A Study to Evaluate the Safety and Tolerability of Valproic Acid in Healthy Volunteers (Part 1)

Part 1 of the study will be a single center study intended to assess the safety and
tolerability of valproic acid dosages at 15 mg/kg, 30 mg/kg, 60 mg/kg, 90 mg/kg, 120 mg/kg,
150 mg/kg 180 mg/kg, 210 mg/kg and 250 mg/kg. Up to 72 healthy subjects (9 dose groups of 8
subjects) will receive single doses of valproic acid or placebo via a 60-min IV infusion in
a ratio of 3:1 active drug: placebo.

Part 2 of the study will be a multicenter, double blind, placebo-controlled study in trauma
patients with hemorrhagic shock who are able to give consent or severe trauma patients with
hemorrhagic shock in whom a legally authorized representative can give consent. Up to 12
patients (2 dose groups of 6 patients) will receive single doses of valproic acid or placebo
via a 60-min IV infusion in a ratio of 2:1 active drug : placebo. The dose levels in Part 2
will be the two highest doses that are demonstrated to have acceptable safety profile based
on the review of safety data from Part 1.

Inclusion Criteria:

1. Male or female volunteers between the ages of 18 and 65 years, inclusive, in good
health based on medical history, physical examination, ECG, and routine laboratory
tests (blood chemistry, hematology, urinalysis, and drug screen).

2. Female subjects must be surgically sterilized or postmenopausal. Criteria for
menopause are surgical menopause (hysterectomy, oophorectomy) or age > 45 years with
absence of menses for greater than 12 months or a serum follicle stimulating hormone
(FSH) elevation > 25m IU/mL.(mIU/mL is the unit used to measure human chorionic
gonadotropin (hCG) in pregnancy test). Tubal ligation with menses within the past 12
months is not considered to be surgical sterilization.

3. Negative urine pregnancy test in female volunteers

4. Body mass index (BMI) between 18 kg/m2 and 30 kg/m2

5. Subjects must be non-smokers

6. Negative alcohol screen

7. Willing and able to be confined to the clinical research facility as required by the
protocol.

8. Willing and able to comply with the investigational nature of the study and able to
communicate well with investigators.

9. Ability to comprehend and willingness to provide written informed consent in
accordance with institutional and regulatory guidelines.

Exclusion Criteria:

1. Subjects with evidence or history of clinically significant hematological, renal,
endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric,
neurologic, or allergic disease (including drug allergies; however, subjects with
untreated, asymptomatic, seasonal allergies may be enrolled).

2. Subjects with a-amylase >130 U/L or lipase >300 U/L or creatinine > upper limit of
normal (ULN)

3. Subjects with >2times ULN aspartate aminotransferase (AST) or alanine amino
transferase (ALT) or >1.5 times total bilirubin

4. Subjects whose screening ECG demonstrates at least one of the following: heart rate >
100 bpm for more than 30 minutes, (the combination of three of the graphical
deflections seen on a typical ECG is called the(QRS)) > 120 msec, corrected QT
interval (QTc) > 440 msec if male or 450 msec if female, prevalence rate (PR) > 220
msec or any rhythm other than sinus rhythm, sinus bradycardia (HR <40 bpm), or sinus
arrhythmia.

5. Subjects with a history of alcohol consumption exceeding 14 drinks/week on average
within the 6 months before study entry.

6. Subjects whose sitting blood pressure is above 140/90 mmHg on 2 evaluations at least
10 minutes apart at screening.

7. Subjects who have donated blood in excess of 500 mL within 60 days prior to the first
dose of study medication.

8. Subjects with a positive result on drug screen, hepatitis B surface antigen (HBsAg),
hepatitis C (HCV), or human immunodeficiency (HIV) tests

9. Subjects who have used prescription or non-prescription drugs, vitamins, herbal
supplements or dietary supplements within 14 days prior to the first dose of study
medication. Subjects who have used acetaminophen at doses of < 2 grams/day will be
eligible for study entry.

10. Subjects who have been treated with an investigational drug within 30 days.

11. Subjects who have previously received or are currently taking valproic acid.

12. Subjects who have a history of drug abuse.

13. Subjects who are not willing to abstain from consuming products containing caffeine
(including chocolate), methyl xanthine, or alcohol from Day -1 through the end of the
pharmacokinetics (PK) study (day 4 for part 1 subjects).

14. Subjects who have had a febrile illness within 5 days prior to the first dose of
study medication.

15. Subjects with inadequate venous access.

16. Subjects vaccinated within 30 days prior to the first dose of study medication. -