec, the ECG should be repeated two more times and the median of the three QTc
values should be used to determine the subject's eligibility. If the median value for
any of these parameters is outside the limit specified, the subject is excluded.

- Use of prescription or nonprescription drugs and dietary supplements, especially
those with anti-inflammatory properties (e.g. fish oil, turmeric, etc.) within 7 days
or 5 half-lives (whichever is longer) prior to receiving endotoxin. Limited use of
non-prescription medications that are not believed to affect subject safety or the
overall results of the study may be permitted on a case-by-case basis. Use of any
steroidal or non-steroidal anti-inflammatory drug (NSAID) within 7 days or 5
half-lives (whichever is longer) of admission of each period is specifically
prohibited due to potential confounding effects on the study PD endpoints

- History of frequent headaches (>2 per month) or migraines or headaches from an
absence of caffeine from coffee, tea, chocolate, or other caffeine-related substances

- Caffeine consumption in excess of 3 cups per day

- Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or more
within 56 days prior to dosing.

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

1. Surgically sterile (removal of both ovaries and/ or uterus at least 12 months
prior to dosing).

2. 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.

3. Women of child-bearing potential must have a negative serum pregnancy test at
screening and negative urine pregnancy at check-in, and must agree to avoid
pregnancy during study. Pregnancy is tested at screening, during check-in, and
at any given time if deemed necessary by the PI or designate. During the study,
women of child-bearing potential must use two acceptable methods of
contraception at the same time. 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 the use of a condom
with a spermicide and (3) hormonal contraception (combination oral
contraceptives, transdermal patch, injectables, implantables or vaginal ring) or
(4) an intrauterine device (IUD) or intrauterine system (IUS). Abstinence is not
an acceptable form of contraception in this study.

- Unwilling or unable to comply with the Lifestyle Guidelines described in this
protocol.

- Other severe acute or chronic medical or psychiatric condition or laboratory
abnormality that may increase the risk associated with study participation or
investigational product administration or may interfere with the interpretation of
study results and, in the judgment of the investigator, would make the subject
inappropriate for entry into this study.

- Subjects who are investigational site staff members directly involved in the conduct
of the study and their family members, site staff members otherwise supervised by the
Investigator directly involved in the conduct of the study.

- The subject has a clinically significant abnormal white blood cell (WBC) count,
differential or presence of clinically significant WBCs on the microscopic
examination of the urinalysis.

- The subject has engaged in sunbathing or in any physical exercise, sports or exertion
other than normal walking within 72h of check-in

- The subject has an elevated temperature, presence of dental/other abscess, chills,
malaise, cough, cold, and/or headache which are suggestive of an occult infection
(viral, bacterial, etc.).

- The subject has donated more than 250 mL of blood within 30 days of Day 1 or has
donated more than 500 mL of blood within 56 days of Day 1

- The subject has a known allergy/sensitivity to lactose and/ or polyethylene glycol
(excipients in the LPS injection).

- Pregnant or breastfeeding females.